Denial of Petition To Initiate Proceedings To Reschedule Marijuana, 40552-40589 [2011-16994]

Agencies

• Drug Enforcement Administration
• Department of Justice

[Federal Register Volume 76, Number 131 (Friday, July 8, 2011)]
[Proposed Rules]
[Pages 40552-40589]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-16994]



[[Page 40551]]

Vol. 76

Friday,

No. 131

July 8, 2011

Part IV





Department of Justice





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Drug Enforcement Administration





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21 CFR Chapter II





Denial of Petition To Initiate Proceedings To Reschedule Marijuana; 
Proposed Rule

Federal Register / Vol. 76 , No. 131 / Friday, July 8, 2011 / 
Proposed Rules

[[Page 40552]]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Chapter II

[Docket No. DEA-352N]


Denial of Petition To Initiate Proceedings To Reschedule 
Marijuana

AGENCY: Drug Enforcement Administration (DEA), Department of Justice.

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

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SUMMARY: By letter dated June 21, 2011, the Drug Enforcement 
Administration (DEA) denied a petition to initiate rulemaking 
proceedings to reschedule marijuana.\1\ Because 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 (denying the 
petition), along with the supporting documentation that was attached to 
the letter.
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    \1\ 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.''

FOR FURTHER INFORMATION CONTACT: Imelda L. Paredes, Office of Diversion 
Control, Drug Enforcement Administration, 8701 Morrissette Drive, 
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Springfield, Virginia 22152; Telephone (202) 307-7165.

SUPPLEMENTARY INFORMATION: 

June 21, 2011.

    Dear Mr. Kennedy:
    On October 9, 2002, 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 as cannabis in schedule III, IV 
or V.
    You requested that DEA remove marijuana from schedule I based on 
your assertion that:
    (1) Cannabis has an accepted medical use in the United States;
    (2) Cannabis is safe for use under medical supervision;
    (3) Cannabis has an abuse potential lower than schedule I or II 
drugs; and
    (4) Cannabis has a dependence liability that is lower than schedule 
I or II drugs.
    In accordance with the CSA rescheduling provisions, after gathering 
the necessary data, DEA requested a scientific and medical evaluation 
and scheduling recommendation from the Department of Health and Human 
Services (DHHS). DHHS 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, DHHS recommended that marijuana remain in schedule I. The 
scientific and medical evaluation and scheduling recommendation that 
DHHS submitted to DEA is attached hereto.
    Based on the DHHS 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 DHHS 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. According to established case law, marijuana has no 
``currently accepted medical use'' because: 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. 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.
    You also argued that cannabis has a dependence liability that is 
lower than schedule I or II drugs. Findings as to the physical or 
psychological dependence of a drug are only one of eight factors to be 
considered. As discussed further in the attached documents, DHHS states 
that long-term, regular use of marijuana can lead to physical 
dependence and withdrawal following discontinuation as well as psychic 
addiction or dependence.
    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).
    Accordingly, and as set forth in detail in the accompanying DHHS 
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,

Michele M. Leonhart,
Administrator.

    Attachments:

Marijuana. Scheduling Review Document: Eight Factor Analysis

Basis for the recommendation for maintaining marijuana in schedule I 
of the Controlled Substances Act

Date: June 30, 2011

Michele M. Leonhart
Administrator

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

December 6, 2006.
The Honorable Karen P. Tandy
Administrator, Drug Enforcement Administration, U.S. Department of 
Justice, Washington, D.C. 20537

    Dear Ms. Tandy:
    This is in response to your request of July 2004, and pursuant 
to the Controlled Substances Act (CSA), 21 U.S.C. 811(b), (c), and 
(f), the Department of Health and Human Services (DHHS) recommends 
that marijuana continue to be subject to control under Schedule I of 
the CSA.
    Marijuana is currently controlled under Schedule I of the CSA. 
Marijuana continues to meet the three criteria for placing a 
substance in Schedule I of the CSA under 21 U.S.C. 812(b)(l). As 
discussed in the attached analysis, marijuana has a high potential 
for abuse, has no currently accepted medical use in treatment in the 
United States, and has a lack of an accepted level of safety for use 
under medical supervision. Accordingly, HHS recommends that 
marijuana continue to be subject to control under Schedule I of the 
CSA. Enclosed is a document prepared by FDA's Controlled Substance 
Staff that is the basis for this recommendation.
    Should you have any questions regarding this recommendation, 
please contact Corinne P. Moody, of the Controlled Substance Staff, 
Center for Drug Evaluation and Research. Ms. Moody can be reached at 
301-827-1999.

    Sincerely yours,
John O. Agwunobi,
Assistant Secretary for Health.

Enclosure:

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

BASIS FOR THE RECOMMENDATION FOR MAINTAINING MARIJUANA IN SCHEDULE I OF 
THE CONTROLLED SUBSTANCES ACT

    On October 9, 2002, the Coalition for Rescheduling Cannabis 
(hereafter known as the Coalition) submitted a petition to the Drug 
Enforcement Administration (DEA) requesting that proceedings be 
initiated to repeal the rules and regulations that place marijuana 
in Schedule I of the Controlled Substances Act (CSA). The petition 
contends that cannabis has an accepted medical use in the United 
States, is safe for use under medical supervision, and has an abuse 
potential and a dependency liability that is lower than Schedule I 
or II drugs. The petition requests that marijuana be rescheduled as 
``cannabis'' in either Schedule III, IV, or V of the CSA. In July 
2004, the DEA Administrator requested that the 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 the provisions of 21 U.S.C. 811(b).
    In accordance with 21 U.S.C. 811(b), DEA has gathered 
information related to the control of marijuana (Cannabis sativa) 
\2\ under the CSA. Pursuant to 21 U.S.C. 811(b), the Secretary 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. The findings relate to a substance's abuse 
potential, legitimate medical use, and safety or dependence 
liability.
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    \2\ The 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)).
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    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).
    In this document, FDA recommends the 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

    The first factor the Secretary must consider is marijuana's 
actual or relative potential for abuse. The term ``abuse'' is not 
defined in the CSA. However, the legislative history of the CSA 
suggests the following in determining whether a particular drug or 
substance has a potential for abuse:
    a. 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.
    b. There is a significant diversion of the drug or substance 
from legitimate drug channels.
    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.
    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.

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.

    In considering these concepts in a variety of scheduling 
analyses over the last three decades, the Secretary has analyzed a 
range of factors when assessing the abuse liability of a substance. 
These factors have included the prevalence and frequency of use in 
the general public and in specific sub-populations, the amount of 
the material that is available for illicit use, the ease with which 
the substance may be obtained or manufactured, the reputation or 
status of the substance ``on the street,'' as well as evidence 
relevant to population groups that may be at particular risk.
    Abuse liability is a complex determination with many dimensions. 
There is no single test or assessment procedure that, by itself, 
provides a full and complete characterization. Thus, no single 
measure of abuse liability is ideal. Scientifically, a comprehensive 
evaluation of the relative abuse potential of a drug substance can 
include consideration of the drug's receptor binding affinity, 
preclinical pharmacology, reinforcing effects, discriminative 
stimulus effects, dependence producing potential, pharmacokinetics 
and route of administration, toxicity, assessment of the clinical 
efficacy-safety database relative to actual abuse, clinical abuse 
liability studies, and the public health risks following 
introduction of the substance to the general population. It is 
important to note that abuse may exist independent of a state of 
tolerance or physical dependence, because drugs may be abused in 
doses or in patterns that do not induce these phenomena. Animal 
data, human data, and epidemiological data are all used in 
determining a substance's abuse liability. Epidemiological data can 
also be an important indicator of actual abuse. Finally, evidence of 
clandestine production and illicit trafficking of a substance are 
also important factors.
    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.
    Marijuana is a widely abused substance. The pharmacology of the 
psychoactive constituents of marijuana, including delta\9\-
tetrahydrocannabinol (delta\9\-THC), the primary psychoactive 
ingredient in marijuana, has been studied extensively in animals and 
humans and is discussed in more detail below in Factor 2, 
``Scientific Evidence of its Pharmacological Effects, if Known.'' 
Data on the extent of marijuana abuse are available from HHS through 
NIDA and the Substance Abuse and Mental Health Services 
Administration (SAMHSA). These data are discussed in detail under 
Factor 4, ``Its History and Current Pattern of Abuse;'' Factor 5, 
``The Scope, Duration, and Significance of Abuse;'' and Factor 6, 
``What, if any, Risk There is to the Public Health?''
    According to SAMHSA's 2004 National Survey on Drug Use and 
Health (NSDUH; the database formerly known as the National Household 
Survey on Drug Abuse (NHSDA)), the latest year for which complete 
data are available, 14.6 million Americans have used marijuana in 
the past month. This is an increase of 3.4 million individuals since 
1999, when 11.2 million individuals reported using marijuana 
monthly. (See the discussion of NSDUH data under Factor 4).
    The Drug Abuse Warning Network (DAWN), sponsored by SAMHSA, is a 
national probability survey of U.S. hospitals with emergency 
departments (EDs) designed to obtain information on ED visits in 
which recent drug use is implicated; 2003 is the latest year for 
which complete data are available. Marijuana was involved in 79,663 
ED visits (13 percent of drug-related visits). There are a number of 
risks resulting from both acute and chronic use of marijuana which 
are discussed in full below under Factors 2 and 6.
    b. There is significant diversion of the substance from 
legitimate drug channels.
    At present, cannabis is legally available through legitimate 
channels for research purposes only and thus has a limited potential 
for diversion. In addition, the lack of significant diversion of 
investigational supplies may result from the ready availability of 
illicit cannabis of equal or greater quality. The magnitude of the 
demand for illicit marijuana is evidenced by DEA/Office of National 
Drug Control Policy (ONDCP) seizure statistics. Data on marijuana 
seizures can often highlight trends in the overall trafficking 
patterns. DEA's Federal-Wide Drug Seizure System (FDSS) provides 
information on total federal drug seizures. FDSS reports total 
federal seizures of 2,700,282 pounds of marijuana in 2003, the 
latest year for which complete data are available (DEA, 2003). This 
represents nearly a doubling of marijuana seizures since 1995, when 
1,381,107 pounds of marijuana were seized by federal agents.
    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.

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    The 2004 NSDUH data show that 14.6 million American adults use 
marijuana on a monthly basis (SAMHSA, 2004), confirming that 
marijuana has reinforcing properties for many individuals. The FDA 
has not evaluated or approved a new drug application (NDA) for 
marijuana for any therapeutic indication, although several 
investigational new drug (IND) applications are currently active. 
Based on the large number of individuals who use marijuana, it can 
be concluded that the majority of individuals using cannabis do so 
on their own initiative, not on the basis of medical advice from a 
practitioner licensed to administer the drug in the course of 
professional practice.
    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.
    The primary psychoactive compound in botanical marijuana is 
delta\9\-THC. Other cannabinoids also present in the marijuana plant 
likely contribute to the psychoactive effects.
    There are two drug products containing cannabinoid compounds 
that are structurally related to the active components in marijuana. 
Both are controlled under the CSA. Marinol is a Schedule III drug 
product containing synthetic delta\9\-THC, known generically as 
dronabinol, formulated in sesame oil in soft gelatin capsules. 
Dronabinol is listed in Schedule I. Marinol was approved by the FDA 
in 1985 for the treatment of two medical conditions: nausea and 
vomiting associated with cancer chemotherapy in patients that had 
failed to respond adequately to conventional anti-emetic treatments, 
and for the treatment of anorexia associated with weight loss in 
patients with acquired immunodeficiency syndrome or AIDS. Cesamet is 
a drug product containing the Schedule II substance, nabilone, that 
was approved for marketing by the FDA in 1985 for the treatment of 
nausea and vomiting associated with cancer chemotherapy. All other 
structurally related cannabinoids in marijuana are already listed as 
Schedule I drugs under the CSA.

2. SCIENTIFIC EVIDENCE OF ITS PHARMACOLOGICAL EFFECTS, IF KNOWN

    The second factor the Secretary must consider is scientific 
evidence of marijuana's pharmacological effects. There are abundant 
scientific data 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

    Some 483 natural constituents have been identified in marijuana, 
including approximately 66 compounds that are classified as 
cannabinoids (Ross and El Sohly, 1995). Cannabinoids are not known 
to exist in plants other than marijuana, and most of the cannabinoid 
compounds that occur naturally have been identified chemically. 
Delta\9\-THC is considered the major psychoactive cannabinoid 
constituent of marijuana (Wachtel et al., 2002). The structure and 
function of delta\9\-THC was first described in 1964 by Gaoni and 
Mechoulam.
    The site of action of delta\9\-THC and other cannabinoids was 
verified with the cloning of cannabinoid receptors, first from rat 
brain tissue (Matsuda et al., 1990) and then from human brain tissue 
(Gerard et al., 1991). Two cannabinoid receptors, CB1 and 
CB2, have subsequently been characterized (Piomelli, 
2005).
    Autoradiographic studies have provided information on the 
distribution of cannabinoid receptors. CB1 receptors are 
found in the basal ganglia, hippocampus, and cerebellum of the brain 
(Howlett et al., 2004) as well as in the immune system. It is 
believed that the localization of these receptors may explain 
cannabinoid interference with movement coordination and effects on 
memory and cognition. The concentration of CB1 receptors 
is considerably lower in peripheral tissues than in the central 
nervous system (Henkerham et al., 1990 and 1992).
    CB2 receptors are found primarily in the immune 
system, predominantly in B lymphocytes and natural killer cells 
(Bouaboula et al., 1993). It is believed that the CB2-
type receptor is responsible for mediating the immunological effects 
of cannabinoids (Galiegue et al., 1995).
    However, CB2 receptors also have recently been 
localized in the brain, primarily in the cerebellum and hippocampus 
(Gong et al., 2006).
    The cannabinoid receptors belong to the family of G-protein-
coupled receptors and present a typical seven transmembrane-spanning 
domain structure. Many G-protein-coupled receptors are linked to 
adenylate cyclase either positively or negatively, depending on the 
receptor system. Cannabinoid receptors are linked to an inhibitory 
G-protein (Gi), so that when the receptor is activated, adenylate 
cyclase activity is inhibited, which prevents the conversion of 
adenosine triphosphate (ATP)to the second messenger cyclic adenosine 
monophosphate (cAMP). Examples of inhibitory-coupled receptors 
include: opioid, muscarinic cholinergic, alpha 2-
adrenoreceptors, dopamine (D2), and serotonin (5-
HT1).
    It has been shown that CB1, but not CB2 
receptors, inhibit N- and P/Q type calcium channels and activate 
inwardly rectifying potassium channels (Mackie et al., 1995; 
Twitchell et al., 1997). Inhibition of the N-type calcium channels 
decreases neurotransmitter release from several tissues and this may 
be the mechanism by which cannabinoids inhibit acetylcholine, 
norepinephrine, and glutamate release from specific areas of the 
brain. These effects might represent a potential cellular mechanism 
underlying the antinociceptive and psychoactive effects of 
cannabinoids (Ameri, 1999). When cannabinoids are given subacutely 
to rats, there is a down-regulation of CB1 receptors, as 
well as a decrease in GTPgammaS binding, the second messenger system 
coupled to CB1 receptors (Breivogel et al., 2001).
    Delta\9\-THC displays similar affinity for CB1 and 
CB2 receptors but behaves as a weak agonist for 
CB2 receptors, based on inhibition of adenylate cyclase. 
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 
psychotropic effects of cannabinoids are mediated through the 
activation of CB1-receptors (Hanus et al., 1999). 
Naturally-occurring cannabinoid agonists, such as delta\9\-THC, and 
the synthetic cannabinoid agonists such as WIN-55,212-2 and CP-
55,940 produce hypothermia, analgesia, hypoactivity, and cataplexy 
in addition to their psychoactive effects.
    In 2000, two endogenous cannabinoid receptor agonists, 
anandamide and arachidonyl glycerol (2-AG), were discovered. 
Anandamide is a low efficacy agonist (Breivogel and Childers, 2000), 
2-AG is a highly efficacious agonist (Gonsiorek et al., 2000). 
Cannabinoid endogenous ligands are present in central as well as 
peripheral tissues. The action of the endogenous ligands is 
terminated by a combination of uptake and hydrolysis. The 
physiological role of endogenous cannabinoids is an active area of 
research (Martin et al., 1999).
    Progress in cannabinoid pharmacology, including further 
characterization of the cannabinoid receptors, isolation of 
endogenous cannabinoid ligands, synthesis of agonists and 
antagonists with variable affinity, and selectivity for cannabinoid 
receptors, provide the foundation for the potential elucidation of 
cannabinoid-mediated effects and their relationship to psychomotor 
disorders, memory, cognitive functions, analgesia, anti-emesis, 
intraocular and systemic blood pressure modulation, bronchodilation, 
and inflammation.

Central Nervous System Effects

Human Physiological and Psychological Effects

Subjective Effects

    The physiological, psychological, and behavioral effects of 
marijuana vary among individuals. Common responses to cannabinoids, 
as described by Adams and Martin (1996) and others (Hollister, 1986 
and 1988; Institute of Medicine, 1982) are listed below:
    1) Dizziness, nausea, tachycardia, facial flushing, dry mouth, 
and tremor initially
    2) Merriment, happiness, and even exhilaration at high doses
    3) Disinhibition, relaxation, increased sociability, and 
talkativeness
    4) Enhanced sensory perception, giving rise to increased 
appreciation of music, art, and touch

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    5) Heightened imagination leading to a subjective sense of 
increased creativity
    6) Time distortions
    7) Illusions, delusions, and hallucinations, especially at high 
doses
    8) Impaired judgment, reduced co-ordination and ataxia, which 
can impede driving ability or lead to an increase in risk-taking 
behavior
    9) Emotional lability, incongruity of affect, dysphoria, 
disorganized thinking, inability to converse logically, agitation, 
paranoia, confusion, restlessness, anxiety, drowsiness, and panic 
attacks, especially in inexperienced users or in those who have 
taken a large dose
    10) Increased appetite and short-term memory impairment
    These subjective responses to marijuana are pleasurable to many 
humans and are associated with drug-seeking and drug-taking 
(Maldonado, 2002).
    The short-term perceptual distortions and psychological 
alterations produced by marijuana have been characterized by some 
researchers as acute or transient psychosis (Favrat et al., 2005). 
However, the full response to cannabinoids is dissimilar to the DSM-
IV-TR criteria for a diagnosis of one of the psychotic disorders 
(DSM-IV-TR, 2000).
    As with many psychoactive drugs, an individual's response to 
marijuana can be influenced by that person's medical/psychiatric 
history and history with drugs. Frequent marijuana users (greater 
than 100 times) were better able to identify a drug effect from low 
dose delta\9\-THC than infrequent users (less than 10 times) and 
were less likely to experience sedative effects from the drug (Kirk 
and deWit, 1999). Dose preferences have been demonstrated for 
marijuana in which higher doses (1.95 percent delta\9\-THC) are 
preferred over lower doses (0.63 percent delta\9\-THC) (Chait and 
Burke, 1994).

Behavioral Impairment

    Acute administration of smoked marijuana impairs performance on 
tests of learning, associative processes, and psychomotor behavior 
(Block et al., 1992). These data demonstrate that the short-term 
effects of marijuana can interfere significantly with an 
individual's ability to learn in the classroom or to operate motor 
vehicles. Administration to human volunteers of 290 micrograms per 
kilogram ([mu]g/kg) delta\9\-THC in a smoked marijuana cigarette 
resulted in impaired perceptual motor speed and accuracy, two skills 
that are critical to driving ability (Kurzthaler et al., 1999). 
Similarly, administration of 3.95 percent delta\9\-THC in a smoked 
marijuana cigarette increased disequilibrium measures, as well as 
the latency in a task of simulated vehicle braking, at a rate 
comparable to an increase in stopping distance of 5 feet at 60 mph 
(Liguori et al., 1998).
    The effects of marijuana may not fully resolve until at least 1 
day after the acute psychoactive effects have subsided, following 
repeated administration. 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 minimal residual alterations in subjective 
or performance measures the day after subjects were exposed to 1.8 
percent or 3.6 percent smoked delta\9\-THC.
    The effects of chronic marijuana use have also been 
investigated. Marijuana did not appear to have residual 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). This conclusion is similar to the results from 
an earlier study of marijuana's effects on cognition in 1,318 
participants over a 15-year period, where there was no evidence of 
long-term residual effects (Lyketsos et al., 1999). In contrast, 
Solowij et al. (2002) demonstrated that 51 long-term cannabis users 
did less well than 33 non-using controls or 51 short-term users on 
certain tasks of memory and attention, but users in this study were 
abstinent for only 17 hours at time of testing. A recent study noted 
that heavy, frequent cannabis users, abstinent for at least 24 
hours, performed significantly worse than controls on verbal memory 
and psychomotor speed tests (Messinis et al, 2006).
    Pope et al. (2003) reported that no differences were seen in 
neuropsychological performance in early- or late-onset users 
compared to non-using controls, after adjustment for intelligence 
quotient (IQ). In another cohort of chronic, heavy marijuana users, 
some deficits were observed on memory tests up to a week following 
supervised abstinence, but these effects disappeared by day 28 of 
abstinence (Harrison et al., 2002). The authors concluded that, 
``cannabis-associated cognitive deficits are reversible and related 
to recent cannabis exposure, rather than irreversible and related to 
cumulative lifetime use.'' Other investigators have reported 
neuropsychological deficits in memory, executive functioning, 
psychomotor speed, and manual dexterity in heavy marijuana smokers 
who had been abstinent for 28 days (Bolla et al., 2002). A follow up 
study of heavy marijuana users noted decision-making deficits after 
25 days of abstinence (Bolla et al., 2005). Finally, when IQ was 
contrasted in adolescents at 9-12 years and at 17-20 years, current 
heavy marijuana users showed a 4-point reduction in IQ in later 
adolescence compared to those who did not use marijuana (Fried et 
al., 2002).
    Age of first use may be a critical factor in persistent 
impairment resulting from chronic marijuana use. Individuals with a 
history of marijuana-only use that began before the age of 16 were 
found to perform more poorly on a visual scanning task measuring 
attention than individuals who started using marijuana after age 16 
(Ehrenreich et al., 1999). Kandel and Chen (2000) assert that the 
majority of early-onset marijuana users do not go on to become heavy 
users of marijuana, and those that do tend to associate with 
delinquent social groups.
    Heavy marijuana users were contrasted with an age matched 
control group in a case-control design. The heavy users reported 
lower educational achievement and lower income than controls, a 
difference that persisted after confounding variables were taken 
into account. Additionally, the users also reported negative effects 
of marijuana use on cognition, memory, career, social life, and 
physical and mental health (Gruber et al., 2003).

Association with Psychosis

    Extensive research has been conducted recently to investigate 
whether exposure to marijuana is associated with schizophrenia or 
other psychoses. While many studies are small and inferential, other 
studies in the literature utilize hundreds to thousands of subjects.
    At present, the data do not suggest a causative link between 
marijuana use and the development of psychosis. Although some 
individuals who use marijuana have received a diagnosis of 
psychosis, most reports conclude that prodromal symptoms of 
schizophrenia appear prior to marijuana use (Schiffman et al., 
2005). When psychiatric symptoms are assessed in individuals with 
chronic psychosis, the ``schizophrenic cluster'' of symptoms is 
significantly observed among individuals who do not have a history 
of marijuana use, while ``mood cluster'' symptoms are significantly 
observed in individuals who do have a history of marijuana use 
(Maremmani et al., 2004).
    In the largest study evaluating the link between psychosis and 
drug use, 3 percent of 50,000 Swedish conscripts who used marijuana 
more than 50 times went on to develop schizophrenia (Andreasson et 
al., 1987). This was interpreted by the authors to suggest that 
marijuana use increased the risk for the disorder only among those 
individuals who were predisposed to develop psychosis. A similar 
conclusion was drawn when the prevalence of schizophrenia was 
modeled against marijuana use across birth cohorts in Australia 
between the years 1940 to 1979 (Degenhardt et al., 2003). Although 
marijuana use increased over time in adults born during the 4-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 induce schizophrenia in the majority of 
individuals who try or continue to use the drug.
    However, as might be expected, the acute intoxication produced 
by marijuana does exacerbate the perceptual and cognitive deficits 
of psychosis in individuals who have been previously diagnosed with 
the condition (Schiffman et al., 2005; Hall et al., 2004; Mathers 
and Ghodse, 1992; Thornicroft, 1990). This is consistent with a 25-
year longitudinal study of over 1,000 individuals who had a higher 
rate of experiencing some symptoms of psychosis (but who did not 
receive a diagnosis of psychosis) if they were daily marijuana users 
than if they were not (Fergusson et al., 2005). A shorter, 3-year 
longitudinal study with over 4,000 subjects similarly showed that 
psychotic symptoms, but not diagnoses, were more prevalent in 
subjects who used marijuana (van Os et al., 2002).

[[Page 40556]]

    Additionally, schizophrenic individuals stabilized with 
antipsychotics do not respond differently to marijuana than healthy 
controls (D'Souza et al., 2005), suggesting that psychosis and/or 
antipsychotics do not biochemically alter cannabinoid systems in the 
brain.
    Interestingly, cannabis use prior to a first psychotic episode 
appeared to spare neurocognitive deficits compared to patients who 
had not used marijuana (Stirling et al., 2005). Although adolescents 
diagnosed with a first psychotic episode used more marijuana than 
adults who had their first psychotic break, adolescents and adults 
had similar clinical outcomes 2 years later (Pencer et al., 2005).
    Heavy marijuana users, though, do not perform differently than 
non-users on the Stroop task, a classic psychometric instrument that 
measures executive cognitive functioning. Since psychotic 
individuals do not perform the Stroop task well, alterations in 
executive functioning consistent with a psychotic profile were not 
apparent following chronic exposure to marijuana (Gruber and 
Yurgelun-Todd, 2005; Eldreth et al., 2004).

Alteration in Brain Structure

    Although evidence suggests that some drugs of abuse can lead to 
changes in the density or structure of the brain in humans, there 
are currently no data showing that exposure to marijuana can induce 
such alterations. A recent comparison of long-term marijuana smokers 
to non-smoking control subjects using magnetic resonance imaging 
(MRI) did not reveal any differences in the volume of grey or white 
matter, in the hippocampus, or in cerebrospinal fluid volume, 
between the two groups (Tzilos et al., 2005).

Behavioral Effects of Prenatal Exposure

    The impact of in utero marijuana exposure on performance in a 
series of cognitive tasks has been studied in children at different 
stages of development. However, since many marijuana users have 
abused other drugs, it is difficult to determine the specific impact 
of marijuana on prenatal exposure.
    Differences in several cognitive domains distinguished the 4-
year-old children of heavy marijuana users. In particular, memory 
and verbal measures are negatively associated with maternal 
marijuana use (Fried and Watkinson, 1987). Maternal marijuana use is 
predictive of poorer performance on abstract/visual reasoning tasks, 
although it is not associated with an overall lowered IQ in 3-year 
old children (Griffith et al., 1994). At 6 years of age, prenatal 
marijuana history is associated with an increase in omission errors 
on a vigilance task, possibly reflecting a deficit in sustained 
attention (Fried et al., 1992). When the effect of prenatal exposure 
in 9-12 year old children is analyzed, in utero marijuana exposure 
is negatively associated with executive function tasks that require 
impulse control, visual analysis, and hypothesis testing, and it is 
not associated with global intelligence (Fried et al., 1998).

Marijuana as a ``Gateway Drug''

    The Institute of Medicine (IOM) reported that the widely held 
belief that marijuana is a ``gateway drug,'' leading to subsequent 
abuse of other illicit drugs, lacks conclusive evidence (Institute 
of Medicine, 1999). Recently, Fergusson et al. (2005) in a 25-year 
study of 1,256 New Zealand children concluded that use of marijuana 
correlates to an increased risk of abuse of other drugs, including 
cocaine and heroin. Other sources, however, do not support a direct 
causal relationship between regular marijuana and other illicit drug 
use. In general, such studies are selective in recruiting 
individuals who, in addition to having extensive histories of 
marijuana use, are influenced by myriad social, biological, and 
economic factors that contribute to extensive drug abuse (Hall and 
Lynskey, 2005). For most studies that test the hypothesis that 
marijuana causes abuse of harder drugs, the determinative measure of 
choice is any drug use, rather than DSM-IV-TR criteria for drug 
abuse or dependence (DSM-IV-TR, 2000).
    According to Golub & Johnson (2001), the rate of progression to 
hard drug use by youth born in the 1970's, as opposed to youth born 
between World War II and the 1960's, is significantly decreased, 
although overall marijuana use among youth appears to be increasing. 
Nace et al. (1975) reported that even in the Vietnam-era soldiers 
who extensively abused marijuana and heroin, there was a lack of 
correlation of a causal relationship demonstrating marijuana use 
leading to heroin addiction. A recent longitudinal study of 708 
adolescents demonstrated that early onset marijuana use did not lead 
to problematic drug use (Kandel and Chen, 2000). Similarly, among 
2,446 adolescents followed longitudinally, cannabis dependence was 
uncommon but when it did occur, it was predicted primarily by 
parental death, deprived socio-economic status, and baseline use of 
illicit drugs other than marijuana (von Sydow et al., 2002).

Animal behavioral effects

Self-Administration

    Self-administration is a method that assesses whether a drug 
produces rewarding effects that increase the likelihood of 
behavioral responses in order to obtain additional drug. Drugs that 
are self-administered by animals are likely to produce rewarding 
effects in humans, which is indicative of abuse liability. 
Generally, a good correlation exists between those drugs that are 
self-administered by rhesus monkeys and those that are abused by 
humans (Balster and Bigelow, 2003).
    Interestingly, self-administration of hallucinogenic-like drugs, 
such as cannabinoids, lysergic acid diethylamide (LSD), and 
mescaline, has been difficult to demonstrate in animals (Yanagita, 
1980). However, when it is known that humans voluntarily consume a 
particular drug (such as cannabis) for its pleasurable effects, the 
inability to establish self-administration with that drug in animals 
has no practical importance in the assessment of abuse potential. 
This is because the animal test is a predictor of human behavioral 
response in the absence of naturalistic data.
    The experimental literature generally reports that na[iuml]ve 
animals will not self-administer cannabinoids unless they have had 
previous experience with other drugs of abuse. However, when 
squirrel monkeys are first trained to self-administer intravenous 
cocaine, they will continue to bar-press at the same rate as when 
delta\9\-THC is substituted for cocaine, at doses that are 
comparable to those used by humans who smoke marijuana (Tanda et 
al., 2000). This effect is blocked by the cannabinoid receptor 
antagonist, SR 141716. New studies show that monkeys without a 
history of any drug exposure can be successfully trained to self-
administer delta\9\-THC intravenously (Justinova et al., 2003). The 
maximal rate of responding is 4 [mu]g/kg/injection, which is 2-3 
times greater than that observed in previous studies using cocaine-
experienced monkeys.
    These data demonstrate that under specific pretreatment 
conditions, an animal model of reinforcement by cannabinoids now 
exists for future investigations. Rats will self-administer 
delta\9\-THC when it is applied intracerebroventricularly (i.c.v.), 
but only at the lowest doses tested (0.01-0.02 [mu]g/infusion) 
(Braida et al., 2004). This effect is antagonized by the cannabinoid 
antagonist SR141716 and by the opioid antagonist naloxone (Braida et 
al., 2004). Additionally, mice will self-administer WIN 55212, a 
CB1 receptor agonist with a non-cannabinoid structure 
(Martellotta et al., 1998).
    There may be a critical dose-dependent effect, though, since 
aversive effects, rather than reinforcing effects, have been 
described in rats that received high doses of WIN 55212 (Chaperon et 
al., 1998) or delta\9\-THC (Sanudo-Pena et al., 1997). SR 141716 
reversed these aversive effects in both studies.

Conditioned Place Preference

    Conditioned place preference (CPP) is a less rigorous method 
than self-administration of determining whether drugs have rewarding 
properties. In this behavioral test, 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 will choose to spend 
more time in the environment paired with the drug than the one 
paired with the placebo, when both options are presented 
simultaneously.
    Animals show CPP to delta\9\-THC, but only at the lowest doses 
tested (0.075-0.75 mg/kg, i.p.) (Braida et al., 2004). This effect 
is antagonized by the cannabinoid antagonist, SR141716, as well as 
by the opioid antagonist, naloxone (Braida et al., 2004). However, 
SR141716 may be a partial agonist, rather than a full antagonist, 
since it is also able to induce CPP (Cheer et al., 2000). 
Interestingly, in knockout mice, animals without [mu]-opioid 
receptors do not develop CPP to delta\9\-THC (Ghozland et al., 
2002).

Drug Discrimination Studies

    Drug discrimination is a method in which 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. A challenge session with the 
test drug determines which of the two

[[Page 40557]]

bars the animal presses more often, as an indicator of whether the 
test drug is like the known drug of abuse.
    Animals, including monkeys and rats (Gold et al., 1992), as well 
as humans (Chait, 1988), can discriminate cannabinoids from other 
drugs or placebo. Discriminative stimulus effects of delta\9\-THC 
are pharmacologically specific for marijuana-containing cannabinoids 
(Balster and Prescott, 1992; Barnett et al., 1985; Browne and 
Weissman, 1981; Wiley et al., 1993; Wiley et al., 1995). 
Additionally, the major active metabolite of delta\9\-THC, 11-
hydroxy-delta\9\-THC, also generalizes to the stimulus cue elicited 
by delta\9\-THC (Browne and Weissman, 1981). Twenty-two other 
cannabinoids found in marijuana also fully substitute for delta\9\-
THC.
    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.

Tolerance and Physical Dependence

    Tolerance is a state of adaptation in which 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). 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).
    The presence of tolerance or physical dependence does not 
determine whether a drug has abuse potential, in the absence of 
other abuse indicators such as rewarding properties. Many 
medications that are not associated with abuse or addiction, such as 
antidepressants, beta-blockers, and centrally acting 
antihypertensive drugs, can produce physical dependence and 
withdrawal symptoms after chronic use.
    Tolerance to the subjective and performance effects of marijuana 
has not been demonstrated in studies with humans. For example, 
reaction times are not altered by acute administration of marijuana 
in long term marijuana users (Block and Wittenborn, 1985). This may 
be related to recent electrophysiological data showing that the 
ability of delta\9\-THC to increase neuronal firing in the ventral 
tegmental area (a region known to play a critical role in drug 
reinforcement and reward) is not reduced following chronic 
administration of the drug (Wu and French, 2000). On the other hand, 
tolerance can develop in humans to marijuana-induced cardiovascular 
and autonomic changes, decreased intraocular pressure, and sleep 
alterations (Jones et al., 1981). Down-regulation of cannabinoid 
receptors has been suggested as the mechanism underlying tolerance 
to the effects of marijuana (Rodriguez de Fonseca et al., 1994; 
Oviedo et al., 1993).
    Acute administration of marijuana containing 2.1 percent 
delta\9\-THC does not produce ``hangover effects'' (Chait et al., 
1985). In chronic marijuana users, though, a marijuana withdrawal 
syndrome has been described that consists of restlessness, 
irritability, mild agitation, insomnia, sleep EEG disturbances, 
nausea, and cramping that resolves within a few days (Haney et al., 
1999). However, the American Psychiatric Association's Diagnostic 
and Statistical Manual (DSM-IV-TR, 2000) does not include a listing 
for cannabis withdrawal syndrome because, ``symptoms of cannabis 
withdrawal . . . have been described . . . but their clinical 
significance is uncertain.'' A review of all current clinical 
studies on cannabis withdrawal led to the recommendation by Budney 
et al. (2004) that the DSM introduce a listing for cannabis 
withdrawal that includes such symptoms as sleep difficulties, 
strange dreams, decreased appetite, decreased weight, anger, 
irritability, and anxiety. 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. A recent study 
comparing marijuana and tobacco withdrawal symptoms in humans 
demonstrated that the magnitude and timecourse of the two withdrawal 
syndromes are similar (Vandrey et al., 2005).
    The production of an overt withdrawal syndrome in animals 
following chronic delta\9\-THC administration has been variably 
demonstrated under conditions of natural discontinuation. This may 
be the result of the slow release of cannabinoids from adipose 
storage, as well as the presence of the major psychoactive 
metabolite, 11-hydroxy-delta\9\-THC. When investigators have shown 
such a withdrawal syndrome in monkeys following the termination of 
cannabinoid administration, the behaviors included transient 
aggression, anorexia, biting, irritability, scratching, and yawning 
(Budney et al., 2004). However, in rodents treated with a 
cannabinoid antagonist following subacute administration of 
delta\9\-THC, pronounced withdrawal symptoms, including wet dog 
shakes, can be provoked (Breivogel et al., 2003).

Behavioral Sensitization

    Sensitization to the effects of drugs is the opposite of 
tolerance: instead of a reduction in behavioral response upon 
repeated drug administration, animals that are sensitized 
demonstrate an increase in behavioral response. Cadoni et al. (2001) 
demonstrated that repeated exposure to delta\9\-THC can induce 
sensitization to a variety of cannabinoids. These same animals also 
have a sensitized response to administration of opioids, an effect 
known as cross-sensitization. Conversely, when animals were 
sensitized to the effects of morphine, there was cross-sensitization 
to cannabinoids. Thus, the cannabinoid and opioids systems appear to 
operate symmetrically in terms of cross-sensitization.

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). However, prolonged delta\9\-THC ingestion produces 
significant heart rate slowing and blood pressure lowering (Benowitz 
and Jones, 1975). Both plant-derived cannabinoids and 
endocannabinoids have been shown to elicit hypotension and 
bradycardia via activation of peripherally-located CB1 
receptors (Wagner et al., 1998). This study suggests that 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.
    The impaired circulatory responses following delta\9\-THC 
administration to standing, exercise, Valsalva maneuver, and cold 
pressor testing suggest that cannabinoids induce a state of 
sympathetic insufficiency. In humans, tolerance can develop to the 
orthostatic hypotension (Jones, 2002; Sidney, 2002), possibly 
related to plasma volume expansion, but does not develop to the 
supine hypotensive effects (Benowitz and Jones, 1975). During 
chronic marijuana ingestion, nearly complete tolerance develops to 
tachycardia and psychological effects when subjects are challenged 
with smoked marijuana. Electrocardiographic changes are minimal even 
after large cumulative doses of delta\9\-THC. (Benowitz and Jones, 
1975).
    It is notable that marijuana smoking by older patients, 
particularly those with some degree of coronary artery or 
cerebrovascular disease, poses risks related to increased cardiac 
work, increased catecholamines, carboxyhemoglobin, and postural 
hypotension (Benowitz and Jones, 1981; Hollister, 1988).

Respiratory Effects

    Transient bronchodilation is the most typical effect following 
acute exposure to marijuana (Gong et al., 1984). Long-term use of 
marijuana can lead to an increased frequency of chronic bronchitis 
and pharyngitis, as well as chronic cough and increased sputum. 
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).
    The evidence that marijuana may lead to cancer associated with 
respiratory effects is inconsistent, with some studies suggesting a 
positive correlation while others do not (Tashkin, 2005). Several 
cases of lung cancer have been reported in young marijuana users 
with no history of tobacco smoking 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 the largest study to date with 1,650 subjects, no 
positive association was found between marijuana use and lung cancer 
(Tashkin et al., 2006). This finding held true regardless of extent 
of marijuana use, when tobacco use and other potential confounding 
factors were controlled.
    The lack of evidence for carcinogenicity related to cannabis may 
be related to the fact that intoxication from marijuana does not 
require large amounts of smoked material.

[[Page 40558]]

This may be especially pertinent since marijuana is reportedly more 
potent today than a generation ago. Thus, individuals may consume 
much less marijuana than in previous decades to reach the desired 
subjective effects, exposing them to less potential carcinogens.

Endocrine System

    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). Acute delta\9\-THC 
releases corticosterone, but tolerance develops to this effect with 
chronic administration (Eldridge et al., 1991).
    Experimental administration of marijuana to humans does not 
consistently alter 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 were observed (Cone et al., 1986). However, two 
later studies showed no changes in hormones. Male subjects who were 
experimentally exposed to smoked delta\9\-THC (18 mg/marijuana 
cigarette) or oral delta\9\-THC (10 mg t.i.d. for 3 days and on the 
morning of the fourth day) showed no changes in plasma prolactin, 
ACTH, cortisol, 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).
    Relatively little research has been performed on the effects of 
experimentally administered marijuana on female reproductive system 
functioning. In monkeys, delta\9\-THC administration suppressed 
ovulation (Asch et al., 1981) and reduced progesterone levels 
(Almirez et al., 1983). However, when women were studied following 
experimental exposure to smoked marijuana, no hormonal or menstrual 
cycle changes were observed (Mendelson and Mello, 1984). Brown and 
Dobs (2002) suggest that the discrepancy between animal and human 
hormonal response to cannabinoids may be attributed to the 
development of tolerance in humans.
    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 cell growth, as well as decreases in expression of androgen 
receptors and prostate-specific antigens (Sarfaraz et al., 2005).

Immune System

    Immune functions are altered by cannabinoids, but there can be 
differences between the effects of synthetic, natural, and 
endogenous cannabinoids, often in an apparently biphasic manner 
depending on dose (Croxford and Yamamura, 2005).
    Abrams et al. (2003) investigated the effect of marijuana on 
immunological functioning in 62 AIDS patients who were taking 
protease inhibitors. Subjects received one of the following three 
times a day: smoked marijuana cigarette containing 3.95 percent 
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 or HIV RNA levels or protease inhibitor levels between 
groups, demonstrating no short-term adverse virologic effects from 
using cannabinoids in individuals with compromised immune systems.
    These human data contrast with data generated in immunodeficient 
mice showing 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

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

Chemistry

    According to the DEA, Cannabis sativa is the primary species of 
cannabis currently marketed illegally in the United States of 
America. From this plant, three derivatives are sold as separate 
illicit drug products: marijuana, hashish, and hashish oil.
    Each of these derivatives contains a complex mixture of 
chemicals. Among the components are the 21 carbon terpenes found in 
the plant as well as their carboxylic acids, analogues, and 
transformation products known as cannabinoids (Agurell et al., 1984 
and 1986; Mechoulam, 1973). The cannabinoids appear to naturally 
occur only in the marijuana plant and most of the botanically-
derived cannabinoids have been identified. Among the cannabinoids, 
delta\9\-THC (alternate name delta\1\-THC) and delta-8-
tetrahydrocannabinol (delta\8\-THC, alternate name delta\6\-THC) are 
both found in marijuana and are able to produce the characteristic 
psychoactive effects of marijuana. Because delta\9\-THC is more 
abundant than delta\8\-THC, the activity of marijuana is largely 
attributed to the former. Delta\8\-THC is found only in few 
varieties of the plant (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-1-ol or (-)-delta\9\-(trans)-
tetrahydrocannabinol. The (-)-trans isomer of delta\9\-THC is 
pharmacologically 6 to 100 times more potent than the (+)-trans 
isomer (Dewey et al., 1984).
    Other cannabinoids, such as cannabidiol (CBD) and cannabinol 
(CBN), have been characterized. CBD is not considered to have 
cannabinol-like psychoactivity, but is thought to have significant 
anticonvulsant, sedative, and anxiolytic activity (Adams and Martin, 
1996; Agurell et al., 1984 and 1986; Hollister, 1986).
    Marijuana is a mixture of the dried flowering tops and leaves 
from the plant and is variable in content and potency (Agurell et 
al., 1984 and 1986; Graham, 1976; Mechoulam, 1973). Marijuana is 
usually smoked in the form of rolled cigarettes while hashish and 
hash oil are smoked in pipes. Potency of marijuana, as indicated by 
cannabinoid content, has been reported to average from as low as 1 
to 2 percent to as high as 17 percent.
    The concentration of delta\9\-THC and other cannabinoids in 
marijuana varies with growing conditions and processing after 
harvest. Other variables that can influence the strength, quality, 
and purity of marijuana are genetic differences among the cannabis 
plant species and which parts of the plant are collected (flowers, 
leaves, stems, etc.) (Adams and Martin, 1996; Agurell et al., 1984; 
Mechoulam, 1973). In the usual mixture of leaves and stems 
distributed as marijuana, the concentration of delta\9\-THC ranges 
widely from 0.3 to 4.0 percent by weight. However, specially grown 
and selected marijuana can contain even 15 percent or greater 
delta\9\-THC. Thus, a 1 gm marijuana cigarette might contain as 
little as 3 mg or as much as 150 mg or more of delta\9\-THC.
    Hashish consists of the cannabinoid-rich resinous material of 
the cannabis plant, which is dried and compressed into a variety of 
forms (balls, cakes, etc.). Pieces are then broken off, placed into 
a pipe and smoked. DEA reports that cannabinoid content in hashish 
averages 6 percent.
    Hash oil is produced by solvent extraction of the cannabinoids 
from plant material. Color and odor of the extract vary, depending 
on the type of solvent used. Hash oil is a viscous brown or amber-
colored liquid that contains approximately 15 percent cannabinoids. 
One or two drops of the liquid placed on a cigarette purportedly 
produce the equivalent of a single marijuana cigarette (DEA, 2005).
    The lack of a consistent concentration of delta\9\-THC in 
botanical marijuana from diverse sources complicates the 
interpretation of clinical data using marijuana. If marijuana is to 
be investigated more widely for medical use, information and data 
regarding the chemistry, manufacturing, and specifications of 
marijuana must be developed.

Human Pharmacokinetics

    Marijuana is generally smoked as a cigarette (weighing between 
0.5 and 1.0 gm), or in a pipe. It can also be taken orally in foods 
or as extracts of plant material in ethanol or other solvents.
    The absorption, metabolism, and pharmacokinetic profile of 
delta\9\-THC (and other cannabinoids) in marijuana or other drug 
products containing delta\9\-THC vary with route of administration 
and formulation (Adams and Martin, 1996; Agurell et al., 1984 and 
1986). When marijuana is administered by smoking, delta\9\-THC in 
the form of an aerosol is absorbed within seconds. The psychoactive 
effects of marijuana occur immediately following absorption, with 
mental and behavioral effects measurable up to 6 hours 
(Grotenhermen, 2003; Hollister,

[[Page 40559]]

1986 and 1988). Delta\9\-THC is delivered to the brain rapidly and 
efficiently as would be 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 the following: 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. A individual's experience and technique 
with smoking marijuana is an important determinant of the dose that 
is absorbed (Herning et al., 1986; Johansson et al., 1989).
    After smoking, venous levels of delta\9\-THC decline 
precipitously within minutes, and within an hour are about 5 to 10 
percent of the peak level (Agurell et al., 1986; Huestis et al., 
1992a and 1992b). Plasma clearance of delta\9\-THC is approximately 
950 ml/min or greater, thus approximating hepatic blood flow. The 
rapid disappearance of delta\9\-THC from blood is largely due to 
redistribution to other tissues in the body, rather than to 
metabolism (Agurell et al., 1984 and 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 is estimated to range from approximately 20 hours to as