Denial of Petition To Initiate Proceedings To Reschedule Marijuana, 53767-53845 [2016-17960]

Download as PDF Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules DEPARTMENT OF JUSTICE Drug Enforcement Administration 21 CFR Chapter II [Docket No. DEA–427] Denial of Petition To Initiate Proceedings To Reschedule Marijuana Drug Enforcement Administration, Department of Justice. ACTION: Denial of petition to initiate proceedings to reschedule marijuana. AGENCY: By letter dated July 19, 2016 the Drug Enforcement Administration (DEA) denied a petition to initiate rulemaking proceedings to reschedule marijuana. Because the DEA believes that this matter is of particular interest to members of the public, the agency is publishing below the letter sent to the petitioner which denied the petition, along with the supporting documentation that was attached to the letter. DATES: August 12, 2016. FOR FURTHER INFORMATION CONTACT: Michael J. Lewis, Office of Diversion Control, Drug Enforcement Administration; Mailing Address: 8701 Morrissette Drive, Springfield, Virginia 22152; Telephone: (202) 598–6812 SUPPLEMENTARY INFORMATION: mstockstill on DSK3G9T082PROD with PROPOSALS2 SUMMARY: July 19, 2016 Dear Mr. Krumm: On December 17, 2009, you petitioned the Drug Enforcement Administration (DEA) to initiate rulemaking proceedings under the rescheduling provisions of the Controlled Substances Act (CSA). Specifically, you petitioned DEA to have marijuana removed from schedule I of the CSA and rescheduled in any schedule other than schedule I of the CSA. You requested that DEA remove marijuana from schedule I based on your assertion that: 1. Marijuana has accepted medical use in the United States; 2. Studies have shown that smoked marijuana has proven safety and efficacy; 3. Marijuana is safe for use under medical supervision; and 4. Marijuana does not have the abuse potential for placement in schedule I In accordance with the CSA scheduling provisions, after gathering the necessary data, DEA requested a scientific and medical evaluation and scheduling recommendation from the Department of Health and Human Services (HHS). HHS concluded that marijuana has a high potential for abuse, has no accepted medical use in the United States, and lacks an acceptable level of safety for use even under medical supervision. Therefore, HHS recommended that marijuana remain in schedule I. The scientific and medical evaluation and scheduling recommendation that HHS submitted to DEA is attached hereto. VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 Based on the HHS evaluation and all other relevant data, DEA has concluded that there is no substantial evidence that marijuana should be removed from schedule I. A document prepared by DEA addressing these materials in detail also is attached hereto. In short, marijuana continues to meet the criteria for schedule I control under the CSA because: (1) Marijuana has a high potential for abuse. The HHS evaluation and the additional data gathered by DEA show that marijuana has a high potential for abuse. (2) Marijuana has no currently accepted medical use in treatment in the United States. Based on the established five-part test for making such determination, marijuana has no ‘‘currently accepted medical use’’ because: As detailed in the HHS evaluation, the drug’s chemistry is not known and reproducible; there are no adequate safety studies; there are no adequate and wellcontrolled studies proving efficacy; the drug is not accepted by qualified experts; and the scientific evidence is not widely available. (3) Marijuana lacks accepted safety for use under medical supervision. At present, there are no U.S. Food and Drug Administration (FDA)-approved marijuana products, nor is marijuana under a New Drug Application (NDA) evaluation at the FDA for any indication. The HHS evaluation states that marijuana does not have a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions. At this time, the known risks of marijuana use have not been shown to be outweighed by specific benefits in wellcontrolled clinical trials that scientifically evaluate safety and efficacy. The statutory mandate of 21 U.S.C. 812(b) is dispositive. Congress established only one schedule, schedule I, for drugs of abuse with ‘‘no currently accepted medical use in treatment in the United States’’ and ‘‘lack of accepted safety for use under medical supervision.’’ 21 U.S.C. 812(b). Although the HHS evaluation and all other relevant data lead to the conclusion that marijuana must remain in schedule I, it should also be noted that, in view of United States obligations under international drug control treaties, marijuana cannot be placed in a schedule less restrictive than schedule II. This is explained in detail in the accompanying document titled ‘‘Preliminary Note Regarding Treaty Considerations.’’ Accordingly, and as set forth in detail in the accompanying HHS and DEA documents, there is no statutory basis under the CSA for DEA to grant your petition to initiate rulemaking proceedings to reschedule marijuana. Your petition is, therefore, hereby denied. Sincerely, Chuck Rosenberg, Acting Administrator Attachments: Preliminary Note Regarding Treaty Considerations Cover Letter from HHS to DEA Summarizing the Scientific and Medical Evaluation and Scheduling Recommendation for Marijuana. PO 00000 Frm 00081 Fmt 4701 Sfmt 4702 53767 U.S. Department of Health and Human Services (HHS)—Basis for the Recommendation for Maintaining Marijuana in Schedule I of the Controlled Substances Act U.S. Department of Justice—Drug Enforcement Administration (DEA), Schedule of Controlled Substances: Maintaining Marijuana in Schedule I of the Controlled Substances Act, Background, Data, and Analysis: Eight Factors Determinative of Control and Findings Pursuant to 21 U.S.C. 812(b) Dated: July 19, 2016. Chuck Rosenberg, Acting Administrator. Preliminary Note Regarding Treaty Considerations As the Controlled Substances Act (CSA) recognizes, the United States is a party to the Single Convention on Narcotic Drugs, 1961 (referred to here as the Single Convention or the treaty). 21 U.S.C. 801(7). Parties to the Single Convention are obligated to maintain various control provisions related to the drugs that are covered by the treaty. Many of the provisions of the CSA were enacted by Congress for the specific purpose of ensuring U.S. compliance with the treaty. Among these is a scheduling provision, 21 U.S.C. 811(d)(1). Section 811(d)(1) provides that, where a drug is subject to control under the Single Convention, the DEA Administrator (by delegation from the Attorney General) must ‘‘issue an order controlling such drug under the schedule he deems most appropriate to carry out such [treaty] obligations, without regard to the findings required by [21 U.S.C. 811(a) or 812(b)] and without regard to the procedures prescribed by [21 U.S.C. 811(a) and (b)].’’ Marijuana is a drug listed in the Single Convention. The Single Convention uses the term ‘‘cannabis’’ to refer to marijuana.1 Thus, the DEA Administrator is obligated under section 811(d) to control marijuana in the 1 Under the Single Convention, ‘‘’cannabis plant’ means any plant of the genus Cannabis.’’ Article 1(c). The Single Convention defines ‘‘cannabis’’ to include ‘‘the flowering or fruiting tops of the cannabis plant (excluding the seeds and leaves when not accompanied by the tops) from which the resin has not been extracted, by whatever name they may be designated.’’ Article 1(b). This definition of ‘‘cannabis’’ under the Single Convention is slightly less inclusive than the CSA definition of ‘‘marihuana,’’ which includes all parts of the cannabis plant except for the mature stalks, sterilized seeds, oil from the seeds, and certain derivatives thereof. See 21 U.S.C. 802(16). Cannabis and cannabis resin are included in the list of drugs in Schedule I and Schedule IV of the Single Convention. In contrast to the CSA, the drugs listed in Schedule IV of the Single Convention are also listed in Schedule I of the Single Convention and are subject to the same controls as Schedule I drugs as well as additional controls. Article 2, par. 5 E:\FR\FM\12AUP2.SGM 12AUP2 53768 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules mstockstill on DSK3G9T082PROD with PROPOSALS2 schedule that he deems most appropriate to carry out the U.S. obligations under the Single Convention. It has been established in prior marijuana rescheduling proceedings that placement of marijuana in either schedule I or schedule II of the CSA is ‘‘necessary as well as sufficient to satisfy our international obligations’’ under the Single Convention. NORML v. DEA, 559 F.2d 735, 751 (D.C. Cir. 1977). As the United States Court of Appeals for the D.C. Circuit has stated, ‘‘several requirements imposed by the Single Convention would not be met if cannabis and cannabis resin were placed in CSA schedule III, IV, or V.’’ 2 Id. Therefore, in accordance with section 811(d)(1), DEA must place marijuana in either schedule I or schedule II. Because schedules I and II are the only possible schedules in which marijuana may be placed, for purposes of evaluating this scheduling petition, it is essential to understand the differences between the criteria for placement of a substance in schedule I and those for placement in schedule II. These criteria are set forth in 21 U.S.C. 812(b)(1) and (b)(2), respectively. As indicated therein, substances in both schedule I and schedule II share the characteristic of ‘‘a high potential for abuse.’’ Where the distinction lies is that schedule I drugs have ‘‘no currently accepted medical use in treatment in the United States’’ and ‘‘a lack of accepted safety for use of the drug . . . under medical supervision,’’ while schedule II drugs do have ‘‘a currently accepted medical use in treatment in the United States.’’ 3 Accordingly, in view of section 811(d)(1), this scheduling petition turns on whether marijuana has a currently accepted medical use in treatment in the United States. If it does not, DEA must, pursuant to section 811(d), deny the petition and keep marijuana in schedule I. As indicated, where section 811(d)(1) applies to a drug that is the subject of a rescheduling petition, the DEA 2 The Court further stated: ‘‘For example, [article 31 paragraph 4 of the Single Convention] requires import and export permits that would not be obtained if the substances were placed in CSA schedules III through V. In addition, the quota and [recordkeeping] requirements of Articles 19 through 21 of the Single Convention would be satisfied only by placing the substances in CSA schedule I or II.’’ Id. n. 71 (internal citations omitted). 3 As DEA has stated in evaluating prior marijuana rescheduling petitions, ‘‘Congress established only one schedule, schedule I, for drugs of abuse with ‘no currently accepted medical use in treatment in the United States’ and ‘lack of accepted safety for use . . . under medical supervision.’ 21 U.S.C. 812(b).’’ 76 FR 40552 (2011); 66 FR 20038 (2001). VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 Administrator must issue an order controlling the drug under the schedule he deems most appropriate to carry out United States obligations under the Single Convention, without regard to the findings required by sections 811(a) or 812(b) and without regard to the procedures prescribed by sections 811(a) and (b). Thus, since the only determinative issue in evaluating the present scheduling petition is whether marijuana has a currently accepted medical use in treatment in the United States, DEA need not consider the findings of sections 811(a) or 812(b) that have no bearing on that determination, and DEA likewise need not follow the procedures prescribed by sections 811(a) and (b) with respect to such irrelevant findings. Specifically, DEA need not evaluate the relative abuse potential of marijuana or the relative extent to which abuse of marijuana may lead to physical or psychological dependence. As explained below, the medical and scientific evaluation and scheduling recommendation issued by the Secretary of Health and Human Services concludes that marijuana has no currently accepted medical use in treatment in the United States, and the DEA Administrator likewise so concludes. For the reasons just indicated, no further analysis beyond this consideration is required. Nonetheless, because of the widespread public interest in understanding all the facts relating to the harms associated with marijuana, DEA is publishing here the entire medical and scientific analysis and scheduling evaluation issued by the Secretary, as well as DEA’s additional analysis. Department of Health and Human Services, Office of the Secretary Assistant Secretary for Health, Office of Public Health and Science Washington DC 20201. June 25, 2015. The Honorable Chuck Rosenberg Acting Administrator, Drug Enforcement Administration, U.S. Department of Justice, 8701 Morrissette Drive, Springfield, VA 22152 Dear Mr. Rosenberg: Pursuant to the Controlled Substances Act (CSA, 21 U.S.C. 811(b), (c), and (f)), the Department of Health and Human Services (HHS) is recommending that marijuana continue to be maintained in Schedule I of the CSA. The Food and Drug Administration (FDA) has considered the abuse potential and dependence-producing characteristics of marijuana. Marijuana meets the three criteria for placing a substance in Schedule I of the CSA under 21 U.S.C. 812(b)(1). As discussed in the enclosed analyses, marijuana has a high potential for abuse, no currently accepted PO 00000 Frm 00082 Fmt 4701 Sfmt 4702 medical use in treatment in the United States, and a lack of accepted safety for use under medical supervision. Accordingly, HHS recommends that marijuana be maintained in Schedule I of the CSA. Enclosed are two documents prepared by FDA’s Controlled Substance Staff (in response to petitions filed in 2009 by Mr. Bryan Krumm and in 2011 by Governors Lincoln D. Chafee and Christine O. Gregoire) that form the basis for the recommendation. Pursuant to the requests in the petitions, FDA broadly evaluated marijuana, and did not focus its evaluation on particular strains of marijuana or components or derivatives of marijuana. FDA’s Center for Drug Evaluation and Research’s current review of the available evidence and the published clinical studies on marijuana demonstrated that since our 2006 scientific and medical evaluation and scheduling recommendation responding to a previous DEA petition, research with marijuana has progressed. However, the available evidence is not sufficient to determine that marijuana has an accepted medical use. Therefore, more research is needed into marijuana’s effects, including potential medical uses for marijuana and its derivatives. Based on the current review, we identified several methodological challenges in the marijuana studies published in the literature. We recommend they be addressed in future clinical studies with marijuana to ensure that valid scientific data are generated in studies evaluating marijuana’s safety and efficacy for therapeutic use. For example, we recommend that studies need to focus on consistent administration and reproducible dosing of marijuana, potentially through the use of administration methods other than smoking. A summary of our review of the published literature on the clinical uses of marijuana, including recommendations for future studies, is attached to this document. FDA and the National Institutes of Health’s National Institute on Drug Abuse (NIDA) also believe that work continues to be needed to ensure support by the federal government for the efficient conduct of clinical research using marijuana. Concerns have been raised about whether the existing federal regulatory system is flexible enough to respond to increased interest in research into the potential therapeutic uses of marijuana and marijuana-derived drugs. HHS welcomes an opportunity to continue to explore these concerns with DEA. Should you have any questions regarding theses recommendations, please contact Corinne P. Moody, Science Policy Analyst, Controlled Substances Staff, Center for Drug Evaluation and Research, FDA, at (301) 796– 3152. Sincerely yours, Karen B. DeSalvo, MD, MPH, MSc Acting Assistant Secretary for Health Enclosure: Basis for the Recommendation for Maintaining Marijuana in Schedule I of the Controlled Substances Act E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules Basis for the Recommendation for Maintaining Marijuana in Schedule I of the Controlled Substances Act mstockstill on DSK3G9T082PROD with PROPOSALS2 On December 17, 2009, Mr. Bryan Krumm submitted a petition to the Drug Enforcement Administration (DEA) requesting that proceedings be initiated to repeal the rules and regulations that place marijuana 4 in Schedule I of the Controlled Substances Act (CSA). The petitioner contends that marijuana has an accepted medical use in the United States, has proven safety and efficacy, is safe for use under medical supervision, and does not have the abuse potential for placement in Schedule I. The petitioner requests that marijuana be rescheduled to any schedule other than Schedule I of the CSA. In May 2011, the DEA Administrator requested that the U.S. Department of Health and Human Services (HHS) provide a sdentific and medical evaluation of the available information and a scheduling recommendation for marijuana, in accordance with the provisions of 21 U.S.C. 811(b). In accordance with 21 U.S.C. 811(b), the DEA has gathered information related to the control of marijuana (Cannabis sativa) 5 under the CSA. Pursuant to 21 U.S.C. 811(b), the Secretary of HHS is required to consider in a scientific and medical evaluation eight factors determinative of control under the CSA. Following consideration of the eight factors, if it is appropriate, the Secretary must make three findings to recommend scheduling a substance in the CSA or transferring a substance from one schedule to another. The findings relate to a substance’s abuse potential, legitimate medical use, and safety or dependence liability. Administrative responsibilities for evaluating a substance for control under the CSA are performed by the Food and Drug Administration (FDA), with the concurrence of the National Institute on Drug Abuse (NIDA), as described in the 4 Note that ‘‘marihuana’’ is the spelling originally used in the Controlled Substances Act (CSA). This document uses the spelling that is more common in current usage, ‘‘marijuana.’’ 5 The CSA defines marihuana (marijuana) as the following: All parts of the plant Cannabis sativa L., whether growing or not; the seeds thereof; the resin extracted from any part of such plant; and every compound, manufacture, salt, derivative, mixture, or preparation of such plant, its seeds or resin. Such term does not include the mature stalks of such plant, fiber produced from such stalks, oil or cake made from the seeds of such plant, any other compound, manufacture, salt, derivative, mixture, or preparation of such mature stalks (except the resin extracted therefrom), fiber, oil, or cake, or the sterilized seed of such plant which is incapable of germination (21 U.S.C. 802(16)). VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 Memorandum of Understanding (MOU) of March 8, 1985 (50 FR 9518–20). In this document, FDA recommends continued control of marijuana in Schedule I of the CSA. Pursuant to 21 U.S.C. 811(c), the eight factors pertaining to the scheduling of marijuana are considered below. 1. Its Actual or Relative Potential for Abuse Under the first factor the Secretary must consider marijuana’s actual or relative potential for abuse. The CSA does not define the term ‘‘abuse.’’ However, the CSA’s legislative history suggests the following in determining whether a particular drug or substance has a potential for abuse: 6 a. There is evidence that individuals are taking the drug or drugs containing such a substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community. b. There is a significant diversion of the drug or drugs containing such a substance from legitimate drug channels. c. Individuals are taking the drug or drugs containing such a substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such drugs in the course of his professional practice. d. The drug or drugs containing such a substance are new drugs so related in their action to a drug or drugs already listed as having a potential for abuse to make it likely that the drug will have the same potentiality for abuse as such drugs, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community. In the development of this scientific and medical evaluation for the purpose of scheduling, the Secretary analyzed considerable data related to the substance’s abuse potential. The data include a discussion of the prevalence and frequency of use, the amount of the substance available for illicit use, the ease of obtaining or manufacturing the substance, the reputation or status of the substance ‘‘on the street,’’ and evidence relevant to at-risk populations. Importantly, the petitioners define marijuana as including all Cannabis 6 Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91–1444, 91st Cong., Sess. 1 (1970) reprinted in U.S.C.C.A.N. 4566, 4603. PO 00000 Frm 00083 Fmt 4701 Sfmt 4702 53769 cultivated strains. Different marijuana samples derived from various cultivated strains may have very differernt chemical consituents, thus the analysis is based on what is known about the range of these constituents across all cultivated strains. Determining the abuse potential of a substance is complex with many dimensions, and no single test or assessment provides a complete characterization. Thus, no single measure of abuse potential is ideal. Scientifically, a comprehensive evaluation of the relative abuse potential of a substance can include consideration of the following elements: Receptor binding affinity, preclinical pharmacology, reinforcing effects, discriminative stimulus effects, dependence producing potential, pharmacokinetics, route of administration, toxicity, data on actual abuse, clinical abuse potential studies, and public health risks. Importantly, abuse can exist independently from tolerance or physical dependence because individuals may abuse drugs in doses or patterns that don not induce these phenomena. Additionally evidence of clandestine population and illicit trafficking of a substance can shed light on both the demand for a substance as well as the ease of obtaining a substance. Animal and human laboratory data and epidemiological data are all used in determining a substance’s abuse potential. Moreover, epidemiological data can indicate actual abuse. The petitioner compares the effects of marijuana to currently controlled Schedule II substances and make repeated claims about their comparative effects. Comparisons between marijuana and the diverse array of Schedule II substances is difficult, because of the pharmacologically dissimilar actions of substances of Schedule II of the CSA. For example, Schedule II substances include stimulant-like drugs (e.g., cocaine, methylphenidate, and amphetamine), opioids (e.g., oxycodone, fentanyl), sedatives (e.g., pentobarbital, amobarbital), dissociative anesthetics (e.g., PCP), and naturally occurring plant components (e.g., coca leaves and poppy straw). The mechanism(s) of action of the above Schedule II substances are wholly different from on another, and they are different from tetrahydrocannabinol (THC) and marijuana as well. For example, Schedule II stimulants typically function by increasing monoaminergic tone via an increase in dopamine and norepinephrine (Schmitt et al., 2013). In contrast, opioid analgesics function via mu-opioid receptor agonist effects. E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53770 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules These differing mechanism(s) of action result in vastly different behavioral and adverse effect profiles, making comparisons across the range of pharmacologically diverse C–II substances inappropriate. In addition, many substances scheduled under the CSA are reviewed and evaluated within the context of commercial drug development, using data submitted in the form of a new drug application (NDA). A new analgesic drug might be compared to a currently scheduled analgesic drug as part of the assessment of its relative abuse potential. However, because the petitioners have not identified a specific indication for the use of marijuana, identifying an appropriate comparator based on indication cannot be done. a. There is evidence that individuals are taking the substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community. Evidence shows that some individuals are taking marijuana in amounts sufficient to create a hazard to their health and to the safety of other individuals and the community. A large number of individuals use marijuana. HHS provides data on the extent of marijuana abuse through NIDA and the Substance Abuse and Mental Health Services Administration (SAMHSA). According to the most recent data from SAMHSA’s 2012 National Survey on Drug Use and Health (NSDUH), which estimates the number of individuals who have use a substance within a month prior to the study (described as ‘‘current use’’), marijuana is the most commonly used illicit drug among American aged 12 years and older, with an estimated 18.9 million Americans having used marijuana within the month prior to the 2012 NSDUH. Compared to 2004, when an estimated 14.6 million individuals reported using marijuana within the month prior to the study, the estimated rates in 2012 show an increase of approximately 4.3 million individuals. The 2013 Monitoring the Future (MTF) survey of 8th, 10th, and 12th grade students also indicates that marijuana is the most widely used illicit substance in this age group. Specifically, current month use was at 7.0 percent of 8th graders, 18.0 percent of 10th, graders and 22.7 percent of 12th graders. Additionally, the 2011 Treatment Episode Data Set (TEDS) reported that primary marijuana abuse accounted for 18.1 percent of nonprivate substance-abuse treatment facility admissions, with 24.3 percent of those admitted reporting daily use. However, of these admissions for primary marijuana abuse, the criminal VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 justice system referred 51.6 percent to treatment. SAMHSA’s Drug Abuse Warning Network (DAWN) was a national probability survey of U.S. hospitals with emergency departments (EDs) and was designed to obtain information on ED visits in which marijuana was mentioned, accounting for 36.4 percent of illicit drug related ED visits. There are some limitations related to DAWN data on ED visits, which are discussed in detail in Factor 4, ‘‘Its History and Current Pattern of Abuse;’’ Factor 5, ‘‘The Scope, Duration, and Significance of Abuse;’’ and Factor 6, ‘‘What, if an, Risk There is to the Public Health.’’ These factors contain detailed discussions of these data. A number of risks can occur with both acute and chronic use of marijuana. Detailed discussions of the risks are addressed in Factor 2, ‘‘Scientific Evidence of its Pharmacological Effect, if Known,’’ and Factor 6, ‘‘What, if any, Risk There is to the Public Health.’’ b. There is significant diversion of the substance from legitimate drug channels. There is a lack of evidence of significant diversion of marijuana from legitimate drug channels, but this is likely due to the fact that marijuana is more widely available from illicit sources rather than through legitimate channels. Marijuana is not an FDAapproved drug product, as an NDA or biologics license application (BLA) has not been approved for marketing in the United States. Numerous states and the District of Columbia have state-level medical marijuana laws that allow for marijuana use within that state. These state-level drug channels do not have sufficient collection of data related to medical treatment, including efficacy and safety. Marijuana is used by researchers for nonclinical research as well as clinical research under investigational new drug (IND) applications; this represents the only legitimate drug channel in the United States. However, marijuana used for research reporesents a very small contribution of the total amount of marijuana available in the United States, and thus provides limited information about diversion. In addition, the lack of significant diversion of investigation supplies is likely because of the widespread availability of illicit marijuana of equal or greater amounts of delta9-THC. The data originating from the DEA on seizure statistics demonstrate the magnitude of the availability for illicit marijuana. DEA’s System to Retrieve Information from Drug Evidence (STRIDE) provides information on total domestic drug seizures, STRIDE reports a total PO 00000 Frm 00084 Fmt 4701 Sfmt 4702 domestic seizure of 573,195 kg of marijuana in 2011, the most recent year with complete data that is currently publically available (DEA Domestic Drug Seizures, n.d.). c. Individuals are taking the substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such substances. Because the FDA has not approved an NDA or BLA for a marijuana drug product for any therapeutic indication, the only way an individual can take marijuana on the basis of medical advice through legitimate channels at the federal level is by participating in research under an IND application. That said, numerous states and the District of Columbia have passed state-level medical marijuana laws allowing for individuals to use marijuana under certain cicrumstances. However, data are not yet available to determine the number of individuals using marijuana under these state-level medical marijuana laws. Regardless, according to the 2012 NSDUH data, 18.9 million American adults currently use marijuana (SAMHSA, 2013). Based on the large number of individuals reporting current use of marijuana and the lack of an FDA-approved drug product in the United States, one can assume that it is likely that the majority of individuals using marijuana do so on their own initiative rather than on the basis of medical advice from a licensed practitioner. d. The substance is so related in its action to a substance already listed as having a potential for abuse to make it likely that it will have the same potential for abuse as such substance, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community. FDA has approved two drug products containing cannabinoid compounds that are structurally related to the active components in marijuana. These two marketed products are controlled under the CSA. Once a specific drug product containing cannabinoids becomes approved, that specific drug product may be moved from Schedule I to a different Schedule (II–V) under the CSA. Firstly, Marinol—generically known as dronabinol—is a Schedule III drug product containing synthetic delta9-THC. Marinol, which is formulated in sesame oil in soft gelatin capsules, was first placed in Schedule II under the CSA following its approval by the FDA. Marinol was later rescheduled E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules to Schedule III under the CSA because of low numbers of reports of abuse relative to marijuana. Dronabinol is listed in Schedule I under the CSA. FDA approved Marinol in 1985 for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who failed to respond adequately to conventional anti-emetic treatments. In 1992, FDA approved Marional for anorexia associated with weight loss in patients with acquired immunodeficiency syndrome (AIDS). Secondly, in 1985, FDA approved Cesamet, a drug product containing the Schedule II substance nabilone, for the treatment of nausea and vomiting associated with cancer chemotherapy. Besides the two cannabinoid-containing drug products FDA approved for marketing, other naturally occurring cannabinoids and their derivatives (from Cannabis) and their synthetic equivalents with similar chemical structure and pharmacological activity are included in the CSA as Schedule I substances. mstockstill on DSK3G9T082PROD with PROPOSALS2 2. Scientific Evidence of Its Pharmacological Effects, if Known Under the second factor, the Secretary must consider the scientific evidence of marijuana’s pharmacological effects. Abundant scientific data are available on the neurochemistry, toxicology, and pharmacology of marijuana. This section includes a scientific evaluation of marijuana’s neurochemistry; pharmacology; and human and animal behavioral, central nervous system, cognitive, cardiovascular, autonomic, endocrinological, and immunological system effects. The overview presented below relies upon the most current research literature on cannabinoids. Neurochemistry and Pharmacology of Marijuana Marijuana is a plant that contains numerous natural constituents, such as cannabinoids, that have a variety of pharmacological actions. The petition defines marijuana as including all Cannabis cultivated strains. Different marijuana samples derived from various cultivated strains may have very different chemical constituents including delta9-THC and other cannabinoids (Appendino et al., 2011). As a consequence, marijuana products from different strains will have different biological and pharmacological profiles. According to ElSohly and Slade (2005) and Appendino et al. (2011), marijuana contains approximately 525 identified natural constituents, including approximately 100 compounds classified as cannabinoids. Cannabinoids primarily exist in VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 Cannabis, and published data suggests that most major cannabinoid compounds occurring naturally have been identified chemically. New and minor cannabinoids and other new compounds are continuously being characterized (Pollastro et al., 2011). So far, only two cannabinoids (cannabigerol and its corresponding acid) have been obtained from a nonCannabis source. A South African Helichrysum (H. umbraculigerum) accumulates these compounds (Appendino et al., 2011). The chemistry of marijuana is described in more detail in Factor 3, ‘‘The State of Current Scientific Knowledge Regarding the Drug or Other Substance.’’ The site of cannabinoid action is at the cannabinoid receptors. Cloning of cannabinoid receptors, first from rat brain tissue (Matsuda et al., 1990) and then from human brain tissue (Gerard et al., 1991), has verified the site of action. Two cannabinoid receptors, CB1 and CB2, were characterized (Battista et al., 2012; Piomelli, 2005). Evidence of a third cannabinoid receptor exists, but it has not been identified (Battista et al., 2012). The cannabinoid receptors, CB1 and CB2, belong to the family of G-proteincoupled receptors, and present a typical seven transmembrane-spanning domain structure. Cannabinoid receptors link to an inhibitory G-protein (Gi), such that adenylate cyclase activity is inhibited when a ligand binds to the receptor. This, in tum, prevents the conversion of ATP to the second messenger, cyclic AMP (cAMP). Examples of inhibitory coupled receptors include opioid, muscarinic cholinergic, alpha2adrenoreceptors, dopamine (D2), and serotonin (5-HT1). Cannabinoid receptor activation inhibits N- and P/Q-type calcium channels and activates inwardly rectifying potassium channels (Mackie et al., 1995; Twitchell et al., 1997). Ntype calcium channel inhibition decreases neurotransmitter release from several tissues. Thus, calcium channel inhibition may be the mechanism by which cannabinoids inhibit acetylcholine, norepinephrine, and glutamate release from specific areas of the brain. These effects may represent a potential cellular mechanism underlying cannabinoids’ antinociceptive and psychoactive effects (Ameri, 1999). CB1 receptors are found primarily in the central nervous system, but are also present in peripheral tissues. CB1 receptors are located mainly in the basal ganglia, hippocarnpus, and cerebellum of the brain (Howlett et al., 2004). The localization of these receptors may PO 00000 Frm 00085 Fmt 4701 Sfmt 4702 53771 explain cannabinoid interference with movement coordination and effects on memory and cognition. Additionally, CB1 receptors are found in the immune system and numerous other peripheral tissues (Petrocellis and Di Marzo, 2009). However, the concentration of CB1 receptors is considerably lower in peripheral tissues than in the central nervous system (Herkenharn et al., 1990 and 1992). CB2 receptors are found primarily in the immune system, but are also present in the central nervous system and other peripheral tissues. In the immune system, CB2 receptors are found predominantly in B lymphocytes and natural killer cells (Bouaboula et al., 1993). CB2 receptors may mediate cannabinoids’ immunological effects (Galiegue et al., 1995). Additionally, CB2 receptors have been localized in the brain, primarily in the cerebellum and hippocampus (Gong et al., 2006). The distribution of CB2 receptors throughout the body is less extensive than the distribution of CB1 receptors (Petrocellis and Di Marzo, 2009). However, both CB1 and CB2 receptors are present in numerous tissues of the body. Cannabinoid receptors have endogenous ligands. In 1992 and 1995, two endogenous cannabinoid receptor agonists, anandamide and arachidonyl glycerol (2-AG), respectively, were identified (Di Marzo, 2006). Anandamide is a low efficacy agonist (Breivogel and Childers, 2000) and 2-AG is a high efficacy agonist (Gonsiorek et al., 2000). Cannabinoid endogenous ligands are present in central as well as peripheral tissues. A combination of uptake and hydrolysis terminate the action of the endogenous ligands. The endogenous cannabinoid system is a locally active signaling system that, to help restore homeostasis, is activated ‘‘on demand’’ in response to changes to the local homeostasis (Petrocellis and Di Marzo, 2009). The endogenous cannabinoid system, including the endogenous cannabinoids and the cannabinoid receptors, demonstrate substantial plasticity in response to several physiological and pathological stimuli (Petrocellis and Di Marzo, 2009). This plasticity is particularly evident in the central nervous system. Delta9-THC and cannabidiol (CBD) are two abundant cannabinoids present in marijuana. Marijuana’s major psychoactive cannabinoid is delta9-THC (Wachtel et al., 2002). In 1964, Gaoni and Mechoularn first described delta9THC’s structure and function. In 1963, Mechoularn and Shvo first described CBD’s structure. The pharmacological actions of CBD have not been fully studied in humans. E:\FR\FM\12AUP2.SGM 12AUP2 53772 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules Delta9-THC and CBD have varying affinity and effects at the cannabinoid receptors. Delta9-THC displays similar affinity for CB1 and CB2 receptors, but behaves as a weak agonist for CB2 receptors. The identification of synthetic cannabinoid ligands that selectively bind to CB2 receptors but do not have the typical delta9-THC-like psychoactive properties suggests that the activation of CB1-receptors mediates cannabinoids’ psychotropic effects (Hanus et al., 1999). CBD has low affinity for both CB1 and CB2 receptors (Mechoulam et al., 2007). According to Mechoulam et al. (2007), CBD has antagonistic effects at CB1 receptors and some inverse agonistic properties at CB2 receptors. When cannabinoids are given subacutely to rats, CB1 receptors downregulate and the binding of the second messenger system coupled to CB1 receptors, GTPgarnmaS, decreases (Breivogel et al., 2001). mstockstill on DSK3G9T082PROD with PROPOSALS2 Animal Behavioral Effects Self-Administration Self-administration is a method that assesses the ability of a drug to produce rewarding effects. The presence of rewarding effects increases the likelihood of behavioral responses to obtain additional drug. Animal selfadministration of a drug is often useful in predicting rewarding effects in humans, and is indicative of abuse liability. A good correlation is often observed between those drugs that rhesus monkeys self-administer and those drugs that humans abuse (Balster and Bigelow, 2003). Initially, researchers could not establish selfadministration of cannabinoids, including delta9-THC, in animal models. However, self-administration of delta9-THC can now be established in a variety of animal models under specific training paradigms (Justinova et al., 2003, 2004, 2005). Squirrel monkeys, with and without prior exposure to other drugs of abuse, self-administer delta9-THC under specific conditions. For instance, Tanda et al. (2000) observed that when squirrel monkeys are initially trained to selfadminister intravenous cocaine, they will continue to bar-press delta9-THC at the same rate as they would with cocaine. The doses were notably comparable to those doses used by humans who smoke marijuana. SR141716, a CB1 cannabinoid receptor agonist-antagonist, can block this rewarding effect. Other studies show ¨ that naıve squirrel monkeys can be successfully trained to self-administer delta9-THC intravenously (Justinova et al., 2003). The maximal responding rate VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 is 4 mg/kg per injection, which is 2–3 times greater than observed in previous studies using cocaine-experienced monkeys. Naltrexone, a mu-opioid antagonist, partially antagonizes these rewarding effects of delta9-THC (Justinova et al., 2004). Additionally, data demonstrate that under specific conditions, rodents selfadminister cannabinoids. Rats will selfadminister delta9-THC when applied intracerebroventricularly (i.c.v.), but only at the lowest doses tested (0.01– 0.02 mg/infusion) (Braida et al., 2004). SR141716 and the opioid antagonist naloxone can antagonize this effect. However, most studies involve rodents self-administrating the synthetic cannabinoid WIN 55212, a CB1 receptor agonist with a non-cannabinoid structure (Deiana et al., 2007; Fattore et al., 2007; Martellotta et al., 1998; Mendizabal et al., 2006). Aversive effects, rather than reinforcing effects, occur in rats that received high doses of WIN 55212 (Chaperon et al., 1998) or delta9-THC (Sanudo-Pena et al., 1997), indicating a possible critical dose-dependent effect. In both studies, SR141716 reversed these aversive effects. Conditioned Place Preference Conditioned place preference (CPP) is a less rigorous method than selfadministration for determining whether or not a drug has rewarding properties. In this behavioral test, animals spend time in two distinct environments: One where they previously received a drug and one where they received a placebo. If the drug is reinforcing, animals will choose to spend more time in the environment paired with the drug, rather than with the placebo, when presented with both options s.imultaneously. Animals show CPP to delta9-THC, but only at the lowest doses tested (0.075– 1.0 mg/kg, intraperitoneal (i.p.)) (Braida et al., 2004). SR141716 and naloxone antagonize this effect (Braida et al., 2004). As a partial agonist, SR141716 can induce CPP at doses of 0.25, 0.5, 2 and 3 mg/kg (Cheer et al., 2000). In knockout mice, those without m-opioid receptors do not develop CPP to delta9THC (Ghozland et al., 2002). Drug Discrimination Studies Drug discrimination is a method where animals indicate whether a test drug produces physical or psychic perceptions similar to those produced by a known drug of abuse. In this test, an animal learns to press one bar when it receives the known drug of abuse and another bar when it receives placebo. To determine whether the test drug is like PO 00000 Frm 00086 Fmt 4701 Sfmt 4702 the known drug of abuse, a challenge session with the test drug demonstrates which of the two bars the animal presses more often. In addition to humans (Lile et al., 2009; Lile et al., 2011), it has been noted that animals, including monkeys (McMahon, 2009), mice (McMahon et al., 2008), and rats (Gold et al., 1992), are able to discriminate cannabinoids from other drugs or placebo. Moreover, the major active metabolite of delta9THC, 11-hydroxy-delta9-THC, also generalizes (following oral administration) to the stimulus cues elicited by delta9-THC (Browne and Weissman, 1981). Twenty-two other cannabinoids found in marijuana also fully substitute for delta9-THC. However, CBD does not substitute for delta9-THC in rats (Vann et al., 2008). Discriminative stimulus effects of delta9-THC are pharmacologically specific for marijuana containing cannabinoids (Balster and Prescott, 1992; Browne and Weissman, 1981; Wiley et al., 1993, 1995). The discriminative stimulus effects of the cannabinoid group appear to provide unique effects because stimulants, hallucinogens, opioids, benzodiazepines, barbiturates, NMDA antagonists, and antipsychotics do not fully substitute for delta9-THC. Central Nervous System Effects Human Physiological and Psychological Effects Psychoactive Effects Below is a list of the common subjective responses to cannabinoids (Adams and Martin, 1996; Gonzalez, 2007; Hollister 1986, 1988; Institute of Medicine, 1982). According to Maldonado (2002), these responses to marijuana are pleasurable to many humans and are often associated with drug-seeking and drug-taking. High levels of positive psychoactive effects are associated with increased marijuana use, abuse, and dependence (Scherrer et al., 2009; Zeiger et al., 2010). (1) Disinhibition, relaxation, increased sociability, and talkativeness. (2) Increased merriment and appetite, and even exhilaration at high doses. (3) Enhanced sensory perception, which can generate an increased appreciation of music, art, and touch. (4) Heightened imagination, which can lead to a subjective sense of increased creativity. (5) Initial dizziness, nausea, tachycardia, facial flushing, dry mouth, and tremor. (6) Disorganized thinking, inability to converse logically, time distortions, and short-term memory impairment. E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules (7) Ataxia and impaired judgment, which can impede driving ability or lead to an increase in risk-tasking behavior. (8) Illusions, delusions, and hallucinations that intensify with higher doses. (9) Emotional lability, incongruity of affect, dysphoria, agitation, paranoia, confusion, drowsiness, and panic attacks, which are more common in inexperienced or high-dosed users. As with many psychoactive drugs, a person’s medical, psychiatric, and drugtaking history can influence the individual’s response to marijuana. Dose preferences to marijuana occur in that marijuana users prefer higher concentrations of the principal psychoactive substance (1.95 percent delta9-THC) over lower concentrations (0.63 percent delta9-THC) (Chait and Burke, 1994). Nonetheless, frequent marijuana users (≤100 times of use) were able to identify a drug effect from low-dose delta9-THC better than occasional users (<10 times of use) while also experiencing fewer sedative effects from marijuana (Kirk and de Wit, 1999). The petitioners contend that many of marijuana’s naturally occurring cannabinoids mitigate the psychoactive effects of delta9-THC, and therefore that marijuana lacks sufficient abuse potential to warrant Schedule I placement, because Marinol, which is in Schedule III, contains only delta9-THC. This theory has not been demonstrated in controlled studies. Moreover, the concept of abuse potential encompasses all properties of a substance, including its chemistry, pharmacology, and pharmacokinetics, as well as usage patterns and diversion history. The abuse potential of a substance is associated with the repeated or sporadic use of a substance in nonmedical situations for the psychoactive effects the substance produces. These psychoactive effects include euphoria, perceptual and other cognitive distortions, hallucinations, and mood changes. However, as stated above, the abuse potential not only includes the psychoactive effects, but also includes other aspects related to a substance. DEA’s final published rule entitled ‘‘Rescheduling of the Food and Drug Administration Approved Product Containing Synthetic Dronabinol [(–)delta9-(trans)-Tetrahydrocannabinol] in Sesame Oil and Encapsulated in Soft Gelatin Capsules From Schedule II to Schedule III’’ (64 FR 35928, July 2, 1999) rescheduled Marinol from Schedule II to Schedule III. The HHS assessment of the abuse potential and subsequent scheduling recommendation VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 compared Marinol to marijuana on different aspects related to abuse potential. Major differences in formulation, availability, and usage between marijuana and the drug product, Marinol, contribute to their differing abuse potentials. Hollister and Gillespie (1973) estimated that delta9-THC by smoking is 2.6 to 3 times more potent than delta9THC ingested orally. The intense psychoactive drug effect achieved, rapidly by smoking is generally considered to produce the effect desired by the abuser. This effect explains why abusers often prefer to administer certain drugs by inhalation, intravenously, or intranasally rather than orally. Such is the case with cocaine, opium, heroin, phencyclidine, methamphetamine, and delta9-THC from marijuana (0.1–9.5 percent delta9THC range) or hashish (10–30 percent delta9-THC range) (Wesson and Washburn, 1990). Thus, the delayed onset and longer duration of action for Marinol may be contributing factors limiting the abuse or appeal of Marinol as a drug of abuse relative to marijuana. The formulation of Marinol is a factor that contributes to differential scheduling of Marinol and marijuana. For example, extraction and purification of dronabinol from the encapsulated sesame oil mixture of Marinol is highly complex and difficult. Additionally, the presence of sesame oil mixture in the formulation may preclude the smoking of Marinol-laced cigarettes. Additionally, there is a dramatic difference between actual abuse and illicit trafficking of Marinol and marijuana. Despite Marinol’s availability in the United States, there have been no significant reports of abuse, diversion, or public health problems due to Marinol. By comparison, 18.9 million American adults report currently using marijuana (SAMHSA, 2013). In addition, FDA’s approval of an NDA for Marinol allowed for Marinol to be rescheduled to Schedule II, and subsequently to Schedule III of the CSA. In conclusion, marijuana and Marinol differ on a wide variety of factors that contribute to each substance’s abuse potential. These differences are major reasons distinguishing the higher abuse potential for marijuana and the different scheduling determinations of marijuana and Marinol. In terms of the petitioners’ claim that different cannabinoids present in marijuana mitigate the psychoactive effects of delta9-THC, only three of the cannabinoids present in marijuana were simultaneously administered with delta9-THC to examine how the PO 00000 Frm 00087 Fmt 4701 Sfmt 4702 53773 combinations of these cannabinoids such as CBD, cannabichromene (CBC) and cannabinol (CBN) influence delta9THC’s psychoactive effects. Dalton et al. (1976) observed that smoked administration of placebo marijuana cigarettes containing injections of 0.15 mg/kg CBD combined with 0.025mg/kg of delta9-THC, in a 7:1 ratio of CBD to delta9-THC, significantly decreased ratings of acute subjective effects and ‘‘high’’ when compared to smoking delta9-THC alone. In contrast, Ilan et al. (2005) calculated the naturally occurring concentrations of CBC and CBD in a batch of marijuana cigarettes with either 1.8 percent or 3.6 percent delta9-THC concentration by weight. For each strength of delta9-THC in marijuana cigarettes, the concentrations of CBC and CBD were classified in groups of either low or high. The study varied the amount of CBC and CBD within each strength of delta9-THC marijuana cigarettes, with administrations consisting of either low CBC (between 0.1–0.2 percent CBC concentration by weight) and low CBD (between 0.1–0.4 percent CBD concentration by weight), high CBC (≤ 0.5 percent CBC concentration by weight) and low CBD, or low CBC and high CBD (≤1.0 percent CBD concentration by weight). Overall, all combinations scored significantly greater than placebo on ratings of subjective effects, and there was no significant difference between any combinations. The oral administration of a combination of either 15, 30, or 60 mg CBD with 30 mg delta9-THC dissolved in liquid (in a ratio of at least 1:2 CBD to delta9-THC) reduced the subjective effects produced by delta9-THC alone (Karniol et al., 1974). Additionally, orally administering a liquid mixture combining 1 mg/kg CBD with 0.5 mg/kg of delta9-THC (ratio of 2:1 CBD to delta9THC) decreased scores of anxiety and marijuana drug effect on the Addiction Research Center Inventory (ARCI) compared to delta9-THC alone (Zuardi et al., 1982). Lastly, oral administration of either 12.5, 25, or 50 mg CBN combined with 25 mg delta9-THC dissolved in liquid (ratio of at least 1:2 CBN to delta9-THC) significantly increased subjective ratings of ‘‘drugged,’’ ‘‘drowsy,’’ ‘‘dizzy,’’ and ‘‘drunk,’’ compared to delta9-THC alone (Karniol et al., 1975). Even though some studies suggest that CBD may decrease some of delta9-THC’s psychoactive effects, the ratios of CBD to delta9-THC administered in these studies are not present in marijuana used by most people. For example, in one study, researchers used smoked E:\FR\FM\12AUP2.SGM 12AUP2 53774 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules mstockstill on DSK3G9T082PROD with PROPOSALS2 marijuana with ratios of CBD to delta9THC naturally present in marijuana plant material and they found out that varying the amount of CBD actually had no effect on delta9-THC’s psychoactive effects (Ilan et al., 2005). Because most marijuana currently available on the street has high amounts of delta9-THC with low amounts of CBD and other cannabinoids, most individuals use marijuana with low levels of CBD present (Mehmedic et al., 2010). Thus, any possible mitigation of delta9-THC’s psychoactive effects by CBD will not occur for most marijuana users. In contrast, one study indicated that another cannabinoid present in marijuana, CBN, may enhance delta9THC’s psychoactive effects (Karniol et al., 1975). Behavioral Impairment Marijuana induces various psychoactive effects that can lead to behavioral impairment. Marijuana’s acute effects can significantly interfere with a person’s ability to learn in the classroom or to operate motor vehicles. Acute administration of smoked marijuana impairs performance on learning, associative processes, and psychomotor behavioral tests (Block et al., 1992). Ramaekers et al. (2006a) showed that acute administration of 250 mg/kg and 500 mg/kg of delta9-THC in smoked marijuana dose-dependently impairs cognition and motor control, including motor impulsivity and tracking impairments (Ramaekers et al., 2006b). Similarly, administration of 290 mg/kg delta9-THC in a smoked marijuana cigarette resulted in impaired perceptual motor speed and accuracy: Two skills which are critical to driving ability (Kurzthaler et al., 1999). Lastly, administration of 3.95 percent delta9THC in a smoked marijuana cigarette not only increased disequilibrium measures, but also increased the latency in a task of simulated vehicle braking at a rate comparable to an increase in stopping distance of five feet at 60 mph (Liguori et al., 1998). However, acute administration of marijuana containing 2.1 percent delta9-THC does not produce ‘‘hangover effects’’ (Chait, 1990). In addition to measuring the acute effects immediately following marijuana administration, researchers have conducted studies to determine how long behavioral impairments last after abstinence. Some of marijuana’s acute effects may not fully resolve until at least one day after the acute psychoactive effects have subsided. Heishman et al. (1990) showed that impairment on memory tasks persists for 24 hours after smoking marijuana VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 cigarettes containing 2.57 percent delta9-THC. However, Fant et al. (1998) showed that the morning after exposure to 1.8 percent or 3.6 percent smoked delta9-THC, subjects had minimal residual alterations in subjective or performance measures. A number of factors may influence marijuana’s behavioral effects including the duration of use (chronic or short term), frequency of use (daily, weekly, or occasionally), and amount of use (heavy or moderate). Researchers also have examined how long behavioral impairments last following chronic marijuana use. These studies used selfreported histories of past duration, frequency, and amount of past marijuana use, and administered a variety of performance and cognitive measures at different time points following marijuana abstinence. In chronic marijuana users, behavioral impairments may persist for up to 28 days of abstinence. Solowij et al. (2002) demonstrated that after 17 hours of abstinence, 51 adult heavy chronic marijuana users performed worse on memory and attention tasks than 33 non-using controls or 51 heavy, shortterm users. Another study noted that heavy, frequent marijuana users, abstinent for at least 24 hours, performed significantly worse than the controls on verbal memory and psychomotor speed tests (Messinis et al., 2006). Additionally, after at least 1 week of abstinence, young adult frequent marijuana users, aged 18–28, showed deficits in psychomotor speed, sustained attention, and cognitive inhibition (Lisdahl and Price, 2012). Adult heavy, chronic marijuana users showed deficits on memory tests after 7 days of supervised abstinence (Pope et al., 2002). However, when these same individuals were again tested after 28 days of abstinence, they did not show significant memory deficits. The authors concluded, ‘‘cannabis-associated cognitive deficits are reversible and related to recent cannabis exposure, rather than irreversible and related to cumulative lifetime use.’’ 7 However, other researchers reported neuropsychological deficits in memory, executive functioning, psychomotor speed and manual dexterity in heavy marijuana users abstinent for 28 days (Bolla et al., 2002). Furthermore, a follow-up study of heavy marijuana users noted decision-making deficits after 25 days of supervised abstinence. (Bolla et al., 2005). However, moderate marijuana users did not show decisionmaking deficits after 25 days of 7 In this quotation the term Cannabis is used interchangeably for marijuana. PO 00000 Frm 00088 Fmt 4701 Sfmt 4702 abstinence, suggesting the amount of marijuana use may impact the duration of residual impairment. The effects of chronic marijuana use do not seem to persist after more than 1 to 3 months of abstinence. After 3 months of abstinence, any deficits observed in IQ, immediate memory, delayed memory, and informationprocessing speeds following heavy marijuana use compared to pre-drug use scores were no longer apparent (Fried et al., 2005). Marijuana did not appear to have lasting effects on performance of a comprehensive neuropsychological battery when 54 monozygotic male twins (one of whom used marijuana, one of whom did not) were compared 1– 20 years after cessation of marijuana use (Lyons et al., 2004). Similarly, following abstinence for a year or more, both light and heavy adult marijuana users did not show deficits on scores of verbal memory compared to non-using controls (Tait et al., 2011). According to a recent meta-analysis looking at non-acute and long-lasting effects of marijuana use on neurocognitive performance, any deficits seen within the first month following abstinence are generally not present after about 1 month of abstinence (Schreiner and Dunn, 2012). Another aspect that may be a critical factor in the intensity and persistence of impairment resulting from chronic marijuana use is the age of first use. Individuals with a diagnosis of marijuana misuse or dependence who were seeking treatment for substance use, who initiated marijuana use before the age of 15 years, showed deficits in performance on tasks assessing sustained attention, impulse control, and general executive functioning compared to non-using controls. These deficits were not seen in individuals who initiated marijuana use after the age of 15 years (Fontes et al., 2011). Similarly, heavy, chronic marijuana users who began using marijuana before the age of 16 years had greater decrements in executive functioning tasks than heavy, chronic marijuana users who started using after the age of 16 years and non-using controls (Gruber et al., 2012). Additionally, in a prospective longitudinal birth cohort study of 1,037 individuals, marijuana dependence or chronic marijuana use was associated with a decrease in IQ and general neuropsychological performance compared to pre-marijuana exposure levels in adolescent onset users (Meier et al., 2012). The decline in adolescent-onset user’s IQ persisted even after reduction or abstinence of marijuana use for at least 1 year. In contrast, the adult-onset chronic marijuana users showed no significant E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules changes in IQ compared to pre-exposure levels whether they were current users or abstinent for at least 1 year (Meier et al., 2012). In addition to the age of onset of use, some evidence suggests that the amount of marijuana used may relate to the intensity of impairments. In the above study by Gruber et al. (2012), where early-onset users had greater deficits than late-onset users, the early-onset users reported using marijuana twice as often and using three times as much marijuana per week than the late-onset users. Meier et al. (2012) showed that the deficits in IQ seen in adolescentonset users increased with the amount of marijuana used. Moreover, when comparing scores for measures of IQ, immediate memory, delayed memory, and information-processing speeds to pre-drug-use levels, the current, heavy, chronic marijuana users showed deficits in all three measures while current, occasional marijuana users did not (Fried et al., 2005). mstockstill on DSK3G9T082PROD with PROPOSALS2 Behavioral Effects of Prenatal Exposure Studies with children at different stages of development are used to examine the impact of prenatal marijuana exposure on performance in a series of cognitive tasks. However, many pregnant women who reported marijuana use were more likely to also report use of alcohol, tobacco, and cocaine (Goldschmidt et al., 2008). Thus, with potential exposure to multiple drugs, it is difficult to determine the specific impact of prenatal marijuana exposure. Most studies assessing the behavioral effects of prenatal marijuana exposure included women who, in addition to using marijuana, also reported using alcohol and tobacco. However, some evidence suggests an association between heavy prenatal marijuana exposure and deficits in some cognitive domains. In both 4-year-old and 6-yearold children, heavy prenatal marijuana use is negatively associated with performance on tasks assessing memory, verbal reasoning, and quantitative reasoning (Fried and Watkinson, 1987; Goldschmidt et al., 2008). Additionally, heavy prenatal marijuana use is associated with deficits in measures of sustained attention in children at the ages of 6 years and 13–16 years (Fried et al., 1992; Fried, 2002). In 9- to 12year-old children, prenatal marijuana exposure is negatively associated with executive functioning tasks that require impulse control, visual analysis, and hypothesis (Fried et al., 1998). VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 Association of Marijuana Use With Psychosis This analysis evaluates only the evidence for a direct link between prior marijuana use and the subsequent development of psychosis. Thus, this discussion does not consider issues such as whether marijuana’s transient effects are similar to psychotic symptoms in healthy individuals or exacerbate psychotic symptoms in individuals already diagnosed with schizophrenia. Extensive research has been conducted to investigate whether exposure to marijuana is associated with the development of schizophrenia or other psychoses. Although many studies are small and inferential, other studies in the literature use hundreds to thousands of subjects. At present, the available data do not suggest a causative link between marijuana use and the development of psychosis (Minozzi et al., 2010). Numerous large, longitudinal studies show that subjects who used marijuana do not have a greater incidence of psychotic diagnoses compared to those who do not use marijuana (Fergusson et al., 2005; Kuepper et al., 2011; Van Os et al., 2002). When analyzing the available evidence of the connection between psychosis and marijuana, it is critical to determine whether the subjects in the studies are patients who are already diagnosed with psychosis or individuals who demonstrate a limited number of symptoms associated with psychosis without qualifying for a diagnosis of the disorder. For example, instead of using a diagnosis of psychosis, some researchers relied on non-standard methods of representing symptoms of psychosis including ‘‘schizophrenic cluster’’ (Maremmani et al., 2004), ‘‘subclinical psychotic symptoms’’ (Van Gastel et al., 2012), ‘‘pre-psychotic clinical high risk’’ (Van der Meer et al., 2012), and symptoms related to ‘‘psychosis vulnerability’’ (GriffithLendering et al., 2012). These groupings do not conform to the criteria in the Diagnostic and Statistical Manual (DSM–5) or the International Classification of Diseases (ICD–10) for a diagnosis of psychosis. Thus, these groupings are not appropriate for use in evaluating marijuana’s impact on the development of actual psychosis. Accordingly, this analysis includes only those studies that use subjects diagnosed with a psychotic disorder. In the largest study evaluating the link between psychosis and drug use, 274 of the approximately 45,500 Swedish conscripts in the study population PO 00000 Frm 00089 Fmt 4701 Sfmt 4702 53775 (<0.01 percent) received a diagnosis of schizophrenia within the 14-year period following military induction from 1969 to 1983 (Andreasson et al., 1987). Of the conscripts diagnosed with psychosis, 7.7 percent (21 of the 274 conscripts with psychosis) had used marijuana more than 50 times at induction, while 72 percent (197 of the 274 conscripts with psychosis) had never used marijuana. Although high marijuana use increased the relative risk for schizophrenia to 6.0, the authors note that substantial marijuana use history ‘‘accounts for only a minority of all cases’’ of psychosis (Andreasson et al., 1987). Instead, the best predictor for whether a conscript would develop psychosis was a non-psychotic psychiatric diagnosis upon induction. The authors concluded that marijuana use increased the risk for psychosis only among individuals predisposed to develop the disorder. In addition, a 35year follow up to this study reported very similar results (Manrique-Garcia et al., 2012). In this follow up study, 354 conscripts developed schizophrenia; of these 354 conscripts, 32 used marijuana more than 50 times at induction (9 percent, an odds ratio of 6.3), while 255 had never used marijuana (72 percent). Additionally, the conclusion that the impact of marijuana may manifest only in individuals likely to develop psychotic disorders has been shown in many other types of studies. For example, although evidence shows that marijuana use may precede the presentation of symptoms in individuals later diagnosed with psychosis (Schimmelmann et al., 2011), most reports conclude that prodromal symptoms of schizophrenia appear prior to marijuana use (Schiffman et al., 2005). Similarly, a review of the geneenvironment interaction model for marijuana and psychosis concluded that some evidence supports marijuana use as a factor that may influence the development of psychosis, but only in those individuals with psychotic liability (Pelayo-Teran et al., 2012). A similar conclusion was drawn when the prevalence of schizophrenia was modeled against marijuana use across eight birth cohorts in Australia in individuals born between the years 1940 to 1979 (Degenhardt et al., 2003). Although marijuana use increased over time in adults born during the fourdecade period, there was not a corresponding increase in diagnoses for psychosis in these individuals. The authors conclude that marijuana may precipitate schizophrenic disorders only in those individuals who are vulnerable to developing psychosis. Thus, marijuana per se does not appear to E:\FR\FM\12AUP2.SGM 12AUP2 53776 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules induce schizophrenia in the majority of individuals who have tried or continue to use marijuana. However, in individuals with a genetic vulnerability for psychosis, marijuana use may influence the development of psychosis. mstockstill on DSK3G9T082PROD with PROPOSALS2 Cardiovascular and Autonomic Effects Single smoked or oral doses of delta9THC produce tachycardia and may increase blood pressure (Capriotti et al., 1988; Benowitz and Jones, 1975). Some evidence associates the tachycardia produced by delta9-THC with excitation of the sympathetic and depression of the parasympathetic nervous systems (Malinowska et al., 2012). During chronic marijuana ingestion, a tolerance to tachycardia develops (Malinowska et al., 2012). However, prolonged delta9-THC ingestion produces bradycardia and hypotension (Benowitz and Jones, 1975). Plant-derived cannabinoids and endocannabinoids elicit hypotension and bradycardia via activation of peripherally-located CB1 receptors (Wagner et al., 1998). Specifically, the mechanism of this effect is through presynaptic CB1 receptor-mediated inhibition of norepinephrine release from peripheral sympathetic nerve terminals, with possible additional direct vasodilation via activation of vascular cannabinoid receptors (Pacher et al., 2006). In humans, tolerance can develop to orthostatic hypotension (Jones, 2002; Sidney, 2002) possibly related to plasma volume expansion, but tolerance does not develop to the supine hypotensive effects (Benowitz and Jones, 1975). Additionally, electrocardiographic changes are minimal, even after large cumulative doses of delta9-THC are administered. (Benowitz and Jones, 1975). Marijuana smoking by individuals, particularly those with some degree of coronary artery or cerebrovascular disease, poses risks such as increased cardiac work, catecholamines and carboxyhemoglobin, myocardial infarction, and postural hypotension (Benowitz and Jones, 1981; Hollister, 1988; Mittleman et al., 2001; Malinowska et al., 2012). Respiratory Effects After acute exposure to marijuana, transient bronchodilation is the most typical respiratory effect (Gong et al., 1984). A recent 20-year longitudinal study with over 5,000 individuals collected information on the amount of marijuana use and pulmonary function data at years 0, 2, 5, 10, and 20 (Pletcher et al., 2012). Among the more than 5,000 individuals who participated in the study, almost 800 of them reported VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 current marijuana use but not tobacco use at the time of assessment. Pletcher et al. (2012) found that the occasional use of marijuana is not associated with decreased pulmonary function. However, some preliminary evidence suggests that heavy marijuana use may be associated with negative pulmonary effects (Pletcher et al., 2012). Long-term use of marijuana can lead to chronic cough and increased sputum, as well as an increased frequency of chronic bronchitis and pharyngitis. In addition, pulmonary function tests reveal that large-airway obstruction can occur with chronic marijuana smoking, as can cellular inflammatory histopathological abnormalities in bronchial epithelium (Adams and Martin 1996; Hollister 1986). Evidence regarding marijuana smoking leading to cancer is inconsistent, as some studies suggest a positive correlation while others do not (Lee and Hancox, 2011; Tashkin, 2005). Several lung cancer cases have been reported in young marijuana users with no tobacco smoking history or other significant risk factors (Fung et al., 1999). Marijuana use may dosedependently interact with mutagenic sensitivity, cigarette smoking, and alcohol use to increase the risk of head and neck cancer (Zhang et al., 1999). However, in a large study with 1,650 subjects, a positive association was not found between marijuana and lung cancer (Tashkin et al., 2006). This finding remained true, regardless of the extent of marijuana use, when controlling for tobacco use and other potential confounding variables. Overall, new evidence suggests that the effects of marijuana smoking on respiratory function and carcinogenicity differ from those of tobacco smoking (Lee and Hancox, 2011). Endocrine System Experimental marijuana administration to humans does not consistently alter many endocrine parameters. In an early study, male subjects who experimentally received smoked marijuana showed a significant depression in luteinizing hormone and a significant increase in cortisol (Cone et al., 1986). However, two later studies showed no changes in hormones. Male subjects experimentally exposed to smoked delta9-THC (18 mg/marijuana cigarette) or oral delta9-THC (10 mg three times per day for 3 days and on the morning of the fourth day) showed no changes in plasma adrenocorticotropic hormone (ACTH), cortisol, prolactin, luteinizing hormone, or testosterone levels (Dax et al., 1989). Similarly, a study with 93 men and 56 PO 00000 Frm 00090 Fmt 4701 Sfmt 4702 women showed that chronic marijuana use did not significantly alter concentrations of testosterone, luteinizing hormone, follicle stimulating hormone, prolactin, or cortisol (Block et al., 1991). Additionally, chronic marijuana use did not affect serum levels of thyrotropin, thyroxine, and triiodothyronine (Bonnet, 2013). However, in a double-blind, placebocontrolled, randomized clinical trial of HIV-positive men, smoking marijuana dose-dependently increased plasma levels of ghrelin and leptin, and decreased plasma levels of peptide YY (Riggs et al., 2012). The effects of marijuana on female reproductive system functionality differ between humans and animals. In monkeys, delta9-THC administration suppressed ovulation (Asch et al., 1981) and reduced progesterone levels (Almirez et al., 1983). However, in women, smoked marijuana did not alter hormone levels or the menstrual cycle (Mendelson and Mello, 1984). Brown and Dobs (2002) suggest that the development of tolerance in humans may be the cause of the discrepancies between animal and human hormonal response to cannabinoids. The presence of in vitro delta9-THC reduces binding of the corticosteroid, dexamethasone, in hippocampal tissue from adrenalectomized rats, suggesting an interaction with the glucocorticoid receptor (Eldridge et al., 1991). Although acute delta9-THC presence releases corticosterone, tolerance develops in rats with chronic administration (Eldridge et al., 1991). Some studies support a possible association between frequent, long-term marijuana use and increased risk of testicular germ cell tumors (Trabert et al., 2011). On the other hand, recent data suggest that cannabinoid agonists may have therapeutic value in the treatment of prostate cancer, a type of carcinoma in which growth is stimulated by androgens. Research with prostate cancer cells shows that the mixed CB1/CB2 agonist, WIN–55212–2, induces apoptosis in prostate cancer cells, as well as decreases the expression of androgen receptors and prostate-specific antigens (Sarfaraz et al., 2005). Immune System Cannabinoids affect the immune system in many different ways. Synthetic, natural, and endogenous cannabinoids often cause different effects in a dose-dependent biphasic manner (Croxford and Yamamura, 2005; Tanasescu and Constantinescu, 2010). Studies in humans and animals give conflicting results about cannabinoid E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules effects on immune functioning in subjects with compromised immune systems. Abrams et al. (2003) investigated marijuana’s effect on immunological functioning in 62 AIDS patients taking protease inhibitors. Subjects received one of the following three times a day: A smoked marijuana cigarette containing 3.95 percent delta9THC, an oral tablet containing delta9THC (2.5 mg oral dronabinol), or an oral placebo. The results showed no changes in CD4+ and CD8+ cell counts, HIV RNA levels, or protease inhibitor levels between groups. Thus, the use of cannabinoids showed no short-term adverse virologic effects in individuals with compromised immune systems. However, these human data contrast with data generated in immunodeficient mice, which demonstrated that exposure to delta9-THC in vivo suppresses immune function, increases HIV co-receptor expression, and acts as a cofactor to enhance HIV replication (Roth et al., 2005). mstockstill on DSK3G9T082PROD with PROPOSALS2 3. The State of Current Scientific Knowledge Regarding the Drug or Other Substance Under the third factor, the Secretary must consider the state of current scientific knowledge regarding marijuana. Thus, this section discusses the chemistry, human pharmacokinetics, and medical uses of marijuana. Chemistry Marijuana is one of the common names of Cannabis sativa L. in the family Cannabaceae. Cannabis is one of the oldest cultivated crops, providing a source of fiber, food, oil, and drug. Botanists still debate whether Cannabis should be considered as a single (The Plant List, 2010) or three species, i.e., C. sativa, C. indica, and C. ruderalis (Hillig, 2005). Specifically, marijuana is developed as sativa and indica cultivated varieties (strains) or various hybrids. The petition defines marijuana as including all Cannabis cultivated strains. Different marijuana samples derived from various cultivated strains may have very different chemical constituents including delta9 -THC and other cannabinoids (Appendino et al., 2011). As a consequence, marijuana products from different strains will have different safety, biological, pharmacological, and toxicological profiles. Thus, all Cannabis strains cannot be considered together because of the varying chemical constituents between strains. Marijuana contains numerous naturally occurring constituents VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 including cannabinoids. Overall, various Cannabis strains contain more than 525 identified natural constituents. Among those constituents, the most important ones are the 21 (or 22) carbon terpenoids found in the plant, as well as their carboxylic acids, analogues, and transformation products, known as cannabinoids (Agurell et al., 1984, 1986; Mechoulam, 1973; Appendino et al., 2011). Thus far, more than 100 compounds classified as cannabinoids have been characterized (ElSohly and Slade, 2005; Radwan, ElSohly et al., 2009; Appendino et al. 2011). Cannabinoids primarily exist in Cannabis, and published data suggest that most major cannabinoid compounds occurring naturally have been chemically identified. New and minor cannabinoids and other new compounds are continuously being characterized (Pollastro et al., 2011). So far, only two cannabinoids (cannabigerol and its corresponding acid) have been obtained from a nonCannabis source. A South African Helichrysum (H umbraculigerum) accumulates these compounds (Appendino et al. 2011). Among the cannabinoids found in marijuana, delta9-THC (alternate name delta1-THC) and delta-8tetrahydrocannibinol (delta8-THC, alternate name delta6-THC) produce marijuana’s characteristic psychoactive effects. Because delta9-THC is more abundant than delta8-THC, marijuana’s psychoactivity is largely attributed to the former. Only a few varieties of marijuana analyzed contain delta8-THC at significant amounts (Hively et al., 1966). Delta9-THC is an optically active resinous substance, insoluble in water, and extremely lipid soluble. Chemically, delta9-THC is (6aR-trans)6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3pentyl-6H-dibenzo-[b,d]pyran-l-ol, or (– )-delta9-(trans)-tetrahydrocannabinol. The (–)-trans isomer of delta9-THC is pharmacologically 6–100 times more potent than the (+)-trans isomer (Dewey et al., 1984). Other cannabinoids present in marijuana include CBD, CBC, and CBN. CBD, a major cannabinoid of marijuana, is insoluble in water and lipid-soluble. Chemically, CBD is 2-[(1R,6R)-3-methyl6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5pentylbenzene-1,3-diol. CBD does not have cannabinol-like psychoactivity (Adams and Martin, 1996; Agurell et al., 1984, 1986; Hollister, 1986). CBC is another major cannabinoid in marijuana. Chemically, CBC is 2methyl-2-(4-methylpent-3-enyl)-7pentyl-5-chromenol. CBN, a major metabolite of delta9-THC, is also a minor naturally-occurring cannabinoid PO 00000 Frm 00091 Fmt 4701 Sfmt 4702 53777 with weak psychoactivity. Chemically, CBN is 6,6,9-trimethyl-3-pentylbenzo[c]chromen-1-ol. Different marijuana samples derived from various cultivated strains may differ in chemical constituents including delta9-THC and other cannabinoids (Appendino et al. 2011). As a consequence, marijuana products from different strains may have different safety, biological, pharmacological, and toxicological profiles. In addition to differences between cultivated strains, the concentration of delta9-THC and other cannabinoids in marijuana may vary with growing conditions and processing after harvest. In addition to genetic differences among Cannabis species, the plant parts collected—for example, flowers, leaves, and stems— can influence marijuana’s potency, quality, and purity (Adams and Martin, 1996; Agurell et al., 1984; Mechoulam, 1973). All these variations produce marijuana with potencies, as indicated by cannabinoid content, on average from as low as 1–2 percent to as high as 17 percent. Overall, these variations in the concentrations of cannabinoids and other chemical constituents in marijuana complicate the interpretation of clinical data using marijuana. The lack of consistent concentrations of delta9-THC and other substances in marijuana from diverse sources makes interpreting the effect of different marijuana constituents difficult. In addition to different cannabinoid concentrations having different pharmacological and toxicological ·profiles, the non-cannabinoid components in marijuana, such as other terpenoids and flavonoids, might also contribute to the overall pharmacological and toxicological profiles of various marijuana strains and products derived from those strains. The term marijuana is often used to refer to a mixture of the dried flowering tops and leaves from Cannabis. Marijuana in this limiting definition is one of three major derivatives sold as separate illicit products, which also include hashish and hash oil. According to the DEA, Cannabis saliva is the primary species of Cannabis currently marketed illegally in the United States. Marijuana can vary in cannabinoid content and potency (Agurell et al., 1984, 1986; Mechoulam 1973, Cascini et al., 2012). In the usual mixture of leaves and stems distributed as marijuana, the concentration of delta9-THC averages over 12 percent by weight. However, specially grown and selected marijuana can contain 15 percent or greater delta9THC (Appendino et al. 2011). Thus, a 1gram marijuana cigarette might contain E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53778 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules delta9-THC in a range from as little as 3 milligrams to as much as 150 milligrams or more. Additionally, a recent systematic review and metaanalysis found that marijuana’s delta9THC content has increased significantly from 1979–2009 (Cascini et al., 2012). In addition to smoking marijuana, individuals ingest marijuana through food made with butter or oil infused with marijuana and its extracts. These marijuana butters are generally made by adding marijuana to butter and heating it. The resultant butter is then used to cook a variety of foods. There are no published studies measuring the concentrations of cannabinoids in these marijuana food products. Hashish consists of the dried and compressed cannabinoid-rich resinous material of Cannabis and comes in a variety of forms (e.g. balls and cakes). Individuals may break off pieces, place it into a pipe and smoke it. DEA reports that cannabinoid content in hashish averages six percent (DEA, 2005). With the development and cultivation of more high potency Cannabis strains, the average cannabinoid content in hashish will likely increase. Hash oil is produced by solvent extraction of the cannabinoids from plant material. The extract’s color and odor vary, depending on the solvent type used. Hash oil is a viscous brownor amber-colored liquid containing approximately 50 percent cannabinoids. One or two drops of the liquid placed on a cigarette purportedly produce the equivalent of a single· marijuana cigarette (DEA, 2005). In conclusion, marijuana has hundreds of cultivars containing variable concentrations of delta9-THC, cannabinoids, and other compounds. Thus, marijuana is not a single chemical with a consistent and reproducible chemical profile or predictable and consistent clinical effects. A guidance for industry, entitled Botanical Drug Products,8 provides information on the approval of botanical drug products. To investigate marijuana for medical use in a manner acceptable as support for marketing approval under an NDA, clinical studies under an IND of consistent batches of a particular marijuana product for particular disease indications should be conducted. In addition, information and data regarding the marijuana product’s chemistry, manufacturing and control, pharmacology, and animal toxicology data, among others must be provided 8 This guidance is available on the Internet at http://www.fda.gov/Drugs/default.htm under Guidance (Drugs). VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 and meet the requirements for new drug approval (See 21 CFR 314.50). Human Pharmacokinetics Marijuana can be taken in a variety of formulations by multiple routes of administration. Individuals smoke marijuana as a cigarette, weighing between 0.5 and 1.0 gram, or in a pipe. Additionally, individuals take marijuana orally in foods or as an extract in ethanol or other solvents. More recently, access to vaporizers provides another means for abusers to inhale marijuana, The absorption, metabolism, and pharmacokinetic profile of delta9-THC, cannabinoids, and drug products containing delta9-THC vary with route of administratfon and formulation (Adams and Martin, 1996; Agurell et al., 1984, 1986). Pharmacokinetics of Smoked Administration of Cannabinoids Characterization of the pharmacokinetics of delta9-THC and other cannabinoids from smoked marijuana is difficult because a subject’s smoking behavior during an experiment varies (Agurell et al., 1986; Heming et al., 1986; Huestis et al., 1992a). Each puff delivers a discrete dose of delta9THC. An experienced marijuana smoker can titrate and regulate the dose to obtain the desired acute psychological effects and minimize undesired effects. For example, under naturalistic conditions, users hold marijuana smoke in their lungs for an extended period of time which causes prolonged absorption and increases psychoactive effects. The effect of experience in the psychological response may explain why delta9-THC venous blood levels correlate poorly with intensity of effects and intoxication level (Agurell et al. 1986; Barnett et al. 1985; Huestis et al., 1992a). Puff and inhalation volumes should be recorded in studies as the concentration (dose) of cannabinoids administered can vary at different stages of smoking. Smoked marijuana results in absorption of delta9-THC in the form of an aerosol within seconds. Psychoactive effects occur immediately following absorption, with mental and behavioral effects measurable for up to 6 hours (Grotenhermen, 2003; Hollister 1986, 1988). Delta9-THC is delivered to the brain rapidly and efficiently as expected of a very lipid soluble drug. The bioavailability of the delta9 -THC, from marijuana in a cigarette or pipe, can range from 1 to 24 percent with the fraction absorbed rarely exceeding 10 to 20 percent (Agurell et al.,1986; Hollister, 1988). The relatively low and variable bioavailability results from PO 00000 Frm 00092 Fmt 4701 Sfmt 4702 significant loss of delta9-THC in sidestream smoke, variation in individual smoking behaviors, cannabinoid pyrolysis, incomplete absorption of inhaled smoke, and metabolism in the lungs. An individual’s experience and technique with smoking marijuana also determines the dose absorbed (Heming et al., 1986; Johansson et al., 1989). After smoking, delta9-THC venous levels decline precipitously within minutes, and continue to go down to about 5 to 10 percent of the peak level within an hour (Agurell et al., 1986, Huestis et al.,1992a, 1992b). Pharmacokinetics for Oral Administration of Cannabinoids After oral administration of delta9THC or marijuana, the onset of effects starts within 30 to 90 minutes, reaches its peak after 2 to 3 hours and then remains for 4 to 12 hours (Grotenhermen, 2003; Adams and Martin, 1996; Agurell et al., 1984, 1986). Due to the delay in onset of effects, users have difficulty in titrating oral delta9-THC doses compared to smoking marijuana. Oral bioavailability of delta9THC, whether pure or in marijuana, is low and extremely variable, ranging between 5 and 20 percent (Agurell et al., 1984, 1986). Following oral administration of radioactive-labeled delta9-THC, delta9-THC plasma levels are low relative to plasma levels after smoking or intravenous administration. Inter- and intra-subject variability occurs even with repeated dosing under controlled conditions. The low and variable oral bioavailability of delta9THC is a consequence of its first-pass hepatic elimination from blood and erratic absorption from stomach and bowel. Cannabinoid Metabolism and Excretion Cannabinoid metabolism is complex. Delta9-THC is metabolized via microsomal hydroxylation to both active and inactive metabolites (Lemberger et al., 1970, 1972a, 1972b; Agurell et al., 1986; Hollister, 1988). The primary active metabolite of delta9-THC following oral ingestion is 11-hydroxydelta9-THC. This metabolite is approximately equipotent to delta9-THC in producing marijuana-like subjective effects (Agurell et al., 1986, Lemberger and Rubin, 1975). After oral administration, metabolite levels may exceed that of delta9-THC and thus contribute greatly to the pharmacological effects of oral delta9THC or marijuana. Plasma clearance of delta9-THC approximates hepatic blood flow at about 950 ml/min or greater. The rapid disappearance of delta9-THC from blood E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules mstockstill on DSK3G9T082PROD with PROPOSALS2 is largely due to redistribution to other tissues in the body, rather than to metabolism (Agurell et al., 1984, 1986). Metabolism in most tissues is relatively slow or absent. Slow release of delta9THC and other cannabinoids from tissues and subsequent metabolism results in a long elimination half-life. The terminal half-life of delta9-THC ranges from approximately 20 hours to as long as 10 to13 days, though reported estimates vary as expected with any slowly cleared substance and the use of assays with variable sensitivities (Hunt and Jones, 1980). Lemberger et al. (1970) determined the half-life of delta9-THC to range from 23 to 28 hours in heavy marijuana users to 60 to 70 hours in naive users. In addition to 11-hydroxydelta9-THC, some inactive carboxy metabolites have terminal half-lives of 50 hours to 6 days or more. The latter substances serve as long-term markers in urine tests for earlier marijuana use. The majority of the absorbed delta9THC dose is eliminated in feces, and about 33 percent in urine. Delta9-THC enters enterohepatic circulation and undergoes hydroxylation and oxidation to 11-nor-9-carboxy-delta9-THC. The glucuronide is excreted as the major urine metabolite along with about 18 non-conjugated metabolites. Frequent and infrequent marijuana users metabolize delta9-THC similarly (Agurell et al., 1986). Status of Research Into the Medical Uses for Marijuana State-level public initiatives, including laws and referenda in support of the medical use of marijuana, have generated interest in the medical community and the need for high quality clinical investigation as well as comprehensive safety and effectiveness data. In order to address the need for high quality clinical investigations, the state of California established the Center for Medicinal Cannabis Research (CMCR, www.cmcr.ucsd.edu) in 2000 ‘‘in response to scientific evidence for therapeutic possibilities of cannabis 9 and local legislative initiatives in favor of compassionate use’’ (Grant, 2005). State legislation establishing the CMCR called for high quality medical research that would ‘‘enhance understanding of the efficacy and adverse effects of marijuana as a pharmacological agent,’’ but stressed the project ‘‘should not be construed as encouraging or sanctioning the social or recreational use of marijuana.’’ The CMCR funded many of the published studies on marijuana’s potential use for treating multiple 9 In this quotation the term cannabis is interchangeable with marijuana. VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 sclerosis, neuropathic pain, appetite suppression and cachexia. However, aside from the data produced by CMCR, no state-level medical marijuana laws have produced scientific data on marijuana’s safety and effectiveness. FDA approves medical use of a drug following a submission and review of an NDA or BLA. The FDA has not approved any drug product containing marijuana for marketing. Even so, results of small clinical exploratory studies have been published in the current medical literature. Many studies describe human research with marijuana in the United States under FDA-regulated IND applications. However, FDA approval of an NDA is not the only means through which a drug can have a currently accepted medical use in treatment in the United States. In general, a drug may have a ‘‘currently accepted medical use’’ in treatment in the United States if the drug meets a five-part test. Established case law (Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994)) upheld the Administrator of DEA’s application of the five-part test to determine whether a drug has a ‘‘currently accepted medical use.’’ The following describes the five elements that characterize ‘‘currently accepted medical use’’ for a drug: 10 i. the drug’s chemistry must be known and reproducible ‘‘The substance’s chemistry must be scientifically established to permit it to be reproduced into dosages which can be standardized. The listing of the substance in a current edition of one of the official compendia, as defined by section 201 G) of the Food, Drug and Cosmetic Act, 21 U.S.C. 321G), is sufficient to meet this requirement.’’ ii. there must be adequate safety studies ‘‘There must be adequate pharmacological and toxicological studies, done by all methods reasonably applicable, on the basis of which it could fairly and responsibly be concluded, by experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, that the substance is safe for treating a specific, recognized disorder.’’ iii. there must be adequate and wellcontrolled studies proving efficacy ‘‘There must be adequate, wellcontrolled, well-designed, wellconducted, and well-documented studies, including clinical investigations, by experts qualified by scientific training and experience to evaluate the safety and effectiveness of 10 57 PO 00000 FR I 0499, 10504–06 (March 26, 1992). Frm 00093 Fmt 4701 Sfmt 4702 53779 drugs, on the basis of which it could be fairly and responsibly concluded by such experts that the substance will have the intended effect in treating a specific, recognized disorder.’’ iv. the drug must be accepted by qualified experts ‘‘The drug has a New Drug Application (NDA) approved by the Food and Drug Administration, pursuant to the Food, Drug and Cosmetic Act, 21 U.S.C. 355. Or, a consensus of the national community of experts, qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, accepts the safety and effectiveness of the substance for use in treating a specific, recognized disorder. A material conflict of opinion among experts precludes a finding of consensus.’’ and v. the scientific evidence must be widely available ‘‘In the absence of NDA approval, information concerning the chemistry, pharmacology, toxicology, and effectiveness of the substance must be reported, published, or otherwise widely available, in sufficient detail to permit experts, qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, to fairly and responsibly conclude the substance is safe and effective for use in treating a specific, recognized disorder.’’ Marijuana does not meet any of the five elements necessary for a drug to have a ‘‘currently accepted medical use.’’ Firstly, the chemistry of marijuana, as defined in the petition, is not reproducible in terms of creating a standardized dose. The petition defines marijuana as including all Cannabis cultivated strains. Different marijuana samples derived from various cultivated strains may have very different chemical constituents including delta9–THC and other cannabinoids (Appendino et al., 2011). As a consequence, marijuana products from different strains will have different safety, biological, pharmacological, and toxicological profiles. Thus, when considering all Cannabis strains together, because of the varying chemical constituents, reproducing consistent standardized doses is not possible. Additionally, smoking marijuana currently has not been shown to allow delivery of consistent and reproducible doses. However, if a specific Cannabis strain is grown and processed under strictly controlled conditions, the plant chemistry may be kept consistent enough to produce reproducible and standardized doses. E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53780 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules As to the second and third criteria; there are neither adequate safety studies nor adequate and well-controlled studies proving marijuana’s efficacy. To support the petitioners’ assertion that marijuana has accepted medical use, the petitioners cite the American Medical Association’s (AMA) 2009 report entitled ‘‘Use of Cannabis for Medicinal Purposes.’’ The petitioners claim the AMA report is evidence the AMA accepts marijuana’s safety and efficacy. However, the 2009 AMA report clarifies that the report ‘‘should not be viewed as an endorsement of state-based medical cannabis programs, the legalization of marijuana, or that scientific evidence on the therapeutic use of cannabis meets the same and current standards for a prescription drug product.’’ 11 Currently, no published studies conducted with marijuana meet the criteria of an adequate and wellcontrolled efficacy study. The criteria for an adequate and well-controlled study for purposes of determining the safety and efficacy of a human drug are defined under the Code of Federal Regulations (CFR) in 21 CFR 314.126. In order to assess this element, FDA conducted a review of clinical studies published and available in the public domain before February, 2013. Studies were identified through a search of PubMed 12 for articles published from inception to February 2013, for randomized controlled trials using marijuana to assess marijuana’s efficacy in any therapeutic indication. Additionally, the review included studies identified through a search of bibliographic references in relevant systematic reviews and identified studies presenting original research in any language. Selected studies needed to be placebo-controlled and doubleblinded. Additionally, studies needed to encompass administered marijuana plant material. There was no requirement for any specific route of administration, nor any age limits on study subjects. Studies were excluded that used placebo marijuana supplemented by the addition of specific amounts of THC or other cannabinoids. Additionally, studies administering marijuana plant extracts were excluded. The PubMed search yielded a total of 566 abstracts of scientific articles. Of 11 In this quotation the term cannabis is used interchangeably for marijuana. 12 The following search strategy was used, ‘‘(cannabis OR marijuana) AND (therapeutic use OR therapy) AND (RCT OR randomized controlled trial OR ‘‘systematic review’’ OR clinical trial OR clinical trials) NOT (‘‘marijuana abuse’’[Mesh] OR addictive behavior OR substance related disorders).’’ VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 these abstracts, a full-text review was conducted with 85 papers to assess eligibility. Of the studies identified through the search of the references and the 566 abstracts from the PubMed search, only 11 studies met all the criteria for selection (Abrams et al., 2007; Corey-Bloom et al., 2012; Crawford and Merritt, 1979; Ellis et al., 2009; Haney et al., 2005; Haney et al., 2007; Merritt et al., 1980; Tashkin et al., 1974; Ware et al., 2010; Wilsey et al., 2008; Wilsey et al., 2013). These 11 studies were published between 197 4 and 2013. Ten of these studies were conducted in the United States and one study was conducted in Canada. The identified studies examine the effects of smoked and vaporized marijuana for the indications of chronic neuropathic pain, spasticity related to Multiple Sclerosis (MS), appetite stimulation in human immunodeficiency virus (HIV) patients, glaucoma, and asthma. All studies used adult subjects. The 11 identified studies were individually evaluated to determine if they successfully meet accepted scientific standards. Specifically, they were evaluated on study design including subject selection criteria, sample size, blinding techniques, dosing paradigms, outcome measures, and the statistical analysis of the results. The analysis relied on published studies, thus information available about protocols, procedures, and results were limited to documents published and widely available in the public domain. The review found that all 11 studies that examined effects of inhaled marijuana do not currently prove efficacy of marijuana in any therapeutic indication based on a number of limitations in their study design; however, they may be considered proof of concept studies. Proof of concept studies provide preliminary evidence on a proposed hypothesis involving a drug’s effect. For drugs under development, the effect often relates to a short-term clinical outcome being investigated. Proof of concept studies often serve as the link between preclinical studies and dose ranging clinical studies. Thus, proof of concept studies generally are not sufficient to prove efficacy of a drug because they provide only preliminary information about the effects of a drug. In addition to the lack of published adequate and well-controlled efficacy studies proving efficacy, the criteria for adequate safety studies has also not been met. Importantly, in its discussion of the five-part test used to determine whether a drug has a ‘‘currently accepted medical use,’’ DEA said, ‘‘No drug can be considered safe in the abstract. Safety has meaning only when PO 00000 Frm 00094 Fmt 4701 Sfmt 4702 judged against the intended use of the drug, its known effectiveness, its known and potential risks, the severity of the illness to be treated, and the availability of alternative remedies’’ (57 FR 10504). When determining whether a drug product is safe and effective for any indication, FDA performs an extensive risk-benefit analysis to determine whether the risks posed by the drug product’s side effects are outweighed by the drug product’s potential benefits for a particular indication. Thus, contrary to the petitioner’s assertion that marijuana has accepted safety, in the absence of an accepted therapeutic indication which can be weighed against marijuana’s risks, marijuana does not satisfy the element for having adequate safety studies such that experts may conclude that it is safe for treating a specific, recognized disorder. The fourth of the five elements for determining ‘‘currently accepted medical use’’ requires that the national community of experts, qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, accepts the safety and effectiveness of the substance for use in treating a specific, recognized disorder. A material conflict of opinion among experts precludes a finding of consensus. Medical practitioners who are not experts in evaluating drugs are not qualified to determine whether a drug is generally recognized as safe and effective or meets NDA requirements (57 FR 10499–10505). There is no evidence that there is a consensus among qualified experts that marijuana is safe and effective for use in treating a specific, recognized disorder. As discussed above, there are not adequate scientific studies that show marijuana is safe and effective in treating a specific, recognized disorder. In addition, there is no evidence that a consensus of qualified experts have accepted the safety and effectiveness of marijuana for use in treating a specific, recognized disorder. Although medical practitioners are not qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, we also note that the AMA’s report, entitled ‘‘Use of Cannabis for Medicinal Purposes,’’ does not accept that marijuana currently has accepted medical use. Furthermore, based on the above definition of a ‘‘qualified expert’’, who is an individual qualified by scientific training and experience to evaluate the safety and effectiveness of a drug, state-level medical marijuana laws do not provide evidence of a consensus among qualified experts that marijuana is safe and effective for use in treating a specific, recognized disorder. E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules As to the fifth part of the test, which requires that information concerning the chemistry, pharmacology, toxicology, and effectiveness of marijuana to be reported in sufficient detail, the scientific evidence regarding all of these aspects is not available in sufficient detail to allow adequate scientific scrutiny. Specifically, the scientific evidence regarding marijuana’s chemistry in terms of a specific Cannabis strain that could produce standardized and reproducible doses is not currently available. Alternately, a drug can be considered to have a ‘‘currently accepted medical use with severe restrictions’’ (21 U.S.C. 812(b)(2)(B)), as allowed under the stipulations for a Schedule II drug. Yet, as stated above, currently marijuana does not have any accepted medical use, even under conditions where its use is severely restricted. In conclusion, to date, research on marijuana’s medical use has not progressed to the point where marijuana is considered to have a ‘‘currently accepted medical use’’ or a ‘‘currently accepted medical use with severe restrictions.’’ 53781 between the ages of 18–25, with 18.7 percent of this age group currently using marijuana. In the 26 and older age group, 5.3 percent of individuals currently use marijuana. Additionally, in individuals aged 12 years and older, males reported more current marijuana use than females. NSDUH includes a series of questions aimed at assessing the prevalence of dependence and abuse of different substances in the past 12 months.15 In 2012, marijuana was the most common illicit drug reported by individuals with past year dependence or abuse. An estimated 4.3 million individuals meet the NSDUH criteria for marijuana dependence or abuse in 2012. The estimated rates and number of individuals with marijuana dependence or abuse has remained similar from 2002 to 2012. In addition to data on dependence and abuse, NSDUH includes questions aimed at assessing treatment for a substance use problem.16 In 2012, an estimated 957,000 persons received treatment for marijuana use during their most recent treatment in the year prior to the survey. National Survey on Drug Use and Health (NSDUH) 13 According to 2012 NSDUH 14 data, the most recent year with complete data, the use of illicit drugs, including marijuana, is increasing. The 2012 NSDUH estimates that 23.9 million individuals over 12 years of age (9.2 percent of the U.S. population) currently use illicit drugs, which is an increase of 4.8 million individuals from 2004 when 19.1 million individuals (7.9 percent of the U.S. population) were current illicit drug users. NSDUH reports marijuana as the most commonly used illicit drug, with 18.9 million individuals (7.3 percent of the U.S. population) currently using marijuana in 2012. This represents an increase of 4.3 million individuals from 2004, when 14.6 million individuals (6.1 percent of the U.S. population) were current marijuana users. The majority of individuals who try marijuana at least once in their lifetime do not currently use marijuana. The 2012 NSDUH estimates that 111.2 million individuals (42.8 percent of the U.S. population) have used marijuana at least once in their lifetime. Based on this estimate and the estimate for the number of individuals currently using marijuana, approximately 16.9 percent of those who have tried marijuana at least once in their lifetime currently use marijuana; conversely, 83.1 percent do not currently use marijuana. In terms of the frequency of marijuana use, an estimated 40.3 percent of individuals who used marijuana in the past month used marijuana on 20 or more days within the past month. This amount corresponds to an estimated 7.6 million individuals who used marijuana on a daily or almost daily basis. Some characteristics of marijuana users are related to age, gender, and criminal justice system involvement. In observing use among different age cohorts, the majority of individuals who currently use marijuana are shown to be According to MTF,18 rates of marijuana and illicit drug use declined for all three grades from 2005 through 2007. However, starting around 2008, rates of annual use of illicit drugs and marijuana increased through 2013 for all three grades. Marijuana remained the most widely used illicit drug during all time periods. The prevalence of annual and past month marijuana use in 10th and 12th graders in 2013 is greater than in 2005. Table 1 lists the lifetime, annual, and monthly prevalence rates of various drugs for 8th, 10th, and 12th graders in 2013. 13 NSDUH provides national estimates of the prevalence and incidence of illicit drug, alcohol and tobacco use in the United States. NSDUH is an annual study conducted by SAMHSA. Prior to 2002, the database was known as the National Household Survey on Drug Abuse (NHSDA). NSDUH utilizes a nationally representative sample of United States civilian, non-institutionalized population aged 12 years and older. The survey excludes homeless people who do not use shelters, active military personnel, and residents of institutional group quarters such as jails and hospitals. The survey identifies whether an individual used a drug within a specific time period, but does not identify the amount of the drug used on each occasion. NSDUH defines ‘‘current use’’ as having used the substance within the month prior to the study. 14 2013; http://www.samhsa.gov/data/ NSDUH.aspx. 15 ‘‘These questions are used to classify persons as dependent on or abusing specific substances based on criteria specified in the Diagnostic and Statistical Manual of Mental Disorder, 4th edition (DSM–IV). The questions related to dependence ask about health and emotional problems associated with substance use, unsuccessful attempts to cut down on use, tolerance, withdrawal, reducing other activities to use substances, spending a lot time engaging in activities related to substance use, or using the substance in greater quantities or for longer time than intended. The questions on abuse ask about problems at work, home, and school; problems with family or friends; physical danger; and trouble with the law due to substance use. Dependence is considered to be a more severe substance use problem than abuse because it involves the psychological and physiological effects of tolerance and withdrawal.’’ (NSDUH, 2013). 16 ‘‘Estimates . . . refer to treatment received for illicit drug or alcohol use, or for medical problems associated with the use of illicit drugs or alcohol. This includes treatment received in the past year at any location, such as a hospital (inpatient), rehabilitation facility (outpatient or inpatient), mental health center, emergency room, private doctor’s office, prison or jail, or a self-help group, such as Alcoholics Anonymous or Narcotics Anonymous.’’ (NSDUH, 2013). 17 Monitoring the Future is a national survey that tracks drug use prevalence and trends among adolescents in the United States. MTF is reported annually by the Institute for Social Research at the University of Michigan under a grant from NIDA. Every spring, MTF surveys 8th, 10th, and 12th graders in randomly selected U.S. schools. MTF has been conducted since 1975 for 12th graders and since 1991 for 8th and 10th graders. The MTF survey presents data in terms of prevalence among the sample interviewed. For 2012, the latest year with complete data, the sample sizes were 15,200— 8th graders; 13,300—10th graders; and 13,200— 12th graders. In all, a total of about 41,700 students of 389 schools participated in the 2013 MTF. 18 2013; http://www.monitoringthefuture.org/ index.html. mstockstill on DSK3G9T082PROD with PROPOSALS2 4. Its History and Current Pattern of Abuse Under the fourth factor, the Secretary must consider the history and current pattern of marijuana abuse. A variety of sources provide data necessary to assess abuse patterns and trends of marijuana. The data indicators of marijuana use include the NSDUH, MTF, DAWN, and TEDS. The following briefly describes each data source, and summarizes the data from each source. VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 PO 00000 Frm 00095 Fmt 4701 Sfmt 4702 Monitoring the Future (MTF) 17 E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules Drug Abuse Warning Network (DAWN) 19 mstockstill on DSK3G9T082PROD with PROPOSALS2 Importantly, many factors can influence the estimates of ED visits, including trends in overall use of a substance as well as trends in the reasons for ED usage. For instance, some drug users may visit EDs for lifethreatening issues while others may visit to seek care for detoxification because they needed certification before entering treatment. Additionally, DAWN data do not distinguish the drug responsible for the ED visit from other drugs that may have been used concomitantly. As stated in a DAWN report, ‘‘Since marijuana/hashish is frequently present in combination with other drugs, the reason for the ED visit may be more relevant to the other drug(s) involved in the episode.’’ For 2011, DAWN 20 estimates a total of 5,067,374 (95 percent confidence interval [CI]: 4,616,753 to 5,517,995) drug-related ED visits from the entire United States. Of these, approximately 19 DAWN is a national probability survey of the U.S. hospitals with ED designed to obtain information on drug related ED visits. DAWN is sponsored by SAMHSA. The DAWN system provides information on the health consequences of drug use in the United States, as manifested by drug-related visits to ED. The ED data from a representative sample of hospital emergency departments are weighted to produce national estimates. Importantly, DAWN data and estimates, starting in 2004, are not comparable to those for prior years because of vast changes in the methodology used to collect the data. Furthermore, estimates for 2004 are the first to be based on a redesigned sample of hospitals, which ended in 2011. 20 2011; http://www.samhsa.gov/data/dawn.aspx. VerDate Sep<11>2014 21:44 Aug 11, 2016 Jkt 238001 2,462,948 ([CI]: 2,112,868 to 2,813,028) visits involved drug misuse or abuse. During the same period, DAWN estimates that 1,252,500 (CI: 976,169 to 1,528,831) drug related ED visits involved illicit drugs. Thus, over half of all drug-related ED visits associated with drug misuse or abuse involved an illicit drug. For ED visits involving illicit drugs, 56.3 percent involved multiple drugs while 43.7 percent involved a single drug. Marijuana was involved in 455,668 ED visits (CI: 370,995 to 540,340), while cocaine was involved in 505,224 (CI: 324,262 to 686,185) ED visits, heroin was involved in 258,482 (CI: 205,046 to 311,918) ED visits and stimulants including amphetamine and methamphetamine were involved in 159,840 (CI: 100,199 to 219,481) ED visits. Other illicit drugs, such as PCP, MDMA, GHB and LSD were much less frequently associated with ED visits. The number of ED visits involving marijuana has increased by 62 percent since 2004. Marijuana-related ED visits were most frequent among young adults and minors. Individuals under the age of 18 accounted for 13.2 percent of these marijuana-related visits, whereas this age group accounted for approximately 1.2 percent of ED visits involving cocaine, and less than 1 percent of ED visits involving heroin. However, the age group with the most marijuanarelated ED visits was between 25 and 29 years old. Yet, because populations differ between age groups, a standardized measure for population PO 00000 Frm 00096 Fmt 4701 Sfmt 4702 size is useful to make comparisons. For marijuana, the rates of ED visits per 100,000 population were highest for patients aged 18 to 20 (443.8 ED visits per 100,000) and for patients aged 21 to 24 (446.9 ED visits per 100,000). While DAWN provides estimates for ED visits associated with the use of medical marijuana for 2009–2011, the validity of these estimates is questionable. Because the drug is not approved by the FDA, reporting medical marijuana may be inconsistent and reliant on a number of factors including whether the patient self-reports the marijuana use as medicinal, how the treating health care provider records the marijuana use, and lastly how the SAMHSA coder interprets the report. All of these aspects will vary greatly between states with medical marijuana laws and states without medical marijuana laws. Thus, even though estimates are reported for medical marijuana related ED visits, medical marijuana estimates cannot be assessed with any acceptable accuracy at this time, as FDA has not approved marijuana treatment of any medical condition. These data show the difficulty in evaluating abuse of a product that is not currently approved by FDA, but authorized for medical use, albeit inconsistently, at the state level. Thus, we believe the likelihood of the treating health care provider or SAMHSA coder attributing the ED visit to ‘‘medical marijuana’’ versus ‘‘marijuana’’ to be very low. Overall, the available data are inadequate to E:\FR\FM\12AUP2.SGM 12AUP2 EP12AU16.005</GPH> 53782 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules characterize its abuse at the community level. Treatment Episode Data Set (TEDS) 21 Primary marijuana abuse accounted for 18.1 percent of all 2011 TEDS 22 admissions. Individuals admitted for primary marijuana abuse were nearly three-quarters (73.4 percent) male, and almost half (45.2 percent) were white. The average age at admission was 24 years old, and 31.1 percent of individuals admitted for primary marijuana abuse were under the age of 18. The reported frequency of marijuana use was 24.3 percent reporting daily use. Almost all (96.8 percent) primary marijuana users utilized the substance by smoking. Additionally, 92.9 percent reported using marijuana for the first time before the age of 18. An important aspect of TEDS admission data for marijuana is of the referral source for treatment. Specifically, primary marijuana admissions were less likely than all other admissions to either be selfreferred or referred by an individual for treatment. Instead, the criminal justice system referred more than half (51.6 percent) of primary marijuana admissions. Since 2003, the percent of admissions for primary marijuana abuse increased from 15.5 percent of all admissions in 2003 to 18.l percent in 2011. This increase is less than the increase seen for admissions for primary opioids other than heroin, which increased from 2.8 percent in 2003 to 7.3 percent in 2011. In contrast, the admissions for primary cocaine abuse declined from 9.8 percent in 2003 to 2.0 percent in 2011. mstockstill on DSK3G9T082PROD with PROPOSALS2 21 The TEDS system is part of SAMHSA’s Drug and Alcohol Services Information System (Office of Applied Science, SAMHSA). The TEDS report presents information on the demographic and substance use characteristics of the 1.8 million annual admissions to treatment for alcohol and drug abuse in facilities that report to individual state administrative data systems. Specifically, TEDS includes facilities licensed or certified by the states to provide substance abuse treatment and is required by the states to provide TEDS client-level data. Facilities that report TEDS data are those receiving State alcohol and drug agency funds for the provision of alcohol and drug treatment services. Since TEDS is based only on reports from these facilities, TEDS data do not represent the total national demand for substance abuse treatment or the prevalence of substance abuse in the general population. The primary goal for TEDS is to monitor the characteristics of treatment episodes for substance abusers. Importantly, TEDS is an admissions-based system, where admittance to treatment is counted as an anonymous tally. For instance, a given individual who is admitted to treatment twice within a given year would be counted as two admissions. The most recent year with complete data is 2011. 22 2011; http://www.samhsa.gov/data/ DASIS.aspx?qr=t#TEDS. VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 5. The Scope, Duration, and Significance of Abuse Under the fifth factor, the Secretary must consider the scope, duration, and significance of marijuana abuse. According to 2012 data from NSDUH and 2013 data from MTF, marijuana remains the most extensively used illegal drug in the United States, with 42.8 percent of U.S. individuals over age 12 (111.2 million) and 45.5 percent of 12th graders having used marijuana at least once in their lifetime. Although the majority of individuals over age 12 (83.1 percent) who have ever used marijuana in their lifetime do not use the drug monthly, 18.9 million individuals (7.3 percent of the U.S. population) report that they used marijuana within the past 30 days. An examination of use among various age cohorts through NSDUH demonstrates that monthly use occurs primarily among college-aged individuals, with use dropping off sharply after age 25. Additionally, NSDUH data show the number of individuals reporting past-month use of marijuana has increased by 4.3 million individuals since 2004. Data from MTF shows that annual prevalence of marijuana use declined for all three grades from 2005 through 2007, then began to rise through 2013. Additionally, in 2013, 1.1 percent of 8th graders, 4.0 percent of 10th graders, and 6.5 percent of 12th graders reported daily use of marijuana, defined as use on 20 or more days within the past 30 days. The 2011 DAWN data show that marijuana use was mentioned in 455,668 ED visits, which amounts to approximately 36.4 percent of all illicit drug-related ED visits.23 TEDS data for 2011 show that 18.1 percent of all admissions were for primary marijuana abuse.24 Between 2003 and 2011, there was a 2.6 percent increase in the number of TEDS admissions for primary marijuana use. 23 Many factors can influence the estimates of ED visits, including trends in the reasons for ED usage. For instance, some drug users may visit EDs for lifethreatening issues while others may visit to seek care for detoxification because they needed certification before entering treatment. Additionally, DAWN data do not distinguish the drug responsible for the ED visit from other drugs that may have been used concomitantly. As stated in a DAWN report, ‘‘Since marijuana/hashish is frequently present in combination with other drugs, the reason for the ED visit may be more relevant to the other drug(s) involved in the episode.’’ 24 An important aspect of TEDS admission data for marijuana is of the referral source for treatment. Specifically, primary marijuana admissions were less likely than all other admissions to either be self-referred or referred by an individual for treatment. Instead, the criminal justice system referred more than half (51.6 percent) of primary marijuana admissions. PO 00000 Frm 00097 Fmt 4701 Sfmt 4702 53783 Approximately 61.5 percent of primary marijuana admissions in 2011 were for individuals under the age of 25 years. 6. What, if Any, Risk There Is to the Public Health Under the sixth factor, the Secretary must consider the risks posed to the public health by marijuana. Factors 1, 4, and 5 include a. discussion of the risk to the public health as measured by emergency room episodes and drug treatment admissions. Additionally, Factor 2 includes a discussion of marijuana’s central nervous system, cognitive, cardiovascular, autonomic, respiratory, and immune system effects. Factor 6 focuses on the health risks to the individual user in terms of the risks from acute and chronic use of marijuana, as well as the ‘‘gateway hypothesis.’’ Risks From Acute Use of Marijuana Acute use of marijuana impairs psychomotor performance, including complex task performance, which makes operating motor vehicles or heavy equipment after using marijuana inadvisable (Ramaekers et al., 2004; Ramaekers et al., 2006a). A metaanalysis conducted by Li et al. (2011) showed an association between marijuana use by the driver and a significantly increased risk of involvement in a car accident. Additionally, in a minority of individuals who use marijuana, some potential responses include dysphoria and psychological distress, including prolonged anxiety reactions (Haney et al., 1999). Risks From Chronic Use of Marijuana A distinctive marijuana withdrawal syndrome following long term or chronic use has been identified. The withdrawal syndrome indicates that marijuana produces physical dependence that is mild, short-lived, and comparable to tobacco withdrawal (Budney et al., 2008). Marijuana withdrawal syndrome is described in detail below under Factor 7. The following states how the DSM–V (2013) of the American Psychiatric Association describes the consequences of Cannabis 25 abuse: Individuals with cannabis use disorder may use cannabis throughout the day over a period of months or years, and thus may spend many hours a day under the influence. Others may use less frequently, but their use causes recurrent problems related to family, 25 Cannabis is the term used in the DSM–V to refer to marijuana. In the following excerpt the term Cannabis is interchangeable for the term marijuana. E:\FR\FM\12AUP2.SGM 12AUP2 53784 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules mstockstill on DSK3G9T082PROD with PROPOSALS2 school, work, or other important activities (e.g., repeated absences at work; neglect of family obligations). Periodic cannabis use and intoxication can negatively affect behavioral and cognitive functioning and thus interfere with optimal performance at work or school, or place the individual at increased physical risk when performing activities that could be physically hazardous (e.g:, driving a car; playing certain sports; performing manual work activities, including operating machinery). Arguments with spouses or parents over the use of cannabis in the home, or its use in the presence of children, can adversely impact family functioning and are common features of those with cannabis use disorder. Last, individuals with cannabis use disorder may continue using marijuana despite knowledge of physical problems (e.g., chronic cough related to smoking) or psychological problems (e.g., excessive sedation or exacerbation of other mental health problems) associated with its use. Marijuana as a ‘‘Gateway Drug’’ Kandel (1975) proposed nearly 40 years ago the hypothesis that marijuana is a ‘‘gateway drug’’ that leads to the use or abuse of other illicit drugs. Since that time, epidemiological research explored this premise. Overall, research does not support a direct causal relationship between regular marijuana use and other illicit drug use. The studies examining the gateway hypothesis are limited. First, in general, studies recruit individuals influenced by a myriad of social, biological, and economic factors that contribute to extensive drug abuse (Hall & Lynskey, 2005). Second, most studies that test the hypothesis that marijuana use causes abuse of illicit drugs use the determinative measure any use of an illicit drug, rather than DSM–5 criteria for drug abuse or dependence on an illicit drug (DSM–5, 2013). Consequently, although an individual who used marijuana may try other illicit drugs, the individual may not regularly use drugs, or have a diagnosis of drug abuse or dependence. Little evidence supports the hypothesis that initiation of marijuana use leads to an abuse disorder with other illicit substances. For example, one longitudinal study of 708 adolescents demonstrated that early onset marijuana use did not lead to problematic drug use (Kandel & Chen, 2000). Similarly, Nace et al. (1975) examined Vietnam-era soldiers who extensively abused marijuana and heroin while they were in the military, and found a lack of correlation of a causal relationship demonstrating VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 marijuana use leading to heroin addiction. Additionally, in another longitudinal study of 2,446 adolescents, marijuana dependence was uncommon but when it did occur, the common predictors of marijuana dependence were the following: parental death, deprived socio-economic status, and baseline illicit drug use other than marijuana (von Sydow et al., 2002). When examining the association between marijuana and illicit drugs, focusing on drug use versus abuse or dependence, different patterns emerge. For example, a study examining the possible causal relationship of the gateway hypothesis found a correlation between marijuana use in adolescents and other illicit drug use in early adulthood and, adjusting for age-linked experiences, did not effect this correlation (Van Gundy and Rebellon, 2010). However, when examining the association in terms of development of drug abuse; age-linked stressors and social roles moderated the correlation between marijuana use in adolescents and other illicit drug abuse. Similarly, Degenhardt et al. (2009) examined the development of drug dependence and found an association that did not support the gateway hypothesis. Specifically, drug dependence was significantly associated with the use of other illicit drugs prior to marijuana use. Interestingly, the order of initiation of drug use seems to depend on the prevalence of use of each drug, which varies by country. Based on the World Health Organization (WHO) World Mental Health Survey that includes data from 17 different countries, the order of drug use initiation varies by country and relates to prevalence of drug use in each country (Degenhardt et al., 2010). Specifically, in the countries with the lowest prevalence of marijuana use, use of other illicit drugs before marijuana was common. This sequence of initiation is less common in countries with higher prevalence of marijuana use. A study of 9,282·households in the United States found that marijuana use often preceded the use of other illicit drugs; however, prior non-marijuana drug dependence was also frequently correlated with higher levels of illicit drug abuse (Degenhardt et al., 2009). Additionally, in a large 25-year longitudinal study of 1,256 New Zealand children, the author concluded that marijuana use correlated to an increased risk of abuse of other drugs, including cocaine and heroin (Fergusson et al., 2005). Although many individuals with a drug abuse disorder may have used marijuana as one of their first illicit PO 00000 Frm 00098 Fmt 4701 Sfmt 4702 drugs, this fact does not correctly lead to the reverse inference that most individuals who used marijuana will inherently go on to try or become regular users of other illicit drugs. Specifically, data from the 2011 NSDUH survey illustrates this issue (SAMHSA, 2012). NSDUH data estimates 107.8 million individuals have a lifetime history of marijuana use, which indicates use on at least one occasion, compared to approximately 36 million individuals having a lifetime history of cocaine use and approximately 4 million individuals having a lifetime history of heroin use. NSDUH data do not provide information about each individual’s specific drug history. However, even if one posits that every cocaine and heroin user previously used marijuana, the NSDUH data show that marijuana use at least once in a lifetime does not predict that an individual will also use another illicit drug at least once. Finally, a review of the gateway hypothesis by Vanyukov et al. (2012) notes that because the gateway hypothesis only addresses the order of drug use initiation, the gateway hypothesis does not specify any mechanistic connections between drug ‘‘stages’’ following exposure to marijuana and does not extend to the risks for addiction. This concept contrasts with the concept of a common liability to addiction that involves mechanisms and biobehavioral characteristics pertaining to the entire course of drug abuse risk and disorders. 7. Its Psychic or Physiologic Dependence Liability Under the seventh factor, the Secretary must consider marijuana’s psychic or physiological dependence liability. Psychic or psychological dependence has been shown in response to marijuana’s psychoactive effects. Psychoactive responses to marijuana are pleasurable to many humans and are associated with drug-seeking and drugtaking (Maldonado, 2002). Moreover, high levels of psychoactive effects, notably positive reinforcement, are associated with increased marijuana use, abuse, and dependence (Scherrer et al., 2009; Zeiger et al., 2010). Epidemiological data support these findings through 2012 NSDUH statistics that show that of individuals years 12 or older who used marijuana in the past month, an estimated 40.3 percent used marijuana on 20 or more days within the past month. This equates to approximately 7.6 million individuals aged 12 or older who used marijuana on a daily or almost daily basis. E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules Additionally, the 2013 MTF data report the prevalence of daily marijuana use, defined as use on 20 or more days within the past 30 days, in 8th, 10th, and 12th graders is 1.1 percent, 4.0 percent, and 6.5 percent, respectively. Tolerance is a state of adaptation where exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time (American Academy of Pain Medicine, American Pain Society and American Society of Addiction Medicine consensus document, 2001). Tolerance can develop to some, but not all, of marijuana’s effects. Specifically, tolerance does not seem to develop in response to many of marijuana’s psychoactive effects. This lack of tolerance may relate to electrophysiological data demonstrating that chronic delta9-THC administration does not affect increased neuronal firing in the ventral tegmental area, a region known to play a critical role in drug reinforcement and reward (Wu and French, 2000). In the absence of other abuse indicators, such as rewarding properties, the presence of tolerance or physical dependence does not determine whether a drug has abuse potential. However, humans can develop tolerance to marijuana’s cardiovascular, autonomic, and behavioral effects (Jones et al., 1981). Tolerance to some of marijuana’s behavioral effects seems to develop after heavy marijuana use, but not after occasional marijuana use. For instance, following acute administration of marijuana, heavy marijuana users did not exhibit impairments in tracking and attention tasks, as were seen in occasional marijuana users (Ramaekers et al., 2009). Furthermore, a neurophysiological assessment administered through an electroencephalograph (EEG) which measures event-related potentials (ERP) conducted in the same subjects as the previous study, found a corresponding effect in the P100 26 component of ERPs. Specifically, corresponding to performance on tracking and attention tasks, heavy marijuana users showed no changes in P100 amplitudes following acute marijuana administration, although occasional users showed a decrease in P100 amplitudes (Theunissen et al., 2012). A possible mechanism underlying tolerance to marijuana’s effects may be the downregulation of cannabinoid receptors (Hirvonen et al., 2012; Gonzalez et al., 26 The P100 component of ERPs is thought to relate to the visual processing of stimuli and can be modulated by attention. VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 2005; Rodriguez de Fonseca et al., 1994; Oviedo et al., 1993). Importantly, pharmacological tolerance alone does not indicate a drug’s physical dependence liability. In order for physical dependence to exist, evidence of a withdrawal syndrome is needed. Physical dependence is a state of adaptation, manifested by a drugclass specific withdrawal syndrome produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist (ibid). Many medications not associated with abuse or addiction can produce physical dependence and withdrawal symptoms after chronic use. Discontinuation of heavy, chronic marijuana use has been shown to lead to physical dependence and withdrawal symptoms (American Psychiatric Association DSM–V, 2013; Budney and Hughes, 2006; Haney et al., 1999). In heavy, chronic marijuana users, the most commonly reported withdrawal symptoms are sleep difficulties, decreased appetite or weight loss, irritability, anger, anxiety or nervousness, and restlessness. Some less commonly reported withdrawal symptoms are depressed mood, sweating, shakiness, physical discomfort, and chills (Budney and Hughes, 2006; Haney et al., 1999). The occurrence of marijuana withdrawal symptoms in light or non-daily marijuana users has not been established. The American Psychiatric Association’s DSM–V (2013) includes a list of symptoms of ‘‘cannabis withdrawal.’’ Most marijuana withdrawal symptoms begin within 24– 48 hours of discontinuation, peak within 4–6 days, and last for 1–3 weeks. Marijuana withdrawal syndrome has been reported in adolescents and adults admitted for substance abuse treatment. Based on clinical descriptions, this syndrome appears to be mild compared to classical alcohol and barbiturate withdrawal syndromes, which can include more serious symptoms such as agitation, paranoia, and seizures. Multiple studies comparing marijuana and tobacco withdrawal symptoms in humans demonstrate that the magnitude and time course of the two withdrawal syndromes are similar (Budney et al., 2008; Vandrey et al., 2005, 2008). 8. Whether the Substance is an Immediate Precursor of a Substance Already Controlled Under This Article Under the eight factor analysis, the Secretary must consider whether marijuana is an immediate precursor of a controlled substance. Marijuana is not an immediate precursor of another controlled substance. PO 00000 Frm 00099 Fmt 4701 Sfmt 4702 53785 Recommendation After consideration of the eight factors discussed above, FDA recommends that marijuana remain in Schedule I of the CSA. NIDA concurs with this scheduling recommendation.Marijuana meets the three criteria for placing a substance in Schedule I of the CSA under 21 U.S.C. 812(b)(l): (1) Marijuana has a high potential for abuse: A number of factors indicate marijuana’s high abuse potential, including the large number of individuals regularly using marijuana, marijuana’s widespread use, and the vast amount of marijuana available for illicit use. Approximately 18.9 million individuals in the United States (7.3 percent of the U.S. population) used marijuana monthly in 2012. Additionally, approximately 4.3 million individuals met diagnostic criteria for marijuana dependence or abuse in the year prior to the 2012 NSDUH survey. A 2013 survey indicates that by 12th grade, 36.4 percent of students report using marijuana within the past year, and 22.7 percent report using marijuana monthly. In 2011, 455,668 ED visits were marijuana-related, representing 36.4 percent of all illicit drug-related episodes. Primary marijuana use accounted for 18.1 percent of admissions to drug treatment programs in 2011. Additionally, marijuana has dose-dependent reinforcing effects, as demonstrated by data showing that humans prefer relatively higher doses to lower doses. Furthermore, marijuana use can result in psychological dependence. (2) Marijuana has no currently accepted medical use in treatment in the United States: FDA has not approved a marketing application for a marijuana drug product for any indication. The opportunity for scientists to conduct clinical research with marijuana exists, and there are active INDs for marijuana; however, marijuana does not have a currently accepted medical use for treatment in the United States, nor does marijuana have an accepted medical use with severe restrictions. A drug has a ‘‘currently accepted medical use’’ if all of the following five elements have been satisfied: a. The drug’s chemistry is known and reproducible; b. there are adequate safety studies; c. there are adequate and wellcontrolled studies proving efficacy; d. the drug is accepted by qualified experts; and e. the scientific evidence is widely available. E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53786 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules [57 FR 10499, March 26, 1992] Marijuana does not meet any of the elements for having a ‘‘currently accepted medical use.’’ First, FDA broadly evaluated marijuana, and did not focus its evaluation on particular strains of marijuana or components or derivatives of marijuana. Since different strains may have different chemical constituents, marijuana, as identified in this petition, does not have a known and reproducible chemistry, which would be needed to provide standardized doses. Second, there are not adequate safety studies on marijuana in the medical literature in relation to a specific, recognized disorder. Third, there are no published adequate and well controlled studies proving efficacy of marijuana. Fourth, there is no evidence that qualified experts accept marijuana for use in treating a specific, recognized disorder. Lastly, the scientific evidence regarding marijuana’s chemistry in terms of a specific Cannabis strain that could produce standardized and reproducible doses is not currently available, so the scientific evidence on marijuana is not widely available. Alternately, a Schedule II drug can be considered to have a ‘‘currently accepted medical use with severe restrictions’’ (21 U.S.C. 812(b)(2)(B)). Yet as stated above, the lack of accepted medical use for a specific, recognized disorder precludes the use of marijuana even under conditions where its use is severely restricted. In conclusion, to date, research on marijuana’s medical use has not developed to the point where marijuana is considered to have a ‘‘currently accepted medical use’’ or a ‘‘currently accepted medical use with severe restrictions.’’ (3) There is a lack of accepted safety for use of marijuana under medical supervision: There are currently no FDA-approved marijuana drug products. Marijuana does not have a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions. Thus, FDA has not determined that marijuana is safe for use under medical supervision. In addition, FDA cannot conclude that marijuana has an acceptable level of safety relative to its effectiveness in treating a specific, recognized disorder without evidence that the substance is contamination free, and assurance of a consistent and predictable dose. Investigations into the medical use of marijuana should include information and data regarding the chemistry, manufacturing, and specifications of marijuana. Additionally, a procedure for VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 delivering a consistent dose of marijuana should also be developed. Therefore, FDA concludes marijuana does not currently have an accepted level of safety for use under medical supervision. References Abrams DI, Hilton JF, Leiser RJ, Shade SB, Elbeik TA, Aweeka FT, Benowitz NL, Bredt BM, Kosel B, Aberg JA, Deeks SG, Mitchell TF, Mulligan K, Bacchetti P, McCune JM, Schambelan M. Short-term effects of cannabinoids in patients with HIV–1 infection: a randomized, placebo controlled clinical trial. Ann Intern Med. 2003 Aug 19; 139(4):258–66. Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME, Rowbotham MC, and Petersen KL. 2007. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebocontrolled trial. Neurology 68(7): 515– 521. Adams, I.B., and Martin, B.R. Cannabis: Pharmacology and toxicology in animals and humans. Addiction 1996, 91(11):1585–1614. Agurell, S., Dewey, W.L., and Willett, R.E., eds. The Cannabinoids: Chemical, Pharmacologic, and Therapeutic Aspects. New York: Academic Press, 1984. Agurell, S.; Halldin, M.; Lindgren, J.E.; Ohlsson, A.; Widman, M.; Gillespie, H.; and Hollister, L. Pharmacokinetics and metabolism of delta 1tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev 1986, 38(1), 21–43. Almirez RG, Smith CG, Asch RH. The effects of marijuana extract and delta 9tetrahydrocannabinol on luteal function in the rhesus monkey. Fertil Steril. 1983 Feb; 39(2):212–7. Ameri, A. The effects of cannabinoids on the brain. Progress in Neurobiology 1999, 58 (4), 315–348. American Academy of Pain Medicine, American Pain Society and American Society of Addiction Medicine Consensus Document. Definitions related to the use of opioids for the treatment of pain. 2001. Andreasson S, Allebeck P, Engstrom A, Rydberg U. Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. Lancet. 1987 Dec 26; 2(8574):1483–6. Appendino G, Chianese G, TaglialatelaScafati O. Cannabinoids: occurrence and medicinal chemistry. Curr Med Chem. 2011; 18(7):1085–99. Asch RH, Smith CG, Siler-Khodr TM, Pauerstein CJ. Effects of delta 9tetrahydrocannabinol during the follicular phase of the rhesus monkey (Macaca mulatta). J Clin Endocrinol Metab. 1981 Jan; 52(1):50–5. Balster, R.L., Prescott, W.R., delta9Tetrahydrocannabinol discrimination in rats as a model for cannabis intoxication. Neurosci. & Biobehav. Rev. 1992, 16(1), 55–62. Balster RL and Bigelow GE. Guidelines arid methodological reviews concerning drug PO 00000 Frm 00100 Fmt 4701 Sfmt 4702 abuse liability assessment. Drug and Alcohol Dependence. 2003; 70: S13–S40. Barnett, G.; Licko, V.; and Thompson, T. Behavioral pharmacokinetics of marijuana. Psychopharmacology 1985, 85(1), 51–56. Battista N, Di TM, Bari M, Maccarrone M. The endocannabinoid system: an overview. Front.Behav.Neurosci. 2012; 6:9. Benowitz NL, Jones RT. Cardiovascular effects of prolonged delta-9tetrahydrocannabinol ingestion. Clin Pharmacol Ther. 1975 Sep; 18(3):287–97. Benowitz NL, Jones RT. Cardiovascular and metabolic considerations in prolonged cannabinoid administration in man. J Clin Pharmacol. 1981 Aug–Sep; 21(8–9 Suppl):214S–223S. Block RI, Farinpour R, Schlechte JA. Effects of chronic marijuana use on testosterone, luteinizing hormone, follicle stimulating hormone, prolactin and cortisol in men and women. Drug Alcohol Depend. 1991 Aug; 28(2):121–8. Block RI, Farinpour R, Braverman K. Acute effects of marijuana on cognition: relationships to chronic effects and smoking techniques. Pharmacol Biochem Behav. 1992 Nov; 43(3):907–17. Bolla KI, Brown K, Eldreth D, Tate K, and Cadet JL. Dose-related neurocognitive effects of marijuana use. Neurology 2002 59:1337–1343. Bolla KI, Eldreth DA, Matochik JA, and Cadet JL. Neural substrates of faulty decisionmaking in abstinent marijuana users. NeuroImage 2005 26:480–492. Bonnet U. Chronic cannabis abuse, delta-9tetrahydrocannabinol and thyroid function. Pharmacopsychiatry. 2013 Jan; 46(1):35–6. Bouaboula M, Rinaldi M, Carayon P, Carillon C, Delpech B, Shire D, Le Fur G, Casellas P. Cannabinoid-receptor expression in human leukocytes. Eur J Biochem. 1993 May 15; 214(1):173–80. Braida D, Iosue S, Pegorini S, Sala M. Delta9tetrahydrocannabinol-induced conditioned place preference and intracerebroventricular selfadministration in rats. Eur J Pharmacol. 2004 Dec 3; 506(1):63–9. Breivogel CS, Childers SR. Cannabinoid agonist signal transduction in rat brain: comparison of cannabinoid agonists in receptor binding, G-protein activation, and adenylyl cyclase inhibition. J Pharmacol Exp Ther. 2000. Oct; 295(1):328–36. Breivogel CS, Griffin G, Di Marzo V, Martin BR. Evidence for a new G proteincoupled cannabinoid receptor in mouse brain. Mol Pharmacol. 2001 Jul; 60(1):155–63. Brown TT, Dobs AS. Endocrine effects of marijuana. J Clin Pharmacol. 2002 Nov; 42(11 Suppl):90S–96S. Browne RG, Weissman A. Discriminative stimulus properties of delta 9tetrahydrocannabinol: mechanistic studies. J Clin Pharmacol. 1981 Aug– Sep; 21(8–9 Suppl):227S–234S. Budney AJ, Hughes JR, Moore BA, Vandrey R. Review of the validity and significance of cannabis withdrawal E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules syndrome. Am J Psychiatry. 2004 Nov; 161(11):1967–77. Budney AJ, Hughes JR. The cannabis withdrawal syndrome. Curr Opin Psychiatry 2006 May; 19(3):233–8. Budney AJ, Vandrey RG, Hughes JR, Thostenson JD, Bursae Z. Comparison of cannabis and tobacco withdrawal: severity and contribution to relapse. J Subst.Abuse Treat. 2008 Dec; 35(4):362– 8. Capriotti RM, Foltin RW, Brady JV, Fischman MW. Effects of marijuana on the taskelicited physiological response. Drug Alcohol Depend. 1988 Jul; 21(3):183–7. Cascini F, Aiello C, Di Tanna G. Increasing delta-9-tetrahydrocannabinol (D-9–THC) content in herbal cannabis over time: systematic review and meta-analysis. Curr Drug Abuse Rev. 2012 Mar; 5(1):32– 40. Chait LD. Subjective and behavioral effects of marijuana the morning after smoking. Psychopharmacology (Berl.) 1990; 100(3):328–33. Chait LD, Burke KA. Preference for highversus low-potency marijuana. Pharmacol Biochem Behav. 1994 Nov; 49(3):643–7. Chaperon F, Soubrie P, Puech AJ, Thiebot MH. Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats. Psychopharmacology (Berl). 1998 Feb; 135(4):324–32. Cheer JF, Kendall DA, Marsden CA. Cannabinoid receptors and reward in the rat: a conditioned place preference study. Psychopharmacology (Berl). 2000 Jul; 151(1):25–30. Cone EJ, Johnson RE, Moore JD, Roache JD. Acute effects of smoking marijuana on hormones, subjective effects and performance in male human subjects. Pharmacol Biochem Behav. 1986 Jun; 24(6): 1749–54. Corey-Bloom J, Wolfson T, Gamst A, Jin S, Marcotte TD, Bentley H, and Gouaux B. 2012. Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. CMAJ 184 (10): 1143–1150. Council on Science and Public Health Report 3. Use of cannabis for medicinal purposes. American Medical Association, Interim Meeting, Houston, Texas; November 2009. Crawford WJ, and Merritt JC. 1979. Effects of tetrahydrocannabinol on arterial and intraocular hypertension. International journal of clinical pharmacology and biopharmacy 17 (5): 191–196. Croxford JL, Yamamura T. Cannabinoids and the immune system: potential for the treatment of inflammatory diseases? J Neuroimmunol. 2005 Sep; 166(1–2):3– 18. Review. Dalton WS, Martz R, Lemberger L, Rodda BE, Forney RB. Influence of cannabidiol on delta-9-tetrahydrocannabinol effects. Clin.Pharmacol. Ther. 1976 Mar; 19(3):300–9. Dax EM, Pilotte NS, Adler WH, Nagel JE, Lange WR. The effects of 9-enetetrahydrocannabinol on hormone release and immune function. J Steroid Biochem. 1989; 34(1–6):263–70. VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 Degenhardt L, Hall W, Lynskey M. Testing hypotheses about the relationship between cannabis use and psychosis. Drug Alcohol Depend. 2003 Jul 20; 71(1):37–48. Degenhardt L, Chiu WT, Conway K, Dierker L, Glantz M, Kalaydjian A, Merikangas K, Sampson N, Swendsen J, Kessler RC. Does the ‘gateway’ matter? Associations between the order of drug use initiation and the development of drug dependence in the National Comorbidity Study Replication. Psychol. Med 2009 Jan; 39(1):157–67. Degenhardt L, Dierker L, Chiu WT, MedinaMora ME, Neumark Y, Sampson N, Alonso J, Angermeyer M, Anthony JC, Bruffaerts R, et al. Evaluating the drug use ‘‘gateway’’ theory using crossnational data: consistency and associations of the order of initiation of drug use among participants in the WHO World Mental Health Surveys. Drug Alcohol. Depend. 2010 Apr 1; 108(1– 2):84–97. Deiana S, Fattore L, Spano MS, Cossu G, Porcu E, Fadda P, Fratta W. Strain and schedule dependent differences in the acquisition, maintenance and extinction of intravenous cannabinoid selfadministration in rats. Neuropharmacology. 2007 Feb; 52(2):646–54. Dewey, W.L., Martin, B.R., May, E.L. Cannabinoid stereoisomers: pharmacological effects. In Smith, D.F. (Ed.) CRC Handbook of stereoisomers: drugs in psychopharmacology, 317–326 (Boca Raton, FL, CRC Press), 1984. Di Marzo, V.A brief history of cannabinoid and endocannabinoid pharmacology as inspired by the work of British scientists. Trends. Pharmacol. Sci 2006 Mar; 27(3):134–40. DEA Statistics and Facts. (n.d.) DEA Domestic Drug Seizures. http:// www.justice.gov/dea/resource-center/ statistics.shtml/ (accessed August 5, 2014) Drug Enforcement Administration, Drugs of Abuse, 2005. Drug Enforcement Administration. Sourcebook of Criminal Justice Statistics, 2003. DSM–V. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Association. Washington, DC: American Psychiatric Publishing, 2013. Eldridge JC, Murphy LL, Landfield PW. Cannabinoids and the hippocampal glucocorticoid receptor: recent findings and possible significance. Steroids. 1991 May; 56(5):226–31. Review. Ellis RJ, Toperoff W, Vaida F, Van Den Brande G, Gonzales J, Gouaux B, Bentley H, and Atkinson JH. 2009. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 34(3): 672– 680. ElSohly MA, Slade D. Chemical constituents of marijuana: The complex mixture of natural cannabinoids. Life Sciences. 2005; 78:539–48. PO 00000 Frm 00101 Fmt 4701 Sfmt 4702 53787 Fant RV, Heishman SJ, Bunker EB, Pickworth WB. Acute and residual effects of marijuana in humans. Pharmacol Biochem Behav. 1998 Aug; 60(4):777–84. Fattore L, Spano MS, Altea S, Angius F, Fadda P, Fratta W. Cannabinoid selfadministration in rats: sex differences and the influence of ovarian function. Br.J Pharmacol. 2007 Nov; 152(5):795– 804. Fergusson DM, Horwood LJ, Ridder EM. Tests of causal linkages between cannabis use and psychotic symptoms. Addiction. 2005 Mar; 100(3):354–66. Fontes MA, Bolla KI, Cunha PJ, Almeida PP, Jungerman F, Laranjeira RR; Bressan RA, Lacerda AL. Cannabis use before age 15 and subsequent executive functioning. Br. J Psychiatry 2011 Jun; 198(6):442–7. Fried, P.A., Watkinson, B. 36- and 48-month neurobehabioral follow-up of children prenatally exposed to marijuana, cigarettes and alcohol. J. Dev. Behav. Pediatr. 1987, 8, 318–326. Fried, P.A., Watkinson, B., Gray, R. A followup study of attentional behavior in 6year-old children exposed prenatally to marihuana, cigarettes and alcohol. Neurotoxicol. Teratol. 1992, 14, 299–311. Fried, P.A., Watkinson, B., Gray, R. Differential effects on cognitive functioning in 9- to 12-year olds prenatally exposed to cigarettes and marihuana. Neurotoxicol. Teratol. 1998, 20(3), 293–306. Fried PA. Adolescents prenatally exposed to marijuana: examination of facets of complex behaviors and comparisons with the influence of in utero cigarettes. J. Clin. Pharmacol. 2002 Nov; 42(11 Suppl):97S–102S. Fried PA, Watkinson B, Gray R. Neurocognitive consequences of marihuana—a comparison with pre-drug performance. Neurotoxicol. Teratol. 2005 Mar; 27(2):231–9. Fung, M., Gallagher, C., Machtay, M. Lung and aeo-digestive cancers in young marijuana smokers. Tumori 1999, 85 (2), 140–142. Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995 Aug 15; 232(1):54–61. Gaoni, Y., Mechoulam, R. Isolation, structure, and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 1964, 86, 1646–1947. Gerard, C.M., Mollereau, C., Vassart, G., Parmentier, M. Molecular cloning of a human cannabinoid receptor which is also expressed in testis.: Biochem J. 1991, 279, 129–34. Ghozland S, Matthes HW, Simonin F, Filliol D, Kieffer BL, Maldonado R. Motivational effects of cannabinoids are mediated by mu-opioid and kappaopioid receptors. J Neurosci. 2002 Feb 1; 22(3):1146–54. Gold LH, Balster RL, Barrett RL, Britt DT, Martin BR. A comparison of the discriminative stimulus properties of delta 9-tetrahydrocannabinol and CP E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53788 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 55,940 in rats and rhesus monkeys. J Pharmacol Exp Ther. 1992 Aug; 262(2):479–86. Goldschmidt L, Richardson GA, Willford J, Day NL. Prenatal marijuana exposure and intelligence test performance at age 6. J. Am. Acad. Child. Adolesc. Psychiatry. 2008 Mar; 47(3):254–63. Gong H Jr, Tashkin DP, Simmons MS, Calvarese B, Shapiro BJ. Acute and subacute bronchial effects of oral cannabinoids. Clin Pharmacol Ther. 1984 Jan; 35(1):26–32. Gong JP, Onaivi ES, Lshiguro H, Liu QR, Tagliaferro PA, Brusco A, Uhl GR. Cannabinoid CB2 receptors: Immunohistochemical localization in rat brain. Brain Res. 2006 Feb 3; 1071(1):10– 23. Gonsiorek W, Lunn C, Fan X, Narula S, Lundell D, Hipkin RW. Endocannabinoid 2-arachidonyl glycerol is a full agonist through human type 2 cannabinoid receptor: Antagonism by anandamide. Mol Pharmacol. 2000 May; 57(5): 1045–50. Gonzalez R. Acute and non-acute effects of cannabis on brain functioning and neuropsychological performance. Neuropsychol.Rev. 2007 Sep; 17(3):347–61. Gonzalez S, Cebeira M, Fernandez-Ruiz J. Cannabinoid tolerance and dependence: A review of studies in laboratory animals. Pharmacol.Biochem.Behav. 2005 Jun; 81(2):300–18. Grant I. Foreword by Igor Grant, M.D., Director, Center for Medicinal Cannabis Research (CMCR). Neuropharmacology. 2005 Jun; 48(8): 1067. Griffith-Lendering MF, Wigman JT, Prince van LA, Huijbregts SC, Huizink AC, Ormel J, Verhulst FC, van OJ, Swaab H, Vollebergh WA. Cannabis use and vulnerability for psychosis in early adolescence-a TRAILS study. Addiction 2012 Dec 7. Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. 2003; 42(4):327–60. Gruber SA, Sagar KA, Dahlgren MK, Racine M, Lukas SE. Age of onset of marijuana use and executive function. Psychol.Addict.Behav. 2012 Sep; 26(3):496–506. Hall WD, Lynskey M. Is cannabis a gateway drug? Testing hypotheses about the relationship between cannabis use and the use of other illicit drugs. Drug Alcohol Rev. 2005 Jan; 24(1):39–48. Haney M, Gunderson EW, Rabkin J, Hart CL, Vosburg SK, Comer SD, and Faltin RW. 2007. Dronabinol and marijuana in HIVpositive marijuana smokers. Caloric.intake, mood, and sleep. Journal of acquired immune deficiency syndromes (1999) 45 (5): 545–554. Haney M, Rabkin J, Gunderson E, and Foltin RW. 2005. Dronabinol and marijuana in HIV(+) marijuana smokers: Acute effects on caloric intake and mood. Psychopharmacology 181(1): 170–178. Haney M, Ward AS, Comer SD, Faltin RW, Fischman MW. Abstinence symptoms following smoked marijuana in humans. Psychopharmacology (Berl) 1999, 141(4):395–404. Hanus, L., Breuer, A., Tchili_bon, S., Shiloah, S., Goldenberg, D., Horowitz, M., Pertwee, VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 R.G., Roos, R.A., Mechoulam, R., Pride, E. HU–308: A specific agonist for CB(2), a peripheral Cannabinoid receptor. Proc. Natl. Acad. Sci. USA 1999, 96, 14228–33. Heishman SJ, Huestis MA, Benningfield JE, Cone EJ. Acute and residual effects of marijuana: Profiles of plasma THC levels, physiological, subjective, and performance measures. Pharmacol Biochem Behav. 1990 Nov; 37(3):561–5. Herkenham, M. Cannabinoid receptor localization in brain: Relationship to motor and reward systems. In: Kalivas, P.W., and Samson, H.H., eds. The neurobiology of drug and alcohol addiction. Ann NY Acad Sci 1992, 654, 19–32. Herkenham, M., Lynn, A.B., Little, M.D., Johnson, M.R., Melvin, L.S., de Costa, B.R., Rice, K.C. Cannabinoid receptor localization in Brain. Proc. Natl. Acad. Sci.US A. 1990, 87, 1932–1936. Herning, R.I.; Hooker, W.D.; and Jones, R.T. Tetrahydrocannabinol content and differences in marijuana smoking behavior. Psychopharmacology 1986, 90(2):160–162. Hillig, K.W. Genetic evidence for speciation in Cannabis (Cannabaceae). Genetic Resources and Crop Evolution 52: 161–180, 2005. Hirvonen, J., Goodwin, R.S., Li, C.T., Terry, G.E., Zoghbi, S.S., Morse, C., Pike, V.W., Volkow, N.D., Huestis, M.A., Innis, R.B. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol. Psychiatry. 2012(Jun), 17(6), 643–649. Hively, R.L., Mosher, W.A., Hoffman, F.W. Isolation of trans-)9-tetrahydrocannabinol from marihuana. J. Am. Chem. Soc. 1966, 88, 1832–1833. Hollister LE, Gillespie HK. Delta-8- and delta9-tetrahydrocannabinol comparison in man by oral and intravenous administration. Clin.Pharmacol.Ther. 1973 May;14(3):353– 7. Hollister, L.E. Health aspects of cannabis. Pharmacological Rev. 1986, 38, 1–20. Hollister, L.E. Cannabis. (Literature review). Acta Psychiatr Scand (Suppl) 1988, 78, 108–118. Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Parrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004; 47 Suppl 1:345–58. Huestis, M.A., Sampson, A.H., Holicky, B.J., Benningfield, J.E., Cone, E.J. Characterization of the absorption phase of marijuana smoking. Clin. PharmacoL Ther. 1992a, 52, 31–41. Huestis, M.A.; Benningfield, J.E.; and Cone, E.J. Blood Cannabinoids. 1. Absorption of THC and formation of 11–0H–THC and THC COOH during and after smoking marijuana. J Anal Toxicol 1992b, 16(5), 276–282. Hunt CA, Jones RT. Tolerance and disposition oftetrahydrocannabinol in man. J Pharmacol Exp Ther. 1980 Oct; 215(1):35–44. Ilan AB, Gevins A, Coleman M, Elsohly MA, de WH. Neurophysiological and subjective profile of marijuana with varying concentrations of cannabinoids. PO 00000 Frm 00102 Fmt 4701 Sfmt 4702 Behav.Pharmacol. 2005 Sep; 16(5–6):487– 96. Institute of Medicine. Division of Health Sciences Policy. Marijuana and Health: Report of a Study by a Committee of the Institute of Medicine, Division of Health Sciences Policy. Washington, DC: National Academy Press, 1982. Institute of Medicine, Division of Neuroscience and Behavioral Health. Marijuana and Medicine: Assessing the Science Base. Washington DC: National Academy Press, 1999. Johansson, E.; Halldin, M.M.; Agurell, S.; Hollister, L.E.; and Gillespie, H.K. Terminal elimination plasma half-life of delta 1-tetrahydrocannabinol (delta 1– THC) in heavy users of marijuana. Eur J Clin Pharmacol 1989, 37(3), 273–277. Johnston, L.D., O’Malley, P.M., Miech, R.A., Bachman, J.G., & Schulenberg, J.E. (2014). Monitoring the Future national survey results on drug use: 1975–2013: Overview, key findings on adolescent drug use. Ann Arbor: Institute for Social Research, The University of Michigan, 84pp. Jones, R.T.; Benowitz, N.L.; and Heming, R.I. Clinical relevance of cannabis tolerance and dependence. J Clin Pharmacol 1981, 21,143S–152S. Jones RT. Cardiovascular system effects of marijuana. J Clin Pharmacol. 2002 Nov;42(11Suppl):58S–63S. Justinova Z, Goldberg SR, Heishman SJ, Tanda G. Self-administration of cannabinoids by experimental animals and human marijuana smokers. Pharmacol Biochem Behav. 2005 Jun; 81(2): 285–299. Justinova Z, Tanda G, Redhi GH, Goldberg SR. Self-administration of delta9tetrahydrocannabinol (THC) by drug naive squirrel monkeys. Psychopharmacology (Berl). 2003 Sep; 169(2): 135–40. Justinova Z, Tanda G, Munzar P, Goldberg SR. The opioid antagonist naltrexone reduces the reinforcing effects of Delta 9 tetrahydrocannabinol (THC) in squirrel monkeys. Psychopharmacology.(Berl.) 2004 Apr;l 73(1–2):186–94. Kandel, D. Stages in adolescent involvement in drug use. Science 1975; 190:912–914. Kandel DB, Chen K. Types of marijuana users by longitudinal course. J Stud Alcohol. 2000 May; 61(3):367–78. Karniol IG, Shirakawa I, Kasinski N, Pfeferman A, Carlini EA. Cannabidiol interferes with the effects of delta 9tetrahydrocannabinol in man. Eur.J Pharmacol. 1974 Sep;28(1):172–7. Karniol IG, Shirakawa I, Takahashi RN, Knobel E, Musty RE. Effects of delta9tetrahydrocannabinol and cannabinol in man. Pharmacology 1975; 13(6):502–12. Kirk JM, de Wit H. Responses to oral delta9tetrahydrocannabinol in frequent and infrequent marijuana users. Pharmacol Biochem Behav. 1999 May; 63(1):137–42. Kuepper R, van OJ, Lieb R, Wittchen HU, Hofler M, Henquet C. Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study. BMJ 2011; 342:d738. Kurzthaler I, Hummer M, Miller C, SpernerUnterweger B, Gunther V, Wechdorn H, Battista HJ, Fleischhacker WW. Effect of cannabis use on cognitive functions and E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules driving ability. J Clin Psychiatry. 1999 Jun; 60(6):395–9. Lee MH, Hancox RJ. Effects of smoking cannabis on lung function. Expert Rev.Respir.Med 2011 Aug; 5(4):537–46. Lemberger L., Silberstein, S. D., Axelrod, J., Kopin, I.J. Marihuana: Studies on the disposition and metabolism of delta-9tetrahydrocannabinol in man. Science 1970, 1 70, 1320–1322. Lemberger L., Weiss, J.L., Watanabe, A. M., Galanter, I.M., Wyatt, R.J., Cardon, P.V. Delta-9-tetrahydrocannabinol: Temporal correlation of the psychological effects and blood levels after various routes of administration. New Eng. J. Med. 1972a, 286(13), 685–688. Lemberger, L., Crabtree, R.E., Rowe, H.M. 11Hydroxy-)9-tetrahydrocannabinol: Pharmacology, disposition and metabolism of a major metabolite of marihuana in man. Science 1972b, 177, 62–63. Lemberger L., Rubin A. The physiologic disposition of marihuana in man, Life Sci. 1975,17, 1637–42. Li M–C., Brady, J.E., DiMaggio, C.J., Lusardi, A.R., Tzong, K.Y., Li, G. Marijuana use and motor vehicle crashes. Epidemiologic Reviews. 2012, 34, 65–72. Liguori A, Gatto CP, Robinson JH. Effects of marijuana on equilibrium, psychomotor performance, and simulated driving. Behav Pharmacol. 1998 Nov; 9(7):599–609. Lile JA, Kelly TH, Hays LR. Separate and combined effects of the cannabinoid agonists nabilone and Delta(9)-THC in humans discriminating Delta(9)-THC. Drug Alcohol Depend. 2011 Jul1; 116(1–3):86– 92. Lile JA, Kelly TH, Pinsky DJ, Hays LR. Substitution profile of Delta9tetrahydrocannabinol, triazolam, hydromorphone, and methylphenidate in humans discriminating Delta9tetrahydrocannabinol. Psychopharmacology (Berl.) 2009 Apr; 203 (2):241–50. Lisdahl KM, Price JS. Increased marijuana use and gender predict poorer cognitive functioning in adolescents and emerging adults. J Int Neuropsychol.Soc 2012 Jul; 18(4):678–88. Lyons MJ, Bar JL, Panizzon MS, Toomey R, Eisen S, Xian H, Tsuang MT. Neuropsychological consequences of regular marijuana use: A twin study. Psychol Med. 2004 Oct; 34(7):1239–50. Mackie K, Lai Y, Westenbroek R, Mitchell R. Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. J Neurosci. 1995 Oct; 15(10):6552–61. Maldonado R. Study of cannabinoid dependence in animals. Pharmacol Ther. 2002 Aug; 95(2): 153–64. Malinowska B, Baranowska-Kuczko M, Schlicker E. Triphasic blood pressure responses to cannabinoids: Do we understand the mechanism? Br.J Pharmacol 2012 Apr; 165(7):2073–88. Manrique-Garcia E, Zammit S, Dalman C, Hemmingsson T, Andreasson S, Allebeck P. Cannabis, schizophrenia and other nonaffective psychoses: 35 years of follow-up VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 of a population-based cohort. Psychol.Med 2012 Jun; 42(6):1321–8. Maremmani I, Lazzeri A, Pacini M, Lovrecic M, Placidi GF, Perugi G. Diagnostic and symptomatological features in chronic psychotic patients according to cannabis use status. J Psychoactive Drugs. 2004 Jun; 36(2):235–41. ‘‘Marijuana Scheduling Petition; Denial of Petition; Remand; Final Order,’’ 57 Federal Register 59 (26 March 1992), pp. 10499– 10508. Martellotta MC, Cossu G, Fattore L, Gessa GL, Fratta W. Self-administration of the cannabinoid receptor agonist WIN 55,212– 2 in drug-naive mice. Neuroscience. 1998 Jul; 85(2):327–30. Matsuda, L.A., Lolait, S.J., Brownstein, M.J., Young, A.C., Bonner, T.I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990, 346, 561–564. McMahon LR. Apparent affinity estimates of rimonabant in combination with anandamide and chemical analogs of anandamide in rhesus monkeys discriminating Delta9tetrahydrocannabinol. Psychopharmacology (Berl.) 2009 Apr; 203(2):219–28. McMahon LR, Ginsburg BC, Lamb RJ. Cannabinoid agonists differentially substitute for the discriminative stimulus effects of Delta(9)-tetrahydrocannabinol in C57BL/6J mice. Psychopharmacology (Berl.) 2008 Jul; l98(4):487–95. Mechoulam, R. Cannabinoid chemistry. In Mechoulam, R. (ED.) Marijuana, pp.2–88 (New York, NY, Academic Press, Inc.), 1973. Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO. Cannabidiol—recent advances. Chem.Biodivers. 2007 Aug;4(8): 1678–92. Mechoulam R, Shvo Y. Hashish-I: The structure of Cannabidiol. Tetrahedron. 1963; 19: 2073–78. Mehmedic Z, Chandra S, Slade D, Denham H, Foster S, Patel AS, Ross SA, Khan IA, ElSohly MA. Potency Trends of D9-THC and other caimabinoids in confiscated cannabis preparations from 1993 to 2008. J Forensic Sci. 2010 Sept; 55(5): 1209– 1217. Meier MH, Caspi A, Ambler A, Harrington H, Houts R, Keefe RS, McDonald K, Ward A, Poulton R, Moffitt TE. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc.Natl.Acad.Sci U.S.A 2012 Oct 2; 109(40):E2657–E2664. Meijer JH, Dekker N, Koeter MW, Quee PI, van Beveren NJ, Meijer CJ. Cannabis and cognitive performance in psychosis: A cross-sectional study in patients with nonaffective psychotic illness and their unaffected siblings. Psychol.Med 2012 Apr; 42(4):705–16. Mendelson JH, Mello NK. Effects of marijuana on neuroendocrine hormones in human males and females. NIDA Res Monogr. 1984; 44:97–114. Mendizabal V, Zimmer A, Maldonado R. Involvement ofkappa/dynorphin system in WIN 55,212–2 self-administration in mice. Neuropsychopharmacology. 2006 Sep; 31(9):1957–66. PO 00000 Frm 00103 Fmt 4701 Sfmt 4702 53789 Merritt JC, Crawford WJ, Alexander PC, Anduze AL, and Gelbart SS. 1980. Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology 87 (3): 222–228. Messinis L, Kyprianidou A, Malefaki S, and Papathanasopoulos P. Neuropsychological deficits in long-term frequent cannabis users. Neurology 2006 66:737–739. Minozzi S, Davoli M, Bargagli AM, Amato L, Vecchi S, Perucci CA. An overview of systematic reviews on cannabis and psychosis: Discussing apparently conflicting results. Drug Alcohol Rev. 2010 May; 29(3):304–17. Mittleman MA, Lewis RA, Maclure M, Sherwood JB, and Muller JE. Triggering myocardial infarction by marijuana. Circulation. 2001; 103:2805–2809. Nace EP, Meyers AL, Rothberg JM, Maleson F. Addicted and nonaddicted drug users. A comparison of drug usage patterns. Arch Gen Psychiatry. 1975; 32(1):77–80. Oviedo, A., Glowa, J., Herkenham, M. Chronic cannabinoid administration alters cannabinoid receptor binding in rat brain: A quantitative autoradiographic study. Brain Res. 1993, 616, 293–302. Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol.Rev. 2006 Sep; 58(3):389–462. Pelayo-Teran JM, Suarez-Pinilla P, Chadi N, Crespo-Pacorro B. Gene-environment interactions underlying the effect of cannabis in first episode psychosis. Curr Pharm Des. 2012; 18(32):5024–35. Petrocellis PL, Di Marzo V. An introduction to the endocannabinoid system: From the early to the latest concepts. Best Pract.Res.Clin.Endocrinol.Metab. 2009 Feb; 23(1):1–15. Piomelli D. The endocannabinoid system: A drug discovery perspective. Curr Opin Investig Drugs. 2005 Jul; 6(7):672–9. Pletcher MJ, Vittinghoff E, Kalhan R, Richman J, Safford M, Sidney S, Lin F, Kertesz S. Association between marijuana exposure and pulmonary function over 20 years. JAMA 2012 Jan 11; 307(2):173–81. Pollastro F, Taglialatela-Scafati 0, Allara M, Munoz E, Di Marzo V, De Petrocellis L, Appendino G. Bioactive prenylogous cannabinoid from fiber hemp (Cannabis sativa). J Nat Prod. 2011 Sep 23;74(9):2019–22. Pope HG Jr, Gruber AJ, Hudson JI, Huestis MA, Yurgelun-Todd D. Cognitive measures in long term cannabis users. J Clin Pharmacol. 2002 Nov; 42(11 Suppl):41S– 47S. Review. Radwan MM, Elsohly MA, Slade D, Ahmed SA, Khan IA, Ross SA. Biologically active cannabinoids from high-potency Cannabis sativa. J Nat Prod. 2009 May 22; 72(5):906– 11. Ramaekers JG, Berghaus G, van Laar M, Drummer OH. Dose related risk of motor vehicle crashes after cannabis use. Drug Alcohol Depend. 2004 Feb 7; 73(2): 109– 19. Ramaekers JG, Kauert G, van RP, Theunissen EL, Schneider E, Moeller MR. Highpotency marijuana impairs executive function and inhibitory motor control. Neuropsychopharmacology 2006 Oct; 31(10):2296–303. E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53790 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules Ramaekers JG, Kauert G, Theunissen EL, Toennes SW., Moeller MR. Neurocognitive performance during acute THC intoxication in heavy and occasional cannabis users. J.Psychopharmacol. 2009 May; 23(3):266–77. Ramaekers JG, Moeller MR, van Ruitenbeek P, Theunissen EL, Schneider E, Kauert G. Cognition and motor control as a function of D9-THC concentration in serum and oral fluid: Limits of impairment. Drug and Alcohol Dependence. 2006; 85:1114–122. ‘‘Rescheduling of the Food and Drug Administration Approved Product Containing Synthetic Dronabinol [(–)-delta 9-(trans)-Tetrahydrocannabinol] in Sesame Oil and Encapsulated in Soft Gelatin Capsules From Schedule II to Schedule III; Final Rule,’’ 64 Federal Register 127 (2 July 1999), pp.35928–35930. Riggs PK, Vaida F, Rossi SS, Sorkin LS, Gouaux B, Grant I, Ellis RJ. A pilot study of the effects of cannabis on appetite hormones in HIV-infected adult men. Brain Res 2012 Jan 11; 1431:46–52. Rodriguez de Fonseca F, Gorriti, M.A., Fernandez-Ruiz, J.J., Palomo, T., Ramos, J.A. Downregulation of rat brain cannabinoid binding sites after chronic delta 9-tetrahydrocannabinoil treatment. Phamacol. Biochem. Behav. 1994, 47 (1), 33–40. Roth MD, Tashkin DP, Whittaker KM, Choi R, Baldwin GC. Tetrahydrocannabinol suppresses immune function and enhances HIV replication in the huPBL–SCID mouse. Life Sci. 2005 Aug 19; 77(14):1711–22. Russo EB. Taming THC: Potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011 Aug; 163(7):1344–64. Sarfaraz S, Afaq F, Adhami VM, Mukhtar H. Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cancer Res. 2005 Mar 1; 65(5):1635–41. Sanudo-Peria M.C., Tsou, K., Delay, E.R., Hohman, A.G., Force, M., Walker, J.M. Endogenous cannabinoids as an aversive or counter-rewarding system in the rat. Neurosci. Lett., 223, 125–128, 1997. Scherrer JF, Grant JD, Duncan AE, Sartor CE, Haber JR, Jacob T, Bucholz KK. Subjective effects to cannabis are associated with use, abuse and dependence after adjusting for genetic and environmental influences. Drug Alcohol Depend. 2009 Nov 1; 105(1– 2):76–82. Schiffman J, Nakamura B, Earleywine Mj LaBrie J. Symptoms of schizotypy precede cannabis use. Psychiatry Res. 2005 Mar 30; 134(1):37–42. Schreiner AM, Dunn ME. Residual effects of cannabis use on neurocognitive performance after prolonged abstinence: A meta-analysis. Exp.Clin Psychopharmacol. 2012 Oct; 20(5):420–9. Sidney S. Cardiovascular consequences of marijuana use. J Clin Pharmacol. 2002 Nov; 42(11 Suppl):64S–70S. Solowij N, Stephens RS, Roffman RA, Babor T, Kadden R, Miller M, Christiansen K, McRee B, Vendetti J; Marijuana Treatment Project Research Group. Cognitive functioning of long-term heavy cannabis users seeking treatment. JAMA. 2002 Mar 6; 287(9): 1123–31. VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 Stirling J, Lewis S, Hopkins R, White C. Cannabis use prior to first onset psychosis predicts spared neurocognition at 10-year follow-up. Schizophr Res. 2005 Jun 1; 75(1):135–7. Substance Abuse and Mental Health Services Administration, Drug Abuse Warning Network, 2011: National Estimates of DrugRelated Emergency Department Visits. HHS Publication No. (SMA) 13–4760, DAWN Series D–39. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013. Substance Abuse and Mental Health Services Administration, Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H–46, HHS Publication No. (SMA) 13–4795. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. Treatment Episode Data Set (FEDS): 2001–2011. National Admissions to Substance Abuse Treatment Services. BHSIS Series S–65, HHS Publication No. (SMA) 13–4772. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013. Tait RJ, Mackinnon A, Christensen H. Cannabis use and cognitive function: 8year trajectory in a young adult cohort. Addiction 2011 Dec; 106(12):2195–203. Tanasescu R, Constantinescu CS. Cannabinoids and the immune system: An overview. Immunobiology. 2010 Aug; 215(8):588–97. Tanda G, Munzar P, Goldberg SR. Selfadministration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys. Nat Neurosci. 2000 Nov; 3(11):1073–4. Tashkin DP. Smoked marijuana as a cause of lung injury. Monaldi Arch Chest Dis. 2005 Jun; 63(2):93–l00. Tashkin DP, Shapiro BJ, and Frank IM. 1974. Acute effects of smoked marijuana and oral delta9-tetrahydrocannabinol on specific airway conductance in asthmatic subjects. The American review of respiratory disease 109 (4): 420–428. Tashkin, DP, Zhang, ZF, Greenland, S, Cozen, W, Mack, TM, Morgenstern, H. Marijuana Use and Lung Cancer: Results of a Case-Control Study. Abstract #A 777, American Thoracic Society meeting, May 24, 2006. The Plant List (2010). Version 1. Published on the Internet; http:// www.theplantlist.org/ (accessed September 20, 2013) Theunissen EL, Kauert GF, Toennes SW., Moeller MR, Sambeth A, Blanchard MM, Ramaekers JG. Neurophysiological functioning of occasional and heavy cannabis users during THC intoxication. Psychopharmacology (Berl.) 2012 Mar;220(2):341–50. Trabert B, Sigurdson AJ, Sweeney AM, Strom SS, McGlynn KA. Marijuana use and testicular germ cell tumors. Cancer. 2011 Feb 15; 117: 848–853. Twitchell W, Brown S, Mackie K. Cannabinoids inhibit N- and P/Q-type PO 00000 Frm 00104 Fmt 4701 Sfmt 4702 calcium channels in cultured rat hippocampal neurons. J Neurophysiol. 1997 Jul; 78(1):43–50. van der Meer FJ, Velthorst E, Meijer CJ, Machielsen MW, de HL. Cannabis use in patients at clinical high risk of psychosis: impact on prodromal symptoms and transition to psychosis. Curr Pharm Des. 2012; 18(32):5036–44. van Gastel WA, Wigman JT, Monshouwer K, Kahn RS, van OJ, Boks MP, Vollebergh WA. Cannabis use and subclinical positive psychotic experiences in early adolescence: findings from a Dutch survey. Addiction 2012 Feb; 107(2):381–7. Van Gundy K, Rebellon CJ. A Life-course Perspective on the ‘‘Gateway Hypothesis.’’ J Health Soc Behav. 2010 Sep; 51(3):244– 59. van Os J, Bak M, Hanssen M, Bijl RV, de Graaf R, Verdoux H. Cannabis use and psychosis: a longitudinal population-based study. Am J Epidemiol. 2002 Aug 15; 156(4):319–27. Vandrey RG, Budney AJ, Moore BA, Hughes JR. A cross-study comparison of cannabis and tobacco withdrawal. Am J Addict. 2005 Jan-Feb; 14(1):54–63. Vandrey RG, Budney AJ, Hughes JR, Liguori A. A within-subject comparison of withdrawal symptoms during abstinence from cannabis, tobacco, and both substances. Drug Alcohol Depend. 2008 Jan 1; 92(1–3):48–54. Vann RE, Gamage TF, Warner JA, Marshall EM, Taylor NL, Martin BR, Wiley JL. Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Delta(9) tetrahydrocannabinol. Drug Alcohol.Depend. 2008 Apr 1; 94(1–3):191– 8. Vanyukov MM, Tarter RE, Kirillova GP, Kirisci L, Reynolds MD, Kreek MJ, Conway KP, Maher BS, Iacono WG, Bierut L, Neale MC, Clark DB, Ridenour TA. Common liability to addiction and ‘‘gateway hypothesis’’: theoretical, empirical and evolutionary perspective’. Drug Alcohol Depend. 2012 Jun; 123 Suppl 1:S3–17 von Sydow K, Lieb R, Pfister H, Hofler M, Wittchen HU.What predicts incident use of cannabis and progression to abuse and dependence? A 4-year prospective examination of risk factors in a community sample of adolescents and young adults. Drug Alcohol Depend. 2002 Sep 1; 68(1):49–64. Wachtel SR, ElSohly MA, Ross SA, Ambre J, de Wit H. Comparison of the subjective effects of Delta (9)-tetrahydrocannabinol and marijuana in humans. Psychopharmacology (Berl). 2002 Jun; 161(4):331–9. Wagner JA, Varga K, Kunos G. Cardiovascular actions of cannabinoids and their generation during shock. J Mol Med. 1998 Nov-Dec; 76(12):824–36. Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, Gamsa A, Bennett GJ, and Collet JP. 2010. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ: Canadian Medical Association journal =journal de !’Association medicate canadienne 182(14): E694–E701. E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules mstockstill on DSK3G9T082PROD with PROPOSALS2 Wesson DR, Washburn P. Current patterns of drug abuse that involve smoking. NIDA. Res. Monogr. 1990; 99:5–11. Wiley JL, Barrett RL, Britt DT, Balster RL, Martin BR. Discriminative stimulus effects of delta 9-tetrahydrocannabinol and delta 9–11-tetrahydrocannabinol in rats and rhesus monkeys. Neuropharmacology. 1993 Apr; 32(4):359–65. Wiley JL, Huffman JW, Balster RL, Martin BR. Pharmacological specificity of the discriminative stimulus effects of delta 9tetrahydrocannabinol in rhesus monkeys. Drug Alcohol Depend. 1995 Nov; 40(1):81– 6. Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, and Donaghe H. 2013. Low-Dose Vaporized Cannabis Significantly Improves Neuropathic Pain. The journal of pain: official journal of the American Pain Society. Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B, and Fishman S. 2008. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. The journal of pain: official journal of the American Pain Society 9 (6): 506–521. Wu X, French ED. Effects of chronic delta9tetrahydrocannabinol on rat midbrain dopamine neurons: an electrophysiological assessment. Neuropharmacology. 2000 Jan 28; 39(3):391–8. Yucel M, Bora E, Lubman DI, Solowij N, Brewer WJ, Cotton SM, Conus P, Takagi MJ, Fomito A, Wood SJ, et al. The impact of cannabis use on cognitive functioning in patients with schizophrenia: a metaanalysis of existing findings and new data in a first-episode sample. Schizophr.Bull. 2012 Mar; 38(2):316–30. Zeiger JS, Haberstick BC, Corley RP, Ehringer MA, Crowley TJ, Hewitt JK, Hopfer CJ, Stallings MC, Young SE., Rhee SH. Subjective effects to marijuana associated with marijuana use in community and clinical subjects. Drug Alcohol Depend. 2010 Jun 1; 109(1–3):161–6. Zhang ZF, Morgenstern H, Spitz MR, Tashkin DP, Yu GP, Marshall JR, Hsu TC, Schantz SP. Marijuana use and increased risk of squamous cell carcinoma of the head and neck. Cancer Epidemiol Biomarkers Prev. 1999 Dec;8(12): 1071–8. Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of cannabidiol on the anxiety and other effects produced by delta 9–THC in normal subjects. Psychopharmacology (Berl.)1982; 76(3):245–50. The Medical Application of Marijuana: A Review of Published Clinical Studies March 19, 2015 Prepared by: U.S. Food and Drug Administration Center for Drug Evaluation and Research (FDA/CDER) Controlled Substance Staff (CSS) TABLE OF CONTENTS 1. Introduction ............................................................................................................................................................................................ 2. Methods .................................................................................................................................................................................................. 2.1 Define the Objective of the Review .............................................................................................................................................. 2.2 Define ‘‘Marijuana’’ ....................................................................................................................................................................... 2.3 Define ‘‘Adequate and Well-Controlled Clinical Studies’’ ......................................................................................................... 2.4 Search Medical Literature Databases and Identify Relevant Studies ........................................................................................ 2.5 Review and Analyze Qualifying Clinical Studies ....................................................................................................................... 3. Results and Discussion .......................................................................................................................................................................... 3.1 Neuropathic Pain .......................................................................................................................................................................... 3.1.1 Neuropathic Pain Associated with HIV-Sensory Neuropathy ......................................................................................... 3.1.2 Central and Peripheral Neuropathic Pain ......................................................................................................................... 3.2 Appetite Stimulation in HIV ........................................................................................................................................................ 3.3 Spasticity in Multiple Sclerosis ................................................................................................................................................... 3.4 Asthma ........................................................................................................................................................................................... 3.5 Glaucoma ....................................................................................................................................................................................... 3.6 Conclusions ................................................................................................................................................................................... 3.6.1 Conclusions for Chronic Neuropathic Pain ....................................................................................................................... 3.6.2 Conclusions for Appetite Stimulation in HIV ................................................................................................................... 3.6.3 Conclusions for Spasticity in MS ...................................................................................................................................... 3.6.4 Conclusions for Asthma ..................................................................................................................................................... 3.6.5 Conclusions for Glaucoma ................................................................................................................................................. 3.7 Design Challenges for Future Studies .......................................................................................................................................... 3.7.1 Sample Size ......................................................................................................................................................................... 3.7.2 Marijuana Dose Standardization ........................................................................................................................................ 3.7.3 Acute vs. Chronic Therapeutic Marijuana Use ................................................................................................................. 3.7.4 Smoking as a Route of Administration .............................................................................................................................. 3.7.5 Difficulty in Blinding of Drug Conditions ......................................................................................................................... 3.7.6 Prior Marijuana Experience ................................................................................................................................................ 3.7.7 Inclusion and Exclusion Criteria ....................................................................................................................................... 3.7.8 Number of Female Subjects ............................................................................................................................................... Appendix (Tables) ...................................................................................................................................................................................... List of Figure Figure 1: Identification of Studies From PubMed Search ....................................................................................................................... List of Tables Table 1: Randomized, controlled, double-blind trials examining smoked marijuana in treatment of neuropathic pain ................... Table 2: Randomized, controlled, double-blind trials examining smoked marijuana in treatment of appetite stimulation in HIV/ AIDS ......................................................................................................................................................................................................... Table 3: Randomized, controlled, double-blind trails examining smoked marijuana in treatment of spasticity in Multiple Sclerosis .......................................................................................................................................................................................................... Table 4: Randomized, controlled, double-blind trails examining smoked marijuana in treatment of intraocular pressure in Glaucoma ......................................................................................................................................................................................................... Table 5: Randomized, controlled, double-blind trails examining smoked marijuana in treatment of asthma .................................... Executive Summary Marijuana is a Schedule I substance under the Controlled Substances Act (CSA). Schedule I indicates a high potential for abuse, no currently VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 accepted medical use in the United States, and a lack of accepted safety for use under medical supervision. To date, marijuana has not been subject to an approved new drug application (NDA) PO 00000 Frm 00105 Fmt 4701 Sfmt 4702 53791 71 73 73 74 74 75 77 77 77 77 81 86 89 90 91 91 92 92 92 93 93 93 93 94 96 96 96 97 98 99 103 76 103 109 112 114 116 that demonstrates its safety and efficacy for a specific indication under the Food Drug and Cosmetic Act (FDCA). Nevertheless, as of October 2014, twenty-three states and the District of E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53792 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules Columbia have passed state-level medical marijuana laws that allow for marijuana use within that state; similar bills are pending in other states. The present review was undertaken by the Food and Drug Administration (FDA) to analyze the clinical studies published in the medical literature investigating the use of marijuana in any therapeutic areas. First, we discuss the context for this scientific review. Next, we describe the methods used in this review to identify adequate and wellcontrolled studies evaluating the safety and efficacy of marijuana for particular therapeutic uses. The FDA conducted a systematic search for published studies in the medical literature that meet the described criteria for study design and outcome measures prior to February 2013. While not part of our systematic review, we have continued to routinely follow the literature beyond that date for subsequent studies. Studies were considered to be relevant to this review if the investigators administered marijuana to patients with a diagnosed medical condition in a well-controlled, double-blind, placebo-controlled clinical trial. Of the eleven studies that met the criteria for review, five different therapeutic areas were investigated: • Five studies examined chronic neuropathic pain • Two studies examined appetite stimulation in human immunodeficiency virus (HIV) patients • Two studies examined glaucoma • One study examined spasticity and pain in multiple sclerosis (MS) • One study examined asthma. For each of these eleven clinical studies, information is provided regarding the subjects studied, the drug conditions tested (including dose and method of administration), other drugs used by subjects during the study, the physiological and subjective measures collected, the outcome of these measures comparing treatment with marijuana to placebo, and the reported and observed adverse events. The conclusions drawn by the investigators are then described, along with potential limitations of these conclusions based on the study design. A brief summary of each study’s findings and limitations is provided at the end of the section. The eleven clinical studies that met the criteria and were evaluated in this review showed positive signals that marijuana may produce a desirable therapeutic outcome, under the specific experimental conditions tested. Notably, it is beyond the scope of this review to determine whether these data VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 demonstrate that marijuana has a currently accepted medical use in the United States. However, this review concludes that these eleven clinical studies serve as proof-of-concept studies, based on the limitations of their study designs, as described in the study summaries. Proof-of-concept studies provide preliminary evidence on a proposed hypothesis regarding a drug’s effect. For drugs under development, the effect often relates to a short-term clinical outcome being investigated. Proof-of-concept studies serve as the link between preclinical studies and dose ranging clinical studies. Therefore, proof-of-concept studies are not sufficient to demonstrate efficacy of a drug because they provide only preliminary information about the effects of a drug. However, the studies reviewed produced positive results, suggesting marijuana should be further evaluated as an adjunct treatment for neuropathic pain, appetite stimulation in HIV patients, and spasticity in MS patients. The main limitations identified in the eleven studies testing the medical applications of marijuana are listed below: • The small numbers of subjects enrolled in the studies, which limits the statistical analyses of safety and efficacy. • The evaluation of marijuana only after acute administration in the studies, which limits the ability to determine efficacy following chronic administration. • The administration of marijuana typically through smoking, which exposes ill patients to combusted material and introduces problems with determining the doses delivered. • The potential for subjects to identify whether they received marijuana or placebo, which breaks the blind of the studies. • The small number of cannabinoid ¨ naıve subjects, which limits the ability to determine safety and tolerability in these subjects. • The low number of female subjects, which makes it difficult to generalize the study findings to subjects of both genders. Thus, this review discusses the following methodological changes that may be made in order to resolve these limitations and improve the design of future studies which examine the safety and efficacy of marijuana for specific therapeutic indications: • Determine the appropriate number of subjects studied based on recommendations in various FDA Guidances for Industry regarding the PO 00000 Frm 00106 Fmt 4701 Sfmt 4702 conduct of clinical trials for specific medical indications. • Administer consistent and reproducible doses of marijuana based on recommendations in the FDA Guidance for Industry: Botanical Drug Products (2004).27 • Evaluate the effects of marijuana under therapeutic conditions following both acute and chronic administration. • Consider alternatives to smoked marijuana (e.g., vaporization). • Address and improve whenever possible the difficulty in blinding of marijuana and placebo treatments in clinical studies. • Evaluate the effect of prior experience with marijuana with regard to the safety and tolerability of marijuana. • Strive for gender balance in the subjects used in studies. In conclusion, the eleven clinical studies conducted to date do not meet the criteria required by the FDA to determine if marijuana is safe and effective in specific therapeutic areas. However, the studies can serve as proofof-concept studies and support further research into the use of marijuana in these therapeutic indications. Additionally, the clinical outcome data and adverse event profiles reported in these published studies can beneficially inform how future research in this area is conducted. Finally, application of the recommendations listed above by investigators when designing future studies could greatly improve the available clinical data that can be used to determine if marijuana has validated and reliable medical applications. 1. Introduction In response to citizen petitions submitted to the Drug Enforcement Administration (DEA) requesting DEA to reschedule marijuana, the DEA Administrator requested that the U.S. Department of Health and Human Services (HHS) provide a scientific and medical evaluation of the available information and a scheduling recommendation for marijuana, in accordance with 21 U.S.C. 811(b). The Secretary of HHS is required to consider in a scientific and medical evaluation eight factors determinative of control under the Controlled Substance Act (CSA). Administrative responsibilities for evaluating a substance for control under the CSA are performed by the Food and Drug Administration (FDA), with the concurrence of the National Institute on Drug Abuse (NIDA). Part of 27 This Guidance is available on the internet at http://www.fda.gov/Drugs/default.htm under Guidance (Drugs). E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules this evaluation includes an assessment of whether marijuana has a currently accepted medical use in the United States. This assessment necessitated a review of the available data from published clinical studies to determine whether there is adequate scientific evidence of marijuana’s effectiveness. Under Section 202 of the CSA, marijuana is currently controlled as a Schedule I substance (21 U.S.C. 812). Schedule I includes those substances that have a high potential for abuse, have no currently accepted medical use in treatment in the United States, and lack accepted safety for use under medical supervision (21 U.S.C. 812(b)(1)(A)–(C)). A drug product which has been approved by FDA for marketing in the United States is considered to have a ‘‘currently accepted medical use.’’ Marijuana is not an FDA-approved drug product, as a New Drug Application (NDA) or Biologics License application (BLA) for marijuana has not been approved by FDA. However, FDA approval of an NDA is not the only means through which a drug can have a currently accepted medical use in the United States. In general, a drug may have a ‘‘currently accepted medical use’’ in the United States if the drug meets a fivepart test. Established case law (Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994)) upheld the Administrator of DEA’s application of the five-part test to determine whether a drug has a ‘‘currently accepted medical use.’’ The following describes the five elements that characterize ‘‘currently accepted medical use’’ for a drug: 28 i. The drug’s chemistry must be known and reproducible ‘‘The substance’s chemistry must be scientifically established to permit it to be reproduced into dosages which can be standardized. The listing of the substance in a current edition of one of the official compendia, as defined by section 201(j) of the Food, Drug and Cosmetic Act, 21 U.S.C. 321(j), is sufficient to meet this requirement.’’ ii. there must be adequate safety studies ‘‘There must be adequate pharmacological and toxicological studies, done by all methods reasonably applicable, on the basis of which it could fairly and responsibly be concluded, by experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, that the substance is safe for treating a specific, recognized disorder.’’ 28 57 FR 10499, 10504–06 (March 26, 1992). VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 iii. there must be adequate and wellcontrolled studies proving efficacy ‘‘There must be adequate, wellcontrolled, well-designed, wellconducted, and well-documented studies, including clinical investigations, by experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, on the basis of which it could be fairly and responsibly concluded by such experts that the substance will have the intended effect in treating a specific, recognized disorder.’’ iv. the drug must be accepted by qualified experts ‘‘The drug has a New Drug Application (NDA) approved by the Food and Drug Administration, pursuant to the Food, Drug and Cosmetic Act, 21 U.S.C. 355. Or, a consensus of the national community of experts, qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, accepts the safety and effectiveness of the substance for use in treating a specific, recognized disorder. A material conflict of opinion among experts precludes a finding of consensus.’’ and v. the scientific evidence must be widely available. ‘‘In the absence of NDA approval, information concerning the chemistry, pharmacology, toxicology, and effectiveness of the substance must be reported, published, or otherwise widely available, in sufficient detail to permit experts, qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, to fairly and responsibly conclude the substance is safe and effective for use in treating a specific, recognized disorder.’’ One way to pass the five-part test for having ‘‘currently accepted medical use’’ is through submission of an NDA or BLA which is approved by FDA. However, FDA approval of an NDA or BLA is not required for a drug to pass the five-part test. This review focuses on FDA’s analysis of one element of the five-part test for determining whether a drug has ‘‘currently accepted medical use’’. Specifically, the present review assesses the 3rd criterion that addresses whether marijuana has ‘‘adequate and wellcontrolled studies proving efficacy’’. Thus, this review evaluates published clinical studies that have been conducted using marijuana in subjects who have a variety of medical conditions by assessing the adequacy of the summarized study designs and the study data. The methodology for selecting the studies that were evaluated is delineated below. PO 00000 Frm 00107 Fmt 4701 Sfmt 4702 53793 FDA’s evaluation and conclusions regarding the remaining four criteria for whether marijuana has a ‘‘currently accepted medical use,’’ as well as the eight factors pertaining to the scheduling of marijuana, are outside the scope of this review. A detailed discussion of these factors is contained in FDA’s scientific and medical evaluation of marijuana. 2. Methods The methods for selecting the studies to include in this review involved the following steps, which are described in detail in the subsections below: 1. Define the objective of the review. 2. Define ‘‘marijuana’’ in order to facilitate the medical literature search for studies that administered the substance, 3. Define ‘‘adequate and wellcontrolled studies’’ in order to facilitate the search for relevant data and literature, 4. Search medical literature databases and identify relevant adequate and wellcontrolled studies, and 5. Review and analyze the adequate and well-controlled clinical studies to determine if they demonstrate efficacy of marijuana for any therapeutic indication. 2.1 Define the Objective of the Review The objective of this review is to assess the study designs and resulting data from clinical studies published in the medical literature that were conducted with marijuana (as defined below) as a treatment for any therapeutic indication, in order to determine if they meet the criteria of ‘‘adequate and well-controlled studies proving efficacy’’. 2.2 Define ‘‘Marijuana’’ In this review, the term ‘‘marijuana’’ refers to the flowering tops or leaves of the Cannabis plant. There were no restrictions on the route of administration used for marijuana in the studies. Studies which administered individual cannabinoids (whether experimental substances or marketed drug products) or marijuana extracts were excluded from this review. Additionally, studies of administered neutral plant material or placebo marijuana (marijuana with all cannabinoids extracted) that had subsequently been supplemented by the addition of specific amounts of THC or other cannabinoids were also excluded (Chang et al., 1979). E:\FR\FM\12AUP2.SGM 12AUP2 53794 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 2.3 Define ‘‘Adequate and WellControlled Clinical Studies’’ mstockstill on DSK3G9T082PROD with PROPOSALS2 The criteria for an ‘‘adequate and well-controlled study’’ for purposes of determining the safety and efficacy of a human drug is defined under the Code of Federal Regulations (CFR) in 21 CFR 314.126. The elements of an adequate and well-controlled study as described in 21 CFR 314.126 can be summarized as follows: 1. The main objective must be to assess a therapeutically relevant outcome. 2. The study must be placebocontrolled. 3. The subjects must qualify as having the medical condition being studied. 4. The study design permits a valid comparison with an appropriate control condition. 5. The assignment of subjects to treatment and control groups must be randomized. 6. There is minimization of bias through the use of a double-blind study design. 7. The study report contains a full protocol and primary data. 8. Analysis of the study data is appropriately conducted. As noted above, the current review examines only those data available in the public domain and thus relies on clinical studies published in the medical literature. Published studies by their nature are summaries that do not include the level of detail required by studies submitted to FDA in an NDA. While the majority of the elements defining an adequate and wellcontrolled study can be satisfied through a published paper (elements #1–6), there are two elements that cannot be met by a study published in the medical literature: element #7 (availability of a study report with full VerDate Sep<11>2014 21:44 Aug 11, 2016 Jkt 238001 protocol and primary data) and element #8 (a determination of whether the data analysis was appropriate). Thus, for purposes of this review, only elements #1–6 will be used to qualify a study as being adequate and well-controlled. 2.4 Search Medical Literature Databases and Identify Relevant Studies We identified randomized, doubleblind, placebo-controlled clinical studies conducted with marijuana to assess marijuana’s efficacy in any therapeutic indication. Two primary medical literature databases were searched for all studies posted to the databases prior to February 2013: 29 • PubMed: PubMed is a database of published medical and scientific studies that is maintained by the U.S. National Library of Medicine (NLM) at NIH as a part of the Entrez system of information retrieval. PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books (http:// www.ncbi.nlm.nih.gov/pubmed). • ClinicalTrials.gov: ClinicalTrials.gov is a database of publicly and privately supported clinical studies that is maintained by the NLM. Information about the clinical studies is provided by the Sponsor or Principal Investigator of the study. Information about the studies is submitted to the Web site (‘‘registered’’) when the studies begin, and is updated throughout the study. In some cases, results of the study or resulting publication citations are submitted to the Web site after the study ends 29 While not a systematic review, we have followed the recent published literature on marijuana use for possible therapeutic purposes and, as of January 2015, we found only one new study that would meet our criteria (Naftali et al., 2013). This study examined the effects of smoked marijuana on Crohn’s disease. PO 00000 Frm 00108 Fmt 4701 Sfmt 4702 (https://clinicaltrials.gov/ct2/about-site/ background). ClinicalTrials.gov was searched for all studies administering marijuana. The results of this search were used to confirm that no completed studies with published data were missed in the literature search. During the literature search, references found in relevant studies and systematic reviews were evaluated for additional relevant citations. All languages were included in the search. The PubMed search yielded a total of 566 abstracts.30 Of these abstracts, a full-text review was conducted with 85 papers to assess eligibility. From this evaluation, only eleven of 85 studies met the 6 CFR elements for inclusion as adequate and well-controlled studies. Figure 1 (below) provides an overview of the process used to identify studies from the PubMed search. The eleven studies reviewed were published between 1974 and 2013. Ten of these studies were conducted in the United States and one study was conducted in Canada. These eleven studies examined the effects of smoked and vaporized marijuana for the indications of chronic neuropathic pain, spasticity related to multiple sclerosis (MS), appetite stimulation in patients with human immunodeficiency virus (HIV), glaucoma, and asthma. All included studies used adult patients as subjects. All studies conducted in the United States were conducted under an IND as Phase 2 investigations. 30 The following search strategy was used, ‘‘(cannabis OR marijuana) AND (therapeutic use OR therapy) AND (RCT OR randomized controlled trial OR ‘‘systematic review’’ OR clinical trial OR clinical trials) NOT (‘‘marijuana abuse’’[Mesh] OR addictive behavior OR substance related disorders)’’. E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 31 In January 1997, the White House Office of National Drug Control Policy (ONDCP) requested that the IOM conduct a review of the scientific evidence to assess the potential health benefits and risks of marijuana and its constituent cannabinoids. Information for this study was gathered through scientific workshops, site visits to cannabis buyers’ clubs and HIV/Acquired Immunodeficiency Syndrome (AIDS) clinics, analysis of the relevant scientific literature, and extensive consultation with biomedical and social scientists. The report was finalized and published in 1999. VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 (Define Adequate and Well-Controlled Clinical Studies), a number of clinical studies that investigated marijuana, as defined in this review, were excluded from this review. Studies that examined the effects of marijuana in healthy subjects were excluded because they did not test a patient population with a medical condition (Flom et al., 1975; Foltin et al., 1986; Foltin et al., 1988; Hill et al., 1974; Milstein et al., 1974; Milstein et al., 1975; Soderpalm et al., 2001; Wallace et al., 2007; Greenwald and Stitzer, 2000). A 1975 study by Tashkin et al. was excluded because it had a single-blind, rather than doubleblind, study design. Two other studies were excluded because the primary outcome measure assessed safety rather than a therapeutic outcome (Greenberg et al., 1994; Abrams et al., 2003). 2.5 Review and Analyze Qualifying Clinical Studies Qualified clinical studies that evaluated marijuana for therapeutic purposes were examined in terms of adequacy of study design including method of drug administration, study PO 00000 Frm 00109 Fmt 4701 Sfmt 4702 size, and subject inclusion and exclusion criteria. Additionally, the measures and methods of analysis used in the studies to assess the treatment effect were examined. 3. Results and Discussion The eleven qualifying studies in this review assessed a variety of therapeutic indications. In order to better facilitate analysis and discussion of the studies, the following sections group the studies by therapeutic area. Within each section, each individual study is summarized in terms of its design, outcome data and important limitations. This information is also provided in the Appendix in tabular form for each study. 3.1 Neuropathic Pain Five randomized, double-blind, placebo-controlled Phase 2 clinical studies have been conducted to examine the effects of inhaled marijuana smoke on neuropathic pain associated with HIV-sensory neuropathy (Abrams et al., 2007; Ellis et al., 2009) and chronic neuropathic pain from multiple causes E:\FR\FM\12AUP2.SGM 12AUP2 EP12AU16.025</GPH> mstockstill on DSK3G9T082PROD with PROPOSALS2 Two qualifying studies, which assessed marijuana for glaucoma, were previously reviewed in the 1999 Institute of Medicine (IOM) report entitled ‘‘Marijuana and Medicine: Assessing the Science Base’’.31 We did our own analysis of these two studies and concurred with the conclusions in the IOM report. Thus, a detailed discussion of the two glaucoma studies is not included in the present review. The present review only discusses 9 of the identified 11 studies. For a summary of the study design for all eleven qualifying studies, see Tables 1–5 (located in the Appendix). Based on the selection criteria for relevant studies described in Section 2.3 53795 53796 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules mstockstill on DSK3G9T082PROD with PROPOSALS2 (Wilsey et al., 2008; Ware et al., 2010; Wilsey et al., 2013). Table 1 of the Appendix summarizes these studies. 3.1.1 Neuropathic Pain Associated With HIV-Sensory Neuropathy Two studies examined the effect of marijuana to reduce the pain induced by HIV-sensory neuropathy. Abrams et al. (2007) conducted the first study entitled, ‘‘Cannabis in painful HIV-associated sensory neuropathy: A randomized placebo-controlled trial’’. The subjects were 50 adult patients with uncontrolled HIV-associated sensory neuropathy, who had at least 6 experiences with smoking marijuana. The subjects were split into two parallel groups of 25 subjects each. More than 68% of subjects were current marijuana users, but all individuals were required to discontinue using marijuana prior to the study. Most subjects were taking medication for pain during the study, with the most common medications being opioids and gabapentin. Upon entry into the study, subjects had an average daily pain score of at least 30 on a 0–100 visual analog scale (VAS). Subjects were randomized to receive either smoked marijuana (3.56% THC 32) or smoked placebo cigarettes three times per day for 5 days, using a standardized cued smoking procedure: (1) 5 second inhale, (2) 10 second holding smoke in the lungs, (3) 40 second exhale and breathing normally between puffs. The authors did not specify how many puffs the subjects smoked at each smoking session, but they stated that one cigarette was smoked per smoking session. Primary outcome measures included daily VAS ratings of chronic pain and the percentage of subjects who reported a result of more than 30% reduction in pain intensity. The ability of smoked marijuana to induce acute analgesia was assessed using both thermal heat model and capsaicin sensitization model, while anti-hyperalgesia was assessed with brush and von Frey hair stimuli. The immediate analgesic effects of smoked marijuana was assessed using a 0–100 point VAS at 40-minute intervals three times before and three times after the first and last smoking sessions, which was done to correspond to the time of peak plasma cannabinoid levels. Notably, not all subjects completed the induced pain portion of the study (n = 11 in marijuana group, 9 in placebo 32 The drug dose is reported as percentage of THC present in the marijuana rather than milligrams of THC present in each cigarette because of the difficulty in determining the amount of THC delivered by inhalation (see discussion in the section entitled ‘‘3.7.2 Marijuana Dose Standardization’’). VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 group) because of their inability to tolerate the stimuli. Throughout the study, subjects also completed the Profile of Mood States (POMS) questionnaire, as well as subjective VAS measures of anxiety, sedation, disorientation, paranoia, confusion, dizziness, and nausea. As a result, the median daily pain was reduced 34% by smoked marijuana compared to 17% by placebo (p = 0.03). Fifty-two percent of subjects who smoked marijuana reported a >30% reduction in pain compared to 24% in the placebo group (p = 0.04). Although marijuana reduced experimentallyinduced hyperalgesia (p ≤ 0.05) during the first smoking sessions, marijuana did not alter responses to acutely painful stimuli. There were no serious AEs and no episodes of hypertension, hypotension, or tachycardia requiring medical intervention. No subjects withdrew from the study for drug related reasons. Subjects in the marijuana group reported higher ratings on the subjective measures of anxiety, sedation, disorientation, confusion, and dizziness compared to the placebo group. There was one case of severe dizziness in a marijuana-treated subject. By the end of the study, subjects treated with marijuana and placebo reported a reduction in total mood disturbance as measured by POMS. The authors conclude that smoked marijuana effectively reduced chronic neuropathic pain from HIV-associated sensory neuropathy with tolerable side effects. However, limitations of this study include: Maintenance of subjects on other analgesic medication while being tested with marijuana and a lack of information about the number of puffs during each inhalation of smoke. These limitations make it difficult to conclude that marijuana has analgesic properties on its own and that the actual AEs experienced during the study in response to marijuana are tolerable. However, the study produced positive results suggesting that marijuana should be studied further as an adjunct treatment for uncontrolled HIVassociated sensory neuropathy. Ellis et al. (2009) conducted a more recent study entitled ‘‘Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial’’. The subjects were 28 HIVpositive adult male patients with intractable neuropathic pain that was refractory to the effects of at least two drugs taken for analgesic purposes. Upon entry into the study, subjects had a mean score of >5 on the Pain Intensity subscale of the Descriptor Differential Scale (DDS). Subjects were allowed to PO 00000 Frm 00110 Fmt 4701 Sfmt 4702 continue taking their current routine of pain medications, which included opioids, non-narcotic analgesics, antidepressants, and anticonvulsants. Previous experience with marijuana was not required for participation in the study, but 27 of 28 subjects (96%) reported previous experience with marijuana. However, of these 27 experienced subjects, 63% (n = 18) reported no marijuana use within the past year. The study procedures compared the effects of the target dose of marijuana and placebo during two treatment periods lasting 5 days, with 2 weeks washout periods. The marijuana strengths available were 1%, 2%, 4%, 6%, or 8% THC concentration by weight. Subjects smoked marijuana or placebo cigarettes four times per day, approximately 90–120 minutes apart, using a standardized cued smoking procedure: (1) 5 second smoke inhalation, (2) 10 second hold of smoke in lungs, (3) 40 second exhale and normal breathing between puffs. The investigators did not provide a description of the number of puffs taken at any smoking session. All subjects practiced the smoking procedures using placebo marijuana prior to test sessions. On the first day of each test period, dose titration occurred throughout the four smoking sessions scheduled for that day, with a starting strength of 4% THC concentration. Subjects were allowed to titrate to a personalized ‘‘target dose’’, which was defined as the dose that provided the best pain relief without intolerable adverse effects. This dose titration was accomplished by allowing subjects to either increase the dose incrementally (to 6% or 8% THC) to improve analgesia, or to decrease the dose incrementally (to 1% or 2% THC) if AEs were intolerable. For the next 4 days of each test period, the subjects smoked their target dose during each of the four daily smoking sessions. To maintain the blind, placebo marijuana was represented as containing 1%–8% THC, even though it did not contain any cannabinoids. The primary outcome measure was the change in pain magnitude on the DDS at the end of each test period compared to baseline, with a clinically significant level of analgesia considered to be a reduction in pain of at least 30%. Additional measures included the POMS, the Sickness Impact Profile (SIP), the Brief Symptom Inventory (BSI) and the UKU Side Effect Rating Scale and a subjective highness/ sedation VAS. During the marijuana treatment week, 19 subjects titrated to the 2%–4% THC dose while the 6%–8% dose was E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules mstockstill on DSK3G9T082PROD with PROPOSALS2 preferred by 8 subjects and 1 subject chose the 1% dose. In contrast, during the placebo treatment week, all 28 subjects titrated to the highest possible dose of ‘‘8% THC’’ that contained no actual cannabinoids, suggesting that placebo treatment provided little analgesic relief. The degree of pain reduction was significantly greater after administration of marijuana compared to placebo (median change of 3.3 points on DDS, p = 0.016). The median change from baseline in VAS pain scores was –17 for marijuana treatment compared to –4 for placebo treatment (p < 0.001). A larger proportion of subjects who were treated with marijuana (0.46) reported a >30% reduction in pain, compared to placebo (0.18). Additionally, the authors report improvements in total mood disturbance, physical disability, and quality of life as measured on POMS, SIP, and BSI scales after both placebo and marijuana treatment (data not provided in paper). In terms of safety, there were no alterations in HIV disease parameters in response to marijuana or placebo. The authors report that marijuana led to a greater degree of UKU responses as well as AEs such as difficulty in concentration, fatigue, sleepiness or sedation, increased duration of sleep, reduced salivation and thirst compared to placebo (data not provided in paper). Two subjects withdrew from the study because of marijuana-related AEs: one subject developed an intractable smoking-related cough during marijuana administration and the sole marijuana¨ naıve subject in the study experienced an incident of acute cannabis-induced psychosis.33 The authors conclude that smoked marijuana effectively reduced chronic neuropathic pain from HIV-associated sensory neuropathy. The limitations of this study include: a lack of information about the number of puffs during each inhalation of smoke; a lack of information about the specific timing of the subjective assessments and collection of AEs relative to initiation of the smoking sessions; and the inclusion ¨ of only one marijuana-naıve subject. These limitations make it difficult to conclude that the actual AEs experienced during the study in 33 At the time of the study, the following criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM–IV–TR, 2000) were used to diagnose substance-induced psychotic disorders: Prominent hallucinations or delusions; Hallucinations and/or delusions that develop during, or within one month of, intoxication or withdrawal; The disturbance is not better accounted for by a psychotic disorder that is not substance induced. The disturbance does not occur exclusively during the course of a delirium. VerDate Sep<11>2014 21:44 Aug 11, 2016 Jkt 238001 response to marijuana are tolerable. It is especially concerning that the only ¨ marijuana-naıve subject left the study because of serious psychiatric responses to marijuana exposure at analgesic doses. However, the study produced positive results suggesting that marijuana should be studied further as an adjunct treatment for uncontrolled HIV-associated sensory neuropathy. 3.1.2 Central and Peripheral Neuropathic Pain Three studies examined the effect of marijuana on chronic neuropathic pain. Wilsey et al. (2008) examined chronic neuropathic pain from multiple causes in the study entitled, ‘‘A Randomized, Placebo-Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic Pain’’. The subjects were 32 patients with a variety of neuropathic pain conditions, including 22 with complex regional pain syndrome, 6 with spinal cord injury, 4 with multiple sclerosis, 3 with diabetic neuropathy, 2 with ilioinguinal neuralgia, and 1 with lumbosacral plexopathy. All subjects reported a pain intensity of at least 30 on a 0–100 VAS and were allowed to continue taking their regular medications during the study period, which included opioids, antidepressants, anticonvulsants, and NSAIDs. All subjects were required to have experience with marijuana but could not use any cannabinoids for 30 days before study sessions. The study consisted of three test sessions with an interval of 3–21 days between sessions. Treatment conditions were high-strength marijuana (7% delta9-THC), low-strength marijuana (3.5% delta-9-THC), and placebo cigarettes, administered through a standardized cued-puff procedure: (1) ‘‘light the cigarette’’ (30 seconds), (2) ‘‘get ready’’ (5 seconds), (3) ‘‘inhale’’ (5 seconds), (4) ‘‘hold smoke in lungs’’ (10 seconds), (5) ‘‘exhale,’’ and (6) wait before repeating the puff cycle (40 seconds). Participants took 2 puffs after baseline measurements, 3 puffs an hour later, and 4 puffs an hour after that, for a cumulative dose of 9 puffs per test session. Hourly assessment periods were scheduled before and after each set of puffs and for 2 additional hours during the recovery period. Plasma cannabinoids were measured at baseline, 5 minutes after the first puff and again at 3 hours after the last puff cycle. The primary outcome measure was spontaneous pain relief, as measured by a 0–100 point VAS for current pain. Pain unpleasantness was measured on a 0–100 point VAS, and degree of pain PO 00000 Frm 00111 Fmt 4701 Sfmt 4702 53797 relief was measured on a 7-point Patient Global Impression of Change (PGIC) scale. Secondary measures included the Neuropathic Pain Scale (NPS), a 0–100 point VAS for allodynia, and changes in thermal pain threshold. Subjective measures were also evaluated with unipolar 0–100 point VAS for any drug effect, good drug effect, bad drug effect, high, drunk, impaired, stoned, like the drug effect, sedated, confused, nauseated, desire more of the drug, anxious, down, hungry, and bipolar 0– 100 point VAS for sad/happy, anxious/ relaxed, jittery/calm, bad/good, paranoid/self-assured, fearful/unafraid. Neurocognitive assessments measured attention and concentration, learning and memory, and fine motor speed. Marijuana produced a reduction in pain compared to placebo, as measured by the pain VAS, the PGIC and on pain descriptors in the NPS, including sharp (P < .001), burning (P < .001), aching (P < .001), sensitive (P = .03), superficial (P < .01) and deep pain (P < .001). Notably, there were no additional benefits from the 7% THC strength of marijuana compared to the 3.5% THC strength, seemingly because of cumulative drug effects over time. There were no changes in allodynia or thermal pain responsivity following administration of either dose of marijuana. Marijuana at both strengths produced increases on measures of any drug effect, good drug effect, high, stoned, impairment, sedation, confusion, and hunger. The 7% THC marijuana increased anxiety scores and bad drug effect (later in session) compared to placebo. Neither strength of marijuana affected the measures of mood. On neurocognitive measures, both the 3.5% THC and 7% THC marijuana produced impairment in learning and memory, while only the 7% THC marijuana impaired attention and psychomotor speed, compared to placebo. There were no adverse cardiovascular side effects and no subjects dropped out because of an adverse event related to marijuana. The authors conclude that marijuana may be effective at ameliorating neuropathic pain at doses that induce mild cognitive effects, but that smoking is not an optimum route of administration. The limitations of this study include: Inclusion of subjects with many forms of neuropathic pain and maintenance of subjects on other analgesic medication while being tested with marijuana. These limitations make it difficult to conclude that marijuana has analgesic properties on its own and that the actual AEs experienced during the study in response to marijuana are tolerable. The authors compared pain score results by the type of pain E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53798 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules condition, with no significant differences found; however, the sample size of this study was small thus a type II error may have been present. Thus, it is difficult to determine if any particular subset of neuropathic pain conditions would benefit specifically from marijuana administration. However, the study produced positive results suggesting that marijuana should be studied further as an adjunct treatment for uncontrolled neuropathic pain. The second study, conducted by Ware et al. (2010) in Canada is entitled, ‘‘Smoked cannabis for chronic neuropathic pain: a randomized controlled trial’’. The subjects were 21 adult patients with neuropathic pain caused by trauma or surgery compounded with allodynia or hyperalgesia, and a pain intensity score greater than 4 on a 10 point VAS. All subjects maintained their current analgesic medication and they were allowed to use acetaminophen for breakthrough pain. Eighteen subjects had previous experience with marijuana but none of them had used marijuana within a year before the study. The study design used a four-period crossover design, testing marijuana (2.5%, 6.0% and 9.4% THC) and placebo marijuana. The 2.5% and 6.0% doses of marijuana were included to increase successful blinding. Each period was 14 days in duration, beginning with 5 days on the study drug followed by a 9-day washout period. Doses were delivered as 25 mg of marijuana that was smoked in a single inhalation using a titanium pipe. The first dose of each period was selfadministered using a standardized puff procedure: (1) Inhale for 5 seconds, (2) hold the smoke in their lungs for 10 seconds, and (3) exhale. Subsequent doses were self-administered in the same manner for a total of three times daily at home on an outpatient basis for the first five days of each period. The primary measure was an 11-point pain intensity scale, averaged over the 5 day treatment period, which was administered once daily for present, worst, least and average pain intensity during the previous 24 hours. Secondary measures included an acute pain 0–100 point VAS, pain quality assessed with the McGill Pain Questionnaire, sleep assessed with the Leeds Sleep Evaluation Questionnaire, mood assessed with the POMS, quality of life assessed using the EQ–5D health outcome instrument. Subjective measures included 0–100 point VAS scales for high, relaxed, stressed and happy. Over the first three hours after smoking marijuana, ratings of pain, VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 high, relaxation, stress, happiness and heart rate were recorded. During the five days of each study period, participants were contacted daily to administer questionnaires on pain intensity, sleep, medication and AEs. Subjects returned on the fifth day to complete questionnaires on pain quality, mood, quality of life and assessments of potency. At the end of the study, participants completed final adverse event reports and potency assessments. The average daily pain intensity was significantly lower on 9.4% THC marijuana (5.4) than on placebo marijuana (6.1) (p = 0.023). The 9.4% THC strength also produced more drowsiness, better sleep, with less anxiety and depression, compared to placebo (all p < 0.05). However, there were no significant differences on POMS scores or on VAS scores for high, happy, relaxed or stressed between THC doses. The most frequent drug-related adverse events reported in the group receiving 9.4% THC marijuana were headache, dry eyes, burning sensation, dizziness, numbness and cough. Reports of high and euphoria occurred on only three occasions, once in each dose of THC. There were no significant changes in vital signs, heart-rate variability, or renal function. One subject withdrew from the study due to increased pain during administration of 6% THC marijuana. The authors conclude that smoked marijuana reduces neuropathic pain, improves mood and aids in sleep, but that smoking marijuana is not a preferable route of administration. The limitations of this study include: The lack of information on timing of assessments during the outpatient portion of the study and maintenance of subjects on other analgesic medication while being tested with marijuana. These limitations make it difficult to conclude that marijuana has analgesic properties on its own and that the actual AEs experienced during the study in response to marijuana are tolerable. However, the study produced positive results suggesting that marijuana should be studied further as an adjunct treatment for uncontrolled neuropathic pain. Wilsey et al. (2013) conducted the most recent study entitled, ‘‘Low-Dose Vaporized Cannabis Significantly Improves Neuropathic Pain’’. This study is the only one in this review that utilized vaporization as a method of marijuana administration. The subjects were 36 patients with a neuropathic pain disorder (CRPS, thalamic pain, spinal cord injury, peripheral neuropathy, radiculopathy, or nerve PO 00000 Frm 00112 Fmt 4701 Sfmt 4702 injury) who were maintained on their current medications (opioids, anticonvulsants, antidepressants, and NSAIDs). Although subjects were required to have a history of marijuana use, they refrained from use of cannabinoids for 30 days before study sessions. Subjects participated in three sessions in which they received 1.29% or 3.53% THC marijuana or placebo marijuana. The marijuana was vaporized using the Volcano vaporizer and a standardized cued-puff procedure: (1) ‘‘hold the vaporizer bag with one hand and put the vaporizer mouthpiece in their mouth’’ (30 seconds), (2) ‘‘get ready’’ (5 seconds), (3) ‘‘inhale’’ (5 seconds), (4) ‘‘hold vapor in lungs’’ (10 seconds), (5) ‘‘exhale and wait’’ before repeating puff cycle (40 seconds). Subjects inhaled 4 puffs at 60 minutes. At 180 minutes, the vaporizer was refilled with marijuana vapor and subjects were allowed to inhale 4 to 8 puffs using the cued procedure. Thus, cumulative dosing allowed for a range of 8 to12 puffs in total for each session, depending on the subjects desired response and tolerance. The washout time between each session ranged from 3–14 days. The primary outcome variable was spontaneous pain relief, as assessed using a 0–100 point VAS for current pain. Secondary measures included the Patient Global Impression of Change (PGIC), the Neuropathic Pain Scale (NPS), a 0–100 point VAS for allodynia. Acute pain threshold was measured with a thermal pain model. Subjective measures included 0–100 point unipolar VAS for any drug effect, good drug effect, bad drug effect, high, drunk, impaired, stoned, drug liking, sedated, confused, nauseated, desire more drug, anxious, down and hungry. Bipolar 0– 100 point VAS included sad/happy, anxious/relaxed, jittery/calm, bad/good, paranoid/self-assured, and fearful/ unafraid. Neurocognitive assessments assessed attention and concentration, learning and memory, and fine motor speed. A 30% reduction in pain was achieved in 61% of subjects who received the 3.53% THC marijuana, in 57% of subjects who received the 1.29% THC marijuana and in 26% of subjects who received the placebo marijuana (p = 0.002 for placebo vs. 3.53% THC, p = 0.007 for placebo vs 1.29% THC; p ≤ 0.05 1.29% THC vs. 3.53% THC). Both strengths of marijuana significantly decreased pain intensity, unpleasantness, sharpness, and deepness on the NPS, as well as pain ratings on the PGIC, compared to placebo. These effects on pain were maximal with cumulative dosing over E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules mstockstill on DSK3G9T082PROD with PROPOSALS2 the course of the study session, with maximal effects at 180 minutes. There were no effects of marijuana compared to placebo on measures of allodynia or thermal pain. Subjects correctly identified the study treatment 63% of the time for placebo, 61% of the time for 1.29% THC, and 89% of the time for 3.53% THC. On subjective measures, marijuana produced dose-dependent increases compared to placebo on ratings for: any drug effect, good drug effect, drug liking, high, stoned, sedated, confused, and hungry. Both strengths of marijuana produced similar increases in drunk or impaired compared to placebo. In contrast, desire for drug was rated as higher for the 1.29% THC marijuana compared to the 3.53% THC marijuana. There were no changes compared to placebo for bad effect, nauseous, anxiety, feeling down or any of the bipolar mood assessments. There was dose-dependent impairment on learning and memory from marijuana compared to placebo, but similar effects between the two strengths of marijuana on attention. The authors conclude that vaporization of relatively low doses of marijuana can produce improvements in analgesia in neuropathic pain patients, especially when patients are allowed to titrate their exposure. However, this individualization of doses may account for the general lack of difference between the two strengths of marijuana. No data were presented regarding the total amount of THC consumed by each subject, so it is difficult to determine a proper dose-response evaluation. Additional limitations of this study are the inclusion of subjects with many forms of neuropathic pain and maintenance of subjects on other analgesic medication while being tested with marijuana. These limitations make it difficult to conclude that marijuana has analgesic properties on its own. It is also difficult to determine if any particular subset of neuropathic pain conditions would benefit specifically from marijuana administration. However, the study produced positive results suggesting that marijuana should be studied further as an adjunct treatment for uncontrolled neuropathic pain. 3.2 Appetite Stimulation in HIV Two randomized, double-blind, placebo-controlled Phase 2 studies examined the effects of smoked marijuana on appetite in HIV-positive subjects (Haney et al., 2005; Haney et al., 2007). Table 2 of the Appendix summarizes both studies. VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 The first study, conducted by Haney et al. (2005) is entitled, ‘‘Dronabinol and marijuana in HIV+ marijuana smokers: Acute effects on caloric intake and mood’’. The subjects were 30 HIVpositive patients who were maintained on two antiretroviral medications and either had clinically significant decreases in lean muscle mass 34 (lowBIA group, n = 15) or normal lean muscle mass (normal-BIA group, n = 15). All subjects had a history of smoking marijuana at least twice weekly for 4 weeks prior to entry into the study. On average, individuals had smoked 3 marijuana cigarettes per day, 5–6 times per week for 10–12 years. Subjects participated in 8 sessions that tested the acute effects of 0, 10, 20, and 30 mg dronabinol oral capsules and marijuana cigarettes with 0%, 1.8%, 2.8%, and 3.9% THC concentration by weight, using a double-dummy design (with only one active drug per session). The doses of dronabinol are higher than those doses typically prescribed for appetite stimulation in order to help preserve the blinding. There was a oneday washout period between test sessions. Marijuana was administered using a standardized cued procedure: (1) ‘‘light the cigarette’’ (30 seconds), (2) ‘‘prepare’’ (5 seconds), (3) ‘‘inhale’’ (5 seconds), (4) ‘‘hold smoke in lungs’’ (10 seconds), and (5) ‘‘exhale.’’ Each subject smoked three puffs in this manner, with a 40-second interval between each puff. Caloric intake was used as a surrogate measure for weight gain. Subjects received a box containing a variety of food and beverage items and were told to record consumption of these items following that day’s administration of the test drug. Subjective measures included 0–100 point VAS for feel drug effect, good effect, bad effect, take drug again, drug liking, hungry, full, nauseated, thirsty, desire to eat. Neurocognitive measures and vital signs were monitored. The low BIA group consumed significantly more calories in the 1.8% and 3.9% THC marijuana conditions (p<0.01) and the 10, 20, and 30 mg dronabinol conditions (p<0.01) compared with the placebo condition. In contrast, in the normal BIA group, neither marijuana nor dronabinol significantly affected caloric intake. This lack of effect may be accountable, however, by the fact that this group consumed approximately 200 calories 34 Lean muscle mass was assessed using bioelectrical impedance analysis (BIA). The lowBIA group was classified with having <90% BIA, and the normal-BIA group was classified with having >90% BIA. PO 00000 Frm 00113 Fmt 4701 Sfmt 4702 53799 more than the low BIA group under baseline conditions. Ratings of high and good drug effect were increased by all drug treatments in both the low-BIA and normal-BIA groups, except in response to the 10 mg dose of dronabinol. The 3.9% THC marijuana increased ratings of good drug effect, drug liking and desire to smoke again compared with placebo. Ratings of sedation were increased in both groups by 10 and 30 mg dronabinol, and in the normal BIA group by the 2.8% THC marijuana. Ratings of stimulation were increased in the normal BIA group by 2.8% and 3.9% THC marijuana and by 20 mg dronabinol. Increases in ratings of forgetfulness, withdrawn, dreaming, clumsy, heavy limbs, heart pounding, jittery, and decreases in ratings of energetic, social, and talkative were reported in the normal BIA group with 30 mg dronabinol. There were no significant changes in vital signs or performance on neurocognitive measures in response to marijuana. Notably, the time course of subjective effects peaked quickly and declined thereafter for smoked marijuana, while oral dronabinol responses took longer to peak and persisted longer. Additionally, marijuana but not dronabinol produced dry mouth and thirst. In general, AEs reported in this study were low in both drug conditions for both subject groups. In the low BIA group, nausea was reported by one subject in both the 10 and 20 mg dronabinol conditions, while an uncomfortable level of intoxication was produced by the 30 mg dose in two subjects. There were no AEs reported in this group following marijuana at any dose. In the normal BIA group, the 30 mg dose of dronabinol produced an uncomfortable level of intoxication in three subjects and headache in one subject, while the 3.9% marijuana produced diarrhea in one subject. The authors conclude that smoked marijuana can acutely increase caloric intake in low BIA subjects without significant cognitive impairment. However, it is possible that the low degree of cognitive impairment reported in this study may reflect the development of tolerance to cannabinoids in this patient population, since all individuals had current histories of chronic marijuana use. Additional limitations in this study include not utilizing actual weight gain as a primary measure. However, the study produced positive results suggesting that marijuana should be studied further as a treatment for appetite stimulation in HIV patients. E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53800 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules A second study conducted by Haney et al. (2007) is entitled, ‘‘Dronabinol and marijuana in HIV-positive marijuana smokers: Caloric intake, mood, and sleep’’. The design of this study was nearly identical to the one conducted by this laboratory in 2005 (see above), but there was no stratification of subjects by BIA. The subjects were 10 HIV-positive patients who were maintained on two antiretroviral medications and had a history of smoking marijuana at least twice weekly for 4 weeks prior to entry into the study. On average, individuals had smoked 3 marijuana cigarettes per day, 5 times per week for 19 years. Subjects participated in 8 sessions that tested the acute effects of 0, 5 and 10 mg dronabinol oral capsules and marijuana cigarettes with 0, 2.0% and 3.9% THC concentration by weight, using a double-dummy design (with 4 sessions involving only one active drug and 4 interspersed placebo sessions). Both drug and placebo sessions lasted for 4 days each, with active drug administration occurring 4 times per day (every 4 hours). Testing occurred in two 16-day inpatient stays. In the intervening outpatient period, subjects were allowed to smoke marijuana prior to re-entry to the study unit for the second inpatient stay. Marijuana was administered using a standardized cued procedure: (1) ‘‘light the cigarette’’ (30 seconds), (2) ‘‘prepare’’ (5 seconds), (3) ‘‘inhale’’ (5 seconds), (4) ‘‘hold smoke in lungs’’ (10 seconds), and (5) ‘‘exhale.’’ Each subject smoked three puffs in this manner, with a 40-second interval between each puff. Caloric intake was used as a surrogate measure for weight gain, but subjects were also weighed throughout the study (a measure which was not collected in the 2005 study by this group). Subjects received a box containing a variety of food and beverage items and were told to record consumption of these items following that day’s administration of the test drug. Subjective measures included 0–100 point VAS for drug effect, good effect, bad effect, take drug again, drug liking, hungry, full, nauseated, thirsty, desire to eat. Neurocognitive measures and vital signs were monitored. Sleep was assessed using both the Nightcap sleep monitoring system and selected VAS measures related to sleep. Both 5 and 10 mg dronabinol (p < 0.008) and 2.0% and 3.9% THC marijuana (p < 0.01) dose-dependently increased caloric intake compared with placebo. This increase was generally accomplished through increases in incidents of eating, rather than an increase in the calories consumed in each incident. Subjects also gained VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 similar amounts of weight after the highest dose of each cannabinoid treatment: 1.2 kg (2.6 lbs) after 4 days of 10 mg dronabinol, and 1.1 kg (2.4 lbs) after 4 days of 3.9% THC marijuana. The 3.9% THC marijuana dose also increased the desire to eat and ratings of hunger. Ratings of good drug effect, high, drug liking, and desire to smoke again were significantly increased by 10 mg dronabinol and 2.0% and 3.9% THC marijuana doses compared to placebo. Both marijuana doses increased ratings of stimulated, friendly, and selfconfident. The 10 mg dose of dronabinol increased ratings of concentration impairment, and the 2.0% THC marijuana dose increased ratings of anxious. Dry mouth was induced by 10 mg dronabinol (10 mg) and 2.0% THC marijuana. There were no changes in neurocognitive performance or objective sleep measures from administration of either cannabinoid. However, 3.9% THC marijuana increased subjective ratings of sleep. The authors conclude that both dronabinol and smoked marijuana increase caloric intake and produce weight gain in HIV-positive patients. However, it is possible that the low degree of cognitive impairment reported in this study may reflect the development of tolerance to cannabinoids in this subject population, since all individuals had current histories of chronic marijuana use. This study produced positive results suggesting that marijuana should be studied further as a treatment for appetite stimulation in HIV patients. 3.3 Spasticity in Multiple Sclerosis Only one randomized, double-blind, placebo-controlled Phase 2 study examined the effects of smoked marijuana on spasticity in MS. This study was conducted by CoreyBloom et al. (2012) and is entitled, ‘‘Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial’’. The subjects were 30 patients with MS-associated spasticity and had moderate increase in tone (score ≥ 3 points on the modified Ashworth scale). Participants were allowed to continue other MS medications, with the exception of benzodiazepines. Eighty percent of subjects had a history of marijuana use and 33% had used marijuana within the previous year. Subjects participated in two 3-day test sessions, with an 11 day washout period. During each test session they smoked a 4.0% THC marijuana cigarette once per day or a placebo cigarette once per day. Smoking occurred through a PO 00000 Frm 00114 Fmt 4701 Sfmt 4702 standardized cued-puff procedure: (1) Inhalation for 5 seconds, (2) breath-hold and exhalation for 10 seconds, (3) pause between puffs for 45 seconds. Subjects completed an average of four puffs per cigarette. The primary outcome measure was change in spasticity on the modified Ashworth scale. Additionally, subjects were assessed using a VAS for pain, a timed walk, and cognitive tests (Paced Auditory Serial Addition Test) and AEs. Treatment with 4.0% THC marijuana reduced subject scores on the modified Ashworth scale by an average of 2.74 points more than placebo (p <0.0001) and reduced VAS pain scores compared to placebo (p = 0.008). Scores on the cognitive measure decreased by 8.7 points more than placebo (p = 0.003). However, marijuana did not affect scores for the timed walk compared to placebo. Marijuana increased rating of feeling high compared to placebo. 7 subjects did not complete the study due to adverse events (two subjects felt uncomfortably ‘‘high’’, two had dizziness and one had fatigue). Of those 7 subjects who withdrew, 5 had little or no previous experience with marijuana. When the data were re-analyzed to include these drop-out subjects, with the presumption they did not have a positive response to treatment, the effect of marijuana was still significant on spasticity. The authors conclude that smoked marijuana had usefulness in reducing pain and spasticity associated with MS. ¨ It is concerning that marijuana-naıve subjects dropped out of the study because they were unable to tolerate the psychiatric AEs induced by marijuana. The authors suggest that future studies should examine whether different doses can result in similar beneficial effects with less cognitive impact. However, the current study produced positive results suggesting that marijuana should be studied further as an adjunct treatment for spasticity in MS patients. 3.4 Asthma Tashkin et al. (1974) examined bronchodilation in 10 subjects with bronchial asthma in the study entitled, ‘‘Acute Effects of Smoked Marijuana and Oral D9-Tetrahydrocannabinol on Specific Airway Conductance in Asthmatic Subjects’’. The study was a double-blind, placebo-controlled, crossover design. All subjects were clinically stable at the time of the study; four subjects were symptom free, and six subjects had chronic symptoms of mild to moderate severity. Subjects were tested with 0.25ml of isoproterenol HCl prior to the study to ensure they responded to bronchodilator E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules medications. Subjects were not allowed to take bronchodilator medication within 8 hours prior to the study. Previous experience with marijuana was not required for participation in the study, but 7 of the 10 subjects reported previous use of marijuana at a rate of less than 1 marijuana cigarette per month. No subjects reported marijuana use within 7 days of the study. The study consisted of four test sessions with an interval of at least 48 hours between sessions. On two test sessions subjects smoked 7 mg/kg of body weight of either marijuana, with 2% THC concentration by weight, or placebo marijuana. During the other two test sessions, subjects ingested capsules with either 15 mg of synthetic THC or placebo. Marijuana was administered using a uniform smoking technique: subjects inhaled deeply for 2–4 seconds, held smoke in lungs for 15 seconds, and resumed normal breathing for approximately 5 seconds. The author did not provide a description of the number of puffs taken at any smoking session. The authors state that the smoking procedure was repeated until the cigarette was consumed, which took approximately 10 minutes. The outcome measure used was specific airway conductance (SGaw), as calculated using measurements of thoracic gas volume (TGV) and airway resistance (Raw) using a variablepressure body plethysmograph. Additionally, an assessment of degree of intoxication was administered only to those subjects reporting previous marijuana use. This assessment consisted of subjects rating ‘‘how ‘high’ they felt’’ on a scale of 0–7, 7 representing ‘‘the ‘highest’ they had ever felt after smoking marijuana’’. Marijuana produced a significant increase of 33–48% in average SGaw compared to both baseline and placebo (P < 0.05). This significant increase in SGaw lasted for at least 2 hours after administration. The average TGV significantly decreased by 4–13% compared to baseline and placebo (P < 0.05). The author stated that all subjects reported feelings of intoxication after marijuana administration. The authors conclude that marijuana produced bronchodilation in clinically stable asthmatic subjects with minimal to moderate bronchospasms. Study limitations include: inclusion of subjects with varying severity of asthmatic symptoms, use of SGaw to measure lung responses to marijuana administration, and administration of smoke to asthmatic subjects. Smoke delivers a number of harmful substances and is not an optimal delivery symptom, especially for asthmatic patients. FEV1 VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 via spirometry is the gold standard to assess changes in lung function, pre and post asthma treatment, by pharmacotherapy. SGaw has been shown to be a valid tool in bronchoconstriction lung assessment; however, since the FEV1 method was not utilized, it is unclear whether these results would correlate if the FEV1 method had been employed. 3.5 Glaucoma Two randomized, double-blind, placebo-controlled Phase 2 clinical studies examined smoked marijuana in glaucoma (Crawford and Merritt, 1979; Merritt et al., 1980). In both studies, intraocular pressure (IOP) was significantly reduced 30 minutes after smoking marijuana. Maximal effects occurred 60–90 minutes after smoking, with IOP returning to baseline within 3– 4 hours. These two studies were included in the 1999 IOM report on the medical uses of marijuana. Because our independent analysis of these studies concurred with the conclusions from the 1999 IOM report, these studies will not be discussed in further detail in this review. No recent studies have been conducted examining the effect of inhaled marijuana on IOP in glaucoma patients. This lack of recent studies may be attributed to the conclusions made in the 1999 IOM report that while cannabinoids can reduce intraocular pressure (IOP), the therapeutic effects require high doses that produce shortlasting responses, with a high degree of AEs. This high degree of AEs means that the potential harmful effects of chronic marijuana smoking may outweigh its modest benefits in the treatment of glaucoma. 3.6 Conclusions Of the eleven randomized, doubleblind, placebo-controlled Phase 2 clinical studies that met the criteria for review (see Sections 2.2 and 2.3), ten studies administered marijuana through smoking, while one study utilized marijuana vaporization. In these eleven studies, there were five different therapeutic indications: five examined chronic neuropathic pain, two examined appetite stimulation in HIV patients, two examined glaucoma, one examined spasticity in MS, and one examined asthma. There are limited conclusions that can be drawn from the data in these published studies evaluating marijuana for the treatment of different therapeutic indications. The analysis relied on published studies, thus information available about protocols, procedures, and results were limited to documents published and widely available in the PO 00000 Frm 00115 Fmt 4701 Sfmt 4702 53801 public domain. The published studies on medical marijuana are effectively proof-of-concept studies. Proof-ofconcept studies provide preliminary evidence on a proposed hypothesis regarding a drug’s effect. For drugs under development, the effect often relates to a short-term clinical outcome being investigated. Proof-of-concept studies serve as the link between preclinical studies and dose ranging clinical studies. Therefore, proof-ofconcept studies are not sufficient to demonstrate efficacy of a drug because they provide only preliminary information about the effects of a drug. Although these studies do not provide evidence that marijuana is effective in treating a specific, recognized disorder, these studies do support future larger well-controlled studies to assess the safety and efficacy of marijuana for a specific medical indication. Overall, the conclusions below are preliminary, based on very limited evidence. 3.6.1 Conclusions for Chronic Neuropathic Pain In subjects with chronic neuropathic pain who are refractory to other pain treatments, five proof-of-concept studies produced positive results regarding the use of smoked marijuana for analgesia. However, the subjects in these studies continued to use their current analgesic drug regime, and thus no conclusions can be made regarding the potential efficacy of marijuana for neuropathic pain in patients not taking other analgesic drugs. Subjects also had numerous forms of neuropathic pain, making it difficult to identify whether a specific set of symptoms might be more responsive to the effects of marijuana. It is especially concerning that some ¨ marijuana-naıve subjects had intolerable psychiatric responses to marijuana exposure at analgesic doses. 3.6.2 Conclusions for Appetite Stimulation in HIV In subjects who were HIV-positive, two proof-of-concept studies produced positive results with the use of both dronabinol and smoked marijuana to increase caloric intake and produce weight gain in HIV-positive patients. However, the amount of THC in the marijuana tested in these studies is four times greater than the dose of dronabinol typically tested for appetite stimulation (10 mg vs. 2.5 mg; Haney et al., 2005). Thus, it is possible that the low degree of AEs reported in this study may reflect the development of tolerance to cannabinoids in this patient population, since all individuals had current histories of chronic marijuana use. Thus, individuals with little prior E:\FR\FM\12AUP2.SGM 12AUP2 53802 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules exposure to marijuana may not respond similarly and may not be able to tolerate sufficient marijuana to produce appetite stimulation. 3.6.3 Conclusions for Spasticity in MS In subjects with MS, a proof of concept study produced positive results using smoked marijuana as a treatment for pain and symptoms associated with treatment-resistant spasticity. The subjects in this study continued to take their current medication regiment, and thus no conclusions can be made regarding the potential efficacy of marijuana when taken on its own. It is ¨ also concerning that marijuana-naıve subjects dropped out of the study because they were unable to tolerate the psychiatric AEs induced by marijuana. The authors suggest that future studies should examine whether different doses can result in similar beneficial effects with less cognitive impact. 3.6.4 Conclusions for Asthma In subjects with clinically stable asthma, a proof of concept study produced positive results of smoked marijuana producing bronchodilation. However, in this study marijuana was administered at rest and not while experiencing bronchospasms. Additionally, the administration of marijuana through smoking introduces harmful and irritating substances to the subject, which is undesirable especially in asthmatic patients. Thus the results suggest marijuana may have bronchodilator effects, but it may also have undesirable adverse effects in subjects with asthma. mstockstill on DSK3G9T082PROD with PROPOSALS2 3.6.5 Conclusions for Glaucoma As noted in Sections 3.5, the two studies that evaluated smoked marijuana for glaucoma were conducted decades ago, and they have been thoroughly evaluated in the 1999 IOM report. The 1999 IOM report concludes that while the studies with marijuana showed positive results for reduction in IOP, the effect is short-lasting, requires a high dose, and is associated with many AEs. Thus, the potential harmful effects may outweigh any modest benefit of marijuana for this condition. We agree with the conclusions drawn in the 1999 IOM report. 3.7 Design Challenges for Future Studies The positive results reported by the studies discussed in this review support the conduct of more rigorous studies in the future. This section discusses methodological challenges that have occurred in clinical studies with smoked marijuana. These design issues VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 should be addressed when larger-scale clinical studies are conducted to ensure that valid scientific data are generated in studies evaluating marijuana’s safety and efficacy for a particular therapeutic use. 3.7.1 Sample Size The ability for results from a clinical study to be generalized to a broader population is reliant on having a sufficiently large study sample size. However, as noted above, all of the 11 studies reviewed in this document were early Phase 2 proof of concept studies for efficacy and safety. Thus, the sample sizes used in these studies were inherently small, ranging from 10 subjects per treatment group (Tashkin et al., 1974; Haney et al., 2007) to 25 subjects per treatment group (Abrams et al., 2007). These sample sizes are statistically inadequate to support a showing of safety or efficacy. FDA’s recommendations about sample sizes for clinical trials can be found in the Guidance for Industry: E9 Statistical Principles for Clinical Trials (1998).35 For example, ‘‘the number of subjects in a clinical trial should always be large enough to provide a reliable answer to the questions addressed. This number is usually determined by the primary objective of the trial. The method by which the sample size is calculated should be given in the protocol, together with the estimates of any quantities used in the calculations (such as variances, mean values, response rates, event rates, difference to be detected).’’ (pg. 21). Other clinical FDA Guidance for Industry 36 may also contain recommendations regarding the appropriate number of subjects that should be investigated for a specific medical indication. 3.7.2 Marijuana Dose Standardization Dose standardization is critical for any clinical study in order to ensure that each subject receives a consistent exposure to the test drug. The Guidance for Industry: Botanical Drug Products (2004) 37 provides specific information on the development of botanical drug products. Specifically, this guidance 35 The Guidance for Industry: E9 Statistical Principles for Clinical Trials can be found at: www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/ Guidances/ucm073137.pdf. 36 Other Guidances for Industry can be found at: www.fda.gov/Drugs/ GuidanceComplianceRegulatoryInformation/ Guidances/ucm064981.htm. 37 The Guidance for Industry: Botanical Drug Products can be found at: http://www.fda.gov/ downloads/Drugs/ GuidanceComplianceRegulatoryInformation/ Guidances/ucm070491.pdf. PO 00000 Frm 00116 Fmt 4701 Sfmt 4702 includes information about the need for well-characterized and consistent chemistry for the botanical plant product and for consistent and reliable dosing. Specifically for marijuana studies, dose standardization is important because if marijuana leads to plasma levels of cannabinoids that are significantly different between subjects, this variation may lead to differences in therapeutic responsivity or in the prevalence of psychiatric AEs. In most marijuana studies discussed in this review, investigators use a standardized cued smoking procedure. In this procedure, a subject is instructed to inhale marijuana smoke for 5 seconds, hold the smoke in the lungs for 10 seconds, exhale and breathe normally for 40 seconds. This process is repeated to obtain the desired dose of the drug. However, this procedure may not lead to equivalent exposure to marijuana and its constituent cannabinoids, based on several factors: • Intentional or unintentional differences in the depth of inhalation may change the amount of smoke in the subject’s lungs. • Smoking results in loss from side stream smoke, such that the entire dose is not delivered to the subject. • There may be differences in THC concentration along the length of a marijuana cigarette. According to Tashkin et al. (1991), the area of the cigarette closest to the mouth tends to accumulate a higher concentration of THC, but this section of the cigarette is not smoked during a study. For example, Wilsey et al. (2008) used this standardized smoking procedure. The reported mean (range) of marijuana cigarettes consumed was 550 mg (200– 830mg) for the low strength marijuana (3.5% THC) and 490 mg (270–870mg) for the high strength marijuana (7% THC). This wide range of amounts of marijuana cigarette smoked by the individual subjects, even with standardized smoking procedure and controlled number of puffs, supports the issues with delivering consistent doses with smoke marijuana. In other marijuana studies that do not use a cued smoking procedure, subjects are simply told to smoke the marijuana cigarette over a specific amount of time (usually 10 minutes) without further instruction (Crawford and Merritt, 1979; Merritt et al., 1980; Ellis et al., 2009). The use of a nonstandardized procedure may lead to non-equivalent exposures to marijuana and its constituent cannabinoids between subjects because of additional factors that are not listed above, such as: • Differences in absorption and drug response if subjects (especially E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules mstockstill on DSK3G9T082PROD with PROPOSALS2 ¨ marijuana-naıve ones) are not instructed to hold marijuana smoke in their lungs for a certain period of time. • Prolonged periods between puffs may increase loss to side stream smoke. • Subjects may attempt to smoke the marijuana cigarette in the way they would smoke a tobacco cigarette, which relies primarily on short, shallow puffs. In both standardized and nonstandardized smoking procedures, subjects may seek to control the dose of THC through self-titration (Crawford and Merritt, 1979; Merritt et al., 1980; Tashkin et al., 1974; Abrams et al., 2007; Ellis et al., 2009). Self-titration involves an individual moderating the amount of marijuana smoke inhaled over time in order to obtain a preferred level of psychoactive or clinical response. The ability of an individual to self-titrate by smoking is one reason given by advocates of ‘‘medical marijuana’’ in support of smoking of marijuana rather than through its ingestion via edibles. However, for research purposes, selftitration interferes with the ability to maintain consistent dosing levels between subjects, and thus, valid comparisons between study groups. All of these factors can make the exact dose of cannabinoids received by a subject in a marijuana study difficult to determine with accuracy. Testing whether plasma levels of THC or other cannabinoids are similar between subjects following the smoking procedure would establish whether the procedure is producing appropriate results. Additionally, studies could be conducted to determine if vaporization can be used to deliver consistent doses of cannabinoids from marijuana plant material. Specifically, vaporization devices that involve the collection of vapors in an enclosed bag or chamber may help with delivery of consistent doses of marijuana. Thus, more information could be collected on whether vaporization is comparable to or different than smoking in terms of producing similar plasma levels of THC in subjects using identical marijuana plant material. 3.7.3 Acute vs. Chronic Therapeutic Marijuana Use The studies that were reviewed administered the drug for short durations lasting no longer than 5 days (Abrams et al., 2007; Ellis et al., 2009; Ware et al., 2010). Thus all studies examined the short-term effect of marijuana administration for therapeutic purposes. However, many of the medical conditions that have been studied are persistent or expected to last the rest of a patient’s life. Therefore, data on chronic exposure to smoked VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 marijuana in clinical studies is needed. In this way, more information will be available regarding whether tolerance, physical dependence, or specific adverse events develop over the course of time with continuing use of therapeutic marijuana. 3.7.4 Smoking as a Route of Administration As has been pointed out by the IOM and other groups, smoking is not an optimum route of administration for marijuana-derived therapeutic drug products, primarily because introducing the smoke from a burnt botanical substance into the lungs of individuals with a disease state is not recommended when their bodies may be physically compromised. The 1999 IOM report on medicinal uses of marijuana noted that alternative delivery methods offering the same ability of dose titration as smoking marijuana will be beneficial and may limit some of the possible longterm health consequences of smoking marijuana. The primary alternative to smoked marijuana is vaporization, which can reduce exposure to combusted plant material containing cannabinoids. The only study to use vaporization as the delivery method was Wilsey et al. (2013). The results from Wilsey et al. (2013) showed a similar effect of decreased pain as seen in the other studies using smoking as the delivery method (Ware et al., 2010; Wilsey et al., 2008). This similar effect of decrease pain supports vaporization as a possibly viable route to administer marijuana in research, while potentially limiting the risks associated with smoking. 3.7.5 Difficulty in Blinding of Drug Conditions An adequate and well-controlled clinical study involves double-blinding, where both the subjects and the investigators are unable to tell the difference between the test treatments (typically consisting of at least a test drug and placebo) when they are administered. All of the studies reviewed in this document administered study treatments under double-blind conditions and thus were considered to have an appropriate study design. However, even under the most rigorous experimental conditions, blinding can be difficult in studies with smoked marijuana because the rapid onset of psychoactive effects readily distinguishes active from placebo marijuana. The presence of psychoactive effects also occurs with other drugs. However, most other drugs have a similar psychoactive effect with substances with similar mechanisms of PO 00000 Frm 00117 Fmt 4701 Sfmt 4702 53803 actions. These substances can be used as positive controls to help maintain blinding to the active drug being tested. Marijuana on the other hand, has a unique set of psychoactive effects which makes the use of appropriate positive controls difficult (Barrett et al., 1995). However, two studies did use Dronabinol as a positive control drug to help maintain blinding (Haney et al., 2005; Haney et al., 2007). When blinding is done using only placebo marijuana, the ability to distinguish active from placebo marijuana may lead to expectation bias and an alteration in perceived responsivity to the therapeutic outcome measures. With marijuana-experienced subjects, for example, there may be an early recognition of the more subtle cannabinoid effects that can serve as a harbinger of stronger effects, which is less likely to occur with marijuana¨ naıve subjects. To reduce this possibility, investigators have tested doses of marijuana other than the one they were interested in experimentally to maintain the blind (Ware et al., 2010). Blinding can also be compromised by differences in the appearance of marijuana plant material based on THC concentration. Marijuana with higher concentrations of THC tends to be heavier and seemingly darker, with more ‘‘tar-like’’ substance. Subjects who have experience with marijuana have reported being able to identify marijuana from placebo cigarettes by sight alone when the plant material in a cigarette was visible (Tashkin et al., 1974; Ware et al., 2010). Thus, to maintain a double-blind design, many studies obscure the appearance of plant material by closing both ends of the marijuana cigarette and placing it in in an opaque plastic tube. While none of these methods to secure blinding may be completely effective, it is important to reduce bias as much as possible to produce consistent results between subjects under the same experimental conditions. 3.7.6 Prior Marijuana Experience Marijuana use histories in test subjects may influence outcomes, related to both therapeutic responsivity ¨ and psychiatric AEs. Marijuana-naıve subjects may also experience a marijuana drug product as so aversive that they would not want to use the drug product. Thus, subjects’ prior experience with marijuana may affect the conduct and results of studies. Most of the studies reviewed in this document required that subjects have a history of marijuana use (see tables in Appendix that describe specific E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53804 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules requirements for each study). However, in studies published in the scientific literature, the full inclusion criteria with regard to specific amount of experience with marijuana may not be provided. For those studies that do provide inclusion criteria, acceptable experience with marijuana can range from once in a lifetime to use multiple times a day. The varying histories of use might affect everything from scores on adverse event measures, safety measures, or efficacy measures. Additionally, varying amounts of experience can impact cognitive effect measures assessed during acute administration studies. For instance, Schreiner and Dunn (2012) contend cognitive deficits in heavy marijuana users continue for approximately 28 days after cessation of smoking. Studies requiring less than a month of abstinence prior to the study may still see residual effects of heavy use at baseline and after placebo marijuana administration, thus showing no significant effects on cognitive measures. However, these same ¨ measurements in occasional or naıve marijuana users may demonstrate a significant effect after acute marijuana administration. Therefore, the amount of experience and the duration of abstinence of marijuana use are important to keep in mind when analyzing results for cognitive and other adverse event measures. Lastly, a study population with previous experience with marijuana may underreport the incidence and severity of adverse events. Because most studies used subjects with prior marijuana experience, we are limited in our ability to generalize the results, especially for ¨ safety measures, to marijuana naıve populations. Five of 11 studies reviewed in this document included both marijuana¨ naıve and marijuana-experienced subjects (Corey-Bloom et al., 2012; Ellis et al., 2009; Ware et al., 2010; Merritt et al., 1980; Tashkin et al., 1974). Since the ¨ number of marijuana-naıve subjects in these studies was low, it was not possible to conduct a separate analysis compared to experienced users. However, systematically evaluating the effect of marijuana experience on study outcomes is important, since many patients who might use a marijuana product for a therapeutic use will be ¨ marijuana-naıve. Research shows that marijuanaexperienced subjects have a higher ability to tolerate stronger doses of oral ¨ dronabinol than marijuana-naıve subjects (Haney et al., 2005). Possibly, this increased tolerance is also the case when subjects smoke or vaporize marijuana. Thus, studies could be VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 conducted that investigate the role of marijuana experience in determining tolerability of and responses to a variety of THC concentrations in marijuana. 3.7.7 Inclusion and Exclusion Criteria For safety reasons, all clinical studies have inclusion and exclusion criteria that restrict the participation of individuals with certain medical conditions. For studies that test marijuana, these criteria may be based on risks associated with exposure to smoked material and the effects of THC. Thus, most studies investigating marijuana require that subjects qualify for the study based on restrictive symptom criteria such that individuals do not have other symptoms that may be known to interact poorly with cannabinoids. Similarly, clinical studies with marijuana typically exclude individuals with cardiac or pulmonary problems, as well as psychiatric disorders. These exclusion criteria are based on the wellknown effects of marijuana smoke to produce increases in heart rate and blood pressure, lung irritation, and the exacerbation of psychiatric disturbances in vulnerable individuals. Although these criteria are medically reasonable for research protocols, it is likely that future marijuana products will be used in patients who have cardiac, pulmonary or psychiatric conditions. Thus, individuals with these conditions should be evaluated, whenever possible. Additionally, all studies reviewed in this document allowed the subjects to continue taking their current regimen of medications. Thus all results evaluated marijuana as an adjunct treatment for each therapeutic indication. 3.7.8 Number of Female Subjects A common problem in clinical research is the limited number of females who participate in the studies. This problem is present in the 11 studies reviewed in this document, in which one study did not include any female subjects (Ellis et al., 2009), and three studies had a low percentage of female subjects (Abrams et al., 2007; Haney et al., 2005; Haney et al., 2007). However, each of these four studies investigated an HIV-positive patient population, where there may have been a larger male population pool from which to recruit compared to females. Since there is some evidence that the density of CB1 receptors in the brain may vary between males and females (Crane et al., 2012), there may be differing therapeutic or subjective responsivity to marijuana. Studies using a study population that is equal parts male and female may show whether and PO 00000 Frm 00118 Fmt 4701 Sfmt 4702 how the effects of marijuana differ between male and female subjects. 4. References 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: National Academy Press. Abrams DI, Hilton JF, Leiser RJ, Shade SB, Elbeik TA, Aweeka FT, Benowitz NL, Bredt BM, Kosel B, Aberg JA, Deeks SG, Mitchell TF, Mulligan K, Bacchetti P, McCune JM, and Schambelan M. 2003. Short-term effects of cannabinoids in patients with HIV–1 infection: a randomized, placebo-controlled clinical trial. Annals of Internal Medicine 139 (4): 258–266. Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME, Rowbotham MC, and Petersen KL. 2007. Cannabis in painful HIV-associated sensory neuropathy: A randomized placebocontrolled trial. Neurology 68 (7): 515– 521. Appendino G, Chianese G, TaglialatelaScafati O. 2011. Cannabinoids: occurrence and medicinal chemistry. Curr Med Chem. 18(7):1085–99. Barrett RL, Wiley JL, Balster RL, and Martin BR. 1995. Pharmacological specificity of D9-tetrahydrocannabinol discrimination in rats. Psychopharmacology 118(4): 419–424. Chait LD, and Pierri J. 1989. Some physical characteristics of NIDA marijuana cigarettes. Addictive Behaviors 14 (1): 61–67. Chang AE, Shiling DJ, Stillman RC, Godlberg NH, Seipp CA, Barofsky I, Simon RM, and Rosenberg SA. 1979. Delta-9tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate. Annals of Internal Medicine 91: 819–824. Corey-Bloom J, Wolfson T, Gamst A, Jin S, Marcotte TD, Bentley H, and Gouaux B. 2012. Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. Canadian Medical Association Journal 184 (10): 1143–1150. Crane NA, Schuster RM, Fusar-Poli P, and Gonzalez R. 2012. Effects of Cannabis on Neurocognitive Functioning: Recent Advances, Neurodevelopmental Influences, and Sex Differences. Neuropsychology Review. Crawford WJ, and Merritt JC. 1979. Effects of tetrahydrocannabinol on arterial and intraocular hypertension. International Journal of Clinical Pharmacology and biopharmacy 17 (5): 191–196. Ellis RJ, Toperoff W, Vaida F, Van Den Brande G, Gonzales J, Gouaux B, Bentley H, and Atkinson JH. 2009. Smoked medicinal cannabis for neuropathic pain in HIV: A randomized, crossover clinical trial. Neuropsychopharmacology 34 (3): 672–680. Flom MC, Adams AJ, and Jones RT. 1975. Marijuana smoking and reduced pressure in human eyes: drug action or epiphenomenon? Investigative Opthalmology 14(1): 52–55. Foltin RW, Brady JV, and Fischamn MW. 1986. Behavioral analysis of marijuana E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules mstockstill on DSK3G9T082PROD with PROPOSALS2 effects on food intake in humans. Pharmacology Biochemistry and Behavior 25: 577–582. Foltin RW, Fischman MW, and Byrne MF. 1988. Effects of smoked marijuana on food intake and body weight of humans living in a residential laboratory. Appetite 11: 1–14. Greenberg HS, Werness SA, Pugh JE, Andrus RO, Anderson DJ, and Domino EF. 1994. Short-term effects of smoking marijuana on balance in patients with multiple sclerosis and normal volunteers. Clinical Pharmacology and Therapeutics 55 (3): 324–328. Greenwald MK and Stitzer ML. 2000. Antinociceptive, subjective, and behavioral effects of smoked marijuana in humans. Drug and Alcohol Dependence 59: 261–275. Haney M, Gunderson EW, Rabkin J, Hart CL, Vosburg SK, Comer SD, and Foltin RW. 2007. Dronabinol and marijuana in HIVpositive marijuana smokers. Caloric intake, mood, and sleep. Journal of Acquired Immune Deficiency Syndromes (1999) 45 (5): 545–554. Haney M, Rabkin J, Gunderson E, and Foltin RW. 2005. Dronabinol and marijuana in HIV(+) marijuana smokers: acute effects on caloric intake and mood. Psychopharmacology 181 (1): 170–178. Hill SY, Schwin R, Goodwin DW, and Powell BJ. 1974. Marihuana and pain. Journal of Pharmacology and Experimental Therapeutics 188(2): 415–418. Jampel H. 2010. American glaucoma society position statement: marijuana and the VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 treatment of glaucoma. Journal of Glaucoma 19 (2): 75–76. Merritt JC, Crawford WJ, Alexander PC, Anduze AL, and Gelbart SS. 1980. Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology 87 (3): 222–228. Milstein SL, MacCannell KL, Karr GW, and Clark S. 1974. Marijuana produced changes in cutaneous sensitivity and affect: users and non-users. Pharmacology Biochemistry and Behavior 2:367–374. Milstein SL, MacCannell K, Karr G, and Clark S. 1975. Marijuana-produced changes in pain tolerance: Experiences and nonexperienced subjects. Int. Pharmacopsychiat 10: 177–182. Naftali T, Schleider LB, Dotan I, Lansky EP, Benjaminov FS, and Konikoff FM. 2013. Cannabis induces a clinical response in patients with Crohn’s disease: A prospective placebo-controlled study. Clinical Gastroenterology and Hepatology 11: 1276–1280. Russo E, Mathre ML, Byrne A, Velin R, Bach PJ, Sanchez-Ramos J, and Kirlin KA. 2002. Chronic Cannabis Use in the Compassionate Investigational New Drug Program: An Examination of Benefits and Adverse Effects of Legal Clinical Cannabis. Journal of Cannabis Therapeutics 2 (1): 3–57. Soderpalm AHV, Schuster A, and de Wit H. 2001. Antiemetic efficacy of smoked marijuana subjective and behavioral effects on nausea induced by syrup of PO 00000 Frm 00119 Fmt 4701 Sfmt 4702 53805 ipecac. Pharmacology Biochemistry and Behavior 69: 343–350. Tashkin DP, Gliederer F, Rose J, Chang P, Hui KK, Yu JL, and Wu TC. 1991. Tar, CO and delta 9THC delivery from the 1st and 2nd halves of a marijuana cigarette. Pharmacology Biochemistry and Behavior 40 (3): 657–661. Tashkin DP, Shapiro BJ, Lee YE, Harper CE. 1975. Effects of smoked marijuana in experimentally induced asthma. American Review of Respiratory Disease 112: 377–386. Wallace M, Schulteis G, Atkinson JH, Wolfson T, Lazzaretto D, Bentley H, Gouaux B, and Abramson I. 2007. Dosedependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology 107 (5): 785–796. Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, Gamsa A, Bennett GJ, and Collet JP. 2010. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. Canadian Medical Association Journal 182 (14): E694–E701. Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B, and Fishman S. 2008. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J. Pain 9 (6): 506–521. Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, and Donaghe H. 2013. Low-dose vaporized cannabis significantly improves neuropathic pain. J. Pain 14(2):136–48. E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53806 VerDate Sep<11>2014 Jkt 238001 PO 00000 Frm 00120 Fmt 4701 Sfmt 4725 E:\FR\FM\12AUP2.SGM 12AUP2 h' Table 1: Randomized lied. -----·--- ·------- --------------------- ---------------------------------------------------------- -----ked f ---·--- ------------------7------------7 double-blind trial Author& Subjects (n) Drugs Study Primary Primary Outcome Date completed/randomized Admin. Methods Type Outcome Measure Results Indication Subject characteristics Duration Measure Abrams et al. Marijuana Group: 25/27 NID A marijuana, Parallel VAS -52% of the marijuana (2007) 22 males smoked Group daily pain group showed >30% 0%, 3.65%THC 5 females score decrease in pain score HIV-Sensory 5-day compared to 24% of Smoking Procedure: Neuropathy; Placebo Group: 25/28 treatment placebo group. -signal light cued -Marijuana group had 26 males period Neuropathic Pain 2 females smoking of marijuana significantly greater cigarette with each reduction in daily pain Inclusion Criteria: puff consisting of: score than placebo -documented HTV 1) 5s inhale smoke, group. -documented HIV-SN 2) lOs hold smoke in -pain score 2:30mm VAS lungs -NNT=3.6 -prior marijuana use of 3) 40s exhale and six or more times in breath normally lifetime 4) repeat procedure for desired number of Previous Marijuana puffs Experience: # of puffs not -marijuana group: 21 specified, only current users specified that subjects smoked the entire -placebo group: 19 current users marijuana/placebo cigarette Exclusion Criteria: On 1st and last day of -substance abuse (including tobacco) intervention period -family history of BID. neuropathy due to causes For all other days not HIV related TID -use of isoniazid, Adverse events/AEs -Rating for adverse events of anxiety, sedation, disorientation, confusion, and dizziness were significantly higher in the marijuana group compared to placebo group. -Marijuana and placebo groups showed a reduction in total mood disturbance on POMS. AEs: -1 grade 3 dizziness in marijuana group -2 grade 3 anxiety, 1 in each group. Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 20:51 Aug 11, 2016 EP12AU16.026</GPH> Appendix (Tables) mstockstill on DSK3G9T082PROD with PROPOSALS2 VerDate Sep<11>2014 PO 00000 HIVSensory Neuropathy; Neuropathic Pain Frm 00121 Jkt 238001 Ellis et al. (2009) Subjects (n) completed/randomized Subject characteristics dapsone, or metronidazole within 8 weeks of enrollment 28/34 28 males Inclusion Criteria: -documented HIV -documented neuropathic pain refractory to 2:2 analgesics -pain score 2:5 on pain intensity subscale of DDS Fmt 4701 Sfmt 4725 E:\FR\FM\12AUP2.SGM Previous Marijuana Experience: -27 subjects had previous experience -63% of subjects had no exposure for > 1 year before study 12AUP2 Exclusion Criteria: -current DSM-IV substance abuse disorder -lifetime history of dependence on marijuana -previous psychosis with or intolerance to cannabinoids -concurrent use of approved cannabinoid medications -positive UDS for Drugs Admin. Methods NID A marijuana, smoked 0%, 1%, 2%, 4%, 6%, 8%THC Smoking Procedures: - Verbally cued smoking of marijuana cigarette with each puff consisting of: 1) 5s inhale smoke, 2) lOs hold smoke in lungs 3) 40s exhale and breath normally 4) repeat procedure for desired number of puffs -unknown number of puffs QID Study Type Duration Primary Outcome Measure Primary Outcome Measure Results Adverse events/AEs Crossover Pain magnitud eon DDS -Pain reduction was significantly greater after marijuana compared to placebo. -Mood disturbance, quality of life, and psychical disability improved for both marijuana and placebo. -Moderate to severe adverse events were more common with marijuana than placebo. -HIV disease parameters did not differ for marijuana or placebo. -Adverse events included: concentration difficulties, fatigue, sleepiness or sedation, increased duration of sleep, reduced salivation, and thirst. These adverse events were more frequent in marijuana compared to placebo. Dosetitration (on 1'1 day) 2, 5-day treatment phase, with 2-week washout period -NNT=3.5 Withdrawals for drug related reasons: -1 cannabis-naive subject had acute cannabis-induced psychosis -1 subjects developed an intractable smoking-related cough during marijuana administration Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 20:51 Aug 11, 2016 Author& Date Indication 53807 EP12AU16.027</GPH> mstockstill on DSK3G9T082PROD with PROPOSALS2 53808 VerDate Sep<11>2014 Jkt 238001 PO 00000 Frm 00122 Wilsey et al. (2008) Fmt 4701 Neuropathic pain; Various Causes Subjects (n) completed/randomized Subject characteristics cannabinoids during wash-in week -serious medical conditions that affect safety -alcohol or drug dependence within 12 months of study 32/38 20 males 18 females Sfmt 4725 Inclusion Criteria: -CRPS type I, spinal cord injury, peripheral neuropathy, or nerve damage -previous marijuana use E:\FR\FM\12AUP2.SGM 12AUP2 Previous Marijuana Experience: -median (range) time from previous exposure: 1.7 years (31 days to 30 years) -median (range) exposure duration: 2 years (1 day to 22 years). Exclusion Criteria: -no marijuana or cannabinoid medication use for 30 days prior to study; confirmed by UDS EP12AU16.028</GPH> Drugs Admin. Methods Study Type Duration Primary Outcome Measure Primary Outcome Measure Results Adverse events/AEs NID A marijuana, smoked 0%, 3.55%, 7% THC Crossover VAS spontaneo us pain intensity -A significant decrease in pain intensity for both strengths of marijuana compared to placebo -7% THC marijuana significantly decreased functioning on neurocognitive measures compared to placebo. -Subjective effects were greater for 7% THC marijuana than 3.55% THC marijuana with significantly more ratings of good drug effect, bad drug effect, feeling high, feeling stoned, impaired, sedation, confusion, and hunger compared to placebo. Smoking Procedure: Verbally cued smoking of marijuana cigarette with each puff consisting of: 1) 5s inhale smoke, 2) lOs hold smoke in lungs 3) 40s exhale and breath normally 4) repeat procedure for desired number of puffs Cumulative dosing procedure: -escalate the number of puffs from 2 to 4 puffs over 3 smoking sessions with 1 hour between sessions 3, 6-hour sessions, with 3-day between sessions Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 20:51 Aug 11, 2016 Author& Date Indication mstockstill on DSK3G9T082PROD with PROPOSALS2 VerDate Sep<11>2014 Jkt 238001 PO 00000 Frm 00123 Ware et al. (2010) Fmt 4701 Posttraumatic or postsurgical neuropathic pain Subjects (n) completed/randomized Subject characteristics -severe depression -history of schizophrenia or bipolar depression -uncontrolled hypertension, cardiovascular disease, and pulmonary disease -active substance abuse 21/23 11 males 12 females Sfmt 4725 E:\FR\FM\12AUP2.SGM Inclusion Criteria: -neuropathic pain for~ 3 months caused by trauma or surgery -allodynia and hyperalgesia -pain score >4cm VAS -no marijuana use for 1 year prior to study -stable analgesic regimen -normal liver and renal function 12AUP2 Previous Marijuana Experience: -18 subjects had used marijuana before Exclusion Criteria: -pain due to cancer or nociceptive causes -significant cardiac or Drugs Admin. Methods Study Type Duration Primary Outcome Measure Primary Outcome Measure Results Adverse events/AEs Crossover Pain intensity on 11itemNRS -Average daily pain intensity was significantly lower after 9.4% THC compared to placebo. -Anxiety and depression were significantly improved with 9. 4% THC compared to placebo. -No significant difference between placebo and 9.4% THC for subjective effects. TID NIDA placebo; Prairie Plant System Inc. (Canada) marijuana, smoked 0%, 2.5%, 6%, 9.4% THC (25 mg of marijuana/placebo plant material was placed in opaque gelatin capsules) Smoking Procedures: -1) Break one capsule open and tip content into the bowl of a titanium pipe 2) light marijuana material 3) 5s inhale smoke 4) lOs hold smoke in lungs 5) Exhale 1 puffburned all25 mg of plant material 4, 5-day outpatient* treatment phase, with 9-day washout periods AEs: -248 mild AEs were reported -6 moderate AEs were reported: 2 fall, 1 increased pain, 1 numbness, 1 drowsiness, 1 pneumonia -Most frequently reported drugrelated AEs for 9.4% THC: headache, dry eyes, burning sensation, dizziness, numbness, and cough. Withdrawals for drug related reason: -1 subject had increased pain after 6% THC administration -1 subject tested positive for cannabinoids in urine test during placebo treatment Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 20:51 Aug 11, 2016 Author& Date Indication 53809 EP12AU16.029</GPH> mstockstill on DSK3G9T082PROD with PROPOSALS2 53810 VerDate Sep<11>2014 Jkt 238001 PO 00000 Frm 00124 Fmt 4701 Sfmt 4725 E:\FR\FM\12AUP2.SGM 12AUP2 EP12AU16.030</GPH> Wilsey et al. (2013) Neuropathic Pain; Various Causes Subjects (n) completed/randomized Subject characteristics pulmonary disease -current substance abuse or dependence (including marijuana) -history of psychotic disorders -current suicidal ideations 36/39 28 males 11 females Inclusion Criteria: -CRPS type 1, thalamic pain, spinal cord injury, peripheral neuropathy, radiculopathy, or nerve injury -previous marijuana use Previous Marijuana Experience: -median (range) time from last exposure prior to screening: 9.6 years (1 day to 45 years) -16 current marijuana users and 23 past users -# smoked daily: 6 current users, 5 past users -# used approx. once every 2 weeks: 8 current users, 6 past users -# used once every 4 weeks or less: 2 current Drugs Admin. Methods Study Type Duration Primary Outcome Measure Primary Outcome Measure Results Crossover VAS spontaneo us pain intensity -Number of subjects that showed a 30% reduction in pain intensity was significantly greater for both strengths of marijuana compared to placebo. -Both strengths of marijuana showed a similar significant decrease in pain compared to placebo. Adverse events/AEs TID Intermediate doses were used to help maintain blinding NIDA marijuana, vaporized 0%, 1.29%, 3.53% THC Smoking Procedures: - Verbally cued inhalation of vaporized material in the balloon with each puff consisting of: 1) 5s inhale vapors, 2) lOs hold vapors in lungs 3) 40s exhale and breath normally 4) repeat procedure for desired number of puffs BID Cumulative & Flexible Dosing: -1st drug admin. consisted of 4 puffs from balloon. 3, 6-hour sessions, with at least 3 days between sessions -NNT=3.2 for 1.29% THC marijuana vs. placebo. -NNT=2.9 for 3.53% THC marijuana vs. placebo. -Scores for feeling stoned, feeling high, like the drug effect, feeling sedated, and feeling confused were significantly greater for 3.53% THC marijuana compared to 1.29% THC marijuana, and for both strengths of marijuana compared to placebo. -Scores for feeling drunk and feeling impaired are significantly greater in both strengths of marijuana compared to placebo. -Scores for desired more of the drug were significantly greater for 1.29% THC marijuana compared to placebo, with no significant difference seen for 3.53% THC marijuana. -3.53% THC marijuana had significantly worse performance thanl.29% THC marijuana for learning and memory. -Both strengths of marijuana significantly reduced scores on attention compared to placebo. Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 20:51 Aug 11, 2016 Author& Date Indication mstockstill on DSK3G9T082PROD with PROPOSALS2 VerDate Sep<11>2014 Jkt 238001 PO 00000 Subjects (n) completed/randomized Subject characteristics users, 12 past users Drugs Admin. Methods Frm 00125 Fmt 4701 Sfmt 4725 E:\FR\FM\12AUP2.SGM -Followed 2 hours later by 2nd drug admin. -2nd drug admin. consisted of 4 to 8 puffs from balloon; number of puffs taken was left up to the subject so they could self-titrate to their target does, which balanced desired response and tolerance levels. Study Type Duration Primary Outcome Measure Primary Outcome Measure Results Adverse events/AEs 12AUP2 Exclusion Criteria: -no marijuana or cannabinoid medication use for 30 days prior to study; confirmed by UDS -severe depression -suicidal ideations -diagnoses of serious mental illness -uncontrolled hypertension, cardiovascular disease, or chronic pulmonary disease -active substance abuse *Out-patient: subjects were given enough doses of marijuana/placebo to last the 5-day treatment phase, and then were sent home for the remainder of the treatment phase. AE=Adverse Event; BID=drug administered two times per day; CRPS=complex regional pain syndrome; DDS=Descriptor Differential Scale; NIDA=National Institute of Drug Abuse; NNT=Number Needed to Treat; NRS=Numeric Rating Scale; QID=drug administered four times per day; THC=delta9-tetrahydrocannbinol; TID=drug administered three times per day; UDS=urine drug screen; VAS= Visual Analog Scale. Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 20:51 Aug 11, 2016 Author& Date Indication 53811 EP12AU16.031</GPH> mstockstill on DSK3G9T082PROD with PROPOSALS2 53812 VerDate Sep<11>2014 Jkt 238001 PO 00000 Frm 00126 Fmt 4701 Sfmt 4725 E:\FR\FM\12AUP2.SGM 12AUP2 Previous Marijuana EX]Jerience: -mean (SD) # of days/week of marijuana use: Low-BIA= 6 (2); Normal-BIA=5 (2) -mean (SD) # marijuana cigarettes/day: LowBIA=3 (2); NormalBIA=3 (l) -mean (SD) years of marijuana use: LowBIA=l2.2 (8.3); Smoking Procedures: Verbally cued smoking of marijuana cigarette with each puff consisting of: 1) 5s inhale smoke, 2) lOs hold smoke in lungs 3) 40s exhale and breath normally Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 20:51 Aug 11, 2016 EP12AU16.032</GPH> Table - · -----------------7------------7 double-blind trial lied. -----·--- ·------- --------------------- - - - - -ked- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -f- - - - - - - - - - - - - - - - - - -lation -in -HIV/AIDS ---·--- 2: Randomized ---------- -- -------·Author & Subjects (n) Drugs Study Type Primary Results Adverse events/AEs Date completed/randomized Admin. Methods Duration Outcome (summary) Indication Subject characteristics Measure Haney et Low-BIA: 15/17 NIDA marijuana, Crossover No primary -In Low-BIA all -Ratings of high and good drug effect al. (2005) 12 males smoked outcome dronabinol doses and were significantly increased for all 8, 7-hour 3 females 0%, 1.8%, 2.8%, measure is 1.8% and 3.9% THC strengths of marijuana and all doses of HIV+ Normal-BIA: 15/18 3.9%THC session, with specified marijuana dronabinol except lOmg dronabinol. with 15 males at least 1 day significantly increased -3.9% THC significantly increased either Dronabinol, oral between Related caloric intake ratings of dry mouth and thirsty normal Inclusion Criteria: 0, 10, 20, 30mg sessions outcome compared with compared to placebo. -21-50 years of age muscle measure was placebo. -Low-BIA group showed no significant mass -prescribed at least 2 Double-dummy caloric intake adverse event ratings, and in the (Normalantiretroviral drug admin. nonnal-BIA group the only significant BIA) or medications Procedures: adverse events in response to marijuana clinically -currently under the -only 1 active dose included: diarrhea after 3.9% THC significant care of a physician for per session marijuana. loss of HIV management -one -Dronabinol had more incidences of muscle -medically and dronabinol!placebo adverse events at all doses compared to mass psychiatrically stable capsule followed l marijuana. (Low-BIA) -smoke marijuana 2: hour later by 2x/week for past 4 marijuana/placebo weeks smoking mstockstill on DSK3G9T082PROD with PROPOSALS2 VerDate Sep<11>2014 Jkt 238001 PO 00000 Frm 00127 Fmt 4701 Sfmt 4725 E:\FR\FM\12AUP2.SGM Haney et al. (2007) Subjects (n) completed/randomized Subject characteristics Nonnal-BIA=l0.8 (2.6) Exclusion Criteria: -diagnosis of nutritional malabsorption, major depression, dementia, chronic diarrhea, weakness, fever, significant pulmonary disease -an opportunistic infection within past 3 months -obesity -use of steroids within past 3 weeks -drug dependence (excluding marijuana or nicotine) 10 9 males l female HIV+ 12AUP2 Inclusion Criteria: -21-50 years of age -taking~ 2 antiretroviral medications -under the care of a physician for HIV management -medically and psychiatrically stable -smoke marijuana ~ Drugs Admin. Methods Study Type Duration Primary Outcome Measure Results (summary) Adverse events/AEs -Both strengths of marijuana significantly increased caloric intake compared to placebo. -3.9% THC marijuana significantly increased body weight compared to placebo. -Both strengths of marijuana significantly increased ratings of: good dmg effect, high, mellow, stimulate, friendly, and self-confident. Only 2% THC marijuana significantly increased ratings of anxious. -Both strengths of marijuana significantly increased subjective measures for satisfied sleep and estimated time of sleep. 4) repeat for 3 puffs per smoking session QD NIDA marijuana, smoked 0%, 2%,3.9% THC Dronabinol, oral 0, 5, lOmg Double-dummy dmgadmin. Procedures: -only l active dose per session -one dronabinol/placebo Crossover 2, 16-day treatment phases, with 5-10 days between phases F:ach 16-day treatment phase consisted of 2, 4-day active drug No primary outcome measure is specified Related outcome measures were Caloric Intake & Body Weight Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 20:51 Aug 11, 2016 Author & Date Indication 53813 EP12AU16.033</GPH> mstockstill on DSK3G9T082PROD with PROPOSALS2 53814 VerDate Sep<11>2014 Subjects (n) completed/randomized Sub.iect characteristics 2x/week for the past 4 weeks Jkt 238001 PO 00000 Frm 00128 Fmt 4701 Previous Marijuaua EX]Jerience: -mean (SD) # of days/week of marijuana use: 4.6 (0.6) -mean (SD) # marijuana cigarettes/day: 3.2 (0.8) -mean (SD) years of marijuana use: 18.6 (3.3) Drugs Admin. Methods Study Type Duration capsule followed 1 hour later by marijuana/placebo smoking period with 4day placebo period between active drug periods. Sfmt 4725 E:\FR\FM\12AUP2.SGM Smoking Procedures: Light cued smoking of marijuana cigarette with each puff consisting of: 1) 5s inhale smoke, 2) lOs hold smoke in lungs 3) 40s exhale aud breath normally 4) repeat for 3 puffs per smoking session Primary Outcome Measure Results (summary) Adverse events/AEs 12AUP2 Exclusion Criteria: -diagnosis of nutritional malabsorption, major depression, dementia, chronic diarrhea. weakness. fever, significant pulmonary disease -au opportmristic QID infection within past 3 months -obesity -use of steroids within past 3 weeks -drug dependence (excluding marijuana or nicotine) AE=Adverse Event: BIA=Bioelectric Impedance Analysis: NIDA=National Institute of Drug Abuse: QD=drug adnrinistered one time per day: QID=drug adnrinistered four times per day; THC=delta-9-tetrahydrocaunbinol Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 20:51 Aug 11, 2016 EP12AU16.034</GPH> Author & Date Indication mstockstill on DSK3G9T082PROD with PROPOSALS2 VerDate Sep<11>2014 Jkt 238001 PO 00000 Frm 00129 Fmt 4701 Sfmt 4725 E:\FR\FM\12AUP2.SGM 12AUP2 Exclusion Criteria: -no marijuana smoking for ::;1 month prior to screening -psychiatric disorder (other than depression) -history of substance use -substantial neurological disease other than MS -severe or unstable Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 20:51 Aug 11, 2016 Table 3: Randomized, controlled, double-blind trails examining smoked marijuana in treatment of spasticity in Multiple Sclerosis Author & I Subjects (n) I Drugs I Study Type I Primary I Primary Outcome Measure I Adverse events/AEs Date completed/randomized Admin. Methods Duration Outcome Results Indication Subj_ect characteristics Measure -Marijuana reduced scores on Corey30/37 NIDA marijuana, Crossover Spasticity -Smoking marijuana Bloom et significantly reduced spasticity cognitive measure compared to 11 males smoked on the scores compared to placebo al. (2012) 19 females 0%,4% THC 2, 3-day Modified placebo. -Marijuana significantly treatment Ashworth increased perceptions of Multiple Inclusion Criteria: periods, Scale Smoking -documented MS with 11 day "highness" compared to placebo Sclerosis; Procedure: -spasticity smoking of washout Spasticity Withdrawals for drug-related -moderate increase in marijuana cigarette period tone (score 2:: 3 on reasons: with each puff -2 subjects felt uncomfortably consisting of: modified Ashworth high scale 1) 5s inhale smoke, 2) lOs hold smoke -2 dizziness Previous Marijuana in lungs -1 fatigue Experience: 3) 45s exhale and breath normally -24 subjects had 4) repeat for an previous exposure to marijuana average of 4 puffs per smoking session -10 subjects used marijuana within the year QD 53815 EP12AU16.035</GPH> mstockstill on DSK3G9T082PROD with PROPOSALS2 53816 VerDate Sep<11>2014 Jkt 238001 PO 00000 Frm 00130 Fmt 4701 Sfmt 4725 E:\FR\FM\12AUP2.SGM Subjects (n) Drugs Study Type Primary Primary Outcome Measure Adverse events/AEs Duration Outcome Results completed/randomized Admin. Methods Subject characteristics Measure medical illnesses -known pulmonary disorders -using high dose narcotic medication for pain -using benzodiazepines to control spasticity AE=Adverse Event: MS= Multiple Sclerosis; NIDA=National Institute of Drug Abuse; QD=dmg administered one time per day; THC=delta-9tetrahydrocannbinol 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 20:51 Aug 11, 2016 EP12AU16.036</GPH> Author & Date Indication mstockstill on DSK3G9T082PROD with PROPOSALS2 VerDate Sep<11>2014 Jkt 238001 Crawford & Merritt (1979) PO 00000 Hypertensive and Normotensive Glaucoma I HT group: 8 4 males 4 females NT group: 8 4 males 4 females Frm 00131 Inclusion Criteria: -documented glaucoma Fmt 4701 Previous Marijuana Experience: -all were marijuana nai:vc Sfmt 4725 E:\FR\FM\12AUP2.SGM Merritt et al. (1980) Glaucoma Exclusion Criteria: -coronary artery disease 18 12 males 6 females (31 glaucoma eyes, analyzed results for each eye) 12AUP2 Inclusion Criteria: -documented glaucoma Previous Marijuana Experience: -9 subjects had used marijuana at least once Exclusion Criteria: I NIDA marijuana, smoked 0%, 2.8% THC Smoking Procedure: -instructed to inhale 20 times deeply and retain smoke in lungs -smoke marijuana/placebo cigarette in 5 minutes Crossover 4. 1-day sessions, no time between sessions No primary outcome measure is specified Related outcome measure was lOP I -Marijuana decreased lOP by 37-44% from baseline. -The maximal decrease in lOP was significantly greater inHT (-14mmHg) than NT(9mmHg) after marijuana . -Placebo marijuana increased heart rate for 10 minutes in both groups. -The maximal increase in heart rate was significantly greater in NT than HT after marijuana. -The maximal decrease in blood pressure was significantly greater in HT than NT after marijuana. QD NIDA marijuana, smoked 0%,2% THC Smoking Procedure: -None described -smoked 1 marijuana/placebo cigarette over 1020 minutes I Crossover I 2, 1-day sessions No primary outcome measure is specified Related outcome measure was lOP -Marijuana significantly decreased lOP compared to placebo -Marijuana significantly increased heart rate compared to placebo -Blood pressure significantly decreased after marijuana -All subjects experienced hunger, thirst, euphoria, drowsy, and feeling cold -Observed adverse events were greater in marijuana nai:ve subjects than in subjects with prior marijuana experience. QD AEs: -5 subjects postural hypotension Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 20:51 Aug 11, 2016 Table 4: Randomized, controlled, double-blind trails examining smoked marijuana in treatment of intraocular pressure in Glaucoma Author & I Subjects (n) Drugs I Study Type Primary I Results I Adverse events/AEs (summary) Duration Outcome Date completed/randomized Admin. Methods Indication Subject characteristics Measure 53817 EP12AU16.037</GPH> mstockstill on DSK3G9T082PROD with PROPOSALS2 53818 VerDate Sep<11>2014 Jkt 238001 PO 00000 Frm 00132 Fmt 4701 Sfmt 4725 E:\FR\FM\12AUP2.SGM Subjects (n) Drugs Study Type Primary Results Adverse events/AEs Duration Outcome (summary) completed/randomized Admin. Methods Subject characteristics Measure -cardiac, neurological, -8 subjects anxiety with and psychiatric tachycardia and palpitations dysfunction AE=Adverse Event; HT=Hypertensive; lOP= Intraocular pressure; NIDA=National Institute of Drug Abuse; NT= Normotensive; QD=dmg administered one time per day; THC=delta-9-tetrahydrocannbinol 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 20:51 Aug 11, 2016 EP12AU16.038</GPH> Author& Date Indication mstockstill on DSK3G9T082PROD with PROPOSALS2 VerDate Sep<11>2014 Adverse events/AEs Jkt 238001 PO 00000 Frm 00133 -Marijuana initially significantly increased pulse rate compared to placebo, and then at 90 minutes pulse rate was significantly decreased compared to baseline. -All subjects felt intoxicated after marijuana. Fmt 4701 Sfmt 4725 E:\FR\FM\12AUP2.SGM 12AUP2 QD AE=Adverse Event: NIDA=National Institute of Drug Abuse; QD=drug administered one time per day; sGaw=Specific Airway Conductance: THC=delta-9tetrahydrocannbinol Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 20:51 Aug 11, 2016 Table 5: Randomized, controlled, double-blind trails examining smoked marijuana in treatment of asthma Author & I Subjects (n) I Drugs I Study I Primary I Results completed/randomized Admin. Methods Design Outcome (summary) Date Indication Subj_ect characteristics Duration Measure Tashkin et 10 I NIMH (NIDA) I Crossover I No primary -Marijuana significantly marijuana, smoked 5 males increased sGaw (33-48%) outcome al. (1974) 4, 1-day 5 females 0%,2%THC compared to placebo and measure is specified baseline Bronchial sessions, Asthma Inclusion Criteria: Dronabinol, oral with at -diagnosis ofbronchial 0, 15mg Related least 48 hours outcome asthma -asthma relieved by Dosing is 7mg/kg of between measure body weight of sessions bronchodilator was sGaw plant material medication -clinically stable Smoking Procedure: smoking of Previous Marijuana Experience: marijuana cigarette -7 subjects had previous with each puff exposure to marijuana consisting of: 1) 2-4s deep inhale -amount of exposure <1 smoke, cigarette/month 2) 15s hold smoke Exclusion Criteria: in lungs -no marijuana use "S.7 3) 5s exhale and days of study breath normally -psychiatric illness 4) repeat till entire cigarette is smoked 53819 EP12AU16.039</GPH> 53820 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules U.S. Department of Justice—Drug Enforcement Administration Schedule of Controlled Substances: Maintaining Marijuana in Schedule I of the Controlled Substances Act Background, Data, and Analysis: Eight Factors Determinative of Control and Findings Pursuant to 21 U.S.C. 812(b) Prepared by: Office of Diversion Control, Drug and Chemical Evaluation Section, Washington, DC 20537 July 2016 mstockstill on DSK3G9T082PROD with PROPOSALS2 Background On December 17, 2009, Bryan Krumm, CNP, submitted a petition to the Drug Enforcement Administration (DEA) to initiate proceedings for a repeal of the rules or regulations that place marijuana 38 in schedule I of the Controlled Substances Act (CSA). The petition requests that marijuana be rescheduled in any schedule other than schedule I of the CSA. The petitioner claims that: 1. Marijuana has accepted medical use in the United States; 2. Studies have shown that smoked marijuana has proven safety and efficacy; 3. Marijuana is safe for use under medical supervision; and 4. Marijuana does not have the abuse potential for placement in schedule I The DEA accepted this petition for filing on April 3, 2010. The Attorney General may by rule transfer a drug or other substance between schedules of the CSA if she finds that such drug or other substance has a potential for abuse, and makes the findings prescribed by 21 U.S.C. 812(b) for the schedule in which such drug is to be placed. 21 U.S.C. 811(a)(1). The Attorney General has delegated this responsibility to the Acting Administrator of the DEA. 28 CFR 0.100(b). In accordance with 21 U.S.C. 811(b), after gathering the necessary data, the DEA submitted the petition and 38 The Controlled Substances Act (CSA) defines marijuana as the following: ‘‘All parts of the plant Cannabis sativa L., whether growing or not; the seeds thereof; the resin extracted from any part of such plant; and every compound, manufacture, salt, derivative, mixture, or preparation of such plant, its seeds or resin. Such term does not include the mature stalks of such plant, fiber produced from such stalks, oil or cake made from the seeds of such plant, any other compound, manufacture, salt, derivative, mixture, or preparation of such mature stalks (except the resin extracted there from), fiber, oil, or cake, or the sterilized seed of such plant which is incapable of germination. 21 U.S.C. 802(16). Note that ‘‘marihuana’’ is the spelling originally used in the CSA. This document uses the spelling that is more common in current usage, ‘‘marijuana.’’ VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 necessary data to the Department of Health and Human Services (HHS) on May 6, 2011, and requested that HHS provide a scientific and medical evaluation and scheduling recommendation for marijuana. In documents dated June 3 and June 25, 2015, the acting Assistant Secretary for Health of the HHS 39 recommended to the DEA that marijuana continue to be controlled in Schedule I of the CSA, and provided to the DEA its scientific and medical evaluation titled ‘‘Basis for the Recommendation for Maintaining Marijuana in Schedule I of the Controlled Substances Act.’’ The HHS’s recommendations are binding on the DEA as to scientific and medical matters. 21 U.S.C. 811(b). Before initiating proceedings to reschedule a substance, the CSA requires the Acting Administrator to determine whether the HHS scheduling recommendation, scientific and medical evaluation, and ‘‘all other relevant data’’ constitute substantial evidence that the drug should be rescheduled as proposed. 21 U.S.C. 811(b). The Acting Administrator must determine whether there is substantial evidence to conclude that the drug meets the criteria for placement in another schedule based on the criteria set forth in 21 U.S.C. 812(b). The CSA requires that both the DEA and the HHS consider the eight factors specified by Congress in 21 U.S.C. 811(c). This document lays out those considerations and is organized according to the eight factors. As DEA sets forth in detail below, the evidence shows: 1. Actual or relative potential for abuse. Marijuana has a high potential for abuse. Preclinical and clinical data show that it has reinforcing effects characteristic of drugs of abuse. National databases on actual abuse show marijuana is the most widely abused drug, including significant numbers of substance abuse treatment admissions. Data on marijuana seizures show widespread availability and trafficking. 2. Scientific evidence of its pharmacological effect. The scientific understanding of marijuana, cannabinoid receptors, and the endocannabinoid system continues to be studied and elucidated. Marijuana 39 As set forth in a memorandum of understanding entered into by the HHS, the Food and Drug Administration (FDA), and the National Institute on Drug Abuse (NIDA), the FDA acts as the lead agency within the HHS in carrying out the Secretary’s scheduling responsibilities under the CSA, with the concurrence of the NIDA. 50 FR 9518, Mar. 8, 1985. The Secretary of the HHS has delegated to the Assistant Secretary for Health of the HHS the authority to make domestic drug scheduling recommendations. PO 00000 Frm 00134 Fmt 4701 Sfmt 4702 produces various pharmacological effects, including subjective (e.g., euphoria, dizziness, disinhibition), cardiovascular, acute and chronic respiratory, immune system, and prenatal exposure effects, as well as behavioral and cognitive impairment. 3. Current scientific knowledge. There is no currently accepted medical use for marijuana in the United States. Marijuana sources are derived from numerous cultivated strains and may have different levels of D9-THC and other cannabinoids. Under the fiveelement test for currently accepted medical use discussed in more detail below and upheld by the Court of Appeals for the District of Columbia in Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994) (hereinafter ‘‘ACT’’), there is no complete scientific analysis of marijuana’s chemical components; there are not adequate safety studies; there are not adequate and well-controlled efficacy studies; there is not a consensus of medical opinion concerning medical applications of marijuana; and the scientific evidence regarding marijuana’s safety and efficacy is not widely available. To date, scientific and medical research has not progressed to the point that marijuana has a currently accepted medical use, even under conditions where its use is severely restricted. 4. History and current pattern of abuse. Marijuana continues to be the most widely used illicit drug. In 2014, there were 22.2 million current users. There were also 2.6 million new users, most of whom were less than 18 years of age. During the same period, marijuana was the most frequently identified drug exhibit in federal, state, and local forensic laboratories. 5. Scope, duration, and significance of abuse. Abuse of marijuana is widespread and significant. In 2014, for example, an estimated 6.5 million people aged 12 or older used marijuana on a daily or almost daily basis over a 12-month period. In addition, a significant proportion of all admissions for substance abuse treatment are for marijuana/hashish as their primary drug of abuse. In 2013, 16.8% of all such admissions—281,991 over the course of the year—were for primary marijuana/ hashish abuse. 6. Risk, if any, to public health. Together with the health risks outlined in terms of pharmacological effects above, public health risks from acute use of marijuana include impaired psychomotor performance, impaired driving, and impaired performance on tests of learning and associative processes. Chronic use of marijuana E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules poses a number of other risks to the public health including physical as well as psychological dependence. 7. Psychic or physiological dependence liability. Long-term, heavy use of marijuana can lead to physical dependence and withdrawal following discontinuation, as well as psychic or psychological dependence. In addition, a significant proportion of all admissions for treatment for substance abuse are for primary marijuana abuse; in 2013, 16.8% of all admissions were for primary marijuana/hashish abuse, representing 281,991 individuals. 8. Immediate precursor. Marijuana is not an immediate precursor of any controlled substance. As specified in 21 U.S.C. 812(b)(1), in order for a substance to be placed in schedule I, the Acting Administrator must find that: A. The drug or other substance has a high potential for abuse. B. The drug or other substance has no currently accepted medical use in treatment in the United States. C. There is a lack of accepted safety for use of the drug or other substance under medical supervision. To be classified in another schedule under the CSA (e.g., II, III, IV, or V), a substance must have a ‘‘currently accepted medical use in treatment in the United States.’’ 21 U.S.C. 812(b)(2)–(5). A substance also may be placed in schedule II if it is found to have ‘‘a currently accepted medical use with severe restrictions.’’ 21 U.S.C. 812(b)(2). If a controlled substance has no such currently accepted medical use, it must be placed in schedule I. See Notice of Denial of Petition, 66 FR 20038 (Apr. 18, 2001) (‘‘Congress established only one schedule—schedule I—for drugs of abuse with ‘no currently accepted medical use in treatment in the United States’ and ‘lack of accepted safety for use . . . under medical supervision.’ ’’). A drug that is the subject of an approved new drug application (NDA) or abbreviated new drug application (ANDA) under Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355), is considered to have a currently accepted medical use in treatment in the United States for purposes of the CSA. The HHS stated in its review, however, that FDA has not approved any NDA for marijuana for any indication. In the absence of NDA or ANDA approval, DEA has established a fiveelement test for determining whether the drug has a currently accepted medical use in treatment in the United States. Under this test, a drug will be considered to have a currently accepted medical use only if the following five elements are satisfied: VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 1. The drug’s chemistry is known and reproducible; 2. There are adequate safety studies; 3. There are adequate and wellcontrolled studies proving efficacy; 4. The drug is accepted by qualified experts; and 5. The scientific evidence is widely available. 57 FR 10499, 10506 (March 26, 1992). See also ACT, 15 F.3d at 1135. As discussed in Factor 3, below, HHS concluded, and DEA agrees, that the scientific evidence is insufficient to demonstrate that marijuana has a currently accepted medical use under the five-element test. The evidence was insufficient in this regard also when the DEA considered petitions to reschedule marijuana in 1992 (57 FR 10499),40 in 2001 (66 FR 20038), and in 2011 (76 FR 40552).41 Little has changed since 2011 with respect to the lack of clinical evidence necessary to establish that marijuana has a currently accepted medical use. No studies have scientifically assessed the efficacy and full safety profile of marijuana for any specific medical condition. The limited existing clinical evidence is not adequate to warrant rescheduling of marijuana under the CSA. To the contrary, the data in this scheduling review document show that marijuana continues to meet the criteria for schedule I control under the CSA for the following reasons: 1. Marijuana has a high potential for abuse. 2. Marijuana has no currently accepted medical use in treatment in the United States. 3. Marijuana lacks accepted safety for use under medical supervision. Factor 1: The Drug’s Actual or Relative Potential for Abuse Marijuana is the most commonly abused illegal drug in the United States. It is also the most commonly used illicit drug by high school students in the United States. Further, marijuana is the most frequently identified drug by state, local and federal forensic laboratories. Marijuana’s main psychoactive ingredient, D9-tetrahydrocannabinol (D9THC),42 is an effective reinforcer in laboratory animals, including primates and rodents. These animal studies both predict and support the observations that marijuana produces reinforcing effects in humans. Such reinforcing 40 See Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131 (D.C. Cir. 1994). 41 See Americans for Safe Access v. DEA, 706 F.3d 438 (D.C. Cir. 2013)(rhg den. 2013). 42 The terms D9-THC and THC are used interchangeably thoughout this document. PO 00000 Frm 00135 Fmt 4701 Sfmt 4702 53821 effects can account for the repeated abuse of marijuana. A. Indicators of Abuse Potential The HHS has concluded in its document, ‘‘Basis for the Recommendation for Maintaining Marijuana in Schedule I of the Controlled Substances Act,’’ that marijuana has a high potential for abuse. The finding of ‘‘abuse potential’’ is critical for control under the Controlled Substances Act (CSA). Although the term is not defined in the CSA, guidance in determining abuse potential is provided in the legislative history of the Act (Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91–1444, 91st Cong., Sess. 2 (1970), reprinted in 1970 U.S.C.C.A.N. 4566, 4603). Accordingly, the following items are indicators that a drug or other substance has potential for abuse: • There is evidence that individuals are taking the drug or drugs containing such a substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or of the community; or • There is significant diversion of the drug or drugs containing such a substance from legitimate drug channels; or • Individuals are taking the drug or drugs containing such a substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such drugs in the course of his professional practice; or • The drug or drugs containing such a substance are new drugs so related in their action to a drug or drugs already listed as having a potential for abuse to make it likely that the drug will have the same potentiality for abuse as such drugs, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community. Of course, evidence of actual abuse of a substance is indicative that a drug has a potential for abuse. In its recommendation, the HHS analyzed and evaluated data on marijuana as applied to each of the above four criteria. The analysis presented in the recommendation (HHS, 2015) is discussed below: 1. There is evidence that individuals are taking the drug or drugs containing such a substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or of the community. E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53822 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules The HHS stated that some individuals are taking marijuana in amounts sufficient to create a hazard to their health and to the safety of other individuals and the community. Data from national databases on actual abuse of marijuana support the idea that a large number of individuals use marijuana. In its recommendation (HHS, 2015), the HHS presented data from the National Survey on Drug and Health (NSDUH) of the Substance Abuse and Mental Health Services Administration (SAMHSA) and the Monitoring the Future (MTF) survey of the National Institute on Drug Abuse (NIDA), and the DEA has since updated this information. The most recent data from SAMHSA’s NSDUH in 2014 reported that marijuana was the most used illicit drug. Among Americans aged 12 years and older, an estimated 22.2 million Americans used marijuana within the past month according to the 2014 NSDUH. In 2004, an estimated 14.6 million individuals reported using marijuana within the month prior to the study. The estimated rates in 2014 thus reflect an increase of approximately 7.6 million individuals over a 10-year period. According to the 2013 NSDUH report, an estimated 19.8 million individuals reported using marijuana. Thus, over a period of one year (2013 NSDUH–2014 NSDUH), there was an estimated increase of 2.4 million individuals in the United States using marijuana. The results from the 2015 Monitoring the Future survey of 8th, 10th, and 12th grade students indicate that marijuana was the most widely used illicit drug in these age groups. Current monthly use was 6.5% of 8th graders, 14.8% of 10th graders, and 21.3% of 12th graders. The Treatment Episode Data Set (TEDS) in 2013 reported that marijuana abuse was the primary factor in 16.8 percent of non-private substance-abuse treatment facility admissions. In 2011, SAMHSA’s Drug Abuse Warning Network (DAWN) reported that marijuana was mentioned in 36.4% (455,668 out of approximately 1.25 million) of illicit drug-related Emergency Department (ED) visits. Data on the extent and scope of marijuana abuse are presented under Factors 4 and 5 of this analysis. Discussion of the health effects of marijuana is presented under Factor 2, and the assessment of risk to the public health posed by acute and chronic marijuana abuse is presented under Factor 6 of this analysis. 2. There is significant diversion of the drug or drugs containing such a substance from legitimate drug channels. In accordance with the CSA, the only lawful source of marijuana in the United VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 States is that produced and distributed for research purposes under the oversight of NIDA and in conformity with United States obligations under the Single Convention on Narcotic Drugs.43 The HHS stated that there is a lack of significant diversion from legitimate drug sources, but that this is likely due to high availability of marijuana from illicit sources. Marijuana is not an FDAapproved drug product. Neither a New Drug Application (NDA) nor a Biologics License Application (BLA) has been approved for marketing in the United States. However, the marijuana used for nonclinical and clinical research represents a very small amount of the total amount of marijuana available in the United States and therefore information about marijuana diversion from legitimate sources is limited or not available. The DEA notes that the magnitude of the demand for illicit marijuana is evidenced by information from a number of databases presented under Factor 4. Briefly, marijuana is the most commonly used illegal drug in the United States. It is also the most commonly used illicit drug by American high schoolers. Marijuana is the most frequently identified drug in state, local, and federal forensic laboratories, with increasing amounts of both domestically grown and of illicitly smuggled marijuana. Given that marijuana has long been the most widely trafficked and abused controlled substance in the United States, and that all aspects of such illicit activity are entirely outside of the closed system of distribution mandated by the CSA, it may well be the case that there is little thought given to diverting marijuana from the small supplies produced for legitimate research purposes. Thus, the lack of data indicating diversion of marijuana from legitimate channels to the illicit market is not indicative of a lack of potential for abuse of the drug. 3. Individuals are taking the drug or drugs containing such a substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such drugs in the course of his professional practice. The HHS stated that the FDA has not evaluated or approved an NDA or BLA for marijuana for any therapeutic indication. Consistent with federal law, therefore, an individual legitimately can take marijuana based on medical advice from a practitioner only by participating 43 See 76 FR 51403, 51409–51410 (2011) (discussing cannabis controls required under the Single Convention). PO 00000 Frm 00136 Fmt 4701 Sfmt 4702 in research that is being conducted under an Investigational New Drug (IND) application. The HHS noted that there are several states as well as the District of Columbia which have passed laws allowing for individuals to use marijuana for purported ‘‘medical’’ use under certain circumstances, but data are not available yet to determine the number of individuals using marijuana under these state laws. Nonetheless, according to 2014 NSDUH data, 22.2 million American adults currently use marijuana (SAMHSA, 2015a). Based on the large number of individuals who use marijuana and the lack of an FDAapproved drug product, the HHS concluded that the majority of individuals using marijuana do so on their own initiative rather than by following medical advice from a licensed practitioner. 4. The drug or drugs containing such a substance are new drugs so related in their action to a drug or drugs already listed as having a potential for abuse to make it likely that the drug will have the same potentiality for abuse as such drugs, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community. Marijuana and its primary psychoactive ingredient, D9-THC, are controlled substances in schedule I under the CSA. The HHS stated that one approved, marketed drug product contains synthetic D9-THC, also known as dronabinol, and another approved, marketed drug product contains a cannabinoid-like synthetic compound that is structurally related to D9-THC, the main active component in marijuana. Both products are controlled under the CSA. Marinol is a schedule III drug product containing synthetic D9-THC (dronabinol) formulated in sesame oil in soft gelatin capsules. Marinol was approved by the FDA in 1985 for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who did not respond to conventional anti-emetic treatments. In 1992, FDA approved Marinol for the treatment of anorexia associated with weight loss in patients with acquired immunodeficiency syndrome (AIDS). Marinol was originally placed into schedule II and later rescheduled to schedule III under the CSA due to the low reports of abuse relative to marijuana. E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules Cesamet is a drug product containing the schedule II substance nabilone, a synthetic substance structurally related to D9-THC. Cesamet was approved for marketing by the FDA in 1985 for the treatment of nausea and vomiting associated with cancer chemotherapy. All other naturally occurring cannabinoids in marijuana and their synthetic equivalents with similar chemical structure and pharmacological activity are already included as schedule I drugs under the CSA. B. Abuse Liability Studies In addition to the indicators suggested by the CSA’s legislative history, data as to preclinical and clinical abuse liability studies, as well as actual abuse, including clandestine manufacture, trafficking, and diversion from legitimate sources, are considered in this factor. Abuse liability evaluations are obtained from studies in the scientific and medical literature. There are many preclinical measures of a drug’s effects that when taken together provide an accurate prediction of the human abuse liability. Clinical studies of the subjective and reinforcing effects in humans and epidemiological studies provide quantitative data on abuse liability in humans and some indication of actual abuse trends. Both preclinical and clinical studies have clearly demonstrated that marijuana and D9THC possess the attributes associated with drugs of abuse: They function as a positive reinforcer to maintain drugseeking behavior, they function as a discriminative stimulus, and they have dependence potential. Preclinical and most clinical abuse liability studies have been conducted with the psychoactive constituents of marijuana, primarily D9-THC and its metabolite, 11-hydroxy-D9-THC. D9THC’s subjective effects are considered to be the basis for marijuana’s abuse liability. The following studies provide a summary of that data. mstockstill on DSK3G9T082PROD with PROPOSALS2 1. Preclinical Studies D9-THC, the primary psychoactive component in marijuana, is an effective reinforcer in laboratory animals, including primates and rodents, as these animals will self-administer D9-THC. These animal studies both predict and support the observations that D9-THC, whether smoked as marijuana or administered by other routes, produces reinforcing effects in humans. Such reinforcing effects can account for the repeated abuse of marijuana. VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 a. Drug Discrimination Studies The drug discrimination paradigm is used as an animal model of human subjective effects (Solinas et al., 2006) and is a method where animals are able to indicate whether a test drug is able to produce physical or psychological changes similar to a known drug of abuse. Animals are trained to press one bar (in an operant chamber) when they receive a known drug of abuse and another bar when they receive a placebo. When a trained animal receives a test drug, if the drug is similar to the known drug of abuse, it will press the bar associated with the drug. Discriminative stimulus effects of D9THC have specificity for the pharmacological effects of cannabinoids found in marijuana (Balster and Prescott, 1992; Browne and Weissman, 1981; Wiley et al., 1993; Wiley et al., 1995). As mentioned by the HHS, the discriminative stimulus effects of cannabinoids appear to be unique because abused drugs of other classes including stimulants, hallucinogens, opioids, benzodiazepines, barbiturates, NMDA antagonists, and antipsychotics do not fully substitute for D9-THC. Laboratory animals including monkeys (McMahon et al., 2009), mice (McMahon et al., 2008), and rats (Gold et al., 1992) are able to discriminate cannabinoids from other drugs and placebo. The major active metabolite of D9-THC, 11-hydroxy-D9-THC, generalizes to D9-THC (Browne and Weissman, 1981). In addition, according to the HHS, twenty-two other cannabinoids found in marijuana also substitute for D9-THC. At least one cannabinoid, CBD, does not substitute for D9-THC in rats (Vann et al., 2008). b. Self-Administration Studies Animal self-administration behavior associated with a drug is a commonly used method for evaluating if the drug produces rewarding effects and for predicting abuse potential (Balster, 1991; Balster and Bigelow, 2003). Drugs that are self-administered by animals are likely to produce rewarding effects in humans. As mentioned in the HHS review document, earlier attempts to demonstrate self-administration of D9THC were unsuccessful and confounded by diet restrictions, animal restraint, and known analgesic activity of D9-THC at testing doses (Tanda and Goldberg, 2003; Justinova et al., 2003). Selfadministration of D9-THC was first demonstrated by Tanda et al. (2000). Tanda et al. (2000) showed that squirrel monkeys that were initially trained to self-administer cocaine (30 mg/kg, i.v.) self-administered 2 mg/kg D9-THC (i.v.) PO 00000 Frm 00137 Fmt 4701 Sfmt 4702 53823 and at a rate of 30 injections per one hour session. Tanda et al. (2000) used a lower dose of D9-THC that was rapidly delivered (0.2 ml injection over 200 ms) than in previous self-administration studies such that analgesic activity of D9-THC was not a confounding factor. The authors also stated that the doses were comparable to those doses used by humans who smoke marijuana. A CB1 receptor antagonist (SR141716) blocked this rewarding effect of THC. Justinova et al. (2003) were able to demonstrate self-administration of D9¨ THC in drug-naıve squirrel monkeys (no previous exposure to other drugs). The authors tested the monkeys with several doses of D9-THC (1, 2, 4, 8, and 16 mg/ kg, i.v.) and found that the maximal rates of self-administration were observed with the 4 mg/kg/infusion. Subsequently, Braida et al. (2004) reported that rats will self-administer D9-THC when delivered intracerebroventricularly (i.c.v.), but only at the lowest doses tested (0.01– 0.02 mg/infusion, i.c.v.). Self-administration behavior with D9THC was found to be antagonized in rats and squirrel monkeys by rimonabant (SR141716A, CB1 antagonist) and the opioid antagonists (naloxone and naltrexone) (Tanda et al., 2000; Braida et al., 2004; Justinova et al., 2004). c. Conditioned Place Preference Studies Conditioned place preference (CPP) is a behavioral assay where animals are given the opportunity to spend time in two distinct environments: one where they previously received a drug and one where they received a placebo. If the drug is reinforcing, animals in a drugfree state will choose to spend more time in the environment paired with the drug when both environments are presented simultaneously. CPP has been demonstrated with D9-THC in rats but only at low doses (0.075–1.0 mg/kg, i.p.; Braida et al., 2004). Rimonabant (0.25–1.0 mg/kg, i.p.) and naloxone (0.5–2.0 mg/kg, i.p.) antagonized D9-THC-mediated CPP (Braida et al., 2004). However, in another study with rats, rimonabant was demonstrated to induce CPP at doses ranging from 0.25–3.0 mg/kg (Cheer et al., 2000). Mice without m-opioid receptors did not exhibit CPP to D9-THC (paired with 1 mg/kg D9-THC, i.p.) (Ghozland et al., 2002). 2. Clinical Studies In its scientific review (HHS, 2015), the HHS provided a list of common subjective psychoactive responses to cannabinoids based on information from several references (Adams and Martin, 1996; Gonzalez, 2007; Hollister, 1986; E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53824 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules Hollister, 1988; Institute of Medicine, 1982). Furthermore, Maldonado (2002) characterized these subjective responses as pleasurable to most humans and are generally associated with drug-seeking and/or drug-taking. Later studies (Scherrer et al., 2009; Zeiger et al., 2010) reported that high levels of positive psychoactive effects correlate with increased marijuana use, abuse, and dependence. The list of the common subjective psychoactive effects provided by the HHS (HHS, 2015) is presented below: (1) Disinhibition, relaxation, increased sociability, and talkativeness. (2) Increased merriment and appetite, and even exhilaration at high doses. (3) Enhanced sensory perception, which can generate an increased appreciation of music, art, and touch. (4) Heightened imagination, which can lead to a subjective sense of increased creativity. (5) Initial dizziness, nausea, tachycardia, facial flushing, dry mouth, and tremor. (6) Disorganized thinking, inability to converse logically, time distortions, and short-term memory impairment. (7) Ataxia and impaired judgment, which can impede driving ability or lead to an increase in risk-taking behavior. (8) Illusions, delusions, and hallucinations that intensify with higher doses. (9) Emotional lability, incongruity of affect, dysphoria, agitation, paranoia, confusion, drowsiness, and panic attacks, which are more common in inexperienced or high-dosed users. The HHS mentioned that marijuana users prefer higher concentrations of the principal psychoactive component (D9THC) over lower concentrations. In a clinical study with marijuana users (n = 12, usage ranged from once a month to 4 times a week), subjects were given a choice of 1.95% D9-THC marijuana or 0.63% D9-THC marijuana after sampling both marijuana cigarettes in two choice sessions. The marijuana cigarette with high THC was chosen in 21 out of 24 choice sessions or 87.5% of the time (Chait and Burke, 1994). Furthermore, in a double-blind study, frequent marijuana users (n = 11, usage at least 2 times per month with at least 100 occasions) when given a low-dose of oral D9-THC (7.5 mg) were able to distinguish the psychoactive effects better than occasional users (n = 10, no use within the past 4 years with 10 or fewer lifetime uses) and also experienced fewer sedative effects (Kirk and de Wit, 1999). Marijuana has also been recognized by scientific experts to have withdrawal symptoms (negative reinforcement) VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 following moderate and heavy use. As discussed further in Factor 7, the DEA notes that the American Psychiatric Association’s (APA) Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM–5) included a list of withdrawal symptoms following marijuana [cannabis] use (DSM–5, 2013). C. Actual Abuse of Marijuana—National Databases Related to Marijuana Abuse and Trafficking Marijuana continues to be the most widely used illicit drug. Evidence of actual abuse can be defined by episodes/mentions in databases indicative of abuse/dependence. The HHS provided in its recommendation (HHS, 2015) information relevant to actual abuse of marijuana including data results from the National Survey on Drug Use and Health (NSDUH), a Monitoring the Future (MTF) survey, the Drug Abuse Warning Network (DAWN), and the Treatment Episode Data Set (TEDS). These data sources provide quantitative information on many factors related to abuse of a particular substance, including incidence and patterns of use, and profile of the abuser of specific substances. The DEA is providing updated information from these databases in this discussion. The DEA also includes data on trafficking and illicit availability of marijuana from DEA databases including the National Forensic Laboratory Information System (NFLIS) and the National Seizure System (NSS), formerly the Federalwide Drug Seizure System (FDSS), as well as other sources of data specific to marijuana, including the Potency Monitoring Project and the Domestic Cannabis Eradication and Suppression Program (DCE/SP). 1. National Survey on Drug Use and Health (NSDUH) The National Survey on Drug Use and Health (NSDUH) is conducted annually by the Department of Health and Human Service’s Substance Abuse and Mental Health Services Administration (SAMHSA). SAMHSA is the primary source of estimates of the prevalence and incidence of pharmaceutical drugs, illicit drugs, alcohol, and tobacco use in the United States. The survey is based on a nationally representative sample of the civilian, non-institutionalized population 12 years of age and older. The survey excludes homeless people who do not use shelters, active military personnel, and residents of institutional group quarters such as jails and hospitals. PO 00000 Frm 00138 Fmt 4701 Sfmt 4702 According to the 2014 NSDUH report, marijuana was the most commonly used and abused illicit drug. That data showed that there were 22.2 million people who were past month users (8.4%) among those aged 12 and older in the United States. (Note: NSDUH figures on marijuana use include hashish use; the relative proportion of hashish use to marijuana use is very low). Marijuana had the highest rate of past-year dependence or abuse in 2014. The NSDUH report estimates that 3.0 million people aged 12 or older used an illicit drug for the first time in 2014; a majority (70.3%) of these past year initiates reported that their first drug used was marijuana. Among those who began using illicit drugs in the past year, 65.6%, 70.3%, and 67.6% reported marijuana as the first illicit drug initiated in 2012, 2013, and 2014 respectively. In 2014, the average age of marijuana initiates among 12- to 49year-olds was 18.5 years. These usage rates and demographics are relevant in light of the risks presented. Marijuana had the highest rate of past year dependence or abuse of any illicit drug in 2014. The 2014 NSDUH report stated that 4.2 million persons were classified with substance dependence or abuse of marijuana in the past year (representing 1.6% of the total population aged 12 or older, and 59.0% of those classified with illicit drug dependence or abuse) based on criteria specified in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM–IV). Among past year marijuana users age 12 or older, 18.5% used marijuana on 300 or more days within the previous 12 months in 2014. This translates into 6.5 million people using marijuana on a daily or almost daily basis over a 12month period, significantly more than the estimated 5.7 million daily or almost daily users in just the year before. Among past month marijuana users, 41.6% (9.2 million) used the drug on 20 or more days in the past month, a significant increase from the 8.1 million who used marijuana 20 days or more in 2013. 2. Monitoring the Future (MTF) Monitoring the Future (MTF) is an ongoing study which is funded under a series of investigator-initiated competing research grants from the National Institute on Drug Abuse (NIDA). MTF tracks drug use trends among American adolescents in the 8th, 10th, and 12th grades. According to its 2015 survey results, marijuana was the most commonly used illicit drug, as was the case in previous years. Approximately 6.5% of 8th graders, E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 14.8% of 10th graders, and 21.3% of 12th graders surveyed in 2015 reported marijuana use during the past month prior to the survey. A number of high school students in 2015 also reported daily use in the past month, including 1.1%, 3.0%, and 6.0% of 8th, 10th, and 12th graders, respectively. mstockstill on DSK3G9T082PROD with PROPOSALS2 3. Drug Abuse Warning Network (DAWN), Emergency Department (ED) Visits The Drug Abuse Warning Network (DAWN) is a public health surveillance system that monitors drug-related hospital emergency department (ED) visits to track the impact of drug use, misuse, and abuse in the United States. For the purposes of DAWN, the term ‘‘drug abuse’’ applies if the following conditions are met: (1) The case involved at least one of the following: use of an illegal drug, use of a legal drug contrary to directions, or inhalation of a non-pharmaceutical substance; and (2) the substance was used for one of the following reasons: because of drug dependence, to commit suicide (or attempt to commit suicide), for recreational purposes, or to achieve other psychic effects. Importantly, many factors can influence the estimates of ED visits, including trends in overall use of a substance as well as trends in the reasons for ED usage. For instance, some drug users may visit EDs for lifethreatening issues while others may visit to seek care for detoxification because they needed certification before entering treatment. Additionally, DAWN data do not distinguish the drug responsible for the ED visit from other drugs that may have been used concomitantly. As stated in a DAWN report, ‘‘Since marijuana/hashish is frequently present in combination with other drugs, the reason for the ED visit may be more relevant to the other drug(s) involved in the episode.’’ In 2011, marijuana was involved in 455,668 ED visits out of 2,462,948 total VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 ED visits involving all abuse or misuse in the United States and out of 1.25 million visits involving abuse or misuse of illicit drugs (excluding alcoholrelated visits), as estimated by DAWN. This is lower than the number of ED visits involving cocaine (505,224) and higher than the number of ED visits involving heroin (258,482) and stimulants (e.g., amphetamine, methamphetamine) (159,840). Visits involving the other major illicit drugs, such as MDMA, GHB, LSD and other hallucinogens, PCP, and inhalants, were much less frequent, comparatively. In young patients, marijuana is the illicit drug most frequently involved in ED visits, according to DAWN estimates, with 240.2 marijuana-related ED visits per 100,000 population ages 12 to 17, 443.8 per 100,000 population ages 18 to 20, and 446.9 per 100,000 population ages 21 to 24. 4. Treatment Episode Data Set (TEDS) System The Treatment Episode Data Set (TEDS) system is part of the SAMHSA Drug and Alcohol Services Information System and is a national census of annual admissions to state licensed or certified, or administratively tracked, substance abuse treatment facilities. The TEDS system contains information on patient demographics and substance abuse problems of admissions to treatment for abuse of alcohol and/or drugs in facilities that report to state administrative data systems. For this database, the primary substance of abuse is defined as the main substance of abuse reported at the time of admission. TEDS also allows for the recording of two other substances of abuse (secondary and tertiary). In 2011, the TEDS system included 1,928,792 admissions to substance abuse treatment; in 2012 there were 1,801,385 admissions; and in 2013 there were 1,683,451 admissions. Marijuana/ hashish was the primary substance of PO 00000 Frm 00139 Fmt 4701 Sfmt 4702 53825 abuse for 18.3% (352,397) of admissions in 2011; 17.5% (315,200) in 2012; and 16.8% (281,991) in 2013. Of the 281,991 admissions for marijuana/hashish treatment in 2013, 24.3% used marijuana/hashish daily. Among those treated for marijuana/hashish as the primary substance in 2013, 27.4% were ages 12 to 17 years and 29.7% were ages 18 to 24 years. Those admitted for marijuana/hashish were mostly male (72.6%) and non-Hispanic (82.2%). Non-hispanic whites (43.2%) represented the largest ethnic group of marijuana admissions. 5. Forensic Laboratory Data Data on marijuana seizures from federal, state, and local forensic laboratories have indicated that there is significant trafficking of marijuana. The National Forensic Laboratory System (NFLIS) is a program sponsored by the Drug Enforcement Administration’s Office of Diversion Control. NFLIS systematically collects drug identification results and associated information from drug exhibits encountered by law enforcement and analyzed in federal, state, and local forensic laboratories. NFLIS is a comprehensive information system that includes data from 278 individual forensic laboratories that report more than 91% of the drug caseload in the U.S. NFLIS captures data for all drugs and chemicals identified and reported by forensic laboratories. More than 1,700 unique substances are represented in the NFLIS database. Data from NFLIS showed that marijuana was the most frequently identified drug in federal, state, and local laboratories from January 2004 through December 2014. Marijuana accounted for between 29.47% and 34.84% of all drug exhibits analyzed annually during that time frame (Table 1). E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules mstockstill on DSK3G9T082PROD with PROPOSALS2 7. Potency Monitoring Project The University of Mississippi’s Potency Monitoring Project (PMP), through a contract with the National Institute on Drug Abuse (NIDA), analyzes and compiles data on the VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 clandestine laboratory and contraband (chemicals and precursors, currency, drugs, equipment and weapons). FDSS reports total federal drug seizures [in kilograms (kg)] of substances such as cocaine, heroin, MDMA, methamphetamine, and cannabis (marijuana and hashish). The yearly volume of cannabis seized (Table 2), consistently exceeding a thousand metric tons per year, shows that cannabis is very widely trafficked in the United States. the percentage of D9-THC increased from 1995 to 2010 with an average THC content of 3.75% in 1995 and 9.53% in 2010. In examining marijuana samples only provided by DEA laboratories, the average D9-THC content was 3.96% in 1995 in comparison to 11.16% in 2015. PO 00000 Frm 00140 Fmt 4701 Sfmt 4702 E:\FR\FM\12AUP2.SGM 12AUP2 EP12AU16.041</GPH> 6. Federal-Wide Drug Seizure System The Federal-wide Drug Seizure System (FDSS) contains information about drug seizures made within the jurisdiction of the United States by the Drug Enforcement Administration, the Federal Bureau of Investigation, United States Customs and Border Protection, and United States Immigration and Customs Enforcement. It also records maritime seizures made by the United States Coast Guard. Drug seizures made by other Federal agencies are included in the FDSS database when drug evidence custody is transferred to one of the agencies identified above. FDSS is now incorporated into the National Seizure System (NSS), which is a repository for information on D9-THC concentrations of marijuana, hashish and hash oil samples provided by DEA regional laboratories and by state and local police agencies. After 2010, PMP has analyzed only marijuana samples provided by DEA regional laboratories. As indicated in Figure 1, Since 2004, the total number of reports of marijuana and the amount of marijuana encountered federally has remained high (see data from Federalwide Drug Seizure System and Domestic Cannabis Eradication and Suppression Program below). EP12AU16.040</GPH> 53826 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 agencies. Only California and Hawaii were active participants in the program at its inception. However, by 1982 the program had expanded to 25 states and by 1985 all 50 states were participants. Cannabis is cultivated in remote locations and frequently on public lands and illicitly grown in all states. Data provided by the DCE/SP (Table 3) show PO 00000 Frm 00141 Fmt 4701 Sfmt 4702 that in the United States in 2014, there were 3,904,213 plants eradicated in outdoor cannabis cultivation areas compared to 2,597,798 plants in 2000. Significant quantities of marijuana were also eradicated from indoor cultivation operations. There were 396,620 indoor plants eradicated in 2014 compared to 217,105 eradicated in 2000. E:\FR\FM\12AUP2.SGM 12AUP2 EP12AU16.042</GPH> mstockstill on DSK3G9T082PROD with PROPOSALS2 8. The Domestic Cannabis Eradication and Suppression Program The Domestic Cannabis Eradication and Suppression Program (DCE/SP) was established in 1979 to reduce the supply of domestically cultivated marijuana in the United States. The program was designed to serve as a partnership between federal, state, and local 53827 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules mstockstill on DSK3G9T082PROD with PROPOSALS2 The recent statistics from these various surveys and databases show that marijuana continues to be the most commonly used illicit drug, with considerable rates of heavy abuse and dependence. They also show that marijuana is the most readily available illicit drug in the United States. Petitioners’ Major Comment in Relation to Factor 1 and the Government’s Responses (1) The petitioner states on pages 1– 2 of the petition that ‘‘[p]ure THC (Marinol), the primary psychoactive ingredient in marijuana has been placed in Schedule III. However, unlike Marinol, marijuana has other cannabinoids that help to mitigate the psychoactive effects of THC and reduce the potential for abuse. Therefore, the THC in marijuana can not have the high potential for abuse required for placement in Schedule I.’’ First, the petitioners failed to review the indicators of abuse potential, as discussed in the legislative history of the CSA. The petitioners did not use data on marijuana usage, diversion, psychoactive properties, and dependence in their evaluation of marijuana abuse potential. The HHS and the DEA discuss those indicators above in this factor. HHS’s evaluation of the full range of data led HHS and DEA to conclude that marijuana has a high potential for abuse. Second, the HHS indicated that modulating effects of the other cannabinoids in marijuana on D9-THC have not been demonstrated in controlled studies. Specifically, HHS concluded in its 8-factor analysis that VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 ‘‘any possible mitigation of delta-9THC’s psychoactive effects by CBD will not occur for most marijuana users.’’ Marinol was rescheduled from schedule II to schedule III on July 2, 1999 (64 FR 35928, DEA 1999). In assessing Marinol, HHS compared Marinol to marijuana on several aspects of abuse potential and found that major differences between the two, such as formulation, availability, and usage, contribute to differences in abuse potential. The psychoactive effects from smoking are generally more rapid and intense that those that occur through oral administration (HHS, 2015; Wesson and Washburn, 1990; Hollister and Gillespie, 1973). Therefore, as concluded by both the HHS and the DEA, the delayed onset of action and longer duration of action from an oral dose of Marinol may contribute in limiting the abuse potential of Marinol relative to marijuana, which is most often smoked. The HHS also stated that the extraction and purification of dronabinol from the encapsulated sesame oil mixture of Marinol is highly complex and difficult and that the presence of sesame oil mixture may preclude the smoking of Marinol-laced cigarettes. Additionally, the FDA approved a New Drug Application (NDA) for Marinol, indicating a legitimate medical use for Marinol in the United States and allowing for Marinol to be rescheduled into schedule II and subsequently into schedule III of the CSA. The HHS mentioned that marijuana and Marinol differ on a wide variety of factors and these differences are major reasons for PO 00000 Frm 00142 Fmt 4701 Sfmt 4702 differential scheduling of marijuana and Marinol. Marijuana, as discussed more fully in Factors 3 and 6, does not have a currently accepted medical use in the United States, is highly abused, and has a lack of accepted safety. Finally, the DEA notes that under the CSA, for a substance to be placed in schedule II, III, IV, or V, it must have a currently accepted medical use in treatment in the United States.44 As DEA has previously stated, Congress established only one schedule, schedule I, for drugs of abuse with ‘‘no currently accepted medical use in treatment in the United States.’’ 76 FR 40552 (2011). Thus, any attempt to compare the relative abuse potential of schedule I substance to that of a substance in another schedule is inconsequential since a schedule I substance must remain in schedule I until it has been found to have a currently accepted medical use in treatment in the United States. Factor 2: Scientific Evidence of the Drug’s Pharmacological Effects, if Known The HHS stated that there are large amounts of scientific data on the neurochemistry, mechanistic effects, toxicology, and pharmacology of marijuana. A scientific evaluation, as conducted by the HHS and the DEA, of marijuana’s neurochemistry, human and animal behavioral pharmacology, central nervous system effects, and other pharmacological effects (e.g. cardiovascular, immunological effects) is presented below. 44 See E:\FR\FM\12AUP2.SGM Americans for Safe Access, 706 F.3d at 440. 12AUP2 EP12AU16.043</GPH> 53828 mstockstill on DSK3G9T082PROD with PROPOSALS2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules Neurochemistry Marijuana contains numerous constituents such as cannabinoids that have a variety of pharmacological actions. The HHS stated that different marijuana samples derived from various cultivated strains may differ in their chemical constituents including D9-THC and other cannabinoids. Therefore marijuana products from different strains will have different biological and pharmacological effects. The chemical constituents of marijuana are discussed further in Factor 3. The primary site of action for cannabinoids such as D9-THC is at the cannabinoid receptor. Two cannabinoid receptors, CB1 and CB2, have been identified and characterized (Battista et al., 2012; Piomelli, 2005) and are Gprotein-coupled receptors. Activation of these inhibitory G-protein-coupled receptors inhibits adenylate cyclase activity, which prevents conversion of ATP to cyclic AMP. Cannabinoid receptor activation also results in inhibition of N- and P/Q-type calcium channels and activates inwardly rectifying potassium channels (Mackie et al., 1995; Twitchell et al., 1997). The HHS mentioned that inhibition of Ntype calcium channels decreases neurotransmitter release and this may be the underlying mechanism in the ability of cannabinoids to inhibit acetylcholine, norepinephrine and glutamate from specific areas of the brain. These cellular actions may underlie the antinociceptive and psychoactive effects of cannabinoids. D9-THC acts as an agonist at cannabinoid receptors. CB1 receptors are primarily found in the central nervous system and are located mainly in the basal ganglia, hippocampus and cerebellum of the brain (Howlett et al., 2004). CB1 receptors are also located in peripheral tissues such as the immune system (De Petrocellis and Di Marzo, 2009), but the concentration of CB1 receptors there is considerably lower than in the central nervous system (Herkenham et al., 1990; 1992). CB2 receptors are found primarily in the immune system and predominantly in B lymphocytes and natural killer cells (Bouaboula et al., 1993). CB2 receptors are also found in the central nervous system, primarily in the cerebellum and hippocampus (Gong et al., 2006). Two endogenous ligands to the cannabinoid receptors, anandamide and arachidonyl glycerol (2–AG), were identified in 1992 (Devane et al., 1992) and 1995 (Mechoulam et al., 1995), respectively. Anandamide is a lowefficacy agonist (Brievogel and Childers, VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 2000) and 2–AG is a high efficacy agonist (Gonsiorek et al., 2000) to the cannabinoid receptors. These endogenous ligands are present in both the central nervous system and in the periphery (HHS, 2015). D9-THC and cannabidiol (CBD) are two of the major cannabinoids in marijuana. D9-THC is the major psychoactive cannabinoid (Wachtel et al., 2002). D9-THC has similar affinity for CB1 and CB2 receptors and acts as a weak agonist at CB2 receptors. The HHS indicated that activation of CB1 receptors mediates psychotropic effects of cannabinoids. CBD has low affinity for both CB1 and CB2 receptors. CBD has antagonistic effects at CB1 receptors, and some inverse agonistic properties at CB2 receptors. Animal Behavioral Effects Animal abuse potential studies (drug discrimination, self-administration, conditioned place preference) are discussed more fully in Factor 1. Briefly, it was consistently demonstrated that D9-THC, the primary psychoactive component in marijuana, and other cannabinoids in marijuana have a distinct drug discriminative profile. In addition, animals selfadminister D9-THC, and D9-THC in low doses produces conditioned place preference. Central Nervous System Effects Psychoactive Effects The clinical psychoactive effects of marijuana are discussed more fully in Factor 1. Briefly, the psychoactive effects from marijuana use are considered pleasurable and associated with drug-seeking or drug-taking (HHS, 2015; Maldonado, 2002). Further, it was noted by HHS that marijuana users prefer higher concentrations of the principal psychoactive component (D9THC) over lower concentrations (HHS, 2015). Studies have evaluated psychoactive effects of THC in the presence of high CBD, CBC, or CBN ratios. Even though some studies suggest that CBD may decrease some of D9-THC’s psychoactive effects, the HHS found that the ratios of CBD to D9-THC administered in the studies were not comparable to the amounts found in marijuana used by most people (Dalton et al., 1976; Karniol et al., 1974; Zwardi et al., 1982). In fact, the CBD ratios in these studies are significantly higher than the CBD found in most marijuana currently found on the streets (Mehmedic et al., 2010). HHS indicated that most of the marijuana available on the street has a high THC and low CBD content and therefore any PO 00000 Frm 00143 Fmt 4701 Sfmt 4702 53829 lessening of THC’s psychoactive effects by CBD will not occur for most marijuana users (HHS, 2015). Dalton et al. (1976) reported that when volunteers smoked cigarettes with a ratio of 7 CBD to 1 D9-THC (0.15 mg/kg CBD and 0.025 mg/kg D9-THC), there was a significant decrease in ratings of acute subjective effects and achieving a ‘‘high’’ in comparison to smoking D9-THC alone. In oral administration studies, the subjective effects and anxiety produced by combination of CBD and THC in a ratio of at least 1:2 CBD to D9-THC (15, 30, 60 mg CBD to 30 mg D9-THC; Karniol et al., 1974) or a ratio of 2:1 CBD to D9-THC (1 mg/kg CBD to 0.5 mg/kg D9-THC; Zuardi et al., 1982) are less than those produced by D9-THC administered alone. In one study (Ilan et al., 2005), the authors calculated the naturally occurring concentrations of CBC and CBD in marijuana cigarettes with either 1.8 or 3.6% D9-THC by weight. The authors varied the concentrations of CBC and CBD for each concentration of D9-THC in the marijuana cigarettes. Administrations in healthy marijuana users (n=23) consisted of either: (1) Low CBC (0.1% by weight) and low CBD (0.2% by weight); (2) high CBC (0.5% by weight) and low CBD; (3) low CBC and high CBD (1.0% by weight); or 4) high CBC and high CBD and the users were divided into low D9-THC (1.8% by weight) and high D9-THC (3.6% by weight) groups. Subjective psychoactive effects were significantly greater for all groups in comparison to placebo and there were no significant differences in effects among the treatments (Ilan et al., 2005). The HHS also referred to a study with D9-THC and cannabinol (CBN) (Karniol et al., 1975). In this study, oral administration of either 12.5, 25, or 50 mg CBN combined with 25 mg D9-THC (ratio of at least 1:2 CBN to D9-THC) significantly increased subjective psychoactive ratings of D9-THC compared to D9-THC alone (Karniol et al., 1975). Behavioral Impairment Several factors may influence marijuana’s behavioral effects including the duration (chronic or short term), frequency (daily, weekly, or occasionally), and amount of use (heavy or moderate). Researchers have examined how long behavioral impairments persist following chronic marijuana use. These studies used selfreported histories of exposure duration, frequency, and amount of marijuana use, and administered several performance and cognitive tests at different time points following E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53830 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules marijuana abstinence. According to HHS, behavioral impairments may persist for up to 28 days of abstinence in chronic marijuana users. Psychoactive effects of marijuana can lead to behavioral impairment including cognitive decrements and decreased ability to operate motor vehicles (HHS, 2015). Block et al. (1992) evaluated cognitive measures in 48 healthy male subjects following smoking a marijuana cigarette that contained 2.57% or 19 mg D9-THC by weight or placebo. Each subject participated in eight sessions (four sessions with marijuana; four sessions with placebo) and several cognitive and psychomotor tests were administered (e.g. verbal recall, facial recognition, text learning, reaction time). Marijuana significantly impaired performances in most of these cognitive and psychomotor tests (Block et al., 1992). Ramaekers et al. (2006) reported that in 20 recreational users of marijuana, acute administration of 250 mg/kg and 500 mg/kg D9-THC in smoked marijuana resulted in dose-dependent impairments in cognition, motor impulsivity, motor control (tracking impairments), and risk taking. In another study (Kurzthaler et al., 1999), when 290 mg/kg D9-THC was administered via a smoked marijuana cigarette in 30 healthy volunteers with no history of substance abuse there were significant impairments of motor speed and accuracy. Furthermore, administration of 3.95% D9-THC in a smoked marijuana cigarette increased the latency in a task of simulated braking in a vehicle (Liguori et al., 1998). The HHS noted that the motor impairments reported in these studies (Kurzthaler et al., 1999; Liguori et al., 1998) are critical skills needed for operating a vehicle. As mentioned in the HHS document, some studies examined the persistence of the behavioral impairments immediately after marijuana administration. Some of marijuana’s acute effects may still be present for at least 24 hours after the acute psychoactive effects have subsided. In a brief communication, Heishmann et al. (1990) reported that there were cognitive impairments (digit recall and arithmetic tasks) in two out of three experienced marijuana smokers for 24 hours after smoking marijuana cigarettes containing 2.57% D9-THC. However, Fant et al. (1998) evaluated subjective effects and performance measures for up to 25 hours in 10 healthy males after exposure to either 1.8% or 3.6% D9-THC in marijuana cigarettes. Peak decrements in subjective and performance measures were noted within 2 hours of marijuana exposure VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 but there were minimal residual alterations in subjective or performance measures at 23–25 hours after exposure. Persistence of behavioral impairments following repeated and chronic use of marijuana has also been investigated and was reviewed in the HHS document (HHS, 2015). In particular, researchers examined how long behavioral impairments last following chronic marijuana use. In studies examining persistence of effects in chronic and heavy marijuana users, there were significant decrements in cognitive and motor function tasks in all studies of up to 27 days, and in most studies at 28 days (Solowij et al., 2002; Messinis et al., 2006; Lisdahl and Price, 2012; Pope et al., 2002; Bolla et al., 2002; Bolla et al., 2005). In studies that followed heavy marijuana users for longer than 28 days and up to 20 years of marijuana abstinence, cognitive and psychomotor impairments were no longer detected (Fried et al., 2005; Lyons et al., 2004; Tait et al., 2011). For example, Fried et al. (2005) reported that after 3 months of abstinence from marijuana, any deficits in intelligence (IQ), memory, and processing speeds following heavy marijuana use were no longer observed (Fried et al., 2005). In a meta-analysis that examined non-acute and longlasting effects of marijuana, any deficits in neurocognitive performance that were observed within the first month were no longer apparent after approximately one month of abstinence (Schreiner and Dunn, 2012). HHS further notes that in moderate marijuana users deficits in decision-making skills were not observed after 25 days of abstinence and additionally IQ, immediate memory and delayed memory skills were not significantly impacted as observed with heavy and chronic marijuana users (Fried et al., 2005; HHS, 2015) As mentioned in the HHS document (HHS, 2015), the intensity and persistence of neurological impairment from chronic marijuana use also may be dependent on the age of first use. In two separate smaller scale studies (less than 100 participants per exposure group), Fontes et al. (2011) and Gruber et al. (2012) compared neurological function in early onset (chronic marijuana use prior to age 15 or 16) and late onset (chronic marijuana use after age 15 or 16) heavy marijuana users and found that there were significant deficits in executive neurological function in early onset users which were not observed or were less apparent in late onset users. In a prospective longitudinal birth cohort study following 1,037 individuals (Meier et al., 2012), a significant decrease in IQ and PO 00000 Frm 00144 Fmt 4701 Sfmt 4702 neuropsychological performance was observed in adolescent-onset users and persisted even after abstinence from marijuana for at least one year. However, Meier et al (2012) reported in there was no significant change in IQ in adult-onset users. The HHS noted that there is some evidence that the severity of the persistent neurological impairments may also be due in part to the amount of marijuana usage. In the study mentioned above, Gruber et al. (2012) found that the early onset users consumed three times as much marijuana per week and used it twice as often as late onset users. Meier et al. (2012) reported in their study, mentioned above, that there was a correlation between IQ deficits in adolescent onset users and the increased amount of marijuana used. Behavioral Effects of Prenatal Exposure In studies that examined effects of prenatal marijuana exposure, many of the pregnant women also used alcohol and tobacco in addition to marijuana. Even though other drugs were used in conjunction with marijuana, there is evidence of an association between heavy prenatal marijuana exposure and deficits in some cognitive function. There have been two prospective longitudinal birth cohort studies following individuals prenatally exposed to marijuana from birth until adulthood: The Ottawa Prenatal Prospective Study (OPPS; Fried et al., 1980), and the Maternal Health Practices and Child Development Project (MHPCD; Day et al., 1985). Both longitudinal studies report that heavy prenatal marijuana use is associated with decreased performance on tasks assessing memory, verbal and quantitative reasoning in 4-year-olds (Fried and Watkinson, 1990) and in 6 year olds (Goldschmidt et al., 2008). In subsequent studies with the OPPS cohort, deficits in sustained attention were reported in children ages 6 and 13–16 years (Fried et al., 1992; Fried, 2002) and deficits in executive neurological function were observed in 9- and 12-year-old children (Fried et al., 1998). DEA further notes that with the MHPCD cohort, follow-up studies reported an increased rate of delinquent behavior (Day et al., 2011) and decreased achievement test scores (Goldschmidt et al., 2012) at age 14. When the MHPCD cohort was followed to age 22, there was a marginal (p = 0.06) increase in psychosis with prenatal marijuana exposure and early onset of marijuana use (Day et al., 2015). E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules Association of Marijuana Use With Psychosis There has been extensive research to determine whether marijuana usage is associated with development of schizophrenia or other psychoses, and the HHS indicated that the available data do not suggest a causative link between marijuana and the development of psychosis (HHS, 2015; Minozzi et al., 2010). As mentioned in the HHS review (HHS, 2015), numerous large scale longitudinal studies demonstrated that subjects who used marijuana do not have a greater incidence of psychotic diagnoses compared to non-marijuana users (van Os et al., 2002; Fergusson et al., 2005; Kuepper et al., 2011). Further, the HHS commented that when analyzing the available data examining the association between marijuana and psychosis, it is critical to differentiate whether the patients in a study are already diagnosed with psychosis or if the individuals have a limited number of symptoms associated with psychosis without qualifying for a diagnosis of the disorder. As mentioned by the HHS, some of the studies examining the association between marijuana and psychosis utilized non-standard methods to categorize psychosis and these methods did not conform to the criteria in the Diagnostic and Statistical Manual (DSM–5) or the International Classification of Diseases (ICD–10) and would not be appropriate for use in evaluating the association between marijuana use and psychosis. For example, researchers characterized psychosis as ‘‘schizophrenic cluster’’ (Maremmani et al., 2004), ‘‘subclinical psychotic symptoms’’ (van Gastel et al., 2012), ‘‘pre-psychotic clinical high risk’’ (van der Meer et al., 2012), and symptoms related to ‘‘psychosis vulnerability’’ (Griffith-Lendering et al., 2012). The HHS discussed an early epidemiological study conducted by Andreasson et al. (1987), which examined the link between psychosis and marijuana use. In this study, about 45,000 18- and 19-year-old male Swedish subjects provided detailed information on their drug-taking history and 274 of these subjects were diagnosed with schizophrenia over a 14year period (1969–1983). Out of the 274 subjects diagnosed with psychosis, 21 individuals (7.7%) had used marijuana more than 50 times, while 197 individuals (72%) never used marijuana. As presented by the authors (Andreasson et al., 1987), individuals who claimed to take marijuana on more VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 than 50 occasions were 6 times more likely to be diagnosed with schizophrenia than those who had never consumed the drug. The authors concluded that marijuana users who are vulnerable to developing psychoses are at the greatest risk for schizophrenia. In a 35 year follow up to the subjects evaluated in Andreasson et al. (1987), Manrique-Garcia et al. (2012) reported similar findings. In the follow up study, 354 individuals developed schizophrenia. Of those, 32 individuals (9%) had used marijuana more than 50 times and were 6.3 times more likely to develop schizophrenia. 255 of the 354 individuals (72%) never used marijuana. The HHS also noted that many studies support the assertion that psychosis from marijuana usage may manifest only in individuals already predisposed to development of psychotic disorders. Marijuana use may precede diagnosis of psychosis (Schimmelmann et al., 2011), but most reports indicate that prodromal symptoms of schizophrenia are observed prior to marijuana use (Schiffman et al., 2005). In a review examining gene-environmental interaction between marijuana exposure and the development of psychosis, it was concluded that there is some evidence to support that marijuana use may influence the development of psychosis but only for susceptible individuals (Pelayo-Teran et al., 2012). Degenhardt et al. (2003) modeled the prevalence of schizophrenia against marijuana use across eight birth cohorts in individuals born during 1940 to 1979 in Australia. Even though there was an increase in marijuana use in the adult subjects over this time period, there was not an increase in diagnoses of psychosis for these same subjects. The authors concluded that use of marijuana may increase schizophrenia only in persons vulnerable to developing psychosis. Cardiovascular and Autonomic Effects The HHS stated that acute use of marijuana causes an increase in heart rate (tachycardia) and may increase blood pressure (Capriotti et al., 1988; Benowitz and Jones, 1975). There is some evidence that associates the increased heart rate from D9-THC exposure with excitation of the sympathetic and depression of the parasympathetic nervous systems (Malinowska et al., 2012). Tolerance to tachycardia develops with chronic exposure to marijuana (Jones, 2002; Sidney, 2002). Prolonged exposure to D9-THC results in a decrease in heart rate (bradycardia) and hypotension (Benowitz and Jones, PO 00000 Frm 00145 Fmt 4701 Sfmt 4702 53831 1975). These effects are thought to be mediated through peripherally located, presynaptic CB1 receptor inhibition of norepinephrine release with possible direct activation of vascular cannabinoid receptors (Wagner et al., 1998; Pacher et al., 2006). As stated in the HHS recommendation (HHS, 2015), marijuana exposure causes orthostatic hypotension (fainting-like feeling; sudden drop in blood pressure upon standing up) and tolerance can develop to this effect upon repeated, chronic exposure (Jones, 2002). Tolerance to orthostatic hypotension is potentially related to plasma volume expansion, but tolerance does not develop to supine hypotensive effects (Benowitz and Jones, 1975). Marijuana smoking, particularly by those with some degree of coronary artery or cerebrovascular disease, poses risks such as increased cardiac work, increased catecholamines and carboxyhemoglobin, myocardial infarction and postural hypotension (Benowitz and Jones, 1981; Hollister, 1988; Mittleman et al., 2001; Malinowska et al., 2012). However, electrocardiographic changes were minimal after administration of large cumulative doses of D9-THC (Benowitz and Jones, 1975) The DEA notes two recent reports that reviewed several case studies on marijuana and cardiovascular complications (Panayiotides, 2015; Hackam, 2015). Panayiotides (2015) reported that approximately 25.6% of the cardiovascular cases from marijuana use resulted in death from data provided by the French Addictovigilance Network during the period of 2006–2010. Several case studies on marijuana usage and cardiovascular events were discussed and it was concluded that although a causal link cannot be established due to not knowing exact amounts of marijuana used in the cases and confounding variables, the available evidence supports a link between marijuana and cardiotoxicity. Hackham (2015) reviewed 34 case reports or case series reports of marijuana and stroke/ ischemia in 64 stroke patients and reported that in 81% of the cases there was a temporal relationship between marijuana usage and stroke or ischemic event. The author concluded that collective analysis of the case reports supports a causal link between marijuana use and stroke. Respiratory Effects The HHS stated that transient bronchodilation is the most typical respiratory effect of acute exposure to marijuana (Gong et al., 1984). In a recent E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53832 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules longitudinal study, information on marijuana use and pulmonary data function were collected from 5,115 individuals over 20 years from 4 communities in the United States (Oakland, CA; Chicago, IL; Minneapolis, MN; Birmingham, AL) (Pletcher et al., 2012). Of the 5,115 individuals, 795 individuals reported use of only marijuana (without tobacco). The authors reported that occasional use of marijuana (7 joint-years for lifetime or 1 joint/day for 7 years or 1 joint/week for 49 years) does not adversely affect pulmonary function. Pletcher et al. (2012) further concluded that there is some preliminary evidence suggesting that heavy marijuana use may have a detrimental effect on pulmonary function, but the sample size of heavy marijuana users in the study was too small. Further, as mentioned in the HHS recommendation document (HHS, 2015), long-term use of marijuana may lead to chronic cough, increased sputum, as well as increased frequency of chronic bronchitis and pharyngitis (Adams and Martin, 1996; Hollister, 1986). The HHS stated that the evidence that marijuana may lead to cancer of the respiratory system is inconsistent, with some studies suggesting a positive correlation while others do not (Lee and Hancox, 2011; Tashkin, 2005). The HHS noted a case series that reported lung cancer occurrences in three marijuana smokers (age range 31–37 years) with no history of tobacco smoking (Fung et al., 1999). Furthermore, in a case-control study (n = 173 individuals with squamous cell carcinoma of the head and neck; n = 176 controls; Zhang et al., 1999), prevalence of marijuana use was 9.7% in controls and 13.9% in cases and the authors reported that marijuana use may dose-dependently interact with mutagenic sensitivity, cigarette smoking, and alcohol use to increase risk associated with head and neck cancers (Zhang et al., 1999). However, in a large clinical study with 1,650 subjects, no positive correlation was found between marijuana use and lung cancer (Tashkin et al., 2006). This finding held true regardless of the extent of marijuana use when both tobacco use and other potential confounding factors were controlled. The HHS concluded that new evidence suggests that the effects of smoking marijuana on respiratory function and cancer are different from the effects of smoking tobacco (Lee and Hancox, 2011). The DEA further notes the publication of recent review articles critically evaluating the association between marijuana and lung cancer. Most of the reviews agree that the association is VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 weak or inconsistent (Huang et al., 2015; Zhang et al., 2015; Gates et al., 2014; Hall and Degenhardt, 2014). Huang et al. (2015) identified and reviewed six studies evaluating the association between marijuana use and lung cancer and the authors concluded that an association is not supported most likely due to the small amounts of marijuana smoked in comparison to tobacco. Zhang et al. (2015) examined six case control studies from the US, UK, New Zealand, and Canada within the International Lung Cancer Consortium and found that there was a weak association between smoking marijuana and lung cancer in individuals who never smoked tobacco, but precision of the association was low at high marijuana exposure levels. Hall and Degenhardt (2014) noted that even though marijuana smoke contains several of the same carcinogens and cocarcinogens as tobacco smoke (Roth et al., 1998) and has been found to be mutagenic and carcinogenic in the mouse skin test, epidemiological studies have been inconsistent, but more consistent positive associations have been reported in case control studies. Finally Gates et al. (2014), reviewed the studies evaluating marijuana use and lung cancer and concluded that there is evidence that marijuana produces changes in the respiratory system (precursors to cancer) that could lead to lung cancer, but overall association is weak between marijuana use and lung cancer especially when controlling for tobacco use. Endocrine System Reproductive Hormones The HHS stated that administration of marijuana to humans does not consistently alter the endocrine system. In a controlled human exposure study (n = 4 males), subjects were acutely administered smoked marijuana containing 2.8% D9-THC or placebo and an immediate significant decrease in luteinizing hormone and an increase in cortisol was reported in the subjects that smoked marijuana (Cone et al., 1986). Furthermore, as cited by the HHS, two later studies (Dax et al., 1989; Block et al., 1991) reported no changes in hormone levels. Dax et al. (1989) recruited male volunteers (n = 17) that were occasional or heavy users of marijuana. Following exposure to smoked D9-THC (18 mg/cigarette) or oral D9-THC (10 mg three times per day for three days and on the morning of the fourth day), the subjects in that study showed no changes in plasma adrenocorticotropic hormone (ACTH), cortisol, prolactin, luteinizing hormone, PO 00000 Frm 00146 Fmt 4701 Sfmt 4702 or testosterone levels. Additionally, Block et al. (1991) compared plasma hormone levels amongst non-users as well as infrequent, moderate, and frequent users of marijuana (n = 93 men and 56 women) and found that chronic use of marijuana (infrequent, moderate, and frequent users) did not significantly alter concentrations of testosterone, luteinizing hormone, follicle stimulating hormone, prolactin, or cortisol. The HHS noted that there is a discrepancy in the effect of marijuana on female reproductive system functionality between animals and humans (HHS, 2015). Female rhesus monkeys that were administered 2.5 mg/kg D9-THC, i.m., during days 1–18 of the menstrual cycle had reduced progesterone levels and ovulation was suppressed (Asch et al., 1981). However, women who smoked marijuana (1 gram marijuana cigarette with 1.8% D9-THC) during the periovulatory period (24–36 hours prior to ovulation) did not exhibit changes in reproductive hormone levels or their menstrual cycles (Mendelson and Mello, 1984). In a review article by Brown and Dobs (2002), the authors state that endocrine changes observed with marijuana are no longer observed with chronic administration and this may be due to drug tolerance. Reproductive Cancers The HHS stated that recent studies support a possible association between frequent, long-term marijuana use and increased risk of testicular germ cell tumors. In a hospital-based case-control study, the frequency of marijuana use was compared between testicular germ cell tumor (TGCT) patients (n = 187) and controls (n = 148) (Trabert et al., 2011). TGCT patients were more likely to be frequent marijuana users than controls with an odds ratio (OR) of 2.2 (95% confidence limits of 1.0–5.1) and were less likely to be infrequent or short-term users with odds ratios of 0.5 and 0.6, respectively in comparison to controls (Trabert et al., 2011). The DEA further notes that in two populationbased case-control studies (Daling et al., 2009; Lacson et al., 2012), marijuana use was compared between patients diagnosed with TGCT and matched controls in Washington State or Los Angeles County. In both studies, it was reported that TCGT patients were twice as likely as controls to use marijuana. Authors of both studies concluded that marijuana use is associated with an elevated risk of TGCT (Daling et al., 2009; Lacson et al., 2012). The HHS cited a study (Sarfaraz et al., 2005) demonstrating that WIN 55,212–2 (a mixed CB1/CB2 agonist) induces apoptosis (one form of cell death) in E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules prostate cancer cells and decreases expression of androgen receptors and prostate specific antigens, suggesting a potential therapeutic value for cannabinoid agonists in the treatment of prostate cancer, an androgen-stimulated type of carcinoma. Other hormones (e.g. Thyroid, Appetite) In more recent studies, as cited by the HHS, chronic marijuana use by subjects (n = 39) characterized as dependent on marijuana according to the ICD–10 criteria did not affect serum levels of thyroid hormones: TSH (thyrotropin), T4 (thyroxine), and T3 (triiodothyronine) (Bonnet, 2013). With respect to appetite hormones, in a pilot study with HIV-positive males, smoking marijuana dose-dependently increased plasma levels of ghrelin and leptin and decreased plasma levels of peptide YY (Riggs et al., 2012). The HHS stated that D9-THC reduces binding of the corticosteroid dexamethasone in hippocampal tissue from adrenalectomized rats and acute D9-THC releases corticosterone, with tolerance developing to this effect with chronic administration (Eldridge ≤et al., 1991). These data suggest that D9-THC may interact with the glucocorticoid receptor system. mstockstill on DSK3G9T082PROD with PROPOSALS2 Immune System The HHS stated that cannabinoids alter immune function but that there can be differences between the effects of synthetic, natural, and endogenous cannabinoids (Croxford and Yamamura, 2005; Tanasescu and Constantinescu, 2010). The HHS noted that there are conflicting results in animal and human studies with respect to cannabinoid effects on immune functioning in subjects with compromised immune systems. Abrams et al. (2003) examined the effects of marijuana and D9-THC in 62 HIV–1-infected patients. Subjects received one of three treatments, three times a day: smoked marijuana cigarette containing 3.95% D9-THC, oral tablet containing D9-THC (2.5 mg oral dronabinol), or oral placebo. There were no changes in CD4+ and CD8+ cell counts, HIV RNA levels, or protease inhibitor levels in any of the treatment groups (Abrams et al., 2003). Therefore, use of cannabinoids showed no shortterm adverse virologic effects in individuals with compromised immune systems. Conversely, Roth et al. (2005) reported that in immunodeficient mice implanted with human blood cells infected with HIV, exposure to D9-THC in vivo suppresses immune function, increases HIV co-receptor expression, VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 and acts as a cofactor to enhance HIV replication. The DEA notes two recent clinical studies reporting a decrease in cytokine and interleukin levels following marijuana use. Keen et al. (2014) compared the differences in the levels of IL–6 (interleukin-6), a proinflammatory cytokine, amongst non-drug users (n = 78), marijuana only users (n = 46) and marijuana plus other drug users (n = 45) in a community-based sample of middle-aged African Americans (Keen et al., 2014). After adjusting for confounders, analyses revealed that lifetime marijuana only users had significantly lower IL–6 levels than the nonuser group. Further, Sexton et al. (2014) compared several immune parameters in healthy individuals and subjects with multiple sclerosis (MS) and found that the chronic use of marijuana resulted in reduced monocyte migration, and decreased levels of CCL2 and IL–17 in both healthy and MS groups. The DEA also notes a review suggesting that D9-THC suppresses the immune responses in experimental animal models and in vitro and that these changes may be primarily mediated through the CB2 cannabinoid receptor (Eisenstein and Meissler, 2015). Factor 3: The State of the Current Scientific Knowledge Regarding the Drug or Substance Chemistry The HHS stated that marijuana, also known as Cannabis sativa L., is part of the Cannabaceae plant family and is one of the oldest cultivated crops. The term ‘‘marijuana’’ is generally used to refer to a mixture of the dried flowering tops and leaves from Cannabis. Marijuana users primarily smoke the marijuana leaves, but individuals also ingest marijuana through food infused with marijuana and its extracts. Cannabis sativa is the primary species of Cannabis that is illegally marketed in the United States. Marijuana is one of three major derivatives sold as separate illicit products, the other two being hashish and hash oil. Hashish is composed of the dried and compressed cannabinoid-rich resinous material of Cannabis and is found as balls and cakes as well as other forms. Individuals may break off pieces and place them into a pipe to smoke. Hash oil, a viscous brown or amber colored liquid, is produced by solvent extraction of cannabinoids from Cannabis and contains approximately 50% cannabinoids. One to two drops of hash oil on a cigarette has been reported to PO 00000 Frm 00147 Fmt 4701 Sfmt 4702 53833 produce the equivalent of a single marijuana cigarette (DEA, 2015). Different marijuana samples are derived from numerous cultivated strains and may have different chemical compositions including levels of D9THC and other cannabinoids (Appendino et al., 2011). A consequence of having different chemical compositions in the various marijuana samples is that there will be significant differences in safety, biological, pharmacological, and toxicological profiles and therefore, according to the HHS, all Cannabis strains cannot be considered collectively because of the variations in chemical composition. Furthermore, the concentration of D9-THC and other cannabinoids present in marijuana may vary due to growing conditions and processing of the plant after harvesting. For example, the plant parts collected such as flowers, leaves and stems can influence marijuana’s potency, quality, and purity (Adams and Martin, 1996; Agurell et al., 1984; Mechoulam, 1973). Variations in marijuana harvesting have resulted in potencies ranging from a low of 1 to 2% up to a high of 17% as indicated by cannabinoid content. The concentration of D9-THC averages approximately 12% by weight in a typical marijuana mixture of leaves and stems. However, some specifically grown and selected marijuana samples can contain 15% or greater D9-THC (Appendino et al., 2011). As a result, the D9-THC content in a 1 gram marijuana cigarette can range from as little as 3 milligrams to 150 milligrams or more. In a systematic review conducted by Cascini et al. (2012), it was reported that marijuana’s D9-THC content has increased significantly from 1979–2009. Since there is considerable variability in the cannabinoid concentrations and chemical constituency among marijuana samples, the interpretation of clinical data with marijuana is complicated. A primary issue is the lack of consistent concentrations of D9-THC and other substances in marijuana which complicates the interpretation of the effects of different marijuana constituents. An added issue is that the non-cannabinoid components in marijuana may potentially modify the overall pharmacological and toxicological properties of various marijuana strains and products. Various Cannabis strains contain more than 525 identified natural constituents including cannabinoids, 21 (or 22) carbon terpenoids found in the plant, as well as their carboxylic acids, analogues, and transformation products (Agurell et al., 1984; 1986; Mechoulam, 1973; Appendino et al., 2011). To date, E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53834 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules more than 100 cannabinoids have been characterized (ElSohly and Slade, 2005; Radwan et al., 2009; Appendino et al., 2011), and most major cannabinoid compounds occurring naturally have been identified. There are still new and comparably more minor cannabinoids being characterized (Pollastro et al., 2011). The majority of the cannabinoids are found in Cannabis. One study reported accumulation of two cannabinoids, cannabigerol and its corresponding acid, in Helichrysum (H. umbraculigerum) which is a nonCannabis source (Appendino et al., 2011). Of the cannabinoids found in marijuana, D9-THC (previously known as D1-THC) and delta-8tetrahydrocannabinol (D8-THC, D6-THC) have been demonstrated to produce marijuana’s psychoactive effects. Psychoactive effects from marijuana usage have been mainly attributed to D9-THC because D9-THC is present in significantly more quantities than D8-THC in most marijuana varieties. There are only a few marijuana strains that contain D8-THC in significant amounts (Hively et al., 1966). D9-THC is an optically active resinous substance that is extremely lipophilic. The chemical name for D9-THC is (6aRtrans)-6a,7,8,10a-tetrahydro-6,6,9trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol, or (–)-delta9-(trans)tetrahydrocannabinol. The (–)-trans D9THC isomer is pharmacologically 6 to 100 times more potent than the (+)-trans isomer (Dewey et al., 1984). Other relatively well-characterized cannabinoids present in marijuana include cannabidiol (CBD), cannabichromene (CBC), and cannabinol (CBN). CBD and CBC are major cannabinoids in marijuana and are both lipophilic. The chemical name for CBD is 2-[(1R,6R)-3-methyl-6-prop-1en-2-ylcyclohex-2-en-1-yl]-5pentylbenzene-1,3-diol and the chemical name for CBC is 2-methyl-2-(4methylpent-3-enyl)-7-pentyl-5chromenol. CBN is a minor naturallyoccurring cannabinoid with weak psychoactivity and is also a major metabolite of D9-THC. The chemical name for CBN is 6,6,9-trimethyl-3pentyl-benzo[c]chromen-1-ol. In summary, marijuana has several strains with high variability in the concentrations of D9-THC, the main psychoactive component, as well as other cannabinoids and compounds. Marijuana is not a single chemical and does not have a consistent and reproducible chemical profile with predictable or consistent clinical effects. In the HHS recommendation for marijuana scheduling (HHS, 2015), it VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 was recommended that investigators consult a guidance for industry entitled, Botanical Drug Products,45 which provides information on the approval of botanical drug products. Specifically, in order to investigate marijuana in support of a New Drug Application (NDA), clinical studies under an Investigational New Drug (IND) application should include ‘‘consistent batches of a particular marijuana product for [a] particular disease.’’ (HHS, 2015). Furthermore, the HHS noted that investigators must provide data meeting the requirements for new drug approval as stipulated in 21 CFR 314.50 (HHS, 2015). Human Pharmacokinetics Pharmacokinetics of marijuana in humans is dependent on the route of administration and formulation (Adams and Martin, 1996; Agurell et al., 1984; Agurell et al., 1986). Individuals primarily smoke marijuana as a cigarette (weighing between 0.5 and 1 gram) or in a pipe. More recently, vaporizers have been used as another means for individuals to inhale marijuana. Marijuana may also be ingested orally in foods or as an extract in ethanol or other solvents. Pharmacokinetic studies with marijuana focused on evaluating the absorption, metabolism, and elimination profile of D9-THC and other cannabinoids (Adams and Martin, 1996; Agurell et al., 1984; Agurell et al., 1986). Absorption and Distribution of Inhaled Marijuana Smoke There is high variability in the pharmacokinetics of D9-THC and other cannabinoids from smoked marijuana due to differences in individual smoking behavior even under controlled experimental conditions (Agurell et al., 1986; Herning et al., 1986; Huestis et al., 1992a). Experienced marijuana users can titrate and regulate the dose by holding marijuana smoke in their lungs for an extended period of time resulting in increased psychoactive effects by prolonging absorption of the smoke. This property may also help explain why there is a poor correlation between venous levels of D9-THC and the intensity of effects and intoxication (Agurell et al., 1986; Barnett et al., 1985; Huestis et al., 1992a). The HHS recommended that puff and inhalation volumes should be tracked in experimental studies because the concentration of cannabinoids can vary at different stages of smoking. D9-THC from smoked marijuana is rapidly absorbed within seconds. 45 Available at http://www.fda.gov/Drugs/ default.htm under Guidance (Drugs). PO 00000 Frm 00148 Fmt 4701 Sfmt 4702 Psychoactive effects are observed immediately following absorption with measurable neurological and behavioral changes for up to 6 hours (Grotenhermen, 2003; Hollister, 1986; Hollister, 1988). D9-THC is distributed to the brain in a rapid and efficient manner. Bioavailability of D9-THC from marijuana (from a cigarette or pipe) ranges from 1 to 24% with the fraction absorbed rarely exceeding 10 to 20% (Agurell et al., 1986; Hollister, 1988). The low and variable bioavailability of D9-THC is due to loss in side-stream smoke, variation in individual smoking behaviors and experience, incomplete absorption of inhaled smoke, and metabolism in lungs (Herning et al., 1986; Johansson et al., 1989). After cessation of smoking, D9-THC venous levels decline within minutes and continue to decline to about 5% to 10% of the peak level within an hour (Agurell et al., 1986; Huestis et al., 1992a; Huestis et al., 1992b). Absorption and Distribution of Orally Administered Marijuana Following oral administration of D9-THC or marijuana, onset of effects start within 30 to 90 minutes, peak after 2 to 3 hours and effects remain for 4 to 12 hours (Grotenhermen, 2003; Adams and Martin, 1996; Agurell et al., 1984; Agurell et al., 1986). Dose titration of D9-THC from orally ingested marijuana is difficult for users in comparison to smoked or inhaled marijuana due to the delay in the onset of effects. Oral bioavailability of D9-THC, either in its pure form or in marijuana, is low and variable with a range from 5% to 20% (Agurell et al., 1984; Agurell et al., 1986). There is also inter- and intrasubject variability of orally administered D9-THC under experimental conditions and even under repeated dosing experiments (HHS, 2015). The HHS noted that in bioavailability studies using radiolabeled D9-THC, D9-THC plasma levels following oral administration of D9-THC were low relative to plasma levels after inhaled or intravenously administered D9-THC. The low and variable bioavailability of orally administered D9-THC is due to first pass hepatic elimination from blood and erratic absorption from stomach and bowel (HHS, 2015). Metabolism and Excretion of Cannabinoids From Marijuana Studies evaluating cannabinoid metabolism and excretion focused on D9-THC because it is the primary psychoactive component in marijuana. D9-THC is metabolized via microsomal hydroxylation and oxidation to both active and inactive E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules mstockstill on DSK3G9T082PROD with PROPOSALS2 metabolites (Lemberger et al., 1970; Lemberger et al., 1972a; Lemberger et al., 1972b; Agurell et al., 1986; Hollister, 1988). Metabolism of D9-THC is consistent among frequent and infrequent marijuana users (Agurell et al., 1986). The primary active metabolite of D9-THC following oral ingestion is 11hydroxy-D9-THC which is equipotent to D9-THC in producing marijuana-like subjective effects (Agurell et al., 1986; Lemberger and Rubin, 1975). Metabolite levels following oral administration may be greater than that of D9-THC and may contribute greatly to the pharmacological effects of oral D9-THC or marijuana. Plasma clearance of D9-THC approximates hepatic blood flow at a rate of approximately 950 ml/min or greater. Rapid clearance of D9-THC from blood is primarily due to redistribution to other tissues in the body rather than to metabolism (Agurell et al., 1984; Agurell et al., 1986). Outside of the liver, metabolism in most tissues is considerably slow or does not occur. The elimination half-life of D9-THC ranges from 20 hours to between 10 and 13 days (Hunt and Jones, 1980). Lemberger et al. (1970) reported that the half-life of D9-THC ranged from 23–28 hours in heavy marijuana users and up ¨ to 60 to 70 hours in naıve users. The long elimination half-life of D9-THC is due to slow release of D9-THC and other cannabinoids from tissues and subsequent metabolism. Inactive carboxy metabolites of D9-THC have terminal half-lives of 50 hours to 6 days or more and serve as long-term markers in urine tests for marijuana use. Most of the absorbed D9-THC dose is eliminated in the feces and about 33% in urine. The glucuronide metabolite of D9-THC is excreted as the major urine metabolite along with 18 nonconjugated metabolites (Agurell et al., 1986). Research Status and Test of Currently Accepted Medical Use for Marijuana According to the HHS, there are numerous human clinical studies with marijuana in the United States under FDA-regulated IND applications. Results of small clinical exploratory studies have been published in the medical literature. Approval of a human drug for marketing, however, is contingent upon FDA approval of a New Drug Application (NDA) or a Biologics License Application (BLA). According to the HHS, the FDA has not approved any drug product containing marijuana for marketing. The HHS noted that a drug may be found to have a medical use in treatment in the United States for VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 purposes of the CSA if the drug meets the five elements described by the DEA in 1992. Those five elements ‘‘are both necessary and sufficient to establish a prima facie case of currently accepted medical use’’ in treatment in the United States.’’ (57 FR 10499, 10504 (March 26, 1992)). This five-element test, which the HHS and DEA have utilized in all such analyses for more than two decades, has been upheld by the Court of Appeals. ACT, 15 F.3d at 1135. The five elements that characterize ‘‘currently accepted medical use’’ for a drug are summarized here and expanded upon in the discussion below: 1. The drug’s chemistry must be known and reproducible; 2. There must be adequate safety studies; 3. There must be adequate and wellcontrolled studies proving efficacy; 4. The drug must be accepted by qualified experts; and 5. Scientific evidence must be widely available. In its review (HHS, 2015), the HHS evaluated the five elements with respect to the currently available research for marijuana. The HHS concluded that marijuana does not meet any of the five elements—all of which must be demonstrated to find that a drug has a ‘‘currently accepted medical use.’’ A brief summary of the HHS’s evaluation is provided below. Element #1: The drug’s chemistry must be known and reproducible. ‘‘The substance’s chemistry must be scientifically established to permit it to be reproduced into dosages which can be standardized. The listing of the substance in a current edition of one of the official compendia, as defined by section 201(j) of the Food, Drug and Cosmetic Act, 21 U.S.C. 321(j), is sufficient generally to meet this requirement.’’ 57 FR 10499, 10506 (March 26, 1992). As defined by the CSA, marijuana includes all species of the genus Cannabis, including all strains therein.46 Chemical constituents 46 Although the CSA definition of marijuana refers only to the species ‘‘Cannabis sativa L.,’’ federal courts have consistently ruled that all species of the genus cannabis are included in this definition. See United States v. Kelly, 527 F.2d 961, 963–964 (9th Cir. 1976) (collecting and examining cases). The Single Convention (article 1, par. 1(c)) likewise defines the ‘‘cannabis plant’’ to mean ‘‘any plant of the genus Cannabis.’’ As explained above in the attachment titled ‘‘Preliminary Note Regarding Treaty Considerations,’’ 21 U.S.C. 811(d)(1) provides that, where a drug is subject to control under the Single Convention, the DEA Administrator must control the drug under the schedule he deems most appropriate to carry out such treaty obligations, without regard to the findings required by 21 U.S.C. 811(a) or 812(b) and without regard to the procedures prescribed by 21 U.S.C. 811(a) and (b). PO 00000 Frm 00149 Fmt 4701 Sfmt 4702 53835 including D9-THC and other cannabinoids vary significantly in marijuana samples derived from different strains (Appendino et al., 2011). As a result, there will be significant differences in safety, biological, pharmacological, and toxicological parameters amongst the various marijuana samples. Due to the variation of the chemical composition in marijuana samples, it is not possible to reproduce a standardized dose when considering all strains together. The HHS does advise that if a specific Cannabis strain is cultivated and processed under controlled conditions, the plant chemistry may be consistent enough to derive reproducible and standardized doses. Element #2: There must be adequate safety studies. ‘‘There must be adequate pharmacological and toxicological studies, done by all methods reasonably applicable, on the basis of which it could fairly and responsibly be concluded, by experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, that the substance is safe for treating a specific, recognized disorder.’’ 57 FR 10499, 10506 (March 26, 1992). The HHS stated that there are no adequate safety studies on marijuana. As indicated in their evaluation of Element #1, the considerable variation in the chemistry of marijuana complicates the safety evaluation. The HHS concluded that marijuana does not satisfy Element #2 for having adequate safety studies such that medical and scientific experts may conclude that it is safe for treating a specific ailment. Element #3: There must be adequate and well-controlled studies of efficacy. ‘‘There must be adequate, wellcontrolled, well-designed, wellconducted and well-documented studies, including clinical investigations, by experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, on the basis of which it could be fairly and responsibly concluded by such exports that the substance will have the intended effect in treating a specific, recognized disorder.’’ 57 FR 10499, 10506 (March 26, 1992). As indicated in the HHS’s review of marijuana (HHS, 2015), there are no adequate or well-controlled studies that prove marijuana’s efficacy. The FDA independently reviewed (FDA, 2015) publicly available clinical studies on marijuana published prior to February 2013 to determine if there were appropriate studies to determine marijuana’s efficacy (please refer to FDA, 2015 and HHS, 2015 for more E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53836 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules details). After review, the FDA determined that out of the identified articles, including those identified through a search of bibliographic references and 566 abstracts located on PubMed, 11 studies met the a priori selection criteria, including placebo control and double-blinding. FDA and HHS critically reviewed each of the 11 studies to determine if the studies met accepted scientific standards. FDA and HHS concluded that these studies do not ‘‘currently prove efficacy of marijuana’’ for any therapeutic indication due to limitations in the study designs. The HHS indicated that these studies could be used as proof of concept studies, providing preliminary evidence on a proposed hypothesis involving a drug’s effect. Element #4: The drug must be accepted by qualified experts. ‘‘[A] consensus of the national community of experts, qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, accepts the safety and effectiveness of the substance for use in treating a specific, recognized disorder. A material conflict of opinion among experts precludes a finding of consensus.’’ 57 FR 10499, 10506 (March 26, 1992). The HHS concluded that there is currently no evidence of a consensus among qualified experts that marijuana is safe and effective in treating a specific and recognized disorder. The HHS indicated that medical practitioners who are not experts in evaluating drugs cannot be considered qualified experts (HHS, 2015; 57 FR 10499, 10505). Further, the HHS noted that the 2009 American Medical Association (AMA) report entitled, ‘‘Use of Cannabis for Medicinal Purposes’’ does not conclude that there is a currently accepted medical use for marijuana. HHS also pointed out that state-level ‘‘medical marijuana’’ laws do not provide evidence of such a consensus among qualified experts. Element #5: The scientific evidence must be widely available. ‘‘In the absence of NDA approval, information concerning the chemistry, pharmacology, toxicology, and effectiveness of the substance must be reported, published, or otherwise widely available, in sufficient detail to permit experts, qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, to fairly and responsibly conclude the substance is safe and effective for use in treating a specific, recognized disorder.’’ 57 FR 10499, 10506 (March 26, 1992). The HHS concluded that the currently available data and information on VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 marijuana is not sufficient to allow scientific scrutiny of the chemistry, pharmacology, toxicology, and effectiveness. In particular, scientific evidence demonstrating the chemistry of a specific Cannabis strain that could provide standardized and reproducible doses is not available. Petitioners’ Major Comments in Relation to Factor 3 and the Government’s Responses (1) The petitioner states on page 2 of the petition, ‘‘Marijuana has accepted medical use in the United States. Thirteen states accept the safety of marijuana for medical use . . . . Marijuana has been accepted as having medical use by dozens of professional medical and nursing organizations throughout the U.S. . . . Even the American Medical Association has now accepted the safety and efficacy of cannabinoid medicines and supports removal of marijuana from schedule I of the CSA in order to support further research.’’ As noted above, the HHS concluded that there is currently no evidence of a consensus among qualified experts that marijuana is safe and effective in treating a specific and recognized disorder, as required by the established standards. HHS pointed out that statelevel ‘‘medical marijuana’’ laws do not provide evidence of such a consensus among qualified experts. HHS also indicated that medical practitioners who are not experts in evaluating drugs cannot be considered qualified experts (HHS, 2015; 57 FR 10499, 10505). Further, the HHS pointed out that the 2009 AMA report entitled, ‘‘Use of Cannabis for Medicinal Purposes’’ does not conclude that there is a currently accepted medical use for marijuana. Instead, the AMA, like several other professional and medical associations, recommended further testing with marijuana to determine its medicinal value. The AMA official policy on medicinal use of marijuana is as follows: ‘‘Our AMA urges that marijuana’s status as a federal Schedule I controlled substance be reviewed with the goal of facilitating the conduct of clinical research and development of cannabinoid-based medicines, and alternative delivery methods. This should not be viewed as an endorsement of state-based medical cannabis programs, the legalization of marijuana, or that scientific evidence on the therapeutic use of cannabis meets the current standards for a prescription drug product.’’ (AMA, 2009). The DEA further notes that the 2013 AMA House of Delegates report states that, ‘‘cannabis is a dangerous drug and as PO 00000 Frm 00150 Fmt 4701 Sfmt 4702 such is a public health concern.’’ (AMA, 2013). (2) The petitioner asserts on page 3 of the petition that, ‘‘Several recent studies of smoked marijuana have confirmed the safety and efficacy of smoked marijuana for medical use.’’ The HHS, in its scientific and medical evaluation, reviewed marijuana clinical studies evaluating therapeutic properties and concluded that there is not enough data to confirm the safety and efficacy of smoked marijuana for use in treating a specific and recognized disorder. Relevant to efficacy, for instance, the HHS concluded, for instance, that ‘‘smoking marijuana currently has not been shown to allow delivery of consistent and reproducible doses,’’ and that the bioavailability of the delta-9 -THC from marijuana in a cigarette or pipe can range from 1 percent to 24 percent with the fraction absorbed rarely exceeding 10 to 20%. Issues relating to the safety of smoked marijuana were discussed above in Factor 2. (3) On page 3, the petitioner states that ‘‘marijuana has been determined to be safe for use under medical supervision by the DEA’s own administrative law judge.’’ As described above, in the absence of NDA or ANDA approval, DEA has established a five-element test for determining whether the drug has a currently accepted medical use in treatment in the United States. 57 FR 10499, 10506 (March 26, 1992)). See also ACT, 15 F.3d at 1135. In response to this petition, HHS concluded, and DEA agrees, that the scientific evidence is insufficient to demonstrate that marijuana has a currently accepted medical use under the five-element test. The evidence was insufficient in this regard also when the DEA considered petitions to reschedule marijuana in 1992 (57 FR 10499), in 2001 (66 FR 20038), and in 2011 (76 FR 40552). Little has changed since 2011 with respect to the lack of clinical evidence necessary to establish that marijuana has a currently accepted medical use. No studies have scientifically assessed the efficacy and full safety profile of marijuana for any specific medical condition. Factor 4: Its History and Current Pattern of Abuse Marijuana continues to be the most widely used illicit drug. In 2013, an estimated 24.6 million Americans age 12 or older were current (past month) illicit drug users. Of those, 19.8 million were current (past month) marijuana users. As of 2013, an estimated 114.7 million Americans age 12 and older had E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules used marijuana or hashish in their lifetime and 33.0 million had used it in the past year. According to the NSDUH estimates, 3.0 million people age 12 or older used an illicit drug for the first time in 2014. Marijuana initiates totaled 2.6 million in 2014. Nearly half (46.8%) of the 2.6 million new users were less than 18 years of age. In 2014, marijuana was used by 82.2% of current (past month) illicit drug users. In 2014, among past year marijuana users age 12 or older, 18.5% used marijuana on 300 or more days within the previous 12 months. This translates into 6.5 million people using marijuana on a daily or almost daily basis over a 12-month period, a significant increase from the 3.1 million daily or almost daily users in 2006 and from the 5.7 million in just the previous year. In 2014, among past month marijuana users, 41.6% (9.2 million people) used the drug on 20 or more days in the past month, a significant increase from the 8.1 million in 2013. Marijuana is also the illicit drug with the highest numbers of past year dependence or abuse in the U.S. population. According to the 2014 NSDUH report, of the 7.1 million persons aged 12 or older who were classified with illicit drug dependence or abuse, 4.2 million of them abused or were dependent on marijuana (representing 59.0% of all those classified with illicit drug dependence or abuse and 1.6% of the total U.S. noninstitutionalized population aged 12 or older). According to the 2015 Monitoring the Future (MTF) survey, marijuana is used by a large percentage of American youths, and is the most commonly used illicit drug among American youth. Among students surveyed in 2015, 15.5% of 8th graders, 31.1% of 10th graders, and 44.7% of 12th graders reported that they had used marijuana in their lifetime. In addition, 11.8%, 25.4%, and 34.9% of 8th, 10th, and 12th graders, respectively, reported using marijuana in the past year. A number of high school students reported daily use in the past month, including 1.1%, 3.0%, and 6.0% of 8th, 10th, and 12th graders, respectively. The prevalence of marijuana use and abuse is also indicated by criminal investigations for which drug evidence was analyzed in federal, state, and local forensic laboratories, as discussed above in Factor 1. The National Forensic Laboratory System (NFLIS), a DEA program, systematically collects drug identification results and associated information from drug cases submitted to and analyzed by federal, state, and local forensic laboratories. NFLIS data VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 53837 shows that marijuana was the most frequently identified drug from January 2001 through December 2014. In 2014, marijuana accounted for 29.3% (432,989) of all drug exhibits in NFLIS. The high consumption of marijuana is being fueled by increasing amounts of domestically grown marijuana as well as increased amounts of foreign source marijuana being illicitly smuggled into the United States. In 2014, the Domestic Cannabis Eradication and Suppression Program (DCE/SP) reported that 3,904,213 plants were eradicated in outdoor cannabis cultivation areas compared to 2,597,798 in 2000, as shown above in Table 3. Significant quantities of marijuana were also eradicated from indoor cultivation operations. There were 396,620 indoor plants eradicated in 2014 compared to 217,105 eradicated in 2000. As shown in Table 2 above, in 2014, the National Seizure System (NSS) reported seizures of 1,767,741 kg of marijuana. substance of abuse in 16.8% of all admissions to substance abuse treatment among patients age 12 and older. TEDS data also show that marijuana/hashish was the primary substance of abuse for 77.0% of all 12- to 14-year-olds admitted for drug treatment and 75.5% of all 15- to 17-year-olds admitted for drug treatment in 2013. Among the 281,991 admissions to drug treatment in 2013 in which marijuana/hashish was the primary drug, the average age at admission was 25 years and the peak age cohort was 15 to 17 years (22.5%). Thirty-nine percent of the 281,991 primary marijuana/hashish admissions (35.9%) were under the age of 20. In summary, the recent statistics from these various surveys and databases (see Factor 1 for more details) demonstrate that marijuana continues to be the most commonly used illicit drug, with large incidences of heavy use and dependence in teenagers and young adults. Factor 5: The Scope, Duration, and Significance of Abuse Abuse of marijuana is widespread and significant. As previously noted, according to the NSDUH, in 2014, an estimated 117.2 million Americans (44.2%) age 12 or older had used marijuana or hashish in their lifetime, 35.1 million (13.2%) had used it in the past year, and 22.2 million (8.4%) had used it in the past month. Past year and past month marijuana use has increased significantly since 2013. Past month marijuana use is highest among 18–21 year olds and it declines among those 22 years of age and older. In 2014, an estimated 18.5% of past year marijuana users age 12 or older used marijuana on 300 or more days within the past 12 months. This translates into 6.5 million persons using marijuana on a daily or almost daily basis over a 12-month period. In 2014, an estimated 41.6% (9.2 million) of past month marijuana users age 12 or older used the drug on 20 or more days in the past month (SAMHSA, NSDUH). Chronic use of marijuana is associated with a number of health risks (see Factors 2 and 6). Furthermore, the average percentage of D9-THC in seized marijuana has increased over the past two decades (The University of Mississippi Potency Monitoring Project). Additional studies are needed to clarify the impact of greater potency, but one study shows that higher levels of D9-THC in the body are associated with greater psychoactive effects (Harder and Rietbrock, 1997), which can be correlated with higher abuse potential (Chait and Burke, 1994). TEDS data show that in 2013, marijuana/hashish was the primary Factor 6: What, if Any, Risk There Is to the Public Health In its recommendation, the HHS discussed public health risks associated with acute and chronic marijuana use in Factor 6. Public health risks as measured by emergency department visits and drug treatment admissions are discussed by HHS and DEA in Factors 1, 4, and 5. Similarly, Factor 2 discusses marijuana’s pharmacology and presents some of the adverse health effects associated with use. Marijuana use may affect the physical and/or psychological functioning of an individual user, but may also have broader public impacts including driving impairments and fatalities from car accidents. PO 00000 Frm 00151 Fmt 4701 Sfmt 4702 Risks From Acute Use of Marijuana As discussed in the HHS review document (HHS, 2015), acute usage of marijuana impairs psychomotor performance including motor control and impulsivity, risk taking and executive function (Ramaekers et al., 2004; Ramaekers et al., 2006). In a minority of individuals using marijuana, dysphoria, prolonged anxiety, and psychological distress may be observed (Haney et al., 1999). The DEA further notes a recent review of acute marijuana effects (Wilkinson et al., 2014) that reported impaired neurological function including altered perception, paranoia, delayed response time, and memory deficits. In its recommendation, HHS references a meta-analysis conducted by Li et al. (2012) where the authors concluded that psychomotor impairments associated with acute marijuana usage have also been E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53838 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules associated with increased risk of car accidents with individuals experiencing acute marijuana intoxication (Li et al., 2012; HHS, 2015). The DEA further notes more recent studies examining the risk associated with marijuana use and driving. Younger drivers (under 21) have been characterized as the highest risk group associated with marijuana use and driving (Whitehill et al., 2014). Furthermore, in 2013, marijuana was found in 13% of the drivers involved in automobile-related fatal accidents (McCartt, 2015). The potential risk of automobile accidents associated with marijuana use appears to be increasing since there has been a steady increase in individuals intoxicated with marijuana over the past 20 years (Wilson et al., 2014). However, a recent study commissioned by the National Highway Traffic Safety Administration (NHTSA) reported that when adjusted for confounders (e.g., alcohol use, age, gender, ethnicity), there was not a significant increase in crash risk (fatal and nonfatal, n = 2,682) associated with marijuana use (Compton and Berning, 2015). The DEA also notes recent studies examining unintentional exposures of children to marijuana (Wang et al., 2013; 2014). Wang et al. (2013) reviewed emergency department (ED) visits at a children’s hospital in Colorado from January 1, 2005 to December 31, 2011. As stated by the authors, in 2000 Colorado passed Amendment 20 which allowed for the use of marijuana. Following the passage of ‘‘a new Justice Department policy’’ instructing ‘‘federal prosecutors not to seek arrest of medical marijuana users and suppliers as long as they conform to state laws’’ (as stated in Wang et al., 2013), 14 patients in Colorado under the age of 12 were admitted to the ED for the unintended use of marijuana over a 27 month period. Prior to the passage of this policy, from January 1, 2005 to September 30, 2009 (57 months), there were no pediatric ED visits due to unintentional marijuana exposure (Wang et al., 2013). The DEA also notes a larger scale evaluation of pediatric exposures using the National Poison Data System (Wang et al., 2014). That study reported that there were 985 unintentional marijuana exposures in children (9 years and younger) between January 1, 2005 to December 31, 2011. The authors stratified the ED visits by states with laws allowing medical use of marijuana, states transitioning to legalization for medical use, and states with no such laws. Out of the 985 exposures, 495 were in non-legal states (n=33 states), 93 in transitional states VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 (n=8 states), and 396 in ‘‘legal’’ states (n=9 states). The authors reported that there was a twofold increase (OR = 2.1) in moderate or major effects in children with unintentional marijuana use and a threefold increase (OR = 3.4) in admissions to critical care units in states allowing medical use of marijuana, in comparison to non-legal states. extensive drug abuse (Hall and Lynskey, 2005), and (2) most studies testing the gateway drug hypothesis for marijuana use the determinative measure any use of an illicit drug rather than applying DSM–5 criteria for drug abuse or dependence (DSM–5, 2013). The HHS cited several studies where marijuana use did not lead to other illicit drug use (Kandel and Chen, 2000; Risks Associated With Chronic Use of von Sydow et al., 2002; Nace et al., Marijuana 1975). Two separate longitudinal The HHS noted that a major risk from studies with adolescents using chronic marijuana use is a distinctive marijuana did not demonstrate an withdrawal syndrome, as described in association with use of other illicit the 2013 DSM–5. The HHS analysis also drugs (Kandel and Chen, 2000; von quoted the following description of risks Sydow et al., 2002). associated with marijuana [cannabis] It was noted by the HHS that, when abuse from the DSM–5: evaluating the gateway hypothesis, differences appear when examining use Individuals with cannabis use disorder versus abuse or dependence of other may use cannabis throughout the day over a period of months or years, and thus may illicit drugs. Van Gundy and Rebellon spend many hours a day under the influence. (2010) reported that there was a Others may use less frequently, but their use correlation between marijuana use in causes recurrent problems related to family, adolescence and other illicit drug use in school, work, or other important activities early adulthood, but when examined in (e.g., repeated absences at work; neglect of terms of drug abuse of other illicit family obligations). Periodic cannabis use drugs, age-linked stressors and social and intoxication can negatively affect roles were confounders in the behavioral and cognitive functioning and association. Degenhardt et al. (2009) thus interfere with optimal performance at work or school, or place the individual at reported that marijuana use often increased physical risk when performing precedes use of other illicit drugs, but activities that could be physically hazardous dependence involving drugs other than (e.g. driving a car; playing certain sports; marijuana frequently correlated with performing manual work activities, including higher levels of illicit drug abuse. operating machinery). Arguments with Furthermore, Degenhardt et al. (2010) spouses or parents over the use of cannabis reported that in countries with lower in the home, or its use in the presence of prevalence of marijuana usage, use of children, can adversely impact family other illicit drugs before marijuana was functioning and are common features of those with cannabis use disorder. Last, often documented. individuals with cannabis use disorder may Based on these studies among others, continue using marijuana despite knowledge the HHS concluded that although many of physical problems (e.g. chronic cough individuals with a drug abuse disorder related to smoking) or psychological may have used marijuana as one of their problems (e.g. excessive sedation or first illicit drugs, this does not mean exacerbation of other mental health problems) associated with its use. (HHS 2015, that individuals initiated with marijuana inherently will go on to page 34). become regular users of other illicit The HHS stated that chronic drugs. marijuana use produces acute and chronic adverse effects on the Factor 7: Its Psychic or Physiological respiratory system, memory and Dependence Liability learning. Regular marijuana smoking Physiological (Physical) Dependence in can produce a number of long-term Humans pulmonary consequences, including The HHS stated that heavy and chronic cough and increased sputum chronic use of marijuana can lead to (Adams and Martin, 1996), and physical dependence (DSM–5, 2013; histopathologic abnormalities in Budney and Hughes, 2006; Haney et al., bronchial epithelium (Adams and 1999). Tolerance is developed following Martin, 1996). repeated administration of marijuana Marijuana as a ‘‘Gateway Drug’’ and withdrawal symptoms are observed The HHS reviewed the clinical as following discontinuation of studies evaluating the gateway marijuana usage (HHS, 2015). The HHS mentioned that tolerance hypothesis in marijuana and found them to be limited. The primary reasons can develop to some of marijuana’s effects, but does not appear to develop were: (1) Recruited participants were with respect to the psychoactive effects. influenced by social, biological, and It is believed that lack of tolerance to economic factors that contribute to PO 00000 Frm 00152 Fmt 4701 Sfmt 4702 E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules psychoactive effects may relate to electrophysiological data demonstrating that chronic D9-THC administration does not affect increased neuronal firing in the ventral tegmental area, a brain region that plays a critical role in drug reinforcement and reward (Wu and French, 2000). Humans can develop tolerance to marijuana’s cardiovascular, autonomic, and behavioral effects (Jones et al., 1981). Tolerance to some behavioral effects appears to develop with heavy and chronic use, but not with occasional usage. Ramaekers et al. (2009) reported that following acute administration of marijuana, occasional marijuana users still exhibited impairments in tracking and attention tasks whereas performance of heavy users on the these tasks was not affected. In a follow-up study with the same subjects that participated in the study by Ramaekers et al. (2009), a neurophysiological assessment was conducted where event-related potentials (ERPs) were measured using electroencephalography (EEG) (Theunissen et al., 2012). Similar to the earlier results, the heavy marijuana users (n = 11; average of 340 marijuana uses per year) had no changes in their ERPs with the acute marijuana exposure. However, occasional users (n = 10; average of 55 marijuana uses per year) had significant decreases in the amplitude of an ERP component (categorized as P100) on tracking and attention tasks and ERP amplitude change is indicative of a change in brain activity (Theunissen et al., 2012). The HHS indicated that downregulation of cannabinoid receptors may be a possible mechanism for tolerance to marijuana’s effects (Hirvonen et al., 2012; Gonzalez et al., 2005; Rodriguez de Fonseca et al., 1994; Oviedo et al., 1993). As indicated by the HHS, the most common withdrawal symptoms in heavy, chronic marijuana users are sleep difficulties, decreased appetite or weight loss, irritability, anger, anxiety or nervousness, and restlessness (Budney and Hughes, 2006; Haney et al., 1999). As reported by HHS, most marijuana withdrawal symptoms begin within 24– 48 hours of discontinuation, peak within 4–6 days, and last for 1–3 weeks. The HHS pointed out that the American Psychiatric Association’s (APA’s) Diagnostic and Statistical Manual of Mental Disorders—5 (DSM– 5) included a list of withdrawal symptoms following marijuana [cannabis] use (DSM–5, 2013). The DEA notes that a DSM–5 working group report indicated that marijuana withdrawal symptoms were added to DSM–5 (they were not previously VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 included in DSM–IV) because marijuana withdrawal has now been reliably presented in several studies (Hasin et al., 2013). In short, marijuana withdrawal signs are reported in up to one-third of regular users and between 50% and 90% of heavy users (Hasin et al., 2013). According to DSM–5 criteria, in order to be characterized as having marijuana withdrawal, an individual must develop at least three of the seven symptoms within one week of decreasing or stopping the heavy and prolonged use (DSM–5, 2013). These seven symptoms are: (1) Irritability; anger or aggression, (2) nervousness or anxiety, (3) sleep difficulty, (4) decreased appetite or weight loss, (5) restlessness, (6) decreased mood, (7) somatic symptoms causing significant discomfort (DSM–5, 2013). Psychological (Psychic) Dependence in Humans High levels of psychoactive effects such as positive reinforcement correlate with increased marijuana abuse and dependence (Scherrer et al., 2009; Zeiger et al., 2010). Epidemiological marijuana use data reported by NSDUH, MTF, and TEDS support this assertion as presented in the HHS 2015 review of marijuana and updated by the DEA. According to the findings in the 2014 NSDUH survey, an estimated 9.2 million individuals 12 years and older used marijuana daily or almost daily (20 or more days within the past month). In the 2015 MTF report, daily marijuana use (20 or more days within the past 30 days) in 8th, 10th, and 12th graders is 1.1%, 3.0%, and 6.0%, respectively. The 2014 NSDUH report stated that 4.2 million persons were classified with dependence on or abuse of marijuana in the past year (representing 1.6% of the total population age 12 or older, and 59.0% of those classified with illicit drug dependence or abuse) based on criteria specified in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM–IV). Furthermore, of the admissions to licensed substance abuse facilities, as presented in TEDS, marijuana/hashish was the primary substance of abuse for; 18.3% (352,297) of 2011 admissions; 17.5% (315,200) of 2012 admissions; and 16.8% (281,991) of 2013 admissions. Of the 281,991 admissions in 2013 for marijuana/ hashish as the primary substance, 24.3% used marijuana/hashish daily. Among admissions to treatment for marijuana/hashish as the primary substance in 2013, 27.4% were ages 12 to 17 years and 29.7% were ages 20 to 24 years. PO 00000 Frm 00153 Fmt 4701 Sfmt 4702 53839 Factor 8: Whether the Substance is an Immediate Precursor of a Substance Already Controlled Under the CSA Marijuana is not an immediate precursor of another controlled substance. Determination After consideration of the eight factors discussed above and of the HHS’s Recommendation, the DEA finds that marijuana meets the three criteria for placing a substance in schedule I of the CSA under 21 U.S.C. 812(b)(1): 1. Marijuana has a high potential for abuse. The HHS concluded that marijuana has a high potential for abuse based on a large number of people regularly using marijuana, its widespread use, and the vast amount of marijuana that is available through illicit channels. Marijuana is the most abused and trafficked illicit substance in the United States. Approximately 22.2 million individuals in the United States (8.4% of the United States population) were past month users of marijuana according to the 2014 NSDUH survey. A 2015 national survey (Monitoring the Future) that tracks drug use trends among high school students showed that by 12th grade, 21.3% of students reported using marijuana in the past month, and 6.0% reported having used it daily in the past month. In 2011, SAMHSA’s Drug Abuse Warning Network (DAWN) reported that marijuana was mentioned in 36.4% of illicit drug-related emergency department (ED) visits, corresponding to 455,668 out of approximately 1.25 million visits. The Treatment Episode Data Set (TEDS) showed that 16.8% of non-private substance-abuse treatment facility admissions in 2013 were for marijuana as the primary drug. Marijuana has dose-dependent reinforcing effects that encourage its abuse. Both clinical and preclinical studies have demonstrated that marijuana and its principle psychoactive constituent, D9-THC, possess the pharmacological attributes associated with drugs of abuse. They function as discriminative stimuli and as positive reinforcers to maintain drug use and drug-seeking behavior. Additionally, use of marijuana can result in psychological dependence. 2. Marijuana has no currently accepted medical use in treatment in the United States. The HHS stated that the FDA has not approved an NDA for marijuana. The HHS noted that there are opportunities for scientists to conduct clinical research with marijuana and there are active INDs for marijuana, but marijuana E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53840 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules does not have a currently accepted medical use in the United States, nor does it have an accepted medical use with severe restrictions. FDA approval of an NDA is not the sole means through which a drug can be determined to have a ‘‘currently accepted medical use’’ under the CSA. Applying the five-part test summarized below, a drug has a currently accepted medical use if all of the following five elements have been satisfied. As detailed in the HHS evaluation and as set forth below, none of these elements has been fulfilled for marijuana: i. The drug’s chemistry must be known and reproducible Chemical constituents including D9THC and other cannabinoids in marijuana vary significantly in different marijuana strains. In addition, the concentration of D9-THC and other cannabinoids may vary between strains. Therefore the chemical composition among different marijuana samples is not reproducible. Due to the variation of the chemical composition in marijuana strains, it is not possible to derive a standardized dose. The HHS does advise that if a specific Cannabis strain is cultivated and processed under controlled conditions, the plant chemistry may be consistent enough to derive standardized doses. ii. There must be adequate safety studies There are not adequate safety studies on marijuana for use in any specific, recognized medical condition. The considerable variation in the chemistry of marijuana results in differences in safety, biological, pharmacological, and toxicological parameters amongst the various marijuana samples. iii. There must be adequate and wellcontrolled studies proving efficacy There are no adequate and wellcontrolled studies that determine marijuana’s efficacy. In an independent review performed by the FDA of publicly available clinical studies on marijuana (FDA, 2015), FDA concluded that these studies do not have enough information to ‘‘currently prove efficacy of marijuana’’ for any therapeutic indication. iv. The drug must be accepted by qualified experts At this time, there is no consensus of opinion among experts concerning the medical utility of marijuana for use in treating specific recognized disorders. v. The scientific evidence must be widely available The currently available data and information on marijuana is not sufficient to address the chemistry, pharmacology, toxicology, and VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 effectiveness. The scientific evidence regarding marijuana’s chemistry with regard to a specific cannabis strain that could be formulated into standardized and reproducible doses is not currently available. 3. There is a lack of accepted safety for use of marijuana under medical supervision. Currently, there are no FDA-approved marijuana products. The HHS also concluded that marijuana does not have a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions. According to the HHS, the FDA is unable to conclude that marijuana has an acceptable level of safety in relation to its effectiveness in treating a specific and recognized disorder due to lack of evidence with respect to a consistent and reproducible dose that is contamination free. The HHS indicated that marijuana research investigating potential medical use should include information on the chemistry, manufacturing, and specifications of marijuana. The HHS further indicated that a procedure for delivering a consistent dose of marijuana should also be developed. Therefore, the HHS concluded that marijuana does not have an acceptable level of safety for use under medical supervision. References 1. Abrams DI, Hilton JF, Reiser RJ, Shade SB, Elbeik TA, Aweeka FT, Benowitz NL, Bredt BM, Kosel B, Aberg JA, Deeks SG, Mitchell TF, Mulligan K, Bacchetti P, McCune JM, Schambelan M (2003). Short-term effects of cannabinoids in patients with HIV–1 infection: a randomized, placebo-controlled clinical trial. Ann Intern Med 139(4):258–266. 2. Adams IB, Martin BR (1996). Cannabis: Pharmacology and toxicology in animals and humans. Addiction 91:1585–1614. 3. Agurell S, Dewey WL, and Willetts RE (eds.) (1984). The Cannabinoids: Chemical, Pharmacologic, and Therapeutic Aspects. New York: Academic Press 4. Agurell S, Halldin M, Lindgren JE, Ohlsson A, Widman M, Gillespie H, Hollister L (1986). Pharmacokinetics and metabolism of delta-1tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev 38(1):21–43. 5. American College of Physicians [ACP]. (2008). Supporting Research Into the Therapeutic Role of Marijuana. Philadelphia: American College of Physicians; 2008: Position Paper (Available from American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106). 6. American Medical Association [AMA]. (2009a). Use of Cannabis for Medical Purposes. Report of the Council on Science and Public Health 3. PO 00000 Frm 00154 Fmt 4701 Sfmt 4702 7. American Medical Association [AMA]. (2009b). AMA Policy: Medical Marijuana. H–95–952 Medical Marijuana. 8. American Medical Association [AMA]. (2013). 2013 Interim Meeting. American Medical Association House of Delegates (I–13). Accessed at www.ama-assn.org/ assets/meeting/2013i/i13-refcommkannotated.pdf. 9. American Society of Addiction Medicine [ASAM]. (2014). New York Times calls for legalization of marijuana, ASAM strongly objects. Accessed at www.asam.org/docs/default-source/ pressreleases/asam-press-releasenytimes-editorial-marijuana-2014-727.pdf?sfvrsn=2. ¨ 10. Andreasson S, Allebeck P, Engstrom A, Rydberg U (1987). Cannabis and schizophrenia: A longitudinal study of Swedish conscripts. Lancet 1:483–1483. 11. Appendino G, Chianese G, TaglialatelaScafati O (2011). Cannabinoids: occurrence and medicinal chemistry. Curr Med Chem 18(7):1085–1099. 12. Asch RH, Smith CG, Siler-Khodr TM, Pauerstein CJ (1981). Effects of delta 9tetrahydrocannabinol during the follicular phase of the rhesus monkey (Macaca mulatta). J Clin Endocrinol Metab 52(1):50–55. 13. Balster RL (1991). Drug abuse potential evaluation in animals. Br J Addict 86(12):1549–1558. 14. Balster RL, Prescott WR (1992). Delta9Tetrahydrocannabinol discrimination in rats as a model for cannabis intoxication. Neurosci Biobehav Res 16(1):55–62. 15. Balster RL, Bigelow GE (2003). Guidelines and methodological reviews concerning drug abuse liability assessment. Drug Alcohol Depend 70:S13–S40. 16. Barnett G, Licko V, Thompson T (1985). Behavioral pharmacokinetics of marijuana. Psychopharmacology 85(1):51–56. 17. Benowitz NL, Jones RT (1975). Cardiovascular effects of prolonged delta-9-tetrahydrocannabinol ingestion. Clin Pharmacol Ther 18(3):287–297. 18. Benowitz NL, Jones RT (1981). Cardiovascular and metabolic considerations in prolonged cannabinoid administration in man. J Clin Pharmacol 21(8–9 Suppl):214S–223S. 19. Block RI, Farinpour R, Schlechte JA (1991). Effects of chronic marijuana use on testosterone, luteinizing hormone, follicle stimulating hormone, prolactin and cortisol in men and women. Drug Alcohol Depend 28(2):121–128. 20. Block RI, Farinpour R, Braverman K (1992). Acute effects of marijuana on cognition: relationships to chronic effects and smoking techniques. Pharmacol Biochem Behav 43(3):907– 917. 21. Bolla KI, Brown K, Eldreth D, Tate K, Cadet JL (2002). Dose-related neurocognitive effects of marijuana use. Neurology 59:1337–1343. 22. Bolla KI, Eldreth DA, Matochik JA, Cadet JL (2005). Neural substrates of faulty decision-making in abstinent marijuana users. NeuroImage 26:480–492. E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 23. Bonnet U (2013). Chronic cannabis abuse, delta-9-tetrahydrocannabinol and thyroid function. Pharmacopsychiatry 46(1):35–36. 24. Bouaboula M, Rinaldi M, Carayon P, Carillon C, Delpech B, Shire D, Le Fur G, Casellas P (1993). Cannabinoidreceptor expression in human leukocytes. Eur J Biochem 214(1):173– 180. 25. Braida D, Iosue S, Pegorini S, Sala M (2004). Delta9-tetrahydrocannabinolinduced conditioned place preference and intracerebroventricular selfadministration in rats. Eur J Pharmacol 506(1):63–69. 26. Brievogel CS, Childers SR (2000). Cannabinoid agonist signal transduction in rat brain: comparison of cannabinoid agonists in receptor binding, G-protein activation, and adenylyl cyclase inhibition. J Pharmacol Exp Ther 295(1):328–336. 27. Brown TT, Dobs AS (2002). Endocrine effects of marijuana. J Clin Pharmacol 42(11 Suppl):90S–96S. 28. Browne RG, Weisman A (1981). Discriminative stimulus properties of delta 9-tetrahydrocannabinol: Mechanistic studies. J Clin Pharmacol 21(8–9 Suppl):227S–234S. 29. Budney AJ, Hughes JR (2006). The cannabis withdrawal syndrome. Curr Opin Psychiatry 19(3):233–238. 30. Capriotti RM, Foltin RW, Brady JV, Fischman MW (1988). Effects of marijuana on the task-elicited physiological response. Drug Alcohol Depend 21(3):183–187. 31. Cascini F, Aiello C, Di Tanna G (2012). Increasing delta-9-tetrahydrocannabinol D-9-THC) content in herbal cannabis over time: systematic review and metaanalysis. Curr Drug Abuse Rev 5(1):32– 40. 32. Chait LD, Burke KA (1994). Preference for ‘‘high’’ versus low-potency marijuana. Pharmacol Biochem Behav 7:357–364. 33. Cheer JF, Kendall DA, Marsden CA (2000). Cannabinoid receptors and reward in the rat: a conditioned place preference study. Psychopharmacology (Berl) 151(1):25–30. 34. Compton RP, Berning A (2015). Drug and Alcohol Crash Risk. Traffic Safety Facts Research Note. DOT HS 812 117. Washington, DC: National Highway Traffic Safety Administration. 35. Cone EJ, Johnson RE, Moore JD, Roache JD (1986). Acute effects of smoking marijuana on hormones, subjective effects and performance in male human subjects. Pharmacol Biochem Behav 24(6):1749–1754. 36. Croxford JL, Yamamura T (2005). Cannabinoids and the immune system: potential for the treatment of inflammatory diseases? J Neuroimmunol 166(1–2):3–18. 37. Daling JR, Doody DR, Sun X, Trabert BL, Weiss NS, Chen C, Biggs ML, Starr JR, Dey SK, Schwartz SM (2009). Association of marijuana use and the incidence of testicular germ cell tumors. Cancer. 115(6):1215–1223. 38. Dalton WS, Martz R, Lemberger L, Rodda BE, Forney RB (1976). Influence of VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 cannabidiol on delta-9tetrahydrocannabinol effects. Clin Pharmacol Ther 19(3):300–309. 39. Dax EM, Pilotte NS, Adler WH, Nagel JE, Lange WR (1989). The effects of 9enetetrahydrocannabinol on hormone release and immune function. J Steroid Biochem 34(1–6):263–270. 40. Day NL, Wagener DK, Taylor PM (1985). Measurement of substance use during pregnancy: methodologic issues. NIDA Res Monogr 59:36–47. 41. Day NL, Leech SL, Goldschmidt L (2011). The effects of prenatal marijuana exposure on delinquent behaviors are mediated by measures of neurocognitive functioning. Neurotoxicol Teratol 33(1):129–136. 42. Day NL, Goldschmidt L, Day R, Larkby C, Richardson GA (2015). Prenatal marijuana exposure, age of marijuana initiation, and the development of psychotic symptoms in young adults. Psychol Med 45(8):1779–1787. 43. Degenhardt L, Hall W, Lynskey M (2003). Testing hypotheses about the relationship between cannabis use and psychosis. Drug Alcohol Depend 71(1):37–48. 44. Degenhardt L, Hall WD, Lynskey M, McGrath J, McLaren J, Calabria B, Whiteford H, Vos T (2009). Should burden of disease estimates include cannabis use as a risk factor for psychosis? PLoS Medicine. 6(9):e1000133. 45. Degenhardt L, Dierker L, Chiu WT, Medina-Mora ME, Neumark Y, Sampson N, Alonso J, Angermeyer M, Anthony JC, Bruffaerts R, et al (2010). Evaluating the drug use ‘‘gateway’’ theory using crossnational data: consistency and associations of the order of initiation of drug use among participants in the WHO World Mental Health Surveys. Drug Alcohol Depend 108(1–2):84–97. 46. De Petrocellis PL, Di Marzo V (2009). An introduction to the endocannabinoid system: From the early to the latest concepts. Best Pract Res Clin Endocrinol Metab 23(1):1–15. 47. Department of Health and Human Services [HHS] (2015). Basis for the recommendation for maintaining marijuana in Schedule I of the Controlled Substances Act. 48. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992). Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258(5090):1946–1949. 49. Dewey WL, Martin BR, May EL (1984). Cannabinoid stereoisomers: pharmacological effects. In Smith DF. (Ed.) CRC Handbook of stereoisomers: drugs in psychopharmacology, 317–26 (Boca Raton, FL, CRC Press). 50. Drug Enforcement Administration (2015). Drugs of Abuse. 51. DSM–5 (2013). Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Association. Washington, DC: American Psychiatric Publishing. 52. Eisenstein TK, Meissler JJ (2015). Effects of cannabinoids on T-cell function and PO 00000 Frm 00155 Fmt 4701 Sfmt 4702 53841 resistance to infection. J Neuroimmune Pharmacol 10(2):204–216. 53. Eldridge JC, Murphy LL, Landfield PW (1991). Cannabinoids and the hippocampal glucocorticoid receptor: Recent findings and possible significance. Steroids 56(5):226–231. 54. ElSohly MA, Slade D (2005). Chemical constituents of marijuana: The complex mixture of natural cannabinoids. Life Sci 78:539–548. 55. Fant RV, Heishman SJ, Bunker EB, Pickworth WB (1998). Acute and residual effects of marijuana in humans. Pharmacol Biochem Behav 60(4):777– 784. 56. Federal Register (1992). ‘‘Marijuana Scheduling Petition; Denial of Petition; Remand’’—Drug Enforcement Administration, Final Order. Fed Registr 57(59):10499–10508. 57. Federal Register (1999). ‘‘Rescheduling of the Food and Drug Administration Approved Product Containing Synthetic Dronabinol [(–)-delta 9-(trans)Tetrahydrocannabinol] in Sesame Oil and Encapsulated in Soft Gelatin Capsules From Schedule II to Schedule III; Final Rule,’’ Fed Registr 64(127):35928–35930. 58. Federal Register (2001). ‘‘Notice of Denial of Petition: Basis for the Recommendation for Maintaining Marijuana in Schedule I of the Controlled Substances Act,’’ Fed Registr 66(75):20038–20076. 59. Fergusson DM, Horwood LJ, Ridder EM (2005). Tests of causal linkages between cannabis use and psychotic symptoms. Addiction. 100(3):354–366. 60. Fontes MA, Bolla KI, Cunha PJ, Almeida PP, Jungerman F, Laranjeira RR, Bressan RA, Lacerda AL (2011). Cannabis use before age 15 and subsequent executive functioning. Br J Psychiatry 198(6):442– 447. 61. Fried PA, Watkinson B, Grant A, Knights RM (1980). Changing patterns of soft drug use prior to and during pregnancy: a prospective study. Drug Alcohol Depend 6(5):323–343. 62. Fried PA, Watkinson B (1990). 36- and 48-month neurobehavioral follow-up of children prenatally exposed to marijuana, cigarettes and alcohol. J Dev Behav Pediatr 11:49–58. 63. Fried PA, Watkinson B, Gray R (1992). A follow-up study of attentional behavior in 6-year-old children exposed prenatally to marihuana, cigarettes and alcohol. Neurotoxicol Teratol 14:299– 311. 64. Fried PA, Watkinson B, Gray R (1998). Differential effects on cognitive functioning in 9- to 12-year olds prenatally exposed to cigarettes and marihuana. Neurotoxicol Teratol 20(3):293–306. 65. Fried PA (2002). Adolescents prenatally exposed to marijuana: Examination of facets of complex behaviors and comparisons with the influence of in utero cigarettes. J Clin Pharmacol 42(11 Suppl):97S–102S. 66. Fried PA, Watkinson B, Gray R (2005). Neurocognitive consequences of E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53842 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules marihuana—a comparison with pre-drug performance. Neurotoxicol Teratol 27(2):231–239. 67. Fung M, Gallagher C, Machtay M (1999). Lung and aero-digestive cancers in young marijuana smokers. Tumori 85(2):140–142. 68. Gates P, Jaffe A, Copeland J (2014). Cannabis smoking and respiratory health: Consideration of the literature. Respirology 19(5):655–662. 69. Ghozland S, Matthes HW, Simonin F, Filliol D, Kieffer BL, Maldonado R (2002). Motivational effects of cannabinoids are mediated by mu-opioid and kappa-opioid receptors. J Neurosci 22(3):1146–1154. 70. Gold LH, Balster RL, Barrett RL, Britt DT, Martin BR (1992). A comparison of the discriminative stimulus properties of delta 9-tetrahydrocannabinol and CP 55,940 in rats and rhesus monkeys. J Pharmacol Exp Ther 262(2):479–486. 71. Goldschmidt L, Richardson GA, Willford JA, Day NL (2008). Prenatal marijuana exposure and intelligence test performance at age 6. J Am Acad Child Adolesc Psychiatry 47(3):254–263. 72. Goldschmidt L, Richardson GA, Willford JA, Severtson SG, Day NL (2012). School achievement in 14-year-old youths prenatally exposed to marijuana. Neurotoxicol Teratol 34(1):161–167. 73. Gong H Jr, Tashkin DP, Simmons MS, Calvarese B, Shapiro BJ (1984). Acute and subacute bronchial effects of oral cannabinoids. Clin Pharmacol Ther 35(1):26–32. 74. Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA, Brusco A, Uhl GR (2006). Cannabinoid CB2 receptors: Immunohistochemical localization in rat brain. Brain Res 1071(1):10–23. 75. Gonsiorek W, Lunn C, Fan X, Narula S, Lundell D, Hipkin RW. Endocannabinoid 2-arachidonyl glycerol is a full agonist through human type 2 cannabinoid receptor: Antagonism by anandamide. Mol Pharmacol 57(5):1045–1050. 76. Gonzalez R (2007). Acute and non-acute effects of cannabis on brain functioning and neuropsychological performance. Neuropsychol Rev 17(3):347–361. 77. Gonzalez S, Cebeira M, Fernandez-Ruiz J (2005). Cannabinoid tolerance and dependence: A review of studies in laboratory animals. Pharmacol Biochem Behav 81(2):300–318. 78. Griffith-Lendering MF, Wigman JT, Prince van Leeuwen A, Huijbregts SC, Huizink AC, Ormel J, Verhulst FC, van Os J, Swaab H, Vollebergh WA (2013). Cannabis use and vulnerability for psychosis in early adolescence—a TRAILS study. Addiction 108(4):733– 740. 79. Grotenhermen F (2003). Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet 42(4):327–360. 80. Gruber SA, Sagar KA, Dahlgren MK, Racine M, Lukas SE (2012). Age of onset of marijuana use and executive function. Psychol Addict Behav 26(3):496–506. 81. Hackam DG (2015). Cannabis and stroke: Systematic appraisal of case reports. Stroke 46(3):852–856. VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 82. Hall WD, Lynskey M (2005). Is cannabis a gateway drug? Testing hypotheses about the relationship between cannabis use and the use of other illicit drugs. Drug Alcohol Rev 24(1):39–48. 83. Hall W, Degenhardt L (2014). The adverse health effects of chronic cannabis use. Drug Test Anal 6(1–2):39–45. 84. Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW (1999). Abstinence symptoms following smoked marijuana in humans. Psychopharmacology (Berl) 141(4):395–404. 85. Harder S, Rietbrock S (1997). Concentration-effect relationship of delta-9-tetrahydrocannabinol and prediction of psychotropic effects after smoking marijuana. International Journal of Clinical Pharmacology and Therapeutics. 35(4):155–159. 86. Hasin DS, O’Brien CP, Auriacombe M, Borges G, Bucholz K, Budney A, Compton WM, Crowley T, Ling W, Petry NM, Schuckit M, Grant BF (2013). DSM– 5 criteria for substance use disorders: Recommendations and rationale. Am J Psychiatry 170(8):834–851. 87. Heishman SJ, Huestis MA, Henningfield JE, Cone EJ (1990). Acute and residual effects of marijuana: Profiles of plasma THC levels, physiological, subjective, and performance measures. Pharmacol Biochem Behav 37(3):561–565. 88. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, Rice KC (1990). Cannabinoid receptor localization in brain. Proc Natl Acad Sci 87:1932–1936. 89. Herkenham M (1992). Cannabinoid receptor localization in brain: Relationship to motor and reward systems. Ann N Y Acad Sci 654:19–32. 90. Herning RI, Hooker WD, Jones RT (1986). Tetrahydrocannabinol content and differences in marijuana smoking behavior. Psychopharmacology (Berl) 90(2):160–162. 91. Hirvonen J, Goodwin RS, Li CT, Terry GE, Zoghbi SS, Morse C, Pike VW, Volkow ND, Huestis MA, Innis RB (2012). Reversible and regionally selective downregulation of brain cannabinoid CB 1 receptors in chronic daily cannabis smokers. Mol Psychiatry 17(6):643–649. 92. Hively RL, Mosher WA, Hoffman FW (1966). Isolation of trans-D9tetrahydrocannabinol from marihuana. J Am Chem Soc 88:1832–1833. 93. Hollister LE, Gillespie HK (1973). Delta8- and delta-9-tetrahydrocannabinol comparison in man by oral and intravenous administration. Clin Pharmacol Ther 14(3):353–357. 94. Hollister LE (1986). Health aspects of cannabis. Pharmacological Rev 3:1–20. 95. Hollister LE (1988). Cannabis (Literature review). Acta Psychiatr Scand (Suppl) 78:108–118. 96. Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ (2004). Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology 47 Suppl:345–358. 97. Huang YH, Zhang ZF, Tashkin DP, Feng B, Straif K, Hashibe K (2015). An epidemiologic review of marijuana and PO 00000 Frm 00156 Fmt 4701 Sfmt 4702 cancer: An update. Cancer Epidemiol Biomarkers Prev 24(1):15–31. 98. Huestis MA, Sampson AH, Holicky BJ, Benningfield JE, Cone EJ (1992a). Characterization of the absorption phase of marijuana smoking. Clin Pharmacol Ther 52:31–41. 99. Huestis MA, Benningfield JE, Cone EJ (1992b). Blood Cannabinoids. 1. Absorption of THC and formation of 11– 0H–THC and THC COOH during and after smoking marijuana. J Anal Toxicol 16(5):276–282. 100. Hunt CA, Jones RT (1980). Tolerance and disposition of tetrahydrocannabinol in man. J Pharmacol Exp Ther 215(1):35– 44. 101. Ilan AB, Gevins A, Coleman M, ElSohly MA, de Wit H (2005). Neurophysiological and subjective profile of marijuana with varying concentrations of cannabinoids. Behav Pharmacol 16(5–6):487–496. 102. Institute of Medicine (1982). Division of Health Sciences Policy. Marijuana and Health: Report of a Study by a Committee of the Institute of Medicine, Division of Health Sciences Policy. Washington, DC: National Academy Press, 1982. 103. Institute of Medicine (1999). Division of Neuroscience and Behavioral Health. Marijuana and Medicine: Assessing the Science Base. Washington, DC: National Academy Press, 1999. 104. Johansson E, Halldin MM, Agurell S, Hollister LE, Gillespie HK (1989). Terminal elimination plasma half-life of delta 1-tetrahydrocannabinol (delta 1– THC) in heavy users of marijuana. Eur J Clin Pharmacol 37(3):273–277. 105. Jones RT, Benowitz NL, Heming RI (1981). Clinical relevance of cannabis tolerance and dependence. J Clin Pharmacol 21:143S–152S. 106. Jones RT (2002). Cardiovascular system effects of marijuana. J Clin Pharmacol 42(11Suppl):58S–63S. 107. Justinova Z, Tanda G, Redhi GH, Goldberg SR (2003). Self-administration of delta9-tetrahydrocannabinol (THC) by ¨ drug naıve squirrel monkeys. Psychopharmacology (Berl) 169(2):135– 140. 108. Justinova Z, Tanda G, Munzar P, Goldberg SR (2004). The opioid antagonist naltrexone reduces the reinforcing effects of delta 9 tetrahydrocannabinol (THC) in squirrel monkeys. Psychopharmacology (Berl) 173(1–2):186–194. 109. Kandel D (1975). Stages in adolescent involvement in drug use. Science 190:912–914. 110. Kandel DB, Chen K (2000). Types of marijuana users by longitudinal course. J Stud Alcohol 61(3):367–378. 111. Karniol IG, Shirakawa I, Kasinski N, Pfeferman A, Carlini EA (1974). Cannabidiol interferes with the effects of delta 9-tetrahydrocannabinol in man. Eur J Pharmacol 28(1):172–177. 112. Karniol IG, Shirakawa I, Takahashi RN, Knobel E, Musty RE (1975). Effects of delta9-tetrahydrocannabinol and cannabinol in man. Pharmacology 13(6):502–512. E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules 113. Keen L 2nd, Pereira D, Latimer W (2014). Self-reported lifetime marijuana use and interleukin-6 levels in middleaged African Americans. Drug Alcohol Depend 140:156–160. 114. Kirk JM, de Wit H (1999). Responses to oral delta9-tetrahydrocannabinol in frequent and infrequent marijuana users. Pharmacol Biochem Behav 63(1):137– 142. 115. Kuepper R, van Os J, Lieb R, Wittchen HU, Henquet C (2011). Do cannabis and urbanicity co-participate in causing psychosis? Evidence from a 10-year follow-up cohort study. Psychol Med 41(10):2121–2129. 116. Kurzthaler I, Hummer M, Miller C, Sperner-Unterweger B, Gunther V, Wechdorn H, Battista HJ, Fleischhacker WW (1999). Effects of cannabis use on cognitive functions and driving ability. J Clin Psychiatry 60(6):395–399. 117. Lacson JC, Carroll JD, Tuazon E, Castelao EJ, Bernstein L, Cortessis VK (2012). Population-based case-control study of recreational drug use and testis cancer risk confirms an association between marijuana use and nonseminoma risk. Cancer 118:5374– 5383. 118. Lee MH, Hancox RJ (2011). Effects of smoking cannabis on lung function. Exp Rev Resp Med 5(4):537–546. 119. Lemberger L, Silberstein SD, Axelrod J, Kopin IJ (1970). Marihuana: Studies on the disposition and metabolism of delta9-tetrahydrocannabinol in man. Science 70:1320–1322. 120. Lemberger L, Weiss JL, Watanabe AM, Galanter IM, Wyatt RJ, Cardon PV (1972a). Delta-9-tetrahydrocannabinol: Temporal correlation of the psychological effects and blood levels after various routes of administration. New Eng J Med 286(13):685–688. 121. Lemberger L, Crabtree RE, Rowe HM (1972b). 11-Hydroxy-delta9tetrahydrocannabinol: Pharmacology, disposition and metabolism of a major metabolite of marihuana in man. Science 77:62–63. 122. Lemberger L, Rubin A (1975). The physiologic disposition of marihuana in man. Life Sci 17:1637–1642. 123. Li M–C, Brady JE, DiMaggio CJ, Lusardi AR, Tzong, KY, Li G (2012). Marijuana use and motor vehicle crashes. Epidemiologic Rev 34:65–72. 124. Liguori A, Gatto CP, Robinson JH (1998). Effects of marijuana on equilibrium, psychomotor performance, and simulated driving. Behav Pharmacol 9(7):599–609. 125. Lisdahl KM, Price JS (2012). Increased marijuana use and gender predict poorer cognitive functioning in adolescents and emerging adults. J Int Neuropsychol Soc 18(4):678–688. 126. Lyons MJ, Bar JL, Panizzon MS, Toomey R, Eisen S, Xian H, Tsuang MT (2004). Neuropsychological consequences of regular marijuana use: a twin study. Psychol Med 34(7):1239–1250. 127. Mackie K, Lai Y, Westenbroek R, Mitchell R (1995). Cannabinoids activate an inwardly rectifying potassium VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. J Neurosci 15(10):6552–6561. 128. Maldonado R (2002). Study of cannabinoid dependence in animals. Pharmacol Ther 95(2):153–164. 129. Malinowska B, Baranowska-Kuczko M, Schlicker E (2012). Triphasic blood pressure responses to cannabinoids: Do we understand the mechanism? Br J Pharmacol 165(7):2073–2088. 130. Manrique-Garcia E, Zammit S, Dalman C, Hemmingson T, Andreasson S, Allebeck P (2012). Cannabis, schizophrenia and other non-affective psychoses: 35 years of follow-up of a population-based cohort. Psychol Med 42(6):1321–1328. 131. Maremmani I, Lazzeri A, Pacini M, Lovrecic M, Placidi GF, Perugi G (2004). Diagnostic and symptomatological features in chronic psychotic patients according to cannabis use status. J Psychoactive Drugs 36(2):235–241. 132. McCartt AT (2015). Marijuana and driving in the United States: Prevalence, risks, and laws. Presented at the Casualty Actuarial Society Spring Meeting. Colorado Springs, CO. May 19, 2015. 133. McMahon LR, Ginsburg BC, Lamb RJ (2008). Cannabinoid agonists differentially substitute for the discriminative stimulus effects of Delta(9)-terahydrocannabinol in C57BL/ 6J mice. Psychopharmacology (Berl) 198(4):487–495. 134. McMahon LR (2009). Apparent affinity estimates of rimonabant in combination with anandamide and chemical analogs of anandamide in rhesus monkeys discriminating Delta9tetrahydrocannabinol. Psychopharmacology (Berl) 203(2):219– 228. 135. Mechoulam R (1973). Cannabinoid chemistry. In Mechoulam, R. (ed.) Marijuana, pp.2–88 (New York, NY, Academic Press, Inc.). 136. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE., Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, Pertwee RG, Griffin G, Bayewitch M, Barg J, Vogel Z (1995). Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50(1):83– 90. 137. Mehmedic Z, Chandra S, Slade D, Denham H, Foster S, Patel AS, Ross SA, Khan IA, ElSohly MA (2010). Potency trends of D9-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008. J Forensic Sci 55(5):1209–1217. 138. Meier MH, Caspi A, Ambler A, Harrington H, Houts R, Keefe RS, McDonald K, Ward A, Poulton R, Moffitt TE (2012). Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci USA 109(40):E2657–E2664. 139. Mendelson JH, Mello NK (1984). Effects of marijuana on neuroendocrine hormones in human males and females. NIDA Res Monogr 44:97–114. PO 00000 Frm 00157 Fmt 4701 Sfmt 4702 53843 140. Messinis L, Kyprianidou A, Malefaki S, Papathanasopoulos P (2006). Neuropsychological deficits in long-term frequent cannabis users. Neurology 66:737–739. 141. Minozzi S, Davoli M, Bargagli AM, Amato L, Vecchi S, Perucci CA (2010). An overview of systematic reviews on cannabis and psychosis: discussing apparently conflicting results. Drug Alcohol Rev 29(3):304–317. 142. Mittleman MA, Lewis RA, Maclure M, Sherwood JB, Muller JE (2001). Triggering myocardial infarction by marijuana. Circulation 103:2805–2809. 143. Nace EP, Meyers AL, Rothberg JM, Maleson F (1975). Addicted and nonaddicted drug users. A comparison of drug usage patterns. Arch Gen Psychiatry 32(1):77–80. 144. Oviedo A, Glowa J, Herkenham M (1993). Chronic cannabinoid administration alters cannabinoid receptor binding in rat brain: A quantitative autoradiographic study. Brain Res 616:293–302. 145. Pacher P, Batkai S, Kunos G (2006). The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58(3):389–462. 146. Panayiotides IM (2015). What is the association between cannabis consumption and cardiovascular complications. Subst Abuse 9:1–3. 147. Pelayo-Teran JM, Suarez-Pinilla P, Chadi N, Crespo-Pacorro B (2012). Geneenvironment interactions underlying the effect of cannabis in first episode psychosis. Curr Pharm Des 18(32):5024– 5035. 148. Piomelli D (2005). The endocannabinoid system: A drug discovery perspective. Curr Opin Investig 6(7):672–679. 149. Pletcher MJ, Vittinghoff E, Kalhan R, Richman J, Safford M, Sidney S, Lin F, Kertesz S (2012). Association between marijuana exposure and pulmonary function over 20 years. Journal of the American Medical Association. 307(2):173–181. 150. Pollastro F, Taglialatela-Scafati O, Allara M, Munoz E, Di Marzo V, De Petrocellis L, Appendino G (2011). Bioactive prenylogous cannabinoid from fiber hemp (Cannabis sativa). J Nat Prod. 74(9):2019–2022. 151. Pope HG Jr, Gruber AJ, Hudson JI, Huestis MA, Yurgelun-Todd D (2002). Cognitive measures in long-term cannabis users. J Clin Pharmacol 42(11 Suppl):41S–47S. 152. Radwan MM, ElSohly MA, Slade D, Ahmed SA, Khan IA, Ross SA (2009). Biologically active cannabinoids from high-potency Cannabis sativa. J Nat Prod 72(5):906–911. 153. Ramaekers JG, Berghaus G, van Laar M, Drummer OH (2004). Dose related risk of motor vehicle crashes after cannabis use. Drug and Alcohol Dependence. 73(2):109–119. 154. Ramaekers JG, Kauert G, van Ruitenbeek P, Theunissen EL, Schneider E, Moeller MR (2006). High-potency marijuana impairs executive functions and inhibitory motor control. E:\FR\FM\12AUP2.SGM 12AUP2 mstockstill on DSK3G9T082PROD with PROPOSALS2 53844 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules Neuropsychopharmacology 31(10):2296– 2303. 155. Ramaekers JG, Kauert G, Theunissen EL, Toennes SW., Moeller MR (2009). Neurocognitive performance during acute THC intoxication in heavy and occasional cannabis users. J Psychopharmacol 23(3):266–277. 156. Riggs PK, Vaida F, Rossi SS, Sorkin LS, Gouaux B, Grant I, Ellis RJ (2012). A pilot study of the effects of cannabis on appetite hormones in HIV-infected adult men. Brain Res 1431:46–52. 157. Rodriguez de Fonseca F, Gorriti MA, Fernandez-Ruiz JJ, Palomo T, Ramos JA (1994). Downregulation of rat brain cannabinoid binding sites after chronic delta 9-tetrahydrocannabinol treatment. Pharmacol Biochem Behav 47(1):33–40. 158. Roth MD, Arora A, Barsky SH, Kleerup EC, Simmons M, Tashkin DP (1998). Airway inflammation in young marijuana and tobacco smokers. American Journal of Respiratory and Crit Care Med 157:928–937. 159. Roth MD, Tashkin DP, Whittaker KM, Choi R, Baldwin GC (2005). Tetrahydrocannabinol suppresses immune function and enhances HIV replication in the huPBL–SCID mouse. Life Sci 77(14):1711–1722. 160. Russo E, Mathre ML, Byrne A, Velin R, Bach PJ, Sanchez-Ramos J, Kirlin KA (2001). Chronic cannabis use in the compassionate investigational new drug program: An examination of benefits and adverse effects of legal clinical cannabis. J Cannabis Ther 2:3–57. 161. Sarfaraz S, Afaq F, Adhami VM, Mukhtar H (2005). Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cancer Res 65(5):1635– 1641. 162. Scherrer JF, Grant JD, Duncan AE, Sartor CE, Haber JR, Jacob T, Bucholz KK (2009). Subjective effects to cannabis are associated with use, abuse and dependence after adjusting for genetic and environmental influences. Drug Alcohol Depend 105(1–2):76–82. 163. Schiffman J, Nakamura B, Earleywine MJ, LaBrie J (2005). Symptoms of schizotypy precede cannabis use. Psychiatry Res 134(1):37–42. 164. Schimmelmann BG, Conus P, Cotton SM, Kupferschmid S, Karow A, Schultze-Lutter F, McGorry PD, Lambert M (2011). Cannabis use disorder and age at onset of psychosis—a study in first episode patients. Schizophr Res 129(1):52–56. 165. Schreiner AM, Dunn ME (2012). Residual effects of cannabis use on neurocognitive performance after prolonged abstinence: A meta-analysis. Exp Clin Psychopharmacol 20(5):420– 429. 166. Sexton M, Cudaback E, Abdullah RA, Finnell J, Mischley LJ, Rozga M, Lichtman AH, Stella N (2014). Cannabis use by individuals with multiple sclerosis: Effects on specific immune parameters. Inflammopharmacology 22(5):295–303. 167. Sidney S (2002). Cardiovascular consequences of marijuana use. J Clin Pharmacol 42(11Suppl):64S–70S. VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 168. Solinas M, Panlilio LV, Justinova Z, Yasar S, Goldberg SR (2006). Using drugdiscrimination techniques to study the abuse-related effects of psychoactive drugs in rats. Nat Protoc 1(3):1194–1206. 169. Solowij N, Stephens RS, Roffman RA, Babor T, Kadden R, Miller M, Christiansen K, McRee B,Vendetti J (2002). Marijuana Treatment Project Research Group. Cognitive functioning of long-term heavy cannabis users seeking treatment. Journal of the American Medical Association 287(9):1123–1131. 170. Substance Abuse and Mental Health Services Administration (2013). Drug Abuse Warning Network, 2011: National Estimates of Drug-Related Emergency Department Visits. HHS Publication No. (SMA) 13–4760, DAWN Series D–39. Rockville, MD. 171. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality (2015a). Results from the 2014 National Survey on Drug Use and Health: Detailed Tables. Rockville, MD. 172. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality (2015b). Treatment Episode Data Set (TEDS): 2003–2013. National Admissions to Substance Abuse Treatment Services. BHSIS Series S–75, HHS Publication No. (SMA) 15–4934. Rockville, MD. 173. Tait RJ, MacKinnon A, Christensen H (2011). Cannabis use and cognitive functioning: 8-year trajectory in a young adult cohort. Addiction 106(12):2195– 2203. 174. Tanasescu R, Constantinescu CS (2010). Cannabinoids and the immune system: An overview. Immunobiology 215(8):588–597. 175. Tanda G, Munzar P, Goldberg SR (2000). Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys. Nat Neurosci 3(11):1073–1074. 176. Tanda G, Goldberg SR (2003). Cannabinoids: Reward, dependence, and underlying neurochemical mechanisms—a review of recent preclinical data. Psychopharmacology (Berl) 169(2):115–134. 177. Tashkin DP (2005). Smoked marijuana as a cause of lung injury. Monaldi Arch Chest Dis 63(2):93–l00. 178. Tashkin DP, Zhang ZF, Greenland S, Cozen W, Mack TM, and Morgenstern H (2006). Marijuana use and lung cancer: Results of a case-control study. American Thoracic Society International Conference. Abstract A777. 179. Theunissen EL, Kauert GF, Toennes SW., Moeller MR, Sambeth A, Blanchard MM, Ramaekers JG (2012). Neurophysiological functioning of occasional and heavy cannabis users during THC intoxication. Psychopharmacology (Berl) 220(2):341– 350. 180. Trabert B, Sigurdson AJ, Sweeney AM, Strom SS, McGlynn KA (2011). Marijuana use and testicular germ cell tumors. Cancer 117(4):848–853. PO 00000 Frm 00158 Fmt 4701 Sfmt 4702 181. Twitchell W, Brown S, Mackie K (1997). Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons. J Neurophysiol 78(1):43–50. 182. U.S. Food and Drug Administration (FDA), Center for Drug and Evaluation Research, Controlled Substances Staff (2015). The Medical Application of Marijuana: A Review of Published Clinical Studies. March 19, 2015. 183. van der Meer FJ, Velthorst E, Meijer CJ, Machielsen MW, de Haan L (2012). Cannabis use in patients at clinical high risk of psychosis: Impact on prodromal symptoms and transition to psychosis. Curr Pharm Des 18(32):5036–5044. 184. van Gastel WA, Wigman JT, Monshouwer K, Kahn RS, van Os J, Boks MP, Volleburgh WA (2012). Cannabis use and subclinical positive psychotic experiences in early adolescence: Findings from a Dutch survey. Addiction 107(2):381–387. 185. Van Gundy K, Rebellon CJ (2010). A Life-course Perspective on the ‘‘Gateway Hypothesis.’’ J Health Soc Behav 51(3):244–259. 186. van Os J, Bak M, Hanssen M, Bijl RV, de Graaf R, Verdoux H. (2002). Cannabis use and psychosis: A longitudinal population-based study. Am J Epi 156(4):319–327. 187. Vann RE, Gamage TF, Warner JA, Marshall EM, Taylor NL, Martin BR, Wiley JL (2008). Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of D(9)-tetrahydrocannabinol. Drug Alcohol Depend 94(1–3):191–198. 188. Volkow ND, Baler RD, Compton WM, Weiss SR (2014). Adverse health effects of marijuana use. N Engl J Med 370(23):2219–2227. 189. von Sydow K, Lieb R, Pfister H, Hofler M, Wittchen HU (2002).What predicts incident use of cannabis and progression to abuse and dependence? A 4-year prospective examination of risk factors in a community sample of adolescents and young adults. Drug Alcohol Depend 68(1):49–64. 190. Wachtel SR, ElSohly MA, Ross SA, Ambre J, de Wit H (2002). Comparison of the subjective effects of D(9)tetrahydrocannabinol and marijuana in humans. Psychopharmacology (Berl) 161(4):331–339. 191. Wagner JA, Varga K, Kunos G (1998). Cardiovascular actions of cannabinoids and their generation during shock. J Mol Med 76(12):824–836. 192. Wang GS, Roosevelt G, Heard K (2013). Pediatric marijuana exposures in a medical marijuana state. JAMA Pediatr 167(7):630–633. 193. Wang GS, Roosevelt G, Le Lait MC, Martinez EM, Bucher-Bartelson B, Bronstein AC, Heard K (2014). Association of unintended pediatric exposures with decriminalization of marijuana in the United States. Ann Emerg Med 63(6):684–689. 194. Wang T, Collet JP, Shapiro S, Ware MA (2008). Adverse effects of medical cannabinoids: A systematic review. CMAJ 178(13):1669–1678. E:\FR\FM\12AUP2.SGM 12AUP2 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules mstockstill on DSK3G9T082PROD with PROPOSALS2 195. Wesson DR, Washburn P (1990). Current patterns of drug abuse that involve smoking. NIDA Res Monogr 99:5–11. 196. Whitehill JM, Rivara FP, Moreno MA (2014). Marijuana-using drivers, alcoholusing drivers, and their passengers: Prevalence and risk factors among underage college students. JAMA Pediatr 168(7):618–624. 197. Wiley JL, Barrett RL, Britt DL, Balster RL, Martin BR (1993). Discriminative stimulus effects of D 9tetrahydrocannabinol and D 9-11tetrahydrocannabinol in rats and rhesus monkeys. Neuropharmacology 32(4):359–365. 198. Wiley JL, Huffman JW, Balster RL, Martin BR (1995). Pharmacological specificity of the discriminative stimulus effects of D 9-tetrahydrocannabinol in rhesus monkeys. Drug Alcohol Depend 40(1):81–86. VerDate Sep<11>2014 20:51 Aug 11, 2016 Jkt 238001 199. Wilkinson ST, Radhakrishnan R, D’Souza DC (2014). Impact of cannabis use on the development of psychotic disorders. Curr Addict Rep 1(2):115–128. ´ 200. Wilson FA, Stimpson JP, Pagan JA (2014). Fatal crashes from drivers testing positive for drugs in the U.S., 1993– 2010. Public Health Rep 129(4):342–350. 201. Wu X, French ED (2000). Effects of chronic D9-tetrahydrocannabinol on rat midbrain dopamine neurons: An electrophysiological assessment. Neuropharmacology 39(3):391–398. 202. Zeiger JS, Haberstick BC, Corley RP, Ehringer MA, Crowley TJ, Hewitt JK, Hopfer CJ, Stallings MC, Young SE., Rhee SH (2010). Subjective effects to marijuana associated with marijuana use in community and clinical subjects. Drug Alcohol Depend 109(1–3):161–66. 203. Zhang ZF, Morgenstern H, Spitz MR, Tashkin DP, Yu GP, Marshall JR, Hsu TC, PO 00000 Frm 00159 Fmt 4701 Sfmt 9990 53845 Schantz, SP (1999). Marijuana use and increased risk of squamous cell carcinoma of the head and neck. Cancer Epidemiol Biomarkers Prev 8(12):1071– 1078. 204. Zhang LR, Morgenstern H, Greenland S, Chang SC, Lazarus P, Teare MD, Woll PJ, Orlow I, Cox B on behalf of the Cannabis and Respiratory Disease Research Group of New Zealand, Brhane Y, Liu G, Hung RJ (2015). Cannabis smoking and lung cancer risk: Pooled analysis in the International Lung Cancer Consortium. Int J Cancer 136(4):894–903. 205. Zwardi AW, Shirakawa I, Finkelfarb E, Karniol IG (1982). Action of cannabidiol on the anxiety and other effects produced by D 9–THC in normal subject. Psychopharmcology (Berl) 76(3):245– 250. [FR Doc. 2016–17960 Filed 8–11–16; 8:45 am] BILLING CODE 4410–09–P E:\FR\FM\12AUP2.SGM 12AUP2

Agencies

[Federal Register Volume 81, Number 156 (Friday, August 12, 2016)]
[Proposed Rules]
[Pages 53767-53845]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-17960]



[[Page 53767]]

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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Chapter II

[Docket No. DEA-427]


Denial of Petition To Initiate Proceedings To Reschedule 
Marijuana

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Denial of petition to initiate proceedings to reschedule 
marijuana.

-----------------------------------------------------------------------

SUMMARY: By letter dated July 19, 2016 the Drug Enforcement 
Administration (DEA) denied a petition to initiate rulemaking 
proceedings to reschedule marijuana. Because the DEA believes that this 
matter is of particular interest to members of the public, the agency 
is publishing below the letter sent to the petitioner which denied the 
petition, along with the supporting documentation that was attached to 
the letter.

DATES: August 12, 2016.

FOR FURTHER INFORMATION CONTACT: Michael J. Lewis, Office of Diversion 
Control, Drug Enforcement Administration; Mailing Address: 8701 
Morrissette Drive, Springfield, Virginia 22152; Telephone: (202) 598-
6812

SUPPLEMENTARY INFORMATION:
July 19, 2016

Dear Mr. Krumm:

    On December 17, 2009, you petitioned the Drug Enforcement 
Administration (DEA) to initiate rulemaking proceedings under the 
rescheduling provisions of the Controlled Substances Act (CSA). 
Specifically, you petitioned DEA to have marijuana removed from 
schedule I of the CSA and rescheduled in any schedule other than 
schedule I of the CSA.
    You requested that DEA remove marijuana from schedule I based on 
your assertion that:
    1. Marijuana has accepted medical use in the United States;
    2. Studies have shown that smoked marijuana has proven safety 
and efficacy;
    3. Marijuana is safe for use under medical supervision; and
    4. Marijuana does not have the abuse potential for placement in 
schedule I
    In accordance with the CSA scheduling provisions, after 
gathering the necessary data, DEA requested a scientific and medical 
evaluation and scheduling recommendation from the Department of 
Health and Human Services (HHS). HHS concluded that marijuana has a 
high potential for abuse, has no accepted medical use in the United 
States, and lacks an acceptable level of safety for use even under 
medical supervision. Therefore, HHS recommended that marijuana 
remain in schedule I. The scientific and medical evaluation and 
scheduling recommendation that HHS submitted to DEA is attached 
hereto.
    Based on the HHS evaluation and all other relevant data, DEA has 
concluded that there is no substantial evidence that marijuana 
should be removed from schedule I. A document prepared by DEA 
addressing these materials in detail also is attached hereto. In 
short, marijuana continues to meet the criteria for schedule I 
control under the CSA because:
    (1) Marijuana has a high potential for abuse. The HHS evaluation 
and the additional data gathered by DEA show that marijuana has a 
high potential for abuse.
    (2) Marijuana has no currently accepted medical use in treatment 
in the United States. Based on the established five-part test for 
making such determination, marijuana has no ``currently accepted 
medical use'' because: As detailed in the HHS evaluation, the drug's 
chemistry is not known and reproducible; there are no adequate 
safety studies; there are no adequate and well-controlled studies 
proving efficacy; the drug is not accepted by qualified experts; and 
the scientific evidence is not widely available.
    (3) Marijuana lacks accepted safety for use under medical 
supervision. At present, there are no U.S. Food and Drug 
Administration (FDA)-approved marijuana products, nor is marijuana 
under a New Drug Application (NDA) evaluation at the FDA for any 
indication. The HHS evaluation states that marijuana does not have a 
currently accepted medical use in treatment in the United States or 
a currently accepted medical use with severe restrictions. At this 
time, the known risks of marijuana use have not been shown to be 
outweighed by specific benefits in well-controlled clinical trials 
that scientifically evaluate safety and efficacy.
    The statutory mandate of 21 U.S.C. 812(b) is dispositive. 
Congress established only one schedule, schedule I, for drugs of 
abuse with ``no currently accepted medical use in treatment in the 
United States'' and ``lack of accepted safety for use under medical 
supervision.'' 21 U.S.C. 812(b).
    Although the HHS evaluation and all other relevant data lead to 
the conclusion that marijuana must remain in schedule I, it should 
also be noted that, in view of United States obligations under 
international drug control treaties, marijuana cannot be placed in a 
schedule less restrictive than schedule II. This is explained in 
detail in the accompanying document titled ``Preliminary Note 
Regarding Treaty Considerations.''
    Accordingly, and as set forth in detail in the accompanying HHS 
and DEA documents, there is no statutory basis under the CSA for DEA 
to grant your petition to initiate rulemaking proceedings to 
reschedule marijuana. Your petition is, therefore, hereby denied.

Sincerely,

Chuck Rosenberg,

Acting Administrator

Attachments:

Preliminary Note Regarding Treaty Considerations

    Cover Letter from HHS to DEA Summarizing the Scientific and 
Medical Evaluation and Scheduling Recommendation for Marijuana.
    U.S. Department of Health and Human Services (HHS)--Basis for 
the Recommendation for Maintaining Marijuana in Schedule I of the 
Controlled Substances Act
    U.S. Department of Justice--Drug Enforcement Administration 
(DEA), Schedule of Controlled Substances: Maintaining Marijuana in 
Schedule I of the Controlled Substances Act, Background, Data, and 
Analysis: Eight Factors Determinative of Control and Findings 
Pursuant to 21 U.S.C. 812(b)

    Dated: July 19, 2016.
Chuck Rosenberg,
Acting Administrator.

Preliminary Note Regarding Treaty Considerations

    As the Controlled Substances Act (CSA) recognizes, the United 
States is a party to the Single Convention on Narcotic Drugs, 1961 
(referred to here as the Single Convention or the treaty). 21 U.S.C. 
801(7). Parties to the Single Convention are obligated to maintain 
various control provisions related to the drugs that are covered by the 
treaty. Many of the provisions of the CSA were enacted by Congress for 
the specific purpose of ensuring U.S. compliance with the treaty. Among 
these is a scheduling provision, 21 U.S.C. 811(d)(1). Section 811(d)(1) 
provides that, where a drug is subject to control under the Single 
Convention, the DEA Administrator (by delegation from the Attorney 
General) must ``issue an order controlling such drug under the schedule 
he deems most appropriate to carry out such [treaty] obligations, 
without regard to the findings required by [21 U.S.C. 811(a) or 812(b)] 
and without regard to the procedures prescribed by [21 U.S.C. 811(a) 
and (b)].''
    Marijuana is a drug listed in the Single Convention. The Single 
Convention uses the term ``cannabis'' to refer to marijuana.\1\ Thus, 
the DEA Administrator is obligated under section 811(d) to control 
marijuana in the

[[Page 53768]]

schedule that he deems most appropriate to carry out the U.S. 
obligations under the Single Convention. It has been established in 
prior marijuana rescheduling proceedings that placement of marijuana in 
either schedule I or schedule II of the CSA is ``necessary as well as 
sufficient to satisfy our international obligations'' under the Single 
Convention. NORML v. DEA, 559 F.2d 735, 751 (D.C. Cir. 1977). As the 
United States Court of Appeals for the D.C. Circuit has stated, 
``several requirements imposed by the Single Convention would not be 
met if cannabis and cannabis resin were placed in CSA schedule III, IV, 
or V.'' \2\ Id. Therefore, in accordance with section 811(d)(1), DEA 
must place marijuana in either schedule I or schedule II.
---------------------------------------------------------------------------

    \1\ Under the Single Convention, ``'cannabis plant' means any 
plant of the genus Cannabis.'' Article 1(c). The Single Convention 
defines ``cannabis'' to include ``the flowering or fruiting tops of 
the cannabis plant (excluding the seeds and leaves when not 
accompanied by the tops) from which the resin has not been 
extracted, by whatever name they may be designated.'' Article 1(b). 
This definition of ``cannabis'' under the Single Convention is 
slightly less inclusive than the CSA definition of ``marihuana,'' 
which includes all parts of the cannabis plant except for the mature 
stalks, sterilized seeds, oil from the seeds, and certain 
derivatives thereof. See 21 U.S.C. 802(16). Cannabis and cannabis 
resin are included in the list of drugs in Schedule I and Schedule 
IV of the Single Convention. In contrast to the CSA, the drugs 
listed in Schedule IV of the Single Convention are also listed in 
Schedule I of the Single Convention and are subject to the same 
controls as Schedule I drugs as well as additional controls. Article 
2, par. 5
    \2\ The Court further stated: ``For example, [article 31 
paragraph 4 of the Single Convention] requires import and export 
permits that would not be obtained if the substances were placed in 
CSA schedules III through V. In addition, the quota and 
[recordkeeping] requirements of Articles 19 through 21 of the Single 
Convention would be satisfied only by placing the substances in CSA 
schedule I or II.'' Id. n. 71 (internal citations omitted).
---------------------------------------------------------------------------

    Because schedules I and II are the only possible schedules in which 
marijuana may be placed, for purposes of evaluating this scheduling 
petition, it is essential to understand the differences between the 
criteria for placement of a substance in schedule I and those for 
placement in schedule II. These criteria are set forth in 21 U.S.C. 
812(b)(1) and (b)(2), respectively. As indicated therein, substances in 
both schedule I and schedule II share the characteristic of ``a high 
potential for abuse.'' Where the distinction lies is that schedule I 
drugs have ``no currently accepted medical use in treatment in the 
United States'' and ``a lack of accepted safety for use of the drug . . 
. under medical supervision,'' while schedule II drugs do have ``a 
currently accepted medical use in treatment in the United States.'' \3\
---------------------------------------------------------------------------

    \3\ As DEA has stated in evaluating prior marijuana rescheduling 
petitions, ``Congress established only one schedule, schedule I, for 
drugs of abuse with `no currently accepted medical use in treatment 
in the United States' and `lack of accepted safety for use . . . 
under medical supervision.' 21 U.S.C. 812(b).'' 76 FR 40552 (2011); 
66 FR 20038 (2001).
---------------------------------------------------------------------------

    Accordingly, in view of section 811(d)(1), this scheduling petition 
turns on whether marijuana has a currently accepted medical use in 
treatment in the United States. If it does not, DEA must, pursuant to 
section 811(d), deny the petition and keep marijuana in schedule I.
    As indicated, where section 811(d)(1) applies to a drug that is the 
subject of a rescheduling petition, the DEA Administrator must issue an 
order controlling the drug under the schedule he deems most appropriate 
to carry out United States obligations under the Single Convention, 
without regard to the findings required by sections 811(a) or 812(b) 
and without regard to the procedures prescribed by sections 811(a) and 
(b). Thus, since the only determinative issue in evaluating the present 
scheduling petition is whether marijuana has a currently accepted 
medical use in treatment in the United States, DEA need not consider 
the findings of sections 811(a) or 812(b) that have no bearing on that 
determination, and DEA likewise need not follow the procedures 
prescribed by sections 811(a) and (b) with respect to such irrelevant 
findings. Specifically, DEA need not evaluate the relative abuse 
potential of marijuana or the relative extent to which abuse of 
marijuana may lead to physical or psychological dependence.
    As explained below, the medical and scientific evaluation and 
scheduling recommendation issued by the Secretary of Health and Human 
Services concludes that marijuana has no currently accepted medical use 
in treatment in the United States, and the DEA Administrator likewise 
so concludes. For the reasons just indicated, no further analysis 
beyond this consideration is required. Nonetheless, because of the 
widespread public interest in understanding all the facts relating to 
the harms associated with marijuana, DEA is publishing here the entire 
medical and scientific analysis and scheduling evaluation issued by the 
Secretary, as well as DEA's additional analysis.

Department of Health and Human Services,
Office of the Secretary Assistant Secretary for Health, Office of 
Public Health and Science
Washington DC 20201.

June 25, 2015.

The Honorable Chuck Rosenberg
Acting Administrator, Drug Enforcement Administration, U.S. 
Department of Justice, 8701 Morrissette Drive, Springfield, VA 22152

Dear Mr. Rosenberg:

    Pursuant to the Controlled Substances Act (CSA, 21 U.S.C. 
811(b), (c), and (f)), the Department of Health and Human Services 
(HHS) is recommending that marijuana continue to be maintained in 
Schedule I of the CSA.
    The Food and Drug Administration (FDA) has considered the abuse 
potential and dependence-producing characteristics of marijuana.
    Marijuana meets the three criteria for placing a substance in 
Schedule I of the CSA under 21 U.S.C. 812(b)(1). As discussed in the 
enclosed analyses, marijuana has a high potential for abuse, no 
currently accepted medical use in treatment in the United States, 
and a lack of accepted safety for use under medical supervision. 
Accordingly, HHS recommends that marijuana be maintained in Schedule 
I of the CSA. Enclosed are two documents prepared by FDA's 
Controlled Substance Staff (in response to petitions filed in 2009 
by Mr. Bryan Krumm and in 2011 by Governors Lincoln D. Chafee and 
Christine O. Gregoire) that form the basis for the recommendation. 
Pursuant to the requests in the petitions, FDA broadly evaluated 
marijuana, and did not focus its evaluation on particular strains of 
marijuana or components or derivatives of marijuana.
    FDA's Center for Drug Evaluation and Research's current review 
of the available evidence and the published clinical studies on 
marijuana demonstrated that since our 2006 scientific and medical 
evaluation and scheduling recommendation responding to a previous 
DEA petition, research with marijuana has progressed. However, the 
available evidence is not sufficient to determine that marijuana has 
an accepted medical use. Therefore, more research is needed into 
marijuana's effects, including potential medical uses for marijuana 
and its derivatives. Based on the current review, we identified 
several methodological challenges in the marijuana studies published 
in the literature. We recommend they be addressed in future clinical 
studies with marijuana to ensure that valid scientific data are 
generated in studies evaluating marijuana's safety and efficacy for 
therapeutic use. For example, we recommend that studies need to 
focus on consistent administration and reproducible dosing of 
marijuana, potentially through the use of administration methods 
other than smoking. A summary of our review of the published 
literature on the clinical uses of marijuana, including 
recommendations for future studies, is attached to this document.
    FDA and the National Institutes of Health's National Institute 
on Drug Abuse (NIDA) also believe that work continues to be needed 
to ensure support by the federal government for the efficient 
conduct of clinical research using marijuana. Concerns have been 
raised about whether the existing federal regulatory system is 
flexible enough to respond to increased interest in research into 
the potential therapeutic uses of marijuana and marijuana-derived 
drugs. HHS welcomes an opportunity to continue to explore these 
concerns with DEA.
    Should you have any questions regarding theses recommendations, 
please contact Corinne P. Moody, Science Policy Analyst, Controlled 
Substances Staff, Center for Drug Evaluation and Research, FDA, at 
(301) 796-3152.

Sincerely yours,

Karen B. DeSalvo, MD, MPH, MSc
Acting Assistant Secretary for Health

Enclosure:

Basis for the Recommendation for Maintaining Marijuana in Schedule I 
of the Controlled Substances Act

[[Page 53769]]

Basis for the Recommendation for Maintaining Marijuana in Schedule I of 
the Controlled Substances Act

    On December 17, 2009, Mr. Bryan Krumm submitted a petition to the 
Drug Enforcement Administration (DEA) requesting that proceedings be 
initiated to repeal the rules and regulations that place marijuana \4\ 
in Schedule I of the Controlled Substances Act (CSA). The petitioner 
contends that marijuana has an accepted medical use in the United 
States, has proven safety and efficacy, is safe for use under medical 
supervision, and does not have the abuse potential for placement in 
Schedule I. The petitioner requests that marijuana be rescheduled to 
any schedule other than Schedule I of the CSA. In May 2011, the DEA 
Administrator requested that the U.S. Department of Health and Human 
Services (HHS) provide a sdentific and medical evaluation of the 
available information and a scheduling recommendation for marijuana, in 
accordance with the provisions of 21 U.S.C. 811(b).
---------------------------------------------------------------------------

    \4\ Note that ``marihuana'' is the spelling originally used in 
the Controlled Substances Act (CSA). This document uses the spelling 
that is more common in current usage, ``marijuana.''
---------------------------------------------------------------------------

    In accordance with 21 U.S.C. 811(b), the DEA has gathered 
information related to the control of marijuana (Cannabis sativa) \5\ 
under the CSA. Pursuant to 21 U.S.C. 811(b), the Secretary of HHS is 
required to consider in a scientific and medical evaluation eight 
factors determinative of control under the CSA. Following consideration 
of the eight factors, if it is appropriate, the Secretary must make 
three findings to recommend scheduling a substance in the CSA or 
transferring a substance from one schedule to another. The findings 
relate to a substance's abuse potential, legitimate medical use, and 
safety or dependence liability. Administrative responsibilities for 
evaluating a substance for control under the CSA are performed by the 
Food and Drug Administration (FDA), with the concurrence of the 
National Institute on Drug Abuse (NIDA), as described in the Memorandum 
of Understanding (MOU) of March 8, 1985 (50 FR 9518-20).
---------------------------------------------------------------------------

    \5\ The CSA defines marihuana (marijuana) as the following:
    All parts of the plant Cannabis sativa L., whether growing or 
not; the seeds thereof; the resin extracted from any part of such 
plant; and every compound, manufacture, salt, derivative, mixture, 
or preparation of such plant, its seeds or resin. Such term does not 
include the mature stalks of such plant, fiber produced from such 
stalks, oil or cake made from the seeds of such plant, any other 
compound, manufacture, salt, derivative, mixture, or preparation of 
such mature stalks (except the resin extracted therefrom), fiber, 
oil, or cake, or the sterilized seed of such plant which is 
incapable of germination (21 U.S.C. 802(16)).
---------------------------------------------------------------------------

    In this document, FDA recommends continued control of marijuana in 
Schedule I of the CSA. Pursuant to 21 U.S.C. 811(c), the eight factors 
pertaining to the scheduling of marijuana are considered below.

1. Its Actual or Relative Potential for Abuse

    Under the first factor the Secretary must consider marijuana's 
actual or relative potential for abuse. The CSA does not define the 
term ``abuse.'' However, the CSA's legislative history suggests the 
following in determining whether a particular drug or substance has a 
potential for abuse: \6\
---------------------------------------------------------------------------

    \6\ Comprehensive Drug Abuse Prevention and Control Act of 1970, 
H.R. Rep. No. 91-1444, 91st Cong., Sess. 1 (1970) reprinted in 
U.S.C.C.A.N. 4566, 4603.
---------------------------------------------------------------------------

    a. There is evidence that individuals are taking the drug or drugs 
containing such a substance in amounts sufficient to create a hazard to 
their health or to the safety of other individuals or to the community.
    b. There is a significant diversion of the drug or drugs containing 
such a substance from legitimate drug channels.
    c. Individuals are taking the drug or drugs containing such a 
substance on their own initiative rather than on the basis of medical 
advice from a practitioner licensed by law to administer such drugs in 
the course of his professional practice.
    d. The drug or drugs containing such a substance are new drugs so 
related in their action to a drug or drugs already listed as having a 
potential for abuse to make it likely that the drug will have the same 
potentiality for abuse as such drugs, thus making it reasonable to 
assume that there may be significant diversions from legitimate 
channels, significant use contrary to or without medical advice, or 
that it has a substantial capability of creating hazards to the health 
of the user or to the safety of the community.
    In the development of this scientific and medical evaluation for 
the purpose of scheduling, the Secretary analyzed considerable data 
related to the substance's abuse potential. The data include a 
discussion of the prevalence and frequency of use, the amount of the 
substance available for illicit use, the ease of obtaining or 
manufacturing the substance, the reputation or status of the substance 
``on the street,'' and evidence relevant to at-risk populations. 
Importantly, the petitioners define marijuana as including all Cannabis 
cultivated strains. Different marijuana samples derived from various 
cultivated strains may have very differernt chemical consituents, thus 
the analysis is based on what is known about the range of these 
constituents across all cultivated strains.
    Determining the abuse potential of a substance is complex with many 
dimensions, and no single test or assessment provides a complete 
characterization. Thus, no single measure of abuse potential is ideal. 
Scientifically, a comprehensive evaluation of the relative abuse 
potential of a substance can include consideration of the following 
elements: Receptor binding affinity, preclinical pharmacology, 
reinforcing effects, discriminative stimulus effects, dependence 
producing potential, pharmacokinetics, route of administration, 
toxicity, data on actual abuse, clinical abuse potential studies, and 
public health risks. Importantly, abuse can exist independently from 
tolerance or physical dependence because individuals may abuse drugs in 
doses or patterns that don not induce these phenomena. Additionally 
evidence of clandestine population and illicit trafficking of a 
substance can shed light on both the demand for a substance as well as 
the ease of obtaining a substance. Animal and human laboratory data and 
epidemiological data are all used in determining a substance's abuse 
potential. Moreover, epidemiological data can indicate actual abuse.
    The petitioner compares the effects of marijuana to currently 
controlled Schedule II substances and make repeated claims about their 
comparative effects. Comparisons between marijuana and the diverse 
array of Schedule II substances is difficult, because of the 
pharmacologically dissimilar actions of substances of Schedule II of 
the CSA. For example, Schedule II substances include stimulant-like 
drugs (e.g., cocaine, methylphenidate, and amphetamine), opioids (e.g., 
oxycodone, fentanyl), sedatives (e.g., pentobarbital, amobarbital), 
dissociative anesthetics (e.g., PCP), and naturally occurring plant 
components (e.g., coca leaves and poppy straw). The mechanism(s) of 
action of the above Schedule II substances are wholly different from on 
another, and they are different from tetrahydrocannabinol (THC) and 
marijuana as well. For example, Schedule II stimulants typically 
function by increasing monoaminergic tone via an increase in dopamine 
and norepinephrine (Schmitt et al., 2013). In contrast, opioid 
analgesics function via mu-opioid receptor agonist effects.

[[Page 53770]]

These differing mechanism(s) of action result in vastly different 
behavioral and adverse effect profiles, making comparisons across the 
range of pharmacologically diverse C-II substances inappropriate.
    In addition, many substances scheduled under the CSA are reviewed 
and evaluated within the context of commercial drug development, using 
data submitted in the form of a new drug application (NDA). A new 
analgesic drug might be compared to a currently scheduled analgesic 
drug as part of the assessment of its relative abuse potential. 
However, because the petitioners have not identified a specific 
indication for the use of marijuana, identifying an appropriate 
comparator based on indication cannot be done.
    a. There is evidence that individuals are taking the substance in 
amounts sufficient to create a hazard to their health or to the safety 
of other individuals or to the community.
    Evidence shows that some individuals are taking marijuana in 
amounts sufficient to create a hazard to their health and to the safety 
of other individuals and the community. A large number of individuals 
use marijuana. HHS provides data on the extent of marijuana abuse 
through NIDA and the Substance Abuse and Mental Health Services 
Administration (SAMHSA). According to the most recent data from 
SAMHSA's 2012 National Survey on Drug Use and Health (NSDUH), which 
estimates the number of individuals who have use a substance within a 
month prior to the study (described as ``current use''), marijuana is 
the most commonly used illicit drug among American aged 12 years and 
older, with an estimated 18.9 million Americans having used marijuana 
within the month prior to the 2012 NSDUH. Compared to 2004, when an 
estimated 14.6 million individuals reported using marijuana within the 
month prior to the study, the estimated rates in 2012 show an increase 
of approximately 4.3 million individuals. The 2013 Monitoring the 
Future (MTF) survey of 8th, 10th, and 12th grade students also 
indicates that marijuana is the most widely used illicit substance in 
this age group. Specifically, current month use was at 7.0 percent of 
8th graders, 18.0 percent of 10th, graders and 22.7 percent of 12th 
graders. Additionally, the 2011 Treatment Episode Data Set (TEDS) 
reported that primary marijuana abuse accounted for 18.1 percent of 
non-private substance-abuse treatment facility admissions, with 24.3 
percent of those admitted reporting daily use. However, of these 
admissions for primary marijuana abuse, the criminal justice system 
referred 51.6 percent to treatment. SAMHSA's Drug Abuse Warning Network 
(DAWN) was a national probability survey of U.S. hospitals with 
emergency departments (EDs) and was designed to obtain information on 
ED visits in which marijuana was mentioned, accounting for 36.4 percent 
of illicit drug related ED visits. There are some limitations related 
to DAWN data on ED visits, which are discussed in detail in Factor 4, 
``Its History and Current Pattern of Abuse;'' Factor 5, ``The Scope, 
Duration, and Significance of Abuse;'' and Factor 6, ``What, if an, 
Risk There is to the Public Health.'' These factors contain detailed 
discussions of these data.
    A number of risks can occur with both acute and chronic use of 
marijuana. Detailed discussions of the risks are addressed in Factor 2, 
``Scientific Evidence of its Pharmacological Effect, if Known,'' and 
Factor 6, ``What, if any, Risk There is to the Public Health.''
    b. There is significant diversion of the substance from legitimate 
drug channels.
    There is a lack of evidence of significant diversion of marijuana 
from legitimate drug channels, but this is likely due to the fact that 
marijuana is more widely available from illicit sources rather than 
through legitimate channels. Marijuana is not an FDA-approved drug 
product, as an NDA or biologics license application (BLA) has not been 
approved for marketing in the United States. Numerous states and the 
District of Columbia have state-level medical marijuana laws that allow 
for marijuana use within that state. These state-level drug channels do 
not have sufficient collection of data related to medical treatment, 
including efficacy and safety.
    Marijuana is used by researchers for nonclinical research as well 
as clinical research under investigational new drug (IND) applications; 
this represents the only legitimate drug channel in the United States. 
However, marijuana used for research reporesents a very small 
contribution of the total amount of marijuana available in the United 
States, and thus provides limited information about diversion. In 
addition, the lack of significant diversion of investigation supplies 
is likely because of the widespread availability of illicit marijuana 
of equal or greater amounts of delta\9\-THC. The data originating from 
the DEA on seizure statistics demonstrate the magnitude of the 
availability for illicit marijuana. DEA's System to Retrieve 
Information from Drug Evidence (STRIDE) provides information on total 
domestic drug seizures, STRIDE reports a total domestic seizure of 
573,195 kg of marijuana in 2011, the most recent year with complete 
data that is currently publically available (DEA Domestic Drug 
Seizures, n.d.).
    c. Individuals are taking the substance on their own initiative 
rather than on the basis of medical advice from a practitioner licensed 
by law to administer such substances.
    Because the FDA has not approved an NDA or BLA for a marijuana drug 
product for any therapeutic indication, the only way an individual can 
take marijuana on the basis of medical advice through legitimate 
channels at the federal level is by participating in research under an 
IND application. That said, numerous states and the District of 
Columbia have passed state-level medical marijuana laws allowing for 
individuals to use marijuana under certain cicrumstances. However, data 
are not yet available to determine the number of individuals using 
marijuana under these state-level medical marijuana laws. Regardless, 
according to the 2012 NSDUH data, 18.9 million American adults 
currently use marijuana (SAMHSA, 2013). Based on the large number of 
individuals reporting current use of marijuana and the lack of an FDA-
approved drug product in the United States, one can assume that it is 
likely that the majority of individuals using marijuana do so on their 
own initiative rather than on the basis of medical advice from a 
licensed practitioner.
    d. The substance is so related in its action to a substance already 
listed as having a potential for abuse to make it likely that it will 
have the same potential for abuse as such substance, thus making it 
reasonable to assume that there may be significant diversions from 
legitimate channels, significant use contrary to or without medical 
advice, or that it has a substantial capability of creating hazards to 
the health of the user or to the safety of the community.
    FDA has approved two drug products containing cannabinoid compounds 
that are structurally related to the active components in marijuana. 
These two marketed products are controlled under the CSA. Once a 
specific drug product containing cannabinoids becomes approved, that 
specific drug product may be moved from Schedule I to a different 
Schedule (II-V) under the CSA. Firstly, Marinol--generically known as 
dronabinol--is a Schedule III drug product containing synthetic 
delta\9\-THC. Marinol, which is formulated in sesame oil in soft 
gelatin capsules, was first placed in Schedule II under the CSA 
following its approval by the FDA. Marinol was later rescheduled

[[Page 53771]]

to Schedule III under the CSA because of low numbers of reports of 
abuse relative to marijuana. Dronabinol is listed in Schedule I under 
the CSA. FDA approved Marinol in 1985 for the treatment of nausea and 
vomiting associated with cancer chemotherapy in patients who failed to 
respond adequately to conventional anti-emetic treatments. In 1992, FDA 
approved Marional for anorexia associated with weight loss in patients 
with acquired immunodeficiency syndrome (AIDS). Secondly, in 1985, FDA 
approved Cesamet, a drug product containing the Schedule II substance 
nabilone, for the treatment of nausea and vomiting associated with 
cancer chemotherapy. Besides the two cannabinoid-containing drug 
products FDA approved for marketing, other naturally occurring 
cannabinoids and their derivatives (from Cannabis) and their synthetic 
equivalents with similar chemical structure and pharmacological 
activity are included in the CSA as Schedule I substances.

2. Scientific Evidence of Its Pharmacological Effects, if Known

    Under the second factor, the Secretary must consider the scientific 
evidence of marijuana's pharmacological effects. Abundant scientific 
data are available on the neurochemistry, toxicology, and pharmacology 
of marijuana. This section includes a scientific evaluation of 
marijuana's neurochemistry; pharmacology; and human and animal 
behavioral, central nervous system, cognitive, cardiovascular, 
autonomic, endocrinological, and immunological system effects. The 
overview presented below relies upon the most current research 
literature on cannabinoids.

Neurochemistry and Pharmacology of Marijuana

    Marijuana is a plant that contains numerous natural constituents, 
such as cannabinoids, that have a variety of pharmacological actions. 
The petition defines marijuana as including all Cannabis cultivated 
strains. Different marijuana samples derived from various cultivated 
strains may have very different chemical constituents including 
delta\9\-THC and other cannabinoids (Appendino et al., 2011). As a 
consequence, marijuana products from different strains will have 
different biological and pharmacological profiles.
    According to ElSohly and Slade (2005) and Appendino et al. (2011), 
marijuana contains approximately 525 identified natural constituents, 
including approximately 100 compounds classified as cannabinoids. 
Cannabinoids primarily exist in Cannabis, and published data suggests 
that most major cannabinoid compounds occurring naturally have been 
identified chemically. New and minor cannabinoids and other new 
compounds are continuously being characterized (Pollastro et al., 
2011). So far, only two cannabinoids (cannabigerol and its 
corresponding acid) have been obtained from a non-Cannabis source. A 
South African Helichrysum (H. umbraculigerum) accumulates these 
compounds (Appendino et al., 2011). The chemistry of marijuana is 
described in more detail in Factor 3, ``The State of Current Scientific 
Knowledge Regarding the Drug or Other Substance.''
    The site of cannabinoid action is at the cannabinoid receptors. 
Cloning of cannabinoid receptors, first from rat brain tissue (Matsuda 
et al., 1990) and then from human brain tissue (Gerard et al., 1991), 
has verified the site of action. Two cannabinoid receptors, 
CB1 and CB2, were characterized (Battista et al., 
2012; Piomelli, 2005). Evidence of a third cannabinoid receptor exists, 
but it has not been identified (Battista et al., 2012).
    The cannabinoid receptors, CB1 and CB2, 
belong to the family of G-protein-coupled receptors, and present a 
typical seven transmembrane-spanning domain structure. Cannabinoid 
receptors link to an inhibitory G-protein (Gi), such that 
adenylate cyclase activity is inhibited when a ligand binds to the 
receptor. This, in tum, prevents the conversion of ATP to the second 
messenger, cyclic AMP (cAMP). Examples of inhibitory coupled receptors 
include opioid, muscarinic cholinergic, alpha2-
adrenoreceptors, dopamine (D2), and serotonin (5-
HT1).
    Cannabinoid receptor activation inhibits N- and P/Q-type calcium 
channels and activates inwardly rectifying potassium channels (Mackie 
et al., 1995; Twitchell et al., 1997). N-type calcium channel 
inhibition decreases neurotransmitter release from several tissues. 
Thus, calcium channel inhibition may be the mechanism by which 
cannabinoids inhibit acetylcholine, norepinephrine, and glutamate 
release from specific areas of the brain. These effects may represent a 
potential cellular mechanism underlying cannabinoids' antinociceptive 
and psychoactive effects (Ameri, 1999).
    CB1 receptors are found primarily in the central nervous 
system, but are also present in peripheral tissues. CB1 
receptors are located mainly in the basal ganglia, hippocarnpus, and 
cerebellum of the brain (Howlett et al., 2004). The localization of 
these receptors may explain cannabinoid interference with movement 
coordination and effects on memory and cognition. Additionally, 
CB1 receptors are found in the immune system and numerous 
other peripheral tissues (Petrocellis and Di Marzo, 2009). However, the 
concentration of CB1 receptors is considerably lower in 
peripheral tissues than in the central nervous system (Herkenharn et 
al., 1990 and 1992).
    CB2 receptors are found primarily in the immune system, 
but are also present in the central nervous system and other peripheral 
tissues. In the immune system, CB2 receptors are found 
predominantly in B lymphocytes and natural killer cells (Bouaboula et 
al., 1993). CB2 receptors may mediate cannabinoids' 
immunological effects (Galiegue et al., 1995). Additionally, 
CB2 receptors have been localized in the brain, primarily in 
the cerebellum and hippocampus (Gong et al., 2006). The distribution of 
CB2 receptors throughout the body is less extensive than the 
distribution of CB1 receptors (Petrocellis and Di Marzo, 
2009). However, both CB1 and CB2 receptors are 
present in numerous tissues of the body.
    Cannabinoid receptors have endogenous ligands. In 1992 and 1995, 
two endogenous cannabinoid receptor agonists, anandamide and 
arachidonyl glycerol (2-AG), respectively, were identified (Di Marzo, 
2006). Anandamide is a low efficacy agonist (Breivogel and Childers, 
2000) and 2-AG is a high efficacy agonist (Gonsiorek et al., 2000). 
Cannabinoid endogenous ligands are present in central as well as 
peripheral tissues. A combination of uptake and hydrolysis terminate 
the action of the endogenous ligands. The endogenous cannabinoid system 
is a locally active signaling system that, to help restore homeostasis, 
is activated ``on demand'' in response to changes to the local 
homeostasis (Petrocellis and Di Marzo, 2009). The endogenous 
cannabinoid system, including the endogenous cannabinoids and the 
cannabinoid receptors, demonstrate substantial plasticity in response 
to several physiological and pathological stimuli (Petrocellis and Di 
Marzo, 2009). This plasticity is particularly evident in the central 
nervous system.
    Delta\9\-THC and cannabidiol (CBD) are two abundant cannabinoids 
present in marijuana. Marijuana's major psychoactive cannabinoid is 
delta\9\-THC (Wachtel et al., 2002). In 1964, Gaoni and Mechoularn 
first described delta\9\-THC's structure and function. In 1963, 
Mechoularn and Shvo first described CBD's structure. The 
pharmacological actions of CBD have not been fully studied in humans.

[[Page 53772]]

    Delta\9\-THC and CBD have varying affinity and effects at the 
cannabinoid receptors. Delta\9\-THC displays similar affinity for 
CB1 and CB2 receptors, but behaves as a weak 
agonist for CB2 receptors. The identification of synthetic 
cannabinoid ligands that selectively bind to CB2 receptors 
but do not have the typical delta\9\-THC-like psychoactive properties 
suggests that the activation of CB1-receptors mediates 
cannabinoids' psychotropic effects (Hanus et al., 1999). CBD has low 
affinity for both CB1 and CB2 receptors 
(Mechoulam et al., 2007). According to Mechoulam et al. (2007), CBD has 
antagonistic effects at CB1 receptors and some inverse 
agonistic properties at CB2 receptors. When cannabinoids are 
given subacutely to rats, CB1 receptors down-regulate and 
the binding of the second messenger system coupled to CB1 
receptors, GTPgarnmaS, decreases (Breivogel et al., 2001).

Animal Behavioral Effects

Self-Administration
    Self-administration is a method that assesses the ability of a drug 
to produce rewarding effects. The presence of rewarding effects 
increases the likelihood of behavioral responses to obtain additional 
drug. Animal self-administration of a drug is often useful in 
predicting rewarding effects in humans, and is indicative of abuse 
liability. A good correlation is often observed between those drugs 
that rhesus monkeys self-administer and those drugs that humans abuse 
(Balster and Bigelow, 2003). Initially, researchers could not establish 
self-administration of cannabinoids, including delta\9\-THC, in animal 
models. However, self-administration of delta\9\-THC can now be 
established in a variety of animal models under specific training 
paradigms (Justinova et al., 2003, 2004, 2005).
    Squirrel monkeys, with and without prior exposure to other drugs of 
abuse, self-administer delta\9\-THC under specific conditions. For 
instance, Tanda et al. (2000) observed that when squirrel monkeys are 
initially trained to self-administer intravenous cocaine, they will 
continue to bar-press delta\9\-THC at the same rate as they would with 
cocaine. The doses were notably comparable to those doses used by 
humans who smoke marijuana. SR141716, a CB1 cannabinoid 
receptor agonist-antagonist, can block this rewarding effect. Other 
studies show that na[iuml]ve squirrel monkeys can be successfully 
trained to self-administer delta\9\-THC intravenously (Justinova et 
al., 2003). The maximal responding rate is 4 [mu]g/kg per injection, 
which is 2-3 times greater than observed in previous studies using 
cocaine-experienced monkeys. Naltrexone, a mu-opioid antagonist, 
partially antagonizes these rewarding effects of delta\9\-THC 
(Justinova et al., 2004).
    Additionally, data demonstrate that under specific conditions, 
rodents self-administer cannabinoids. Rats will self-administer 
delta\9\-THC when applied intracerebroventricularly (i.c.v.), but only 
at the lowest doses tested (0.01-0.02 [mu]g/infusion) (Braida et al., 
2004). SR141716 and the opioid antagonist naloxone can antagonize this 
effect. However, most studies involve rodents self-administrating the 
synthetic cannabinoid WIN 55212, a CB1 receptor agonist with 
a non-cannabinoid structure (Deiana et al., 2007; Fattore et al., 2007; 
Martellotta et al., 1998; Mendizabal et al., 2006).
    Aversive effects, rather than reinforcing effects, occur in rats 
that received high doses of WIN 55212 (Chaperon et al., 1998) or 
delta\9\-THC (Sanudo-Pena et al., 1997), indicating a possible critical 
dose-dependent effect. In both studies, SR141716 reversed these 
aversive effects.
Conditioned Place Preference
    Conditioned place preference (CPP) is a less rigorous method than 
self-administration for determining whether or not a drug has rewarding 
properties. In this behavioral test, animals spend time in two distinct 
environments: One where they previously received a drug and one where 
they received a placebo. If the drug is reinforcing, animals will 
choose to spend more time in the environment paired with the drug, 
rather than with the placebo, when presented with both options 
s.imultaneously.
    Animals show CPP to delta\9\-THC, but only at the lowest doses 
tested (0.075-1.0 mg/kg, intraperitoneal (i.p.)) (Braida et al., 2004). 
SR141716 and naloxone antagonize this effect (Braida et al., 2004). As 
a partial agonist, SR141716 can induce CPP at doses of 0.25, 0.5, 2 and 
3 mg/kg (Cheer et al., 2000). In knockout mice, those without [mu]-
opioid receptors do not develop CPP to delta\9\-THC (Ghozland et al., 
2002).
Drug Discrimination Studies
    Drug discrimination is a method where animals indicate whether a 
test drug produces physical or psychic perceptions similar to those 
produced by a known drug of abuse. In this test, an animal learns to 
press one bar when it receives the known drug of abuse and another bar 
when it receives placebo. To determine whether the test drug is like 
the known drug of abuse, a challenge session with the test drug 
demonstrates which of the two bars the animal presses more often.
    In addition to humans (Lile et al., 2009; Lile et al., 2011), it 
has been noted that animals, including monkeys (McMahon, 2009), mice 
(McMahon et al., 2008), and rats (Gold et al., 1992), are able to 
discriminate cannabinoids from other drugs or placebo. Moreover, the 
major active metabolite of delta\9\-THC, 11-hydroxy-delta\9\-THC, also 
generalizes (following oral administration) to the stimulus cues 
elicited by delta\9\-THC (Browne and Weissman, 1981). Twenty-two other 
cannabinoids found in marijuana also fully substitute for delta\9\-THC. 
However, CBD does not substitute for delta\9\-THC in rats (Vann et al., 
2008).
    Discriminative stimulus effects of delta\9\-THC are 
pharmacologically specific for marijuana containing cannabinoids 
(Balster and Prescott, 1992; Browne and Weissman, 1981; Wiley et al., 
1993, 1995). The discriminative stimulus effects of the cannabinoid 
group appear to provide unique effects because stimulants, 
hallucinogens, opioids, benzodiazepines, barbiturates, NMDA 
antagonists, and antipsychotics do not fully substitute for delta\9\-
THC.

Central Nervous System Effects

Human Physiological and Psychological Effects

Psychoactive Effects
    Below is a list of the common subjective responses to cannabinoids 
(Adams and Martin, 1996; Gonzalez, 2007; Hollister 1986, 1988; 
Institute of Medicine, 1982). According to Maldonado (2002), these 
responses to marijuana are pleasurable to many humans and are often 
associated with drug-seeking and drug-taking. High levels of positive 
psychoactive effects are associated with increased marijuana use, 
abuse, and dependence (Scherrer et al., 2009; Zeiger et al., 2010).
    (1) Disinhibition, relaxation, increased sociability, and 
talkativeness.
    (2) Increased merriment and appetite, and even exhilaration at high 
doses.
    (3) Enhanced sensory perception, which can generate an increased 
appreciation of music, art, and touch.
    (4) Heightened imagination, which can lead to a subjective sense of 
increased creativity.
    (5) Initial dizziness, nausea, tachycardia, facial flushing, dry 
mouth, and tremor.
    (6) Disorganized thinking, inability to converse logically, time 
distortions, and short-term memory impairment.

[[Page 53773]]

    (7) Ataxia and impaired judgment, which can impede driving ability 
or lead to an increase in risk-tasking behavior.
    (8) Illusions, delusions, and hallucinations that intensify with 
higher doses.
    (9) Emotional lability, incongruity of affect, dysphoria, 
agitation, paranoia, confusion, drowsiness, and panic attacks, which 
are more common in inexperienced or high-dosed users.
    As with many psychoactive drugs, a person's medical, psychiatric, 
and drug-taking history can influence the individual's response to 
marijuana. Dose preferences to marijuana occur in that marijuana users 
prefer higher concentrations of the principal psychoactive substance 
(1.95 percent delta\9\-THC) over lower concentrations (0.63 percent 
delta\9\-THC) (Chait and Burke, 1994). Nonetheless, frequent marijuana 
users (>100 times of use) were able to identify a drug effect from low-
dose delta\9\-THC better than occasional users (<10 times of use) while 
also experiencing fewer sedative effects from marijuana (Kirk and de 
Wit, 1999).
    The petitioners contend that many of marijuana's naturally 
occurring cannabinoids mitigate the psychoactive effects of delta\9\-
THC, and therefore that marijuana lacks sufficient abuse potential to 
warrant Schedule I placement, because Marinol, which is in Schedule 
III, contains only delta\9\-THC. This theory has not been demonstrated 
in controlled studies. Moreover, the concept of abuse potential 
encompasses all properties of a substance, including its chemistry, 
pharmacology, and pharmacokinetics, as well as usage patterns and 
diversion history. The abuse potential of a substance is associated 
with the repeated or sporadic use of a substance in nonmedical 
situations for the psychoactive effects the substance produces. These 
psychoactive effects include euphoria, perceptual and other cognitive 
distortions, hallucinations, and mood changes. However, as stated 
above, the abuse potential not only includes the psychoactive effects, 
but also includes other aspects related to a substance.
    DEA's final published rule entitled ``Rescheduling of the Food and 
Drug Administration Approved Product Containing Synthetic Dronabinol 
[(-)-delta\9\-(trans)-Tetrahydrocannabinol] in Sesame Oil and 
Encapsulated in Soft Gelatin Capsules From Schedule II to Schedule 
III'' (64 FR 35928, July 2, 1999) rescheduled Marinol from Schedule II 
to Schedule III. The HHS assessment of the abuse potential and 
subsequent scheduling recommendation compared Marinol to marijuana on 
different aspects related to abuse potential. Major differences in 
formulation, availability, and usage between marijuana and the drug 
product, Marinol, contribute to their differing abuse potentials.
    Hollister and Gillespie (1973) estimated that delta\9\-THC by 
smoking is 2.6 to 3 times more potent than delta\9\-THC ingested 
orally. The intense psychoactive drug effect achieved, rapidly by 
smoking is generally considered to produce the effect desired by the 
abuser. This effect explains why abusers often prefer to administer 
certain drugs by inhalation, intravenously, or intranasally rather than 
orally. Such is the case with cocaine, opium, heroin, phencyclidine, 
methamphetamine, and delta\9\-THC from marijuana (0.1-9.5 percent 
delta\9\-THC range) or hashish (10-30 percent delta\9\-THC range) 
(Wesson and Washburn, 1990). Thus, the delayed onset and longer 
duration of action for Marinol may be contributing factors limiting the 
abuse or appeal of Marinol as a drug of abuse relative to marijuana.
    The formulation of Marinol is a factor that contributes to 
differential scheduling of Marinol and marijuana. For example, 
extraction and purification of dronabinol from the encapsulated sesame 
oil mixture of Marinol is highly complex and difficult. Additionally, 
the presence of sesame oil mixture in the formulation may preclude the 
smoking of Marinol-laced cigarettes.
    Additionally, there is a dramatic difference between actual abuse 
and illicit trafficking of Marinol and marijuana. Despite Marinol's 
availability in the United States, there have been no significant 
reports of abuse, diversion, or public health problems due to Marinol. 
By comparison, 18.9 million American adults report currently using 
marijuana (SAMHSA, 2013).
    In addition, FDA's approval of an NDA for Marinol allowed for 
Marinol to be rescheduled to Schedule II, and subsequently to Schedule 
III of the CSA. In conclusion, marijuana and Marinol differ on a wide 
variety of factors that contribute to each substance's abuse potential. 
These differences are major reasons distinguishing the higher abuse 
potential for marijuana and the different scheduling determinations of 
marijuana and Marinol.
    In terms of the petitioners' claim that different cannabinoids 
present in marijuana mitigate the psychoactive effects of delta\9\-THC, 
only three of the cannabinoids present in marijuana were simultaneously 
administered with delta\9\-THC to examine how the combinations of these 
cannabinoids such as CBD, cannabichromene (CBC) and cannabinol (CBN) 
influence delta\9\-THC's psychoactive effects. Dalton et al. (1976) 
observed that smoked administration of placebo marijuana cigarettes 
containing injections of 0.15 mg/kg CBD combined with 0.025mg/kg of 
delta\9\-THC, in a 7:1 ratio of CBD to delta\9\-THC, significantly 
decreased ratings of acute subjective effects and ``high'' when 
compared to smoking delta\9\-THC alone. In contrast, Ilan et al. (2005) 
calculated the naturally occurring concentrations of CBC and CBD in a 
batch of marijuana cigarettes with either 1.8 percent or 3.6 percent 
delta\9\-THC concentration by weight. For each strength of delta\9\-THC 
in marijuana cigarettes, the concentrations of CBC and CBD were 
classified in groups of either low or high. The study varied the amount 
of CBC and CBD within each strength of delta\9\-THC marijuana 
cigarettes, with administrations consisting of either low CBC (between 
0.1-0.2 percent CBC concentration by weight) and low CBD (between 0.1-
0.4 percent CBD concentration by weight), high CBC (>0.5 percent CBC 
concentration by weight) and low CBD, or low CBC and high CBD (>1.0 
percent CBD concentration by weight). Overall, all combinations scored 
significantly greater than placebo on ratings of subjective effects, 
and there was no significant difference between any combinations.
    The oral administration of a combination of either 15, 30, or 60 mg 
CBD with 30 mg delta\9\-THC dissolved in liquid (in a ratio of at least 
1:2 CBD to delta\9\-THC) reduced the subjective effects produced by 
delta\9\-THC alone (Karniol et al., 1974). Additionally, orally 
administering a liquid mixture combining 1 mg/kg CBD with 0.5 mg/kg of 
delta\9\-THC (ratio of 2:1 CBD to delta\9\-THC) decreased scores of 
anxiety and marijuana drug effect on the Addiction Research Center 
Inventory (ARCI) compared to delta\9\-THC alone (Zuardi et al., 1982). 
Lastly, oral administration of either 12.5, 25, or 50 mg CBN combined 
with 25 mg delta\9\-THC dissolved in liquid (ratio of at least 1:2 CBN 
to delta\9\-THC) significantly increased subjective ratings of 
``drugged,'' ``drowsy,'' ``dizzy,'' and ``drunk,'' compared to 
delta\9\-THC alone (Karniol et al., 1975).
    Even though some studies suggest that CBD may decrease some of 
delta\9\-THC's psychoactive effects, the ratios of CBD to delta\9\-THC 
administered in these studies are not present in marijuana used by most 
people. For example, in one study, researchers used smoked

[[Page 53774]]

marijuana with ratios of CBD to delta\9\-THC naturally present in 
marijuana plant material and they found out that varying the amount of 
CBD actually had no effect on delta\9\-THC's psychoactive effects (Ilan 
et al., 2005). Because most marijuana currently available on the street 
has high amounts of delta\9\-THC with low amounts of CBD and other 
cannabinoids, most individuals use marijuana with low levels of CBD 
present (Mehmedic et al., 2010). Thus, any possible mitigation of 
delta\9\-THC's psychoactive effects by CBD will not occur for most 
marijuana users. In contrast, one study indicated that another 
cannabinoid present in marijuana, CBN, may enhance delta\9\-THC's 
psychoactive effects (Karniol et al., 1975).
Behavioral Impairment
    Marijuana induces various psychoactive effects that can lead to 
behavioral impairment. Marijuana's acute effects can significantly 
interfere with a person's ability to learn in the classroom or to 
operate motor vehicles. Acute administration of smoked marijuana 
impairs performance on learning, associative processes, and psychomotor 
behavioral tests (Block et al., 1992). Ramaekers et al. (2006a) showed 
that acute administration of 250 [mu]g/kg and 500 [mu]g/kg of delta\9\-
THC in smoked marijuana dose-dependently impairs cognition and motor 
control, including motor impulsivity and tracking impairments 
(Ramaekers et al., 2006b). Similarly, administration of 290 [mu]g/kg 
delta\9\-THC in a smoked marijuana cigarette resulted in impaired 
perceptual motor speed and accuracy: Two skills which are critical to 
driving ability (Kurzthaler et al., 1999). Lastly, administration of 
3.95 percent delta\9\-THC in a smoked marijuana cigarette not only 
increased disequilibrium measures, but also increased the latency in a 
task of simulated vehicle braking at a rate comparable to an increase 
in stopping distance of five feet at 60 mph (Liguori et al., 1998). 
However, acute administration of marijuana containing 2.1 percent 
delta\9\-THC does not produce ``hangover effects'' (Chait, 1990).
    In addition to measuring the acute effects immediately following 
marijuana administration, researchers have conducted studies to 
determine how long behavioral impairments last after abstinence. Some 
of marijuana's acute effects may not fully resolve until at least one 
day after the acute psychoactive effects have subsided. Heishman et al. 
(1990) showed that impairment on memory tasks persists for 24 hours 
after smoking marijuana cigarettes containing 2.57 percent delta\9\-
THC. However, Fant et al. (1998) showed that the morning after exposure 
to 1.8 percent or 3.6 percent smoked delta\9\-THC, subjects had minimal 
residual alterations in subjective or performance measures.
    A number of factors may influence marijuana's behavioral effects 
including the duration of use (chronic or short term), frequency of use 
(daily, weekly, or occasionally), and amount of use (heavy or 
moderate). Researchers also have examined how long behavioral 
impairments last following chronic marijuana use. These studies used 
self-reported histories of past duration, frequency, and amount of past 
marijuana use, and administered a variety of performance and cognitive 
measures at different time points following marijuana abstinence. In 
chronic marijuana users, behavioral impairments may persist for up to 
28 days of abstinence. Solowij et al. (2002) demonstrated that after 17 
hours of abstinence, 51 adult heavy chronic marijuana users performed 
worse on memory and attention tasks than 33 non-using controls or 51 
heavy, short-term users. Another study noted that heavy, frequent 
marijuana users, abstinent for at least 24 hours, performed 
significantly worse than the controls on verbal memory and psychomotor 
speed tests (Messinis et al., 2006). Additionally, after at least 1 
week of abstinence, young adult frequent marijuana users, aged 18-28, 
showed deficits in psychomotor speed, sustained attention, and 
cognitive inhibition (Lisdahl and Price, 2012). Adult heavy, chronic 
marijuana users showed deficits on memory tests after 7 days of 
supervised abstinence (Pope et al., 2002). However, when these same 
individuals were again tested after 28 days of abstinence, they did not 
show significant memory deficits. The authors concluded, ``cannabis-
associated cognitive deficits are reversible and related to recent 
cannabis exposure, rather than irreversible and related to cumulative 
lifetime use.'' \7\ However, other researchers reported 
neuropsychological deficits in memory, executive functioning, 
psychomotor speed and manual dexterity in heavy marijuana users 
abstinent for 28 days (Bolla et al., 2002). Furthermore, a follow-up 
study of heavy marijuana users noted decision-making deficits after 25 
days of supervised abstinence. (Bolla et al., 2005). However, moderate 
marijuana users did not show decision-making deficits after 25 days of 
abstinence, suggesting the amount of marijuana use may impact the 
duration of residual impairment.
---------------------------------------------------------------------------

    \7\ In this quotation the term Cannabis is used interchangeably 
for marijuana.
---------------------------------------------------------------------------

    The effects of chronic marijuana use do not seem to persist after 
more than 1 to 3 months of abstinence. After 3 months of abstinence, 
any deficits observed in IQ, immediate memory, delayed memory, and 
information-processing speeds following heavy marijuana use compared to 
pre-drug use scores were no longer apparent (Fried et al., 2005). 
Marijuana did not appear to have lasting effects on performance of a 
comprehensive neuropsychological battery when 54 monozygotic male twins 
(one of whom used marijuana, one of whom did not) were compared 1-20 
years after cessation of marijuana use (Lyons et al., 2004). Similarly, 
following abstinence for a year or more, both light and heavy adult 
marijuana users did not show deficits on scores of verbal memory 
compared to non-using controls (Tait et al., 2011). According to a 
recent meta-analysis looking at non-acute and long-lasting effects of 
marijuana use on neurocognitive performance, any deficits seen within 
the first month following abstinence are generally not present after 
about 1 month of abstinence (Schreiner and Dunn, 2012).
    Another aspect that may be a critical factor in the intensity and 
persistence of impairment resulting from chronic marijuana use is the 
age of first use. Individuals with a diagnosis of marijuana misuse or 
dependence who were seeking treatment for substance use, who initiated 
marijuana use before the age of 15 years, showed deficits in 
performance on tasks assessing sustained attention, impulse control, 
and general executive functioning compared to non-using controls. These 
deficits were not seen in individuals who initiated marijuana use after 
the age of 15 years (Fontes et al., 2011). Similarly, heavy, chronic 
marijuana users who began using marijuana before the age of 16 years 
had greater decrements in executive functioning tasks than heavy, 
chronic marijuana users who started using after the age of 16 years and 
non-using controls (Gruber et al., 2012). Additionally, in a 
prospective longitudinal birth cohort study of 1,037 individuals, 
marijuana dependence or chronic marijuana use was associated with a 
decrease in IQ and general neuropsychological performance compared to 
pre-marijuana exposure levels in adolescent onset users (Meier et al., 
2012). The decline in adolescent-onset user's IQ persisted even after 
reduction or abstinence of marijuana use for at least 1 year. In 
contrast, the adult-onset chronic marijuana users showed no significant

[[Page 53775]]

changes in IQ compared to pre-exposure levels whether they were current 
users or abstinent for at least 1 year (Meier et al., 2012).
    In addition to the age of onset of use, some evidence suggests that 
the amount of marijuana used may relate to the intensity of 
impairments. In the above study by Gruber et al. (2012), where early-
onset users had greater deficits than late-onset users, the early-onset 
users reported using marijuana twice as often and using three times as 
much marijuana per week than the late-onset users. Meier et al. (2012) 
showed that the deficits in IQ seen in adolescent-onset users increased 
with the amount of marijuana used. Moreover, when comparing scores for 
measures of IQ, immediate memory, delayed memory, and information-
processing speeds to pre-drug-use levels, the current, heavy, chronic 
marijuana users showed deficits in all three measures while current, 
occasional marijuana users did not (Fried et al., 2005).
Behavioral Effects of Prenatal Exposure
    Studies with children at different stages of development are used 
to examine the impact of prenatal marijuana exposure on performance in 
a series of cognitive tasks. However, many pregnant women who reported 
marijuana use were more likely to also report use of alcohol, tobacco, 
and cocaine (Goldschmidt et al., 2008). Thus, with potential exposure 
to multiple drugs, it is difficult to determine the specific impact of 
prenatal marijuana exposure.
    Most studies assessing the behavioral effects of prenatal marijuana 
exposure included women who, in addition to using marijuana, also 
reported using alcohol and tobacco. However, some evidence suggests an 
association between heavy prenatal marijuana exposure and deficits in 
some cognitive domains. In both 4-year-old and 6-year-old children, 
heavy prenatal marijuana use is negatively associated with performance 
on tasks assessing memory, verbal reasoning, and quantitative reasoning 
(Fried and Watkinson, 1987; Goldschmidt et al., 2008). Additionally, 
heavy prenatal marijuana use is associated with deficits in measures of 
sustained attention in children at the ages of 6 years and 13-16 years 
(Fried et al., 1992; Fried, 2002). In 9- to 12-year-old children, 
prenatal marijuana exposure is negatively associated with executive 
functioning tasks that require impulse control, visual analysis, and 
hypothesis (Fried et al., 1998).
Association of Marijuana Use With Psychosis
    This analysis evaluates only the evidence for a direct link between 
prior marijuana use and the subsequent development of psychosis. Thus, 
this discussion does not consider issues such as whether marijuana's 
transient effects are similar to psychotic symptoms in healthy 
individuals or exacerbate psychotic symptoms in individuals already 
diagnosed with schizophrenia.
    Extensive research has been conducted to investigate whether 
exposure to marijuana is associated with the development of 
schizophrenia or other psychoses. Although many studies are small and 
inferential, other studies in the literature use hundreds to thousands 
of subjects. At present, the available data do not suggest a causative 
link between marijuana use and the development of psychosis (Minozzi et 
al., 2010). Numerous large, longitudinal studies show that subjects who 
used marijuana do not have a greater incidence of psychotic diagnoses 
compared to those who do not use marijuana (Fergusson et al., 2005; 
Kuepper et al., 2011; Van Os et al., 2002).
    When analyzing the available evidence of the connection between 
psychosis and marijuana, it is critical to determine whether the 
subjects in the studies are patients who are already diagnosed with 
psychosis or individuals who demonstrate a limited number of symptoms 
associated with psychosis without qualifying for a diagnosis of the 
disorder. For example, instead of using a diagnosis of psychosis, some 
researchers relied on non-standard methods of representing symptoms of 
psychosis including ``schizophrenic cluster'' (Maremmani et al., 2004), 
``subclinical psychotic symptoms'' (Van Gastel et al., 2012), ``pre-
psychotic clinical high risk'' (Van der Meer et al., 2012), and 
symptoms related to ``psychosis vulnerability'' (Griffith-Lendering et 
al., 2012). These groupings do not conform to the criteria in the 
Diagnostic and Statistical Manual (DSM-5) or the International 
Classification of Diseases (ICD-10) for a diagnosis of psychosis. Thus, 
these groupings are not appropriate for use in evaluating marijuana's 
impact on the development of actual psychosis. Accordingly, this 
analysis includes only those studies that use subjects diagnosed with a 
psychotic disorder.
    In the largest study evaluating the link between psychosis and drug 
use, 274 of the approximately 45,500 Swedish conscripts in the study 
population (<0.01 percent) received a diagnosis of schizophrenia within 
the 14-year period following military induction from 1969 to 1983 
(Andreasson et al., 1987). Of the conscripts diagnosed with psychosis, 
7.7 percent (21 of the 274 conscripts with psychosis) had used 
marijuana more than 50 times at induction, while 72 percent (197 of the 
274 conscripts with psychosis) had never used marijuana. Although high 
marijuana use increased the relative risk for schizophrenia to 6.0, the 
authors note that substantial marijuana use history ``accounts for only 
a minority of all cases'' of psychosis (Andreasson et al., 1987). 
Instead, the best predictor for whether a conscript would develop 
psychosis was a non-psychotic psychiatric diagnosis upon induction. The 
authors concluded that marijuana use increased the risk for psychosis 
only among individuals predisposed to develop the disorder. In 
addition, a 35-year follow up to this study reported very similar 
results (Manrique-Garcia et al., 2012). In this follow up study, 354 
conscripts developed schizophrenia; of these 354 conscripts, 32 used 
marijuana more than 50 times at induction (9 percent, an odds ratio of 
6.3), while 255 had never used marijuana (72 percent).
    Additionally, the conclusion that the impact of marijuana may 
manifest only in individuals likely to develop psychotic disorders has 
been shown in many other types of studies. For example, although 
evidence shows that marijuana use may precede the presentation of 
symptoms in individuals later diagnosed with psychosis (Schimmelmann et 
al., 2011), most reports conclude that prodromal symptoms of 
schizophrenia appear prior to marijuana use (Schiffman et al., 2005). 
Similarly, a review of the gene-environment interaction model for 
marijuana and psychosis concluded that some evidence supports marijuana 
use as a factor that may influence the development of psychosis, but 
only in those individuals with psychotic liability (Pelayo-Teran et 
al., 2012).
    A similar conclusion was drawn when the prevalence of schizophrenia 
was modeled against marijuana use across eight birth cohorts in 
Australia in individuals born between the years 1940 to 1979 
(Degenhardt et al., 2003). Although marijuana use increased over time 
in adults born during the four-decade period, there was not a 
corresponding increase in diagnoses for psychosis in these individuals. 
The authors conclude that marijuana may precipitate schizophrenic 
disorders only in those individuals who are vulnerable to developing 
psychosis. Thus, marijuana per se does not appear to

[[Page 53776]]

induce schizophrenia in the majority of individuals who have tried or 
continue to use marijuana. However, in individuals with a genetic 
vulnerability for psychosis, marijuana use may influence the 
development of psychosis.

Cardiovascular and Autonomic Effects

    Single smoked or oral doses of delta\9\-THC produce tachycardia and 
may increase blood pressure (Capriotti et al., 1988; Benowitz and 
Jones, 1975). Some evidence associates the tachycardia produced by 
delta\9\-THC with excitation of the sympathetic and depression of the 
parasympathetic nervous systems (Malinowska et al., 2012). During 
chronic marijuana ingestion, a tolerance to tachycardia develops 
(Malinowska et al., 2012).
    However, prolonged delta\9\-THC ingestion produces bradycardia and 
hypotension (Benowitz and Jones, 1975). Plant-derived cannabinoids and 
endocannabinoids elicit hypotension and bradycardia via activation of 
peripherally-located CB1 receptors (Wagner et al., 1998). 
Specifically, the mechanism of this effect is through presynaptic CB1 
receptor-mediated inhibition of norepinephrine release from peripheral 
sympathetic nerve terminals, with possible additional direct 
vasodilation via activation of vascular cannabinoid receptors (Pacher 
et al., 2006). In humans, tolerance can develop to orthostatic 
hypotension (Jones, 2002; Sidney, 2002) possibly related to plasma 
volume expansion, but tolerance does not develop to the supine 
hypotensive effects (Benowitz and Jones, 1975). Additionally, 
electrocardiographic changes are minimal, even after large cumulative 
doses of delta\9\-THC are administered. (Benowitz and Jones, 1975).
    Marijuana smoking by individuals, particularly those with some 
degree of coronary artery or cerebrovascular disease, poses risks such 
as increased cardiac work, catecholamines and carboxyhemoglobin, 
myocardial infarction, and postural hypotension (Benowitz and Jones, 
1981; Hollister, 1988; Mittleman et al., 2001; Malinowska et al., 
2012).

Respiratory Effects

    After acute exposure to marijuana, transient bronchodilation is the 
most typical respiratory effect (Gong et al., 1984). A recent 20-year 
longitudinal study with over 5,000 individuals collected information on 
the amount of marijuana use and pulmonary function data at years 0, 2, 
5, 10, and 20 (Pletcher et al., 2012). Among the more than 5,000 
individuals who participated in the study, almost 800 of them reported 
current marijuana use but not tobacco use at the time of assessment. 
Pletcher et al. (2012) found that the occasional use of marijuana is 
not associated with decreased pulmonary function. However, some 
preliminary evidence suggests that heavy marijuana use may be 
associated with negative pulmonary effects (Pletcher et al., 2012). 
Long-term use of marijuana can lead to chronic cough and increased 
sputum, as well as an increased frequency of chronic bronchitis and 
pharyngitis. In addition, pulmonary function tests reveal that large-
airway obstruction can occur with chronic marijuana smoking, as can 
cellular inflammatory histopathological abnormalities in bronchial 
epithelium (Adams and Martin 1996; Hollister 1986).
    Evidence regarding marijuana smoking leading to cancer is 
inconsistent, as some studies suggest a positive correlation while 
others do not (Lee and Hancox, 2011; Tashkin, 2005). Several lung 
cancer cases have been reported in young marijuana users with no 
tobacco smoking history or other significant risk factors (Fung et al., 
1999). Marijuana use may dose-dependently interact with mutagenic 
sensitivity, cigarette smoking, and alcohol use to increase the risk of 
head and neck cancer (Zhang et al., 1999). However, in a large study 
with 1,650 subjects, a positive association was not found between 
marijuana and lung cancer (Tashkin et al., 2006). This finding remained 
true, regardless of the extent of marijuana use, when controlling for 
tobacco use and other potential confounding variables. Overall, new 
evidence suggests that the effects of marijuana smoking on respiratory 
function and carcinogenicity differ from those of tobacco smoking (Lee 
and Hancox, 2011).

Endocrine System

    Experimental marijuana administration to humans does not 
consistently alter many endocrine parameters. In an early study, male 
subjects who experimentally received smoked marijuana showed a 
significant depression in luteinizing hormone and a significant 
increase in cortisol (Cone et al., 1986). However, two later studies 
showed no changes in hormones. Male subjects experimentally exposed to 
smoked delta\9\-THC (18 mg/marijuana cigarette) or oral delta\9\-THC 
(10 mg three times per day for 3 days and on the morning of the fourth 
day) showed no changes in plasma adrenocorticotropic hormone (ACTH), 
cortisol, prolactin, luteinizing hormone, or testosterone levels (Dax 
et al., 1989). Similarly, a study with 93 men and 56 women showed that 
chronic marijuana use did not significantly alter concentrations of 
testosterone, luteinizing hormone, follicle stimulating hormone, 
prolactin, or cortisol (Block et al., 1991). Additionally, chronic 
marijuana use did not affect serum levels of thyrotropin, thyroxine, 
and triiodothyronine (Bonnet, 2013). However, in a double-blind, 
placebo-controlled, randomized clinical trial of HIV-positive men, 
smoking marijuana dose-dependently increased plasma levels of ghrelin 
and leptin, and decreased plasma levels of peptide YY (Riggs et al., 
2012).
    The effects of marijuana on female reproductive system 
functionality differ between humans and animals. In monkeys, delta\9\-
THC administration suppressed ovulation (Asch et al., 1981) and reduced 
progesterone levels (Almirez et al., 1983). However, in women, smoked 
marijuana did not alter hormone levels or the menstrual cycle 
(Mendelson and Mello, 1984). Brown and Dobs (2002) suggest that the 
development of tolerance in humans may be the cause of the 
discrepancies between animal and human hormonal response to 
cannabinoids.
    The presence of in vitro delta\9\-THC reduces binding of the 
corticosteroid, dexamethasone, in hippocampal tissue from 
adrenalectomized rats, suggesting an interaction with the 
glucocorticoid receptor (Eldridge et al., 1991). Although acute 
delta\9\-THC presence releases corticosterone, tolerance develops in 
rats with chronic administration (Eldridge et al., 1991).
    Some studies support a possible association between frequent, long-
term marijuana use and increased risk of testicular germ cell tumors 
(Trabert et al., 2011). On the other hand, recent data suggest that 
cannabinoid agonists may have therapeutic value in the treatment of 
prostate cancer, a type of carcinoma in which growth is stimulated by 
androgens. Research with prostate cancer cells shows that the mixed 
CB1/CB2 agonist, WIN-55212-2, induces apoptosis 
in prostate cancer cells, as well as decreases the expression of 
androgen receptors and prostate-specific antigens (Sarfaraz et al., 
2005).

Immune System

    Cannabinoids affect the immune system in many different ways. 
Synthetic, natural, and endogenous cannabinoids often cause different 
effects in a dose-dependent biphasic manner (Croxford and Yamamura, 
2005; Tanasescu and Constantinescu, 2010).
    Studies in humans and animals give conflicting results about 
cannabinoid

[[Page 53777]]

effects on immune functioning in subjects with compromised immune 
systems. Abrams et al. (2003) investigated marijuana's effect on 
immunological functioning in 62 AIDS patients taking protease 
inhibitors. Subjects received one of the following three times a day: A 
smoked marijuana cigarette containing 3.95 percent delta\9\-THC, an 
oral tablet containing delta\9\-THC (2.5 mg oral dronabinol), or an 
oral placebo. The results showed no changes in CD4+ and CD8+ cell 
counts, HIV RNA levels, or protease inhibitor levels between groups. 
Thus, the use of cannabinoids showed no short-term adverse virologic 
effects in individuals with compromised immune systems. However, these 
human data contrast with data generated in immunodeficient mice, which 
demonstrated that exposure to delta\9\-THC in vivo suppresses immune 
function, increases HIV co-receptor expression, and acts as a cofactor 
to enhance HIV replication (Roth et al., 2005).

3. The State of Current Scientific Knowledge Regarding the Drug or 
Other Substance

    Under the third factor, the Secretary must consider the state of 
current scientific knowledge regarding marijuana. Thus, this section 
discusses the chemistry, human pharmacokinetics, and medical uses of 
marijuana.

Chemistry

    Marijuana is one of the common names of Cannabis sativa L. in the 
family Cannabaceae. Cannabis is one of the oldest cultivated crops, 
providing a source of fiber, food, oil, and drug. Botanists still 
debate whether Cannabis should be considered as a single (The Plant 
List, 2010) or three species, i.e., C. sativa, C. indica, and C. 
ruderalis (Hillig, 2005). Specifically, marijuana is developed as 
sativa and indica cultivated varieties (strains) or various hybrids.
    The petition defines marijuana as including all Cannabis cultivated 
strains. Different marijuana samples derived from various cultivated 
strains may have very different chemical constituents including 
delta\9\ -THC and other cannabinoids (Appendino et al., 2011). As a 
consequence, marijuana products from different strains will have 
different safety, biological, pharmacological, and toxicological 
profiles. Thus, all Cannabis strains cannot be considered together 
because of the varying chemical constituents between strains.
    Marijuana contains numerous naturally occurring constituents 
including cannabinoids. Overall, various Cannabis strains contain more 
than 525 identified natural constituents. Among those constituents, the 
most important ones are the 21 (or 22) carbon terpenoids found in the 
plant, as well as their carboxylic acids, analogues, and transformation 
products, known as cannabinoids (Agurell et al., 1984, 1986; Mechoulam, 
1973; Appendino et al., 2011). Thus far, more than 100 compounds 
classified as cannabinoids have been characterized (ElSohly and Slade, 
2005; Radwan, ElSohly et al., 2009; Appendino et al. 2011).
    Cannabinoids primarily exist in Cannabis, and published data 
suggest that most major cannabinoid compounds occurring naturally have 
been chemically identified. New and minor cannabinoids and other new 
compounds are continuously being characterized (Pollastro et al., 
2011). So far, only two cannabinoids (cannabigerol and its 
corresponding acid) have been obtained from a non-Cannabis source. A 
South African Helichrysum (H umbraculigerum) accumulates these 
compounds (Appendino et al. 2011).
    Among the cannabinoids found in marijuana, delta\9\-THC (alternate 
name delta\1\-THC) and delta-8-tetrahydrocannibinol (delta\8\-THC, 
alternate name delta\6\-THC) produce marijuana's characteristic 
psychoactive effects. Because delta\9\-THC is more abundant than 
delta\8\-THC, marijuana's psychoactivity is largely attributed to the 
former. Only a few varieties of marijuana analyzed contain delta\8\-THC 
at significant amounts (Hively et al., 1966). Delta\9\-THC is an 
optically active resinous substance, insoluble in water, and extremely 
lipid soluble. Chemically, delta\9\-THC is (6aR-trans)-6a,7,8,10a-
tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo-[b,d]pyran-l-ol, or (-)-
delta\9\-(trans)-tetrahydrocannabinol. The (-)-trans isomer of 
delta\9\-THC is pharmacologically 6-100 times more potent than the (+)-
trans isomer (Dewey et al., 1984).
    Other cannabinoids present in marijuana include CBD, CBC, and CBN. 
CBD, a major cannabinoid of marijuana, is insoluble in water and lipid-
soluble. Chemically, CBD is 2-[(1R,6R)-3-methyl-6-prop-1-en-2-
ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol. CBD does not have 
cannabinol-like psychoactivity (Adams and Martin, 1996; Agurell et al., 
1984, 1986; Hollister, 1986). CBC is another major cannabinoid in 
marijuana. Chemically, CBC is 2-methyl-2-(4-methylpent-3-enyl)-7-
pentyl-5-chromenol. CBN, a major metabolite of delta\9\-THC, is also a 
minor naturally-occurring cannabinoid with weak psychoactivity. 
Chemically, CBN is 6,6,9-trimethyl-3-pentyl-benzo[c]chromen-1-ol.
    Different marijuana samples derived from various cultivated strains 
may differ in chemical constituents including delta\9\-THC and other 
cannabinoids (Appendino et al. 2011). As a consequence, marijuana 
products from different strains may have different safety, biological, 
pharmacological, and toxicological profiles. In addition to differences 
between cultivated strains, the concentration of delta\9\-THC and other 
cannabinoids in marijuana may vary with growing conditions and 
processing after harvest. In addition to genetic differences among 
Cannabis species, the plant parts collected--for example, flowers, 
leaves, and stems--can influence marijuana's potency, quality, and 
purity (Adams and Martin, 1996; Agurell et al., 1984; Mechoulam, 1973). 
All these variations produce marijuana with potencies, as indicated by 
cannabinoid content, on average from as low as 1-2 percent to as high 
as 17 percent.
    Overall, these variations in the concentrations of cannabinoids and 
other chemical constituents in marijuana complicate the interpretation 
of clinical data using marijuana. The lack of consistent concentrations 
of delta\9\-THC and other substances in marijuana from diverse sources 
makes interpreting the effect of different marijuana constituents 
difficult. In addition to different cannabinoid concentrations having 
different pharmacological and toxicological [middot]profiles, the non-
cannabinoid components in marijuana, such as other terpenoids and 
flavonoids, might also contribute to the overall pharmacological and 
toxicological profiles of various marijuana strains and products 
derived from those strains.
    The term marijuana is often used to refer to a mixture of the dried 
flowering tops and leaves from Cannabis. Marijuana in this limiting 
definition is one of three major derivatives sold as separate illicit 
products, which also include hashish and hash oil. According to the 
DEA, Cannabis saliva is the primary species of Cannabis currently 
marketed illegally in the United States.
    Marijuana can vary in cannabinoid content and potency (Agurell et 
al., 1984, 1986; Mechoulam 1973, Cascini et al., 2012). In the usual 
mixture of leaves and stems distributed as marijuana, the concentration 
of delta\9\-THC averages over 12 percent by weight. However, specially 
grown and selected marijuana can contain 15 percent or greater 
delta\9\-THC (Appendino et al. 2011). Thus, a 1-gram marijuana 
cigarette might contain

[[Page 53778]]

delta\9\-THC in a range from as little as 3 milligrams to as much as 
150 milligrams or more. Additionally, a recent systematic review and 
meta-analysis found that marijuana's delta\9\-THC content has increased 
significantly from 1979-2009 (Cascini et al., 2012). In addition to 
smoking marijuana, individuals ingest marijuana through food made with 
butter or oil infused with marijuana and its extracts. These marijuana 
butters are generally made by adding marijuana to butter and heating 
it. The resultant butter is then used to cook a variety of foods. There 
are no published studies measuring the concentrations of cannabinoids 
in these marijuana food products.
    Hashish consists of the dried and compressed cannabinoid-rich 
resinous material of Cannabis and comes in a variety of forms (e.g. 
balls and cakes). Individuals may break off pieces, place it into a 
pipe and smoke it. DEA reports that cannabinoid content in hashish 
averages six percent (DEA, 2005). With the development and cultivation 
of more high potency Cannabis strains, the average cannabinoid content 
in hashish will likely increase.
    Hash oil is produced by solvent extraction of the cannabinoids from 
plant material. The extract's color and odor vary, depending on the 
solvent type used. Hash oil is a viscous brown- or amber-colored liquid 
containing approximately 50 percent cannabinoids. One or two drops of 
the liquid placed on a cigarette purportedly produce the equivalent of 
a single[middot] marijuana cigarette (DEA, 2005).
    In conclusion, marijuana has hundreds of cultivars containing 
variable concentrations of delta\9\-THC, cannabinoids, and other 
compounds. Thus, marijuana is not a single chemical with a consistent 
and reproducible chemical profile or predictable and consistent 
clinical effects. A guidance for industry, entitled Botanical Drug 
Products,\8\ provides information on the approval of botanical drug 
products. To investigate marijuana for medical use in a manner 
acceptable as support for marketing approval under an NDA, clinical 
studies under an IND of consistent batches of a particular marijuana 
product for particular disease indications should be conducted. In 
addition, information and data regarding the marijuana product's 
chemistry, manufacturing and control, pharmacology, and animal 
toxicology data, among others must be provided and meet the 
requirements for new drug approval (See 21 CFR 314.50).
---------------------------------------------------------------------------

    \8\ This guidance is available on the Internet at http://www.fda.gov/Drugs/default.htm under Guidance (Drugs).
---------------------------------------------------------------------------

Human Pharmacokinetics

    Marijuana can be taken in a variety of formulations by multiple 
routes of administration. Individuals smoke marijuana as a cigarette, 
weighing between 0.5 and 1.0 gram, or in a pipe. Additionally, 
individuals take marijuana orally in foods or as an extract in ethanol 
or other solvents. More recently, access to vaporizers provides another 
means for abusers to inhale marijuana,
    The absorption, metabolism, and pharmacokinetic profile of 
delta\9\-THC, cannabinoids, and drug products containing delta\9\-THC 
vary with route of administratfon and formulation (Adams and Martin, 
1996; Agurell et al., 1984, 1986).

Pharmacokinetics of Smoked Administration of Cannabinoids

    Characterization of the pharmacokinetics of delta\9\-THC and other 
cannabinoids from smoked marijuana is difficult because a subject's 
smoking behavior during an experiment varies (Agurell et al., 1986; 
Heming et al., 1986; Huestis et al., 1992a). Each puff delivers a 
discrete dose of delta\9\-THC. An experienced marijuana smoker can 
titrate and regulate the dose to obtain the desired acute psychological 
effects and minimize undesired effects. For example, under naturalistic 
conditions, users hold marijuana smoke in their lungs for an extended 
period of time which causes prolonged absorption and increases 
psychoactive effects. The effect of experience in the psychological 
response may explain why delta\9\-THC venous blood levels correlate 
poorly with intensity of effects and intoxication level (Agurell et al. 
1986; Barnett et al. 1985; Huestis et al., 1992a). Puff and inhalation 
volumes should be recorded in studies as the concentration (dose) of 
cannabinoids administered can vary at different stages of smoking.
    Smoked marijuana results in absorption of delta\9\-THC in the form 
of an aerosol within seconds. Psychoactive effects occur immediately 
following absorption, with mental and behavioral effects measurable for 
up to 6 hours (Grotenhermen, 2003; Hollister 1986, 1988). Delta\9\-THC 
is delivered to the brain rapidly and efficiently as expected of a very 
lipid soluble drug.
    The bioavailability of the delta\9\ -THC, from marijuana in a 
cigarette or pipe, can range from 1 to 24 percent with the fraction 
absorbed rarely exceeding 10 to 20 percent (Agurell et al.,1986; 
Hollister, 1988). The relatively low and variable bioavailability 
results from significant loss of delta\9\-THC in side-stream smoke, 
variation in individual smoking behaviors, cannabinoid pyrolysis, 
incomplete absorption of inhaled smoke, and metabolism in the lungs. An 
individual's experience and technique with smoking marijuana also 
determines the dose absorbed (Heming et al., 1986; Johansson et al., 
1989). After smoking, delta\9\-THC venous levels decline precipitously 
within minutes, and continue to go down to about 5 to 10 percent of the 
peak level within an hour (Agurell et al., 1986, Huestis et al.,1992a, 
1992b).

Pharmacokinetics for Oral Administration of Cannabinoids

    After oral administration of delta\9\-THC or marijuana, the onset 
of effects starts within 30 to 90 minutes, reaches its peak after 2 to 
3 hours and then remains for 4 to 12 hours (Grotenhermen, 2003; Adams 
and Martin, 1996; Agurell et al., 1984, 1986). Due to the delay in 
onset of effects, users have difficulty in titrating oral delta\9\-THC 
doses compared to smoking marijuana. Oral bioavailability of delta\9\-
THC, whether pure or in marijuana, is low and extremely variable, 
ranging between 5 and 20 percent (Agurell et al., 1984, 1986). 
Following oral administration of radioactive-labeled delta\9\-THC, 
delta\9\-THC plasma levels are low relative to plasma levels after 
smoking or intravenous administration. Inter- and intra-subject 
variability occurs even with repeated dosing under controlled 
conditions. The low and variable oral bioavailability of delta\9\-THC 
is a consequence of its first-pass hepatic elimination from blood and 
erratic absorption from stomach and bowel.

Cannabinoid Metabolism and Excretion

    Cannabinoid metabolism is complex. Delta\9\-THC is metabolized via 
microsomal hydroxylation to both active and inactive metabolites 
(Lemberger et al., 1970, 1972a, 1972b; Agurell et al., 1986; Hollister, 
1988). The primary active metabolite of delta\9\-THC following oral 
ingestion is 11-hydroxy-delta\9\-THC. This metabolite is approximately 
equipotent to delta\9\-THC in producing marijuana-like subjective 
effects (Agurell et al., 1986, Lemberger and Rubin, 1975). After oral 
administration, metabolite levels may exceed that of delta\9\-THC and 
thus contribute greatly to the pharmacological effects of oral 
delta\9\-THC or marijuana.
    Plasma clearance of delta\9\-THC approximates hepatic blood flow at 
about 950 ml/min or greater. The rapid disappearance of delta\9\-THC 
from blood

[[Page 53779]]

is largely due to redistribution to other tissues in the body, rather 
than to metabolism (Agurell et al., 1984, 1986). Metabolism in most 
tissues is relatively slow or absent. Slow release of delta\9\-THC and 
other cannabinoids from tissues and subsequent metabolism results in a 
long elimination half-life. The terminal half-life of delta\9\-THC 
ranges from approximately 20 hours to as long as 10 to13 days, though 
reported estimates vary as expected with any slowly cleared substance 
and the use of assays with variable sensitivities (Hunt and Jones, 
1980). Lemberger et al. (1970) determined the half-life of delta\9\-THC 
to range from 23 to 28 hours in heavy marijuana users to 60 to 70 hours 
in naive users. In addition to 11-hydroxy-delta\9\-THC, some inactive 
carboxy metabolites have terminal half-lives of 50 hours to 6 days or 
more. The latter substances serve as long-term markers in urine tests 
for earlier marijuana use.
    The majority of the absorbed delta\9\-THC dose is eliminated in 
feces, and about 33 percent in urine. Delta\9\-THC enters enterohepatic 
circulation and undergoes hydroxylation and oxidation to 11-nor-9-
carboxy-delta\9\-THC. The glucuronide is excreted as the major urine 
metabolite along with about 18 non-conjugated metabolites. Frequent and 
infrequent marijuana users metabolize delta\9\-THC similarly (Agurell 
et al., 1986).

Status of Research Into the Medical Uses for Marijuana

    State-level public initiatives, including laws and referenda in 
support of the medical use of marijuana, have generated interest in the 
medical community and the need for high quality clinical investigation 
as well as comprehensive safety and effectiveness data. In order to 
address the need for high quality clinical investigations, the state of 
California established the Center for Medicinal Cannabis Research 
(CMCR, www.cmcr.ucsd.edu) in 2000 ``in response to scientific evidence 
for therapeutic possibilities of cannabis \9\ and local legislative 
initiatives in favor of compassionate use'' (Grant, 2005). State 
legislation establishing the CMCR called for high quality medical 
research that would ``enhance understanding of the efficacy and adverse 
effects of marijuana as a pharmacological agent,'' but stressed the 
project ``should not be construed as encouraging or sanctioning the 
social or recreational use of marijuana.'' The CMCR funded many of the 
published studies on marijuana's potential use for treating multiple 
sclerosis, neuropathic pain, appetite suppression and cachexia. 
However, aside from the data produced by CMCR, no state-level medical 
marijuana laws have produced scientific data on marijuana's safety and 
effectiveness.
---------------------------------------------------------------------------

    \9\ In this quotation the term cannabis is interchangeable with 
marijuana.
---------------------------------------------------------------------------

    FDA approves medical use of a drug following a submission and 
review of an NDA or BLA. The FDA has not approved any drug product 
containing marijuana for marketing. Even so, results of small clinical 
exploratory studies have been published in the current medical 
literature. Many studies describe human research with marijuana in the 
United States under FDA-regulated IND applications.
    However, FDA approval of an NDA is not the only means through which 
a drug can have a currently accepted medical use in treatment in the 
United States. In general, a drug may have a ``currently accepted 
medical use'' in treatment in the United States if the drug meets a 
five-part test. Established case law (Alliance for Cannabis 
Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994)) upheld the 
Administrator of DEA's application of the five-part test to determine 
whether a drug has a ``currently accepted medical use.'' The following 
describes the five elements that characterize ``currently accepted 
medical use'' for a drug: \10\
---------------------------------------------------------------------------

    \10\ 57 FR I 0499, 10504-06 (March 26, 1992).

---------------------------------------------------------------------------
i. the drug's chemistry must be known and reproducible

    ``The substance's chemistry must be scientifically established to 
permit it to be reproduced into dosages which can be standardized. The 
listing of the substance in a current edition of one of the official 
compendia, as defined by section 201 G) of the Food, Drug and Cosmetic 
Act, 21 U.S.C. 321G), is sufficient to meet this requirement.''

ii. there must be adequate safety studies

    ``There must be adequate pharmacological and toxicological studies, 
done by all methods reasonably applicable, on the basis of which it 
could fairly and responsibly be concluded, by experts qualified by 
scientific training and experience to evaluate the safety and 
effectiveness of drugs, that the substance is safe for treating a 
specific, recognized disorder.''

iii. there must be adequate and well-controlled studies proving 
efficacy

    ``There must be adequate, well-controlled, well-designed, well-
conducted, and well-documented studies, including clinical 
investigations, by experts qualified by scientific training and 
experience to evaluate the safety and effectiveness of drugs, on the 
basis of which it could be fairly and responsibly concluded by such 
experts that the substance will have the intended effect in treating a 
specific, recognized disorder.''

iv. the drug must be accepted by qualified experts

    ``The drug has a New Drug Application (NDA) approved by the Food 
and Drug Administration, pursuant to the Food, Drug and Cosmetic Act, 
21 U.S.C. 355. Or, a consensus of the national community of experts, 
qualified by scientific training and experience to evaluate the safety 
and effectiveness of drugs, accepts the safety and effectiveness of the 
substance for use in treating a specific, recognized disorder. A 
material conflict of opinion among experts precludes a finding of 
consensus.'' and

v. the scientific evidence must be widely available

    ``In the absence of NDA approval, information concerning the 
chemistry, pharmacology, toxicology, and effectiveness of the substance 
must be reported, published, or otherwise widely available, in 
sufficient detail to permit experts, qualified by scientific training 
and experience to evaluate the safety and effectiveness of drugs, to 
fairly and responsibly conclude the substance is safe and effective for 
use in treating a specific, recognized disorder.''

    Marijuana does not meet any of the five elements necessary for a 
drug to have a ``currently accepted medical use.''
    Firstly, the chemistry of marijuana, as defined in the petition, is 
not reproducible in terms of creating a standardized dose. The petition 
defines marijuana as including all Cannabis cultivated strains. 
Different marijuana samples derived from various cultivated strains may 
have very different chemical constituents including delta9-THC and 
other cannabinoids (Appendino et al., 2011). As a consequence, 
marijuana products from different strains will have different safety, 
biological, pharmacological, and toxicological profiles. Thus, when 
considering all Cannabis strains together, because of the varying 
chemical constituents, reproducing consistent standardized doses is not 
possible. Additionally, smoking marijuana currently has not been shown 
to allow delivery of consistent and reproducible doses. However, if a 
specific Cannabis strain is grown and processed under strictly 
controlled conditions, the plant chemistry may be kept consistent 
enough to produce reproducible and standardized doses.

[[Page 53780]]

    As to the second and third criteria; there are neither adequate 
safety studies nor adequate and well-controlled studies proving 
marijuana's efficacy. To support the petitioners' assertion that 
marijuana has accepted medical use, the petitioners cite the American 
Medical Association's (AMA) 2009 report entitled ``Use of Cannabis for 
Medicinal Purposes.'' The petitioners claim the AMA report is evidence 
the AMA accepts marijuana's safety and efficacy. However, the 2009 AMA 
report clarifies that the report ``should not be viewed as an 
endorsement of state-based medical cannabis programs, the legalization 
of marijuana, or that scientific evidence on the therapeutic use of 
cannabis meets the same and current standards for a prescription drug 
product.'' \11\
---------------------------------------------------------------------------

    \11\ In this quotation the term cannabis is used interchangeably 
for marijuana.
---------------------------------------------------------------------------

    Currently, no published studies conducted with marijuana meet the 
criteria of an adequate and well-controlled efficacy study. The 
criteria for an adequate and well-controlled study for purposes of 
determining the safety and efficacy of a human drug are defined under 
the Code of Federal Regulations (CFR) in 21 CFR 314.126. In order to 
assess this element, FDA conducted a review of clinical studies 
published and available in the public domain before February, 2013. 
Studies were identified through a search of PubMed \12\ for articles 
published from inception to February 2013, for randomized controlled 
trials using marijuana to assess marijuana's efficacy in any 
therapeutic indication. Additionally, the review included studies 
identified through a search of bibliographic references in relevant 
systematic reviews and identified studies presenting original research 
in any language. Selected studies needed to be placebo-controlled and 
double-blinded. Additionally, studies needed to encompass administered 
marijuana plant material. There was no requirement for any specific 
route of administration, nor any age limits on study subjects. Studies 
were excluded that used placebo marijuana supplemented by the addition 
of specific amounts of THC or other cannabinoids. Additionally, studies 
administering marijuana plant extracts were excluded.
---------------------------------------------------------------------------

    \12\ The following search strategy was used, ``(cannabis OR 
marijuana) AND (therapeutic use OR therapy) AND (RCT OR randomized 
controlled trial OR ``systematic review'' OR clinical trial OR 
clinical trials) NOT (``marijuana abuse''[Mesh] OR addictive 
behavior OR substance related disorders).''
---------------------------------------------------------------------------

    The PubMed search yielded a total of 566 abstracts of scientific 
articles. Of these abstracts, a full-text review was conducted with 85 
papers to assess eligibility. Of the studies identified through the 
search of the references and the 566 abstracts from the PubMed search, 
only 11 studies met all the criteria for selection (Abrams et al., 
2007; Corey-Bloom et al., 2012; Crawford and Merritt, 1979; Ellis et 
al., 2009; Haney et al., 2005; Haney et al., 2007; Merritt et al., 
1980; Tashkin et al., 1974; Ware et al., 2010; Wilsey et al., 2008; 
Wilsey et al., 2013). These 11 studies were published between 197 4 and 
2013. Ten of these studies were conducted in the United States and one 
study was conducted in Canada. The identified studies examine the 
effects of smoked and vaporized marijuana for the indications of 
chronic neuropathic pain, spasticity related to Multiple Sclerosis 
(MS), appetite stimulation in human immunodeficiency virus (HIV) 
patients, glaucoma, and asthma. All studies used adult subjects.
    The 11 identified studies were individually evaluated to determine 
if they successfully meet accepted scientific standards. Specifically, 
they were evaluated on study design including subject selection 
criteria, sample size, blinding techniques, dosing paradigms, outcome 
measures, and the statistical analysis of the results. The analysis 
relied on published studies, thus information available about 
protocols, procedures, and results were limited to documents published 
and widely available in the public domain. The review found that all 11 
studies that examined effects of inhaled marijuana do not currently 
prove efficacy of marijuana in any therapeutic indication based on a 
number of limitations in their study design; however, they may be 
considered proof of concept studies. Proof of concept studies provide 
preliminary evidence on a proposed hypothesis involving a drug's 
effect. For drugs under development, the effect often relates to a 
short-term clinical outcome being investigated. Proof of concept 
studies often serve as the link between preclinical studies and dose 
ranging clinical studies. Thus, proof of concept studies generally are 
not sufficient to prove efficacy of a drug because they provide only 
preliminary information about the effects of a drug.
    In addition to the lack of published adequate and well-controlled 
efficacy studies proving efficacy, the criteria for adequate safety 
studies has also not been met. Importantly, in its discussion of the 
five-part test used to determine whether a drug has a ``currently 
accepted medical use,'' DEA said, ``No drug can be considered safe in 
the abstract. Safety has meaning only when judged against the intended 
use of the drug, its known effectiveness, its known and potential 
risks, the severity of the illness to be treated, and the availability 
of alternative remedies'' (57 FR 10504). When determining whether a 
drug product is safe and effective for any indication, FDA performs an 
extensive risk-benefit analysis to determine whether the risks posed by 
the drug product's side effects are outweighed by the drug product's 
potential benefits for a particular indication. Thus, contrary to the 
petitioner's assertion that marijuana has accepted safety, in the 
absence of an accepted therapeutic indication which can be weighed 
against marijuana's risks, marijuana does not satisfy the element for 
having adequate safety studies such that experts may conclude that it 
is safe for treating a specific, recognized disorder.
    The fourth of the five elements for determining ``currently 
accepted medical use'' requires that the national community of experts, 
qualified by scientific training and experience to evaluate the safety 
and effectiveness of drugs, accepts the safety and effectiveness of the 
substance for use in treating a specific, recognized disorder. A 
material conflict of opinion among experts precludes a finding of 
consensus. Medical practitioners who are not experts in evaluating 
drugs are not qualified to determine whether a drug is generally 
recognized as safe and effective or meets NDA requirements (57 FR 
10499-10505).
    There is no evidence that there is a consensus among qualified 
experts that marijuana is safe and effective for use in treating a 
specific, recognized disorder. As discussed above, there are not 
adequate scientific studies that show marijuana is safe and effective 
in treating a specific, recognized disorder. In addition, there is no 
evidence that a consensus of qualified experts have accepted the safety 
and effectiveness of marijuana for use in treating a specific, 
recognized disorder. Although medical practitioners are not qualified 
by scientific training and experience to evaluate the safety and 
effectiveness of drugs, we also note that the AMA's report, entitled 
``Use of Cannabis for Medicinal Purposes,'' does not accept that 
marijuana currently has accepted medical use. Furthermore, based on the 
above definition of a ``qualified expert'', who is an individual 
qualified by scientific training and experience to evaluate the safety 
and effectiveness of a drug, state-level medical marijuana laws do not 
provide evidence of a consensus among qualified experts that marijuana 
is safe and effective for use in treating a specific, recognized 
disorder.

[[Page 53781]]

    As to the fifth part of the test, which requires that information 
concerning the chemistry, pharmacology, toxicology, and effectiveness 
of marijuana to be reported in sufficient detail, the scientific 
evidence regarding all of these aspects is not available in sufficient 
detail to allow adequate scientific scrutiny. Specifically, the 
scientific evidence regarding marijuana's chemistry in terms of a 
specific Cannabis strain that could produce standardized and 
reproducible doses is not currently available.
    Alternately, a drug can be considered to have a ``currently 
accepted medical use with severe restrictions'' (21 U.S.C. 
812(b)(2)(B)), as allowed under the stipulations for a Schedule II 
drug. Yet, as stated above, currently marijuana does not have any 
accepted medical use, even under conditions where its use is severely 
restricted.
    In conclusion, to date, research on marijuana's medical use has not 
progressed to the point where marijuana is considered to have a 
``currently accepted medical use'' or a ``currently accepted medical 
use with severe restrictions.''

4. Its History and Current Pattern of Abuse

    Under the fourth factor, the Secretary must consider the history 
and current pattern of marijuana abuse. A variety of sources provide 
data necessary to assess abuse patterns and trends of marijuana. The 
data indicators of marijuana use include the NSDUH, MTF, DAWN, and 
TEDS. The following briefly describes each data source, and summarizes 
the data from each source.

National Survey on Drug Use and Health (NSDUH) 13
---------------------------------------------------------------------------

    \13\ NSDUH provides national estimates of the prevalence and 
incidence of illicit drug, alcohol and tobacco use in the United 
States. NSDUH is an annual study conducted by SAMHSA. Prior to 2002, 
the database was known as the National Household Survey on Drug 
Abuse (NHSDA). NSDUH utilizes a nationally representative sample of 
United States civilian, non-institutionalized population aged 12 
years and older. The survey excludes homeless people who do not use 
shelters, active military personnel, and residents of institutional 
group quarters such as jails and hospitals. The survey identifies 
whether an individual used a drug within a specific time period, but 
does not identify the amount of the drug used on each occasion. 
NSDUH defines ``current use'' as having used the substance within 
the month prior to the study.
---------------------------------------------------------------------------

    According to 2012 NSDUH \14\ data, the most recent year with 
complete data, the use of illicit drugs, including marijuana, is 
increasing. The 2012 NSDUH estimates that 23.9 million individuals over 
12 years of age (9.2 percent of the U.S. population) currently use 
illicit drugs, which is an increase of 4.8 million individuals from 
2004 when 19.1 million individuals (7.9 percent of the U.S. population) 
were current illicit drug users. NSDUH reports marijuana as the most 
commonly used illicit drug, with 18.9 million individuals (7.3 percent 
of the U.S. population) currently using marijuana in 2012. This 
represents an increase of 4.3 million individuals from 2004, when 14.6 
million individuals (6.1 percent of the U.S. population) were current 
marijuana users.
---------------------------------------------------------------------------

    \14\ 2013; http://www.samhsa.gov/data/NSDUH.aspx.
---------------------------------------------------------------------------

    The majority of individuals who try marijuana at least once in 
their lifetime do not currently use marijuana. The 2012 NSDUH estimates 
that 111.2 million individuals (42.8 percent of the U.S. population) 
have used marijuana at least once in their lifetime. Based on this 
estimate and the estimate for the number of individuals currently using 
marijuana, approximately 16.9 percent of those who have tried marijuana 
at least once in their lifetime currently use marijuana; conversely, 
83.1 percent do not currently use marijuana. In terms of the frequency 
of marijuana use, an estimated 40.3 percent of individuals who used 
marijuana in the past month used marijuana on 20 or more days within 
the past month. This amount corresponds to an estimated 7.6 million 
individuals who used marijuana on a daily or almost daily basis.
    Some characteristics of marijuana users are related to age, gender, 
and criminal justice system involvement. In observing use among 
different age cohorts, the majority of individuals who currently use 
marijuana are shown to be between the ages of 18-25, with 18.7 percent 
of this age group currently using marijuana. In the 26 and older age 
group, 5.3 percent of individuals currently use marijuana. 
Additionally, in individuals aged 12 years and older, males reported 
more current marijuana use than females.
    NSDUH includes a series of questions aimed at assessing the 
prevalence of dependence and abuse of different substances in the past 
12 months.\15\ In 2012, marijuana was the most common illicit drug 
reported by individuals with past year dependence or abuse. An 
estimated 4.3 million individuals meet the NSDUH criteria for marijuana 
dependence or abuse in 2012. The estimated rates and number of 
individuals with marijuana dependence or abuse has remained similar 
from 2002 to 2012. In addition to data on dependence and abuse, NSDUH 
includes questions aimed at assessing treatment for a substance use 
problem.\16\ In 2012, an estimated 957,000 persons received treatment 
for marijuana use during their most recent treatment in the year prior 
to the survey.
---------------------------------------------------------------------------

    \15\ ``These questions are used to classify persons as dependent 
on or abusing specific substances based on criteria specified in the 
Diagnostic and Statistical Manual of Mental Disorder, 4th edition 
(DSM-IV). The questions related to dependence ask about health and 
emotional problems associated with substance use, unsuccessful 
attempts to cut down on use, tolerance, withdrawal, reducing other 
activities to use substances, spending a lot time engaging in 
activities related to substance use, or using the substance in 
greater quantities or for longer time than intended. The questions 
on abuse ask about problems at work, home, and school; problems with 
family or friends; physical danger; and trouble with the law due to 
substance use. Dependence is considered to be a more severe 
substance use problem than abuse because it involves the 
psychological and physiological effects of tolerance and 
withdrawal.'' (NSDUH, 2013).
    \16\ ``Estimates . . . refer to treatment received for illicit 
drug or alcohol use, or for medical problems associated with the use 
of illicit drugs or alcohol. This includes treatment received in the 
past year at any location, such as a hospital (inpatient), 
rehabilitation facility (outpatient or inpatient), mental health 
center, emergency room, private doctor's office, prison or jail, or 
a self-help group, such as Alcoholics Anonymous or Narcotics 
Anonymous.'' (NSDUH, 2013).
---------------------------------------------------------------------------

Monitoring the Future (MTF) 17
---------------------------------------------------------------------------

    \17\ Monitoring the Future is a national survey that tracks drug 
use prevalence and trends among adolescents in the United States. 
MTF is reported annually by the Institute for Social Research at the 
University of Michigan under a grant from NIDA. Every spring, MTF 
surveys 8th, 10th, and 12th graders in randomly selected U.S. 
schools. MTF has been conducted since 1975 for 12th graders and 
since 1991 for 8th and 10th graders. The MTF survey presents data in 
terms of prevalence among the sample interviewed. For 2012, the 
latest year with complete data, the sample sizes were 15,200--8th 
graders; 13,300--10th graders; and 13,200--12th graders. In all, a 
total of about 41,700 students of 389 schools participated in the 
2013 MTF.
---------------------------------------------------------------------------

    According to MTF,\18\ rates of marijuana and illicit drug use 
declined for all three grades from 2005 through 2007. However, starting 
around 2008, rates of annual use of illicit drugs and marijuana 
increased through 2013 for all three grades. Marijuana remained the 
most widely used illicit drug during all time periods. The prevalence 
of annual and past month marijuana use in 10th and 12th graders in 2013 
is greater than in 2005. Table 1 lists the lifetime, annual, and 
monthly prevalence rates of various drugs for 8th, 10th, and 12th 
graders in 2013.
---------------------------------------------------------------------------

    \18\ 2013; http://www.monitoringthefuture.org/index.html.

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[[Page 53782]]

[GRAPHIC] [TIFF OMITTED] TP12AU16.005

''-->Drug Abuse Warning Network (DAWN) \19\
---------------------------------------------------------------------------

    \19\ DAWN is a national probability survey of the U.S. hospitals 
with ED designed to obtain information on drug related ED visits. 
DAWN is sponsored by SAMHSA. The DAWN system provides information on 
the health consequences of drug use in the United States, as 
manifested by drug-related visits to ED. The ED data from a 
representative sample of hospital emergency departments are weighted 
to produce national estimates. Importantly, DAWN data and estimates, 
starting in 2004, are not comparable to those for prior years 
because of vast changes in the methodology used to collect the data. 
Furthermore, estimates for 2004 are the first to be based on a 
redesigned sample of hospitals, which ended in 2011.
---------------------------------------------------------------------------

    Importantly, many factors can influence the estimates of ED visits, 
including trends in overall use of a substance as well as trends in the 
reasons for ED usage. For instance, some drug users may visit EDs for 
life-threatening issues while others may visit to seek care for 
detoxification because they needed certification before entering 
treatment. Additionally, DAWN data do not distinguish the drug 
responsible for the ED visit from other drugs that may have been used 
concomitantly. As stated in a DAWN report, ``Since marijuana/hashish is 
frequently present in combination with other drugs, the reason for the 
ED visit may be more relevant to the other drug(s) involved in the 
episode.''
    For 2011, DAWN \20\ estimates a total of 5,067,374 (95 percent 
confidence interval [CI]: 4,616,753 to 5,517,995) drug-related ED 
visits from the entire United States. Of these, approximately 2,462,948 
([CI]: 2,112,868 to 2,813,028) visits involved drug misuse or abuse.
---------------------------------------------------------------------------

    \20\ 2011; http://www.samhsa.gov/data/dawn.aspx.
---------------------------------------------------------------------------

    During the same period, DAWN estimates that 1,252,500 (CI: 976,169 
to 1,528,831) drug related ED visits involved illicit drugs. Thus, over 
half of all drug-related ED visits associated with drug misuse or abuse 
involved an illicit drug. For ED visits involving illicit drugs, 56.3 
percent involved multiple drugs while 43.7 percent involved a single 
drug.
    Marijuana was involved in 455,668 ED visits (CI: 370,995 to 
540,340), while cocaine was involved in 505,224 (CI: 324,262 to 
686,185) ED visits, heroin was involved in 258,482 (CI: 205,046 to 
311,918) ED visits and stimulants including amphetamine and 
methamphetamine were involved in 159,840 (CI: 100,199 to 219,481) ED 
visits. Other illicit drugs, such as PCP, MDMA, GHB and LSD were much 
less frequently associated with ED visits. The number of ED visits 
involving marijuana has increased by 62 percent since 2004.
    Marijuana-related ED visits were most frequent among young adults 
and minors. Individuals under the age of 18 accounted for 13.2 percent 
of these marijuana-related visits, whereas this age group accounted for 
approximately 1.2 percent of ED visits involving cocaine, and less than 
1 percent of ED visits involving heroin. However, the age group with 
the most marijuana-related ED visits was between 25 and 29 years old. 
Yet, because populations differ between age groups, a standardized 
measure for population size is useful to make comparisons. For 
marijuana, the rates of ED visits per 100,000 population were highest 
for patients aged 18 to 20 (443.8 ED visits per 100,000) and for 
patients aged 21 to 24 (446.9 ED visits per 100,000).
    While DAWN provides estimates for ED visits associated with the use 
of medical marijuana for 2009-2011, the validity of these estimates is 
questionable. Because the drug is not approved by the FDA, reporting 
medical marijuana may be inconsistent and reliant on a number of 
factors including whether the patient self-reports the marijuana use as 
medicinal, how the treating health care provider records the marijuana 
use, and lastly how the SAMHSA coder interprets the report. All of 
these aspects will vary greatly between states with medical marijuana 
laws and states without medical marijuana laws. Thus, even though 
estimates are reported for medical marijuana related ED visits, medical 
marijuana estimates cannot be assessed with any acceptable accuracy at 
this time, as FDA has not approved marijuana treatment of any medical 
condition. These data show the difficulty in evaluating abuse of a 
product that is not currently approved by FDA, but authorized for 
medical use, albeit inconsistently, at the state level. Thus, we 
believe the likelihood of the treating health care provider or SAMHSA 
coder attributing the ED visit to ``medical marijuana'' versus 
``marijuana'' to be very low. Overall, the available data are 
inadequate to

[[Page 53783]]

characterize its abuse at the community level.

Treatment Episode Data Set (TEDS) \21\
---------------------------------------------------------------------------

    \21\ The TEDS system is part of SAMHSA's Drug and Alcohol 
Services Information System (Office of Applied Science, SAMHSA). The 
TEDS report presents information on the demographic and substance 
use characteristics of the 1.8 million annual admissions to 
treatment for alcohol and drug abuse in facilities that report to 
individual state administrative data systems. Specifically, TEDS 
includes facilities licensed or certified by the states to provide 
substance abuse treatment and is required by the states to provide 
TEDS client-level data. Facilities that report TEDS data are those 
receiving State alcohol and drug agency funds for the provision of 
alcohol and drug treatment services. Since TEDS is based only on 
reports from these facilities, TEDS data do not represent the total 
national demand for substance abuse treatment or the prevalence of 
substance abuse in the general population. The primary goal for TEDS 
is to monitor the characteristics of treatment episodes for 
substance abusers. Importantly, TEDS is an admissions-based system, 
where admittance to treatment is counted as an anonymous tally. For 
instance, a given individual who is admitted to treatment twice 
within a given year would be counted as two admissions. The most 
recent year with complete data is 2011.
---------------------------------------------------------------------------

    Primary marijuana abuse accounted for 18.1 percent of all 2011 TEDS 
\22\ admissions. Individuals admitted for primary marijuana abuse were 
nearly three-quarters (73.4 percent) male, and almost half (45.2 
percent) were white. The average age at admission was 24 years old, and 
31.1 percent of individuals admitted for primary marijuana abuse were 
under the age of 18. The reported frequency of marijuana use was 24.3 
percent reporting daily use. Almost all (96.8 percent) primary 
marijuana users utilized the substance by smoking. Additionally, 92.9 
percent reported using marijuana for the first time before the age of 
18.
---------------------------------------------------------------------------

    \22\ 2011; http://www.samhsa.gov/data/DASIS.aspx?qr=t#TEDS.
---------------------------------------------------------------------------

    An important aspect of TEDS admission data for marijuana is of the 
referral source for treatment. Specifically, primary marijuana 
admissions were less likely than all other admissions to either be 
self-referred or referred by an individual for treatment. Instead, the 
criminal justice system referred more than half (51.6 percent) of 
primary marijuana admissions.
    Since 2003, the percent of admissions for primary marijuana abuse 
increased from 15.5 percent of all admissions in 2003 to 18.l percent 
in 2011. This increase is less than the increase seen for admissions 
for primary opioids other than heroin, which increased from 2.8 percent 
in 2003 to 7.3 percent in 2011. In contrast, the admissions for primary 
cocaine abuse declined from 9.8 percent in 2003 to 2.0 percent in 2011.

5. The Scope, Duration, and Significance of Abuse

    Under the fifth factor, the Secretary must consider the scope, 
duration, and significance of marijuana abuse. According to 2012 data 
from NSDUH and 2013 data from MTF, marijuana remains the most 
extensively used illegal drug in the United States, with 42.8 percent 
of U.S. individuals over age 12 (111.2 million) and 45.5 percent of 
12th graders having used marijuana at least once in their lifetime. 
Although the majority of individuals over age 12 (83.1 percent) who 
have ever used marijuana in their lifetime do not use the drug monthly, 
18.9 million individuals (7.3 percent of the U.S. population) report 
that they used marijuana within the past 30 days. An examination of use 
among various age cohorts through NSDUH demonstrates that monthly use 
occurs primarily among college-aged individuals, with use dropping off 
sharply after age 25. Additionally, NSDUH data show the number of 
individuals reporting past-month use of marijuana has increased by 4.3 
million individuals since 2004. Data from MTF shows that annual 
prevalence of marijuana use declined for all three grades from 2005 
through 2007, then began to rise through 2013. Additionally, in 2013, 
1.1 percent of 8th graders, 4.0 percent of 10th graders, and 6.5 
percent of 12th graders reported daily use of marijuana, defined as use 
on 20 or more days within the past 30 days.
    The 2011 DAWN data show that marijuana use was mentioned in 455,668 
ED visits, which amounts to approximately 36.4 percent of all illicit 
drug-related ED visits.\23\
---------------------------------------------------------------------------

    \23\ Many factors can influence the estimates of ED visits, 
including trends in the reasons for ED usage. For instance, some 
drug users may visit EDs for life-threatening issues while others 
may visit to seek care for detoxification because they needed 
certification before entering treatment. Additionally, DAWN data do 
not distinguish the drug responsible for the ED visit from other 
drugs that may have been used concomitantly. As stated in a DAWN 
report, ``Since marijuana/hashish is frequently present in 
combination with other drugs, the reason for the ED visit may be 
more relevant to the other drug(s) involved in the episode.''
---------------------------------------------------------------------------

    TEDS data for 2011 show that 18.1 percent of all admissions were 
for primary marijuana abuse.\24\ Between 2003 and 2011, there was a 2.6 
percent increase in the number of TEDS admissions for primary marijuana 
use. Approximately 61.5 percent of primary marijuana admissions in 2011 
were for individuals under the age of 25 years.
---------------------------------------------------------------------------

    \24\ An important aspect of TEDS admission data for marijuana is 
of the referral source for treatment. Specifically, primary 
marijuana admissions were less likely than all other admissions to 
either be self-referred or referred by an individual for treatment. 
Instead, the criminal justice system referred more than half (51.6 
percent) of primary marijuana admissions.
---------------------------------------------------------------------------

6. What, if Any, Risk There Is to the Public Health

    Under the sixth factor, the Secretary must consider the risks posed 
to the public health by marijuana. Factors 1, 4, and 5 include a. 
discussion of the risk to the public health as measured by emergency 
room episodes and drug treatment admissions. Additionally, Factor 2 
includes a discussion of marijuana's central nervous system, cognitive, 
cardiovascular, autonomic, respiratory, and immune system effects. 
Factor 6 focuses on the health risks to the individual user in terms of 
the risks from acute and chronic use of marijuana, as well as the 
``gateway hypothesis.''

Risks From Acute Use of Marijuana

    Acute use of marijuana impairs psychomotor performance, including 
complex task performance, which makes operating motor vehicles or heavy 
equipment after using marijuana inadvisable (Ramaekers et al., 2004; 
Ramaekers et al., 2006a). A meta-analysis conducted by Li et al. (2011) 
showed an association between marijuana use by the driver and a 
significantly increased risk of involvement in a car accident. 
Additionally, in a minority of individuals who use marijuana, some 
potential responses include dysphoria and psychological distress, 
including prolonged anxiety reactions (Haney et al., 1999).

Risks From Chronic Use of Marijuana

    A distinctive marijuana withdrawal syndrome following long term or 
chronic use has been identified. The withdrawal syndrome indicates that 
marijuana produces physical dependence that is mild, short-lived, and 
comparable to tobacco withdrawal (Budney et al., 2008). Marijuana 
withdrawal syndrome is described in detail below under Factor 7.
    The following states how the DSM-V (2013) of the American 
Psychiatric Association describes the consequences of Cannabis \25\ 
abuse:
---------------------------------------------------------------------------

    \25\ Cannabis is the term used in the DSM-V to refer to 
marijuana. In the following excerpt the term Cannabis is 
interchangeable for the term marijuana.
---------------------------------------------------------------------------

    Individuals with cannabis use disorder may use cannabis throughout 
the day over a period of months or years, and thus may spend many hours 
a day under the influence. Others may use less frequently, but their 
use causes recurrent problems related to family,

[[Page 53784]]

school, work, or other important activities (e.g., repeated absences at 
work; neglect of family obligations). Periodic cannabis use and 
intoxication can negatively affect behavioral and cognitive functioning 
and thus interfere with optimal performance at work or school, or place 
the individual at increased physical risk when performing activities 
that could be physically hazardous (e.g:, driving a car; playing 
certain sports; performing manual work activities, including operating 
machinery). Arguments with spouses or parents over the use of cannabis 
in the home, or its use in the presence of children, can adversely 
impact family functioning and are common features of those with 
cannabis use disorder. Last, individuals with cannabis use disorder may 
continue using marijuana despite knowledge of physical problems (e.g., 
chronic cough related to smoking) or psychological problems (e.g., 
excessive sedation or exacerbation of other mental health problems) 
associated with its use.

Marijuana as a ``Gateway Drug''

    Kandel (1975) proposed nearly 40 years ago the hypothesis that 
marijuana is a ``gateway drug'' that leads to the use or abuse of other 
illicit drugs. Since that time, epidemiological research explored this 
premise. Overall, research does not support a direct causal 
relationship between regular marijuana use and other illicit drug use. 
The studies examining the gateway hypothesis are limited. First, in 
general, studies recruit individuals influenced by a myriad of social, 
biological, and economic factors that contribute to extensive drug 
abuse (Hall & Lynskey, 2005). Second, most studies that test the 
hypothesis that marijuana use causes abuse of illicit drugs use the 
determinative measure any use of an illicit drug, rather than DSM-5 
criteria for drug abuse or dependence on an illicit drug (DSM-5, 2013). 
Consequently, although an individual who used marijuana may try other 
illicit drugs, the individual may not regularly use drugs, or have a 
diagnosis of drug abuse or dependence.
    Little evidence supports the hypothesis that initiation of 
marijuana use leads to an abuse disorder with other illicit substances. 
For example, one longitudinal study of 708 adolescents demonstrated 
that early onset marijuana use did not lead to problematic drug use 
(Kandel & Chen, 2000). Similarly, Nace et al. (1975) examined Vietnam-
era soldiers who extensively abused marijuana and heroin while they 
were in the military, and found a lack of correlation of a causal 
relationship demonstrating marijuana use leading to heroin addiction. 
Additionally, in another longitudinal study of 2,446 adolescents, 
marijuana dependence was uncommon but when it did occur, the common 
predictors of marijuana dependence were the following: parental death, 
deprived socio-economic status, and baseline illicit drug use other 
than marijuana (von Sydow et al., 2002).
    When examining the association between marijuana and illicit drugs, 
focusing on drug use versus abuse or dependence, different patterns 
emerge. For example, a study examining the possible causal relationship 
of the gateway hypothesis found a correlation between marijuana use in 
adolescents and other illicit drug use in early adulthood and, 
adjusting for age-linked experiences, did not effect this correlation 
(Van Gundy and Rebellon, 2010). However, when examining the association 
in terms of development of drug abuse; age-linked stressors and social 
roles moderated the correlation between marijuana use in adolescents 
and other illicit drug abuse. Similarly, Degenhardt et al. (2009) 
examined the development of drug dependence and found an association 
that did not support the gateway hypothesis. Specifically, drug 
dependence was significantly associated with the use of other illicit 
drugs prior to marijuana use.
    Interestingly, the order of initiation of drug use seems to depend 
on the prevalence of use of each drug, which varies by country. Based 
on the World Health Organization (WHO) World Mental Health Survey that 
includes data from 17 different countries, the order of drug use 
initiation varies by country and relates to prevalence of drug use in 
each country (Degenhardt et al., 2010). Specifically, in the countries 
with the lowest prevalence of marijuana use, use of other illicit drugs 
before marijuana was common. This sequence of initiation is less common 
in countries with higher prevalence of marijuana use. A study of 
9,282[middot]households in the United States found that marijuana use 
often preceded the use of other illicit drugs; however, prior non-
marijuana drug dependence was also frequently correlated with higher 
levels of illicit drug abuse (Degenhardt et al., 2009). Additionally, 
in a large 25-year longitudinal study of 1,256 New Zealand children, 
the author concluded that marijuana use correlated to an increased risk 
of abuse of other drugs, including cocaine and heroin (Fergusson et 
al., 2005).
    Although many individuals with a drug abuse disorder may have used 
marijuana as one of their first illicit drugs, this fact does not 
correctly lead to the reverse inference that most individuals who used 
marijuana will inherently go on to try or become regular users of other 
illicit drugs. Specifically, data from the 2011 NSDUH survey 
illustrates this issue (SAMHSA, 2012). NSDUH data estimates 107.8 
million individuals have a lifetime history of marijuana use, which 
indicates use on at least one occasion, compared to approximately 36 
million individuals having a lifetime history of cocaine use and 
approximately 4 million individuals having a lifetime history of heroin 
use. NSDUH data do not provide information about each individual's 
specific drug history. However, even if one posits that every cocaine 
and heroin user previously used marijuana, the NSDUH data show that 
marijuana use at least once in a lifetime does not predict that an 
individual will also use another illicit drug at least once.
    Finally, a review of the gateway hypothesis by Vanyukov et al. 
(2012) notes that because the gateway hypothesis only addresses the 
order of drug use initiation, the gateway hypothesis does not specify 
any mechanistic connections between drug ``stages'' following exposure 
to marijuana and does not extend to the risks for addiction. This 
concept contrasts with the concept of a common liability to addiction 
that involves mechanisms and biobehavioral characteristics pertaining 
to the entire course of drug abuse risk and disorders.

7. Its Psychic or Physiologic Dependence Liability

    Under the seventh factor, the Secretary must consider marijuana's 
psychic or physiological dependence liability.
    Psychic or psychological dependence has been shown in response to 
marijuana's psychoactive effects. Psychoactive responses to marijuana 
are pleasurable to many humans and are associated with drug-seeking and 
drug-taking (Maldonado, 2002). Moreover, high levels of psychoactive 
effects, notably positive reinforcement, are associated with increased 
marijuana use, abuse, and dependence (Scherrer et al., 2009; Zeiger et 
al., 2010). Epidemiological data support these findings through 2012 
NSDUH statistics that show that of individuals years 12 or older who 
used marijuana in the past month, an estimated 40.3 percent used 
marijuana on 20 or more days within the past month. This equates to 
approximately 7.6 million individuals aged 12 or older who used 
marijuana on a daily or almost daily basis.

[[Page 53785]]

Additionally, the 2013 MTF data report the prevalence of daily 
marijuana use, defined as use on 20 or more days within the past 30 
days, in 8th, 10th, and 12th graders is 1.1 percent, 4.0 percent, and 
6.5 percent, respectively.
    Tolerance is a state of adaptation where exposure to a drug induces 
changes that result in a diminution of one or more of the drug's 
effects over time (American Academy of Pain Medicine, American Pain 
Society and American Society of Addiction Medicine consensus document, 
2001). Tolerance can develop to some, but not all, of marijuana's 
effects. Specifically, tolerance does not seem to develop in response 
to many of marijuana's psychoactive effects. This lack of tolerance may 
relate to electrophysiological data demonstrating that chronic 
delta\9\-THC administration does not affect increased neuronal firing 
in the ventral tegmental area, a region known to play a critical role 
in drug reinforcement and reward (Wu and French, 2000). In the absence 
of other abuse indicators, such as rewarding properties, the presence 
of tolerance or physical dependence does not determine whether a drug 
has abuse potential.
    However, humans can develop tolerance to marijuana's 
cardiovascular, autonomic, and behavioral effects (Jones et al., 1981). 
Tolerance to some of marijuana's behavioral effects seems to develop 
after heavy marijuana use, but not after occasional marijuana use. For 
instance, following acute administration of marijuana, heavy marijuana 
users did not exhibit impairments in tracking and attention tasks, as 
were seen in occasional marijuana users (Ramaekers et al., 2009). 
Furthermore, a neurophysiological assessment administered through an 
electroencephalograph (EEG) which measures event-related potentials 
(ERP) conducted in the same subjects as the previous study, found a 
corresponding effect in the P100 \26\ component of ERPs. Specifically, 
corresponding to performance on tracking and attention tasks, heavy 
marijuana users showed no changes in P100 amplitudes following acute 
marijuana administration, although occasional users showed a decrease 
in P100 amplitudes (Theunissen et al., 2012). A possible mechanism 
underlying tolerance to marijuana's effects may be the down-regulation 
of cannabinoid receptors (Hirvonen et al., 2012; Gonzalez et al., 2005; 
Rodriguez de Fonseca et al., 1994; Oviedo et al., 1993).
---------------------------------------------------------------------------

    \26\ The P100 component of ERPs is thought to relate to the 
visual processing of stimuli and can be modulated by attention.
---------------------------------------------------------------------------

    Importantly, pharmacological tolerance alone does not indicate a 
drug's physical dependence liability. In order for physical dependence 
to exist, evidence of a withdrawal syndrome is needed. Physical 
dependence is a state of adaptation, manifested by a drug-class 
specific withdrawal syndrome produced by abrupt cessation, rapid dose 
reduction, decreasing blood level of the drug, and/or administration of 
an antagonist (ibid). Many medications not associated with abuse or 
addiction can produce physical dependence and withdrawal symptoms after 
chronic use.
    Discontinuation of heavy, chronic marijuana use has been shown to 
lead to physical dependence and withdrawal symptoms (American 
Psychiatric Association DSM-V, 2013; Budney and Hughes, 2006; Haney et 
al., 1999). In heavy, chronic marijuana users, the most commonly 
reported withdrawal symptoms are sleep difficulties, decreased appetite 
or weight loss, irritability, anger, anxiety or nervousness, and 
restlessness. Some less commonly reported withdrawal symptoms are 
depressed mood, sweating, shakiness, physical discomfort, and chills 
(Budney and Hughes, 2006; Haney et al., 1999). The occurrence of 
marijuana withdrawal symptoms in light or non-daily marijuana users has 
not been established. The American Psychiatric Association's DSM-V 
(2013) includes a list of symptoms of ``cannabis withdrawal.'' Most 
marijuana withdrawal symptoms begin within 24-48 hours of 
discontinuation, peak within 4-6 days, and last for 1-3 weeks. 
Marijuana withdrawal syndrome has been reported in adolescents and 
adults admitted for substance abuse treatment.
    Based on clinical descriptions, this syndrome appears to be mild 
compared to classical alcohol and barbiturate withdrawal syndromes, 
which can include more serious symptoms such as agitation, paranoia, 
and seizures. Multiple studies comparing marijuana and tobacco 
withdrawal symptoms in humans demonstrate that the magnitude and time 
course of the two withdrawal syndromes are similar (Budney et al., 
2008; Vandrey et al., 2005, 2008).

8. Whether the Substance is an Immediate Precursor of a Substance 
Already Controlled Under This Article

    Under the eight factor analysis, the Secretary must consider 
whether marijuana is an immediate precursor of a controlled substance. 
Marijuana is not an immediate precursor of another controlled 
substance.

Recommendation

    After consideration of the eight factors discussed above, FDA 
recommends that marijuana remain in Schedule I of the CSA. NIDA concurs 
with this scheduling recommendation.Marijuana meets the three criteria 
for placing a substance in Schedule I of the CSA under 21 U.S.C. 
812(b)(l):
    (1) Marijuana has a high potential for abuse:
    A number of factors indicate marijuana's high abuse potential, 
including the large number of individuals regularly using marijuana, 
marijuana's widespread use, and the vast amount of marijuana available 
for illicit use. Approximately 18.9 million individuals in the United 
States (7.3 percent of the U.S. population) used marijuana monthly in 
2012. Additionally, approximately 4.3 million individuals met 
diagnostic criteria for marijuana dependence or abuse in the year prior 
to the 2012 NSDUH survey. A 2013 survey indicates that by 12th grade, 
36.4 percent of students report using marijuana within the past year, 
and 22.7 percent report using marijuana monthly. In 2011, 455,668 ED 
visits were marijuana-related, representing 36.4 percent of all illicit 
drug-related episodes. Primary marijuana use accounted for 18.1 percent 
of admissions to drug treatment programs in 2011. Additionally, 
marijuana has dose-dependent reinforcing effects, as demonstrated by 
data showing that humans prefer relatively higher doses to lower doses. 
Furthermore, marijuana use can result in psychological dependence.
    (2) Marijuana has no currently accepted medical use in treatment in 
the United States:
    FDA has not approved a marketing application for a marijuana drug 
product for any indication. The opportunity for scientists to conduct 
clinical research with marijuana exists, and there are active INDs for 
marijuana; however, marijuana does not have a currently accepted 
medical use for treatment in the United States, nor does marijuana have 
an accepted medical use with severe restrictions.
    A drug has a ``currently accepted medical use'' if all of the 
following five elements have been satisfied:
    a. The drug's chemistry is known and reproducible;
    b. there are adequate safety studies;
    c. there are adequate and well-controlled studies proving efficacy;
    d. the drug is accepted by qualified experts; and
    e. the scientific evidence is widely available.


[[Page 53786]]


[57 FR 10499, March 26, 1992]
    Marijuana does not meet any of the elements for having a 
``currently accepted medical use.'' First, FDA broadly evaluated 
marijuana, and did not focus its evaluation on particular strains of 
marijuana or components or derivatives of marijuana. Since different 
strains may have different chemical constituents, marijuana, as 
identified in this petition, does not have a known and reproducible 
chemistry, which would be needed to provide standardized doses. Second, 
there are not adequate safety studies on marijuana in the medical 
literature in relation to a specific, recognized disorder. Third, there 
are no published adequate and well controlled studies proving efficacy 
of marijuana. Fourth, there is no evidence that qualified experts 
accept marijuana for use in treating a specific, recognized disorder. 
Lastly, the scientific evidence regarding marijuana's chemistry in 
terms of a specific Cannabis strain that could produce standardized and 
reproducible doses is not currently available, so the scientific 
evidence on marijuana is not widely available.
    Alternately, a Schedule II drug can be considered to have a 
``currently accepted medical use with severe restrictions'' (21 U.S.C. 
812(b)(2)(B)). Yet as stated above, the lack of accepted medical use 
for a specific, recognized disorder precludes the use of marijuana even 
under conditions where its use is severely restricted.
    In conclusion, to date, research on marijuana's medical use has not 
developed to the point where marijuana is considered to have a 
``currently accepted medical use'' or a ``currently accepted medical 
use with severe restrictions.''
    (3) There is a lack of accepted safety for use of marijuana under 
medical supervision:
    There are currently no FDA-approved marijuana drug products. 
Marijuana does not have a currently accepted medical use in treatment 
in the United States or a currently accepted medical use with severe 
restrictions. Thus, FDA has not determined that marijuana is safe for 
use under medical supervision.
    In addition, FDA cannot conclude that marijuana has an acceptable 
level of safety relative to its effectiveness in treating a specific, 
recognized disorder without evidence that the substance is 
contamination free, and assurance of a consistent and predictable dose. 
Investigations into the medical use of marijuana should include 
information and data regarding the chemistry, manufacturing, and 
specifications of marijuana. Additionally, a procedure for delivering a 
consistent dose of marijuana should also be developed. Therefore, FDA 
concludes marijuana does not currently have an accepted level of safety 
for use under medical supervision.

References

Abrams DI, Hilton JF, Leiser RJ, Shade SB, Elbeik TA, Aweeka FT, 
Benowitz NL, Bredt BM, Kosel B, Aberg JA, Deeks SG, Mitchell TF, 
Mulligan K, Bacchetti P, McCune JM, Schambelan M. Short-term effects 
of cannabinoids in patients with HIV-1 infection: a randomized, 
placebo controlled clinical trial. Ann Intern Med. 2003 Aug 19; 
139(4):258-66.
Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME, 
Rowbotham MC, and Petersen KL. 2007. Cannabis in painful HIV-
associated sensory neuropathy: a randomized placebo-controlled 
trial. Neurology 68(7): 515-521.
Adams, I.B., and Martin, B.R. Cannabis: Pharmacology and toxicology 
in animals and humans. Addiction 1996, 91(11):1585-1614.
Agurell, S., Dewey, W.L., and Willett, R.E., eds. The Cannabinoids: 
Chemical, Pharmacologic, and Therapeutic Aspects. New York: Academic 
Press, 1984.
Agurell, S.; Halldin, M.; Lindgren, J.E.; Ohlsson, A.; Widman, M.; 
Gillespie, H.; and Hollister, L. Pharmacokinetics and metabolism of 
delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on 
man. Pharmacol Rev 1986, 38(1), 21-43.
Almirez RG, Smith CG, Asch RH. The effects of marijuana extract and 
delta 9-tetrahydrocannabinol on luteal function in the rhesus 
monkey. Fertil Steril. 1983 Feb; 39(2):212-7.
Ameri, A. The effects of cannabinoids on the brain. Progress in 
Neurobiology 1999, 58 (4), 315-348.
American Academy of Pain Medicine, American Pain Society and 
American Society of Addiction Medicine Consensus Document. 
Definitions related to the use of opioids for the treatment of pain. 
2001.
Andreasson S, Allebeck P, Engstrom A, Rydberg U. Cannabis and 
schizophrenia. A longitudinal study of Swedish conscripts. Lancet. 
1987 Dec 26; 2(8574):1483-6.
Appendino G, Chianese G, Taglialatela-Scafati O. Cannabinoids: 
occurrence and medicinal chemistry. Curr Med Chem. 2011; 18(7):1085-
99.
Asch RH, Smith CG, Siler-Khodr TM, Pauerstein CJ. Effects of delta 
9-tetrahydrocannabinol during the follicular phase of the rhesus 
monkey (Macaca mulatta). J Clin Endocrinol Metab. 1981 Jan; 
52(1):50-5.
Balster, R.L., Prescott, W.R., delta\9\-Tetrahydrocannabinol 
discrimination in rats as a model for cannabis intoxication. 
Neurosci. & Biobehav. Rev. 1992, 16(1), 55-62.
Balster RL and Bigelow GE. Guidelines arid methodological reviews 
concerning drug abuse liability assessment. Drug and Alcohol 
Dependence. 2003; 70: S13-S40.
Barnett, G.; Licko, V.; and Thompson, T. Behavioral pharmacokinetics 
of marijuana. Psychopharmacology 1985, 85(1), 51-56.
Battista N, Di TM, Bari M, Maccarrone M. The endocannabinoid system: 
an overview. Front.Behav.Neurosci. 2012; 6:9.
Benowitz NL, Jones RT. Cardiovascular effects of prolonged delta-9-
tetrahydrocannabinol ingestion. Clin Pharmacol Ther. 1975 Sep; 
18(3):287-97.
Benowitz NL, Jones RT. Cardiovascular and metabolic considerations 
in prolonged cannabinoid administration in man. J Clin Pharmacol. 
1981 Aug-Sep; 21(8-9 Suppl):214S-223S.
Block RI, Farinpour R, Schlechte JA. Effects of chronic marijuana 
use on testosterone, luteinizing hormone, follicle stimulating 
hormone, prolactin and cortisol in men and women. Drug Alcohol 
Depend. 1991 Aug; 28(2):121-8.
Block RI, Farinpour R, Braverman K. Acute effects of marijuana on 
cognition: relationships to chronic effects and smoking techniques. 
Pharmacol Biochem Behav. 1992 Nov; 43(3):907-17.
Bolla KI, Brown K, Eldreth D, Tate K, and Cadet JL. Dose-related 
neurocognitive effects of marijuana use. Neurology 2002 59:1337-
1343.
Bolla KI, Eldreth DA, Matochik JA, and Cadet JL. Neural substrates 
of faulty decision-making in abstinent marijuana users. NeuroImage 
2005 26:480-492.
Bonnet U. Chronic cannabis abuse, delta-9-tetrahydrocannabinol and 
thyroid function. Pharmacopsychiatry. 2013 Jan; 46(1):35-6.
Bouaboula M, Rinaldi M, Carayon P, Carillon C, Delpech B, Shire D, 
Le Fur G, Casellas P. Cannabinoid-receptor expression in human 
leukocytes. Eur J Biochem. 1993 May 15; 214(1):173-80.
Braida D, Iosue S, Pegorini S, Sala M. Delta9-tetrahydrocannabinol-
induced conditioned place preference and intracerebroventricular 
self-administration in rats. Eur J Pharmacol. 2004 Dec 3; 506(1):63-
9.
Breivogel CS, Childers SR. Cannabinoid agonist signal transduction 
in rat brain: comparison of cannabinoid agonists in receptor 
binding, G-protein activation, and adenylyl cyclase inhibition. J 
Pharmacol Exp Ther. 2000. Oct; 295(1):328-36.
Breivogel CS, Griffin G, Di Marzo V, Martin BR. Evidence for a new G 
protein-coupled cannabinoid receptor in mouse brain. Mol Pharmacol. 
2001 Jul; 60(1):155-63.
Brown TT, Dobs AS. Endocrine effects of marijuana. J Clin Pharmacol. 
2002 Nov; 42(11 Suppl):90S-96S.
Browne RG, Weissman A. Discriminative stimulus properties of delta 
9-tetrahydrocannabinol: mechanistic studies. J Clin Pharmacol. 1981 
Aug-Sep; 21(8-9 Suppl):227S-234S.
Budney AJ, Hughes JR, Moore BA, Vandrey R. Review of the validity 
and significance of cannabis withdrawal

[[Page 53787]]

syndrome. Am J Psychiatry. 2004 Nov; 161(11):1967-77.
Budney AJ, Hughes JR. The cannabis withdrawal syndrome. Curr Opin 
Psychiatry 2006 May; 19(3):233-8.
Budney AJ, Vandrey RG, Hughes JR, Thostenson JD, Bursae Z. 
Comparison of cannabis and tobacco withdrawal: severity and 
contribution to relapse. J Subst.Abuse Treat. 2008 Dec; 35(4):362-8.
Capriotti RM, Foltin RW, Brady JV, Fischman MW. Effects of marijuana 
on the task-elicited physiological response. Drug Alcohol Depend. 
1988 Jul; 21(3):183-7.
Cascini F, Aiello C, Di Tanna G. Increasing delta-9-
tetrahydrocannabinol ([Delta]-9-THC) content in herbal cannabis over 
time: systematic review and meta-analysis. Curr Drug Abuse Rev. 2012 
Mar; 5(1):32-40.
Chait LD. Subjective and behavioral effects of marijuana the morning 
after smoking. Psychopharmacology (Berl.) 1990; 100(3):328-33.
Chait LD, Burke KA. Preference for high- versus low-potency 
marijuana. Pharmacol Biochem Behav. 1994 Nov; 49(3):643-7.
Chaperon F, Soubrie P, Puech AJ, Thiebot MH. Involvement of central 
cannabinoid (CB1) receptors in the establishment of place 
conditioning in rats. Psychopharmacology (Berl). 1998 Feb; 
135(4):324-32.
Cheer JF, Kendall DA, Marsden CA. Cannabinoid receptors and reward 
in the rat: a conditioned place preference study. Psychopharmacology 
(Berl). 2000 Jul; 151(1):25-30.
Cone EJ, Johnson RE, Moore JD, Roache JD. Acute effects of smoking 
marijuana on hormones, subjective effects and performance in male 
human subjects. Pharmacol Biochem Behav. 1986 Jun; 24(6): 1749-54.
Corey-Bloom J, Wolfson T, Gamst A, Jin S, Marcotte TD, Bentley H, 
and Gouaux B. 2012. Smoked cannabis for spasticity in multiple 
sclerosis: a randomized, placebo-controlled trial. CMAJ 184 (10): 
1143-1150.
Council on Science and Public Health Report 3. Use of cannabis for 
medicinal purposes. American Medical Association, Interim Meeting, 
Houston, Texas; November 2009.
Crawford WJ, and Merritt JC. 1979. Effects of tetrahydrocannabinol 
on arterial and intraocular hypertension. International journal of 
clinical pharmacology and biopharmacy 17 (5): 191-196.
Croxford JL, Yamamura T. Cannabinoids and the immune system: 
potential for the treatment of inflammatory diseases? J 
Neuroimmunol. 2005 Sep; 166(1-2):3-18. Review.
Dalton WS, Martz R, Lemberger L, Rodda BE, Forney RB. Influence of 
cannabidiol on delta-9-tetrahydrocannabinol effects. Clin.Pharmacol. 
Ther. 1976 Mar; 19(3):300-9.
Dax EM, Pilotte NS, Adler WH, Nagel JE, Lange WR. The effects of 9-
ene-tetrahydrocannabinol on hormone release and immune function. J 
Steroid Biochem. 1989; 34(1-6):263-70.
Degenhardt L, Hall W, Lynskey M. Testing hypotheses about the 
relationship between cannabis use and psychosis. Drug Alcohol 
Depend. 2003 Jul 20; 71(1):37-48.
Degenhardt L, Chiu WT, Conway K, Dierker L, Glantz M, Kalaydjian A, 
Merikangas K, Sampson N, Swendsen J, Kessler RC. Does the `gateway' 
matter? Associations between the order of drug use initiation and 
the development of drug dependence in the National Comorbidity Study 
Replication. Psychol. Med 2009 Jan; 39(1):157-67.
Degenhardt L, Dierker L, Chiu WT, Medina-Mora ME, Neumark Y, Sampson 
N, Alonso J, Angermeyer M, Anthony JC, Bruffaerts R, et al. 
Evaluating the drug use ``gateway'' theory using cross-national 
data: consistency and associations of the order of initiation of 
drug use among participants in the WHO World Mental Health Surveys. 
Drug Alcohol. Depend. 2010 Apr 1; 108(1-2):84-97.
Deiana S, Fattore L, Spano MS, Cossu G, Porcu E, Fadda P, Fratta W. 
Strain and schedule dependent differences in the acquisition, 
maintenance and extinction of intravenous cannabinoid self-
administration in rats. Neuropharmacology. 2007 Feb; 52(2):646-54.
Dewey, W.L., Martin, B.R., May, E.L. Cannabinoid stereoisomers: 
pharmacological effects. In Smith, D.F. (Ed.) CRC Handbook of 
stereoisomers: drugs in psychopharmacology, 317-326 (Boca Raton, FL, 
CRC Press), 1984.
Di Marzo, V.A brief history of cannabinoid and endocannabinoid 
pharmacology as inspired by the work of British scientists. Trends. 
Pharmacol. Sci 2006 Mar; 27(3):134-40.
DEA Statistics and Facts. (n.d.) DEA Domestic Drug Seizures. http://www.justice.gov/dea/resource-center/statistics.shtml/ (accessed 
August 5, 2014)
Drug Enforcement Administration, Drugs of Abuse, 2005.
Drug Enforcement Administration. Sourcebook of Criminal Justice 
Statistics, 2003.
DSM-V. Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition. American Psychiatric Association. Washington, DC: American 
Psychiatric Publishing, 2013.
Eldridge JC, Murphy LL, Landfield PW. Cannabinoids and the 
hippocampal glucocorticoid receptor: recent findings and possible 
significance. Steroids. 1991 May; 56(5):226-31. Review.
Ellis RJ, Toperoff W, Vaida F, Van Den Brande G, Gonzales J, Gouaux 
B, Bentley H, and Atkinson JH. 2009. Smoked medicinal cannabis for 
neuropathic pain in HIV: a randomized, crossover clinical trial. 
Neuropsychopharmacology: official publication of the American 
College of Neuropsychopharmacology 34(3): 672-680.
ElSohly MA, Slade D. Chemical constituents of marijuana: The complex 
mixture of natural cannabinoids. Life Sciences. 2005; 78:539-48.
Fant RV, Heishman SJ, Bunker EB, Pickworth WB. Acute and residual 
effects of marijuana in humans. Pharmacol Biochem Behav. 1998 Aug; 
60(4):777-84.
Fattore L, Spano MS, Altea S, Angius F, Fadda P, Fratta W. 
Cannabinoid self-administration in rats: sex differences and the 
influence of ovarian function. Br.J Pharmacol. 2007 Nov; 152(5):795-
804.
Fergusson DM, Horwood LJ, Ridder EM. Tests of causal linkages 
between cannabis use and psychotic symptoms. Addiction. 2005 Mar; 
100(3):354-66.
Fontes MA, Bolla KI, Cunha PJ, Almeida PP, Jungerman F, Laranjeira 
RR; Bressan RA, Lacerda AL. Cannabis use before age 15 and 
subsequent executive functioning. Br. J Psychiatry 2011 Jun; 
198(6):442-7.
Fried, P.A., Watkinson, B. 36- and 48-month neurobehabioral follow-
up of children prenatally exposed to marijuana, cigarettes and 
alcohol. J. Dev. Behav. Pediatr. 1987, 8, 318-326.
Fried, P.A., Watkinson, B., Gray, R. A follow-up study of 
attentional behavior in 6-year-old children exposed prenatally to 
marihuana, cigarettes and alcohol. Neurotoxicol. Teratol. 1992, 14, 
299-311.
Fried, P.A., Watkinson, B., Gray, R. Differential effects on 
cognitive functioning in 9- to 12-year olds prenatally exposed to 
cigarettes and marihuana. Neurotoxicol. Teratol. 1998, 20(3), 293-
306.
Fried PA. Adolescents prenatally exposed to marijuana: examination 
of facets of complex behaviors and comparisons with the influence of 
in utero cigarettes. J. Clin. Pharmacol. 2002 Nov; 42(11 Suppl):97S-
102S.
Fried PA, Watkinson B, Gray R. Neurocognitive consequences of 
marihuana--a comparison with pre-drug performance. Neurotoxicol. 
Teratol. 2005 Mar; 27(2):231-9.
Fung, M., Gallagher, C., Machtay, M. Lung and aeo-digestive cancers 
in young marijuana smokers. Tumori 1999, 85 (2), 140-142.
Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, 
Bouaboula M, Shire D, Le Fur G, Casellas P. Expression of central 
and peripheral cannabinoid receptors in human immune tissues and 
leukocyte subpopulations. Eur J Biochem. 1995 Aug 15; 232(1):54-61.
Gaoni, Y., Mechoulam, R. Isolation, structure, and partial synthesis 
of an active constituent of hashish. J. Am. Chem. Soc. 1964, 86, 
1646-1947.
Gerard, C.M., Mollereau, C., Vassart, G., Parmentier, M. Molecular 
cloning of a human cannabinoid receptor which is also expressed in 
testis.: Biochem J. 1991, 279, 129-34.
Ghozland S, Matthes HW, Simonin F, Filliol D, Kieffer BL, Maldonado 
R. Motivational effects of cannabinoids are mediated by mu-opioid 
and kappa-opioid receptors. J Neurosci. 2002 Feb 1; 22(3):1146-54.
Gold LH, Balster RL, Barrett RL, Britt DT, Martin BR. A comparison 
of the discriminative stimulus properties of delta 9-
tetrahydrocannabinol and CP

[[Page 53788]]

55,940 in rats and rhesus monkeys. J Pharmacol Exp Ther. 1992 Aug; 
262(2):479-86.
Goldschmidt L, Richardson GA, Willford J, Day NL. Prenatal marijuana 
exposure and intelligence test performance at age 6. J. Am. Acad. 
Child. Adolesc. Psychiatry. 2008 Mar; 47(3):254-63.
Gong H Jr, Tashkin DP, Simmons MS, Calvarese B, Shapiro BJ. Acute 
and subacute bronchial effects of oral cannabinoids. Clin Pharmacol 
Ther. 1984 Jan; 35(1):26-32.
Gong JP, Onaivi ES, Lshiguro H, Liu QR, Tagliaferro PA, Brusco A, 
Uhl GR. Cannabinoid CB2 receptors: Immunohistochemical localization 
in rat brain. Brain Res. 2006 Feb 3; 1071(1):10-23.
Gonsiorek W, Lunn C, Fan X, Narula S, Lundell D, Hipkin RW. 
Endocannabinoid 2-arachidonyl glycerol is a full agonist through 
human type 2 cannabinoid receptor: Antagonism by anandamide. Mol 
Pharmacol. 2000 May; 57(5): 1045-50.
Gonzalez R. Acute and non-acute effects of cannabis on brain 
functioning and neuropsychological performance. Neuropsychol.Rev. 
2007 Sep; 17(3):347-61.
Gonzalez S, Cebeira M, Fernandez-Ruiz J. Cannabinoid tolerance and 
dependence: A review of studies in laboratory animals. 
Pharmacol.Biochem.Behav. 2005 Jun; 81(2):300-18.
Grant I. Foreword by Igor Grant, M.D., Director, Center for 
Medicinal Cannabis Research (CMCR). Neuropharmacology. 2005 Jun; 
48(8): 1067.
Griffith-Lendering MF, Wigman JT, Prince van LA, Huijbregts SC, 
Huizink AC, Ormel J, Verhulst FC, van OJ, Swaab H, Vollebergh WA. 
Cannabis use and vulnerability for psychosis in early adolescence-a 
TRAILS study. Addiction 2012 Dec 7.
Grotenhermen F. Pharmacokinetics and pharmacodynamics of 
cannabinoids. Clin Pharmacokinet. 2003; 42(4):327-60.
Gruber SA, Sagar KA, Dahlgren MK, Racine M, Lukas SE. Age of onset 
of marijuana use and executive function. Psychol.Addict.Behav. 2012 
Sep; 26(3):496-506.
Hall WD, Lynskey M. Is cannabis a gateway drug? Testing hypotheses 
about the relationship between cannabis use and the use of other 
illicit drugs. Drug Alcohol Rev. 2005 Jan; 24(1):39-48.
Haney M, Gunderson EW, Rabkin J, Hart CL, Vosburg SK, Comer SD, and 
Faltin RW. 2007. Dronabinol and marijuana in HIV-positive marijuana 
smokers. Caloric.intake, mood, and sleep. Journal of acquired immune 
deficiency syndromes (1999) 45 (5): 545-554.
Haney M, Rabkin J, Gunderson E, and Foltin RW. 2005. Dronabinol and 
marijuana in HIV(+) marijuana smokers: Acute effects on caloric 
intake and mood. Psychopharmacology 181(1): 170-178.
Haney M, Ward AS, Comer SD, Faltin RW, Fischman MW. Abstinence 
symptoms following smoked marijuana in humans. Psychopharmacology 
(Berl) 1999, 141(4):395-404.
Hanus, L., Breuer, A., Tchili_bon, S., Shiloah, S., Goldenberg, D., 
Horowitz, M., Pertwee, R.G., Roos, R.A., Mechoulam, R., Pride, E. 
HU-308: A specific agonist for CB(2), a peripheral Cannabinoid 
receptor. Proc. Natl. Acad. Sci. USA 1999, 96, 14228-33.
Heishman SJ, Huestis MA, Benningfield JE, Cone EJ. Acute and 
residual effects of marijuana: Profiles of plasma THC levels, 
physiological, subjective, and performance measures. Pharmacol 
Biochem Behav. 1990 Nov; 37(3):561-5.
Herkenham, M. Cannabinoid receptor localization in brain: 
Relationship to motor and reward systems. In: Kalivas, P.W., and 
Samson, H.H., eds. The neurobiology of drug and alcohol addiction. 
Ann NY Acad Sci 1992, 654, 19-32.
Herkenham, M., Lynn, A.B., Little, M.D., Johnson, M.R., Melvin, 
L.S., de Costa, B.R., Rice, K.C. Cannabinoid receptor localization 
in Brain. Proc. Natl. Acad. Sci.US A. 1990, 87, 1932-1936.
Herning, R.I.; Hooker, W.D.; and Jones, R.T. Tetrahydrocannabinol 
content and differences in marijuana smoking behavior. 
Psychopharmacology 1986, 90(2):160-162.
Hillig, K.W. Genetic evidence for speciation in Cannabis 
(Cannabaceae). Genetic Resources and Crop Evolution 52: 161-180, 
2005.
Hirvonen, J., Goodwin, R.S., Li, C.T., Terry, G.E., Zoghbi, S.S., 
Morse, C., Pike, V.W., Volkow, N.D., Huestis, M.A., Innis, R.B. 
Reversible and regionally selective downregulation of brain 
cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol. 
Psychiatry. 2012(Jun), 17(6), 643-649.
Hively, R.L., Mosher, W.A., Hoffman, F.W. Isolation of trans-)\9\-
tetrahydrocannabinol from marihuana. J. Am. Chem. Soc. 1966, 88, 
1832-1833.
Hollister LE, Gillespie HK. Delta-8- and delta-9-
tetrahydrocannabinol comparison in man by oral and intravenous 
administration. Clin.Pharmacol.Ther. 1973 May;14(3):353-7.
Hollister, L.E. Health aspects of cannabis. Pharmacological Rev. 
1986, 38, 1-20.
Hollister, L.E. Cannabis. (Literature review). Acta Psychiatr Scand 
(Suppl) 1988, 78, 108-118.
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, 
Parrino LJ. Cannabinoid physiology and pharmacology: 30 years of 
progress. Neuropharmacology. 2004; 47 Suppl 1:345-58.
Huestis, M.A., Sampson, A.H., Holicky, B.J., Benningfield, J.E., 
Cone, E.J. Characterization of the absorption phase of marijuana 
smoking. Clin. PharmacoL Ther. 1992a, 52, 31-41.
Huestis, M.A.; Benningfield, J.E.; and Cone, E.J. Blood 
Cannabinoids. 1. Absorption of THC and formation of 11-0H-THC and 
THC COOH during and after smoking marijuana. J Anal Toxicol 1992b, 
16(5), 276-282.
Hunt CA, Jones RT. Tolerance and disposition oftetrahydrocannabinol 
in man. J Pharmacol Exp Ther. 1980 Oct; 215(1):35-44.
Ilan AB, Gevins A, Coleman M, Elsohly MA, de WH. Neurophysiological 
and subjective profile of marijuana with varying concentrations of 
cannabinoids. Behav.Pharmacol. 2005 Sep; 16(5-6):487-96.
Institute of Medicine. Division of Health Sciences Policy. Marijuana 
and Health: Report of a Study by a Committee of the Institute of 
Medicine, Division of Health Sciences Policy. Washington, DC: 
National Academy Press, 1982.
Institute of Medicine, Division of Neuroscience and Behavioral 
Health. Marijuana and Medicine: Assessing the Science Base. 
Washington DC: National Academy Press, 1999.
Johansson, E.; Halldin, M.M.; Agurell, S.; Hollister, L.E.; and 
Gillespie, H.K. Terminal elimination plasma half-life of delta 1-
tetrahydrocannabinol (delta 1-THC) in heavy users of marijuana. Eur 
J Clin Pharmacol 1989, 37(3), 273-277.
Johnston, L.D., O'Malley, P.M., Miech, R.A., Bachman, J.G., & 
Schulenberg, J.E. (2014). Monitoring the Future national survey 
results on drug use: 1975-2013: Overview, key findings on adolescent 
drug use. Ann Arbor: Institute for Social Research, The University 
of Michigan, 84pp.
Jones, R.T.; Benowitz, N.L.; and Heming, R.I. Clinical relevance of 
cannabis tolerance and dependence. J Clin Pharmacol 1981, 21,143S-
152S.
Jones RT. Cardiovascular system effects of marijuana. J Clin 
Pharmacol. 2002 Nov;42(11Suppl):58S-63S.
Justinova Z, Goldberg SR, Heishman SJ, Tanda G. Self-administration 
of cannabinoids by experimental animals and human marijuana smokers. 
Pharmacol Biochem Behav. 2005 Jun; 81(2): 285-299.
Justinova Z, Tanda G, Redhi GH, Goldberg SR. Self-administration of 
delta9-tetrahydrocannabinol (THC) by drug naive squirrel monkeys. 
Psychopharmacology (Berl). 2003 Sep; 169(2): 135-40.
Justinova Z, Tanda G, Munzar P, Goldberg SR. The opioid antagonist 
naltrexone reduces the reinforcing effects of Delta 9 
tetrahydrocannabinol (THC) in squirrel monkeys. 
Psychopharmacology.(Berl.) 2004 Apr;l 73(1-2):186-94.
Kandel, D. Stages in adolescent involvement in drug use. Science 
1975; 190:912-914.
Kandel DB, Chen K. Types of marijuana users by longitudinal course. 
J Stud Alcohol. 2000 May; 61(3):367-78.
Karniol IG, Shirakawa I, Kasinski N, Pfeferman A, Carlini EA. 
Cannabidiol interferes with the effects of delta 9-
tetrahydrocannabinol in man. Eur.J Pharmacol. 1974 Sep;28(1):172-7.
Karniol IG, Shirakawa I, Takahashi RN, Knobel E, Musty RE. Effects 
of delta9-tetrahydrocannabinol and cannabinol in man. Pharmacology 
1975; 13(6):502-12.
Kirk JM, de Wit H. Responses to oral delta9-tetrahydrocannabinol in 
frequent and infrequent marijuana users. Pharmacol Biochem Behav. 
1999 May; 63(1):137-42.
Kuepper R, van OJ, Lieb R, Wittchen HU, Hofler M, Henquet C. 
Continued cannabis use and risk of incidence and persistence of 
psychotic symptoms: 10 year follow-up cohort study. BMJ 2011; 
342:d738.
Kurzthaler I, Hummer M, Miller C, Sperner-Unterweger B, Gunther V, 
Wechdorn H, Battista HJ, Fleischhacker WW. Effect of cannabis use on 
cognitive functions and

[[Page 53789]]

driving ability. J Clin Psychiatry. 1999 Jun; 60(6):395-9.
Lee MH, Hancox RJ. Effects of smoking cannabis on lung function. 
Expert Rev.Respir.Med 2011 Aug; 5(4):537-46.
Lemberger L., Silberstein, S. D., Axelrod, J., Kopin, I.J. 
Marihuana: Studies on the disposition and metabolism of delta-9-
tetrahydrocannabinol in man. Science 1970, 1 70, 1320-1322.
Lemberger L., Weiss, J.L., Watanabe, A. M., Galanter, I.M., Wyatt, 
R.J., Cardon, P.V. Delta-9-tetrahydrocannabinol: Temporal 
correlation of the psychological effects and blood levels after 
various routes of administration. New Eng. J. Med. 1972a, 286(13), 
685-688.
Lemberger, L., Crabtree, R.E., Rowe, H.M. 11-Hydroxy-)\9\-
tetrahydrocannabinol: Pharmacology, disposition and metabolism of a 
major metabolite of marihuana in man. Science 1972b, 177, 62-63.
Lemberger L., Rubin A. The physiologic disposition of marihuana in 
man, Life Sci. 1975,17, 1637-42.
Li M-C., Brady, J.E., DiMaggio, C.J., Lusardi, A.R., Tzong, K.Y., 
Li, G. Marijuana use and motor vehicle crashes. Epidemiologic 
Reviews. 2012, 34, 65-72.
Liguori A, Gatto CP, Robinson JH. Effects of marijuana on 
equilibrium, psychomotor performance, and simulated driving. Behav 
Pharmacol. 1998 Nov; 9(7):599-609.
Lile JA, Kelly TH, Hays LR. Separate and combined effects of the 
cannabinoid agonists nabilone and Delta(9)-THC in humans 
discriminating Delta(9)-THC. Drug Alcohol Depend. 2011 Jul1; 116(1-
3):86-92.
Lile JA, Kelly TH, Pinsky DJ, Hays LR. Substitution profile of 
Delta9-tetrahydrocannabinol, triazolam, hydromorphone, and 
methylphenidate in humans discriminating Delta9-
tetrahydrocannabinol. Psychopharmacology (Berl.) 2009 Apr; 203 
(2):241-50.
Lisdahl KM, Price JS. Increased marijuana use and gender predict 
poorer cognitive functioning in adolescents and emerging adults. J 
Int Neuropsychol.Soc 2012 Jul; 18(4):678-88.
Lyons MJ, Bar JL, Panizzon MS, Toomey R, Eisen S, Xian H, Tsuang MT. 
Neuropsychological consequences of regular marijuana use: A twin 
study. Psychol Med. 2004 Oct; 34(7):1239-50.
Mackie K, Lai Y, Westenbroek R, Mitchell R. Cannabinoids activate an 
inwardly rectifying potassium conductance and inhibit Q-type calcium 
currents in AtT20 cells transfected with rat brain cannabinoid 
receptor. J Neurosci. 1995 Oct; 15(10):6552-61.
Maldonado R. Study of cannabinoid dependence in animals. Pharmacol 
Ther. 2002 Aug; 95(2): 153-64.
Malinowska B, Baranowska-Kuczko M, Schlicker E. Triphasic blood 
pressure responses to cannabinoids: Do we understand the mechanism? 
Br.J Pharmacol 2012 Apr; 165(7):2073-88.
Manrique-Garcia E, Zammit S, Dalman C, Hemmingsson T, Andreasson S, 
Allebeck P. Cannabis, schizophrenia and other non-affective 
psychoses: 35 years of follow-up of a population-based cohort. 
Psychol.Med 2012 Jun; 42(6):1321-8.
Maremmani I, Lazzeri A, Pacini M, Lovrecic M, Placidi GF, Perugi G. 
Diagnostic and symptomatological features in chronic psychotic 
patients according to cannabis use status. J Psychoactive Drugs. 
2004 Jun; 36(2):235-41.
``Marijuana Scheduling Petition; Denial of Petition; Remand; Final 
Order,'' 57 Federal Register 59 (26 March 1992), pp. 10499-10508.
Martellotta MC, Cossu G, Fattore L, Gessa GL, Fratta W. Self-
administration of the cannabinoid receptor agonist WIN 55,212-2 in 
drug-naive mice. Neuroscience. 1998 Jul; 85(2):327-30.
Matsuda, L.A., Lolait, S.J., Brownstein, M.J., Young, A.C., Bonner, 
T.I. Structure of a cannabinoid receptor and functional expression 
of the cloned cDNA. Nature 1990, 346, 561-564.
McMahon LR. Apparent affinity estimates of rimonabant in combination 
with anandamide and chemical analogs of anandamide in rhesus monkeys 
discriminating Delta9-tetrahydrocannabinol. Psychopharmacology 
(Berl.) 2009 Apr; 203(2):219-28.
McMahon LR, Ginsburg BC, Lamb RJ. Cannabinoid agonists 
differentially substitute for the discriminative stimulus effects of 
Delta(9)-tetrahydrocannabinol in C57BL/6J mice. Psychopharmacology 
(Berl.) 2008 Jul; l98(4):487-95.
Mechoulam, R. Cannabinoid chemistry. In Mechoulam, R. (ED.) 
Marijuana, pp.2-88 (New York, NY, Academic Press, Inc.), 1973.
Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO. Cannabidiol--
recent advances. Chem.Biodivers. 2007 Aug;4(8): 1678-92.
Mechoulam R, Shvo Y. Hashish-I: The structure of Cannabidiol. 
Tetrahedron. 1963; 19: 2073-78.
Mehmedic Z, Chandra S, Slade D, Denham H, Foster S, Patel AS, Ross 
SA, Khan IA, ElSohly MA. Potency Trends of [Delta]\9\-THC and other 
caimabinoids in confiscated cannabis preparations from 1993 to 2008. 
J Forensic Sci. 2010 Sept; 55(5): 1209-1217.
Meier MH, Caspi A, Ambler A, Harrington H, Houts R, Keefe RS, 
McDonald K, Ward A, Poulton R, Moffitt TE. Persistent cannabis users 
show neuropsychological decline from childhood to midlife. 
Proc.Natl.Acad.Sci U.S.A 2012 Oct 2; 109(40):E2657-E2664.
Meijer JH, Dekker N, Koeter MW, Quee PI, van Beveren NJ, Meijer CJ. 
Cannabis and cognitive performance in psychosis: A cross-sectional 
study in patients with non-affective psychotic illness and their 
unaffected siblings. Psychol.Med 2012 Apr; 42(4):705-16.
Mendelson JH, Mello NK. Effects of marijuana on neuroendocrine 
hormones in human males and females. NIDA Res Monogr. 1984; 44:97-
114.
Mendizabal V, Zimmer A, Maldonado R. Involvement ofkappa/dynorphin 
system in WIN 55,212-2 self-administration in mice. 
Neuropsychopharmacology. 2006 Sep; 31(9):1957-66.
Merritt JC, Crawford WJ, Alexander PC, Anduze AL, and Gelbart SS. 
1980. Effect of marihuana on intraocular and blood pressure in 
glaucoma. Ophthalmology 87 (3): 222-228.
Messinis L, Kyprianidou A, Malefaki S, and Papathanasopoulos P. 
Neuropsychological deficits in long-term frequent cannabis users. 
Neurology 2006 66:737-739.
Minozzi S, Davoli M, Bargagli AM, Amato L, Vecchi S, Perucci CA. An 
overview of systematic reviews on cannabis and psychosis: Discussing 
apparently conflicting results. Drug Alcohol Rev. 2010 May; 
29(3):304-17.
Mittleman MA, Lewis RA, Maclure M, Sherwood JB, and Muller JE. 
Triggering myocardial infarction by marijuana. Circulation. 2001; 
103:2805-2809.
Nace EP, Meyers AL, Rothberg JM, Maleson F. Addicted and nonaddicted 
drug users. A comparison of drug usage patterns. Arch Gen 
Psychiatry. 1975; 32(1):77-80.
Oviedo, A., Glowa, J., Herkenham, M. Chronic cannabinoid 
administration alters cannabinoid receptor binding in rat brain: A 
quantitative autoradiographic study. Brain Res. 1993, 616, 293-302.
Pacher P, Batkai S, Kunos G. The endocannabinoid system as an 
emerging target of pharmacotherapy. Pharmacol.Rev. 2006 Sep; 
58(3):389-462.
Pelayo-Teran JM, Suarez-Pinilla P, Chadi N, Crespo-Pacorro B. Gene-
environment interactions underlying the effect of cannabis in first 
episode psychosis. Curr Pharm Des. 2012; 18(32):5024-35.
Petrocellis PL, Di Marzo V. An introduction to the endocannabinoid 
system: From the early to the latest concepts. Best 
Pract.Res.Clin.Endocrinol.Metab. 2009 Feb; 23(1):1-15.
Piomelli D. The endocannabinoid system: A drug discovery 
perspective. Curr Opin Investig Drugs. 2005 Jul; 6(7):672-9.
Pletcher MJ, Vittinghoff E, Kalhan R, Richman J, Safford M, Sidney 
S, Lin F, Kertesz S. Association between marijuana exposure and 
pulmonary function over 20 years. JAMA 2012 Jan 11; 307(2):173-81.
Pollastro F, Taglialatela-Scafati 0, Allara M, Munoz E, Di Marzo V, 
De Petrocellis L, Appendino G. Bioactive prenylogous cannabinoid 
from fiber hemp (Cannabis sativa). J Nat Prod. 2011 Sep 
23;74(9):2019-22.
Pope HG Jr, Gruber AJ, Hudson JI, Huestis MA, Yurgelun-Todd D. 
Cognitive measures in long term cannabis users. J Clin Pharmacol. 
2002 Nov; 42(11 Suppl):41S-47S. Review.
Radwan MM, Elsohly MA, Slade D, Ahmed SA, Khan IA, Ross SA. 
Biologically active cannabinoids from high-potency Cannabis sativa. 
J Nat Prod. 2009 May 22; 72(5):906-11.
Ramaekers JG, Berghaus G, van Laar M, Drummer OH. Dose related risk 
of motor vehicle crashes after cannabis use. Drug Alcohol Depend. 
2004 Feb 7; 73(2): 109-19.
Ramaekers JG, Kauert G, van RP, Theunissen EL, Schneider E, Moeller 
MR. High-potency marijuana impairs executive function and inhibitory 
motor control. Neuropsychopharmacology 2006 Oct; 31(10):2296-303.

[[Page 53790]]

Ramaekers JG, Kauert G, Theunissen EL, Toennes SW., Moeller MR. 
Neurocognitive performance during acute THC intoxication in heavy 
and occasional cannabis users. J.Psychopharmacol. 2009 May; 
23(3):266-77.
Ramaekers JG, Moeller MR, van Ruitenbeek P, Theunissen EL, Schneider 
E, Kauert G. Cognition and motor control as a function of 
[Delta]\9\-THC concentration in serum and oral fluid: Limits of 
impairment. Drug and Alcohol Dependence. 2006; 85:1114-122.
``Rescheduling of the Food and Drug Administration Approved Product 
Containing Synthetic Dronabinol [(-)-delta 9-(trans)-
Tetrahydrocannabinol] in Sesame Oil and Encapsulated in Soft Gelatin 
Capsules From Schedule II to Schedule III; Final Rule,'' 64 Federal 
Register 127 (2 July 1999), pp.35928-35930.
Riggs PK, Vaida F, Rossi SS, Sorkin LS, Gouaux B, Grant I, Ellis RJ. 
A pilot study of the effects of cannabis on appetite hormones in 
HIV-infected adult men. Brain Res 2012 Jan 11; 1431:46-52.
Rodriguez de Fonseca F, Gorriti, M.A., Fernandez-Ruiz, J.J., Palomo, 
T., Ramos, J.A. Downregulation of rat brain cannabinoid binding 
sites after chronic delta 9-tetrahydrocannabinoil treatment. 
Phamacol. Biochem. Behav. 1994, 47 (1), 33-40.
Roth MD, Tashkin DP, Whittaker KM, Choi R, Baldwin GC. 
Tetrahydrocannabinol suppresses immune function and enhances HIV 
replication in the huPBL-SCID mouse. Life Sci. 2005 Aug 19; 
77(14):1711-22.
Russo EB. Taming THC: Potential cannabis synergy and 
phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011 
Aug; 163(7):1344-64.
Sarfaraz S, Afaq F, Adhami VM, Mukhtar H. Cannabinoid receptor as a 
novel target for the treatment of prostate cancer. Cancer Res. 2005 
Mar 1; 65(5):1635-41.
Sanudo-Peria M.C., Tsou, K., Delay, E.R., Hohman, A.G., Force, M., 
Walker, J.M. Endogenous cannabinoids as an aversive or counter-
rewarding system in the rat. Neurosci. Lett., 223, 125-128, 1997.
Scherrer JF, Grant JD, Duncan AE, Sartor CE, Haber JR, Jacob T, 
Bucholz KK. Subjective effects to cannabis are associated with use, 
abuse and dependence after adjusting for genetic and environmental 
influences. Drug Alcohol Depend. 2009 Nov 1; 105(1-2):76-82.
Schiffman J, Nakamura B, Earleywine Mj LaBrie J. Symptoms of 
schizotypy precede cannabis use. Psychiatry Res. 2005 Mar 30; 
134(1):37-42.
Schreiner AM, Dunn ME. Residual effects of cannabis use on 
neurocognitive performance after prolonged abstinence: A meta-
analysis. Exp.Clin Psychopharmacol. 2012 Oct; 20(5):420-9.
Sidney S. Cardiovascular consequences of marijuana use. J Clin 
Pharmacol. 2002 Nov; 42(11 Suppl):64S-70S.
Solowij N, Stephens RS, Roffman RA, Babor T, Kadden R, Miller M, 
Christiansen K, McRee B, Vendetti J; Marijuana Treatment Project 
Research Group. Cognitive functioning of long-term heavy cannabis 
users seeking treatment. JAMA. 2002 Mar 6; 287(9): 1123-31.
Stirling J, Lewis S, Hopkins R, White C. Cannabis use prior to first 
onset psychosis predicts spared neurocognition at 10-year follow-up. 
Schizophr Res. 2005 Jun 1; 75(1):135-7.
Substance Abuse and Mental Health Services Administration, Drug 
Abuse Warning Network, 2011: National Estimates of Drug-Related 
Emergency Department Visits. HHS Publication No. (SMA) 13-4760, DAWN 
Series D-39. Rockville, MD: Substance Abuse and Mental Health 
Services Administration, 2013.
Substance Abuse and Mental Health Services Administration, Results 
from the 2012 National Survey on Drug Use and Health: Summary of 
National Findings, NSDUH Series H-46, HHS Publication No. (SMA) 13-
4795. Rockville, MD: Substance Abuse and Mental Health Services 
Administration, 2013.
Substance Abuse and Mental Health Services Administration, Center 
for Behavioral Health Statistics and Quality. Treatment Episode Data 
Set (FEDS): 2001-2011. National Admissions to Substance Abuse 
Treatment Services. BHSIS Series S-65, HHS Publication No. (SMA) 13-
4772. Rockville, MD: Substance Abuse and Mental Health Services 
Administration, 2013.
Tait RJ, Mackinnon A, Christensen H. Cannabis use and cognitive 
function: 8-year trajectory in a young adult cohort. Addiction 2011 
Dec; 106(12):2195-203.
Tanasescu R, Constantinescu CS. Cannabinoids and the immune system: 
An overview. Immunobiology. 2010 Aug; 215(8):588-97.
Tanda G, Munzar P, Goldberg SR. Self-administration behavior is 
maintained by the psychoactive ingredient of marijuana in squirrel 
monkeys. Nat Neurosci. 2000 Nov; 3(11):1073-4.
Tashkin DP. Smoked marijuana as a cause of lung injury. Monaldi Arch 
Chest Dis. 2005 Jun; 63(2):93-l00.
Tashkin DP, Shapiro BJ, and Frank IM. 1974. Acute effects of smoked 
marijuana and oral delta9-tetrahydrocannabinol on specific airway 
conductance in asthmatic subjects. The American review of 
respiratory disease 109 (4): 420-428.
Tashkin, DP, Zhang, ZF, Greenland, S, Cozen, W, Mack, TM, 
Morgenstern, H. Marijuana Use and Lung Cancer: Results of a Case-
Control Study. Abstract #A 777, American Thoracic Society meeting, 
May 24, 2006.
The Plant List (2010). Version 1. Published on the Internet; http://www.theplantlist.org/ (accessed September 20, 2013)
Theunissen EL, Kauert GF, Toennes SW., Moeller MR, Sambeth A, 
Blanchard MM, Ramaekers JG. Neurophysiological functioning of 
occasional and heavy cannabis users during THC intoxication. 
Psychopharmacology (Berl.) 2012 Mar;220(2):341-50.
Trabert B, Sigurdson AJ, Sweeney AM, Strom SS, McGlynn KA. Marijuana 
use and testicular germ cell tumors. Cancer. 2011 Feb 15; 117: 848-
853.
Twitchell W, Brown S, Mackie K. Cannabinoids inhibit N- and P/Q-type 
calcium channels in cultured rat hippocampal neurons. J 
Neurophysiol. 1997 Jul; 78(1):43-50.
van der Meer FJ, Velthorst E, Meijer CJ, Machielsen MW, de HL. 
Cannabis use in patients at clinical high risk of psychosis: impact 
on prodromal symptoms and transition to psychosis. Curr Pharm Des. 
2012; 18(32):5036-44.
van Gastel WA, Wigman JT, Monshouwer K, Kahn RS, van OJ, Boks MP, 
Vollebergh WA. Cannabis use and subclinical positive psychotic 
experiences in early adolescence: findings from a Dutch survey. 
Addiction 2012 Feb; 107(2):381-7.
Van Gundy K, Rebellon CJ. A Life-course Perspective on the ``Gateway 
Hypothesis.'' J Health Soc Behav. 2010 Sep; 51(3):244-59.
van Os J, Bak M, Hanssen M, Bijl RV, de Graaf R, Verdoux H. Cannabis 
use and psychosis: a longitudinal population-based study. Am J 
Epidemiol. 2002 Aug 15; 156(4):319-27.
Vandrey RG, Budney AJ, Moore BA, Hughes JR. A cross-study comparison 
of cannabis and tobacco withdrawal. Am J Addict. 2005 Jan-Feb; 
14(1):54-63.
Vandrey RG, Budney AJ, Hughes JR, Liguori A. A within-subject 
comparison of withdrawal symptoms during abstinence from cannabis, 
tobacco, and both substances. Drug Alcohol Depend. 2008 Jan 1; 92(1-
3):48-54.
Vann RE, Gamage TF, Warner JA, Marshall EM, Taylor NL, Martin BR, 
Wiley JL. Divergent effects of cannabidiol on the discriminative 
stimulus and place conditioning effects of Delta(9) 
tetrahydrocannabinol. Drug Alcohol.Depend. 2008 Apr 1; 94(1-3):191-
8.
Vanyukov MM, Tarter RE, Kirillova GP, Kirisci L, Reynolds MD, Kreek 
MJ, Conway KP, Maher BS, Iacono WG, Bierut L, Neale MC, Clark DB, 
Ridenour TA. Common liability to addiction and ``gateway 
hypothesis'': theoretical, empirical and evolutionary perspective'. 
Drug Alcohol Depend. 2012 Jun; 123 Suppl 1:S3-17
von Sydow K, Lieb R, Pfister H, Hofler M, Wittchen HU.What predicts 
incident use of cannabis and progression to abuse and dependence? A 
4-year prospective examination of risk factors in a community sample 
of adolescents and young adults. Drug Alcohol Depend. 2002 Sep 1; 
68(1):49-64.
Wachtel SR, ElSohly MA, Ross SA, Ambre J, de Wit H. Comparison of 
the subjective effects of Delta (9)-tetrahydrocannabinol and 
marijuana in humans. Psychopharmacology (Berl). 2002 Jun; 
161(4):331-9.
Wagner JA, Varga K, Kunos G. Cardiovascular actions of cannabinoids 
and their generation during shock. J Mol Med. 1998 Nov-Dec; 
76(12):824-36.
Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, Gamsa A, 
Bennett GJ, and Collet JP. 2010. Smoked cannabis for chronic 
neuropathic pain: a randomized controlled trial. CMAJ: Canadian 
Medical Association journal =journal de !'Association medicate 
canadienne 182(14): E694-E701.

[[Page 53791]]

Wesson DR, Washburn P. Current patterns of drug abuse that involve 
smoking. NIDA. Res. Monogr. 1990; 99:5-11.
Wiley JL, Barrett RL, Britt DT, Balster RL, Martin BR. 
Discriminative stimulus effects of delta 9-tetrahydrocannabinol and 
delta 9-11-tetrahydrocannabinol in rats and rhesus monkeys. 
Neuropharmacology. 1993 Apr; 32(4):359-65.
Wiley JL, Huffman JW, Balster RL, Martin BR. Pharmacological 
specificity of the discriminative stimulus effects of delta 9-
tetrahydrocannabinol in rhesus monkeys. Drug Alcohol Depend. 1995 
Nov; 40(1):81-6.
Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, and Donaghe H. 
2013. Low-Dose Vaporized Cannabis Significantly Improves Neuropathic 
Pain. The journal of pain: official journal of the American Pain 
Society.
Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B, 
and Fishman S. 2008. A randomized, placebo-controlled, crossover 
trial of cannabis cigarettes in neuropathic pain. The journal of 
pain: official journal of the American Pain Society 9 (6): 506-521.
Wu X, French ED. Effects of chronic delta9-tetrahydrocannabinol on 
rat midbrain dopamine neurons: an electrophysiological assessment. 
Neuropharmacology. 2000 Jan 28; 39(3):391-8.
Yucel M, Bora E, Lubman DI, Solowij N, Brewer WJ, Cotton SM, Conus 
P, Takagi MJ, Fomito A, Wood SJ, et al. The impact of cannabis use 
on cognitive functioning in patients with schizophrenia: a meta-
analysis of existing findings and new data in a first-episode 
sample. Schizophr.Bull. 2012 Mar; 38(2):316-30.
Zeiger JS, Haberstick BC, Corley RP, Ehringer MA, Crowley TJ, Hewitt 
JK, Hopfer CJ, Stallings MC, Young SE., Rhee SH. Subjective effects 
to marijuana associated with marijuana use in community and clinical 
subjects. Drug Alcohol Depend. 2010 Jun 1; 109(1-3):161-6.
Zhang ZF, Morgenstern H, Spitz MR, Tashkin DP, Yu GP, Marshall JR, 
Hsu TC, Schantz SP. Marijuana use and increased risk of squamous 
cell carcinoma of the head and neck. Cancer Epidemiol Biomarkers 
Prev. 1999 Dec;8(12): 1071-8.
Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of 
cannabidiol on the anxiety and other effects produced by delta 9-THC 
in normal subjects. Psychopharmacology (Berl.)1982; 76(3):245-50.

The Medical Application of Marijuana: A Review of Published Clinical 
Studies

March 19, 2015

Prepared by:

U.S. Food and Drug Administration
Center for Drug Evaluation and Research (FDA/CDER)
Controlled Substance Staff (CSS)

                            Table of Contents
1. Introduction..............................................         71
2. Methods...................................................         73
    2.1 Define the Objective of the Review...................         73
    2.2 Define ``Marijuana''.................................         74
    2.3 Define ``Adequate and Well-Controlled Clinical                74
     Studies''...............................................
    2.4 Search Medical Literature Databases and Identify              75
     Relevant Studies........................................
    2.5 Review and Analyze Qualifying Clinical Studies.......         77
3. Results and Discussion....................................         77
    3.1 Neuropathic Pain.....................................         77
        3.1.1 Neuropathic Pain Associated with HIV-Sensory            77
         Neuropathy..........................................
        3.1.2 Central and Peripheral Neuropathic Pain........         81
    3.2 Appetite Stimulation in HIV..........................         86
    3.3 Spasticity in Multiple Sclerosis.....................         89
    3.4 Asthma...............................................         90
    3.5 Glaucoma.............................................         91
    3.6 Conclusions..........................................         91
        3.6.1 Conclusions for Chronic Neuropathic Pain.......         92
        3.6.2 Conclusions for Appetite Stimulation in HIV....         92
        3.6.3 Conclusions for Spasticity in MS...............         92
        3.6.4 Conclusions for Asthma.........................         93
        3.6.5 Conclusions for Glaucoma.......................         93
    3.7 Design Challenges for Future Studies.................         93
        3.7.1 Sample Size....................................         93
        3.7.2 Marijuana Dose Standardization.................         94
        3.7.3 Acute vs. Chronic Therapeutic Marijuana Use....         96
        3.7.4 Smoking as a Route of Administration...........         96
        3.7.5 Difficulty in Blinding of Drug Conditions......         96
        3.7.6 Prior Marijuana Experience.....................         97
        3.7.7 Inclusion and Exclusion Criteria...............         98
        3.7.8 Number of Female Subjects......................         99
Appendix (Tables)............................................        103
List of Figure
Figure 1: Identification of Studies From PubMed Search.......         76
List of Tables
Table 1: Randomized, controlled, double-blind trials                 103
 examining smoked marijuana in treatment of neuropathic pain.
Table 2: Randomized, controlled, double-blind trials                 109
 examining smoked marijuana in treatment of appetite
 stimulation in HIV/AIDS.....................................
Table 3: Randomized, controlled, double-blind trails                 112
 examining smoked marijuana in treatment of spasticity in
 Multiple Sclerosis..........................................
Table 4: Randomized, controlled, double-blind trails                 114
 examining smoked marijuana in treatment of intraocular
 pressure in Glaucoma........................................
Table 5: Randomized, controlled, double-blind trails                 116
 examining smoked marijuana in treatment of asthma...........
 

Executive Summary

    Marijuana is a Schedule I substance under the Controlled Substances 
Act (CSA). Schedule I indicates a high potential for abuse, no 
currently accepted medical use in the United States, and a lack of 
accepted safety for use under medical supervision. To date, marijuana 
has not been subject to an approved new drug application (NDA) that 
demonstrates its safety and efficacy for a specific indication under 
the Food Drug and Cosmetic Act (FDCA).
    Nevertheless, as of October 2014, twenty-three states and the 
District of

[[Page 53792]]

Columbia have passed state-level medical marijuana laws that allow for 
marijuana use within that state; similar bills are pending in other 
states.
    The present review was undertaken by the Food and Drug 
Administration (FDA) to analyze the clinical studies published in the 
medical literature investigating the use of marijuana in any 
therapeutic areas. First, we discuss the context for this scientific 
review. Next, we describe the methods used in this review to identify 
adequate and well-controlled studies evaluating the safety and efficacy 
of marijuana for particular therapeutic uses.
    The FDA conducted a systematic search for published studies in the 
medical literature that meet the described criteria for study design 
and outcome measures prior to February 2013. While not part of our 
systematic review, we have continued to routinely follow the literature 
beyond that date for subsequent studies. Studies were considered to be 
relevant to this review if the investigators administered marijuana to 
patients with a diagnosed medical condition in a well-controlled, 
double-blind, placebo-controlled clinical trial. Of the eleven studies 
that met the criteria for review, five different therapeutic areas were 
investigated:

 Five studies examined chronic neuropathic pain
 Two studies examined appetite stimulation in human 
immunodeficiency virus (HIV) patients
 Two studies examined glaucoma
 One study examined spasticity and pain in multiple sclerosis 
(MS)
 One study examined asthma.
    For each of these eleven clinical studies, information is provided 
regarding the subjects studied, the drug conditions tested (including 
dose and method of administration), other drugs used by subjects during 
the study, the physiological and subjective measures collected, the 
outcome of these measures comparing treatment with marijuana to 
placebo, and the reported and observed adverse events. The conclusions 
drawn by the investigators are then described, along with potential 
limitations of these conclusions based on the study design. A brief 
summary of each study's findings and limitations is provided at the end 
of the section.
    The eleven clinical studies that met the criteria and were 
evaluated in this review showed positive signals that marijuana may 
produce a desirable therapeutic outcome, under the specific 
experimental conditions tested. Notably, it is beyond the scope of this 
review to determine whether these data demonstrate that marijuana has a 
currently accepted medical use in the United States. However, this 
review concludes that these eleven clinical studies serve as proof-of-
concept studies, based on the limitations of their study designs, as 
described in the study summaries. Proof-of-concept studies provide 
preliminary evidence on a proposed hypothesis regarding a drug's 
effect. For drugs under development, the effect often relates to a 
short-term clinical outcome being investigated. Proof-of-concept 
studies serve as the link between preclinical studies and dose ranging 
clinical studies. Therefore, proof-of-concept studies are not 
sufficient to demonstrate efficacy of a drug because they provide only 
preliminary information about the effects of a drug. However, the 
studies reviewed produced positive results, suggesting marijuana should 
be further evaluated as an adjunct treatment for neuropathic pain, 
appetite stimulation in HIV patients, and spasticity in MS patients.
    The main limitations identified in the eleven studies testing the 
medical applications of marijuana are listed below:
     The small numbers of subjects enrolled in the studies, 
which limits the statistical analyses of safety and efficacy.
     The evaluation of marijuana only after acute 
administration in the studies, which limits the ability to determine 
efficacy following chronic administration.
     The administration of marijuana typically through smoking, 
which exposes ill patients to combusted material and introduces 
problems with determining the doses delivered.
     The potential for subjects to identify whether they 
received marijuana or placebo, which breaks the blind of the studies.
     The small number of cannabinoid na[iuml]ve subjects, which 
limits the ability to determine safety and tolerability in these 
subjects.
     The low number of female subjects, which makes it 
difficult to generalize the study findings to subjects of both genders.
    Thus, this review discusses the following methodological changes 
that may be made in order to resolve these limitations and improve the 
design of future studies which examine the safety and efficacy of 
marijuana for specific therapeutic indications:
     Determine the appropriate number of subjects studied based 
on recommendations in various FDA Guidances for Industry regarding the 
conduct of clinical trials for specific medical indications.
     Administer consistent and reproducible doses of marijuana 
based on recommendations in the FDA Guidance for Industry: Botanical 
Drug Products (2004).\27\
---------------------------------------------------------------------------

    \27\ This Guidance is available on the internet at http://www.fda.gov/Drugs/default.htm under Guidance (Drugs).
---------------------------------------------------------------------------

     Evaluate the effects of marijuana under therapeutic 
conditions following both acute and chronic administration.
     Consider alternatives to smoked marijuana (e.g., 
vaporization).
     Address and improve whenever possible the difficulty in 
blinding of marijuana and placebo treatments in clinical studies.
     Evaluate the effect of prior experience with marijuana 
with regard to the safety and tolerability of marijuana.
     Strive for gender balance in the subjects used in studies.
    In conclusion, the eleven clinical studies conducted to date do not 
meet the criteria required by the FDA to determine if marijuana is safe 
and effective in specific therapeutic areas. However, the studies can 
serve as proof-of-concept studies and support further research into the 
use of marijuana in these therapeutic indications. Additionally, the 
clinical outcome data and adverse event profiles reported in these 
published studies can beneficially inform how future research in this 
area is conducted. Finally, application of the recommendations listed 
above by investigators when designing future studies could greatly 
improve the available clinical data that can be used to determine if 
marijuana has validated and reliable medical applications.

1. Introduction

    In response to citizen petitions submitted to the Drug Enforcement 
Administration (DEA) requesting DEA to reschedule marijuana, the DEA 
Administrator requested that the U.S. Department of Health and Human 
Services (HHS) provide a scientific and medical evaluation of the 
available information and a scheduling recommendation for marijuana, in 
accordance with 21 U.S.C. 811(b). The Secretary of HHS is required to 
consider in a scientific and medical evaluation eight factors 
determinative of control under the Controlled Substance Act (CSA). 
Administrative responsibilities for evaluating a substance for control 
under the CSA are performed by the Food and Drug Administration (FDA), 
with the concurrence of the National Institute on Drug Abuse (NIDA). 
Part of

[[Page 53793]]

this evaluation includes an assessment of whether marijuana has a 
currently accepted medical use in the United States. This assessment 
necessitated a review of the available data from published clinical 
studies to determine whether there is adequate scientific evidence of 
marijuana's effectiveness.
    Under Section 202 of the CSA, marijuana is currently controlled as 
a Schedule I substance (21 U.S.C. 812). Schedule I includes those 
substances that have a high potential for abuse, have no currently 
accepted medical use in treatment in the United States, and lack 
accepted safety for use under medical supervision (21 U.S.C. 
812(b)(1)(A)-(C)).
    A drug product which has been approved by FDA for marketing in the 
United States is considered to have a ``currently accepted medical 
use.'' Marijuana is not an FDA-approved drug product, as a New Drug 
Application (NDA) or Biologics License application (BLA) for marijuana 
has not been approved by FDA. However, FDA approval of an NDA is not 
the only means through which a drug can have a currently accepted 
medical use in the United States.
    In general, a drug may have a ``currently accepted medical use'' in 
the United States if the drug meets a five-part test. Established case 
law (Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131, 1135 
(D.C. Cir. 1994)) upheld the Administrator of DEA's application of the 
five-part test to determine whether a drug has a ``currently accepted 
medical use.'' The following describes the five elements that 
characterize ``currently accepted medical use'' for a drug: \28\
---------------------------------------------------------------------------

    \28\ 57 FR 10499, 10504-06 (March 26, 1992).

---------------------------------------------------------------------------
i. The drug's chemistry must be known and reproducible

    ``The substance's chemistry must be scientifically established to 
permit it to be reproduced into dosages which can be standardized. The 
listing of the substance in a current edition of one of the official 
compendia, as defined by section 201(j) of the Food, Drug and Cosmetic 
Act, 21 U.S.C. 321(j), is sufficient to meet this requirement.''

ii. there must be adequate safety studies

    ``There must be adequate pharmacological and toxicological studies, 
done by all methods reasonably applicable, on the basis of which it 
could fairly and responsibly be concluded, by experts qualified by 
scientific training and experience to evaluate the safety and 
effectiveness of drugs, that the substance is safe for treating a 
specific, recognized disorder.''

iii. there must be adequate and well-controlled studies proving 
efficacy

    ``There must be adequate, well-controlled, well-designed, well-
conducted, and well-documented studies, including clinical 
investigations, by experts qualified by scientific training and 
experience to evaluate the safety and effectiveness of drugs, on the 
basis of which it could be fairly and responsibly concluded by such 
experts that the substance will have the intended effect in treating a 
specific, recognized disorder.''

iv. the drug must be accepted by qualified experts

    ``The drug has a New Drug Application (NDA) approved by the Food 
and Drug Administration, pursuant to the Food, Drug and Cosmetic Act, 
21 U.S.C. 355. Or, a consensus of the national community of experts, 
qualified by scientific training and experience to evaluate the safety 
and effectiveness of drugs, accepts the safety and effectiveness of the 
substance for use in treating a specific, recognized disorder. A 
material conflict of opinion among experts precludes a finding of 
consensus.'' and

v. the scientific evidence must be widely available.

    ``In the absence of NDA approval, information concerning the 
chemistry, pharmacology, toxicology, and effectiveness of the substance 
must be reported, published, or otherwise widely available, in 
sufficient detail to permit experts, qualified by scientific training 
and experience to evaluate the safety and effectiveness of drugs, to 
fairly and responsibly conclude the substance is safe and effective for 
use in treating a specific, recognized disorder.''
    One way to pass the five-part test for having ``currently accepted 
medical use'' is through submission of an NDA or BLA which is approved 
by FDA. However, FDA approval of an NDA or BLA is not required for a 
drug to pass the five-part test.
    This review focuses on FDA's analysis of one element of the five-
part test for determining whether a drug has ``currently accepted 
medical use''. Specifically, the present review assesses the 3rd 
criterion that addresses whether marijuana has ``adequate and well-
controlled studies proving efficacy''. Thus, this review evaluates 
published clinical studies that have been conducted using marijuana in 
subjects who have a variety of medical conditions by assessing the 
adequacy of the summarized study designs and the study data. The 
methodology for selecting the studies that were evaluated is delineated 
below.
    FDA's evaluation and conclusions regarding the remaining four 
criteria for whether marijuana has a ``currently accepted medical 
use,'' as well as the eight factors pertaining to the scheduling of 
marijuana, are outside the scope of this review. A detailed discussion 
of these factors is contained in FDA's scientific and medical 
evaluation of marijuana.

2. Methods

    The methods for selecting the studies to include in this review 
involved the following steps, which are described in detail in the 
subsections below:
    1. Define the objective of the review.
    2. Define ``marijuana'' in order to facilitate the medical 
literature search for studies that administered the substance,
    3. Define ``adequate and well-controlled studies'' in order to 
facilitate the search for relevant data and literature,
    4. Search medical literature databases and identify relevant 
adequate and well-controlled studies, and
    5. Review and analyze the adequate and well-controlled clinical 
studies to determine if they demonstrate efficacy of marijuana for any 
therapeutic indication.

2.1 Define the Objective of the Review

    The objective of this review is to assess the study designs and 
resulting data from clinical studies published in the medical 
literature that were conducted with marijuana (as defined below) as a 
treatment for any therapeutic indication, in order to determine if they 
meet the criteria of ``adequate and well-controlled studies proving 
efficacy''.

2.2 Define ``Marijuana''

    In this review, the term ``marijuana'' refers to the flowering tops 
or leaves of the Cannabis plant. There were no restrictions on the 
route of administration used for marijuana in the studies.
    Studies which administered individual cannabinoids (whether 
experimental substances or marketed drug products) or marijuana 
extracts were excluded from this review. Additionally, studies of 
administered neutral plant material or placebo marijuana (marijuana 
with all cannabinoids extracted) that had subsequently been 
supplemented by the addition of specific amounts of THC or other 
cannabinoids were also excluded (Chang et al., 1979).

[[Page 53794]]

2.3 Define ``Adequate and Well-Controlled Clinical Studies''

    The criteria for an ``adequate and well-controlled study'' for 
purposes of determining the safety and efficacy of a human drug is 
defined under the Code of Federal Regulations (CFR) in 21 CFR 314.126. 
The elements of an adequate and well-controlled study as described in 
21 CFR 314.126 can be summarized as follows:
    1. The main objective must be to assess a therapeutically relevant 
outcome.
    2. The study must be placebo-controlled.
    3. The subjects must qualify as having the medical condition being 
studied.
    4. The study design permits a valid comparison with an appropriate 
control condition.
    5. The assignment of subjects to treatment and control groups must 
be randomized.
    6. There is minimization of bias through the use of a double-blind 
study design.
    7. The study report contains a full protocol and primary data.
    8. Analysis of the study data is appropriately conducted.
    As noted above, the current review examines only those data 
available in the public domain and thus relies on clinical studies 
published in the medical literature. Published studies by their nature 
are summaries that do not include the level of detail required by 
studies submitted to FDA in an NDA.
    While the majority of the elements defining an adequate and well-
controlled study can be satisfied through a published paper (elements 
#1-6), there are two elements that cannot be met by a study published 
in the medical literature: element #7 (availability of a study report 
with full protocol and primary data) and element #8 (a determination of 
whether the data analysis was appropriate). Thus, for purposes of this 
review, only elements #1-6 will be used to qualify a study as being 
adequate and well-controlled.

2.4 Search Medical Literature Databases and Identify Relevant Studies

    We identified randomized, double-blind, placebo-controlled clinical 
studies conducted with marijuana to assess marijuana's efficacy in any 
therapeutic indication. Two primary medical literature databases were 
searched for all studies posted to the databases prior to February 
2013: \29\
---------------------------------------------------------------------------

    \29\ While not a systematic review, we have followed the recent 
published literature on marijuana use for possible therapeutic 
purposes and, as of January 2015, we found only one new study that 
would meet our criteria (Naftali et al., 2013). This study examined 
the effects of smoked marijuana on Crohn's disease.
---------------------------------------------------------------------------

     PubMed: PubMed is a database of published medical and 
scientific studies that is maintained by the U.S. National Library of 
Medicine (NLM) at NIH as a part of the Entrez system of information 
retrieval. PubMed comprises more than 24 million citations for 
biomedical literature from MEDLINE, life science journals, and online 
books (http://www.ncbi.nlm.nih.gov/pubmed).
     ClinicalTrials.gov: ClinicalTrials.gov is a database of 
publicly and privately supported clinical studies that is maintained by 
the NLM. Information about the clinical studies is provided by the 
Sponsor or Principal Investigator of the study. Information about the 
studies is submitted to the Web site (``registered'') when the studies 
begin, and is updated throughout the study. In some cases, results of 
the study or resulting publication citations are submitted to the Web 
site after the study ends (https://clinicaltrials.gov/ct2/about-site/background).
    ClinicalTrials.gov was searched for all studies administering 
marijuana. The results of this search were used to confirm that no 
completed studies with published data were missed in the literature 
search. During the literature search, references found in relevant 
studies and systematic reviews were evaluated for additional relevant 
citations. All languages were included in the search. The PubMed search 
yielded a total of 566 abstracts.\30\ Of these abstracts, a full-text 
review was conducted with 85 papers to assess eligibility. From this 
evaluation, only eleven of 85 studies met the 6 CFR elements for 
inclusion as adequate and well-controlled studies.
---------------------------------------------------------------------------

    \30\ The following search strategy was used, ``(cannabis OR 
marijuana) AND (therapeutic use OR therapy) AND (RCT OR randomized 
controlled trial OR ``systematic review'' OR clinical trial OR 
clinical trials) NOT (``marijuana abuse''[Mesh] OR addictive 
behavior OR substance related disorders)''.
---------------------------------------------------------------------------

    Figure 1 (below) provides an overview of the process used to 
identify studies from the PubMed search. The eleven studies reviewed 
were published between 1974 and 2013. Ten of these studies were 
conducted in the United States and one study was conducted in Canada. 
These eleven studies examined the effects of smoked and vaporized 
marijuana for the indications of chronic neuropathic pain, spasticity 
related to multiple sclerosis (MS), appetite stimulation in patients 
with human immunodeficiency virus (HIV), glaucoma, and asthma. All 
included studies used adult patients as subjects. All studies conducted 
in the United States were conducted under an IND as Phase 2 
investigations.

[[Page 53795]]

[GRAPHIC] [TIFF OMITTED] TP12AU16.025

    Two qualifying studies, which assessed marijuana for glaucoma, were 
previously reviewed in the 1999 Institute of Medicine (IOM) report 
entitled ``Marijuana and Medicine: Assessing the Science Base''.\31\ We 
did our own analysis of these two studies and concurred with the 
conclusions in the IOM report. Thus, a detailed discussion of the two 
glaucoma studies is not included in the present review. The present 
review only discusses 9 of the identified 11 studies. For a summary of 
the study design for all eleven qualifying studies, see Tables 1-5 
(located in the Appendix).
---------------------------------------------------------------------------

    \31\ In January 1997, the White House Office of National Drug 
Control Policy (ONDCP) requested that the IOM conduct a review of 
the scientific evidence to assess the potential health benefits and 
risks of marijuana and its constituent cannabinoids. Information for 
this study was gathered through scientific workshops, site visits to 
cannabis buyers' clubs and HIV/Acquired Immunodeficiency Syndrome 
(AIDS) clinics, analysis of the relevant scientific literature, and 
extensive consultation with biomedical and social scientists. The 
report was finalized and published in 1999.
---------------------------------------------------------------------------

    Based on the selection criteria for relevant studies described in 
Section 2.3 (Define Adequate and Well-Controlled Clinical Studies), a 
number of clinical studies that investigated marijuana, as defined in 
this review, were excluded from this review. Studies that examined the 
effects of marijuana in healthy subjects were excluded because they did 
not test a patient population with a medical condition (Flom et al., 
1975; Foltin et al., 1986; Foltin et al., 1988; Hill et al., 1974; 
Milstein et al., 1974; Milstein et al., 1975; Soderpalm et al., 2001; 
Wallace et al., 2007; Greenwald and Stitzer, 2000). A 1975 study by 
Tashkin et al. was excluded because it had a single-blind, rather than 
double-blind, study design. Two other studies were excluded because the 
primary outcome measure assessed safety rather than a therapeutic 
outcome (Greenberg et al., 1994; Abrams et al., 2003).

2.5 Review and Analyze Qualifying Clinical Studies

    Qualified clinical studies that evaluated marijuana for therapeutic 
purposes were examined in terms of adequacy of study design including 
method of drug administration, study size, and subject inclusion and 
exclusion criteria. Additionally, the measures and methods of analysis 
used in the studies to assess the treatment effect were examined.

3. Results and Discussion

    The eleven qualifying studies in this review assessed a variety of 
therapeutic indications. In order to better facilitate analysis and 
discussion of the studies, the following sections group the studies by 
therapeutic area. Within each section, each individual study is 
summarized in terms of its design, outcome data and important 
limitations. This information is also provided in the Appendix in 
tabular form for each study.

3.1 Neuropathic Pain

    Five randomized, double-blind, placebo-controlled Phase 2 clinical 
studies have been conducted to examine the effects of inhaled marijuana 
smoke on neuropathic pain associated with HIV-sensory neuropathy 
(Abrams et al., 2007; Ellis et al., 2009) and chronic neuropathic pain 
from multiple causes

[[Page 53796]]

(Wilsey et al., 2008; Ware et al., 2010; Wilsey et al., 2013). Table 1 
of the Appendix summarizes these studies.
3.1.1 Neuropathic Pain Associated With HIV-Sensory Neuropathy
    Two studies examined the effect of marijuana to reduce the pain 
induced by HIV-sensory neuropathy.
    Abrams et al. (2007) conducted the first study entitled, ``Cannabis 
in painful HIV-associated sensory neuropathy: A randomized placebo-
controlled trial''. The subjects were 50 adult patients with 
uncontrolled HIV-associated sensory neuropathy, who had at least 6 
experiences with smoking marijuana. The subjects were split into two 
parallel groups of 25 subjects each. More than 68% of subjects were 
current marijuana users, but all individuals were required to 
discontinue using marijuana prior to the study. Most subjects were 
taking medication for pain during the study, with the most common 
medications being opioids and gabapentin. Upon entry into the study, 
subjects had an average daily pain score of at least 30 on a 0-100 
visual analog scale (VAS).
    Subjects were randomized to receive either smoked marijuana (3.56% 
THC \32\) or smoked placebo cigarettes three times per day for 5 days, 
using a standardized cued smoking procedure: (1) 5 second inhale, (2) 
10 second holding smoke in the lungs, (3) 40 second exhale and 
breathing normally between puffs. The authors did not specify how many 
puffs the subjects smoked at each smoking session, but they stated that 
one cigarette was smoked per smoking session.
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    \32\ The drug dose is reported as percentage of THC present in 
the marijuana rather than milligrams of THC present in each 
cigarette because of the difficulty in determining the amount of THC 
delivered by inhalation (see discussion in the section entitled 
``3.7.2 Marijuana Dose Standardization'').
---------------------------------------------------------------------------

    Primary outcome measures included daily VAS ratings of chronic pain 
and the percentage of subjects who reported a result of more than 30% 
reduction in pain intensity. The ability of smoked marijuana to induce 
acute analgesia was assessed using both thermal heat model and 
capsaicin sensitization model, while anti-hyperalgesia was assessed 
with brush and von Frey hair stimuli. The immediate analgesic effects 
of smoked marijuana was assessed using a 0-100 point VAS at 40-minute 
intervals three times before and three times after the first and last 
smoking sessions, which was done to correspond to the time of peak 
plasma cannabinoid levels. Notably, not all subjects completed the 
induced pain portion of the study (n = 11 in marijuana group, 9 in 
placebo group) because of their inability to tolerate the stimuli. 
Throughout the study, subjects also completed the Profile of Mood 
States (POMS) questionnaire, as well as subjective VAS measures of 
anxiety, sedation, disorientation, paranoia, confusion, dizziness, and 
nausea.
    As a result, the median daily pain was reduced 34% by smoked 
marijuana compared to 17% by placebo (p = 0.03). Fifty-two percent of 
subjects who smoked marijuana reported a >30% reduction in pain 
compared to 24% in the placebo group (p = 0.04). Although marijuana 
reduced experimentally-induced hyperalgesia (p <= 0.05) during the 
first smoking sessions, marijuana did not alter responses to acutely 
painful stimuli.
    There were no serious AEs and no episodes of hypertension, 
hypotension, or tachycardia requiring medical intervention. No subjects 
withdrew from the study for drug related reasons. Subjects in the 
marijuana group reported higher ratings on the subjective measures of 
anxiety, sedation, disorientation, confusion, and dizziness compared to 
the placebo group. There was one case of severe dizziness in a 
marijuana-treated subject. By the end of the study, subjects treated 
with marijuana and placebo reported a reduction in total mood 
disturbance as measured by POMS.
    The authors conclude that smoked marijuana effectively reduced 
chronic neuropathic pain from HIV-associated sensory neuropathy with 
tolerable side effects. However, limitations of this study include: 
Maintenance of subjects on other analgesic medication while being 
tested with marijuana and a lack of information about the number of 
puffs during each inhalation of smoke. These limitations make it 
difficult to conclude that marijuana has analgesic properties on its 
own and that the actual AEs experienced during the study in response to 
marijuana are tolerable. However, the study produced positive results 
suggesting that marijuana should be studied further as an adjunct 
treatment for uncontrolled HIV-associated sensory neuropathy.
    Ellis et al. (2009) conducted a more recent study entitled ``Smoked 
medicinal cannabis for neuropathic pain in HIV: a randomized, crossover 
clinical trial''. The subjects were 28 HIV-positive adult male patients 
with intractable neuropathic pain that was refractory to the effects of 
at least two drugs taken for analgesic purposes. Upon entry into the 
study, subjects had a mean score of >5 on the Pain Intensity subscale 
of the Descriptor Differential Scale (DDS). Subjects were allowed to 
continue taking their current routine of pain medications, which 
included opioids, non-narcotic analgesics, antidepressants, and 
anticonvulsants. Previous experience with marijuana was not required 
for participation in the study, but 27 of 28 subjects (96%) reported 
previous experience with marijuana. However, of these 27 experienced 
subjects, 63% (n = 18) reported no marijuana use within the past year.
    The study procedures compared the effects of the target dose of 
marijuana and placebo during two treatment periods lasting 5 days, with 
2 weeks washout periods. The marijuana strengths available were 1%, 2%, 
4%, 6%, or 8% THC concentration by weight. Subjects smoked marijuana or 
placebo cigarettes four times per day, approximately 90-120 minutes 
apart, using a standardized cued smoking procedure: (1) 5 second smoke 
inhalation, (2) 10 second hold of smoke in lungs, (3) 40 second exhale 
and normal breathing between puffs. The investigators did not provide a 
description of the number of puffs taken at any smoking session. All 
subjects practiced the smoking procedures using placebo marijuana prior 
to test sessions.
    On the first day of each test period, dose titration occurred 
throughout the four smoking sessions scheduled for that day, with a 
starting strength of 4% THC concentration. Subjects were allowed to 
titrate to a personalized ``target dose'', which was defined as the 
dose that provided the best pain relief without intolerable adverse 
effects. This dose titration was accomplished by allowing subjects to 
either increase the dose incrementally (to 6% or 8% THC) to improve 
analgesia, or to decrease the dose incrementally (to 1% or 2% THC) if 
AEs were intolerable. For the next 4 days of each test period, the 
subjects smoked their target dose during each of the four daily smoking 
sessions. To maintain the blind, placebo marijuana was represented as 
containing 1%-8% THC, even though it did not contain any cannabinoids.
    The primary outcome measure was the change in pain magnitude on the 
DDS at the end of each test period compared to baseline, with a 
clinically significant level of analgesia considered to be a reduction 
in pain of at least 30%. Additional measures included the POMS, the 
Sickness Impact Profile (SIP), the Brief Symptom Inventory (BSI) and 
the UKU Side Effect Rating Scale and a subjective highness/sedation 
VAS.
    During the marijuana treatment week, 19 subjects titrated to the 
2%-4% THC dose while the 6%-8% dose was

[[Page 53797]]

preferred by 8 subjects and 1 subject chose the 1% dose. In contrast, 
during the placebo treatment week, all 28 subjects titrated to the 
highest possible dose of ``8% THC'' that contained no actual 
cannabinoids, suggesting that placebo treatment provided little 
analgesic relief.
    The degree of pain reduction was significantly greater after 
administration of marijuana compared to placebo (median change of 3.3 
points on DDS, p = 0.016). The median change from baseline in VAS pain 
scores was -17 for marijuana treatment compared to -4 for placebo 
treatment (p < 0.001). A larger proportion of subjects who were treated 
with marijuana (0.46) reported a >30% reduction in pain, compared to 
placebo (0.18). Additionally, the authors report improvements in total 
mood disturbance, physical disability, and quality of life as measured 
on POMS, SIP, and BSI scales after both placebo and marijuana treatment 
(data not provided in paper).
    In terms of safety, there were no alterations in HIV disease 
parameters in response to marijuana or placebo. The authors report that 
marijuana led to a greater degree of UKU responses as well as AEs such 
as difficulty in concentration, fatigue, sleepiness or sedation, 
increased duration of sleep, reduced salivation and thirst compared to 
placebo (data not provided in paper). Two subjects withdrew from the 
study because of marijuana-related AEs: one subject developed an 
intractable smoking-related cough during marijuana administration and 
the sole marijuana-na[iuml]ve subject in the study experienced an 
incident of acute cannabis-induced psychosis.\33\
---------------------------------------------------------------------------

    \33\ At the time of the study, the following criteria from the 
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR, 
2000) were used to diagnose substance-induced psychotic disorders: 
Prominent hallucinations or delusions; Hallucinations and/or 
delusions that develop during, or within one month of, intoxication 
or withdrawal; The disturbance is not better accounted for by a 
psychotic disorder that is not substance induced. The disturbance 
does not occur exclusively during the course of a delirium.
---------------------------------------------------------------------------

    The authors conclude that smoked marijuana effectively reduced 
chronic neuropathic pain from HIV-associated sensory neuropathy. The 
limitations of this study include: a lack of information about the 
number of puffs during each inhalation of smoke; a lack of information 
about the specific timing of the subjective assessments and collection 
of AEs relative to initiation of the smoking sessions; and the 
inclusion of only one marijuana-na[iuml]ve subject. These limitations 
make it difficult to conclude that the actual AEs experienced during 
the study in response to marijuana are tolerable. It is especially 
concerning that the only marijuana-na[iuml]ve subject left the study 
because of serious psychiatric responses to marijuana exposure at 
analgesic doses. However, the study produced positive results 
suggesting that marijuana should be studied further as an adjunct 
treatment for uncontrolled HIV-associated sensory neuropathy.
3.1.2 Central and Peripheral Neuropathic Pain
    Three studies examined the effect of marijuana on chronic 
neuropathic pain.
    Wilsey et al. (2008) examined chronic neuropathic pain from 
multiple causes in the study entitled, ``A Randomized, Placebo-
Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic 
Pain''. The subjects were 32 patients with a variety of neuropathic 
pain conditions, including 22 with complex regional pain syndrome, 6 
with spinal cord injury, 4 with multiple sclerosis, 3 with diabetic 
neuropathy, 2 with ilioinguinal neuralgia, and 1 with lumbosacral 
plexopathy. All subjects reported a pain intensity of at least 30 on a 
0-100 VAS and were allowed to continue taking their regular medications 
during the study period, which included opioids, antidepressants, 
anticonvulsants, and NSAIDs. All subjects were required to have 
experience with marijuana but could not use any cannabinoids for 30 
days before study sessions.
    The study consisted of three test sessions with an interval of 3-21 
days between sessions. Treatment conditions were high-strength 
marijuana (7% delta-9-THC), low-strength marijuana (3.5% delta-9-THC), 
and placebo cigarettes, administered through a standardized cued-puff 
procedure: (1) ``light the cigarette'' (30 seconds), (2) ``get ready'' 
(5 seconds), (3) ``inhale'' (5 seconds), (4) ``hold smoke in lungs'' 
(10 seconds), (5) ``exhale,'' and (6) wait before repeating the puff 
cycle (40 seconds). Participants took 2 puffs after baseline 
measurements, 3 puffs an hour later, and 4 puffs an hour after that, 
for a cumulative dose of 9 puffs per test session.
    Hourly assessment periods were scheduled before and after each set 
of puffs and for 2 additional hours during the recovery period. Plasma 
cannabinoids were measured at baseline, 5 minutes after the first puff 
and again at 3 hours after the last puff cycle.
    The primary outcome measure was spontaneous pain relief, as 
measured by a 0-100 point VAS for current pain. Pain unpleasantness was 
measured on a 0-100 point VAS, and degree of pain relief was measured 
on a 7-point Patient Global Impression of Change (PGIC) scale. 
Secondary measures included the Neuropathic Pain Scale (NPS), a 0-100 
point VAS for allodynia, and changes in thermal pain threshold. 
Subjective measures were also evaluated with unipolar 0-100 point VAS 
for any drug effect, good drug effect, bad drug effect, high, drunk, 
impaired, stoned, like the drug effect, sedated, confused, nauseated, 
desire more of the drug, anxious, down, hungry, and bipolar 0-100 point 
VAS for sad/happy, anxious/relaxed, jittery/calm, bad/good, paranoid/
self-assured, fearful/unafraid. Neurocognitive assessments measured 
attention and concentration, learning and memory, and fine motor speed.
    Marijuana produced a reduction in pain compared to placebo, as 
measured by the pain VAS, the PGIC and on pain descriptors in the NPS, 
including sharp (P < .001), burning (P < .001), aching (P < .001), 
sensitive (P = .03), superficial (P < .01) and deep pain (P < .001). 
Notably, there were no additional benefits from the 7% THC strength of 
marijuana compared to the 3.5% THC strength, seemingly because of 
cumulative drug effects over time. There were no changes in allodynia 
or thermal pain responsivity following administration of either dose of 
marijuana.
    Marijuana at both strengths produced increases on measures of any 
drug effect, good drug effect, high, stoned, impairment, sedation, 
confusion, and hunger. The 7% THC marijuana increased anxiety scores 
and bad drug effect (later in session) compared to placebo. Neither 
strength of marijuana affected the measures of mood. On neurocognitive 
measures, both the 3.5% THC and 7% THC marijuana produced impairment in 
learning and memory, while only the 7% THC marijuana impaired attention 
and psychomotor speed, compared to placebo. There were no adverse 
cardiovascular side effects and no subjects dropped out because of an 
adverse event related to marijuana.
    The authors conclude that marijuana may be effective at 
ameliorating neuropathic pain at doses that induce mild cognitive 
effects, but that smoking is not an optimum route of administration. 
The limitations of this study include: Inclusion of subjects with many 
forms of neuropathic pain and maintenance of subjects on other 
analgesic medication while being tested with marijuana. These 
limitations make it difficult to conclude that marijuana has analgesic 
properties on its own and that the actual AEs experienced during the 
study in response to marijuana are tolerable. The authors compared pain 
score results by the type of pain

[[Page 53798]]

condition, with no significant differences found; however, the sample 
size of this study was small thus a type II error may have been 
present. Thus, it is difficult to determine if any particular subset of 
neuropathic pain conditions would benefit specifically from marijuana 
administration. However, the study produced positive results suggesting 
that marijuana should be studied further as an adjunct treatment for 
uncontrolled neuropathic pain.
    The second study, conducted by Ware et al. (2010) in Canada is 
entitled, ``Smoked cannabis for chronic neuropathic pain: a randomized 
controlled trial''. The subjects were 21 adult patients with 
neuropathic pain caused by trauma or surgery compounded with allodynia 
or hyperalgesia, and a pain intensity score greater than 4 on a 10 
point VAS. All subjects maintained their current analgesic medication 
and they were allowed to use acetaminophen for breakthrough pain. 
Eighteen subjects had previous experience with marijuana but none of 
them had used marijuana within a year before the study.
    The study design used a four-period crossover design, testing 
marijuana (2.5%, 6.0% and 9.4% THC) and placebo marijuana. The 2.5% and 
6.0% doses of marijuana were included to increase successful blinding. 
Each period was 14 days in duration, beginning with 5 days on the study 
drug followed by a 9-day washout period. Doses were delivered as 25 mg 
of marijuana that was smoked in a single inhalation using a titanium 
pipe. The first dose of each period was self-administered using a 
standardized puff procedure: (1) Inhale for 5 seconds, (2) hold the 
smoke in their lungs for 10 seconds, and (3) exhale. Subsequent doses 
were self-administered in the same manner for a total of three times 
daily at home on an outpatient basis for the first five days of each 
period.
    The primary measure was an 11-point pain intensity scale, averaged 
over the 5 day treatment period, which was administered once daily for 
present, worst, least and average pain intensity during the previous 24 
hours. Secondary measures included an acute pain 0-100 point VAS, pain 
quality assessed with the McGill Pain Questionnaire, sleep assessed 
with the Leeds Sleep Evaluation Questionnaire, mood assessed with the 
POMS, quality of life assessed using the EQ-5D health outcome 
instrument. Subjective measures included 0-100 point VAS scales for 
high, relaxed, stressed and happy.
    Over the first three hours after smoking marijuana, ratings of 
pain, high, relaxation, stress, happiness and heart rate were recorded. 
During the five days of each study period, participants were contacted 
daily to administer questionnaires on pain intensity, sleep, medication 
and AEs. Subjects returned on the fifth day to complete questionnaires 
on pain quality, mood, quality of life and assessments of potency. At 
the end of the study, participants completed final adverse event 
reports and potency assessments.
    The average daily pain intensity was significantly lower on 9.4% 
THC marijuana (5.4) than on placebo marijuana (6.1) (p = 0.023). The 
9.4% THC strength also produced more drowsiness, better sleep, with 
less anxiety and depression, compared to placebo (all p < 0.05). 
However, there were no significant differences on POMS scores or on VAS 
scores for high, happy, relaxed or stressed between THC doses.
    The most frequent drug-related adverse events reported in the group 
receiving 9.4% THC marijuana were headache, dry eyes, burning 
sensation, dizziness, numbness and cough. Reports of high and euphoria 
occurred on only three occasions, once in each dose of THC. There were 
no significant changes in vital signs, heart-rate variability, or renal 
function. One subject withdrew from the study due to increased pain 
during administration of 6% THC marijuana.
    The authors conclude that smoked marijuana reduces neuropathic 
pain, improves mood and aids in sleep, but that smoking marijuana is 
not a preferable route of administration. The limitations of this study 
include: The lack of information on timing of assessments during the 
outpatient portion of the study and maintenance of subjects on other 
analgesic medication while being tested with marijuana. These 
limitations make it difficult to conclude that marijuana has analgesic 
properties on its own and that the actual AEs experienced during the 
study in response to marijuana are tolerable. However, the study 
produced positive results suggesting that marijuana should be studied 
further as an adjunct treatment for uncontrolled neuropathic pain.
    Wilsey et al. (2013) conducted the most recent study entitled, 
``Low-Dose Vaporized Cannabis Significantly Improves Neuropathic 
Pain''. This study is the only one in this review that utilized 
vaporization as a method of marijuana administration. The subjects were 
36 patients with a neuropathic pain disorder (CRPS, thalamic pain, 
spinal cord injury, peripheral neuropathy, radiculopathy, or nerve 
injury) who were maintained on their current medications (opioids, 
anticonvulsants, antidepressants, and NSAIDs). Although subjects were 
required to have a history of marijuana use, they refrained from use of 
cannabinoids for 30 days before study sessions.
    Subjects participated in three sessions in which they received 
1.29% or 3.53% THC marijuana or placebo marijuana. The marijuana was 
vaporized using the Volcano vaporizer and a standardized cued-puff 
procedure: (1) ``hold the vaporizer bag with one hand and put the 
vaporizer mouthpiece in their mouth'' (30 seconds), (2) ``get ready'' 
(5 seconds), (3) ``inhale'' (5 seconds), (4) ``hold vapor in lungs'' 
(10 seconds), (5) ``exhale and wait'' before repeating puff cycle (40 
seconds). Subjects inhaled 4 puffs at 60 minutes. At 180 minutes, the 
vaporizer was refilled with marijuana vapor and subjects were allowed 
to inhale 4 to 8 puffs using the cued procedure. Thus, cumulative 
dosing allowed for a range of 8 to12 puffs in total for each session, 
depending on the subjects desired response and tolerance. The washout 
time between each session ranged from 3-14 days.
    The primary outcome variable was spontaneous pain relief, as 
assessed using a 0-100 point VAS for current pain. Secondary measures 
included the Patient Global Impression of Change (PGIC), the 
Neuropathic Pain Scale (NPS), a 0-100 point VAS for allodynia. Acute 
pain threshold was measured with a thermal pain model. Subjective 
measures included 0-100 point unipolar VAS for any drug effect, good 
drug effect, bad drug effect, high, drunk, impaired, stoned, drug 
liking, sedated, confused, nauseated, desire more drug, anxious, down 
and hungry. Bipolar 0-100 point VAS included sad/happy, anxious/
relaxed, jittery/calm, bad/good, paranoid/self-assured, and fearful/
unafraid.
    Neurocognitive assessments assessed attention and concentration, 
learning and memory, and fine motor speed.
    A 30% reduction in pain was achieved in 61% of subjects who 
received the 3.53% THC marijuana, in 57% of subjects who received the 
1.29% THC marijuana and in 26% of subjects who received the placebo 
marijuana (p = 0.002 for placebo vs. 3.53% THC, p = 0.007 for placebo 
vs 1.29% THC; p > 0.05 1.29% THC vs. 3.53% THC). Both strengths of 
marijuana significantly decreased pain intensity, unpleasantness, 
sharpness, and deepness on the NPS, as well as pain ratings on the 
PGIC, compared to placebo. These effects on pain were maximal with 
cumulative dosing over

[[Page 53799]]

the course of the study session, with maximal effects at 180 minutes. 
There were no effects of marijuana compared to placebo on measures of 
allodynia or thermal pain. Subjects correctly identified the study 
treatment 63% of the time for placebo, 61% of the time for 1.29% THC, 
and 89% of the time for 3.53% THC.
    On subjective measures, marijuana produced dose-dependent increases 
compared to placebo on ratings for: any drug effect, good drug effect, 
drug liking, high, stoned, sedated, confused, and hungry. Both 
strengths of marijuana produced similar increases in drunk or impaired 
compared to placebo. In contrast, desire for drug was rated as higher 
for the 1.29% THC marijuana compared to the 3.53% THC marijuana. There 
were no changes compared to placebo for bad effect, nauseous, anxiety, 
feeling down or any of the bipolar mood assessments. There was dose-
dependent impairment on learning and memory from marijuana compared to 
placebo, but similar effects between the two strengths of marijuana on 
attention.
    The authors conclude that vaporization of relatively low doses of 
marijuana can produce improvements in analgesia in neuropathic pain 
patients, especially when patients are allowed to titrate their 
exposure. However, this individualization of doses may account for the 
general lack of difference between the two strengths of marijuana. No 
data were presented regarding the total amount of THC consumed by each 
subject, so it is difficult to determine a proper dose-response 
evaluation. Additional limitations of this study are the inclusion of 
subjects with many forms of neuropathic pain and maintenance of 
subjects on other analgesic medication while being tested with 
marijuana. These limitations make it difficult to conclude that 
marijuana has analgesic properties on its own. It is also difficult to 
determine if any particular subset of neuropathic pain conditions would 
benefit specifically from marijuana administration. However, the study 
produced positive results suggesting that marijuana should be studied 
further as an adjunct treatment for uncontrolled neuropathic pain.

3.2 Appetite Stimulation in HIV

    Two randomized, double-blind, placebo-controlled Phase 2 studies 
examined the effects of smoked marijuana on appetite in HIV-positive 
subjects (Haney et al., 2005; Haney et al., 2007). Table 2 of the 
Appendix summarizes both studies.
    The first study, conducted by Haney et al. (2005) is entitled, 
``Dronabinol and marijuana in HIV+ marijuana smokers: Acute effects on 
caloric intake and mood''. The subjects were 30 HIV-positive patients 
who were maintained on two antiretroviral medications and either had 
clinically significant decreases in lean muscle mass \34\ (low-BIA 
group, n = 15) or normal lean muscle mass (normal-BIA group, n = 15). 
All subjects had a history of smoking marijuana at least twice weekly 
for 4 weeks prior to entry into the study. On average, individuals had 
smoked 3 marijuana cigarettes per day, 5-6 times per week for 10-12 
years.
---------------------------------------------------------------------------

    \34\ Lean muscle mass was assessed using bioelectrical impedance 
analysis (BIA). The low-BIA group was classified with having <90% 
BIA, and the normal-BIA group was classified with having >90% BIA.
---------------------------------------------------------------------------

    Subjects participated in 8 sessions that tested the acute effects 
of 0, 10, 20, and 30 mg dronabinol oral capsules and marijuana 
cigarettes with 0%, 1.8%, 2.8%, and 3.9% THC concentration by weight, 
using a double-dummy design (with only one active drug per session). 
The doses of dronabinol are higher than those doses typically 
prescribed for appetite stimulation in order to help preserve the 
blinding. There was a one-day washout period between test sessions.
    Marijuana was administered using a standardized cued procedure: (1) 
``light the cigarette'' (30 seconds), (2) ``prepare'' (5 seconds), (3) 
``inhale'' (5 seconds), (4) ``hold smoke in lungs'' (10 seconds), and 
(5) ``exhale.'' Each subject smoked three puffs in this manner, with a 
40-second interval between each puff.
    Caloric intake was used as a surrogate measure for weight gain. 
Subjects received a box containing a variety of food and beverage items 
and were told to record consumption of these items following that day's 
administration of the test drug. Subjective measures included 0-100 
point VAS for feel drug effect, good effect, bad effect, take drug 
again, drug liking, hungry, full, nauseated, thirsty, desire to eat. 
Neurocognitive measures and vital signs were monitored.
    The low BIA group consumed significantly more calories in the 1.8% 
and 3.9% THC marijuana conditions (p<0.01) and the 10, 20, and 30 mg 
dronabinol conditions (p<0.01) compared with the placebo condition. In 
contrast, in the normal BIA group, neither marijuana nor dronabinol 
significantly affected caloric intake. This lack of effect may be 
accountable, however, by the fact that this group consumed 
approximately 200 calories more than the low BIA group under baseline 
conditions.
    Ratings of high and good drug effect were increased by all drug 
treatments in both the low-BIA and normal-BIA groups, except in 
response to the 10 mg dose of dronabinol. The 3.9% THC marijuana 
increased ratings of good drug effect, drug liking and desire to smoke 
again compared with placebo. Ratings of sedation were increased in both 
groups by 10 and 30 mg dronabinol, and in the normal BIA group by the 
2.8% THC marijuana. Ratings of stimulation were increased in the normal 
BIA group by 2.8% and 3.9% THC marijuana and by 20 mg dronabinol. 
Increases in ratings of forgetfulness, withdrawn, dreaming, clumsy, 
heavy limbs, heart pounding, jittery, and decreases in ratings of 
energetic, social, and talkative were reported in the normal BIA group 
with 30 mg dronabinol. There were no significant changes in vital signs 
or performance on neurocognitive measures in response to marijuana. 
Notably, the time course of subjective effects peaked quickly and 
declined thereafter for smoked marijuana, while oral dronabinol 
responses took longer to peak and persisted longer. Additionally, 
marijuana but not dronabinol produced dry mouth and thirst.
    In general, AEs reported in this study were low in both drug 
conditions for both subject groups. In the low BIA group, nausea was 
reported by one subject in both the 10 and 20 mg dronabinol conditions, 
while an uncomfortable level of intoxication was produced by the 30 mg 
dose in two subjects. There were no AEs reported in this group 
following marijuana at any dose. In the normal BIA group, the 30 mg 
dose of dronabinol produced an uncomfortable level of intoxication in 
three subjects and headache in one subject, while the 3.9% marijuana 
produced diarrhea in one subject.
    The authors conclude that smoked marijuana can acutely increase 
caloric intake in low BIA subjects without significant cognitive 
impairment. However, it is possible that the low degree of cognitive 
impairment reported in this study may reflect the development of 
tolerance to cannabinoids in this patient population, since all 
individuals had current histories of chronic marijuana use. Additional 
limitations in this study include not utilizing actual weight gain as a 
primary measure. However, the study produced positive results 
suggesting that marijuana should be studied further as a treatment for 
appetite stimulation in HIV patients.

[[Page 53800]]

    A second study conducted by Haney et al. (2007) is entitled, 
``Dronabinol and marijuana in HIV-positive marijuana smokers: Caloric 
intake, mood, and sleep''. The design of this study was nearly 
identical to the one conducted by this laboratory in 2005 (see above), 
but there was no stratification of subjects by BIA. The subjects were 
10 HIV-positive patients who were maintained on two antiretroviral 
medications and had a history of smoking marijuana at least twice 
weekly for 4 weeks prior to entry into the study. On average, 
individuals had smoked 3 marijuana cigarettes per day, 5 times per week 
for 19 years.
    Subjects participated in 8 sessions that tested the acute effects 
of 0, 5 and 10 mg dronabinol oral capsules and marijuana cigarettes 
with 0, 2.0% and 3.9% THC concentration by weight, using a double-dummy 
design (with 4 sessions involving only one active drug and 4 
interspersed placebo sessions). Both drug and placebo sessions lasted 
for 4 days each, with active drug administration occurring 4 times per 
day (every 4 hours). Testing occurred in two 16-day inpatient stays. In 
the intervening outpatient period, subjects were allowed to smoke 
marijuana prior to re-entry to the study unit for the second inpatient 
stay.
    Marijuana was administered using a standardized cued procedure: (1) 
``light the cigarette'' (30 seconds), (2) ``prepare'' (5 seconds), (3) 
``inhale'' (5 seconds), (4) ``hold smoke in lungs'' (10 seconds), and 
(5) ``exhale.'' Each subject smoked three puffs in this manner, with a 
40-second interval between each puff.
    Caloric intake was used as a surrogate measure for weight gain, but 
subjects were also weighed throughout the study (a measure which was 
not collected in the 2005 study by this group). Subjects received a box 
containing a variety of food and beverage items and were told to record 
consumption of these items following that day's administration of the 
test drug. Subjective measures included 0-100 point VAS for drug 
effect, good effect, bad effect, take drug again, drug liking, hungry, 
full, nauseated, thirsty, desire to eat. Neurocognitive measures and 
vital signs were monitored. Sleep was assessed using both the Nightcap 
sleep monitoring system and selected VAS measures related to sleep.
    Both 5 and 10 mg dronabinol (p < 0.008) and 2.0% and 3.9% THC 
marijuana (p < 0.01) dose-dependently increased caloric intake compared 
with placebo. This increase was generally accomplished through 
increases in incidents of eating, rather than an increase in the 
calories consumed in each incident. Subjects also gained similar 
amounts of weight after the highest dose of each cannabinoid treatment: 
1.2 kg (2.6 lbs) after 4 days of 10 mg dronabinol, and 1.1 kg (2.4 lbs) 
after 4 days of 3.9% THC marijuana. The 3.9% THC marijuana dose also 
increased the desire to eat and ratings of hunger.
    Ratings of good drug effect, high, drug liking, and desire to smoke 
again were significantly increased by 10 mg dronabinol and 2.0% and 
3.9% THC marijuana doses compared to placebo. Both marijuana doses 
increased ratings of stimulated, friendly, and self-confident. The 10 
mg dose of dronabinol increased ratings of concentration impairment, 
and the 2.0% THC marijuana dose increased ratings of anxious. Dry mouth 
was induced by 10 mg dronabinol (10 mg) and 2.0% THC marijuana. There 
were no changes in neurocognitive performance or objective sleep 
measures from administration of either cannabinoid. However, 3.9% THC 
marijuana increased subjective ratings of sleep.
    The authors conclude that both dronabinol and smoked marijuana 
increase caloric intake and produce weight gain in HIV-positive 
patients. However, it is possible that the low degree of cognitive 
impairment reported in this study may reflect the development of 
tolerance to cannabinoids in this subject population, since all 
individuals had current histories of chronic marijuana use. This study 
produced positive results suggesting that marijuana should be studied 
further as a treatment for appetite stimulation in HIV patients.

3.3 Spasticity in Multiple Sclerosis

    Only one randomized, double-blind, placebo-controlled Phase 2 study 
examined the effects of smoked marijuana on spasticity in MS.
    This study was conducted by Corey-Bloom et al. (2012) and is 
entitled, ``Smoked cannabis for spasticity in multiple sclerosis: a 
randomized, placebo-controlled trial''. The subjects were 30 patients 
with MS-associated spasticity and had moderate increase in tone (score 
>= 3 points on the modified Ashworth scale). Participants were allowed 
to continue other MS medications, with the exception of 
benzodiazepines. Eighty percent of subjects had a history of marijuana 
use and 33% had used marijuana within the previous year.
    Subjects participated in two 3-day test sessions, with an 11 day 
washout period. During each test session they smoked a 4.0% THC 
marijuana cigarette once per day or a placebo cigarette once per day. 
Smoking occurred through a standardized cued-puff procedure: (1) 
Inhalation for 5 seconds, (2) breath-hold and exhalation for 10 
seconds, (3) pause between puffs for 45 seconds. Subjects completed an 
average of four puffs per cigarette.
    The primary outcome measure was change in spasticity on the 
modified Ashworth scale. Additionally, subjects were assessed using a 
VAS for pain, a timed walk, and cognitive tests (Paced Auditory Serial 
Addition Test) and AEs.
    Treatment with 4.0% THC marijuana reduced subject scores on the 
modified Ashworth scale by an average of 2.74 points more than placebo 
(p <0.0001) and reduced VAS pain scores compared to placebo (p = 
0.008). Scores on the cognitive measure decreased by 8.7 points more 
than placebo (p = 0.003). However, marijuana did not affect scores for 
the timed walk compared to placebo. Marijuana increased rating of 
feeling high compared to placebo.
    7 subjects did not complete the study due to adverse events (two 
subjects felt uncomfortably ``high'', two had dizziness and one had 
fatigue). Of those 7 subjects who withdrew, 5 had little or no previous 
experience with marijuana. When the data were re-analyzed to include 
these drop-out subjects, with the presumption they did not have a 
positive response to treatment, the effect of marijuana was still 
significant on spasticity.
    The authors conclude that smoked marijuana had usefulness in 
reducing pain and spasticity associated with MS. It is concerning that 
marijuana-na[iuml]ve subjects dropped out of the study because they 
were unable to tolerate the psychiatric AEs induced by marijuana. The 
authors suggest that future studies should examine whether different 
doses can result in similar beneficial effects with less cognitive 
impact. However, the current study produced positive results suggesting 
that marijuana should be studied further as an adjunct treatment for 
spasticity in MS patients.

3.4 Asthma

    Tashkin et al. (1974) examined bronchodilation in 10 subjects with 
bronchial asthma in the study entitled, ``Acute Effects of Smoked 
Marijuana and Oral [Delta]\9\-Tetrahydrocannabinol on Specific Airway 
Conductance in Asthmatic Subjects''. The study was a double-blind, 
placebo-controlled, crossover design. All subjects were clinically 
stable at the time of the study; four subjects were symptom free, and 
six subjects had chronic symptoms of mild to moderate severity. 
Subjects were tested with 0.25ml of isoproterenol HCl prior to the 
study to ensure they responded to bronchodilator

[[Page 53801]]

medications. Subjects were not allowed to take bronchodilator 
medication within 8 hours prior to the study. Previous experience with 
marijuana was not required for participation in the study, but 7 of the 
10 subjects reported previous use of marijuana at a rate of less than 1 
marijuana cigarette per month. No subjects reported marijuana use 
within 7 days of the study.
    The study consisted of four test sessions with an interval of at 
least 48 hours between sessions. On two test sessions subjects smoked 7 
mg/kg of body weight of either marijuana, with 2% THC concentration by 
weight, or placebo marijuana. During the other two test sessions, 
subjects ingested capsules with either 15 mg of synthetic THC or 
placebo. Marijuana was administered using a uniform smoking technique: 
subjects inhaled deeply for 2-4 seconds, held smoke in lungs for 15 
seconds, and resumed normal breathing for approximately 5 seconds. The 
author did not provide a description of the number of puffs taken at 
any smoking session. The authors state that the smoking procedure was 
repeated until the cigarette was consumed, which took approximately 10 
minutes.
    The outcome measure used was specific airway conductance (SGaw), as 
calculated using measurements of thoracic gas volume (TGV) and airway 
resistance (Raw) using a variable-pressure body plethysmograph. 
Additionally, an assessment of degree of intoxication was administered 
only to those subjects reporting previous marijuana use. This 
assessment consisted of subjects rating ``how `high' they felt'' on a 
scale of 0-7, 7 representing ``the `highest' they had ever felt after 
smoking marijuana''.
    Marijuana produced a significant increase of 33-48% in average SGaw 
compared to both baseline and placebo (P < 0.05). This significant 
increase in SGaw lasted for at least 2 hours after administration. The 
average TGV significantly decreased by 4-13% compared to baseline and 
placebo (P < 0.05). The author stated that all subjects reported 
feelings of intoxication after marijuana administration.
    The authors conclude that marijuana produced bronchodilation in 
clinically stable asthmatic subjects with minimal to moderate 
bronchospasms. Study limitations include: inclusion of subjects with 
varying severity of asthmatic symptoms, use of SGaw to measure lung 
responses to marijuana administration, and administration of smoke to 
asthmatic subjects. Smoke delivers a number of harmful substances and 
is not an optimal delivery symptom, especially for asthmatic patients. 
FEV1 via spirometry is the gold standard to assess changes in lung 
function, pre and post asthma treatment, by pharmacotherapy. SGaw has 
been shown to be a valid tool in bronchoconstriction lung assessment; 
however, since the FEV1 method was not utilized, it is unclear whether 
these results would correlate if the FEV1 method had been employed.

3.5 Glaucoma

    Two randomized, double-blind, placebo-controlled Phase 2 clinical 
studies examined smoked marijuana in glaucoma (Crawford and Merritt, 
1979; Merritt et al., 1980). In both studies, intraocular pressure 
(IOP) was significantly reduced 30 minutes after smoking marijuana. 
Maximal effects occurred 60-90 minutes after smoking, with IOP 
returning to baseline within 3-4 hours. These two studies were included 
in the 1999 IOM report on the medical uses of marijuana. Because our 
independent analysis of these studies concurred with the conclusions 
from the 1999 IOM report, these studies will not be discussed in 
further detail in this review. No recent studies have been conducted 
examining the effect of inhaled marijuana on IOP in glaucoma patients. 
This lack of recent studies may be attributed to the conclusions made 
in the 1999 IOM report that while cannabinoids can reduce intraocular 
pressure (IOP), the therapeutic effects require high doses that produce 
short-lasting responses, with a high degree of AEs. This high degree of 
AEs means that the potential harmful effects of chronic marijuana 
smoking may outweigh its modest benefits in the treatment of glaucoma.

3.6 Conclusions

    Of the eleven randomized, double-blind, placebo-controlled Phase 2 
clinical studies that met the criteria for review (see Sections 2.2 and 
2.3), ten studies administered marijuana through smoking, while one 
study utilized marijuana vaporization. In these eleven studies, there 
were five different therapeutic indications: five examined chronic 
neuropathic pain, two examined appetite stimulation in HIV patients, 
two examined glaucoma, one examined spasticity in MS, and one examined 
asthma.
    There are limited conclusions that can be drawn from the data in 
these published studies evaluating marijuana for the treatment of 
different therapeutic indications. The analysis relied on published 
studies, thus information available about protocols, procedures, and 
results were limited to documents published and widely available in the 
public domain. The published studies on medical marijuana are 
effectively proof-of-concept studies. Proof-of-concept studies provide 
preliminary evidence on a proposed hypothesis regarding a drug's 
effect. For drugs under development, the effect often relates to a 
short-term clinical outcome being investigated. Proof-of-concept 
studies serve as the link between preclinical studies and dose ranging 
clinical studies. Therefore, proof-of-concept studies are not 
sufficient to demonstrate efficacy of a drug because they provide only 
preliminary information about the effects of a drug. Although these 
studies do not provide evidence that marijuana is effective in treating 
a specific, recognized disorder, these studies do support future larger 
well-controlled studies to assess the safety and efficacy of marijuana 
for a specific medical indication. Overall, the conclusions below are 
preliminary, based on very limited evidence.
3.6.1 Conclusions for Chronic Neuropathic Pain
    In subjects with chronic neuropathic pain who are refractory to 
other pain treatments, five proof-of-concept studies produced positive 
results regarding the use of smoked marijuana for analgesia. However, 
the subjects in these studies continued to use their current analgesic 
drug regime, and thus no conclusions can be made regarding the 
potential efficacy of marijuana for neuropathic pain in patients not 
taking other analgesic drugs. Subjects also had numerous forms of 
neuropathic pain, making it difficult to identify whether a specific 
set of symptoms might be more responsive to the effects of marijuana. 
It is especially concerning that some marijuana-na[iuml]ve subjects had 
intolerable psychiatric responses to marijuana exposure at analgesic 
doses.
3.6.2 Conclusions for Appetite Stimulation in HIV
    In subjects who were HIV-positive, two proof-of-concept studies 
produced positive results with the use of both dronabinol and smoked 
marijuana to increase caloric intake and produce weight gain in HIV-
positive patients. However, the amount of THC in the marijuana tested 
in these studies is four times greater than the dose of dronabinol 
typically tested for appetite stimulation (10 mg vs. 2.5 mg; Haney et 
al., 2005). Thus, it is possible that the low degree of AEs reported in 
this study may reflect the development of tolerance to cannabinoids in 
this patient population, since all individuals had current histories of 
chronic marijuana use. Thus, individuals with little prior

[[Page 53802]]

exposure to marijuana may not respond similarly and may not be able to 
tolerate sufficient marijuana to produce appetite stimulation.
3.6.3 Conclusions for Spasticity in MS
    In subjects with MS, a proof of concept study produced positive 
results using smoked marijuana as a treatment for pain and symptoms 
associated with treatment-resistant spasticity. The subjects in this 
study continued to take their current medication regiment, and thus no 
conclusions can be made regarding the potential efficacy of marijuana 
when taken on its own. It is also concerning that marijuana-na[iuml]ve 
subjects dropped out of the study because they were unable to tolerate 
the psychiatric AEs induced by marijuana. The authors suggest that 
future studies should examine whether different doses can result in 
similar beneficial effects with less cognitive impact.
3.6.4 Conclusions for Asthma
    In subjects with clinically stable asthma, a proof of concept study 
produced positive results of smoked marijuana producing 
bronchodilation. However, in this study marijuana was administered at 
rest and not while experiencing bronchospasms. Additionally, the 
administration of marijuana through smoking introduces harmful and 
irritating substances to the subject, which is undesirable especially 
in asthmatic patients. Thus the results suggest marijuana may have 
bronchodilator effects, but it may also have undesirable adverse 
effects in subjects with asthma.
3.6.5 Conclusions for Glaucoma
    As noted in Sections 3.5, the two studies that evaluated smoked 
marijuana for glaucoma were conducted decades ago, and they have been 
thoroughly evaluated in the 1999 IOM report. The 1999 IOM report 
concludes that while the studies with marijuana showed positive results 
for reduction in IOP, the effect is short-lasting, requires a high 
dose, and is associated with many AEs. Thus, the potential harmful 
effects may outweigh any modest benefit of marijuana for this 
condition. We agree with the conclusions drawn in the 1999 IOM report.

3.7 Design Challenges for Future Studies

    The positive results reported by the studies discussed in this 
review support the conduct of more rigorous studies in the future. This 
section discusses methodological challenges that have occurred in 
clinical studies with smoked marijuana. These design issues should be 
addressed when larger-scale clinical studies are conducted to ensure 
that valid scientific data are generated in studies evaluating 
marijuana's safety and efficacy for a particular therapeutic use.
3.7.1 Sample Size
    The ability for results from a clinical study to be generalized to 
a broader population is reliant on having a sufficiently large study 
sample size. However, as noted above, all of the 11 studies reviewed in 
this document were early Phase 2 proof of concept studies for efficacy 
and safety. Thus, the sample sizes used in these studies were 
inherently small, ranging from 10 subjects per treatment group (Tashkin 
et al., 1974; Haney et al., 2007) to 25 subjects per treatment group 
(Abrams et al., 2007). These sample sizes are statistically inadequate 
to support a showing of safety or efficacy. FDA's recommendations about 
sample sizes for clinical trials can be found in the Guidance for 
Industry: E9 Statistical Principles for Clinical Trials (1998).\35\ For 
example, ``the number of subjects in a clinical trial should always be 
large enough to provide a reliable answer to the questions addressed. 
This number is usually determined by the primary objective of the 
trial. The method by which the sample size is calculated should be 
given in the protocol, together with the estimates of any quantities 
used in the calculations (such as variances, mean values, response 
rates, event rates, difference to be detected).'' (pg. 21). Other 
clinical FDA Guidance for Industry \36\ may also contain 
recommendations regarding the appropriate number of subjects that 
should be investigated for a specific medical indication.
---------------------------------------------------------------------------

    \35\ The Guidance for Industry: E9 Statistical Principles for 
Clinical Trials can be found at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073137.pdf.
    \36\ Other Guidances for Industry can be found at: www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064981.htm.
---------------------------------------------------------------------------

3.7.2 Marijuana Dose Standardization
    Dose standardization is critical for any clinical study in order to 
ensure that each subject receives a consistent exposure to the test 
drug. The Guidance for Industry: Botanical Drug Products (2004) \37\ 
provides specific information on the development of botanical drug 
products. Specifically, this guidance includes information about the 
need for well-characterized and consistent chemistry for the botanical 
plant product and for consistent and reliable dosing. Specifically for 
marijuana studies, dose standardization is important because if 
marijuana leads to plasma levels of cannabinoids that are significantly 
different between subjects, this variation may lead to differences in 
therapeutic responsivity or in the prevalence of psychiatric AEs.
---------------------------------------------------------------------------

    \37\ The Guidance for Industry: Botanical Drug Products can be 
found at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070491.pdf.
---------------------------------------------------------------------------

    In most marijuana studies discussed in this review, investigators 
use a standardized cued smoking procedure. In this procedure, a subject 
is instructed to inhale marijuana smoke for 5 seconds, hold the smoke 
in the lungs for 10 seconds, exhale and breathe normally for 40 
seconds. This process is repeated to obtain the desired dose of the 
drug. However, this procedure may not lead to equivalent exposure to 
marijuana and its constituent cannabinoids, based on several factors:
     Intentional or unintentional differences in the depth of 
inhalation may change the amount of smoke in the subject's lungs.
     Smoking results in loss from side stream smoke, such that 
the entire dose is not delivered to the subject.
     There may be differences in THC concentration along the 
length of a marijuana cigarette. According to Tashkin et al. (1991), 
the area of the cigarette closest to the mouth tends to accumulate a 
higher concentration of THC, but this section of the cigarette is not 
smoked during a study.
    For example, Wilsey et al. (2008) used this standardized smoking 
procedure. The reported mean (range) of marijuana cigarettes consumed 
was 550 mg (200-830mg) for the low strength marijuana (3.5% THC) and 
490 mg (270-870mg) for the high strength marijuana (7% THC). This wide 
range of amounts of marijuana cigarette smoked by the individual 
subjects, even with standardized smoking procedure and controlled 
number of puffs, supports the issues with delivering consistent doses 
with smoke marijuana.
    In other marijuana studies that do not use a cued smoking 
procedure, subjects are simply told to smoke the marijuana cigarette 
over a specific amount of time (usually 10 minutes) without further 
instruction (Crawford and Merritt, 1979; Merritt et al., 1980; Ellis et 
al., 2009). The use of a nonstandardized procedure may lead to non-
equivalent exposures to marijuana and its constituent cannabinoids 
between subjects because of additional factors that are not listed 
above, such as:
     Differences in absorption and drug response if subjects 
(especially

[[Page 53803]]

marijuana-na[iuml]ve ones) are not instructed to hold marijuana smoke 
in their lungs for a certain period of time.
     Prolonged periods between puffs may increase loss to side 
stream smoke.
     Subjects may attempt to smoke the marijuana cigarette in 
the way they would smoke a tobacco cigarette, which relies primarily on 
short, shallow puffs.
    In both standardized and non-standardized smoking procedures, 
subjects may seek to control the dose of THC through self-titration 
(Crawford and Merritt, 1979; Merritt et al., 1980; Tashkin et al., 
1974; Abrams et al., 2007; Ellis et al., 2009). Self-titration involves 
an individual moderating the amount of marijuana smoke inhaled over 
time in order to obtain a preferred level of psychoactive or clinical 
response. The ability of an individual to self-titrate by smoking is 
one reason given by advocates of ``medical marijuana'' in support of 
smoking of marijuana rather than through its ingestion via edibles. 
However, for research purposes, self-titration interferes with the 
ability to maintain consistent dosing levels between subjects, and 
thus, valid comparisons between study groups.
    All of these factors can make the exact dose of cannabinoids 
received by a subject in a marijuana study difficult to determine with 
accuracy. Testing whether plasma levels of THC or other cannabinoids 
are similar between subjects following the smoking procedure would 
establish whether the procedure is producing appropriate results. 
Additionally, studies could be conducted to determine if vaporization 
can be used to deliver consistent doses of cannabinoids from marijuana 
plant material. Specifically, vaporization devices that involve the 
collection of vapors in an enclosed bag or chamber may help with 
delivery of consistent doses of marijuana. Thus, more information could 
be collected on whether vaporization is comparable to or different than 
smoking in terms of producing similar plasma levels of THC in subjects 
using identical marijuana plant material.
3.7.3 Acute vs. Chronic Therapeutic Marijuana Use
    The studies that were reviewed administered the drug for short 
durations lasting no longer than 5 days (Abrams et al., 2007; Ellis et 
al., 2009; Ware et al., 2010). Thus all studies examined the short-term 
effect of marijuana administration for therapeutic purposes. However, 
many of the medical conditions that have been studied are persistent or 
expected to last the rest of a patient's life. Therefore, data on 
chronic exposure to smoked marijuana in clinical studies is needed. In 
this way, more information will be available regarding whether 
tolerance, physical dependence, or specific adverse events develop over 
the course of time with continuing use of therapeutic marijuana.
3.7.4 Smoking as a Route of Administration
    As has been pointed out by the IOM and other groups, smoking is not 
an optimum route of administration for marijuana-derived therapeutic 
drug products, primarily because introducing the smoke from a burnt 
botanical substance into the lungs of individuals with a disease state 
is not recommended when their bodies may be physically compromised. The 
1999 IOM report on medicinal uses of marijuana noted that alternative 
delivery methods offering the same ability of dose titration as smoking 
marijuana will be beneficial and may limit some of the possible long-
term health consequences of smoking marijuana. The primary alternative 
to smoked marijuana is vaporization, which can reduce exposure to 
combusted plant material containing cannabinoids. The only study to use 
vaporization as the delivery method was Wilsey et al. (2013). The 
results from Wilsey et al. (2013) showed a similar effect of decreased 
pain as seen in the other studies using smoking as the delivery method 
(Ware et al., 2010; Wilsey et al., 2008). This similar effect of 
decrease pain supports vaporization as a possibly viable route to 
administer marijuana in research, while potentially limiting the risks 
associated with smoking.
3.7.5 Difficulty in Blinding of Drug Conditions
    An adequate and well-controlled clinical study involves double-
blinding, where both the subjects and the investigators are unable to 
tell the difference between the test treatments (typically consisting 
of at least a test drug and placebo) when they are administered. All of 
the studies reviewed in this document administered study treatments 
under double-blind conditions and thus were considered to have an 
appropriate study design.
    However, even under the most rigorous experimental conditions, 
blinding can be difficult in studies with smoked marijuana because the 
rapid onset of psychoactive effects readily distinguishes active from 
placebo marijuana. The presence of psychoactive effects also occurs 
with other drugs. However, most other drugs have a similar psychoactive 
effect with substances with similar mechanisms of actions. These 
substances can be used as positive controls to help maintain blinding 
to the active drug being tested. Marijuana on the other hand, has a 
unique set of psychoactive effects which makes the use of appropriate 
positive controls difficult (Barrett et al., 1995). However, two 
studies did use Dronabinol as a positive control drug to help maintain 
blinding (Haney et al., 2005; Haney et al., 2007).
    When blinding is done using only placebo marijuana, the ability to 
distinguish active from placebo marijuana may lead to expectation bias 
and an alteration in perceived responsivity to the therapeutic outcome 
measures. With marijuana-experienced subjects, for example, there may 
be an early recognition of the more subtle cannabinoid effects that can 
serve as a harbinger of stronger effects, which is less likely to occur 
with marijuana-na[iuml]ve subjects. To reduce this possibility, 
investigators have tested doses of marijuana other than the one they 
were interested in experimentally to maintain the blind (Ware et al., 
2010).
    Blinding can also be compromised by differences in the appearance 
of marijuana plant material based on THC concentration. Marijuana with 
higher concentrations of THC tends to be heavier and seemingly darker, 
with more ``tar-like'' substance. Subjects who have experience with 
marijuana have reported being able to identify marijuana from placebo 
cigarettes by sight alone when the plant material in a cigarette was 
visible (Tashkin et al., 1974; Ware et al., 2010). Thus, to maintain a 
double-blind design, many studies obscure the appearance of plant 
material by closing both ends of the marijuana cigarette and placing it 
in in an opaque plastic tube.
    While none of these methods to secure blinding may be completely 
effective, it is important to reduce bias as much as possible to 
produce consistent results between subjects under the same experimental 
conditions.
3.7.6 Prior Marijuana Experience
    Marijuana use histories in test subjects may influence outcomes, 
related to both therapeutic responsivity and psychiatric AEs. 
Marijuana-na[iuml]ve subjects may also experience a marijuana drug 
product as so aversive that they would not want to use the drug 
product. Thus, subjects' prior experience with marijuana may affect the 
conduct and results of studies.
    Most of the studies reviewed in this document required that 
subjects have a history of marijuana use (see tables in Appendix that 
describe specific

[[Page 53804]]

requirements for each study). However, in studies published in the 
scientific literature, the full inclusion criteria with regard to 
specific amount of experience with marijuana may not be provided. For 
those studies that do provide inclusion criteria, acceptable experience 
with marijuana can range from once in a lifetime to use multiple times 
a day.
    The varying histories of use might affect everything from scores on 
adverse event measures, safety measures, or efficacy measures. 
Additionally, varying amounts of experience can impact cognitive effect 
measures assessed during acute administration studies. For instance, 
Schreiner and Dunn (2012) contend cognitive deficits in heavy marijuana 
users continue for approximately 28 days after cessation of smoking. 
Studies requiring less than a month of abstinence prior to the study 
may still see residual effects of heavy use at baseline and after 
placebo marijuana administration, thus showing no significant effects 
on cognitive measures. However, these same measurements in occasional 
or na[iuml]ve marijuana users may demonstrate a significant effect 
after acute marijuana administration. Therefore, the amount of 
experience and the duration of abstinence of marijuana use are 
important to keep in mind when analyzing results for cognitive and 
other adverse event measures. Lastly, a study population with previous 
experience with marijuana may underreport the incidence and severity of 
adverse events. Because most studies used subjects with prior marijuana 
experience, we are limited in our ability to generalize the results, 
especially for safety measures, to marijuana na[iuml]ve populations.
    Five of 11 studies reviewed in this document included both 
marijuana-na[iuml]ve and marijuana-experienced subjects (Corey-Bloom et 
al., 2012; Ellis et al., 2009; Ware et al., 2010; Merritt et al., 1980; 
Tashkin et al., 1974). Since the number of marijuana-na[iuml]ve 
subjects in these studies was low, it was not possible to conduct a 
separate analysis compared to experienced users. However, 
systematically evaluating the effect of marijuana experience on study 
outcomes is important, since many patients who might use a marijuana 
product for a therapeutic use will be marijuana-na[iuml]ve.
    Research shows that marijuana-experienced subjects have a higher 
ability to tolerate stronger doses of oral dronabinol than marijuana-
na[iuml]ve subjects (Haney et al., 2005). Possibly, this increased 
tolerance is also the case when subjects smoke or vaporize marijuana. 
Thus, studies could be conducted that investigate the role of marijuana 
experience in determining tolerability of and responses to a variety of 
THC concentrations in marijuana.
3.7.7 Inclusion and Exclusion Criteria
    For safety reasons, all clinical studies have inclusion and 
exclusion criteria that restrict the participation of individuals with 
certain medical conditions. For studies that test marijuana, these 
criteria may be based on risks associated with exposure to smoked 
material and the effects of THC. Thus, most studies investigating 
marijuana require that subjects qualify for the study based on 
restrictive symptom criteria such that individuals do not have other 
symptoms that may be known to interact poorly with cannabinoids.
    Similarly, clinical studies with marijuana typically exclude 
individuals with cardiac or pulmonary problems, as well as psychiatric 
disorders. These exclusion criteria are based on the well-known effects 
of marijuana smoke to produce increases in heart rate and blood 
pressure, lung irritation, and the exacerbation of psychiatric 
disturbances in vulnerable individuals. Although these criteria are 
medically reasonable for research protocols, it is likely that future 
marijuana products will be used in patients who have cardiac, pulmonary 
or psychiatric conditions. Thus, individuals with these conditions 
should be evaluated, whenever possible.
    Additionally, all studies reviewed in this document allowed the 
subjects to continue taking their current regimen of medications. Thus 
all results evaluated marijuana as an adjunct treatment for each 
therapeutic indication.
3.7.8 Number of Female Subjects
    A common problem in clinical research is the limited number of 
females who participate in the studies. This problem is present in the 
11 studies reviewed in this document, in which one study did not 
include any female subjects (Ellis et al., 2009), and three studies had 
a low percentage of female subjects (Abrams et al., 2007; Haney et al., 
2005; Haney et al., 2007). However, each of these four studies 
investigated an HIV-positive patient population, where there may have 
been a larger male population pool from which to recruit compared to 
females.
    Since there is some evidence that the density of CB1 receptors in 
the brain may vary between males and females (Crane et al., 2012), 
there may be differing therapeutic or subjective responsivity to 
marijuana. Studies using a study population that is equal parts male 
and female may show whether and how the effects of marijuana differ 
between male and female subjects.

4. References

1999. Marijuana and Medicine: Assessing the Science Base. 
Washington, DC: National Academy Press.
Abrams DI, Hilton JF, Leiser RJ, Shade SB, Elbeik TA, Aweeka FT, 
Benowitz NL, Bredt BM, Kosel B, Aberg JA, Deeks SG, Mitchell TF, 
Mulligan K, Bacchetti P, McCune JM, and Schambelan M. 2003. Short-
term effects of cannabinoids in patients with HIV-1 infection: a 
randomized, placebo-controlled clinical trial. Annals of Internal 
Medicine 139 (4): 258-266.
Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME, 
Rowbotham MC, and Petersen KL. 2007. Cannabis in painful HIV-
associated sensory neuropathy: A randomized placebo-controlled 
trial. Neurology 68 (7): 515-521.
Appendino G, Chianese G, Taglialatela-Scafati O. 2011. Cannabinoids: 
occurrence and medicinal chemistry. Curr Med Chem. 18(7):1085-99.
Barrett RL, Wiley JL, Balster RL, and Martin BR. 1995. 
Pharmacological specificity of [Delta]\9\-tetrahydrocannabinol 
discrimination in rats. Psychopharmacology 118(4): 419-424.
Chait LD, and Pierri J. 1989. Some physical characteristics of NIDA 
marijuana cigarettes. Addictive Behaviors 14 (1): 61-67.
Chang AE, Shiling DJ, Stillman RC, Godlberg NH, Seipp CA, Barofsky 
I, Simon RM, and Rosenberg SA. 1979. Delta-9-tetrahydrocannabinol as 
an antiemetic in cancer patients receiving high-dose methotrexate. 
Annals of Internal Medicine 91: 819-824.
Corey-Bloom J, Wolfson T, Gamst A, Jin S, Marcotte TD, Bentley H, 
and Gouaux B. 2012. Smoked cannabis for spasticity in multiple 
sclerosis: a randomized, placebo-controlled trial. Canadian Medical 
Association Journal 184 (10): 1143-1150.
Crane NA, Schuster RM, Fusar-Poli P, and Gonzalez R. 2012. Effects 
of Cannabis on Neurocognitive Functioning: Recent Advances, 
Neurodevelopmental Influences, and Sex Differences. Neuropsychology 
Review.
Crawford WJ, and Merritt JC. 1979. Effects of tetrahydrocannabinol 
on arterial and intraocular hypertension. International Journal of 
Clinical Pharmacology and biopharmacy 17 (5): 191-196.
Ellis RJ, Toperoff W, Vaida F, Van Den Brande G, Gonzales J, Gouaux 
B, Bentley H, and Atkinson JH. 2009. Smoked medicinal cannabis for 
neuropathic pain in HIV: A randomized, crossover clinical trial. 
Neuropsychopharmacology 34 (3): 672-680.
Flom MC, Adams AJ, and Jones RT. 1975. Marijuana smoking and reduced 
pressure in human eyes: drug action or epiphenomenon? Investigative 
Opthalmology 14(1): 52-55.
Foltin RW, Brady JV, and Fischamn MW. 1986. Behavioral analysis of 
marijuana

[[Page 53805]]

effects on food intake in humans. Pharmacology Biochemistry and 
Behavior 25: 577-582.
Foltin RW, Fischman MW, and Byrne MF. 1988. Effects of smoked 
marijuana on food intake and body weight of humans living in a 
residential laboratory. Appetite 11: 1-14.
Greenberg HS, Werness SA, Pugh JE, Andrus RO, Anderson DJ, and 
Domino EF. 1994. Short-term effects of smoking marijuana on balance 
in patients with multiple sclerosis and normal volunteers. Clinical 
Pharmacology and Therapeutics 55 (3): 324-328.
Greenwald MK and Stitzer ML. 2000. Antinociceptive, subjective, and 
behavioral effects of smoked marijuana in humans. Drug and Alcohol 
Dependence 59: 261-275.
Haney M, Gunderson EW, Rabkin J, Hart CL, Vosburg SK, Comer SD, and 
Foltin RW. 2007. Dronabinol and marijuana in HIV-positive marijuana 
smokers. Caloric intake, mood, and sleep. Journal of Acquired Immune 
Deficiency Syndromes (1999) 45 (5): 545-554.
Haney M, Rabkin J, Gunderson E, and Foltin RW. 2005. Dronabinol and 
marijuana in HIV(+) marijuana smokers: acute effects on caloric 
intake and mood. Psychopharmacology 181 (1): 170-178.
Hill SY, Schwin R, Goodwin DW, and Powell BJ. 1974. Marihuana and 
pain. Journal of Pharmacology and Experimental Therapeutics 188(2): 
415-418.
Jampel H. 2010. American glaucoma society position statement: 
marijuana and the treatment of glaucoma. Journal of Glaucoma 19 (2): 
75-76.
Merritt JC, Crawford WJ, Alexander PC, Anduze AL, and Gelbart SS. 
1980. Effect of marihuana on intraocular and blood pressure in 
glaucoma. Ophthalmology 87 (3): 222-228.
Milstein SL, MacCannell KL, Karr GW, and Clark S. 1974. Marijuana 
produced changes in cutaneous sensitivity and affect: users and non-
users. Pharmacology Biochemistry and Behavior 2:367-374.
Milstein SL, MacCannell K, Karr G, and Clark S. 1975. Marijuana-
produced changes in pain tolerance: Experiences and non-experienced 
subjects. Int. Pharmacopsychiat 10: 177-182.
Naftali T, Schleider LB, Dotan I, Lansky EP, Benjaminov FS, and 
Konikoff FM. 2013. Cannabis induces a clinical response in patients 
with Crohn's disease: A prospective placebo-controlled study. 
Clinical Gastroenterology and Hepatology 11: 1276-1280.
Russo E, Mathre ML, Byrne A, Velin R, Bach PJ, Sanchez-Ramos J, and 
Kirlin KA. 2002. Chronic Cannabis Use in the Compassionate 
Investigational New Drug Program: An Examination of Benefits and 
Adverse Effects of Legal Clinical Cannabis. Journal of Cannabis 
Therapeutics 2 (1): 3-57.
Soderpalm AHV, Schuster A, and de Wit H. 2001. Antiemetic efficacy 
of smoked marijuana subjective and behavioral effects on nausea 
induced by syrup of ipecac. Pharmacology Biochemistry and Behavior 
69: 343-350.
Tashkin DP, Gliederer F, Rose J, Chang P, Hui KK, Yu JL, and Wu TC. 
1991. Tar, CO and delta 9THC delivery from the 1st and 2nd halves of 
a marijuana cigarette. Pharmacology Biochemistry and Behavior 40 
(3): 657-661.
Tashkin DP, Shapiro BJ, Lee YE, Harper CE. 1975. Effects of smoked 
marijuana in experimentally induced asthma. American Review of 
Respiratory Disease 112: 377-386.
Wallace M, Schulteis G, Atkinson JH, Wolfson T, Lazzaretto D, 
Bentley H, Gouaux B, and Abramson I. 2007. Dose-dependent effects of 
smoked cannabis on capsaicin-induced pain and hyperalgesia in 
healthy volunteers. Anesthesiology 107 (5): 785-796.
Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, Gamsa A, 
Bennett GJ, and Collet JP. 2010. Smoked cannabis for chronic 
neuropathic pain: a randomized controlled trial. Canadian Medical 
Association Journal 182 (14): E694-E701.
Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B, 
and Fishman S. 2008. A randomized, placebo-controlled, crossover 
trial of cannabis cigarettes in neuropathic pain. J. Pain 9 (6): 
506-521.
Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, and Donaghe H. 
2013. Low-dose vaporized cannabis significantly improves neuropathic 
pain. J. Pain 14(2):136-48.


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[[Page 53820]]



U.S. Department of Justice--Drug Enforcement Administration

Schedule of Controlled Substances: Maintaining Marijuana in Schedule I 
of the Controlled Substances Act

Background, Data, and Analysis: Eight Factors Determinative of Control 
and Findings Pursuant to 21 U.S.C. 812(b)

Prepared by: Office of Diversion Control, Drug and Chemical Evaluation 
Section, Washington, DC 20537

July 2016

Background

    On December 17, 2009, Bryan Krumm, CNP, submitted a petition to the 
Drug Enforcement Administration (DEA) to initiate proceedings for a 
repeal of the rules or regulations that place marijuana \38\ in 
schedule I of the Controlled Substances Act (CSA). The petition 
requests that marijuana be rescheduled in any schedule other than 
schedule I of the CSA. The petitioner claims that:
---------------------------------------------------------------------------

    \38\ The Controlled Substances Act (CSA) defines marijuana as 
the following: ``All parts of the plant Cannabis sativa L., whether 
growing or not; the seeds thereof; the resin extracted from any part 
of such plant; and every compound, manufacture, salt, derivative, 
mixture, or preparation of such plant, its seeds or resin. Such term 
does not include the mature stalks of such plant, fiber produced 
from such stalks, oil or cake made from the seeds of such plant, any 
other compound, manufacture, salt, derivative, mixture, or 
preparation of such mature stalks (except the resin extracted there 
from), fiber, oil, or cake, or the sterilized seed of such plant 
which is incapable of germination. 21 U.S.C. 802(16). Note that 
``marihuana'' is the spelling originally used in the CSA. This 
document uses the spelling that is more common in current usage, 
``marijuana.''
---------------------------------------------------------------------------

    1. Marijuana has accepted medical use in the United States;
    2. Studies have shown that smoked marijuana has proven safety and 
efficacy;
    3. Marijuana is safe for use under medical supervision; and
    4. Marijuana does not have the abuse potential for placement in 
schedule I
    The DEA accepted this petition for filing on April 3, 2010.
    The Attorney General may by rule transfer a drug or other substance 
between schedules of the CSA if she finds that such drug or other 
substance has a potential for abuse, and makes the findings prescribed 
by 21 U.S.C. 812(b) for the schedule in which such drug is to be 
placed. 21 U.S.C. 811(a)(1). The Attorney General has delegated this 
responsibility to the Acting Administrator of the DEA. 28 CFR 0.100(b).
    In accordance with 21 U.S.C. 811(b), after gathering the necessary 
data, the DEA submitted the petition and necessary data to the 
Department of Health and Human Services (HHS) on May 6, 2011, and 
requested that HHS provide a scientific and medical evaluation and 
scheduling recommendation for marijuana. In documents dated June 3 and 
June 25, 2015, the acting Assistant Secretary for Health of the HHS 
\39\ recommended to the DEA that marijuana continue to be controlled in 
Schedule I of the CSA, and provided to the DEA its scientific and 
medical evaluation titled ``Basis for the Recommendation for 
Maintaining Marijuana in Schedule I of the Controlled Substances Act.'' 
The HHS's recommendations are binding on the DEA as to scientific and 
medical matters. 21 U.S.C. 811(b).
---------------------------------------------------------------------------

    \39\ As set forth in a memorandum of understanding entered into 
by the HHS, the Food and Drug Administration (FDA), and the National 
Institute on Drug Abuse (NIDA), the FDA acts as the lead agency 
within the HHS in carrying out the Secretary's scheduling 
responsibilities under the CSA, with the concurrence of the NIDA. 50 
FR 9518, Mar. 8, 1985. The Secretary of the HHS has delegated to the 
Assistant Secretary for Health of the HHS the authority to make 
domestic drug scheduling recommendations.
---------------------------------------------------------------------------

    Before initiating proceedings to reschedule a substance, the CSA 
requires the Acting Administrator to determine whether the HHS 
scheduling recommendation, scientific and medical evaluation, and ``all 
other relevant data'' constitute substantial evidence that the drug 
should be rescheduled as proposed. 21 U.S.C. 811(b). The Acting 
Administrator must determine whether there is substantial evidence to 
conclude that the drug meets the criteria for placement in another 
schedule based on the criteria set forth in 21 U.S.C. 812(b). The CSA 
requires that both the DEA and the HHS consider the eight factors 
specified by Congress in 21 U.S.C. 811(c). This document lays out those 
considerations and is organized according to the eight factors. As DEA 
sets forth in detail below, the evidence shows:
    1. Actual or relative potential for abuse. Marijuana has a high 
potential for abuse. Preclinical and clinical data show that it has 
reinforcing effects characteristic of drugs of abuse. National 
databases on actual abuse show marijuana is the most widely abused 
drug, including significant numbers of substance abuse treatment 
admissions. Data on marijuana seizures show widespread availability and 
trafficking.
    2. Scientific evidence of its pharmacological effect. The 
scientific understanding of marijuana, cannabinoid receptors, and the 
endocannabinoid system continues to be studied and elucidated. 
Marijuana produces various pharmacological effects, including 
subjective (e.g., euphoria, dizziness, disinhibition), cardiovascular, 
acute and chronic respiratory, immune system, and prenatal exposure 
effects, as well as behavioral and cognitive impairment.
    3. Current scientific knowledge. There is no currently accepted 
medical use for marijuana in the United States. Marijuana sources are 
derived from numerous cultivated strains and may have different levels 
of [Delta]\9\-THC and other cannabinoids. Under the five-element test 
for currently accepted medical use discussed in more detail below and 
upheld by the Court of Appeals for the District of Columbia in Alliance 
for Cannabis Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994) 
(hereinafter ``ACT''), there is no complete scientific analysis of 
marijuana's chemical components; there are not adequate safety studies; 
there are not adequate and well-controlled efficacy studies; there is 
not a consensus of medical opinion concerning medical applications of 
marijuana; and the scientific evidence regarding marijuana's safety and 
efficacy is not widely available. To date, scientific and medical 
research has not progressed to the point that marijuana has a currently 
accepted medical use, even under conditions where its use is severely 
restricted.
    4. History and current pattern of abuse. Marijuana continues to be 
the most widely used illicit drug. In 2014, there were 22.2 million 
current users. There were also 2.6 million new users, most of whom were 
less than 18 years of age. During the same period, marijuana was the 
most frequently identified drug exhibit in federal, state, and local 
forensic laboratories.
    5. Scope, duration, and significance of abuse. Abuse of marijuana 
is widespread and significant. In 2014, for example, an estimated 6.5 
million people aged 12 or older used marijuana on a daily or almost 
daily basis over a 12-month period. In addition, a significant 
proportion of all admissions for substance abuse treatment are for 
marijuana/hashish as their primary drug of abuse. In 2013, 16.8% of all 
such admissions--281,991 over the course of the year--were for primary 
marijuana/hashish abuse.
    6. Risk, if any, to public health. Together with the health risks 
outlined in terms of pharmacological effects above, public health risks 
from acute use of marijuana include impaired psychomotor performance, 
impaired driving, and impaired performance on tests of learning and 
associative processes. Chronic use of marijuana

[[Page 53821]]

poses a number of other risks to the public health including physical 
as well as psychological dependence.
    7. Psychic or physiological dependence liability. Long-term, heavy 
use of marijuana can lead to physical dependence and withdrawal 
following discontinuation, as well as psychic or psychological 
dependence. In addition, a significant proportion of all admissions for 
treatment for substance abuse are for primary marijuana abuse; in 2013, 
16.8% of all admissions were for primary marijuana/hashish abuse, 
representing 281,991 individuals.
    8. Immediate precursor. Marijuana is not an immediate precursor of 
any controlled substance.
    As specified in 21 U.S.C. 812(b)(1), in order for a substance to be 
placed in schedule I, the Acting Administrator must find that:
    A. The drug or other substance has a high potential for abuse.
    B. The drug or other substance has no currently accepted medical 
use in treatment in the United States.
    C. There is a lack of accepted safety for use of the drug or other 
substance under medical supervision.
    To be classified in another schedule under the CSA (e.g., II, III, 
IV, or V), a substance must have a ``currently accepted medical use in 
treatment in the United States.'' 21 U.S.C. 812(b)(2)-(5). A substance 
also may be placed in schedule II if it is found to have ``a currently 
accepted medical use with severe restrictions.'' 21 U.S.C. 812(b)(2). 
If a controlled substance has no such currently accepted medical use, 
it must be placed in schedule I. See Notice of Denial of Petition, 66 
FR 20038 (Apr. 18, 2001) (``Congress established only one schedule--
schedule I--for drugs of abuse with `no currently accepted medical use 
in treatment in the United States' and `lack of accepted safety for use 
. . . under medical supervision.' '').
    A drug that is the subject of an approved new drug application 
(NDA) or abbreviated new drug application (ANDA) under Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 355), is considered to have a 
currently accepted medical use in treatment in the United States for 
purposes of the CSA. The HHS stated in its review, however, that FDA 
has not approved any NDA for marijuana for any indication.
    In the absence of NDA or ANDA approval, DEA has established a five-
element test for determining whether the drug has a currently accepted 
medical use in treatment in the United States. Under this test, a drug 
will be considered to have a currently accepted medical use only if the 
following five elements are satisfied:
    1. The drug's chemistry is known and reproducible;
    2. There are adequate safety studies;
    3. There are adequate and well-controlled studies proving efficacy;
    4. The drug is accepted by qualified experts; and
    5. The scientific evidence is widely available.

57 FR 10499, 10506 (March 26, 1992). See also ACT, 15 F.3d at 1135.
    As discussed in Factor 3, below, HHS concluded, and DEA agrees, 
that the scientific evidence is insufficient to demonstrate that 
marijuana has a currently accepted medical use under the five-element 
test. The evidence was insufficient in this regard also when the DEA 
considered petitions to reschedule marijuana in 1992 (57 FR 10499),\40\ 
in 2001 (66 FR 20038), and in 2011 (76 FR 40552).\41\ Little has 
changed since 2011 with respect to the lack of clinical evidence 
necessary to establish that marijuana has a currently accepted medical 
use. No studies have scientifically assessed the efficacy and full 
safety profile of marijuana for any specific medical condition.
---------------------------------------------------------------------------

    \40\ See Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131 
(D.C. Cir. 1994).
    \41\ See Americans for Safe Access v. DEA, 706 F.3d 438 (D.C. 
Cir. 2013)(rhg den. 2013).
---------------------------------------------------------------------------

    The limited existing clinical evidence is not adequate to warrant 
rescheduling of marijuana under the CSA. To the contrary, the data in 
this scheduling review document show that marijuana continues to meet 
the criteria for schedule I control under the CSA for the following 
reasons:
    1. Marijuana has a high potential for abuse.
    2. Marijuana has no currently accepted medical use in treatment in 
the United States.
    3. Marijuana lacks accepted safety for use under medical 
supervision.

Factor 1: The Drug's Actual or Relative Potential for Abuse

    Marijuana is the most commonly abused illegal drug in the United 
States. It is also the most commonly used illicit drug by high school 
students in the United States. Further, marijuana is the most 
frequently identified drug by state, local and federal forensic 
laboratories. Marijuana's main psychoactive ingredient, [Delta]\9\-
tetrahydrocannabinol ([Delta]\9\-THC),\42\ is an effective reinforcer 
in laboratory animals, including primates and rodents. These animal 
studies both predict and support the observations that marijuana 
produces reinforcing effects in humans. Such reinforcing effects can 
account for the repeated abuse of marijuana.
---------------------------------------------------------------------------

    \42\ The terms [Delta]\9\-THC and THC are used interchangeably 
thoughout this document.
---------------------------------------------------------------------------

A. Indicators of Abuse Potential

    The HHS has concluded in its document, ``Basis for the 
Recommendation for Maintaining Marijuana in Schedule I of the 
Controlled Substances Act,'' that marijuana has a high potential for 
abuse. The finding of ``abuse potential'' is critical for control under 
the Controlled Substances Act (CSA). Although the term is not defined 
in the CSA, guidance in determining abuse potential is provided in the 
legislative history of the Act (Comprehensive Drug Abuse Prevention and 
Control Act of 1970, H.R. Rep. No. 91-1444, 91st Cong., Sess. 2 (1970), 
reprinted in 1970 U.S.C.C.A.N. 4566, 4603). Accordingly, the following 
items are indicators that a drug or other substance has potential for 
abuse:
     There is evidence that individuals are taking the drug or 
drugs containing such a substance in amounts sufficient to create a 
hazard to their health or to the safety of other individuals or of the 
community; or
     There is significant diversion of the drug or drugs 
containing such a substance from legitimate drug channels; or
     Individuals are taking the drug or drugs containing such a 
substance on their own initiative rather than on the basis of medical 
advice from a practitioner licensed by law to administer such drugs in 
the course of his professional practice; or
     The drug or drugs containing such a substance are new 
drugs so related in their action to a drug or drugs already listed as 
having a potential for abuse to make it likely that the drug will have 
the same potentiality for abuse as such drugs, thus making it 
reasonable to assume that there may be significant diversions from 
legitimate channels, significant use contrary to or without medical 
advice, or that it has a substantial capability of creating hazards to 
the health of the user or to the safety of the community.
    Of course, evidence of actual abuse of a substance is indicative 
that a drug has a potential for abuse.
    In its recommendation, the HHS analyzed and evaluated data on 
marijuana as applied to each of the above four criteria. The analysis 
presented in the recommendation (HHS, 2015) is discussed below:
    1. There is evidence that individuals are taking the drug or drugs 
containing such a substance in amounts sufficient to create a hazard to 
their health or to the safety of other individuals or of the community.

[[Page 53822]]

    The HHS stated that some individuals are taking marijuana in 
amounts sufficient to create a hazard to their health and to the safety 
of other individuals and the community. Data from national databases on 
actual abuse of marijuana support the idea that a large number of 
individuals use marijuana. In its recommendation (HHS, 2015), the HHS 
presented data from the National Survey on Drug and Health (NSDUH) of 
the Substance Abuse and Mental Health Services Administration (SAMHSA) 
and the Monitoring the Future (MTF) survey of the National Institute on 
Drug Abuse (NIDA), and the DEA has since updated this information. The 
most recent data from SAMHSA's NSDUH in 2014 reported that marijuana 
was the most used illicit drug. Among Americans aged 12 years and 
older, an estimated 22.2 million Americans used marijuana within the 
past month according to the 2014 NSDUH. In 2004, an estimated 14.6 
million individuals reported using marijuana within the month prior to 
the study. The estimated rates in 2014 thus reflect an increase of 
approximately 7.6 million individuals over a 10-year period. According 
to the 2013 NSDUH report, an estimated 19.8 million individuals 
reported using marijuana. Thus, over a period of one year (2013 NSDUH-
2014 NSDUH), there was an estimated increase of 2.4 million individuals 
in the United States using marijuana.
    The results from the 2015 Monitoring the Future survey of 8th, 
10th, and 12th grade students indicate that marijuana was the most 
widely used illicit drug in these age groups. Current monthly use was 
6.5% of 8th graders, 14.8% of 10th graders, and 21.3% of 12th graders. 
The Treatment Episode Data Set (TEDS) in 2013 reported that marijuana 
abuse was the primary factor in 16.8 percent of non-private substance-
abuse treatment facility admissions. In 2011, SAMHSA's Drug Abuse 
Warning Network (DAWN) reported that marijuana was mentioned in 36.4% 
(455,668 out of approximately 1.25 million) of illicit drug-related 
Emergency Department (ED) visits.
    Data on the extent and scope of marijuana abuse are presented under 
Factors 4 and 5 of this analysis. Discussion of the health effects of 
marijuana is presented under Factor 2, and the assessment of risk to 
the public health posed by acute and chronic marijuana abuse is 
presented under Factor 6 of this analysis.
    2. There is significant diversion of the drug or drugs containing 
such a substance from legitimate drug channels.
    In accordance with the CSA, the only lawful source of marijuana in 
the United States is that produced and distributed for research 
purposes under the oversight of NIDA and in conformity with United 
States obligations under the Single Convention on Narcotic Drugs.\43\ 
The HHS stated that there is a lack of significant diversion from 
legitimate drug sources, but that this is likely due to high 
availability of marijuana from illicit sources. Marijuana is not an 
FDA-approved drug product. Neither a New Drug Application (NDA) nor a 
Biologics License Application (BLA) has been approved for marketing in 
the United States. However, the marijuana used for nonclinical and 
clinical research represents a very small amount of the total amount of 
marijuana available in the United States and therefore information 
about marijuana diversion from legitimate sources is limited or not 
available.
---------------------------------------------------------------------------

    \43\ See 76 FR 51403, 51409-51410 (2011) (discussing cannabis 
controls required under the Single Convention).
---------------------------------------------------------------------------

    The DEA notes that the magnitude of the demand for illicit 
marijuana is evidenced by information from a number of databases 
presented under Factor 4. Briefly, marijuana is the most commonly used 
illegal drug in the United States. It is also the most commonly used 
illicit drug by American high schoolers. Marijuana is the most 
frequently identified drug in state, local, and federal forensic 
laboratories, with increasing amounts of both domestically grown and of 
illicitly smuggled marijuana.
    Given that marijuana has long been the most widely trafficked and 
abused controlled substance in the United States, and that all aspects 
of such illicit activity are entirely outside of the closed system of 
distribution mandated by the CSA, it may well be the case that there is 
little thought given to diverting marijuana from the small supplies 
produced for legitimate research purposes. Thus, the lack of data 
indicating diversion of marijuana from legitimate channels to the 
illicit market is not indicative of a lack of potential for abuse of 
the drug.
    3. Individuals are taking the drug or drugs containing such a 
substance on their own initiative rather than on the basis of medical 
advice from a practitioner licensed by law to administer such drugs in 
the course of his professional practice.
    The HHS stated that the FDA has not evaluated or approved an NDA or 
BLA for marijuana for any therapeutic indication. Consistent with 
federal law, therefore, an individual legitimately can take marijuana 
based on medical advice from a practitioner only by participating in 
research that is being conducted under an Investigational New Drug 
(IND) application. The HHS noted that there are several states as well 
as the District of Columbia which have passed laws allowing for 
individuals to use marijuana for purported ``medical'' use under 
certain circumstances, but data are not available yet to determine the 
number of individuals using marijuana under these state laws. 
Nonetheless, according to 2014 NSDUH data, 22.2 million American adults 
currently use marijuana (SAMHSA, 2015a). Based on the large number of 
individuals who use marijuana and the lack of an FDA-approved drug 
product, the HHS concluded that the majority of individuals using 
marijuana do so on their own initiative rather than by following 
medical advice from a licensed practitioner.
    4. The drug or drugs containing such a substance are new drugs so 
related in their action to a drug or drugs already listed as having a 
potential for abuse to make it likely that the drug will have the same 
potentiality for abuse as such drugs, thus making it reasonable to 
assume that there may be significant diversions from legitimate 
channels, significant use contrary to or without medical advice, or 
that it has a substantial capability of creating hazards to the health 
of the user or to the safety of the community.
    Marijuana and its primary psychoactive ingredient, [Delta]\9\-THC, 
are controlled substances in schedule I under the CSA.
    The HHS stated that one approved, marketed drug product contains 
synthetic [Delta]\9\-THC, also known as dronabinol, and another 
approved, marketed drug product contains a cannabinoid-like synthetic 
compound that is structurally related to [Delta]\9\-THC, the main 
active component in marijuana. Both products are controlled under the 
CSA.
    Marinol is a schedule III drug product containing synthetic 
[Delta]\9\-THC (dronabinol) formulated in sesame oil in soft gelatin 
capsules. Marinol was approved by the FDA in 1985 for the treatment of 
nausea and vomiting associated with cancer chemotherapy in patients who 
did not respond to conventional anti-emetic treatments. In 1992, FDA 
approved Marinol for the treatment of anorexia associated with weight 
loss in patients with acquired immunodeficiency syndrome (AIDS). 
Marinol was originally placed into schedule II and later rescheduled to 
schedule III under the CSA due to the low reports of abuse relative to 
marijuana.

[[Page 53823]]

    Cesamet is a drug product containing the schedule II substance 
nabilone, a synthetic substance structurally related to [Delta]\9\-THC. 
Cesamet was approved for marketing by the FDA in 1985 for the treatment 
of nausea and vomiting associated with cancer chemotherapy. All other 
naturally occurring cannabinoids in marijuana and their synthetic 
equivalents with similar chemical structure and pharmacological 
activity are already included as schedule I drugs under the CSA.

B. Abuse Liability Studies

    In addition to the indicators suggested by the CSA's legislative 
history, data as to preclinical and clinical abuse liability studies, 
as well as actual abuse, including clandestine manufacture, 
trafficking, and diversion from legitimate sources, are considered in 
this factor.
    Abuse liability evaluations are obtained from studies in the 
scientific and medical literature. There are many preclinical measures 
of a drug's effects that when taken together provide an accurate 
prediction of the human abuse liability. Clinical studies of the 
subjective and reinforcing effects in humans and epidemiological 
studies provide quantitative data on abuse liability in humans and some 
indication of actual abuse trends. Both preclinical and clinical 
studies have clearly demonstrated that marijuana and [Delta]\9\-THC 
possess the attributes associated with drugs of abuse: They function as 
a positive reinforcer to maintain drug-seeking behavior, they function 
as a discriminative stimulus, and they have dependence potential.
    Preclinical and most clinical abuse liability studies have been 
conducted with the psychoactive constituents of marijuana, primarily 
[Delta]\9\-THC and its metabolite, 11-hydroxy-[Delta]\9\-THC. 
[Delta]\9\-THC's subjective effects are considered to be the basis for 
marijuana's abuse liability. The following studies provide a summary of 
that data.
1. Preclinical Studies
    [Delta]\9\-THC, the primary psychoactive component in marijuana, is 
an effective reinforcer in laboratory animals, including primates and 
rodents, as these animals will self-administer [Delta]\9\-THC. These 
animal studies both predict and support the observations that 
[Delta]\9\-THC, whether smoked as marijuana or administered by other 
routes, produces reinforcing effects in humans. Such reinforcing 
effects can account for the repeated abuse of marijuana.
a. Drug Discrimination Studies
    The drug discrimination paradigm is used as an animal model of 
human subjective effects (Solinas et al., 2006) and is a method where 
animals are able to indicate whether a test drug is able to produce 
physical or psychological changes similar to a known drug of abuse. 
Animals are trained to press one bar (in an operant chamber) when they 
receive a known drug of abuse and another bar when they receive a 
placebo. When a trained animal receives a test drug, if the drug is 
similar to the known drug of abuse, it will press the bar associated 
with the drug.
    Discriminative stimulus effects of [Delta]\9\-THC have specificity 
for the pharmacological effects of cannabinoids found in marijuana 
(Balster and Prescott, 1992; Browne and Weissman, 1981; Wiley et al., 
1993; Wiley et al., 1995). As mentioned by the HHS, the discriminative 
stimulus effects of cannabinoids appear to be unique because abused 
drugs of other classes including stimulants, hallucinogens, opioids, 
benzodiazepines, barbiturates, NMDA antagonists, and antipsychotics do 
not fully substitute for [Delta]\9\-THC.
    Laboratory animals including monkeys (McMahon et al., 2009), mice 
(McMahon et al., 2008), and rats (Gold et al., 1992) are able to 
discriminate cannabinoids from other drugs and placebo. The major 
active metabolite of [Delta]\9\-THC, 11-hydroxy-[Delta]\9\-THC, 
generalizes to [Delta]\9\-THC (Browne and Weissman, 1981). In addition, 
according to the HHS, twenty-two other cannabinoids found in marijuana 
also substitute for [Delta]\9\-THC. At least one cannabinoid, CBD, does 
not substitute for [Delta]\9\-THC in rats (Vann et al., 2008).
b. Self-Administration Studies
    Animal self-administration behavior associated with a drug is a 
commonly used method for evaluating if the drug produces rewarding 
effects and for predicting abuse potential (Balster, 1991; Balster and 
Bigelow, 2003). Drugs that are self-administered by animals are likely 
to produce rewarding effects in humans. As mentioned in the HHS review 
document, earlier attempts to demonstrate self-administration of 
[Delta]\9\-THC were unsuccessful and confounded by diet restrictions, 
animal restraint, and known analgesic activity of [Delta]\9\-THC at 
testing doses (Tanda and Goldberg, 2003; Justinova et al., 2003). Self-
administration of [Delta]\9\-THC was first demonstrated by Tanda et al. 
(2000). Tanda et al. (2000) showed that squirrel monkeys that were 
initially trained to self-administer cocaine (30 [micro]g/kg, i.v.) 
self-administered 2 [micro]g/kg [Delta]\9\-THC (i.v.) and at a rate of 
30 injections per one hour session. Tanda et al. (2000) used a lower 
dose of [Delta]\9\-THC that was rapidly delivered (0.2 ml injection 
over 200 ms) than in previous self-administration studies such that 
analgesic activity of [Delta]\9\-THC was not a confounding factor. The 
authors also stated that the doses were comparable to those doses used 
by humans who smoke marijuana. A CB1 receptor antagonist (SR141716) 
blocked this rewarding effect of THC.
    Justinova et al. (2003) were able to demonstrate self-
administration of [Delta]\9\-THC in drug-na[iuml]ve squirrel monkeys 
(no previous exposure to other drugs). The authors tested the monkeys 
with several doses of [Delta]\9\-THC (1, 2, 4, 8, and 16 [micro]g/kg, 
i.v.) and found that the maximal rates of self-administration were 
observed with the 4 [micro]g/kg/infusion. Subsequently, Braida et al. 
(2004) reported that rats will self-administer [Delta]\9\-THC when 
delivered intracerebroventricularly (i.c.v.), but only at the lowest 
doses tested (0.01-0.02 [micro]g/infusion, i.c.v.).
    Self-administration behavior with [Delta]\9\-THC was found to be 
antagonized in rats and squirrel monkeys by rimonabant (SR141716A, CB1 
antagonist) and the opioid antagonists (naloxone and naltrexone) (Tanda 
et al., 2000; Braida et al., 2004; Justinova et al., 2004).
c. Conditioned Place Preference Studies
    Conditioned place preference (CPP) is a behavioral assay where 
animals are given the opportunity to spend time in two distinct 
environments: one where they previously received a drug and one where 
they received a placebo. If the drug is reinforcing, animals in a drug-
free state will choose to spend more time in the environment paired 
with the drug when both environments are presented simultaneously.
    CPP has been demonstrated with [Delta]\9\-THC in rats but only at 
low doses (0.075-1.0 mg/kg, i.p.; Braida et al., 2004). Rimonabant 
(0.25-1.0 mg/kg, i.p.) and naloxone (0.5-2.0 mg/kg, i.p.) antagonized 
[Delta]\9\-THC-mediated CPP (Braida et al., 2004). However, in another 
study with rats, rimonabant was demonstrated to induce CPP at doses 
ranging from 0.25-3.0 mg/kg (Cheer et al., 2000). Mice without [micro]-
opioid receptors did not exhibit CPP to [Delta]\9\-THC (paired with 1 
mg/kg [Delta]\9\-THC, i.p.) (Ghozland et al., 2002).
2. Clinical Studies
    In its scientific review (HHS, 2015), the HHS provided a list of 
common subjective psychoactive responses to cannabinoids based on 
information from several references (Adams and Martin, 1996; Gonzalez, 
2007; Hollister, 1986;

[[Page 53824]]

Hollister, 1988; Institute of Medicine, 1982). Furthermore, Maldonado 
(2002) characterized these subjective responses as pleasurable to most 
humans and are generally associated with drug-seeking and/or drug-
taking. Later studies (Scherrer et al., 2009; Zeiger et al., 2010) 
reported that high levels of positive psychoactive effects correlate 
with increased marijuana use, abuse, and dependence. The list of the 
common subjective psychoactive effects provided by the HHS (HHS, 2015) 
is presented below:
    (1) Disinhibition, relaxation, increased sociability, and 
talkativeness.
    (2) Increased merriment and appetite, and even exhilaration at high 
doses.
    (3) Enhanced sensory perception, which can generate an increased 
appreciation of music, art, and touch.
    (4) Heightened imagination, which can lead to a subjective sense of 
increased creativity.
    (5) Initial dizziness, nausea, tachycardia, facial flushing, dry 
mouth, and tremor.
    (6) Disorganized thinking, inability to converse logically, time 
distortions, and short-term memory impairment.
    (7) Ataxia and impaired judgment, which can impede driving ability 
or lead to an increase in risk-taking behavior.
    (8) Illusions, delusions, and hallucinations that intensify with 
higher doses.
    (9) Emotional lability, incongruity of affect, dysphoria, 
agitation, paranoia, confusion, drowsiness, and panic attacks, which 
are more common in inexperienced or high-dosed users.
    The HHS mentioned that marijuana users prefer higher concentrations 
of the principal psychoactive component ([Delta]\9\-THC) over lower 
concentrations. In a clinical study with marijuana users (n = 12, usage 
ranged from once a month to 4 times a week), subjects were given a 
choice of 1.95% [Delta]\9\-THC marijuana or 0.63% [Delta]\9\-THC 
marijuana after sampling both marijuana cigarettes in two choice 
sessions. The marijuana cigarette with high THC was chosen in 21 out of 
24 choice sessions or 87.5% of the time (Chait and Burke, 1994). 
Furthermore, in a double-blind study, frequent marijuana users (n = 11, 
usage at least 2 times per month with at least 100 occasions) when 
given a low-dose of oral [Delta]\9\-THC (7.5 mg) were able to 
distinguish the psychoactive effects better than occasional users (n = 
10, no use within the past 4 years with 10 or fewer lifetime uses) and 
also experienced fewer sedative effects (Kirk and de Wit, 1999).
    Marijuana has also been recognized by scientific experts to have 
withdrawal symptoms (negative reinforcement) following moderate and 
heavy use. As discussed further in Factor 7, the DEA notes that the 
American Psychiatric Association's (APA) Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5) included a list of 
withdrawal symptoms following marijuana [cannabis] use (DSM-5, 2013).

C. Actual Abuse of Marijuana--National Databases Related to Marijuana 
Abuse and Trafficking

    Marijuana continues to be the most widely used illicit drug. 
Evidence of actual abuse can be defined by episodes/mentions in 
databases indicative of abuse/dependence. The HHS provided in its 
recommendation (HHS, 2015) information relevant to actual abuse of 
marijuana including data results from the National Survey on Drug Use 
and Health (NSDUH), a Monitoring the Future (MTF) survey, the Drug 
Abuse Warning Network (DAWN), and the Treatment Episode Data Set 
(TEDS). These data sources provide quantitative information on many 
factors related to abuse of a particular substance, including incidence 
and patterns of use, and profile of the abuser of specific substances. 
The DEA is providing updated information from these databases in this 
discussion. The DEA also includes data on trafficking and illicit 
availability of marijuana from DEA databases including the National 
Forensic Laboratory Information System (NFLIS) and the National Seizure 
System (NSS), formerly the Federal-wide Drug Seizure System (FDSS), as 
well as other sources of data specific to marijuana, including the 
Potency Monitoring Project and the Domestic Cannabis Eradication and 
Suppression Program (DCE/SP).
1. National Survey on Drug Use and Health (NSDUH)
    The National Survey on Drug Use and Health (NSDUH) is conducted 
annually by the Department of Health and Human Service's Substance 
Abuse and Mental Health Services Administration (SAMHSA). SAMHSA is the 
primary source of estimates of the prevalence and incidence of 
pharmaceutical drugs, illicit drugs, alcohol, and tobacco use in the 
United States. The survey is based on a nationally representative 
sample of the civilian, non-institutionalized population 12 years of 
age and older. The survey excludes homeless people who do not use 
shelters, active military personnel, and residents of institutional 
group quarters such as jails and hospitals.
    According to the 2014 NSDUH report, marijuana was the most commonly 
used and abused illicit drug. That data showed that there were 22.2 
million people who were past month users (8.4%) among those aged 12 and 
older in the United States. (Note: NSDUH figures on marijuana use 
include hashish use; the relative proportion of hashish use to 
marijuana use is very low). Marijuana had the highest rate of past-year 
dependence or abuse in 2014. The NSDUH report estimates that 3.0 
million people aged 12 or older used an illicit drug for the first time 
in 2014; a majority (70.3%) of these past year initiates reported that 
their first drug used was marijuana. Among those who began using 
illicit drugs in the past year, 65.6%, 70.3%, and 67.6% reported 
marijuana as the first illicit drug initiated in 2012, 2013, and 2014 
respectively. In 2014, the average age of marijuana initiates among 12- 
to 49-year-olds was 18.5 years. These usage rates and demographics are 
relevant in light of the risks presented.
    Marijuana had the highest rate of past year dependence or abuse of 
any illicit drug in 2014. The 2014 NSDUH report stated that 4.2 million 
persons were classified with substance dependence or abuse of marijuana 
in the past year (representing 1.6% of the total population aged 12 or 
older, and 59.0% of those classified with illicit drug dependence or 
abuse) based on criteria specified in the Diagnostic and Statistical 
Manual of Mental Disorders, 4th edition (DSM-IV).
    Among past year marijuana users age 12 or older, 18.5% used 
marijuana on 300 or more days within the previous 12 months in 2014. 
This translates into 6.5 million people using marijuana on a daily or 
almost daily basis over a 12-month period, significantly more than the 
estimated 5.7 million daily or almost daily users in just the year 
before. Among past month marijuana users, 41.6% (9.2 million) used the 
drug on 20 or more days in the past month, a significant increase from 
the 8.1 million who used marijuana 20 days or more in 2013.
2. Monitoring the Future (MTF)
    Monitoring the Future (MTF) is an ongoing study which is funded 
under a series of investigator-initiated competing research grants from 
the National Institute on Drug Abuse (NIDA). MTF tracks drug use trends 
among American adolescents in the 8th, 10th, and 12th grades. According 
to its 2015 survey results, marijuana was the most commonly used 
illicit drug, as was the case in previous years. Approximately 6.5% of 
8th graders,

[[Page 53825]]

14.8% of 10th graders, and 21.3% of 12th graders surveyed in 2015 
reported marijuana use during the past month prior to the survey. A 
number of high school students in 2015 also reported daily use in the 
past month, including 1.1%, 3.0%, and 6.0% of 8th, 10th, and 12th 
graders, respectively.
3. Drug Abuse Warning Network (DAWN), Emergency Department (ED) Visits
    The Drug Abuse Warning Network (DAWN) is a public health 
surveillance system that monitors drug-related hospital emergency 
department (ED) visits to track the impact of drug use, misuse, and 
abuse in the United States. For the purposes of DAWN, the term ``drug 
abuse'' applies if the following conditions are met: (1) The case 
involved at least one of the following: use of an illegal drug, use of 
a legal drug contrary to directions, or inhalation of a non-
pharmaceutical substance; and (2) the substance was used for one of the 
following reasons: because of drug dependence, to commit suicide (or 
attempt to commit suicide), for recreational purposes, or to achieve 
other psychic effects. Importantly, many factors can influence the 
estimates of ED visits, including trends in overall use of a substance 
as well as trends in the reasons for ED usage. For instance, some drug 
users may visit EDs for life-threatening issues while others may visit 
to seek care for detoxification because they needed certification 
before entering treatment. Additionally, DAWN data do not distinguish 
the drug responsible for the ED visit from other drugs that may have 
been used concomitantly. As stated in a DAWN report, ``Since marijuana/
hashish is frequently present in combination with other drugs, the 
reason for the ED visit may be more relevant to the other drug(s) 
involved in the episode.''
    In 2011, marijuana was involved in 455,668 ED visits out of 
2,462,948 total ED visits involving all abuse or misuse in the United 
States and out of 1.25 million visits involving abuse or misuse of 
illicit drugs (excluding alcohol-related visits), as estimated by DAWN. 
This is lower than the number of ED visits involving cocaine (505,224) 
and higher than the number of ED visits involving heroin (258,482) and 
stimulants (e.g., amphetamine, methamphetamine) (159,840). Visits 
involving the other major illicit drugs, such as MDMA, GHB, LSD and 
other hallucinogens, PCP, and inhalants, were much less frequent, 
comparatively.
    In young patients, marijuana is the illicit drug most frequently 
involved in ED visits, according to DAWN estimates, with 240.2 
marijuana-related ED visits per 100,000 population ages 12 to 17, 443.8 
per 100,000 population ages 18 to 20, and 446.9 per 100,000 population 
ages 21 to 24.
4. Treatment Episode Data Set (TEDS) System
    The Treatment Episode Data Set (TEDS) system is part of the SAMHSA 
Drug and Alcohol Services Information System and is a national census 
of annual admissions to state licensed or certified, or 
administratively tracked, substance abuse treatment facilities. The 
TEDS system contains information on patient demographics and substance 
abuse problems of admissions to treatment for abuse of alcohol and/or 
drugs in facilities that report to state administrative data systems. 
For this database, the primary substance of abuse is defined as the 
main substance of abuse reported at the time of admission. TEDS also 
allows for the recording of two other substances of abuse (secondary 
and tertiary).
    In 2011, the TEDS system included 1,928,792 admissions to substance 
abuse treatment; in 2012 there were 1,801,385 admissions; and in 2013 
there were 1,683,451 admissions. Marijuana/hashish was the primary 
substance of abuse for 18.3% (352,397) of admissions in 2011; 17.5% 
(315,200) in 2012; and 16.8% (281,991) in 2013. Of the 281,991 
admissions for marijuana/hashish treatment in 2013, 24.3% used 
marijuana/hashish daily. Among those treated for marijuana/hashish as 
the primary substance in 2013, 27.4% were ages 12 to 17 years and 29.7% 
were ages 18 to 24 years. Those admitted for marijuana/hashish were 
mostly male (72.6%) and non-Hispanic (82.2%). Non-hispanic whites 
(43.2%) represented the largest ethnic group of marijuana admissions.
5. Forensic Laboratory Data
    Data on marijuana seizures from federal, state, and local forensic 
laboratories have indicated that there is significant trafficking of 
marijuana. The National Forensic Laboratory System (NFLIS) is a program 
sponsored by the Drug Enforcement Administration's Office of Diversion 
Control. NFLIS systematically collects drug identification results and 
associated information from drug exhibits encountered by law 
enforcement and analyzed in federal, state, and local forensic 
laboratories. NFLIS is a comprehensive information system that includes 
data from 278 individual forensic laboratories that report more than 
91% of the drug caseload in the U.S. NFLIS captures data for all drugs 
and chemicals identified and reported by forensic laboratories. More 
than 1,700 unique substances are represented in the NFLIS database.
    Data from NFLIS showed that marijuana was the most frequently 
identified drug in federal, state, and local laboratories from January 
2004 through December 2014. Marijuana accounted for between 29.47% and 
34.84% of all drug exhibits analyzed annually during that time frame 
(Table 1).

[[Page 53826]]

[GRAPHIC] [TIFF OMITTED] TP12AU16.040

    Since 2004, the total number of reports of marijuana and the amount 
of marijuana encountered federally has remained high (see data from 
Federal-wide Drug Seizure System and Domestic Cannabis Eradication and 
Suppression Program below).
6. Federal-Wide Drug Seizure System
    The Federal-wide Drug Seizure System (FDSS) contains information 
about drug seizures made within the jurisdiction of the United States 
by the Drug Enforcement Administration, the Federal Bureau of 
Investigation, United States Customs and Border Protection, and United 
States Immigration and Customs Enforcement. It also records maritime 
seizures made by the United States Coast Guard. Drug seizures made by 
other Federal agencies are included in the FDSS database when drug 
evidence custody is transferred to one of the agencies identified 
above. FDSS is now incorporated into the National Seizure System (NSS), 
which is a repository for information on clandestine laboratory and 
contraband (chemicals and precursors, currency, drugs, equipment and 
weapons). FDSS reports total federal drug seizures [in kilograms (kg)] 
of substances such as cocaine, heroin, MDMA, methamphetamine, and 
cannabis (marijuana and hashish). The yearly volume of cannabis seized 
(Table 2), consistently exceeding a thousand metric tons per year, 
shows that cannabis is very widely trafficked in the United States. 
[GRAPHIC] [TIFF OMITTED] TP12AU16.041

7. Potency Monitoring Project
    The University of Mississippi's Potency Monitoring Project (PMP), 
through a contract with the National Institute on Drug Abuse (NIDA), 
analyzes and compiles data on the [Delta]\9\-THC concentrations of 
marijuana, hashish and hash oil samples provided by DEA regional 
laboratories and by state and local police agencies. After 2010, PMP 
has analyzed only marijuana samples provided by DEA regional 
laboratories. As indicated in Figure 1, the percentage of [Delta]\9\-
THC increased from 1995 to 2010 with an average THC content of 3.75% in 
1995 and 9.53% in 2010. In examining marijuana samples only provided by 
DEA laboratories, the average [Delta]\9\-THC content was 3.96% in 1995 
in comparison to 11.16% in 2015.

[[Page 53827]]

[GRAPHIC] [TIFF OMITTED] TP12AU16.042

8. The Domestic Cannabis Eradication and Suppression Program
    The Domestic Cannabis Eradication and Suppression Program (DCE/SP) 
was established in 1979 to reduce the supply of domestically cultivated 
marijuana in the United States. The program was designed to serve as a 
partnership between federal, state, and local agencies. Only California 
and Hawaii were active participants in the program at its inception. 
However, by 1982 the program had expanded to 25 states and by 1985 all 
50 states were participants. Cannabis is cultivated in remote locations 
and frequently on public lands and illicitly grown in all states. Data 
provided by the DCE/SP (Table 3) show that in the United States in 
2014, there were 3,904,213 plants eradicated in outdoor cannabis 
cultivation areas compared to 2,597,798 plants in 2000. Significant 
quantities of marijuana were also eradicated from indoor cultivation 
operations. There were 396,620 indoor plants eradicated in 2014 
compared to 217,105 eradicated in 2000.

[[Page 53828]]

[GRAPHIC] [TIFF OMITTED] TP12AU16.043

    The recent statistics from these various surveys and databases show 
that marijuana continues to be the most commonly used illicit drug, 
with considerable rates of heavy abuse and dependence. They also show 
that marijuana is the most readily available illicit drug in the United 
States.

Petitioners' Major Comment in Relation to Factor 1 and the Government's 
Responses

    (1) The petitioner states on pages 1-2 of the petition that 
``[p]ure THC (Marinol), the primary psychoactive ingredient in 
marijuana has been placed in Schedule III. However, unlike Marinol, 
marijuana has other cannabinoids that help to mitigate the psychoactive 
effects of THC and reduce the potential for abuse. Therefore, the THC 
in marijuana can not have the high potential for abuse required for 
placement in Schedule I.''
    First, the petitioners failed to review the indicators of abuse 
potential, as discussed in the legislative history of the CSA. The 
petitioners did not use data on marijuana usage, diversion, 
psychoactive properties, and dependence in their evaluation of 
marijuana abuse potential. The HHS and the DEA discuss those indicators 
above in this factor. HHS's evaluation of the full range of data led 
HHS and DEA to conclude that marijuana has a high potential for abuse.
    Second, the HHS indicated that modulating effects of the other 
cannabinoids in marijuana on [Delta]\9\-THC have not been demonstrated 
in controlled studies. Specifically, HHS concluded in its 8-factor 
analysis that ``any possible mitigation of delta-9-THC's psychoactive 
effects by CBD will not occur for most marijuana users.''
    Marinol was rescheduled from schedule II to schedule III on July 2, 
1999 (64 FR 35928, DEA 1999). In assessing Marinol, HHS compared 
Marinol to marijuana on several aspects of abuse potential and found 
that major differences between the two, such as formulation, 
availability, and usage, contribute to differences in abuse potential. 
The psychoactive effects from smoking are generally more rapid and 
intense that those that occur through oral administration (HHS, 2015; 
Wesson and Washburn, 1990; Hollister and Gillespie, 1973). Therefore, 
as concluded by both the HHS and the DEA, the delayed onset of action 
and longer duration of action from an oral dose of Marinol may 
contribute in limiting the abuse potential of Marinol relative to 
marijuana, which is most often smoked. The HHS also stated that the 
extraction and purification of dronabinol from the encapsulated sesame 
oil mixture of Marinol is highly complex and difficult and that the 
presence of sesame oil mixture may preclude the smoking of Marinol-
laced cigarettes.
    Additionally, the FDA approved a New Drug Application (NDA) for 
Marinol, indicating a legitimate medical use for Marinol in the United 
States and allowing for Marinol to be rescheduled into schedule II and 
subsequently into schedule III of the CSA. The HHS mentioned that 
marijuana and Marinol differ on a wide variety of factors and these 
differences are major reasons for differential scheduling of marijuana 
and Marinol. Marijuana, as discussed more fully in Factors 3 and 6, 
does not have a currently accepted medical use in the United States, is 
highly abused, and has a lack of accepted safety.
    Finally, the DEA notes that under the CSA, for a substance to be 
placed in schedule II, III, IV, or V, it must have a currently accepted 
medical use in treatment in the United States.\44\ As DEA has 
previously stated, Congress established only one schedule, schedule I, 
for drugs of abuse with ``no currently accepted medical use in 
treatment in the United States.'' 76 FR 40552 (2011). Thus, any attempt 
to compare the relative abuse potential of schedule I substance to that 
of a substance in another schedule is inconsequential since a schedule 
I substance must remain in schedule I until it has been found to have a 
currently accepted medical use in treatment in the United States.
---------------------------------------------------------------------------

    \44\ See Americans for Safe Access, 706 F.3d at 440.
---------------------------------------------------------------------------

Factor 2: Scientific Evidence of the Drug's Pharmacological Effects, if 
Known

    The HHS stated that there are large amounts of scientific data on 
the neurochemistry, mechanistic effects, toxicology, and pharmacology 
of marijuana. A scientific evaluation, as conducted by the HHS and the 
DEA, of marijuana's neurochemistry, human and animal behavioral 
pharmacology, central nervous system effects, and other pharmacological 
effects (e.g. cardiovascular, immunological effects) is presented 
below.

[[Page 53829]]

Neurochemistry

    Marijuana contains numerous constituents such as cannabinoids that 
have a variety of pharmacological actions. The HHS stated that 
different marijuana samples derived from various cultivated strains may 
differ in their chemical constituents including [Delta]\9\-THC and 
other cannabinoids. Therefore marijuana products from different strains 
will have different biological and pharmacological effects. The 
chemical constituents of marijuana are discussed further in Factor 3.
    The primary site of action for cannabinoids such as [Delta]\9\-THC 
is at the cannabinoid receptor. Two cannabinoid receptors, CB1 and CB2, 
have been identified and characterized (Battista et al., 2012; 
Piomelli, 2005) and are G-protein-coupled receptors. Activation of 
these inhibitory G-protein-coupled receptors inhibits adenylate cyclase 
activity, which prevents conversion of ATP to cyclic AMP. Cannabinoid 
receptor activation also results in inhibition of N- and P/Q-type 
calcium channels and activates inwardly rectifying potassium channels 
(Mackie et al., 1995; Twitchell et al., 1997). The HHS mentioned that 
inhibition of N-type calcium channels decreases neurotransmitter 
release and this may be the underlying mechanism in the ability of 
cannabinoids to inhibit acetylcholine, norepinephrine and glutamate 
from specific areas of the brain. These cellular actions may underlie 
the antinociceptive and psychoactive effects of cannabinoids. 
[Delta]\9\-THC acts as an agonist at cannabinoid receptors.
    CB1 receptors are primarily found in the central nervous system and 
are located mainly in the basal ganglia, hippocampus and cerebellum of 
the brain (Howlett et al., 2004). CB1 receptors are also located in 
peripheral tissues such as the immune system (De Petrocellis and Di 
Marzo, 2009), but the concentration of CB1 receptors there is 
considerably lower than in the central nervous system (Herkenham et 
al., 1990; 1992). CB2 receptors are found primarily in the immune 
system and predominantly in B lymphocytes and natural killer cells 
(Bouaboula et al., 1993). CB2 receptors are also found in the central 
nervous system, primarily in the cerebellum and hippocampus (Gong et 
al., 2006).
    Two endogenous ligands to the cannabinoid receptors, anandamide and 
arachidonyl glycerol (2-AG), were identified in 1992 (Devane et al., 
1992) and 1995 (Mechoulam et al., 1995), respectively. Anandamide is a 
low-efficacy agonist (Brievogel and Childers, 2000) and 2-AG is a high 
efficacy agonist (Gonsiorek et al., 2000) to the cannabinoid receptors. 
These endogenous ligands are present in both the central nervous system 
and in the periphery (HHS, 2015).
    [Delta]\9\-THC and cannabidiol (CBD) are two of the major 
cannabinoids in marijuana. [Delta]\9\-THC is the major psychoactive 
cannabinoid (Wachtel et al., 2002). [Delta]\9\-THC has similar affinity 
for CB1 and CB2 receptors and acts as a weak agonist at CB2 receptors. 
The HHS indicated that activation of CB1 receptors mediates 
psychotropic effects of cannabinoids. CBD has low affinity for both CB1 
and CB2 receptors. CBD has antagonistic effects at CB1 receptors, and 
some inverse agonistic properties at CB2 receptors.

Animal Behavioral Effects

    Animal abuse potential studies (drug discrimination, self-
administration, conditioned place preference) are discussed more fully 
in Factor 1. Briefly, it was consistently demonstrated that [Delta]\9\-
THC, the primary psychoactive component in marijuana, and other 
cannabinoids in marijuana have a distinct drug discriminative profile. 
In addition, animals self-administer [Delta]\9\-THC, and [Delta]\9\-THC 
in low doses produces conditioned place preference.

Central Nervous System Effects

Psychoactive Effects

    The clinical psychoactive effects of marijuana are discussed more 
fully in Factor 1. Briefly, the psychoactive effects from marijuana use 
are considered pleasurable and associated with drug-seeking or drug-
taking (HHS, 2015; Maldonado, 2002). Further, it was noted by HHS that 
marijuana users prefer higher concentrations of the principal 
psychoactive component ([Delta]\9\-THC) over lower concentrations (HHS, 
2015).
    Studies have evaluated psychoactive effects of THC in the presence 
of high CBD, CBC, or CBN ratios. Even though some studies suggest that 
CBD may decrease some of [Delta]\9\-THC's psychoactive effects, the HHS 
found that the ratios of CBD to [Delta]\9\-THC administered in the 
studies were not comparable to the amounts found in marijuana used by 
most people (Dalton et al., 1976; Karniol et al., 1974; Zwardi et al., 
1982). In fact, the CBD ratios in these studies are significantly 
higher than the CBD found in most marijuana currently found on the 
streets (Mehmedic et al., 2010). HHS indicated that most of the 
marijuana available on the street has a high THC and low CBD content 
and therefore any lessening of THC's psychoactive effects by CBD will 
not occur for most marijuana users (HHS, 2015). Dalton et al. (1976) 
reported that when volunteers smoked cigarettes with a ratio of 7 CBD 
to 1 [Delta]\9\-THC (0.15 mg/kg CBD and 0.025 mg/kg [Delta]\9\-THC), 
there was a significant decrease in ratings of acute subjective effects 
and achieving a ``high'' in comparison to smoking [Delta]\9\-THC alone. 
In oral administration studies, the subjective effects and anxiety 
produced by combination of CBD and THC in a ratio of at least 1:2 CBD 
to [Delta]\9\-THC (15, 30, 60 mg CBD to 30 mg [Delta]\9\-THC; Karniol 
et al., 1974) or a ratio of 2:1 CBD to [Delta]\9\-THC (1 mg/kg CBD to 
0.5 mg/kg [Delta]\9\-THC; Zuardi et al., 1982) are less than those 
produced by [Delta]\9\-THC administered alone.
    In one study (Ilan et al., 2005), the authors calculated the 
naturally occurring concentrations of CBC and CBD in marijuana 
cigarettes with either 1.8 or 3.6% [Delta]\9\-THC by weight. The 
authors varied the concentrations of CBC and CBD for each concentration 
of [Delta]\9\-THC in the marijuana cigarettes. Administrations in 
healthy marijuana users (n=23) consisted of either: (1) Low CBC (0.1% 
by weight) and low CBD (0.2% by weight); (2) high CBC (0.5% by weight) 
and low CBD; (3) low CBC and high CBD (1.0% by weight); or 4) high CBC 
and high CBD and the users were divided into low [Delta]\9\-THC (1.8% 
by weight) and high [Delta]\9\-THC (3.6% by weight) groups. Subjective 
psychoactive effects were significantly greater for all groups in 
comparison to placebo and there were no significant differences in 
effects among the treatments (Ilan et al., 2005).
    The HHS also referred to a study with [Delta]\9\-THC and cannabinol 
(CBN) (Karniol et al., 1975). In this study, oral administration of 
either 12.5, 25, or 50 mg CBN combined with 25 mg [Delta]\9\-THC (ratio 
of at least 1:2 CBN to [Delta]\9\-THC) significantly increased 
subjective psychoactive ratings of [Delta]\9\-THC compared to 
[Delta]\9\-THC alone (Karniol et al., 1975).

Behavioral Impairment

    Several factors may influence marijuana's behavioral effects 
including the duration (chronic or short term), frequency (daily, 
weekly, or occasionally), and amount of use (heavy or moderate). 
Researchers have examined how long behavioral impairments persist 
following chronic marijuana use. These studies used self-reported 
histories of exposure duration, frequency, and amount of marijuana use, 
and administered several performance and cognitive tests at different 
time points following

[[Page 53830]]

marijuana abstinence. According to HHS, behavioral impairments may 
persist for up to 28 days of abstinence in chronic marijuana users.
    Psychoactive effects of marijuana can lead to behavioral impairment 
including cognitive decrements and decreased ability to operate motor 
vehicles (HHS, 2015). Block et al. (1992) evaluated cognitive measures 
in 48 healthy male subjects following smoking a marijuana cigarette 
that contained 2.57% or 19 mg [Delta]\9\-THC by weight or placebo. Each 
subject participated in eight sessions (four sessions with marijuana; 
four sessions with placebo) and several cognitive and psychomotor tests 
were administered (e.g. verbal recall, facial recognition, text 
learning, reaction time). Marijuana significantly impaired performances 
in most of these cognitive and psychomotor tests (Block et al., 1992).
    Ramaekers et al. (2006) reported that in 20 recreational users of 
marijuana, acute administration of 250 [micro]g/kg and 500 [micro]g/kg 
[Delta]\9\-THC in smoked marijuana resulted in dose-dependent 
impairments in cognition, motor impulsivity, motor control (tracking 
impairments), and risk taking. In another study (Kurzthaler et al., 
1999), when 290 [micro]g/kg [Delta]\9\-THC was administered via a 
smoked marijuana cigarette in 30 healthy volunteers with no history of 
substance abuse there were significant impairments of motor speed and 
accuracy. Furthermore, administration of 3.95% [Delta]\9\-THC in a 
smoked marijuana cigarette increased the latency in a task of simulated 
braking in a vehicle (Liguori et al., 1998). The HHS noted that the 
motor impairments reported in these studies (Kurzthaler et al., 1999; 
Liguori et al., 1998) are critical skills needed for operating a 
vehicle.
    As mentioned in the HHS document, some studies examined the 
persistence of the behavioral impairments immediately after marijuana 
administration. Some of marijuana's acute effects may still be present 
for at least 24 hours after the acute psychoactive effects have 
subsided. In a brief communication, Heishmann et al. (1990) reported 
that there were cognitive impairments (digit recall and arithmetic 
tasks) in two out of three experienced marijuana smokers for 24 hours 
after smoking marijuana cigarettes containing 2.57% [Delta]\9\-THC. 
However, Fant et al. (1998) evaluated subjective effects and 
performance measures for up to 25 hours in 10 healthy males after 
exposure to either 1.8% or 3.6% [Delta]\9\-THC in marijuana cigarettes. 
Peak decrements in subjective and performance measures were noted 
within 2 hours of marijuana exposure but there were minimal residual 
alterations in subjective or performance measures at 23-25 hours after 
exposure.
    Persistence of behavioral impairments following repeated and 
chronic use of marijuana has also been investigated and was reviewed in 
the HHS document (HHS, 2015). In particular, researchers examined how 
long behavioral impairments last following chronic marijuana use. In 
studies examining persistence of effects in chronic and heavy marijuana 
users, there were significant decrements in cognitive and motor 
function tasks in all studies of up to 27 days, and in most studies at 
28 days (Solowij et al., 2002; Messinis et al., 2006; Lisdahl and 
Price, 2012; Pope et al., 2002; Bolla et al., 2002; Bolla et al., 
2005). In studies that followed heavy marijuana users for longer than 
28 days and up to 20 years of marijuana abstinence, cognitive and 
psychomotor impairments were no longer detected (Fried et al., 2005; 
Lyons et al., 2004; Tait et al., 2011). For example, Fried et al. 
(2005) reported that after 3 months of abstinence from marijuana, any 
deficits in intelligence (IQ), memory, and processing speeds following 
heavy marijuana use were no longer observed (Fried et al., 2005). In a 
meta-analysis that examined non-acute and long-lasting effects of 
marijuana, any deficits in neurocognitive performance that were 
observed within the first month were no longer apparent after 
approximately one month of abstinence (Schreiner and Dunn, 2012). HHS 
further notes that in moderate marijuana users deficits in decision-
making skills were not observed after 25 days of abstinence and 
additionally IQ, immediate memory and delayed memory skills were not 
significantly impacted as observed with heavy and chronic marijuana 
users (Fried et al., 2005; HHS, 2015)
    As mentioned in the HHS document (HHS, 2015), the intensity and 
persistence of neurological impairment from chronic marijuana use also 
may be dependent on the age of first use. In two separate smaller scale 
studies (less than 100 participants per exposure group), Fontes et al. 
(2011) and Gruber et al. (2012) compared neurological function in early 
onset (chronic marijuana use prior to age 15 or 16) and late onset 
(chronic marijuana use after age 15 or 16) heavy marijuana users and 
found that there were significant deficits in executive neurological 
function in early onset users which were not observed or were less 
apparent in late onset users. In a prospective longitudinal birth 
cohort study following 1,037 individuals (Meier et al., 2012), a 
significant decrease in IQ and neuropsychological performance was 
observed in adolescent-onset users and persisted even after abstinence 
from marijuana for at least one year. However, Meier et al (2012) 
reported in there was no significant change in IQ in adult-onset users.
    The HHS noted that there is some evidence that the severity of the 
persistent neurological impairments may also be due in part to the 
amount of marijuana usage. In the study mentioned above, Gruber et al. 
(2012) found that the early onset users consumed three times as much 
marijuana per week and used it twice as often as late onset users. 
Meier et al. (2012) reported in their study, mentioned above, that 
there was a correlation between IQ deficits in adolescent onset users 
and the increased amount of marijuana used.

Behavioral Effects of Prenatal Exposure

    In studies that examined effects of prenatal marijuana exposure, 
many of the pregnant women also used alcohol and tobacco in addition to 
marijuana. Even though other drugs were used in conjunction with 
marijuana, there is evidence of an association between heavy prenatal 
marijuana exposure and deficits in some cognitive function. There have 
been two prospective longitudinal birth cohort studies following 
individuals prenatally exposed to marijuana from birth until adulthood: 
The Ottawa Prenatal Prospective Study (OPPS; Fried et al., 1980), and 
the Maternal Health Practices and Child Development Project (MHPCD; Day 
et al., 1985). Both longitudinal studies report that heavy prenatal 
marijuana use is associated with decreased performance on tasks 
assessing memory, verbal and quantitative reasoning in 4-year-olds 
(Fried and Watkinson, 1990) and in 6 year olds (Goldschmidt et al., 
2008). In subsequent studies with the OPPS cohort, deficits in 
sustained attention were reported in children ages 6 and 13-16 years 
(Fried et al., 1992; Fried, 2002) and deficits in executive 
neurological function were observed in 9- and 12-year-old children 
(Fried et al., 1998). DEA further notes that with the MHPCD cohort, 
follow-up studies reported an increased rate of delinquent behavior 
(Day et al., 2011) and decreased achievement test scores (Goldschmidt 
et al., 2012) at age 14. When the MHPCD cohort was followed to age 22, 
there was a marginal (p = 0.06) increase in psychosis with prenatal 
marijuana exposure and early onset of marijuana use (Day et al., 2015).

[[Page 53831]]

Association of Marijuana Use With Psychosis

    There has been extensive research to determine whether marijuana 
usage is associated with development of schizophrenia or other 
psychoses, and the HHS indicated that the available data do not suggest 
a causative link between marijuana and the development of psychosis 
(HHS, 2015; Minozzi et al., 2010). As mentioned in the HHS review (HHS, 
2015), numerous large scale longitudinal studies demonstrated that 
subjects who used marijuana do not have a greater incidence of 
psychotic diagnoses compared to non-marijuana users (van Os et al., 
2002; Fergusson et al., 2005; Kuepper et al., 2011). Further, the HHS 
commented that when analyzing the available data examining the 
association between marijuana and psychosis, it is critical to 
differentiate whether the patients in a study are already diagnosed 
with psychosis or if the individuals have a limited number of symptoms 
associated with psychosis without qualifying for a diagnosis of the 
disorder.
    As mentioned by the HHS, some of the studies examining the 
association between marijuana and psychosis utilized non-standard 
methods to categorize psychosis and these methods did not conform to 
the criteria in the Diagnostic and Statistical Manual (DSM-5) or the 
International Classification of Diseases (ICD-10) and would not be 
appropriate for use in evaluating the association between marijuana use 
and psychosis. For example, researchers characterized psychosis as 
``schizophrenic cluster'' (Maremmani et al., 2004), ``subclinical 
psychotic symptoms'' (van Gastel et al., 2012), ``pre-psychotic 
clinical high risk'' (van der Meer et al., 2012), and symptoms related 
to ``psychosis vulnerability'' (Griffith-Lendering et al., 2012).
    The HHS discussed an early epidemiological study conducted by 
Andreasson et al. (1987), which examined the link between psychosis and 
marijuana use. In this study, about 45,000 18- and 19-year-old male 
Swedish subjects provided detailed information on their drug-taking 
history and 274 of these subjects were diagnosed with schizophrenia 
over a 14-year period (1969-1983). Out of the 274 subjects diagnosed 
with psychosis, 21 individuals (7.7%) had used marijuana more than 50 
times, while 197 individuals (72%) never used marijuana. As presented 
by the authors (Andreasson et al., 1987), individuals who claimed to 
take marijuana on more than 50 occasions were 6 times more likely to be 
diagnosed with schizophrenia than those who had never consumed the 
drug. The authors concluded that marijuana users who are vulnerable to 
developing psychoses are at the greatest risk for schizophrenia. In a 
35 year follow up to the subjects evaluated in Andreasson et al. 
(1987), Manrique-Garcia et al. (2012) reported similar findings. In the 
follow up study, 354 individuals developed schizophrenia. Of those, 32 
individuals (9%) had used marijuana more than 50 times and were 6.3 
times more likely to develop schizophrenia. 255 of the 354 individuals 
(72%) never used marijuana.
    The HHS also noted that many studies support the assertion that 
psychosis from marijuana usage may manifest only in individuals already 
predisposed to development of psychotic disorders. Marijuana use may 
precede diagnosis of psychosis (Schimmelmann et al., 2011), but most 
reports indicate that prodromal symptoms of schizophrenia are observed 
prior to marijuana use (Schiffman et al., 2005). In a review examining 
gene-environmental interaction between marijuana exposure and the 
development of psychosis, it was concluded that there is some evidence 
to support that marijuana use may influence the development of 
psychosis but only for susceptible individuals (Pelayo-Teran et al., 
2012).
    Degenhardt et al. (2003) modeled the prevalence of schizophrenia 
against marijuana use across eight birth cohorts in individuals born 
during 1940 to 1979 in Australia. Even though there was an increase in 
marijuana use in the adult subjects over this time period, there was 
not an increase in diagnoses of psychosis for these same subjects. The 
authors concluded that use of marijuana may increase schizophrenia only 
in persons vulnerable to developing psychosis.

Cardiovascular and Autonomic Effects

    The HHS stated that acute use of marijuana causes an increase in 
heart rate (tachycardia) and may increase blood pressure (Capriotti et 
al., 1988; Benowitz and Jones, 1975). There is some evidence that 
associates the increased heart rate from [Delta]\9\-THC exposure with 
excitation of the sympathetic and depression of the parasympathetic 
nervous systems (Malinowska et al., 2012). Tolerance to tachycardia 
develops with chronic exposure to marijuana (Jones, 2002; Sidney, 
2002).
    Prolonged exposure to [Delta]\9\-THC results in a decrease in heart 
rate (bradycardia) and hypotension (Benowitz and Jones, 1975). These 
effects are thought to be mediated through peripherally located, 
presynaptic CB1 receptor inhibition of norepinephrine release with 
possible direct activation of vascular cannabinoid receptors (Wagner et 
al., 1998; Pacher et al., 2006).
    As stated in the HHS recommendation (HHS, 2015), marijuana exposure 
causes orthostatic hypotension (fainting-like feeling; sudden drop in 
blood pressure upon standing up) and tolerance can develop to this 
effect upon repeated, chronic exposure (Jones, 2002). Tolerance to 
orthostatic hypotension is potentially related to plasma volume 
expansion, but tolerance does not develop to supine hypotensive effects 
(Benowitz and Jones, 1975).
    Marijuana smoking, particularly by those with some degree of 
coronary artery or cerebrovascular disease, poses risks such as 
increased cardiac work, increased catecholamines and carboxyhemoglobin, 
myocardial infarction and postural hypotension (Benowitz and Jones, 
1981; Hollister, 1988; Mittleman et al., 2001; Malinowska et al., 
2012). However, electrocardiographic changes were minimal after 
administration of large cumulative doses of [Delta]\9\-THC (Benowitz 
and Jones, 1975)
    The DEA notes two recent reports that reviewed several case studies 
on marijuana and cardiovascular complications (Panayiotides, 2015; 
Hackam, 2015). Panayiotides (2015) reported that approximately 25.6% of 
the cardiovascular cases from marijuana use resulted in death from data 
provided by the French Addictovigilance Network during the period of 
2006-2010. Several case studies on marijuana usage and cardiovascular 
events were discussed and it was concluded that although a causal link 
cannot be established due to not knowing exact amounts of marijuana 
used in the cases and confounding variables, the available evidence 
supports a link between marijuana and cardiotoxicity. Hackham (2015) 
reviewed 34 case reports or case series reports of marijuana and 
stroke/ischemia in 64 stroke patients and reported that in 81% of the 
cases there was a temporal relationship between marijuana usage and 
stroke or ischemic event. The author concluded that collective analysis 
of the case reports supports a causal link between marijuana use and 
stroke.

Respiratory Effects

    The HHS stated that transient bronchodilation is the most typical 
respiratory effect of acute exposure to marijuana (Gong et al., 1984). 
In a recent

[[Page 53832]]

longitudinal study, information on marijuana use and pulmonary data 
function were collected from 5,115 individuals over 20 years from 4 
communities in the United States (Oakland, CA; Chicago, IL; 
Minneapolis, MN; Birmingham, AL) (Pletcher et al., 2012). Of the 5,115 
individuals, 795 individuals reported use of only marijuana (without 
tobacco). The authors reported that occasional use of marijuana (7 
joint-years for lifetime or 1 joint/day for 7 years or 1 joint/week for 
49 years) does not adversely affect pulmonary function. Pletcher et al. 
(2012) further concluded that there is some preliminary evidence 
suggesting that heavy marijuana use may have a detrimental effect on 
pulmonary function, but the sample size of heavy marijuana users in the 
study was too small. Further, as mentioned in the HHS recommendation 
document (HHS, 2015), long-term use of marijuana may lead to chronic 
cough, increased sputum, as well as increased frequency of chronic 
bronchitis and pharyngitis (Adams and Martin, 1996; Hollister, 1986).
    The HHS stated that the evidence that marijuana may lead to cancer 
of the respiratory system is inconsistent, with some studies suggesting 
a positive correlation while others do not (Lee and Hancox, 2011; 
Tashkin, 2005). The HHS noted a case series that reported lung cancer 
occurrences in three marijuana smokers (age range 31-37 years) with no 
history of tobacco smoking (Fung et al., 1999). Furthermore, in a case-
control study (n = 173 individuals with squamous cell carcinoma of the 
head and neck; n = 176 controls; Zhang et al., 1999), prevalence of 
marijuana use was 9.7% in controls and 13.9% in cases and the authors 
reported that marijuana use may dose-dependently interact with 
mutagenic sensitivity, cigarette smoking, and alcohol use to increase 
risk associated with head and neck cancers (Zhang et al., 1999). 
However, in a large clinical study with 1,650 subjects, no positive 
correlation was found between marijuana use and lung cancer (Tashkin et 
al., 2006). This finding held true regardless of the extent of 
marijuana use when both tobacco use and other potential confounding 
factors were controlled. The HHS concluded that new evidence suggests 
that the effects of smoking marijuana on respiratory function and 
cancer are different from the effects of smoking tobacco (Lee and 
Hancox, 2011).
    The DEA further notes the publication of recent review articles 
critically evaluating the association between marijuana and lung 
cancer. Most of the reviews agree that the association is weak or 
inconsistent (Huang et al., 2015; Zhang et al., 2015; Gates et al., 
2014; Hall and Degenhardt, 2014). Huang et al. (2015) identified and 
reviewed six studies evaluating the association between marijuana use 
and lung cancer and the authors concluded that an association is not 
supported most likely due to the small amounts of marijuana smoked in 
comparison to tobacco. Zhang et al. (2015) examined six case control 
studies from the US, UK, New Zealand, and Canada within the 
International Lung Cancer Consortium and found that there was a weak 
association between smoking marijuana and lung cancer in individuals 
who never smoked tobacco, but precision of the association was low at 
high marijuana exposure levels. Hall and Degenhardt (2014) noted that 
even though marijuana smoke contains several of the same carcinogens 
and co-carcinogens as tobacco smoke (Roth et al., 1998) and has been 
found to be mutagenic and carcinogenic in the mouse skin test, 
epidemiological studies have been inconsistent, but more consistent 
positive associations have been reported in case control studies. 
Finally Gates et al. (2014), reviewed the studies evaluating marijuana 
use and lung cancer and concluded that there is evidence that marijuana 
produces changes in the respiratory system (precursors to cancer) that 
could lead to lung cancer, but overall association is weak between 
marijuana use and lung cancer especially when controlling for tobacco 
use.

Endocrine System

Reproductive Hormones

    The HHS stated that administration of marijuana to humans does not 
consistently alter the endocrine system. In a controlled human exposure 
study (n = 4 males), subjects were acutely administered smoked 
marijuana containing 2.8% [Delta]\9\-THC or placebo and an immediate 
significant decrease in luteinizing hormone and an increase in cortisol 
was reported in the subjects that smoked marijuana (Cone et al., 1986). 
Furthermore, as cited by the HHS, two later studies (Dax et al., 1989; 
Block et al., 1991) reported no changes in hormone levels. Dax et al. 
(1989) recruited male volunteers (n = 17) that were occasional or heavy 
users of marijuana. Following exposure to smoked [Delta]\9\-THC (18 mg/
cigarette) or oral [Delta]\9\-THC (10 mg three times per day for three 
days and on the morning of the fourth day), the subjects in that study 
showed no changes in plasma adrenocorticotropic hormone (ACTH), 
cortisol, prolactin, luteinizing hormone, or testosterone levels. 
Additionally, Block et al. (1991) compared plasma hormone levels 
amongst non-users as well as infrequent, moderate, and frequent users 
of marijuana (n = 93 men and 56 women) and found that chronic use of 
marijuana (infrequent, moderate, and frequent users) did not 
significantly alter concentrations of testosterone, luteinizing 
hormone, follicle stimulating hormone, prolactin, or cortisol.
    The HHS noted that there is a discrepancy in the effect of 
marijuana on female reproductive system functionality between animals 
and humans (HHS, 2015). Female rhesus monkeys that were administered 
2.5 mg/kg [Delta]\9\-THC, i.m., during days 1-18 of the menstrual cycle 
had reduced progesterone levels and ovulation was suppressed (Asch et 
al., 1981). However, women who smoked marijuana (1 gram marijuana 
cigarette with 1.8% [Delta]\9\-THC) during the periovulatory period 
(24-36 hours prior to ovulation) did not exhibit changes in 
reproductive hormone levels or their menstrual cycles (Mendelson and 
Mello, 1984). In a review article by Brown and Dobs (2002), the authors 
state that endocrine changes observed with marijuana are no longer 
observed with chronic administration and this may be due to drug 
tolerance.

Reproductive Cancers

    The HHS stated that recent studies support a possible association 
between frequent, long-term marijuana use and increased risk of 
testicular germ cell tumors. In a hospital-based case-control study, 
the frequency of marijuana use was compared between testicular germ 
cell tumor (TGCT) patients (n = 187) and controls (n = 148) (Trabert et 
al., 2011). TGCT patients were more likely to be frequent marijuana 
users than controls with an odds ratio (OR) of 2.2 (95% confidence 
limits of 1.0-5.1) and were less likely to be infrequent or short-term 
users with odds ratios of 0.5 and 0.6, respectively in comparison to 
controls (Trabert et al., 2011). The DEA further notes that in two 
population-based case-control studies (Daling et al., 2009; Lacson et 
al., 2012), marijuana use was compared between patients diagnosed with 
TGCT and matched controls in Washington State or Los Angeles County. In 
both studies, it was reported that TCGT patients were twice as likely 
as controls to use marijuana. Authors of both studies concluded that 
marijuana use is associated with an elevated risk of TGCT (Daling et 
al., 2009; Lacson et al., 2012).
    The HHS cited a study (Sarfaraz et al., 2005) demonstrating that 
WIN 55,212-2 (a mixed CB1/CB2 agonist) induces apoptosis (one form of 
cell death) in

[[Page 53833]]

prostate cancer cells and decreases expression of androgen receptors 
and prostate specific antigens, suggesting a potential therapeutic 
value for cannabinoid agonists in the treatment of prostate cancer, an 
androgen-stimulated type of carcinoma.

Other hormones (e.g. Thyroid, Appetite)

    In more recent studies, as cited by the HHS, chronic marijuana use 
by subjects (n = 39) characterized as dependent on marijuana according 
to the ICD-10 criteria did not affect serum levels of thyroid hormones: 
TSH (thyrotropin), T4 (thyroxine), and T3 (triiodothyronine) (Bonnet, 
2013). With respect to appetite hormones, in a pilot study with HIV-
positive males, smoking marijuana dose-dependently increased plasma 
levels of ghrelin and leptin and decreased plasma levels of peptide YY 
(Riggs et al., 2012).
    The HHS stated that [Delta]\9\-THC reduces binding of the 
corticosteroid dexamethasone in hippocampal tissue from 
adrenalectomized rats and acute [Delta]\9\-THC releases corticosterone, 
with tolerance developing to this effect with chronic administration 
(Eldridge >et al., 1991). These data suggest that [Delta]\9\-THC may 
interact with the glucocorticoid receptor system.

Immune System

    The HHS stated that cannabinoids alter immune function but that 
there can be differences between the effects of synthetic, natural, and 
endogenous cannabinoids (Croxford and Yamamura, 2005; Tanasescu and 
Constantinescu, 2010).
    The HHS noted that there are conflicting results in animal and 
human studies with respect to cannabinoid effects on immune functioning 
in subjects with compromised immune systems. Abrams et al. (2003) 
examined the effects of marijuana and [Delta]\9\-THC in 62 HIV-1-
infected patients. Subjects received one of three treatments, three 
times a day: smoked marijuana cigarette containing 3.95% [Delta]\9\-
THC, oral tablet containing [Delta]\9\-THC (2.5 mg oral dronabinol), or 
oral placebo. There were no changes in CD4+ and CD8+ cell counts, HIV 
RNA levels, or protease inhibitor levels in any of the treatment groups 
(Abrams et al., 2003). Therefore, use of cannabinoids showed no short-
term adverse virologic effects in individuals with compromised immune 
systems. Conversely, Roth et al. (2005) reported that in 
immunodeficient mice implanted with human blood cells infected with 
HIV, exposure to [Delta]\9\-THC in vivo suppresses immune function, 
increases HIV co-receptor expression, and acts as a cofactor to enhance 
HIV replication.
    The DEA notes two recent clinical studies reporting a decrease in 
cytokine and interleukin levels following marijuana use. Keen et al. 
(2014) compared the differences in the levels of IL-6 (interleukin-6), 
a proinflammatory cytokine, amongst non-drug users (n = 78), marijuana 
only users (n = 46) and marijuana plus other drug users (n = 45) in a 
community-based sample of middle-aged African Americans (Keen et al., 
2014). After adjusting for confounders, analyses revealed that lifetime 
marijuana only users had significantly lower IL-6 levels than the 
nonuser group. Further, Sexton et al. (2014) compared several immune 
parameters in healthy individuals and subjects with multiple sclerosis 
(MS) and found that the chronic use of marijuana resulted in reduced 
monocyte migration, and decreased levels of CCL2 and IL-17 in both 
healthy and MS groups.
    The DEA also notes a review suggesting that [Delta]\9\-THC 
suppresses the immune responses in experimental animal models and in 
vitro and that these changes may be primarily mediated through the CB2 
cannabinoid receptor (Eisenstein and Meissler, 2015).

Factor 3: The State of the Current Scientific Knowledge Regarding the 
Drug or Substance

Chemistry

    The HHS stated that marijuana, also known as Cannabis sativa L., is 
part of the Cannabaceae plant family and is one of the oldest 
cultivated crops. The term ``marijuana'' is generally used to refer to 
a mixture of the dried flowering tops and leaves from Cannabis. 
Marijuana users primarily smoke the marijuana leaves, but individuals 
also ingest marijuana through food infused with marijuana and its 
extracts. Cannabis sativa is the primary species of Cannabis that is 
illegally marketed in the United States. Marijuana is one of three 
major derivatives sold as separate illicit products, the other two 
being hashish and hash oil. Hashish is composed of the dried and 
compressed cannabinoid-rich resinous material of Cannabis and is found 
as balls and cakes as well as other forms. Individuals may break off 
pieces and place them into a pipe to smoke. Hash oil, a viscous brown 
or amber colored liquid, is produced by solvent extraction of 
cannabinoids from Cannabis and contains approximately 50% cannabinoids. 
One to two drops of hash oil on a cigarette has been reported to 
produce the equivalent of a single marijuana cigarette (DEA, 2015).
    Different marijuana samples are derived from numerous cultivated 
strains and may have different chemical compositions including levels 
of [Delta]\9\-THC and other cannabinoids (Appendino et al., 2011). A 
consequence of having different chemical compositions in the various 
marijuana samples is that there will be significant differences in 
safety, biological, pharmacological, and toxicological profiles and 
therefore, according to the HHS, all Cannabis strains cannot be 
considered collectively because of the variations in chemical 
composition. Furthermore, the concentration of [Delta]\9\-THC and other 
cannabinoids present in marijuana may vary due to growing conditions 
and processing of the plant after harvesting. For example, the plant 
parts collected such as flowers, leaves and stems can influence 
marijuana's potency, quality, and purity (Adams and Martin, 1996; 
Agurell et al., 1984; Mechoulam, 1973). Variations in marijuana 
harvesting have resulted in potencies ranging from a low of 1 to 2% up 
to a high of 17% as indicated by cannabinoid content. The concentration 
of [Delta]\9\-THC averages approximately 12% by weight in a typical 
marijuana mixture of leaves and stems. However, some specifically grown 
and selected marijuana samples can contain 15% or greater [Delta]\9\-
THC (Appendino et al., 2011). As a result, the [Delta]\9\-THC content 
in a 1 gram marijuana cigarette can range from as little as 3 
milligrams to 150 milligrams or more. In a systematic review conducted 
by Cascini et al. (2012), it was reported that marijuana's [Delta]\9\-
THC content has increased significantly from 1979-2009.
    Since there is considerable variability in the cannabinoid 
concentrations and chemical constituency among marijuana samples, the 
interpretation of clinical data with marijuana is complicated. A 
primary issue is the lack of consistent concentrations of [Delta]\9\-
THC and other substances in marijuana which complicates the 
interpretation of the effects of different marijuana constituents. An 
added issue is that the non-cannabinoid components in marijuana may 
potentially modify the overall pharmacological and toxicological 
properties of various marijuana strains and products.
    Various Cannabis strains contain more than 525 identified natural 
constituents including cannabinoids, 21 (or 22) carbon terpenoids found 
in the plant, as well as their carboxylic acids, analogues, and 
transformation products (Agurell et al., 1984; 1986; Mechoulam, 1973; 
Appendino et al., 2011). To date,

[[Page 53834]]

more than 100 cannabinoids have been characterized (ElSohly and Slade, 
2005; Radwan et al., 2009; Appendino et al., 2011), and most major 
cannabinoid compounds occurring naturally have been identified. There 
are still new and comparably more minor cannabinoids being 
characterized (Pollastro et al., 2011). The majority of the 
cannabinoids are found in Cannabis. One study reported accumulation of 
two cannabinoids, cannabigerol and its corresponding acid, in 
Helichrysum (H. umbraculigerum) which is a non-Cannabis source 
(Appendino et al., 2011).
    Of the cannabinoids found in marijuana, [Delta]\9\-THC (previously 
known as [Delta]\1\-THC) and delta-8-tetrahydrocannabinol ([Delta]\8\-
THC, [Delta]\6\-THC) have been demonstrated to produce marijuana's 
psychoactive effects. Psychoactive effects from marijuana usage have 
been mainly attributed to [Delta]\9\-THC because [Delta]\9\-THC is 
present in significantly more quantities than [Delta]\8\-THC in most 
marijuana varieties. There are only a few marijuana strains that 
contain [Delta]\8\-THC in significant amounts (Hively et al., 1966). 
[Delta]\9\-THC is an optically active resinous substance that is 
extremely lipophilic. The chemical name for [Delta]\9\-THC is (6aR-
trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo-
[b,d]pyran-1-ol, or (-)-delta9-(trans)-tetrahydrocannabinol. The (-)-
trans [Delta]\9\-THC isomer is pharmacologically 6 to 100 times more 
potent than the (+)-trans isomer (Dewey et al., 1984).
    Other relatively well-characterized cannabinoids present in 
marijuana include cannabidiol (CBD), cannabichromene (CBC), and 
cannabinol (CBN). CBD and CBC are major cannabinoids in marijuana and 
are both lipophilic. The chemical name for CBD is 2-[(1R,6R)-3-methyl-
6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol and the 
chemical name for CBC is 2-methyl-2-(4-methylpent-3-enyl)-7-pentyl-5-
chromenol. CBN is a minor naturally-occurring cannabinoid with weak 
psychoactivity and is also a major metabolite of [Delta]\9\-THC. The 
chemical name for CBN is 6,6,9-trimethyl-3-pentyl-benzo[c]chromen-1-ol.
    In summary, marijuana has several strains with high variability in 
the concentrations of [Delta]\9\-THC, the main psychoactive component, 
as well as other cannabinoids and compounds. Marijuana is not a single 
chemical and does not have a consistent and reproducible chemical 
profile with predictable or consistent clinical effects. In the HHS 
recommendation for marijuana scheduling (HHS, 2015), it was recommended 
that investigators consult a guidance for industry entitled, Botanical 
Drug Products,\45\ which provides information on the approval of 
botanical drug products. Specifically, in order to investigate 
marijuana in support of a New Drug Application (NDA), clinical studies 
under an Investigational New Drug (IND) application should include 
``consistent batches of a particular marijuana product for [a] 
particular disease.'' (HHS, 2015). Furthermore, the HHS noted that 
investigators must provide data meeting the requirements for new drug 
approval as stipulated in 21 CFR 314.50 (HHS, 2015).
---------------------------------------------------------------------------

    \45\ Available at http://www.fda.gov/Drugs/default.htm under 
Guidance (Drugs).
---------------------------------------------------------------------------

Human Pharmacokinetics

    Pharmacokinetics of marijuana in humans is dependent on the route 
of administration and formulation (Adams and Martin, 1996; Agurell et 
al., 1984; Agurell et al., 1986). Individuals primarily smoke marijuana 
as a cigarette (weighing between 0.5 and 1 gram) or in a pipe. More 
recently, vaporizers have been used as another means for individuals to 
inhale marijuana. Marijuana may also be ingested orally in foods or as 
an extract in ethanol or other solvents. Pharmacokinetic studies with 
marijuana focused on evaluating the absorption, metabolism, and 
elimination profile of [Delta]\9\-THC and other cannabinoids (Adams and 
Martin, 1996; Agurell et al., 1984; Agurell et al., 1986).

Absorption and Distribution of Inhaled Marijuana Smoke

    There is high variability in the pharmacokinetics of [Delta]\9\-THC 
and other cannabinoids from smoked marijuana due to differences in 
individual smoking behavior even under controlled experimental 
conditions (Agurell et al., 1986; Herning et al., 1986; Huestis et al., 
1992a). Experienced marijuana users can titrate and regulate the dose 
by holding marijuana smoke in their lungs for an extended period of 
time resulting in increased psychoactive effects by prolonging 
absorption of the smoke. This property may also help explain why there 
is a poor correlation between venous levels of [Delta]\9\-THC and the 
intensity of effects and intoxication (Agurell et al., 1986; Barnett et 
al., 1985; Huestis et al., 1992a). The HHS recommended that puff and 
inhalation volumes should be tracked in experimental studies because 
the concentration of cannabinoids can vary at different stages of 
smoking.
    [Delta]\9\-THC from smoked marijuana is rapidly absorbed within 
seconds. Psychoactive effects are observed immediately following 
absorption with measurable neurological and behavioral changes for up 
to 6 hours (Grotenhermen, 2003; Hollister, 1986; Hollister, 1988). 
[Delta]\9\-THC is distributed to the brain in a rapid and efficient 
manner. Bioavailability of [Delta]\9\-THC from marijuana (from a 
cigarette or pipe) ranges from 1 to 24% with the fraction absorbed 
rarely exceeding 10 to 20% (Agurell et al., 1986; Hollister, 1988). The 
low and variable bioavailability of [Delta]\9\-THC is due to loss in 
side-stream smoke, variation in individual smoking behaviors and 
experience, incomplete absorption of inhaled smoke, and metabolism in 
lungs (Herning et al., 1986; Johansson et al., 1989). After cessation 
of smoking, [Delta]\9\-THC venous levels decline within minutes and 
continue to decline to about 5% to 10% of the peak level within an hour 
(Agurell et al., 1986; Huestis et al., 1992a; Huestis et al., 1992b).

Absorption and Distribution of Orally Administered Marijuana

    Following oral administration of [Delta]\9\-THC or marijuana, onset 
of effects start within 30 to 90 minutes, peak after 2 to 3 hours and 
effects remain for 4 to 12 hours (Grotenhermen, 2003; Adams and Martin, 
1996; Agurell et al., 1984; Agurell et al., 1986). Dose titration of 
[Delta]\9\-THC from orally ingested marijuana is difficult for users in 
comparison to smoked or inhaled marijuana due to the delay in the onset 
of effects. Oral bioavailability of [Delta]\9\-THC, either in its pure 
form or in marijuana, is low and variable with a range from 5% to 20% 
(Agurell et al., 1984; Agurell et al., 1986). There is also inter- and 
intra-subject variability of orally administered [Delta]\9\-THC under 
experimental conditions and even under repeated dosing experiments 
(HHS, 2015). The HHS noted that in bioavailability studies using 
radiolabeled [Delta]\9\-THC, [Delta]\9\-THC plasma levels following 
oral administration of [Delta]\9\-THC were low relative to plasma 
levels after inhaled or intravenously administered [Delta]\9\-THC. The 
low and variable bioavailability of orally administered [Delta]\9\-THC 
is due to first pass hepatic elimination from blood and erratic 
absorption from stomach and bowel (HHS, 2015).

Metabolism and Excretion of Cannabinoids From Marijuana

    Studies evaluating cannabinoid metabolism and excretion focused on 
[Delta]\9\-THC because it is the primary psychoactive component in 
marijuana.
    [Delta]\9\-THC is metabolized via microsomal hydroxylation and 
oxidation to both active and inactive

[[Page 53835]]

metabolites (Lemberger et al., 1970; Lemberger et al., 1972a; Lemberger 
et al., 1972b; Agurell et al., 1986; Hollister, 1988). Metabolism of 
[Delta]\9\-THC is consistent among frequent and infrequent marijuana 
users (Agurell et al., 1986). The primary active metabolite of 
[Delta]\9\-THC following oral ingestion is 11-hydroxy-[Delta]\9\-THC 
which is equipotent to [Delta]\9\-THC in producing marijuana-like 
subjective effects (Agurell et al., 1986; Lemberger and Rubin, 1975). 
Metabolite levels following oral administration may be greater than 
that of [Delta]\9\-THC and may contribute greatly to the 
pharmacological effects of oral [Delta]\9\-THC or marijuana.
    Plasma clearance of [Delta]\9\-THC approximates hepatic blood flow 
at a rate of approximately 950 ml/min or greater. Rapid clearance of 
[Delta]\9\-THC from blood is primarily due to redistribution to other 
tissues in the body rather than to metabolism (Agurell et al., 1984; 
Agurell et al., 1986). Outside of the liver, metabolism in most tissues 
is considerably slow or does not occur. The elimination half-life of 
[Delta]\9\-THC ranges from 20 hours to between 10 and 13 days (Hunt and 
Jones, 1980). Lemberger et al. (1970) reported that the half-life of 
[Delta]\9\-THC ranged from 23-28 hours in heavy marijuana users and up 
to 60 to 70 hours in na[iuml]ve users. The long elimination half-life 
of [Delta]\9\-THC is due to slow release of [Delta]\9\-THC and other 
cannabinoids from tissues and subsequent metabolism. Inactive carboxy 
metabolites of [Delta]\9\-THC have terminal half-lives of 50 hours to 6 
days or more and serve as long-term markers in urine tests for 
marijuana use.
    Most of the absorbed [Delta]\9\-THC dose is eliminated in the feces 
and about 33% in urine. The glucuronide metabolite of [Delta]\9\-THC is 
excreted as the major urine metabolite along with 18 non-conjugated 
metabolites (Agurell et al., 1986).

Research Status and Test of Currently Accepted Medical Use for 
Marijuana

    According to the HHS, there are numerous human clinical studies 
with marijuana in the United States under FDA-regulated IND 
applications. Results of small clinical exploratory studies have been 
published in the medical literature. Approval of a human drug for 
marketing, however, is contingent upon FDA approval of a New Drug 
Application (NDA) or a Biologics License Application (BLA). According 
to the HHS, the FDA has not approved any drug product containing 
marijuana for marketing.
    The HHS noted that a drug may be found to have a medical use in 
treatment in the United States for purposes of the CSA if the drug 
meets the five elements described by the DEA in 1992. Those five 
elements ``are both necessary and sufficient to establish a prima facie 
case of currently accepted medical use'' in treatment in the United 
States.'' (57 FR 10499, 10504 (March 26, 1992)). This five-element 
test, which the HHS and DEA have utilized in all such analyses for more 
than two decades, has been upheld by the Court of Appeals. ACT, 15 F.3d 
at 1135. The five elements that characterize ``currently accepted 
medical use'' for a drug are summarized here and expanded upon in the 
discussion below:
    1. The drug's chemistry must be known and reproducible;
    2. There must be adequate safety studies;
    3. There must be adequate and well-controlled studies proving 
efficacy;
    4. The drug must be accepted by qualified experts; and
    5. Scientific evidence must be widely available.
    In its review (HHS, 2015), the HHS evaluated the five elements with 
respect to the currently available research for marijuana. The HHS 
concluded that marijuana does not meet any of the five elements--all of 
which must be demonstrated to find that a drug has a ``currently 
accepted medical use.'' A brief summary of the HHS's evaluation is 
provided below.
    Element #1: The drug's chemistry must be known and reproducible.
    ``The substance's chemistry must be scientifically established to 
permit it to be reproduced into dosages which can be standardized. The 
listing of the substance in a current edition of one of the official 
compendia, as defined by section 201(j) of the Food, Drug and Cosmetic 
Act, 21 U.S.C. 321(j), is sufficient generally to meet this 
requirement.'' 57 FR 10499, 10506 (March 26, 1992).
    As defined by the CSA, marijuana includes all species of the genus 
Cannabis, including all strains therein.\46\ Chemical constituents 
including [Delta]\9\-THC and other cannabinoids vary significantly in 
marijuana samples derived from different strains (Appendino et al., 
2011). As a result, there will be significant differences in safety, 
biological, pharmacological, and toxicological parameters amongst the 
various marijuana samples. Due to the variation of the chemical 
composition in marijuana samples, it is not possible to reproduce a 
standardized dose when considering all strains together. The HHS does 
advise that if a specific Cannabis strain is cultivated and processed 
under controlled conditions, the plant chemistry may be consistent 
enough to derive reproducible and standardized doses.
---------------------------------------------------------------------------

    \46\ Although the CSA definition of marijuana refers only to the 
species ``Cannabis sativa L.,'' federal courts have consistently 
ruled that all species of the genus cannabis are included in this 
definition. See United States v. Kelly, 527 F.2d 961, 963-964 (9th 
Cir. 1976) (collecting and examining cases). The Single Convention 
(article 1, par. 1(c)) likewise defines the ``cannabis plant'' to 
mean ``any plant of the genus Cannabis.'' As explained above in the 
attachment titled ``Preliminary Note Regarding Treaty 
Considerations,'' 21 U.S.C. 811(d)(1) provides that, where a drug is 
subject to control under the Single Convention, the DEA 
Administrator must control the drug under the schedule he deems most 
appropriate to carry out such treaty obligations, without regard to 
the findings required by 21 U.S.C. 811(a) or 812(b) and without 
regard to the procedures prescribed by 21 U.S.C. 811(a) and (b).
---------------------------------------------------------------------------

    Element #2: There must be adequate safety studies.
    ``There must be adequate pharmacological and toxicological studies, 
done by all methods reasonably applicable, on the basis of which it 
could fairly and responsibly be concluded, by experts qualified by 
scientific training and experience to evaluate the safety and 
effectiveness of drugs, that the substance is safe for treating a 
specific, recognized disorder.'' 57 FR 10499, 10506 (March 26, 1992).
    The HHS stated that there are no adequate safety studies on 
marijuana. As indicated in their evaluation of Element #1, the 
considerable variation in the chemistry of marijuana complicates the 
safety evaluation. The HHS concluded that marijuana does not satisfy 
Element #2 for having adequate safety studies such that medical and 
scientific experts may conclude that it is safe for treating a specific 
ailment.
    Element #3: There must be adequate and well-controlled studies of 
efficacy.
    ``There must be adequate, well-controlled, well-designed, well-
conducted and well-documented studies, including clinical 
investigations, by experts qualified by scientific training and 
experience to evaluate the safety and effectiveness of drugs, on the 
basis of which it could be fairly and responsibly concluded by such 
exports that the substance will have the intended effect in treating a 
specific, recognized disorder.'' 57 FR 10499, 10506 (March 26, 1992).
    As indicated in the HHS's review of marijuana (HHS, 2015), there 
are no adequate or well-controlled studies that prove marijuana's 
efficacy. The FDA independently reviewed (FDA, 2015) publicly available 
clinical studies on marijuana published prior to February 2013 to 
determine if there were appropriate studies to determine marijuana's 
efficacy (please refer to FDA, 2015 and HHS, 2015 for more

[[Page 53836]]

details). After review, the FDA determined that out of the identified 
articles, including those identified through a search of bibliographic 
references and 566 abstracts located on PubMed, 11 studies met the a 
priori selection criteria, including placebo control and double-
blinding. FDA and HHS critically reviewed each of the 11 studies to 
determine if the studies met accepted scientific standards. FDA and HHS 
concluded that these studies do not ``currently prove efficacy of 
marijuana'' for any therapeutic indication due to limitations in the 
study designs. The HHS indicated that these studies could be used as 
proof of concept studies, providing preliminary evidence on a proposed 
hypothesis involving a drug's effect.
    Element #4: The drug must be accepted by qualified experts.
    ``[A] consensus of the national community of experts, qualified by 
scientific training and experience to evaluate the safety and 
effectiveness of drugs, accepts the safety and effectiveness of the 
substance for use in treating a specific, recognized disorder. A 
material conflict of opinion among experts precludes a finding of 
consensus.'' 57 FR 10499, 10506 (March 26, 1992).
    The HHS concluded that there is currently no evidence of a 
consensus among qualified experts that marijuana is safe and effective 
in treating a specific and recognized disorder. The HHS indicated that 
medical practitioners who are not experts in evaluating drugs cannot be 
considered qualified experts (HHS, 2015; 57 FR 10499, 10505). Further, 
the HHS noted that the 2009 American Medical Association (AMA) report 
entitled, ``Use of Cannabis for Medicinal Purposes'' does not conclude 
that there is a currently accepted medical use for marijuana. HHS also 
pointed out that state-level ``medical marijuana'' laws do not provide 
evidence of such a consensus among qualified experts.
    Element #5: The scientific evidence must be widely available.
    ``In the absence of NDA approval, information concerning the 
chemistry, pharmacology, toxicology, and effectiveness of the substance 
must be reported, published, or otherwise widely available, in 
sufficient detail to permit experts, qualified by scientific training 
and experience to evaluate the safety and effectiveness of drugs, to 
fairly and responsibly conclude the substance is safe and effective for 
use in treating a specific, recognized disorder.'' 57 FR 10499, 10506 
(March 26, 1992).
    The HHS concluded that the currently available data and information 
on marijuana is not sufficient to allow scientific scrutiny of the 
chemistry, pharmacology, toxicology, and effectiveness. In particular, 
scientific evidence demonstrating the chemistry of a specific Cannabis 
strain that could provide standardized and reproducible doses is not 
available.

Petitioners' Major Comments in Relation to Factor 3 and the 
Government's Responses

    (1) The petitioner states on page 2 of the petition, ``Marijuana 
has accepted medical use in the United States. Thirteen states accept 
the safety of marijuana for medical use . . . . Marijuana has been 
accepted as having medical use by dozens of professional medical and 
nursing organizations throughout the U.S. . . . Even the American 
Medical Association has now accepted the safety and efficacy of 
cannabinoid medicines and supports removal of marijuana from schedule I 
of the CSA in order to support further research.''
    As noted above, the HHS concluded that there is currently no 
evidence of a consensus among qualified experts that marijuana is safe 
and effective in treating a specific and recognized disorder, as 
required by the established standards. HHS pointed out that state-level 
``medical marijuana'' laws do not provide evidence of such a consensus 
among qualified experts. HHS also indicated that medical practitioners 
who are not experts in evaluating drugs cannot be considered qualified 
experts (HHS, 2015; 57 FR 10499, 10505).
    Further, the HHS pointed out that the 2009 AMA report entitled, 
``Use of Cannabis for Medicinal Purposes'' does not conclude that there 
is a currently accepted medical use for marijuana. Instead, the AMA, 
like several other professional and medical associations, recommended 
further testing with marijuana to determine its medicinal value. The 
AMA official policy on medicinal use of marijuana is as follows: ``Our 
AMA urges that marijuana's status as a federal Schedule I controlled 
substance be reviewed with the goal of facilitating the conduct of 
clinical research and development of cannabinoid-based medicines, and 
alternative delivery methods. This should not be viewed as an 
endorsement of state-based medical cannabis programs, the legalization 
of marijuana, or that scientific evidence on the therapeutic use of 
cannabis meets the current standards for a prescription drug product.'' 
(AMA, 2009). The DEA further notes that the 2013 AMA House of Delegates 
report states that, ``cannabis is a dangerous drug and as such is a 
public health concern.'' (AMA, 2013).
    (2) The petitioner asserts on page 3 of the petition that, 
``Several recent studies of smoked marijuana have confirmed the safety 
and efficacy of smoked marijuana for medical use.''
    The HHS, in its scientific and medical evaluation, reviewed 
marijuana clinical studies evaluating therapeutic properties and 
concluded that there is not enough data to confirm the safety and 
efficacy of smoked marijuana for use in treating a specific and 
recognized disorder. Relevant to efficacy, for instance, the HHS 
concluded, for instance, that ``smoking marijuana currently has not 
been shown to allow delivery of consistent and reproducible doses,'' 
and that the bioavailability of the delta-9 -THC from marijuana in a 
cigarette or pipe can range from 1 percent to 24 percent with the 
fraction absorbed rarely exceeding 10 to 20%. Issues relating to the 
safety of smoked marijuana were discussed above in Factor 2.
    (3) On page 3, the petitioner states that ``marijuana has been 
determined to be safe for use under medical supervision by the DEA's 
own administrative law judge.''
    As described above, in the absence of NDA or ANDA approval, DEA has 
established a five-element test for determining whether the drug has a 
currently accepted medical use in treatment in the United States. 57 FR 
10499, 10506 (March 26, 1992)). See also ACT, 15 F.3d at 1135. In 
response to this petition, HHS concluded, and DEA agrees, that the 
scientific evidence is insufficient to demonstrate that marijuana has a 
currently accepted medical use under the five-element test. The 
evidence was insufficient in this regard also when the DEA considered 
petitions to reschedule marijuana in 1992 (57 FR 10499), in 2001 (66 FR 
20038), and in 2011 (76 FR 40552). Little has changed since 2011 with 
respect to the lack of clinical evidence necessary to establish that 
marijuana has a currently accepted medical use. No studies have 
scientifically assessed the efficacy and full safety profile of 
marijuana for any specific medical condition.

Factor 4: Its History and Current Pattern of Abuse

    Marijuana continues to be the most widely used illicit drug. In 
2013, an estimated 24.6 million Americans age 12 or older were current 
(past month) illicit drug users. Of those, 19.8 million were current 
(past month) marijuana users. As of 2013, an estimated 114.7 million 
Americans age 12 and older had

[[Page 53837]]

used marijuana or hashish in their lifetime and 33.0 million had used 
it in the past year.
    According to the NSDUH estimates, 3.0 million people age 12 or 
older used an illicit drug for the first time in 2014. Marijuana 
initiates totaled 2.6 million in 2014. Nearly half (46.8%) of the 2.6 
million new users were less than 18 years of age. In 2014, marijuana 
was used by 82.2% of current (past month) illicit drug users. In 2014, 
among past year marijuana users age 12 or older, 18.5% used marijuana 
on 300 or more days within the previous 12 months. This translates into 
6.5 million people using marijuana on a daily or almost daily basis 
over a 12-month period, a significant increase from the 3.1 million 
daily or almost daily users in 2006 and from the 5.7 million in just 
the previous year. In 2014, among past month marijuana users, 41.6% 
(9.2 million people) used the drug on 20 or more days in the past 
month, a significant increase from the 8.1 million in 2013.
    Marijuana is also the illicit drug with the highest numbers of past 
year dependence or abuse in the U.S. population. According to the 2014 
NSDUH report, of the 7.1 million persons aged 12 or older who were 
classified with illicit drug dependence or abuse, 4.2 million of them 
abused or were dependent on marijuana (representing 59.0% of all those 
classified with illicit drug dependence or abuse and 1.6% of the total 
U.S. non-institutionalized population aged 12 or older).
    According to the 2015 Monitoring the Future (MTF) survey, marijuana 
is used by a large percentage of American youths, and is the most 
commonly used illicit drug among American youth. Among students 
surveyed in 2015, 15.5% of 8th graders, 31.1% of 10th graders, and 
44.7% of 12th graders reported that they had used marijuana in their 
lifetime. In addition, 11.8%, 25.4%, and 34.9% of 8th, 10th, and 12th 
graders, respectively, reported using marijuana in the past year. A 
number of high school students reported daily use in the past month, 
including 1.1%, 3.0%, and 6.0% of 8th, 10th, and 12th graders, 
respectively.
    The prevalence of marijuana use and abuse is also indicated by 
criminal investigations for which drug evidence was analyzed in 
federal, state, and local forensic laboratories, as discussed above in 
Factor 1. The National Forensic Laboratory System (NFLIS), a DEA 
program, systematically collects drug identification results and 
associated information from drug cases submitted to and analyzed by 
federal, state, and local forensic laboratories. NFLIS data shows that 
marijuana was the most frequently identified drug from January 2001 
through December 2014. In 2014, marijuana accounted for 29.3% (432,989) 
of all drug exhibits in NFLIS.
    The high consumption of marijuana is being fueled by increasing 
amounts of domestically grown marijuana as well as increased amounts of 
foreign source marijuana being illicitly smuggled into the United 
States. In 2014, the Domestic Cannabis Eradication and Suppression 
Program (DCE/SP) reported that 3,904,213 plants were eradicated in 
outdoor cannabis cultivation areas compared to 2,597,798 in 2000, as 
shown above in Table 3. Significant quantities of marijuana were also 
eradicated from indoor cultivation operations. There were 396,620 
indoor plants eradicated in 2014 compared to 217,105 eradicated in 
2000. As shown in Table 2 above, in 2014, the National Seizure System 
(NSS) reported seizures of 1,767,741 kg of marijuana.

Factor 5: The Scope, Duration, and Significance of Abuse

    Abuse of marijuana is widespread and significant. As previously 
noted, according to the NSDUH, in 2014, an estimated 117.2 million 
Americans (44.2%) age 12 or older had used marijuana or hashish in 
their lifetime, 35.1 million (13.2%) had used it in the past year, and 
22.2 million (8.4%) had used it in the past month. Past year and past 
month marijuana use has increased significantly since 2013. Past month 
marijuana use is highest among 18-21 year olds and it declines among 
those 22 years of age and older. In 2014, an estimated 18.5% of past 
year marijuana users age 12 or older used marijuana on 300 or more days 
within the past 12 months. This translates into 6.5 million persons 
using marijuana on a daily or almost daily basis over a 12-month 
period. In 2014, an estimated 41.6% (9.2 million) of past month 
marijuana users age 12 or older used the drug on 20 or more days in the 
past month (SAMHSA, NSDUH). Chronic use of marijuana is associated with 
a number of health risks (see Factors 2 and 6).
    Furthermore, the average percentage of [Delta]\9\-THC in seized 
marijuana has increased over the past two decades (The University of 
Mississippi Potency Monitoring Project). Additional studies are needed 
to clarify the impact of greater potency, but one study shows that 
higher levels of [Delta]\9\-THC in the body are associated with greater 
psychoactive effects (Harder and Rietbrock, 1997), which can be 
correlated with higher abuse potential (Chait and Burke, 1994).
    TEDS data show that in 2013, marijuana/hashish was the primary 
substance of abuse in 16.8% of all admissions to substance abuse 
treatment among patients age 12 and older. TEDS data also show that 
marijuana/hashish was the primary substance of abuse for 77.0% of all 
12- to 14-year-olds admitted for drug treatment and 75.5% of all 15- to 
17-year-olds admitted for drug treatment in 2013. Among the 281,991 
admissions to drug treatment in 2013 in which marijuana/hashish was the 
primary drug, the average age at admission was 25 years and the peak 
age cohort was 15 to 17 years (22.5%). Thirty-nine percent of the 
281,991 primary marijuana/hashish admissions (35.9%) were under the age 
of 20.
    In summary, the recent statistics from these various surveys and 
databases (see Factor 1 for more details) demonstrate that marijuana 
continues to be the most commonly used illicit drug, with large 
incidences of heavy use and dependence in teenagers and young adults.

Factor 6: What, if Any, Risk There Is to the Public Health

    In its recommendation, the HHS discussed public health risks 
associated with acute and chronic marijuana use in Factor 6. Public 
health risks as measured by emergency department visits and drug 
treatment admissions are discussed by HHS and DEA in Factors 1, 4, and 
5. Similarly, Factor 2 discusses marijuana's pharmacology and presents 
some of the adverse health effects associated with use. Marijuana use 
may affect the physical and/or psychological functioning of an 
individual user, but may also have broader public impacts including 
driving impairments and fatalities from car accidents.

Risks From Acute Use of Marijuana

    As discussed in the HHS review document (HHS, 2015), acute usage of 
marijuana impairs psychomotor performance including motor control and 
impulsivity, risk taking and executive function (Ramaekers et al., 
2004; Ramaekers et al., 2006). In a minority of individuals using 
marijuana, dysphoria, prolonged anxiety, and psychological distress may 
be observed (Haney et al., 1999). The DEA further notes a recent review 
of acute marijuana effects (Wilkinson et al., 2014) that reported 
impaired neurological function including altered perception, paranoia, 
delayed response time, and memory deficits.
    In its recommendation, HHS references a meta-analysis conducted by 
Li et al. (2012) where the authors concluded that psychomotor 
impairments associated with acute marijuana usage have also been

[[Page 53838]]

associated with increased risk of car accidents with individuals 
experiencing acute marijuana intoxication (Li et al., 2012; HHS, 2015). 
The DEA further notes more recent studies examining the risk associated 
with marijuana use and driving. Younger drivers (under 21) have been 
characterized as the highest risk group associated with marijuana use 
and driving (Whitehill et al., 2014). Furthermore, in 2013, marijuana 
was found in 13% of the drivers involved in automobile-related fatal 
accidents (McCartt, 2015). The potential risk of automobile accidents 
associated with marijuana use appears to be increasing since there has 
been a steady increase in individuals intoxicated with marijuana over 
the past 20 years (Wilson et al., 2014). However, a recent study 
commissioned by the National Highway Traffic Safety Administration 
(NHTSA) reported that when adjusted for confounders (e.g., alcohol use, 
age, gender, ethnicity), there was not a significant increase in crash 
risk (fatal and nonfatal, n = 2,682) associated with marijuana use 
(Compton and Berning, 2015).
    The DEA also notes recent studies examining unintentional exposures 
of children to marijuana (Wang et al., 2013; 2014). Wang et al. (2013) 
reviewed emergency department (ED) visits at a children's hospital in 
Colorado from January 1, 2005 to December 31, 2011. As stated by the 
authors, in 2000 Colorado passed Amendment 20 which allowed for the use 
of marijuana. Following the passage of ``a new Justice Department 
policy'' instructing ``federal prosecutors not to seek arrest of 
medical marijuana users and suppliers as long as they conform to state 
laws'' (as stated in Wang et al., 2013), 14 patients in Colorado under 
the age of 12 were admitted to the ED for the unintended use of 
marijuana over a 27 month period. Prior to the passage of this policy, 
from January 1, 2005 to September 30, 2009 (57 months), there were no 
pediatric ED visits due to unintentional marijuana exposure (Wang et 
al., 2013). The DEA also notes a larger scale evaluation of pediatric 
exposures using the National Poison Data System (Wang et al., 2014). 
That study reported that there were 985 unintentional marijuana 
exposures in children (9 years and younger) between January 1, 2005 to 
December 31, 2011. The authors stratified the ED visits by states with 
laws allowing medical use of marijuana, states transitioning to 
legalization for medical use, and states with no such laws. Out of the 
985 exposures, 495 were in non-legal states (n=33 states), 93 in 
transitional states (n=8 states), and 396 in ``legal'' states (n=9 
states). The authors reported that there was a twofold increase (OR = 
2.1) in moderate or major effects in children with unintentional 
marijuana use and a threefold increase (OR = 3.4) in admissions to 
critical care units in states allowing medical use of marijuana, in 
comparison to non-legal states.

Risks Associated With Chronic Use of Marijuana

    The HHS noted that a major risk from chronic marijuana use is a 
distinctive withdrawal syndrome, as described in the 2013 DSM-5. The 
HHS analysis also quoted the following description of risks associated 
with marijuana [cannabis] abuse from the DSM-5:

    Individuals with cannabis use disorder may use cannabis 
throughout the day over a period of months or years, and thus may 
spend many hours a day under the influence. Others may use less 
frequently, but their use causes recurrent problems related to 
family, school, work, or other important activities (e.g., repeated 
absences at work; neglect of family obligations). Periodic cannabis 
use and intoxication can negatively affect behavioral and cognitive 
functioning and thus interfere with optimal performance at work or 
school, or place the individual at increased physical risk when 
performing activities that could be physically hazardous (e.g. 
driving a car; playing certain sports; performing manual work 
activities, including operating machinery). Arguments with spouses 
or parents over the use of cannabis in the home, or its use in the 
presence of children, can adversely impact family functioning and 
are common features of those with cannabis use disorder. Last, 
individuals with cannabis use disorder may continue using marijuana 
despite knowledge of physical problems (e.g. chronic cough related 
to smoking) or psychological problems (e.g. excessive sedation or 
exacerbation of other mental health problems) associated with its 
use. (HHS 2015, page 34).

    The HHS stated that chronic marijuana use produces acute and 
chronic adverse effects on the respiratory system, memory and learning. 
Regular marijuana smoking can produce a number of long-term pulmonary 
consequences, including chronic cough and increased sputum (Adams and 
Martin, 1996), and histopathologic abnormalities in bronchial 
epithelium (Adams and Martin, 1996).

Marijuana as a ``Gateway Drug''

    The HHS reviewed the clinical studies evaluating the gateway 
hypothesis in marijuana and found them to be limited. The primary 
reasons were: (1) Recruited participants were influenced by social, 
biological, and economic factors that contribute to extensive drug 
abuse (Hall and Lynskey, 2005), and (2) most studies testing the 
gateway drug hypothesis for marijuana use the determinative measure any 
use of an illicit drug rather than applying DSM-5 criteria for drug 
abuse or dependence (DSM-5, 2013).
    The HHS cited several studies where marijuana use did not lead to 
other illicit drug use (Kandel and Chen, 2000; von Sydow et al., 2002; 
Nace et al., 1975). Two separate longitudinal studies with adolescents 
using marijuana did not demonstrate an association with use of other 
illicit drugs (Kandel and Chen, 2000; von Sydow et al., 2002).
    It was noted by the HHS that, when evaluating the gateway 
hypothesis, differences appear when examining use versus abuse or 
dependence of other illicit drugs. Van Gundy and Rebellon (2010) 
reported that there was a correlation between marijuana use in 
adolescence and other illicit drug use in early adulthood, but when 
examined in terms of drug abuse of other illicit drugs, age-linked 
stressors and social roles were confounders in the association. 
Degenhardt et al. (2009) reported that marijuana use often precedes use 
of other illicit drugs, but dependence involving drugs other than 
marijuana frequently correlated with higher levels of illicit drug 
abuse. Furthermore, Degenhardt et al. (2010) reported that in countries 
with lower prevalence of marijuana usage, use of other illicit drugs 
before marijuana was often documented.
    Based on these studies among others, the HHS concluded that 
although many individuals with a drug abuse disorder may have used 
marijuana as one of their first illicit drugs, this does not mean that 
individuals initiated with marijuana inherently will go on to become 
regular users of other illicit drugs.

Factor 7: Its Psychic or Physiological Dependence Liability

Physiological (Physical) Dependence in Humans

    The HHS stated that heavy and chronic use of marijuana can lead to 
physical dependence (DSM-5, 2013; Budney and Hughes, 2006; Haney et 
al., 1999). Tolerance is developed following repeated administration of 
marijuana and withdrawal symptoms are observed as following 
discontinuation of marijuana usage (HHS, 2015).
    The HHS mentioned that tolerance can develop to some of marijuana's 
effects, but does not appear to develop with respect to the 
psychoactive effects. It is believed that lack of tolerance to

[[Page 53839]]

psychoactive effects may relate to electrophysiological data 
demonstrating that chronic [Delta]\9\-THC administration does not 
affect increased neuronal firing in the ventral tegmental area, a brain 
region that plays a critical role in drug reinforcement and reward (Wu 
and French, 2000). Humans can develop tolerance to marijuana's 
cardiovascular, autonomic, and behavioral effects (Jones et al., 1981). 
Tolerance to some behavioral effects appears to develop with heavy and 
chronic use, but not with occasional usage. Ramaekers et al. (2009) 
reported that following acute administration of marijuana, occasional 
marijuana users still exhibited impairments in tracking and attention 
tasks whereas performance of heavy users on the these tasks was not 
affected. In a follow-up study with the same subjects that participated 
in the study by Ramaekers et al. (2009), a neurophysiological 
assessment was conducted where event-related potentials (ERPs) were 
measured using electroencephalography (EEG) (Theunissen et al., 2012). 
Similar to the earlier results, the heavy marijuana users (n = 11; 
average of 340 marijuana uses per year) had no changes in their ERPs 
with the acute marijuana exposure. However, occasional users (n = 10; 
average of 55 marijuana uses per year) had significant decreases in the 
amplitude of an ERP component (categorized as P100) on tracking and 
attention tasks and ERP amplitude change is indicative of a change in 
brain activity (Theunissen et al., 2012).
    The HHS indicated that down-regulation of cannabinoid receptors may 
be a possible mechanism for tolerance to marijuana's effects (Hirvonen 
et al., 2012; Gonzalez et al., 2005; Rodriguez de Fonseca et al., 1994; 
Oviedo et al., 1993).
    As indicated by the HHS, the most common withdrawal symptoms in 
heavy, chronic marijuana users are sleep difficulties, decreased 
appetite or weight loss, irritability, anger, anxiety or nervousness, 
and restlessness (Budney and Hughes, 2006; Haney et al., 1999). As 
reported by HHS, most marijuana withdrawal symptoms begin within 24-48 
hours of discontinuation, peak within 4-6 days, and last for 1-3 weeks.
    The HHS pointed out that the American Psychiatric Association's 
(APA's) Diagnostic and Statistical Manual of Mental Disorders--5 (DSM-
5) included a list of withdrawal symptoms following marijuana 
[cannabis] use (DSM-5, 2013). The DEA notes that a DSM-5 working group 
report indicated that marijuana withdrawal symptoms were added to DSM-5 
(they were not previously included in DSM-IV) because marijuana 
withdrawal has now been reliably presented in several studies (Hasin et 
al., 2013). In short, marijuana withdrawal signs are reported in up to 
one-third of regular users and between 50% and 90% of heavy users 
(Hasin et al., 2013). According to DSM-5 criteria, in order to be 
characterized as having marijuana withdrawal, an individual must 
develop at least three of the seven symptoms within one week of 
decreasing or stopping the heavy and prolonged use (DSM-5, 2013). These 
seven symptoms are: (1) Irritability; anger or aggression, (2) 
nervousness or anxiety, (3) sleep difficulty, (4) decreased appetite or 
weight loss, (5) restlessness, (6) decreased mood, (7) somatic symptoms 
causing significant discomfort (DSM-5, 2013).

Psychological (Psychic) Dependence in Humans

    High levels of psychoactive effects such as positive reinforcement 
correlate with increased marijuana abuse and dependence (Scherrer et 
al., 2009; Zeiger et al., 2010). Epidemiological marijuana use data 
reported by NSDUH, MTF, and TEDS support this assertion as presented in 
the HHS 2015 review of marijuana and updated by the DEA. According to 
the findings in the 2014 NSDUH survey, an estimated 9.2 million 
individuals 12 years and older used marijuana daily or almost daily (20 
or more days within the past month). In the 2015 MTF report, daily 
marijuana use (20 or more days within the past 30 days) in 8th, 10th, 
and 12th graders is 1.1%, 3.0%, and 6.0%, respectively.
    The 2014 NSDUH report stated that 4.2 million persons were 
classified with dependence on or abuse of marijuana in the past year 
(representing 1.6% of the total population age 12 or older, and 59.0% 
of those classified with illicit drug dependence or abuse) based on 
criteria specified in the Diagnostic and Statistical Manual of Mental 
Disorders, 4th edition (DSM-IV). Furthermore, of the admissions to 
licensed substance abuse facilities, as presented in TEDS, marijuana/
hashish was the primary substance of abuse for; 18.3% (352,297) of 2011 
admissions; 17.5% (315,200) of 2012 admissions; and 16.8% (281,991) of 
2013 admissions. Of the 281,991 admissions in 2013 for marijuana/
hashish as the primary substance, 24.3% used marijuana/hashish daily. 
Among admissions to treatment for marijuana/hashish as the primary 
substance in 2013, 27.4% were ages 12 to 17 years and 29.7% were ages 
20 to 24 years.

Factor 8: Whether the Substance is an Immediate Precursor of a 
Substance Already Controlled Under the CSA

    Marijuana is not an immediate precursor of another controlled 
substance.

Determination

    After consideration of the eight factors discussed above and of the 
HHS's Recommendation, the DEA finds that marijuana meets the three 
criteria for placing a substance in schedule I of the CSA under 21 
U.S.C. 812(b)(1):
    1. Marijuana has a high potential for abuse.
    The HHS concluded that marijuana has a high potential for abuse 
based on a large number of people regularly using marijuana, its 
widespread use, and the vast amount of marijuana that is available 
through illicit channels.
    Marijuana is the most abused and trafficked illicit substance in 
the United States. Approximately 22.2 million individuals in the United 
States (8.4% of the United States population) were past month users of 
marijuana according to the 2014 NSDUH survey. A 2015 national survey 
(Monitoring the Future) that tracks drug use trends among high school 
students showed that by 12th grade, 21.3% of students reported using 
marijuana in the past month, and 6.0% reported having used it daily in 
the past month. In 2011, SAMHSA's Drug Abuse Warning Network (DAWN) 
reported that marijuana was mentioned in 36.4% of illicit drug-related 
emergency department (ED) visits, corresponding to 455,668 out of 
approximately 1.25 million visits. The Treatment Episode Data Set 
(TEDS) showed that 16.8% of non-private substance-abuse treatment 
facility admissions in 2013 were for marijuana as the primary drug.
    Marijuana has dose-dependent reinforcing effects that encourage its 
abuse. Both clinical and preclinical studies have demonstrated that 
marijuana and its principle psychoactive constituent, [Delta]\9\-THC, 
possess the pharmacological attributes associated with drugs of abuse. 
They function as discriminative stimuli and as positive reinforcers to 
maintain drug use and drug-seeking behavior. Additionally, use of 
marijuana can result in psychological dependence.
    2. Marijuana has no currently accepted medical use in treatment in 
the United States.
    The HHS stated that the FDA has not approved an NDA for marijuana. 
The HHS noted that there are opportunities for scientists to conduct 
clinical research with marijuana and there are active INDs for 
marijuana, but marijuana

[[Page 53840]]

does not have a currently accepted medical use in the United States, 
nor does it have an accepted medical use with severe restrictions.
    FDA approval of an NDA is not the sole means through which a drug 
can be determined to have a ``currently accepted medical use'' under 
the CSA. Applying the five-part test summarized below, a drug has a 
currently accepted medical use if all of the following five elements 
have been satisfied. As detailed in the HHS evaluation and as set forth 
below, none of these elements has been fulfilled for marijuana:

i. The drug's chemistry must be known and reproducible

    Chemical constituents including [Delta]\9\-THC and other 
cannabinoids in marijuana vary significantly in different marijuana 
strains. In addition, the concentration of [Delta]\9\-THC and other 
cannabinoids may vary between strains. Therefore the chemical 
composition among different marijuana samples is not reproducible. Due 
to the variation of the chemical composition in marijuana strains, it 
is not possible to derive a standardized dose. The HHS does advise that 
if a specific Cannabis strain is cultivated and processed under 
controlled conditions, the plant chemistry may be consistent enough to 
derive standardized doses.

ii. There must be adequate safety studies

    There are not adequate safety studies on marijuana for use in any 
specific, recognized medical condition. The considerable variation in 
the chemistry of marijuana results in differences in safety, 
biological, pharmacological, and toxicological parameters amongst the 
various marijuana samples.

iii. There must be adequate and well-controlled studies proving 
efficacy

    There are no adequate and well-controlled studies that determine 
marijuana's efficacy. In an independent review performed by the FDA of 
publicly available clinical studies on marijuana (FDA, 2015), FDA 
concluded that these studies do not have enough information to 
``currently prove efficacy of marijuana'' for any therapeutic 
indication.

iv. The drug must be accepted by qualified experts

    At this time, there is no consensus of opinion among experts 
concerning the medical utility of marijuana for use in treating 
specific recognized disorders.

v. The scientific evidence must be widely available

    The currently available data and information on marijuana is not 
sufficient to address the chemistry, pharmacology, toxicology, and 
effectiveness. The scientific evidence regarding marijuana's chemistry 
with regard to a specific cannabis strain that could be formulated into 
standardized and reproducible doses is not currently available.
    3. There is a lack of accepted safety for use of marijuana under 
medical supervision.
    Currently, there are no FDA-approved marijuana products. The HHS 
also concluded that marijuana does not have a currently accepted 
medical use in treatment in the United States or a currently accepted 
medical use with severe restrictions. According to the HHS, the FDA is 
unable to conclude that marijuana has an acceptable level of safety in 
relation to its effectiveness in treating a specific and recognized 
disorder due to lack of evidence with respect to a consistent and 
reproducible dose that is contamination free. The HHS indicated that 
marijuana research investigating potential medical use should include 
information on the chemistry, manufacturing, and specifications of 
marijuana. The HHS further indicated that a procedure for delivering a 
consistent dose of marijuana should also be developed. Therefore, the 
HHS concluded that marijuana does not have an acceptable level of 
safety for use under medical supervision.

References

1. Abrams DI, Hilton JF, Reiser RJ, Shade SB, Elbeik TA, Aweeka FT, 
Benowitz NL, Bredt BM, Kosel B, Aberg JA, Deeks SG, Mitchell TF, 
Mulligan K, Bacchetti P, McCune JM, Schambelan M (2003). Short-term 
effects of cannabinoids in patients with HIV-1 infection: a 
randomized, placebo-controlled clinical trial. Ann Intern Med 
139(4):258-266.
2. Adams IB, Martin BR (1996). Cannabis: Pharmacology and toxicology 
in animals and humans. Addiction 91:1585-1614.
3. Agurell S, Dewey WL, and Willetts RE (eds.) (1984). The 
Cannabinoids: Chemical, Pharmacologic, and Therapeutic Aspects. New 
York: Academic Press
4. Agurell S, Halldin M, Lindgren JE, Ohlsson A, Widman M, Gillespie 
H, Hollister L (1986). Pharmacokinetics and metabolism of delta-1-
tetrahydrocannabinol and other cannabinoids with emphasis on man. 
Pharmacol Rev 38(1):21-43.
5. American College of Physicians [ACP]. (2008). Supporting Research 
Into the Therapeutic Role of Marijuana. Philadelphia: American 
College of Physicians; 2008: Position Paper (Available from American 
College of Physicians, 190 N. Independence Mall West, Philadelphia, 
PA 19106).
6. American Medical Association [AMA]. (2009a). Use of Cannabis for 
Medical Purposes. Report of the Council on Science and Public Health 
3.
7. American Medical Association [AMA]. (2009b). AMA Policy: Medical 
Marijuana. H-95-952 Medical Marijuana.
8. American Medical Association [AMA]. (2013). 2013 Interim Meeting. 
American Medical Association House of Delegates (I-13). Accessed at 
www.ama-assn.org/assets/meeting/2013i/i13-refcommk-annotated.pdf.
9. American Society of Addiction Medicine [ASAM]. (2014). New York 
Times calls for legalization of marijuana, ASAM strongly objects. 
Accessed at www.asam.org/docs/default-source/pressreleases/asam-press-release-nytimes-editorial-marijuana-2014-7-27.pdf?sfvrsn=2.
10. Andreasson S, Allebeck P, Engstr[ouml]m A, Rydberg U (1987). 
Cannabis and schizophrenia: A longitudinal study of Swedish 
conscripts. Lancet 1:483-1483.
11. Appendino G, Chianese G, Taglialatela-Scafati O (2011). 
Cannabinoids: occurrence and medicinal chemistry. Curr Med Chem 
18(7):1085-1099.
12. Asch RH, Smith CG, Siler-Khodr TM, Pauerstein CJ (1981). Effects 
of delta 9-tetrahydrocannabinol during the follicular phase of the 
rhesus monkey (Macaca mulatta). J Clin Endocrinol Metab 52(1):50-55.
13. Balster RL (1991). Drug abuse potential evaluation in animals. 
Br J Addict 86(12):1549-1558.
14. Balster RL, Prescott WR (1992). Delta9-Tetrahydrocannabinol 
discrimination in rats as a model for cannabis intoxication. 
Neurosci Biobehav Res 16(1):55-62.
15. Balster RL, Bigelow GE (2003). Guidelines and methodological 
reviews concerning drug abuse liability assessment. Drug Alcohol 
Depend 70:S13-S40.
16. Barnett G, Licko V, Thompson T (1985). Behavioral 
pharmacokinetics of marijuana. Psychopharmacology 85(1):51-56.
17. Benowitz NL, Jones RT (1975). Cardiovascular effects of 
prolonged delta-9-tetrahydrocannabinol ingestion. Clin Pharmacol 
Ther 18(3):287-297.
18. Benowitz NL, Jones RT (1981). Cardiovascular and metabolic 
considerations in prolonged cannabinoid administration in man. J 
Clin Pharmacol 21(8-9 Suppl):214S-223S.
19. Block RI, Farinpour R, Schlechte JA (1991). Effects of chronic 
marijuana use on testosterone, luteinizing hormone, follicle 
stimulating hormone, prolactin and cortisol in men and women. Drug 
Alcohol Depend 28(2):121-128.
20. Block RI, Farinpour R, Braverman K (1992). Acute effects of 
marijuana on cognition: relationships to chronic effects and smoking 
techniques. Pharmacol Biochem Behav 43(3):907-917.
21. Bolla KI, Brown K, Eldreth D, Tate K, Cadet JL (2002). Dose-
related neurocognitive effects of marijuana use. Neurology 59:1337-
1343.
22. Bolla KI, Eldreth DA, Matochik JA, Cadet JL (2005). Neural 
substrates of faulty decision-making in abstinent marijuana users. 
NeuroImage 26:480-492.

[[Page 53841]]

23. Bonnet U (2013). Chronic cannabis abuse, delta-9-
tetrahydrocannabinol and thyroid function. Pharmacopsychiatry 
46(1):35-36.
24. Bouaboula M, Rinaldi M, Carayon P, Carillon C, Delpech B, Shire 
D, Le Fur G, Casellas P (1993). Cannabinoid-receptor expression in 
human leukocytes. Eur J Biochem 214(1):173-180.
25. Braida D, Iosue S, Pegorini S, Sala M (2004). Delta9-
tetrahydrocannabinol-induced conditioned place preference and 
intracerebroventricular self-administration in rats. Eur J Pharmacol 
506(1):63-69.
26. Brievogel CS, Childers SR (2000). Cannabinoid agonist signal 
transduction in rat brain: comparison of cannabinoid agonists in 
receptor binding, G-protein activation, and adenylyl cyclase 
inhibition. J Pharmacol Exp Ther 295(1):328-336.
27. Brown TT, Dobs AS (2002). Endocrine effects of marijuana. J Clin 
Pharmacol 42(11 Suppl):90S-96S.
28. Browne RG, Weisman A (1981). Discriminative stimulus properties 
of delta 9-tetrahydrocannabinol: Mechanistic studies. J Clin 
Pharmacol 21(8-9 Suppl):227S-234S.
29. Budney AJ, Hughes JR (2006). The cannabis withdrawal syndrome. 
Curr Opin Psychiatry 19(3):233-238.
30. Capriotti RM, Foltin RW, Brady JV, Fischman MW (1988). Effects 
of marijuana on the task-elicited physiological response. Drug 
Alcohol Depend 21(3):183-187.
31. Cascini F, Aiello C, Di Tanna G (2012). Increasing delta-9-
tetrahydrocannabinol [Delta]-9-THC) content in herbal cannabis over 
time: systematic review and meta-analysis. Curr Drug Abuse Rev 
5(1):32-40.
32. Chait LD, Burke KA (1994). Preference for ``high'' versus low-
potency marijuana. Pharmacol Biochem Behav 7:357-364.
33. Cheer JF, Kendall DA, Marsden CA (2000). Cannabinoid receptors 
and reward in the rat: a conditioned place preference study. 
Psychopharmacology (Berl) 151(1):25-30.
34. Compton RP, Berning A (2015). Drug and Alcohol Crash Risk. 
Traffic Safety Facts Research Note. DOT HS 812 117. Washington, DC: 
National Highway Traffic Safety Administration.
35. Cone EJ, Johnson RE, Moore JD, Roache JD (1986). Acute effects 
of smoking marijuana on hormones, subjective effects and performance 
in male human subjects. Pharmacol Biochem Behav 24(6):1749-1754.
36. Croxford JL, Yamamura T (2005). Cannabinoids and the immune 
system: potential for the treatment of inflammatory diseases? J 
Neuroimmunol 166(1-2):3-18.
37. Daling JR, Doody DR, Sun X, Trabert BL, Weiss NS, Chen C, Biggs 
ML, Starr JR, Dey SK, Schwartz SM (2009). Association of marijuana 
use and the incidence of testicular germ cell tumors. Cancer. 
115(6):1215-1223.
38. Dalton WS, Martz R, Lemberger L, Rodda BE, Forney RB (1976). 
Influence of cannabidiol on delta-9-tetrahydrocannabinol effects. 
Clin Pharmacol Ther 19(3):300-309.
39. Dax EM, Pilotte NS, Adler WH, Nagel JE, Lange WR (1989). The 
effects of 9-enetetrahydrocannabinol on hormone release and immune 
function. J Steroid Biochem 34(1-6):263-270.
40. Day NL, Wagener DK, Taylor PM (1985). Measurement of substance 
use during pregnancy: methodologic issues. NIDA Res Monogr 59:36-47.
41. Day NL, Leech SL, Goldschmidt L (2011). The effects of prenatal 
marijuana exposure on delinquent behaviors are mediated by measures 
of neurocognitive functioning. Neurotoxicol Teratol 33(1):129-136.
42. Day NL, Goldschmidt L, Day R, Larkby C, Richardson GA (2015). 
Prenatal marijuana exposure, age of marijuana initiation, and the 
development of psychotic symptoms in young adults. Psychol Med 
45(8):1779-1787.
43. Degenhardt L, Hall W, Lynskey M (2003). Testing hypotheses about 
the relationship between cannabis use and psychosis. Drug Alcohol 
Depend 71(1):37-48.
44. Degenhardt L, Hall WD, Lynskey M, McGrath J, McLaren J, Calabria 
B, Whiteford H, Vos T (2009). Should burden of disease estimates 
include cannabis use as a risk factor for psychosis? PLoS Medicine. 
6(9):e1000133.
45. Degenhardt L, Dierker L, Chiu WT, Medina-Mora ME, Neumark Y, 
Sampson N, Alonso J, Angermeyer M, Anthony JC, Bruffaerts R, et al 
(2010). Evaluating the drug use ``gateway'' theory using cross-
national data: consistency and associations of the order of 
initiation of drug use among participants in the WHO World Mental 
Health Surveys. Drug Alcohol Depend 108(1-2):84-97.
46. De Petrocellis PL, Di Marzo V (2009). An introduction to the 
endocannabinoid system: From the early to the latest concepts. Best 
Pract Res Clin Endocrinol Metab 23(1):1-15.
47. Department of Health and Human Services [HHS] (2015). Basis for 
the recommendation for maintaining marijuana in Schedule I of the 
Controlled Substances Act.
48. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin 
G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992). Isolation 
and structure of a brain constituent that binds to the cannabinoid 
receptor. Science 258(5090):1946-1949.
49. Dewey WL, Martin BR, May EL (1984). Cannabinoid stereoisomers: 
pharmacological effects. In Smith DF. (Ed.) CRC Handbook of 
stereoisomers: drugs in psychopharmacology, 317-26 (Boca Raton, FL, 
CRC Press).
50. Drug Enforcement Administration (2015). Drugs of Abuse.
51. DSM-5 (2013). Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition. American Psychiatric Association. 
Washington, DC: American Psychiatric Publishing.
52. Eisenstein TK, Meissler JJ (2015). Effects of cannabinoids on T-
cell function and resistance to infection. J Neuroimmune Pharmacol 
10(2):204-216.
53. Eldridge JC, Murphy LL, Landfield PW (1991). Cannabinoids and 
the hippocampal glucocorticoid receptor: Recent findings and 
possible significance. Steroids 56(5):226-231.
54. ElSohly MA, Slade D (2005). Chemical constituents of marijuana: 
The complex mixture of natural cannabinoids. Life Sci 78:539-548.
55. Fant RV, Heishman SJ, Bunker EB, Pickworth WB (1998). Acute and 
residual effects of marijuana in humans. Pharmacol Biochem Behav 
60(4):777-784.
56. Federal Register (1992). ``Marijuana Scheduling Petition; Denial 
of Petition; Remand''--Drug Enforcement Administration, Final Order. 
Fed Registr 57(59):10499-10508.
57. Federal Register (1999). ``Rescheduling of the Food and Drug 
Administration Approved Product Containing Synthetic Dronabinol [(-
)-delta 9-(trans)-Tetrahydrocannabinol] in Sesame Oil and 
Encapsulated in Soft Gelatin Capsules From Schedule II to Schedule 
III; Final Rule,'' Fed Registr 64(127):35928-35930.
58. Federal Register (2001). ``Notice of Denial of Petition: Basis 
for the Recommendation for Maintaining Marijuana in Schedule I of 
the Controlled Substances Act,'' Fed Registr 66(75):20038-20076.
59. Fergusson DM, Horwood LJ, Ridder EM (2005). Tests of causal 
linkages between cannabis use and psychotic symptoms. Addiction. 
100(3):354-366.
60. Fontes MA, Bolla KI, Cunha PJ, Almeida PP, Jungerman F, 
Laranjeira RR, Bressan RA, Lacerda AL (2011). Cannabis use before 
age 15 and subsequent executive functioning. Br J Psychiatry 
198(6):442-447.
61. Fried PA, Watkinson B, Grant A, Knights RM (1980). Changing 
patterns of soft drug use prior to and during pregnancy: a 
prospective study. Drug Alcohol Depend 6(5):323-343.
62. Fried PA, Watkinson B (1990). 36- and 48-month neurobehavioral 
follow-up of children prenatally exposed to marijuana, cigarettes 
and alcohol. J Dev Behav Pediatr 11:49-58.
63. Fried PA, Watkinson B, Gray R (1992). A follow-up study of 
attentional behavior in 6-year-old children exposed prenatally to 
marihuana, cigarettes and alcohol. Neurotoxicol Teratol 14:299-311.
64. Fried PA, Watkinson B, Gray R (1998). Differential effects on 
cognitive functioning in 9- to 12-year olds prenatally exposed to 
cigarettes and marihuana. Neurotoxicol Teratol 20(3):293-306.
65. Fried PA (2002). Adolescents prenatally exposed to marijuana: 
Examination of facets of complex behaviors and comparisons with the 
influence of in utero cigarettes. J Clin Pharmacol 42(11 Suppl):97S-
102S.
66. Fried PA, Watkinson B, Gray R (2005). Neurocognitive 
consequences of

[[Page 53842]]

marihuana--a comparison with pre-drug performance. Neurotoxicol 
Teratol 27(2):231-239.
67. Fung M, Gallagher C, Machtay M (1999). Lung and aero-digestive 
cancers in young marijuana smokers. Tumori 85(2):140-142.
68. Gates P, Jaffe A, Copeland J (2014). Cannabis smoking and 
respiratory health: Consideration of the literature. Respirology 
19(5):655-662.
69. Ghozland S, Matthes HW, Simonin F, Filliol D, Kieffer BL, 
Maldonado R (2002). Motivational effects of cannabinoids are 
mediated by mu-opioid and kappa-opioid receptors. J Neurosci 
22(3):1146-1154.
70. Gold LH, Balster RL, Barrett RL, Britt DT, Martin BR (1992). A 
comparison of the discriminative stimulus properties of delta 9-
tetrahydrocannabinol and CP 55,940 in rats and rhesus monkeys. J 
Pharmacol Exp Ther 262(2):479-486.
71. Goldschmidt L, Richardson GA, Willford JA, Day NL (2008). 
Prenatal marijuana exposure and intelligence test performance at age 
6. J Am Acad Child Adolesc Psychiatry 47(3):254-263.
72. Goldschmidt L, Richardson GA, Willford JA, Severtson SG, Day NL 
(2012). School achievement in 14-year-old youths prenatally exposed 
to marijuana. Neurotoxicol Teratol 34(1):161-167.
73. Gong H Jr, Tashkin DP, Simmons MS, Calvarese B, Shapiro BJ 
(1984). Acute and subacute bronchial effects of oral cannabinoids. 
Clin Pharmacol Ther 35(1):26-32.
74. Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA, Brusco 
A, Uhl GR (2006). Cannabinoid CB2 receptors: Immunohistochemical 
localization in rat brain. Brain Res 1071(1):10-23.
75. Gonsiorek W, Lunn C, Fan X, Narula S, Lundell D, Hipkin RW. 
Endocannabinoid 2-arachidonyl glycerol is a full agonist through 
human type 2 cannabinoid receptor: Antagonism by anandamide. Mol 
Pharmacol 57(5):1045-1050.
76. Gonzalez R (2007). Acute and non-acute effects of cannabis on 
brain functioning and neuropsychological performance. Neuropsychol 
Rev 17(3):347-361.
77. Gonzalez S, Cebeira M, Fernandez-Ruiz J (2005). Cannabinoid 
tolerance and dependence: A review of studies in laboratory animals. 
Pharmacol Biochem Behav 81(2):300-318.
78. Griffith-Lendering MF, Wigman JT, Prince van Leeuwen A, 
Huijbregts SC, Huizink AC, Ormel J, Verhulst FC, van Os J, Swaab H, 
Vollebergh WA (2013). Cannabis use and vulnerability for psychosis 
in early adolescence--a TRAILS study. Addiction 108(4):733-740.
79. Grotenhermen F (2003). Pharmacokinetics and pharmacodynamics of 
cannabinoids. Clin Pharmacokinet 42(4):327-360.
80. Gruber SA, Sagar KA, Dahlgren MK, Racine M, Lukas SE (2012). Age 
of onset of marijuana use and executive function. Psychol Addict 
Behav 26(3):496-506.
81. Hackam DG (2015). Cannabis and stroke: Systematic appraisal of 
case reports. Stroke 46(3):852-856.
82. Hall WD, Lynskey M (2005). Is cannabis a gateway drug? Testing 
hypotheses about the relationship between cannabis use and the use 
of other illicit drugs. Drug Alcohol Rev 24(1):39-48.
83. Hall W, Degenhardt L (2014). The adverse health effects of 
chronic cannabis use. Drug Test Anal 6(1-2):39-45.
84. Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW (1999). 
Abstinence symptoms following smoked marijuana in humans. 
Psychopharmacology (Berl) 141(4):395-404.
85. Harder S, Rietbrock S (1997). Concentration-effect relationship 
of delta-9-tetrahydrocannabinol and prediction of psychotropic 
effects after smoking marijuana. International Journal of Clinical 
Pharmacology and Therapeutics. 35(4):155-159.
86. Hasin DS, O'Brien CP, Auriacombe M, Borges G, Bucholz K, Budney 
A, Compton WM, Crowley T, Ling W, Petry NM, Schuckit M, Grant BF 
(2013). DSM-5 criteria for substance use disorders: Recommendations 
and rationale. Am J Psychiatry 170(8):834-851.
87. Heishman SJ, Huestis MA, Henningfield JE, Cone EJ (1990). Acute 
and residual effects of marijuana: Profiles of plasma THC levels, 
physiological, subjective, and performance measures. Pharmacol 
Biochem Behav 37(3):561-565.
88. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa 
BR, Rice KC (1990). Cannabinoid receptor localization in brain. Proc 
Natl Acad Sci 87:1932-1936.
89. Herkenham M (1992). Cannabinoid receptor localization in brain: 
Relationship to motor and reward systems. Ann N Y Acad Sci 654:19-
32.
90. Herning RI, Hooker WD, Jones RT (1986). Tetrahydrocannabinol 
content and differences in marijuana smoking behavior. 
Psychopharmacology (Berl) 90(2):160-162.
91. Hirvonen J, Goodwin RS, Li CT, Terry GE, Zoghbi SS, Morse C, 
Pike VW, Volkow ND, Huestis MA, Innis RB (2012). Reversible and 
regionally selective downregulation of brain cannabinoid CB 1 
receptors in chronic daily cannabis smokers. Mol Psychiatry 
17(6):643-649.
92. Hively RL, Mosher WA, Hoffman FW (1966). Isolation of trans-
[Delta]9-tetrahydrocannabinol from marihuana. J Am Chem Soc 88:1832-
1833.
93. Hollister LE, Gillespie HK (1973). Delta-8- and delta-9-
tetrahydrocannabinol comparison in man by oral and intravenous 
administration. Clin Pharmacol Ther 14(3):353-357.
94. Hollister LE (1986). Health aspects of cannabis. Pharmacological 
Rev 3:1-20.
95. Hollister LE (1988). Cannabis (Literature review). Acta 
Psychiatr Scand (Suppl) 78:108-118.
96. Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, 
Porrino LJ (2004). Cannabinoid physiology and pharmacology: 30 years 
of progress. Neuropharmacology 47 Suppl:345-358.
97. Huang YH, Zhang ZF, Tashkin DP, Feng B, Straif K, Hashibe K 
(2015). An epidemiologic review of marijuana and cancer: An update. 
Cancer Epidemiol Biomarkers Prev 24(1):15-31.
98. Huestis MA, Sampson AH, Holicky BJ, Benningfield JE, Cone EJ 
(1992a). Characterization of the absorption phase of marijuana 
smoking. Clin Pharmacol Ther 52:31-41.
99. Huestis MA, Benningfield JE, Cone EJ (1992b). Blood 
Cannabinoids. 1. Absorption of THC and formation of 11-0H-THC and 
THC COOH during and after smoking marijuana. J Anal Toxicol 
16(5):276-282.
100. Hunt CA, Jones RT (1980). Tolerance and disposition of 
tetrahydrocannabinol in man. J Pharmacol Exp Ther 215(1):35-44.
101. Ilan AB, Gevins A, Coleman M, ElSohly MA, de Wit H (2005). 
Neurophysiological and subjective profile of marijuana with varying 
concentrations of cannabinoids. Behav Pharmacol 16(5-6):487-496.
102. Institute of Medicine (1982). Division of Health Sciences 
Policy. Marijuana and Health: Report of a Study by a Committee of 
the Institute of Medicine, Division of Health Sciences Policy. 
Washington, DC: National Academy Press, 1982.
103. Institute of Medicine (1999). Division of Neuroscience and 
Behavioral Health. Marijuana and Medicine: Assessing the Science 
Base. Washington, DC: National Academy Press, 1999.
104. Johansson E, Halldin MM, Agurell S, Hollister LE, Gillespie HK 
(1989). Terminal elimination plasma half-life of delta 1-
tetrahydrocannabinol (delta 1-THC) in heavy users of marijuana. Eur 
J Clin Pharmacol 37(3):273-277.
105. Jones RT, Benowitz NL, Heming RI (1981). Clinical relevance of 
cannabis tolerance and dependence. J Clin Pharmacol 21:143S-152S.
106. Jones RT (2002). Cardiovascular system effects of marijuana. J 
Clin Pharmacol 42(11Suppl):58S-63S.
107. Justinova Z, Tanda G, Redhi GH, Goldberg SR (2003). Self-
administration of delta9-tetrahydrocannabinol (THC) by drug 
na[iuml]ve squirrel monkeys. Psychopharmacology (Berl) 169(2):135-
140.
108. Justinova Z, Tanda G, Munzar P, Goldberg SR (2004). The opioid 
antagonist naltrexone reduces the reinforcing effects of delta 9 
tetrahydrocannabinol (THC) in squirrel monkeys. Psychopharmacology 
(Berl) 173(1-2):186-194.
109. Kandel D (1975). Stages in adolescent involvement in drug use. 
Science 190:912-914.
110. Kandel DB, Chen K (2000). Types of marijuana users by 
longitudinal course. J Stud Alcohol 61(3):367-378.
111. Karniol IG, Shirakawa I, Kasinski N, Pfeferman A, Carlini EA 
(1974). Cannabidiol interferes with the effects of delta 9-
tetrahydrocannabinol in man. Eur J Pharmacol 28(1):172-177.
112. Karniol IG, Shirakawa I, Takahashi RN, Knobel E, Musty RE 
(1975). Effects of delta9-tetrahydrocannabinol and cannabinol in 
man. Pharmacology 13(6):502-512.

[[Page 53843]]

113. Keen L 2nd, Pereira D, Latimer W (2014). Self-reported lifetime 
marijuana use and interleukin-6 levels in middle-aged African 
Americans. Drug Alcohol Depend 140:156-160.
114. Kirk JM, de Wit H (1999). Responses to oral delta9-
tetrahydrocannabinol in frequent and infrequent marijuana users. 
Pharmacol Biochem Behav 63(1):137-142.
115. Kuepper R, van Os J, Lieb R, Wittchen HU, Henquet C (2011). Do 
cannabis and urbanicity co-participate in causing psychosis? 
Evidence from a 10-year follow-up cohort study. Psychol Med 
41(10):2121-2129.
116. Kurzthaler I, Hummer M, Miller C, Sperner-Unterweger B, Gunther 
V, Wechdorn H, Battista HJ, Fleischhacker WW (1999). Effects of 
cannabis use on cognitive functions and driving ability. J Clin 
Psychiatry 60(6):395-399.
117. Lacson JC, Carroll JD, Tuazon E, Castelao EJ, Bernstein L, 
Cortessis VK (2012). Population-based case-control study of 
recreational drug use and testis cancer risk confirms an association 
between marijuana use and nonseminoma risk. Cancer 118:5374-5383.
118. Lee MH, Hancox RJ (2011). Effects of smoking cannabis on lung 
function. Exp Rev Resp Med 5(4):537-546.
119. Lemberger L, Silberstein SD, Axelrod J, Kopin IJ (1970). 
Marihuana: Studies on the disposition and metabolism of delta-9-
tetrahydrocannabinol in man. Science 70:1320-1322.
120. Lemberger L, Weiss JL, Watanabe AM, Galanter IM, Wyatt RJ, 
Cardon PV (1972a). Delta-9-tetrahydrocannabinol: Temporal 
correlation of the psychological effects and blood levels after 
various routes of administration. New Eng J Med 286(13):685-688.
121. Lemberger L, Crabtree RE, Rowe HM (1972b). 11-Hydroxy-delta9-
tetrahydrocannabinol: Pharmacology, disposition and metabolism of a 
major metabolite of marihuana in man. Science 77:62-63.
122. Lemberger L, Rubin A (1975). The physiologic disposition of 
marihuana in man. Life Sci 17:1637-1642.
123. Li M-C, Brady JE, DiMaggio CJ, Lusardi AR, Tzong, KY, Li G 
(2012). Marijuana use and motor vehicle crashes. Epidemiologic Rev 
34:65-72.
124. Liguori A, Gatto CP, Robinson JH (1998). Effects of marijuana 
on equilibrium, psychomotor performance, and simulated driving. 
Behav Pharmacol 9(7):599-609.
125. Lisdahl KM, Price JS (2012). Increased marijuana use and gender 
predict poorer cognitive functioning in adolescents and emerging 
adults. J Int Neuropsychol Soc 18(4):678-688.
126. Lyons MJ, Bar JL, Panizzon MS, Toomey R, Eisen S, Xian H, 
Tsuang MT (2004). Neuropsychological consequences of regular 
marijuana use: a twin study. Psychol Med 34(7):1239-1250.
127. Mackie K, Lai Y, Westenbroek R, Mitchell R (1995). Cannabinoids 
activate an inwardly rectifying potassium conductance and inhibit Q-
type calcium currents in AtT20 cells transfected with rat brain 
cannabinoid receptor. J Neurosci 15(10):6552-6561.
128. Maldonado R (2002). Study of cannabinoid dependence in animals. 
Pharmacol Ther 95(2):153-164.
129. Malinowska B, Baranowska-Kuczko M, Schlicker E (2012). 
Triphasic blood pressure responses to cannabinoids: Do we understand 
the mechanism? Br J Pharmacol 165(7):2073-2088.
130. Manrique-Garcia E, Zammit S, Dalman C, Hemmingson T, Andreasson 
S, Allebeck P (2012). Cannabis, schizophrenia and other non-
affective psychoses: 35 years of follow-up of a population-based 
cohort. Psychol Med 42(6):1321-1328.
131. Maremmani I, Lazzeri A, Pacini M, Lovrecic M, Placidi GF, 
Perugi G (2004). Diagnostic and symptomatological features in 
chronic psychotic patients according to cannabis use status. J 
Psychoactive Drugs 36(2):235-241.
132. McCartt AT (2015). Marijuana and driving in the United States: 
Prevalence, risks, and laws. Presented at the Casualty Actuarial 
Society Spring Meeting. Colorado Springs, CO. May 19, 2015.
133. McMahon LR, Ginsburg BC, Lamb RJ (2008). Cannabinoid agonists 
differentially substitute for the discriminative stimulus effects of 
Delta(9)-terahydrocannabinol in C57BL/6J mice. Psychopharmacology 
(Berl) 198(4):487-495.
134. McMahon LR (2009). Apparent affinity estimates of rimonabant in 
combination with anandamide and chemical analogs of anandamide in 
rhesus monkeys discriminating Delta9-tetrahydrocannabinol. 
Psychopharmacology (Berl) 203(2):219-228.
135. Mechoulam R (1973). Cannabinoid chemistry. In Mechoulam, R. 
(ed.) Marijuana, pp.2-88 (New York, NY, Academic Press, Inc.).
136. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE., 
Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, Pertwee RG, 
Griffin G, Bayewitch M, Barg J, Vogel Z (1995). Identification of an 
endogenous 2-monoglyceride, present in canine gut, that binds to 
cannabinoid receptors. Biochem Pharmacol 50(1):83-90.
137. Mehmedic Z, Chandra S, Slade D, Denham H, Foster S, Patel AS, 
Ross SA, Khan IA, ElSohly MA (2010). Potency trends of [Delta]\9\-
THC and other cannabinoids in confiscated cannabis preparations from 
1993 to 2008. J Forensic Sci 55(5):1209-1217.
138. Meier MH, Caspi A, Ambler A, Harrington H, Houts R, Keefe RS, 
McDonald K, Ward A, Poulton R, Moffitt TE (2012). Persistent 
cannabis users show neuropsychological decline from childhood to 
midlife. Proc Natl Acad Sci USA 109(40):E2657-E2664.
139. Mendelson JH, Mello NK (1984). Effects of marijuana on 
neuroendocrine hormones in human males and females. NIDA Res Monogr 
44:97-114.
140. Messinis L, Kyprianidou A, Malefaki S, Papathanasopoulos P 
(2006). Neuropsychological deficits in long-term frequent cannabis 
users. Neurology 66:737-739.
141. Minozzi S, Davoli M, Bargagli AM, Amato L, Vecchi S, Perucci CA 
(2010). An overview of systematic reviews on cannabis and psychosis: 
discussing apparently conflicting results. Drug Alcohol Rev 
29(3):304-317.
142. Mittleman MA, Lewis RA, Maclure M, Sherwood JB, Muller JE 
(2001). Triggering myocardial infarction by marijuana. Circulation 
103:2805-2809.
143. Nace EP, Meyers AL, Rothberg JM, Maleson F (1975). Addicted and 
nonaddicted drug users. A comparison of drug usage patterns. Arch 
Gen Psychiatry 32(1):77-80.
144. Oviedo A, Glowa J, Herkenham M (1993). Chronic cannabinoid 
administration alters cannabinoid receptor binding in rat brain: A 
quantitative autoradiographic study. Brain Res 616:293-302.
145. Pacher P, Batkai S, Kunos G (2006). The endocannabinoid system 
as an emerging target of pharmacotherapy. Pharmacol Rev 58(3):389-
462.
146. Panayiotides IM (2015). What is the association between 
cannabis consumption and cardiovascular complications. Subst Abuse 
9:1-3.
147. Pelayo-Teran JM, Suarez-Pinilla P, Chadi N, Crespo-Pacorro B 
(2012). Gene-environment interactions underlying the effect of 
cannabis in first episode psychosis. Curr Pharm Des 18(32):5024-
5035.
148. Piomelli D (2005). The endocannabinoid system: A drug discovery 
perspective. Curr Opin Investig 6(7):672-679.
149. Pletcher MJ, Vittinghoff E, Kalhan R, Richman J, Safford M, 
Sidney S, Lin F, Kertesz S (2012). Association between marijuana 
exposure and pulmonary function over 20 years. Journal of the 
American Medical Association. 307(2):173-181.
150. Pollastro F, Taglialatela-Scafati O, Allara M, Munoz E, Di 
Marzo V, De Petrocellis L, Appendino G (2011). Bioactive prenylogous 
cannabinoid from fiber hemp (Cannabis sativa). J Nat Prod. 
74(9):2019-2022.
151. Pope HG Jr, Gruber AJ, Hudson JI, Huestis MA, Yurgelun-Todd D 
(2002). Cognitive measures in long-term cannabis users. J Clin 
Pharmacol 42(11 Suppl):41S-47S.
152. Radwan MM, ElSohly MA, Slade D, Ahmed SA, Khan IA, Ross SA 
(2009). Biologically active cannabinoids from high-potency Cannabis 
sativa. J Nat Prod 72(5):906-911.
153. Ramaekers JG, Berghaus G, van Laar M, Drummer OH (2004). Dose 
related risk of motor vehicle crashes after cannabis use. Drug and 
Alcohol Dependence. 73(2):109-119.
154. Ramaekers JG, Kauert G, van Ruitenbeek P, Theunissen EL, 
Schneider E, Moeller MR (2006). High-potency marijuana impairs 
executive functions and inhibitory motor control.

[[Page 53844]]

Neuropsychopharmacology 31(10):2296-2303.
155. Ramaekers JG, Kauert G, Theunissen EL, Toennes SW., Moeller MR 
(2009). Neurocognitive performance during acute THC intoxication in 
heavy and occasional cannabis users. J Psychopharmacol 23(3):266-
277.
156. Riggs PK, Vaida F, Rossi SS, Sorkin LS, Gouaux B, Grant I, 
Ellis RJ (2012). A pilot study of the effects of cannabis on 
appetite hormones in HIV-infected adult men. Brain Res 1431:46-52.
157. Rodriguez de Fonseca F, Gorriti MA, Fernandez-Ruiz JJ, Palomo 
T, Ramos JA (1994). Downregulation of rat brain cannabinoid binding 
sites after chronic delta 9-tetrahydrocannabinol treatment. 
Pharmacol Biochem Behav 47(1):33-40.
158. Roth MD, Arora A, Barsky SH, Kleerup EC, Simmons M, Tashkin DP 
(1998). Airway inflammation in young marijuana and tobacco smokers. 
American Journal of Respiratory and Crit Care Med 157:928-937.
159. Roth MD, Tashkin DP, Whittaker KM, Choi R, Baldwin GC (2005). 
Tetrahydrocannabinol suppresses immune function and enhances HIV 
replication in the huPBL-SCID mouse. Life Sci 77(14):1711-1722.
160. Russo E, Mathre ML, Byrne A, Velin R, Bach PJ, Sanchez-Ramos J, 
Kirlin KA (2001). Chronic cannabis use in the compassionate 
investigational new drug program: An examination of benefits and 
adverse effects of legal clinical cannabis. J Cannabis Ther 2:3-57.
161. Sarfaraz S, Afaq F, Adhami VM, Mukhtar H (2005). Cannabinoid 
receptor as a novel target for the treatment of prostate cancer. 
Cancer Res 65(5):1635-1641.
162. Scherrer JF, Grant JD, Duncan AE, Sartor CE, Haber JR, Jacob T, 
Bucholz KK (2009). Subjective effects to cannabis are associated 
with use, abuse and dependence after adjusting for genetic and 
environmental influences. Drug Alcohol Depend 105(1-2):76-82.
163. Schiffman J, Nakamura B, Earleywine MJ, LaBrie J (2005). 
Symptoms of schizotypy precede cannabis use. Psychiatry Res 
134(1):37-42.
164. Schimmelmann BG, Conus P, Cotton SM, Kupferschmid S, Karow A, 
Schultze-Lutter F, McGorry PD, Lambert M (2011). Cannabis use 
disorder and age at onset of psychosis--a study in first episode 
patients. Schizophr Res 129(1):52-56.
165. Schreiner AM, Dunn ME (2012). Residual effects of cannabis use 
on neurocognitive performance after prolonged abstinence: A meta-
analysis. Exp Clin Psychopharmacol 20(5):420-429.
166. Sexton M, Cudaback E, Abdullah RA, Finnell J, Mischley LJ, 
Rozga M, Lichtman AH, Stella N (2014). Cannabis use by individuals 
with multiple sclerosis: Effects on specific immune parameters. 
Inflammopharmacology 22(5):295-303.
167. Sidney S (2002). Cardiovascular consequences of marijuana use. 
J Clin Pharmacol 42(11Suppl):64S-70S.
168. Solinas M, Panlilio LV, Justinova Z, Yasar S, Goldberg SR 
(2006). Using drug-discrimination techniques to study the abuse-
related effects of psychoactive drugs in rats. Nat Protoc 1(3):1194-
1206.
169. Solowij N, Stephens RS, Roffman RA, Babor T, Kadden R, Miller 
M, Christiansen K, McRee B,Vendetti J (2002). Marijuana Treatment 
Project Research Group. Cognitive functioning of long-term heavy 
cannabis users seeking treatment. Journal of the American Medical 
Association 287(9):1123-1131.
170. Substance Abuse and Mental Health Services Administration 
(2013). Drug Abuse Warning Network, 2011: National Estimates of 
Drug-Related Emergency Department Visits. HHS Publication No. (SMA) 
13-4760, DAWN Series D-39. Rockville, MD.
171. Substance Abuse and Mental Health Services Administration, 
Center for Behavioral Health Statistics and Quality (2015a). Results 
from the 2014 National Survey on Drug Use and Health: Detailed 
Tables. Rockville, MD.
172. Substance Abuse and Mental Health Services Administration, 
Center for Behavioral Health Statistics and Quality (2015b). 
Treatment Episode Data Set (TEDS): 2003-2013. National Admissions to 
Substance Abuse Treatment Services. BHSIS Series S-75, HHS 
Publication No. (SMA) 15-4934. Rockville, MD.
173. Tait RJ, MacKinnon A, Christensen H (2011). Cannabis use and 
cognitive functioning: 8-year trajectory in a young adult cohort. 
Addiction 106(12):2195-2203.
174. Tanasescu R, Constantinescu CS (2010). Cannabinoids and the 
immune system: An overview. Immunobiology 215(8):588-597.
175. Tanda G, Munzar P, Goldberg SR (2000). Self-administration 
behavior is maintained by the psychoactive ingredient of marijuana 
in squirrel monkeys. Nat Neurosci 3(11):1073-1074.
176. Tanda G, Goldberg SR (2003). Cannabinoids: Reward, dependence, 
and underlying neurochemical mechanisms--a review of recent 
preclinical data. Psychopharmacology (Berl) 169(2):115-134.
177. Tashkin DP (2005). Smoked marijuana as a cause of lung injury. 
Monaldi Arch Chest Dis 63(2):93-l00.
178. Tashkin DP, Zhang ZF, Greenland S, Cozen W, Mack TM, and 
Morgenstern H (2006). Marijuana use and lung cancer: Results of a 
case-control study. American Thoracic Society International 
Conference. Abstract A777.
179. Theunissen EL, Kauert GF, Toennes SW., Moeller MR, Sambeth A, 
Blanchard MM, Ramaekers JG (2012). Neurophysiological functioning of 
occasional and heavy cannabis users during THC intoxication. 
Psychopharmacology (Berl) 220(2):341-350.
180. Trabert B, Sigurdson AJ, Sweeney AM, Strom SS, McGlynn KA 
(2011). Marijuana use and testicular germ cell tumors. Cancer 
117(4):848-853.
181. Twitchell W, Brown S, Mackie K (1997). Cannabinoids inhibit N- 
and P/Q-type calcium channels in cultured rat hippocampal neurons. J 
Neurophysiol 78(1):43-50.
182. U.S. Food and Drug Administration (FDA), Center for Drug and 
Evaluation Research, Controlled Substances Staff (2015). The Medical 
Application of Marijuana: A Review of Published Clinical Studies. 
March 19, 2015.
183. van der Meer FJ, Velthorst E, Meijer CJ, Machielsen MW, de Haan 
L (2012). Cannabis use in patients at clinical high risk of 
psychosis: Impact on prodromal symptoms and transition to psychosis. 
Curr Pharm Des 18(32):5036-5044.
184. van Gastel WA, Wigman JT, Monshouwer K, Kahn RS, van Os J, Boks 
MP, Volleburgh WA (2012). Cannabis use and subclinical positive 
psychotic experiences in early adolescence: Findings from a Dutch 
survey. Addiction 107(2):381-387.
185. Van Gundy K, Rebellon CJ (2010). A Life-course Perspective on 
the ``Gateway Hypothesis.'' J Health Soc Behav 51(3):244-259.
186. van Os J, Bak M, Hanssen M, Bijl RV, de Graaf R, Verdoux H. 
(2002). Cannabis use and psychosis: A longitudinal population-based 
study. Am J Epi 156(4):319-327.
187. Vann RE, Gamage TF, Warner JA, Marshall EM, Taylor NL, Martin 
BR, Wiley JL (2008). Divergent effects of cannabidiol on the 
discriminative stimulus and place conditioning effects of 
[Delta](9)-tetrahydrocannabinol. Drug Alcohol Depend 94(1-3):191-
198.
188. Volkow ND, Baler RD, Compton WM, Weiss SR (2014). Adverse 
health effects of marijuana use. N Engl J Med 370(23):2219-2227.
189. von Sydow K, Lieb R, Pfister H, Hofler M, Wittchen HU 
(2002).What predicts incident use of cannabis and progression to 
abuse and dependence? A 4-year prospective examination of risk 
factors in a community sample of adolescents and young adults. Drug 
Alcohol Depend 68(1):49-64.
190. Wachtel SR, ElSohly MA, Ross SA, Ambre J, de Wit H (2002). 
Comparison of the subjective effects of [Delta](9)-
tetrahydrocannabinol and marijuana in humans. Psychopharmacology 
(Berl) 161(4):331-339.
191. Wagner JA, Varga K, Kunos G (1998). Cardiovascular actions of 
cannabinoids and their generation during shock. J Mol Med 
76(12):824-836.
192. Wang GS, Roosevelt G, Heard K (2013). Pediatric marijuana 
exposures in a medical marijuana state. JAMA Pediatr 167(7):630-633.
193. Wang GS, Roosevelt G, Le Lait MC, Martinez EM, Bucher-Bartelson 
B, Bronstein AC, Heard K (2014). Association of unintended pediatric 
exposures with decriminalization of marijuana in the United States. 
Ann Emerg Med 63(6):684-689.
194. Wang T, Collet JP, Shapiro S, Ware MA (2008). Adverse effects 
of medical cannabinoids: A systematic review. CMAJ 178(13):1669-
1678.

[[Page 53845]]

195. Wesson DR, Washburn P (1990). Current patterns of drug abuse 
that involve smoking. NIDA Res Monogr 99:5-11.
196. Whitehill JM, Rivara FP, Moreno MA (2014). Marijuana-using 
drivers, alcohol-using drivers, and their passengers: Prevalence and 
risk factors among underage college students. JAMA Pediatr 
168(7):618-624.
197. Wiley JL, Barrett RL, Britt DL, Balster RL, Martin BR (1993). 
Discriminative stimulus effects of [Delta] 9-tetrahydrocannabinol 
and [Delta] 9-11-tetrahydrocannabinol in rats and rhesus monkeys. 
Neuropharmacology 32(4):359-365.
198. Wiley JL, Huffman JW, Balster RL, Martin BR (1995). 
Pharmacological specificity of the discriminative stimulus effects 
of [Delta] 9-tetrahydrocannabinol in rhesus monkeys. Drug Alcohol 
Depend 40(1):81-86.
199. Wilkinson ST, Radhakrishnan R, D'Souza DC (2014). Impact of 
cannabis use on the development of psychotic disorders. Curr Addict 
Rep 1(2):115-128.
200. Wilson FA, Stimpson JP, Pag[aacute]n JA (2014). Fatal crashes 
from drivers testing positive for drugs in the U.S., 1993-2010. 
Public Health Rep 129(4):342-350.
201. Wu X, French ED (2000). Effects of chronic [Delta]9-
tetrahydrocannabinol on rat midbrain dopamine neurons: An 
electrophysiological assessment. Neuropharmacology 39(3):391-398.
202. Zeiger JS, Haberstick BC, Corley RP, Ehringer MA, Crowley TJ, 
Hewitt JK, Hopfer CJ, Stallings MC, Young SE., Rhee SH (2010). 
Subjective effects to marijuana associated with marijuana use in 
community and clinical subjects. Drug Alcohol Depend 109(1-3):161-
66.
203. Zhang ZF, Morgenstern H, Spitz MR, Tashkin DP, Yu GP, Marshall 
JR, Hsu TC, Schantz, SP (1999). Marijuana use and increased risk of 
squamous cell carcinoma of the head and neck. Cancer Epidemiol 
Biomarkers Prev 8(12):1071-1078.
204. Zhang LR, Morgenstern H, Greenland S, Chang SC, Lazarus P, 
Teare MD, Woll PJ, Orlow I, Cox B on behalf of the Cannabis and 
Respiratory Disease Research Group of New Zealand, Brhane Y, Liu G, 
Hung RJ (2015). Cannabis smoking and lung cancer risk: Pooled 
analysis in the International Lung Cancer Consortium. Int J Cancer 
136(4):894-903.
205. Zwardi AW, Shirakawa I, Finkelfarb E, Karniol IG (1982). Action 
of cannabidiol on the anxiety and other effects produced by [Delta] 
9-THC in normal subject. Psychopharmcology (Berl) 76(3):245-250.
[FR Doc. 2016-17960 Filed 8-11-16; 8:45 am]
 BILLING CODE 4410-09-P