International Drug Scheduling; Convention on Psychotropic Substances; Single Convention on Narcotic Drugs; World Health Organization; Scheduling Recommendations; ADB-BUTINACA; Alpha-PiHP; 3-Methylmethcathinone; Request for Comments, 10344-10352 [2023-03375]
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10344
Federal Register / Vol. 88, No. 33 / Friday, February 17, 2023 / Notices
Dated: February 13, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023–03367 Filed 2–16–23; 8:45 am]
BILLING CODE 4164–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2022–P–2842]
Determination That Dihydroergotamine
Mesylate 45 Injection USP, 1 Milligram/
Milliliter, Was Not Withdrawn From
Sale for Reasons of Safety or
Effectiveness
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice.
The Food and Drug
Administration (FDA or Agency) has
determined that D.H.E. 45
(dihydroergotamine mesylate) injection
USP, 1 milligram (mg)/milliliter (mL),
was not withdrawn from sale for reasons
of safety or effectiveness. This
determination means that FDA will not
begin procedures to withdraw approval
of abbreviated new drug applications
(ANDAs) that refer to this drug product,
and it will allow FDA to continue to
approve ANDAs that refer to the
product as long as they meet relevant
legal and regulatory requirements.
FOR FURTHER INFORMATION CONTACT:
Donna Tran, Center for Drug Evaluation
and Research, Food and Drug
Administration, 10903 New Hampshire
Ave., Bldg. 51, Rm. 6213, Silver Spring,
MD 20993–0002, 301–796–3600,
Donna.Tran@fda.hhs.gov.
SUPPLEMENTARY INFORMATION: Section
505(j) of the Federal Food, Drug, and
Cosmetic Act (FD&C Act) (21 U.S.C.
355(j)) allows the submission of an
ANDA to market a generic version of a
previously approved drug product. To
obtain approval, the ANDA applicant
must show, among other things, that the
generic drug product: (1) has the same
active ingredient(s), dosage form, route
of administration, strength, conditions
of use, and (with certain exceptions)
labeling as the listed drug, which is a
version of the drug that was previously
approved, and (2) is bioequivalent to the
listed drug. ANDA applicants do not
have to repeat the extensive clinical
testing otherwise necessary to gain
approval of a new drug application
(NDA).
Section 505(j)(7) of the FD&C Act
requires FDA to publish a list of all
approved drugs. FDA publishes this list
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SUMMARY:
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as part of the ‘‘Approved Drug Products
With Therapeutic Equivalence
Evaluations,’’ which is known generally
as the ‘‘Orange Book.’’ Under FDA
regulations, drugs are removed from the
list if the Agency withdraws or
suspends approval of the drug’s NDA or
ANDA for reasons of safety or
effectiveness or if FDA determines that
the listed drug was withdrawn from sale
for reasons of safety or effectiveness (21
CFR 314.162).
A person may petition the Agency to
determine, or the Agency may
determine on its own initiative, whether
a listed drug was withdrawn from sale
for reasons of safety or effectiveness.
This determination may be made at any
time after the drug has been withdrawn
from sale, but must be made prior to
approving an ANDA that refers to the
listed drug (§ 314.161 (21 CFR 314.161)).
FDA may not approve an ANDA that
does not refer to a listed drug.
D.H.E. 45 (dihydroergotamine
mesylate) injection USP, 1 mg/mL, is
the subject of NDA 005929, held by
Bausch Health US, LLC, and initially
approved on April 12, 1946. D.H.E. 45
(dihydroergotamine mesylate) is
indicated for the acute treatment of
migraine headaches with or without
aura and the acute treatment of cluster
headache episodes.
In a letter dated June 13, 2022, Bausch
Health US, LLC notified FDA that
D.H.E. 45 (dihydroergotamine mesylate)
injection USP, 1 mg/mL, was being
discontinued, and FDA moved the drug
product to the ‘‘Discontinued Drug
Product List’’ section of the Orange
Book.
Baxter Healthcare Corporation
submitted a citizen petition dated
November 11, 2022 (Docket No. FDA–
2022–P–2842), under 21 CFR 10.30,
requesting that the Agency determine
whether D.H.E. 45 (dihydroergotamine
mesylate) injection USP, 1 mg/mL, was
withdrawn from sale for reasons of
safety or effectiveness.
After considering the citizen petition
and reviewing Agency records and
based on the information we have at this
time, FDA has determined under
§ 314.161 that D.H.E. 45
(dihydroergotamine mesylate) injection
USP, 1 mg/mL, was not withdrawn for
reasons of safety or effectiveness. The
petitioner has identified no data or other
information suggesting that D.H.E. 45
(dihydroergotamine mesylate) injection
USP, 1 mg/mL, was withdrawn for
reasons of safety or effectiveness. We
have carefully reviewed our files for
records concerning the withdrawal of
D.H.E. 45 (dihydroergotamine mesylate)
injection USP, 1 mg/mL, from sale. We
have also independently evaluated
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relevant literature and data for possible
postmarketing adverse events. We have
found no information that would
indicate that this drug product was
withdrawn from sale for reasons of
safety or effectiveness.
Accordingly, the Agency will
continue to list D.H.E. 45
(dihydroergotamine mesylate) injection
USP, 1 mg/mL, in the ‘‘Discontinued
Drug Product List’’ section of the Orange
Book. The ‘‘Discontinued Drug Product
List’’ delineates, among other items,
drug products that have been
discontinued from marketing for reasons
other than safety or effectiveness. FDA
will not begin procedures to withdraw
approval of approved ANDAs that refer
to this drug product. Additional ANDAs
for this drug product may also be
approved by the Agency as long as they
meet all other legal and regulatory
requirements for the approval of
ANDAs. If FDA determines that labeling
for this drug product should be revised
to meet current standards, the Agency
will advise ANDA applicants to submit
such labeling.
Dated: February 13, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023–03381 Filed 2–16–23; 8:45 am]
BILLING CODE 4164–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2023–N–0438]
International Drug Scheduling;
Convention on Psychotropic
Substances; Single Convention on
Narcotic Drugs; World Health
Organization; Scheduling
Recommendations; ADB-BUTINACA;
Alpha-PiHP; 3-Methylmethcathinone;
Request for Comments
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice.
The Food and Drug
Administration (FDA) is providing
interested persons with the opportunity
to submit written comments concerning
recommendations by the World Health
Organization (WHO) to impose
international manufacturing and
distributing restrictions, under
international treaties, on certain drug
substances. The comments received in
response to this notice will be
considered in preparing the United
States’ position on these proposals for a
meeting of the United Nations
SUMMARY:
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Federal Register / Vol. 88, No. 33 / Friday, February 17, 2023 / Notices
Commission on Narcotic Drugs (CND) in
Vienna, Austria, in March 2023. This
notice is issued under the Controlled
Substances Act (CSA).
DATES: Submit either electronic or
written comments by February 28, 2023.
ADDRESSES: You may submit comments
as follows. Please note that late,
untimely filed comments will not be
considered. The https://
www.regulations.gov electronic filing
system will accept comments until
11:59 p.m. Eastern Time at the end of
February 28, 2023. Comments received
by mail/hand delivery/courier (for
written/paper submissions) will be
considered timely if they are received
on or before that date.
Electronic Submissions
Submit electronic comments in the
following way:
• Federal eRulemaking Portal:
https://www.regulations.gov. Follow the
instructions for submitting comments.
Comments submitted electronically,
including attachments, to https://
www.regulations.gov will be posted to
the docket unchanged. Because your
comment will be made public, you are
solely responsible for ensuring that your
comment does not include any
confidential information that you or a
third party may not wish to be posted,
such as medical information, your or
anyone else’s Social Security number, or
confidential business information, such
as a manufacturing process. Please note
that if you include your name, contact
information, or other information that
identifies you in the body of your
comments, that information will be
posted on https://www.regulations.gov.
• If you want to submit a comment
with confidential information that you
do not wish to be made available to the
public, submit the comment as a
written/paper submission and in the
manner detailed (see ‘‘Written/Paper
Submissions’’ and ‘‘Instructions’’).
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Written/Paper Submissions
Submit written/paper submissions as
follows:
• Mail/Hand Delivery/Courier (for
written/paper submissions): Dockets
Management Staff (HFA–305), Food and
Drug Administration, 5630 Fishers
Lane, Rm. 1061, Rockville, MD 20852.
• For written/paper comments
submitted to the Dockets Management
Staff, FDA will post your comment, as
well as any attachments, except for
information submitted, marked and
identified, as confidential, if submitted
as detailed in ‘‘Instructions.’’
Instructions: All submissions received
must include the Docket No. FDA–
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2023–N–0438 for ‘‘International Drug
Scheduling; Convention on
Psychotropic Substances; Single
Convention on Narcotic Drugs; World
Health Organization; Scheduling
Recommendations; ADB-BUTINACA;
alpha-PiHP; 3-Methylmethcathinone;
Request for Comments.’’ Received
comments, those filed in a timely
manner (see ADDRESSES), will be placed
in the docket and, except for those
submitted as ‘‘Confidential
Submissions,’’ publicly viewable at
https://www.regulations.gov or at the
Dockets Management Staff between 9
a.m. and 4 p.m., Monday through
Friday, 240–402–7500.
• Confidential Submissions—To
submit a comment with confidential
information that you do not wish to be
made publicly available, submit your
comments only as a written/paper
submission. You should submit two
copies total. One copy will include the
information you claim to be confidential
with a heading or cover note that states
‘‘THIS DOCUMENT CONTAINS
CONFIDENTIAL INFORMATION.’’ The
Agency will review this copy, including
the claimed confidential information, in
its consideration of comments. The
second copy, which will have the
claimed confidential information
redacted/blacked out, will be available
for public viewing and posted on
https://www.regulations.gov. Submit
both copies to the Dockets Management
Staff. If you do not wish your name and
contact information to be made publicly
available, you can provide this
information on the cover sheet and not
in the body of your comments and you
must identify this information as
‘‘confidential.’’ Any information marked
as ‘‘confidential’’ will not be disclosed
except in accordance with 21 CFR 10.20
and other applicable disclosure law. For
more information about FDA’s posting
of comments to public dockets, see 80
FR 56469, September 18, 2015, or access
the information at: https://
www.govinfo.gov/content/pkg/FR-201509-18/pdf/2015-23389.pdf.
Docket: For access to the docket to
read background documents or the
electronic and written/paper comments
received, go to https://
www.regulations.gov and insert the
docket number, found in brackets in the
heading of this document, into the
‘‘Search’’ box and follow the prompts
and/or go to the Dockets Management
Staff, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852, 240–402–7500.
FOR FURTHER INFORMATION CONTACT:
Edward (Greg) Hawkins, Center for Drug
Evaluation and Research, Controlled
Substance Staff, Food and Drug
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10345
Administration, 10903 New Hampshire
Ave., Bldg. 51, Rm. 5150, Silver Spring,
MD 20993–0002, 202–713–8981,
Edward.Hawkins@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
I. Background
The United States is a party to the
1971 Convention on Psychotropic
Substances (1971 Convention). Section
201(d)(2)(B) of the CSA (21 U.S.C.
811(d)(2)(B)) provides that when the
United States is notified under Article 2
of the 1971 Convention that the CND
proposes to decide whether to add a
drug or other substance to one of the
schedules of the 1971 Convention,
transfer a drug or substance from one
schedule to another, or delete it from
the schedules, the Secretary of State
must transmit notice of such
information to the Secretary of Health
and Human Services (Secretary of HHS).
The Secretary of HHS must then publish
a summary of such information in the
Federal Register and provide
opportunity for interested persons to
submit comments. The Secretary of HHS
must then evaluate the proposal and
furnish a recommendation to the
Secretary of State that shall be binding
on the representative of the United
States in discussions and negotiations
relating to the proposal.
As detailed in the following
paragraphs, the Secretary of State has
received notification from the SecretaryGeneral of the United Nations (the
Secretary-General) regarding three
substances to be considered for control
under the 1971 Convention. This
notification reflects the
recommendation from the 45th WHO
Expert Committee for Drug Dependence
(ECDD), which met in October 2022. In
the Federal Register of August 3, 2022
(87 FR 47428), FDA announced the
WHO ECDD review and invited
interested persons to submit
information for WHO’s consideration.
The full text of the notification from
the Secretary-General is provided in
section II of this document. Section
201(d)(2)(B) of the CSA requires the
Secretary of HHS, after receiving a
notification proposing scheduling, to
publish a notice in the Federal Register
to provide the opportunity for interested
persons to submit information and
comments on the proposed scheduling
action.
The United States is also a party to
the 1961 Single Convention on Narcotic
Drugs (1961 Convention). The Secretary
of State has received a notification from
the Secretary-General regarding four
substances to be considered for control
under this convention. The CSA does
not require HHS to publish a summary
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Federal Register / Vol. 88, No. 33 / Friday, February 17, 2023 / Notices
of such information in the Federal
Register. Nevertheless, to provide
interested and affected persons an
opportunity to submit comments
regarding the WHO recommendations
for drugs under the 1961 Convention,
the notification regarding these
substances is also included in this
Federal Register notice. The comments
will be shared with other relevant
Agencies to assist the Secretary of State
in formulating the position of the
United States on the control of these
substances. The HHS recommendations
are not binding on the representative of
the United States in discussions and
negotiations relating to the proposal
regarding control of substances under
the 1961 Convention.
II. United Nations Notification
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The formal notification from the
United Nations that identifies the drug
substances and explains the basis for the
scheduling recommendations is
reproduced as follows (non-relevant text
removed):
Reference:
NAR/CL.6/2022
WHO/ECDD45; 1961C-Art.3, 1971C-Art.2
CU 2022/386/DTA/SGB
The Secretariat of the United Nations
presents its compliments to the Permanent
Mission of the United States of America to
the United Nations (Vienna) and has the
honour to inform the Mission that, in a letter
dated 24 November 2022, the DirectorGeneral of the World Health Organization
(WHO), pursuant to article 3, paragraphs 1
and 3 of the Single Convention on Narcotic
Drugs of 1961 as amended by the 1972
Protocol (1961 Convention), and article 2,
paragraphs 1 and 4 of the Convention on
Psychotropic Substances of 1971 (1971
Convention), notified the Secretary-General
of the following recommendations of the
Forty-fifth Meeting of the WHO’s Expert
Committee on Drug Dependence (ECDD):
Substances recommended to be added to
Schedule I of the 1961 Convention:
—2-Methyl-AP-237
IUPAC (International Union of Pure and
Applied Chemistry) name: 1-[2-Methyl-4(3-phenyl-2-propen-1-yl)-1-piperazinyl]-1butanone
—Etazene
IUPAC name: 2-[(4-Ethoxyphenyl)methyl]N,N-diethyl-1H-benzimidazole-1ethanamine
—Etonitazepyne
IUPAC name: 2-[(4-Ethoxyphenyl)methyl]-5nitro-1-(2-pyrrolidin-1-ylethyl)-1Hbenzoimidazole
—Protonitazene
IUPAC name: N,N-Diethyl-5-nitro-2-[(4propoxyphenyl)methyl]-1H-benzimidazole1-ethanamine
Substance recommended to be added to
Schedule II of the 1971 Convention:
—ADB-BUTINACA
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IUPAC name: N-[1-(Aminocarbonyl)-2,2dimethylpropyl]-1-butyl-1H-indazole-3carboxamide
—alpha-PiHP
IUPAC name: 4-Methyl-1-phenyl-2(pyrrolidin-1-yl)pentan-1-one
—3-Methylmethcathinone
IUPAC name: 2-(Methylamino)-1-(3methylphenyl)propan-1-one
Substances to be kept under surveillance:
In the letter from the Director-General of
WHO to the Secretary-General, reference is
also made to the recommendation made by
the WHO Expert Committee on Drug
Dependence (ECDD), at its forty-fifth
meeting, to keep the following substances
under surveillance:
—Adinazolam
IUPAC name: 8-Chloro-N,N-dimethyl-6phenyl-4H-[1,2,4]triazolo[4,3a][1,4]benzodiazepine-1-methanamine
—Bromazolam
IUPAC name: 8-Bromo-1-methyl-6-phenyl4H-[1,2,4]triazolo[4,3a][1,4]benzodiazepine
—Zopiclone
IUPAC name: 6-(5-Chloropyridin-2-yl)-7-oxo6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl
4-methylpiperazine-1-Carboxylate
In accordance with the provisions of article
3, paragraph 2, of the 1961 Convention and
article 2, paragraph 2, of the 1971
Convention, the notification is hereby
transmitted as Annex I to the present note.
In connection with the notification, WHO
also submitted a summary of the assessments
and findings for these recommendations
made by ECDD in Annex 1 to the letter to the
Secretary-General, which is transmitted
herewith in Annex II.
Also, in accordance with the same
provisions, the notification from WHO will
be brought to the attention of the sixty-sixth
session of the Commission on Narcotic Drugs
(13–17 March 2023) in a pre-session
document that will be made available in the
six official languages of the United Nations
on the website of the 66th session of the
Commission on Narcotic Drugs: https://
www.unodc.org/unodc/en/commissions/
CND/session/66_Session_2023/66CND_
Main.html.
In order to assist the Commission in
reaching a decision, it would be appreciated
if the Mission could communicate any
comments it considers relevant to the
possible scheduling of substances
recommended by WHO to be placed under
international control under the 1961
Convention, namely:
—2-Methyl-AP-237
—Etazene
—Etonitazepyne
—Protonitazene;
as well as any economic, social, legal,
administrative, or other factors that it
considers relevant to the possible scheduling
of substances recommended by WHO to be
placed under international control under the
1971 Convention, namely:
—ADB-BUTINACA
—alpha-PiHP
—3-Methylmethcathinone
The Secretariat of the United Nations
avails itself of this opportunity to renew to
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the Permanent Mission of the United States
of America to the United Nations (Vienna)
the assurances of its highest consideration.
Annex I
Letter addressed to the Secretary-General
of the United Nations from the DirectorGeneral of the World Health Organization,
dated 24 November 2022:
‘‘I have the honour to refer to the Fortyfifth Meeting of the World Health
Organization (WHO) Expert Committee on
Drug Dependence (ECDD) that was convened
in Geneva, Switzerland from 10 to 13 October
2022.
WHO is mandated by the 1961 and 1971
International Drug Control Conventions to
make recommendations to the United
Nations Secretary-General on the need for a
level of international control of psychoactive
substances based on the advice of its
independent scientific advisory body, the
ECDD. To assess the appropriate control of a
psychoactive substance, WHO convenes
ECDD annually to review the potential of a
substance to cause dependence, abuse and
harm to health, as well as any therapeutic
applications.
The Forty-fifth WHO ECDD Meeting
critically reviewed nine new psychoactive
substances: one synthetic cannabinoid
receptor agonist (ADB-BUTINACA), four
novel synthetic opioids (2-Methyl-AP-237,
etazene, etonitazepyne, and protonitazene),
two cathinones/stimulants (alpha-PiHP, 3methylmethcathinone), and two
benzodiazepines (adinozolam, bromazolam).
These substances had not previously been
formally reviewed by WHO and are currently
not under international control.
Information was brought to WHO’s
attention that these substances are
clandestinely manufactured, of risk to public
health and society, and of no recognized
therapeutic use by any party. Therefore, a
critical review to consider international
scheduling measures was undertaken for
each substance so that the Expert Committee
could consider whether information about
these substances may justify the scheduling
of a substance in the 1961 or 1971
Conventions. In addition, the Forty-fifth
ECDD carried out a pre-review of zopiclone
to consider whether current information
justified a critical review.
With reference to Article 3, paragraphs 1
and 3 of the Single Convention on Narcotic
Drugs (1961), as amended by the 1972
Protocol, and Article 2, paragraphs 1 and 4
of the Convention on Psychotropic
Substances (1971), WHO is pleased to
endorse and submit the following
recommendations of the Forty-fifth Meeting
of the ECDD:
To be added to Schedule I of the Single
Convention on Narcotic Drugs (1961):
—2-Methyl-AP-237
IUPAC (International Union of Pure and
Applied Chemistry) name: 1-[2-Methyl-4(3-phenyl-2-propen-1-yl)-1-piperazinyl]-1butanone
—Etazene
IUPAC name: 2-[(4-Ethoxyphenyl)methyl]N,N-diethyl-1H-benzimidazole-1ethanamine
—Etonitazepyne
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IUPAC name: 2-[(4-Ethoxyphenyl)methyl]-5nitro-1-(2-pyrrolidin-1-ylethyl)-1Hbenzoimidazole
—Protonitazene
IUPAC name: N,N-Diethyl-5-nitro-2-[(4propoxyphenyl)methyl]-1H-benzimidazole1-ethanamine
To be added to Schedule II of the
Convention on Psychotropic Substances
(1971):
—ADB-BUTINACA
IUPAC name: N-[1-(Aminocarbonyl)-2,2dimethylpropyl]-1-butyl-1H-indazole-3carboxamide
—alpha-PiHP
IUPAC name: 4-Methyl-1-phenyl-2(pyrrolidin-1-yl)pentan-1-one
—3-Methylmethcathinone
IUPAC name: 2-(Methylamino)-1-(3methylphenyl)propan-1-one
To be kept under surveillance:
—Adinazolam
IUPAC name: 8-Chloro-N,N-dimethyl-6phenyl-4H-[1,2,4]triazolo[4,3a][1,4]benzodiazepine-1-methanamine
—Bromazolam
IUPAC name: 8-Bromo-1-methyl-6-phenyl4H-[1,2,4]triazolo[4,3a][1,4]benzodiazepine
—Zopiclone
IUPAC name: 6-(5-Chloropyridin-2-yl)-7-oxo6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl
4-methylpiperazine-1-Carboxylate
The assessments and findings on which
these recommendations are based are set out
in detail in the Forty-fifth Meeting report of
the WHO Expert Committee on Drug
Dependence. A summary of the assessment
and recommendations made by the ECDD is
contained in Annex 1 to this letter.
I am pleased with the ongoing
collaboration between WHO, the United
Nations Office on Drugs and Crime, and the
International Narcotics Control Board, and in
particular, how this collaboration has
benefited the work of the WHO Expert
Committee on Drug Dependence and more
generally, the implementation of the
operational recommendations of the United
Nations General Assembly Special Session
2016.’’
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Annex II
45th WHO ECDD Summary Assessments,
Findings and Recommendations, 10–13
October 2022
Substances to be added to Schedule I of
the Single Convention on Narcotic Drugs
(1961).
2-Methyl-AP-237
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Similarity to Known Substances and Effects
on the Central Nervous System
2-Methyl-AP-237 is an opioid analgesic
with a rapid onset of action and a potency
and analgesic effects similar to those of
fentanyl, which is listed under Schedule I of
the Single Convention on Narcotic Drugs,
1961. In animals, it produces acute toxic
effects typical of opioids, including
respiratory depression. Limited research has
been reported on the effects of 2-methyl-AP237 in humans, although its respiratory
depressant effects have been observed, which
can be reversed by the opioid antagonist,
naloxone.
Dependence Potential
No controlled studies of the dependence
potential of 2-methyl-AP-237 have been
reported in animals or humans. As it is a mopioid receptor agonist, it would be expected
to produce dependence similar to that
induced by other opioids, such as morphine
and fentanyl. Online self-reports described
tolerance and withdrawal.
Actual Abuse and/or Evidence of Likelihood
of Abuse
In an animal model predictive of abuse
potential, 2-methyl-AP-237 was shown to
produce opioid-like effects with a potency
between those of morphine and fentanyl.
These effects were blocked by the opioid
antagonist, naltrexone.
No controlled studies on the abuse
potential of 2-methyl-AP-237 in humans have
been reported, but, as it is a m-opioid receptor
agonist, it would be expected to produce
euphoria and other effects predictive of high
abuse liability. Online self-reports support its
euphoric and other opioid effects.
Seizures of 2-methyl-AP-237 have been
reported in multiple countries in two regions.
A number of deaths in which 2-methyl-AP237 has been found have been reported, often
with multiple substances involved. The
deaths occurred in a number of countries and
regions.
Therapeutic Usefulness
2-Methyl-AP-237 is not known to have any
therapeutic use.
Recommendation
Substance Identification
2-Methyl-AP-237 (IUPAC chemical name:
1-[2-Methyl-4-(3-phenyl-2-propen-1-yl)-1piperazinyl]-1-butanone) is a methyl
derivative of the opioid analgesic AP-237 (or
bucinnazine). 2-Methyl-AP-237 has been
described as a white crystalline powder, a
crystalline solid, and a white solid.
WHO Review History
2-Methyl-AP-237 has been under WHO
surveillance but has not been formally
reviewed by WHO, and is not currently
under international control. Information was
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brought to the attention of WHO that this
substance is manufactured clandestinely,
poses a risk to public health and has no
recognized therapeutic use.
2-Methyl-AP-237 (IUPAC chemical name:
1-[2-Methyl-4-(3-phenyl-2-propen-1-yl)-1piperazinyl]-1-butanone) is a synthetic
opioid that is liable to abuse and to have ill
effects similar to those of other opioids that
are controlled under Schedule I of the 1961
Single Convention on Narcotic Drugs. Its use
has been reported in a number of countries
and has been associated with adverse effects,
including death. It has no known therapeutic
use and is likely to cause substantial harm.
Recommendation: The Committee
recommended that 2-methyl-AP-237 (IUPAC
chemical name: 1-[2-Methyl-4-(3-phenyl-2propen-1-yl)-1-piperazinyl]-1-butanone) be
added to Schedule I of the 1961 Single
Convention on Narcotic Drugs.
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Etazene
Substance Identification
Etazene (IUPAC chemical name: 2-[(4ethoxyphenyl)methyl]-N,N-diethyl-1Hbenzimidazole-1-ethanamine), also known as
etodesnitazene, is a benzimidazole-derived
synthetic opioid. Etazene has been described
as a grey crystalline, light-yellow, white, or
beige powder. It has also been identified in
liquid form and in falsified pharmaceutical
opioids.
WHO Review History
Etazene has not been formally reviewed by
WHO and is not currently under
international control. Information was
brought to the attention of WHO that this
substance is manufactured clandestinely,
poses a risk to public health and has no
recognized therapeutic use.
Similarity to Known Substances and Effects
on the Central Nervous System
Etazene binds to the m-opioid receptor with
a potency greater than that of morphine. In
studies of analgesia in animals, etazene had
full agonist effects, with a potency between
those of morphine and fentanyl, which are
both controlled under Schedule I of the
Single Convention on Narcotic Drugs, 1961.
The effects of etazene are reversed by the
opioid antagonist, naltrexone.
Dependence Potential
No controlled studies of the dependence
potential of etazene in animals or in humans
have been reported. As it is a potent m-opioid
receptor agonist, it would be expected to
produce dependence similar to other opioids,
such as morphine and fentanyl. Online selfreports described tolerance with repeated use
of etazene.
Actual Abuse and/or Evidence of Likelihood
of Abuse
In an animal model predictive of abuse
potential, etazene had effects similar to those
of morphine. No controlled studies have been
conducted of the abuse potential of etazene
in humans, but, as it is a potent m-opioid
receptor agonist, it would be expected to
produce euphoria and other effects predictive
of high abuse liability. Online self-reports
support its euphoric and other opioid effects.
Seizures of etazene have been reported in
multiple countries in two regions.
A number of deaths have occurred in
which the presence of etazene was confirmed
analytically and in which it was considered
to have contributed to death, although other
substances were also identified in these
cases.
Therapeutic Usefulness
Etazene is not known to have any
therapeutic use.
Recommendation
Etazene (IUPAC chemical name: 2-[(4ethoxyphenyl)methyl]-N,N-diethyl-1Hbenzimidazole-1-ethanamine), also known as
etodesnitazene, is a synthetic opioid that is
liable to abuse and produces ill effects
similar to other opioids that are controlled
under Schedule I of the 1961 Single
Convention on Narcotic Drugs. Its use has
been reported in a number of countries and
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has been associated with adverse effects,
including death. It has no known therapeutic
use and poses a significant risk to public
health.
Recommendation: The Committee
recommended that etazene (IUPAC chemical
name: 2-[(4-ethoxyphenyl)methyl]-N,Ndiethyl-1H-benzimidazole-1-ethanamine),
also known as etodesnitazene, be added to
Schedule I of the 1961 Single Convention on
Narcotic Drugs.
Etonitazepyne
Substance Identification
Etonitazepyne (IUPAC chemical name: 2[(4-ethoxyphenyl)methyl]-5-nitro-1-(2pyrrolidin-1-ylethyl)-1H-benzoimidazole),
also known as N-pyrrolidino etonitazene, is
a benzimidazole-derived synthetic opioid.
Etonitazepyne is found as a yellow powder
and crystalline solid and has been identified
in falsified pharmaceutical opioid tablets.
WHO Review History
Etonitazepyne has not been formally
reviewed by WHO and is not currently under
international control. Information was
brought to the attention of WHO that this
substance is manufactured clandestinely,
poses a risk to public health, and has no
recognized therapeutic use.
Similarity to Known Substances and Effects
on the Central Nervous System
Studies in animals have demonstrated that
etonitazepyne is a potent, full agonist at mopioid receptors. In animals, it produces
effects similar to those of opioids such as
morphine, fentanyl, and isotonitazene but
with greater potency. There is limited
information about the effects of
etonitazepyne alone in humans.
Dependence Potential
No controlled studies of the dependence
potential of etonitazepyne in animals or
humans have been reported. As it is a potent
m-opioid receptor agonist, it would be
expected to produce dependence similarly to
other opioids, such as morphine and
fentanyl. Online self-reports describe
tolerance and withdrawal after repeated
etonitazepyne use.
Actual Abuse and/or Evidence of Likelihood
of Abuse
In an animal model predictive of abuse
potential, etonitazepyne was shown to
produce effects that indicated greater potency
compared to morphine and fentanyl, and
these effects were reversed by the opioid
antagonist, naltrexone.
Seizures of etonitazepyne have been
reported in multiple countries in two regions.
It is reported to be administered by various
routes, including snorting, sniffing, and oral
administration. Etonitazepyne has been
identified in falsified medicines, suggesting
that its use may sometimes be unintentional.
Etonitazepyne is a relatively new drug on
the illicit market, and there is limited
information on the prevalence of its use and
of its harm, although non-fatal and fatal
intoxications have been documented in a
number of countries. The number of deaths
involving etonitazepyne has increased over a
relatively short time but may be
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underreported because of its recent, rapid
appearance.
Therapeutic Usefulness
Etonitazepyne is not known to have any
therapeutic use.
Recommendation
Etonitazepyne (IUPAC chemical name: 2[(4-ethoxyphenyl)methyl]-5-nitro-1-(2pyrrolidin-1-ylethyl)-1H-benzoimidazole),
also known as N-pyrrolidino etonitazene, is
a synthetic opioid that is liable to abuse and
to produce ill effects similar to other opioids
that are controlled under Schedule I of the
1961 Single Convention on Narcotic Drugs.
Its use has been reported in a number of
countries and has been associated with
adverse effects, including death. It has no
known therapeutic use and poses a
significant risk to public health.
Recommendation: The Committee
recommended that etonitazepyne (IUPAC
chemical name: 2-[(4-ethoxyphenyl)methyl]5-nitro-1-(2-pyrrolidin-1-ylethyl)-1Hbenzoimidazole), also known as Npyrrolidino etonitazene, be added to
Schedule I of the 1961 Single Convention on
Narcotic Drugs.
Protonitazene
Substance Identification
Protonitazene (IUPAC chemical name:
N,N-Diethyl-5-nitro-2-[(4propoxyphenyl)methyl]-1H-benzimidazole-1ethanamine), also known as
propoxynitazene, is a 5-nitro-2benzylbenzimidazole synthetic opioid.
Protonitazene has been described as a white,
yellow, or brown powder and as a crystalline
solid.
WHO Review History
Protonitazene has not been formally
reviewed by WHO and is not currently under
international control. Information was
brought to the attention of WHO that this
substance is manufactured clandestinely,
poses a risk to public health and has no
recognized therapeutic use.
Similarity to Known Substances and Effects
on the Central Nervous System
Protonitazene is a chemical analogue of
metonitazene and etonitazene, which are
controlled under Schedule I of the Single
Convention on Narcotic Drugs of 1961.
Studies in animals have demonstrated that
protonitazene is a full agonist at m-opioid
receptors, with greater potency than
morphine and similar potency to fentanyl. Its
effects are blocked by the opioid antagonist,
naltrexone.
Dependence Potential
No controlled studies of the dependence
potential of protonitazene in animals or
humans have been reported. As it is a potent
m-opioid receptor agonist, it would be
expected to produce dependence similar to
other opioids such as morphine and fentanyl.
Actual Abuse and/or Evidence of Likelihood
of Abuse
In animals, protonitazene showed potent
opioid effects and abuse potential, similar to
those of morphine and fentanyl. Its abuse
potential has not been studied in humans;
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however, online self-reports indicate typical
opioid effects, including sedation and
euphoria.
Protonitazene is relatively new on the
illicit drug market, and there is limited
information on the prevalence of its use or
of its harm. The only available information
is that several fatalities have occurred in
which the presence of protonitazene was
confirmed, usually with other substances.
The number of deaths may be underreported
because of limitations in testing, including
difficulty in differentiating this substance
from isotonitazene.
Protonitazene is reported to be
administered through various routes,
including intranasally and intravenously.
Seizures of protonitazene have been
reported in multiple countries in two regions.
Therapeutic Usefulness
Protonitazene is not known to have any
therapeutic use.
Recommendation
Protonitazene (IUPAC chemical name:
N,N-Diethyl-5-nitro-2-[(4propoxyphenyl)methyl]-1H-benzimidazole-1ethanamine), also known as
propoxynitazene, is a synthetic opioid that is
liable to abuse and to produce ill effects
similar to other opioids that are controlled
under Schedule I of the 1961 Single
Convention on Narcotic Drugs. Its use has
been reported in a number of countries and
has been associated with adverse effects,
including death. It has no known therapeutic
use and is likely to cause substantial harm.
Recommendation: The Committee
recommended that protonitazene (IUPAC
chemical name: N,N-Diethyl-5-nitro-2-[(4propoxyphenyl)methyl]-1H-benzimidazole-1ethanamine), also known as
propoxynitazene, be added to Schedule I of
the 1961 Single Convention on Narcotic
Drugs.
Substances to be added to Schedule II of
the Convention on Psychotropic Substances
(1971).
ADB-BUTINACA
Substance Identification
ADB-BUTINACA (IUPAC chemical name:
N-[1-(aminocarbonyl)-2,2-dimethylpropyl]-1butyl-1H-indazole-3-carboxamide) is an
indazole-derived synthetic cannabinoid. It is
described as a crystalline solid or a beige or
yellowish powder and has also been found
sprayed onto plant material and paper. It is
commonly smoked or vaped, although
isolated cases of oral use have also been
reported.
WHO Review History
ADB-BUTINACA has not been formally
reviewed by WHO and is not currently under
international control. Information was
brought to the attention of WHO that this
substance is manufactured clandestinely,
poses a risk to public health, and has no
recognized therapeutic use.
Similarity to Known Substances and Effects
on the Central Nervous System
ADB-BUTINACA is a synthetic
cannabinoid that binds to CB1 and CB2
receptors with high affinity and is a potent
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full agonist at both receptors. Its effects are
similar to those of other potent CB1 agonists
that are currently controlled under Schedule
II of the Convention on Psychotropic
Substances of 1971.
No controlled studies of the effects of ADBBUTINACA have been reported. Online selfreports describe euphoria, appetite
stimulation, sedation, and paranoia after its
use. These effects are consistent with the
known effects of cannabinoid agonists.
Dependence Potential
No controlled studies of the dependence
potential of ADB-BUTINACA in animals or
humans have been reported. However, its
effects at the CB1 receptor suggest that it
would be expected to produce dependence
similar to other synthetic cannabinoids.
Actual Abuse and/or Evidence of Likelihood
of Abuse
In an animal model predictive of abuse
potential, ADB-BUTINACA had effects
similar to the CB1 receptor agonist delta-9tetrahydrocannabinol. No studies have been
conducted to determine the likelihood of
abuse of ADB-BUTINACA in humans;
however, CB1 receptor agonists have known
abuse potential.
A number of countries in various regions
have reported use of ADB-BUTINACA and
harm related to its use, including multiple
deaths and presentations of patients to
emergency departments with altered
consciousness and loss of consciousness.
Other substances were usually also involved
in these cases, although a number of deaths
involved only ADB-BUTINACA.
Therapeutic Usefulness
ADB-BUTINACA is not known to have any
therapeutic use.
Recommendation
ADB-BUTINACA (N-[1-(aminocarbonyl)2,2-dimethylpropyl]-1-butyl-1H-indazole-3carboxamide) is a potent synthetic
cannabinoid receptor agonist with a
mechanism of action and effects similar to
those of a number of other synthetic
cannabinoids that are controlled under
Schedule II of the Convention on
Psychotropic Substances of 1971. Its mode of
action suggests the likelihood of abuse and
potential for dependence. Use of ADBBUTINACA has been associated with severe
adverse effects, including fatal intoxications.
ADB-BUTINACA has no known therapeutic
use.
Recommendation: The Committee
recommended that ADB-BUTINACA (N-[1(aminocarbonyl)-2,2-dimethylpropyl]-1butyl-1H-indazole-3-carboxamide) be added
to Schedule II of the Convention on
Psychotropic Substances of 1971.
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Alpha-PiHP
Substance Identification
Alpha-pyrrolidinoisohexanophenone
(IUPAC chemical name: 4-Methyl-1-phenyl2-(pyrrolidin-1-yl)pentan-1-one), also known
as alpha-PiHP, is a synthetic cathinone. It
has been described as an off-white solid, a
white powder, and a crystalline solid.
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WHO Review History
Alpha-PiHP has been under WHO
surveillance but has not been formally
reviewed by WHO and is not currently under
international control. Information was
brought to the attention of WHO that this
substance is manufactured clandestinely,
poses a risk to public health, and has no
recognized therapeutic use.
Similarity to Known Substances and Effects
on the Central Nervous System
Alpha-PiHP is an isomer of alpha-PHP,
which is controlled under Schedule II of the
Convention on Psychotropic Substances of
1971. Laboratory studies suggest that alphaPiHP can inhibit the uptake of dopamine and
norepinephrine more potently than
substances with known abuse potential,
including methcathinone, cocaine, and
methamphetamine. Studies in animals have
shown that alpha-PiHP is a psychomotor
stimulant, with effects comparable to those of
cocaine and methamphetamine.
Online self-reports by people who use
alpha-PiHP describe stimulant effects similar
to those of alpha-PVP and alpha-PHP.
Dependence Potential
No controlled studies of the dependence
potential of alpha-PiHP in animals or
humans have been reported. In view of its
actions and effects on the central nervous
system, it would be expected to produce
dependence similarly to other
psychostimulants such as methamphetamine.
Actual Abuse and/or Evidence of Likelihood
of Abuse
Studies in animals predictive of abuse
liability indicate that alpha-PiHP produces
effects similar to those of methamphetamine
and cocaine. No controlled studies of the
abuse potential of alpha-PiHP in humans
have been reported.
Seizures of alpha-PiHP have been
described in multiple countries in three
regions.
Alpha-PiHP has been identified in a
number of serious adverse events and drugrelated deaths. As it is usually detected with
other substances, including opioids and
benzodiazepines, the role of alpha-PiHP is
unclear in some instances.
Therapeutic Usefulness
Alpha-PiHP is not known to have any
therapeutic use.
Recommendation
Alpha-pyrrolidinoisohexanophenone
(IUPAC chemical name: 4-Methyl-1-phenyl2-(pyrrolidin-1-yl)pentan-1-one), also known
as alpha-PiHP, is a synthetic cathinone with
effects similar to those of other synthetic
cathinones and other psychostimulants, such
as methamphetamine, that are listed under
Schedule II of the Convention on
Psychotropic Substances of 1971. There is
evidence that its abuse is likely to constitute
a substantial public health and social
problem. It has no known therapeutic use.
Recommendation: The Committee
recommended that alphapyrrolidinoisohexanophenone (IUPAC
chemical name: 4-Methyl-1-phenyl-2(pyrrolidin-1-yl)pentan-1-one), also known as
alpha-PiHP, be added to Schedule II of the
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1971 Convention on Psychotropic
Substances.
3-Methylmethcathinone
Substance Identification
3-Methylmethcathinone (IUPAC chemical
name: 2-(methylamino)-1-(3methylphenyl)propan-1-one), also known as
3-MMC, is a synthetic cathinone. 3Methylmethcathinone has been found as a
white or off-white powder, a white, yellow,
or orange solid, and a crystalline solid. It has
been detected in tablet, capsule, and liquid
forms.
WHO Review History
3-Methylmethcathinone was critically
reviewed by the Committee at its 38th
meeting, in 2016, when it decided to request
a further critical review once more
information became available and to consider
it at a subsequent meeting. Information was
brought to the attention of WHO that this
substance is manufactured clandestinely,
poses a risk to public health, and has no
recognized therapeutic use. Information from
international agencies suggests that there has
been a significant increase in the availability
of and harm due to 3-methylmethcathinone
in recent years.
Similarity to Known Substances and Effects
on the Central Nervous System
3-Methylmethcathinone is an isomer of 4methylmethcathinone (mephedrone), which
is a synthetic cathinone listed under
Schedule II of the Convention on
Psychotropic Substances of 1971.
3-Methylmethcathinone has a typical
psychostimulant profile, similar to that of 4methylmethcathinone, including inhibition
of the reuptake of dopamine, norepinephrine,
and serotonin, and increased release of
dopamine and serotonin.
Clinical features of 3-methylmethcathinone
intoxication are consistent with those
produced by other stimulants and include
tachycardia, hypertension, agitation,
aggression, hallucinations, rhabdomyolysis,
and kidney failure.
Dependence Potential
No controlled studies of the dependence
potential of 3-methylmethcathinone in
animals or humans have been reported.
Withdrawal symptoms indicative of physical
dependence have been documented in
people who use 3-methylmethcathinone. In
view of its actions and effects on the central
nervous system, 3-methylmethcathinone
would be expected to produce dependence
similar to other psychostimulants, such as
methamphetamine.
Actual Abuse and/or Evidence of Likelihood
of Abuse
In animal models predictive of rewarding
effects, 3-methylmethcathinone produced
effects that were similar to those of
methamphetamine. 3-Methylmethcathinone
also produced behavioural (stimulant) effects
similar to methamphetamine. No controlled
studies in humans have examined the abuse
potential of 3-methylmethcathinone.
3-Methylmethcathinone has been seized in
multiple countries in several regions. Many
fatal and non-fatal intoxications involving 3-
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methylmethcathinone have been reported.
Other substances were commonly involved
in these cases, although severe intoxication
and death have been reported in cases in
which 3-methylmethcathinone was the only
substance identified.
Therapeutic Usefulness
3-Methylmethcathinone is not known to
have any therapeutic use.
Recommendation
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3-Methylmethcathinone (IUPAC chemical
name: 2-(methylamino)-1-(3methylphenyl)propan-1-one), also known as
3-MMC, is a synthetic cathinone with effects
similar to those of other synthetic cathinones
and other psychostimulants such as
methamphetamine that are listed under
Schedule II of the Convention on
Psychotropic Substances of 1971. There is
evidence that its abuse is likely to constitute
a substantial public health and social
problem. It has no known therapeutic use.
Recommendation: The Committee
recommended that 3-Methylmethcathinone
(IUPAC chemical name: 2-(methylamino)-1(3-methylphenyl)propan-1-one), also known
as 3-MMC, be added to Schedule II of the
Convention on Psychotropic Substances of
1971.
Substances to be kept under surveillance:
Adinazolam
Substance Identification
Adinazolam (IUPAC chemical name: 8Chloro-N,N-dimethyl-6-phenyl-4H[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1methanamine) is a triazolobenzodiazepine.
Adinazolam appears as a white or yellow
powder and is also sold as tablets and
capsules, including as falsified
pharmaceuticals.
WHO Review History
Adinazolam has not been formally
reviewed by WHO and is not currently under
international control. Information was
brought to the attention of WHO that this
substance is manufactured clandestinely,
poses a risk to public health, and has no
recognized therapeutic use.
Similarity to Known Substances and Effects
on the Central Nervous System
Adinazolam is a short-acting
benzodiazepine with moderate affinity for
the benzodiazepine receptor. It is a chemical
analogue of alprazolam and triazolam.
Consistent with its benzodiazepine
receptor action, adinazolam showed
anticonvulsant, anxiolytic and antidepressant
properties in animals. In humans,
adinazolam (and its metabolite Ndesmethyladinazolam) produced a dosedependent decrease in psychomotor
performance and increased sedation and
amnesia. It also had some subjective effects
similar to those of benzodiazepines such as
diazepam and lorazepam, which are
controlled under Schedule IV of the 1971
Convention on Psychotropic Substances.
Dependence Potential
No studies have been conducted in animals
or humans on the dependence potential of
adinazolam. In view of its mechanism of
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action, however, it would be expected to
produce typical benzodiazepine dependence.
Actual Abuse and/or Evidence of Likelihood
of Abuse
In animals, adinazolam shows behavioural
effects consistent with those of drugs with
abuse liability. In controlled studies in
humans, adinazolam produced sedation, and,
in one controlled study, adinazolam
produced a self-reported ‘‘high’’ feeling, with
a greater estimated street value than placebo.
While seizures of adinazolam have been
reported in a few countries in two regions,
currently there is insufficient evidence that it
is being abused to such an extent as to
constitute a public health problem.
Adinazolam was identified in a few drugrelated deaths in combination with other
psychoactive substances, including opioids
and other benzodiazepines; however, there
was no evidence that adinazolam played a
causative role in these deaths.
Therapeutic Usefulness
Adinazolam is not known to have any
therapeutic use.
Recommendation
Adinazolam (IUPAC chemical name: 8Chloro-N,N-dimethyl-6-phenyl-4H[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1methanamine) has effects similar to those of
substances listed under Schedule IV of the
Convention on Psychotropic Substances of
1971. There is, however, insufficient
evidence that its use is a public health and
social problem to justify its placement under
international control.
Recommendation: The Committee
recommended that adinazolam (IUPAC
chemical name: 8-Chloro-N,N-dimethyl-6phenyl-4H-[1,2,4]triazolo[4,3a][1,4]benzodiazepine-1-methanamine) be
kept under surveillance by the WHO
Secretariat.
Bromazolam
Substance Identification
Bromazolam (8-Bromo-1-methyl-6-phenyl4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine)
is a triazolobenzodiazepine. Bromazolam has
been described as a white or crystalline solid
and has been identified in tablets, capsules,
powders, solutions, and edible products.
Bromazolam has been identified in falsified
pharmaceutical benzodiazepine products.
WHO Review History
Bromazolam has not been formally
reviewed by WHO and is not currently under
international control. Information was
brought to the attention of WHO that this
substance is manufactured clandestinely,
poses a risk to public health and has no
recognized therapeutic use.
Similarity to Known Substances and Effects
on the Central Nervous System
There is currently insufficient information
on the pharmacological profile of
bromazolam from controlled studies in
animals or humans to conclude that it has
effects similar to those of benzodiazepines,
which are controlled under the 1971
Convention on Psychotropic Substances.
Online self-reports by people who claim to
have used bromazolam describe
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benzodiazepine-like effects, including
hypnotic, sedative, muscle relaxant, and
euphoric effects. There are, however, no
clinical reports or analytical confirmation of
bromazolam to confirm these effects.
Dependence Potential
No controlled studies in animals or
humans have been reported on the
dependence potential of bromazolam. Online
self-reports describe withdrawal symptoms
after cessation of chronic use.
Actual Abuse and/or Evidence of Likelihood
of Abuse
No controlled studies in animals or
humans have been reported on the abuse
liability of bromazolam. In self-reports
online, people have described using the drug
for its euphoric and other benzodiazepinelike effects; however, there is no
confirmation that that the substance used
was bromazolam.
Seizures of bromazolam have been
reported in multiple countries in several
regions. Bromazolam has been analytically
confirmed in a number of deaths, non-fatal
intoxications, and instances of driving under
the influence of drugs. Because of the
presence of other drugs, especially other
benzodiazepines; however, the contribution
of bromazolam cannot be determined.
Therapeutic Usefulness
Bromazolam is not known to have any
therapeutic uses and has never been
marketed as a medicinal product.
Recommendation
While the chemical structure of
bromazolam (8-Bromo-1-methyl-6-phenyl4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine)
is similar to those of other benzodiazepines
listed under the Convention on Psychotropic
Substances of 1971, its mechanism of action
and effects are yet to be confirmed. Although
there is increasing evidence of its use, no
studies in animals or humans have been
reported on the effects or abuse potential of
bromazolam. The limited information on its
effects provides insufficient evidence to
justify placement of bromazolam under
international control.
Recommendation: The Committee
recommended that bromazolam (8-Bromo-1methyl-6-phenyl-4H-[1,2,4]triazolo[4,3a][1,4]benzodiazepine) be kept under
surveillance by the WHO Secretariat.
Zopiclone
Substance Identification
Zopiclone (IUPAC chemical name: 6-(5Chloropyridin-2-yl)-7-oxo-6,7-dihydro-5Hpyrrolo[3,4-b]pyrazin-5-yl 4methylpiperazine-1-carboxylate) is a sedative
hypnotic drug of the cyclopyrrolone class.
Zopiclone has been reported as a white or
slightly yellowish powder. Zopiclone is
available as pharmaceutical products in
tablet form for oral use. Eszopiclone (the Senantiomer of zopiclone) is marketed as a
pharmaceutical product in some countries.
WHO Review History
Zopiclone was pre-reviewed by the
Committee at its 29th meeting, when it
recommended that surveillance be continued
but that a critical review was not required.
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In view of the abuse liability of the drug and
the significant number of reports of adverse
drug reactions related to zopiclone abuse sent
to the WHO international drug monitoring
programme; however, zopiclone was prereviewed by the Committee at its 33rd
meeting, when it recommended a critical
review. Zopiclone was critically reviewed at
the 34th meeting, in 2006, when the
Committee rated its abuse liability as low and
its therapeutic usefulness considerable and
recommended continued surveillance by
WHO. A pre-review was initiated after a
proposal was received from an international
agency that suggested a significant increase
in the reported number of trafficking cases
and seizures involving zopiclone.
Similarity to Known Substances and Effects
on the Central Nervous System
Zopiclone binds to the benzodiazepine
receptor that forms part of the GABAA
receptor complex. It may bind to different
parts of the receptor or cause different
changes in the GABAA receptor complex
than benzodiazepines.
In animals, zopiclone has sedative,
anxiolytic, anticonvulsant, and muscle
relaxant properties similar to those of
benzodiazepines. In studies in humans, it
was less effective than benzodiazepines for
treatment of anxiety.
Dependence Potential
Studies in animals show evidence of
zopiclone tolerance and withdrawal,
indicating the development of physical
dependence. A number of published reports
have described physical dependence
associated with zopiclone use in humans.
Withdrawal symptoms such as increased
anxiety and insomnia have been described in
people who cease zopiclone use, usually after
prolonged use and dose escalation from
clinical use. Tolerance and withdrawal have
also been reported in clinical trials.
Dependence is documented in databases on
adverse events associated with
pharmaceutical use.
Actual Abuse and/or Evidence of Likelihood
of Abuse
Studies in animals suggest that zopiclone
may have abuse liability similar to that of
benzodiazepines such as midazolam,
diazepam, nitrazepam, and alprazolam. The
effects indicative of abuse liability were
blocked by the benzodiazepine antagonist
flumazenil, indicating a mechanism of action
involving the benzodiazepine receptor.
No controlled studies in humans have been
reported on the abuse potential of zopiclone.
Published reports describe effects consistent
with benzodiazepine-like abuse potential, its
use with alcohol and other drugs and
escalation to high-dose use. The extent of
harm related to the use of zopiclone is,
however, unclear.
Zopiclone is widely used therapeutically
in many countries and regions, and it is also
listed in databases of adverse events
associated with pharmaceutical use.
Zopiclone is most likely to be misused by
individuals to whom it is prescribed for long
periods, who are using other psychoactive
drugs or in those with psychiatric
comorbidities. While seizures of zopiclone
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have been reported in multiple countries in
several regions, the prevalence of nonmedical use of zopiclone by the general
population is unknown. Furthermore, there
is insufficient evidence that significant
public health and social problems related to
abuse can be directly attributed to sole use
of zopiclone.
Therapeutic Usefulness
Zopiclone is a widely used medicine
primarily indicated for the short-term
treatment of insomnia, with marketing
authorisations in many countries. It is not
listed on the WHO Model List of Essential
Medicines.
Recommendation
Zopiclone (IUPAC chemical name: 6-(5Chloropyridin-2-yl)-7-oxo-6,7-dihydro-5Hpyrrolo[3,4-b]pyrazin-5-yl 4methylpiperazine-1-carboxylate) is a sedative
hypnotic drug of the cyclopyrrolone class.
The Committee noted that concern has been
expressed in several countries regarding nonprescription use of zopiclone. While there
have been reports of adverse effects,
overdose, withdrawal symptoms and an
increased number of seizures of the
substance, there is still insufficient evidence
that zopiclone is or is likely to be abused to
such an extent as to constitute a public
health and social problem.
The Committee also noted that zopiclone is
widely used therapeutically in many
countries.
Recommendation: The Committee
recommended that zopiclone (IUPAC
chemical name: 6-(5-Chloropyridin-2-yl)-7oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5yl 4-methylpiperazine-1-carboxylate) not
proceed to critical review but be kept under
surveillance by the WHO Secretariat.
III. Discussion
Although WHO has made specific
scheduling recommendations for each of
the drug substances, the CND is not
obliged to follow the WHO
recommendations. Options available to
the CND for substances considered for
control under the 1971 Convention
include the following: (1) accept the
WHO recommendations; (2) accept the
recommendations to control but control
the drug substance in a schedule other
than that recommended; or (3) reject the
recommendations entirely.
ADB-BUTINACA (chemical name: N[1-(Aminocarbonyl)-2,2dimethylpropyl]-1-butyl-1H-indazole-3carboxamide) is a synthetic cannabinoid
that is a potent agonist of the
cannabinoid (CB) 1 and CB2 receptors.
Adverse effects associated with
synthetic cannabinoids include
euphoria, appetite stimulation, sedation,
loss of consciousness, and paranoia. The
use of ADB-BUTINACA has been
associated with fatalities in the United
States in which other drugs were also
detected. ADB-BUTINACA is not
approved for medical use in the United
States. ADB-BUTINACA has been
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Sfmt 4703
10351
detected in the illicit drug market in the
United States since 2020 as evidenced
by drug seizures. As a positional isomer
of AB-PINACA (N-(1-amino-3-methyl-1oxobutan-2-yl)-1-pentyl-1H-indazole-3carboxamide), ADB-BUTINACA is
controlled under schedule I of the CSA.
As such, additional permanent controls
will not be needed if ADB-BUTINACA
is placed under schedule II of the
Convention on Psychotropic
Substances.
Alpha-PiHP (4-methyl-1-phenyl-2(pyrrolidin-1-yl)pentan-1-one) is a
synthetic cathinone with chemical and
pharmacological properties similar to
schedule I and II amphetamines and
cathinones such as alpha-PHP, alphaPVP, and MDPV. Reports of intoxication
indicate that alpha-PiHP produces
psychoactive effects similar to
methamphetamine and cocaine.
Adverse events associated with the
abuse of synthetic cathinones include,
but are not limited to, agitation,
hypertension, tachycardia, and death.
Alpha-PiHP is not approved for medical
use in the United States. Alpha-PiHP
has been identified in a number of drug
seizures in the United States and has
been detected in mixtures with other
drugs including opioids and
benzodiazepines. As a positional isomer
of alpha-PHP (1-phenyl-2-(pyrrolidin-1yl)hexan-1-one), alpha-PiHP is
controlled under schedule I of the CSA.
As such, additional permanent controls
will not be needed if alpha-PiHP is
placed in Schedule II of the Convention
on Psychotropic Substances.
3-Methylmethcathinone (2(methylamino)-1-(3methylphenyl)propan-1-one) is a
synthetic cathinone with chemical and
pharmacological properties similar to
schedule I and II amphetamines and
cathinones such as amphetamine and 4methylmethcathinone (mephedrone, 4MMC). Reports of intoxication of 3methylmethcathinone indicate that it
produces psychoactive effects similar to
stimulants such as methamphetamine.
These reports also indicate that it
produces adverse events which include
tachycardia, hypertension, agitation,
aggression, hallucinations,
rhabdomyolysis, and kidney failure.
Several fatalities have been reported in
which 3-methylmethcathinone was the
only drug detected, however, in some
other cases other drugs were detected. 3Methylmethcathinone is not approved
for medical use in the United States. 3Methylmethcathinone has been
identified in a number of drug seizures
in the United States and has been
detected in mixtures with other drugs
including opioids and benzodiazepines.
As a positional isomer of 4-
E:\FR\FM\17FEN1.SGM
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10352
Federal Register / Vol. 88, No. 33 / Friday, February 17, 2023 / Notices
methylmethcathinone (2(methylamino)-1-(4methylphenyl)propan-1-one;
mephedrone), 3-methylmethcathinone
is controlled under schedule I of the
CSA. As such, additional permanent
controls will not be needed if 3methylmethcathinone is placed in
Schedule II of the Convention on
Psychotropic Substances.
FDA, on behalf of the Secretary of
HHS, invites interested persons to
submit comments on the notifications
from the United Nations concerning
these drug substances. FDA, in
cooperation with the National Institute
on Drug Abuse, will consider the
comments on behalf of HHS in
evaluating the WHO scheduling
recommendations. Then, under section
201(d)(2)(B) of the CSA, HHS will
recommend to the Secretary of State
what position the United States should
take when voting on the
recommendations for control of
substances under the 1971 Convention
at the CND meeting in March 2023.
Comments regarding the WHO
recommendations for control of 2methyl-AP-237, etazene, etonitazepyne,
and protonitazene under the 1961
Single Convention will also be
forwarded to the relevant Agencies for
consideration in developing the U.S.
position regarding narcotic substances
at the CND meeting.
Dated: February 13, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023–03375 Filed 2–16–23; 8:45 am]
BILLING CODE 4164–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2007–D–0369]
Product-Specific Guidances; Draft and
Revised Draft Guidances for Industry;
Reopening of the Comment Period
AGENCY:
Food and Drug Administration,
HHS.
Notice; reopening of the
comment period.
ACTION:
The Food and Drug
Administration (FDA or Agency) is
reopening the comment period for the
notice entitled ‘‘Product-Specific
Guidances; Draft and Revised Draft
Guidances for Industry,’’ published in
the Federal Register of November 18,
2022. The Agency is taking this action
to allow interested persons additional
time to submit comments.
lotter on DSK11XQN23PROD with NOTICES1
SUMMARY:
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FDA is reopening the comment
period for the notice published on
November 18, 2022 at 87 FR 69278.
Either electronic or written comments
must be submitted by April 18, 2023.
ADDRESSES: You may submit comments
on any guidance at any time as follows:
DATES:
Electronic Submissions
Submit electronic comments in the
following way:
• Federal eRulemaking Portal:
https://www.regulations.gov. Follow the
instructions for submitting comments.
Comments submitted electronically,
including attachments, to https://
www.regulations.gov will be posted to
the docket unchanged. Because your
comment will be made public, you are
solely responsible for ensuring that your
comment does not include any
confidential information that you or a
third party may not wish to be posted,
such as medical information, your or
anyone else’s Social Security number, or
confidential business information, such
as a manufacturing process. Please note
that if you include your name, contact
information, or other information that
identifies you in the body of your
comments, that information will be
posted on https://www.regulations.gov.
• If you want to submit a comment
with confidential information that you
do not wish to be made available to the
public, submit the comment as a
written/paper submission and in the
manner detailed (see ‘‘Written/Paper
Submissions’’ and ‘‘Instructions’’).
Written/Paper Submissions
Submit written/paper submissions as
follows:
• Mail/Hand Delivery/Courier (for
written/paper submissions): Dockets
Management Staff (HFA–305), Food and
Drug Administration, 5630 Fishers
Lane, Rm. 1061, Rockville, MD 20852.
• For written/paper comments
submitted to the Dockets Management
Staff, FDA will post your comment, as
well as any attachments, except for
information submitted, marked and
identified, as confidential, if submitted
as detailed in ‘‘Instructions.’’
Instructions: All submissions received
must include the Docket No. FDA–
2007–D–0369 for ‘‘Product-Specific
Guidances; Draft and Revised Draft
Guidances for Industry.’’ Received
comments will be placed in the docket
and, except for those submitted as
‘‘Confidential Submissions,’’ publicly
viewable at https://www.regulations.gov
or at the Dockets Management Staff
between 9 a.m. and 4 p.m., Monday
through Friday, 240–402–7500.
• Confidential Submissions—To
submit a comment with confidential
PO 00000
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Fmt 4703
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information that you do not wish to be
made publicly available, submit your
comments only as a written/paper
submission. You should submit two
copies total. One copy will include the
information you claim to be confidential
with a heading or cover note that states
‘‘THIS DOCUMENT CONTAINS
CONFIDENTIAL INFORMATION.’’ The
Agency will review this copy, including
the claimed confidential information, in
its consideration of comments. The
second copy, which will have the
claimed confidential information
redacted/blacked out, will be available
for public viewing and posted on
https://www.regulations.gov. Submit
both copies to the Dockets Management
Staff. If you do not wish your name and
contact information to be made publicly
available, you can provide this
information on the cover sheet and not
in the body of your comments and you
must identify this information as
‘‘confidential.’’ Any information marked
as ‘‘confidential’’ will not be disclosed
except in accordance with 21 CFR 10.20
and other applicable disclosure law. For
more information about FDA’s posting
of comments to public dockets, see 80
FR 56469, September 18, 2015, or access
the information at: https://
www.govinfo.gov/content/pkg/FR-201509-18/pdf/2015-23389.pdf.
Docket: For access to the docket to
read background documents or the
electronic and written/paper comments
received, go to https://
www.regulations.gov and insert the
docket number, found in brackets in the
heading of this document, into the
‘‘Search’’ box and follow the prompts
and/or go to the Dockets Management
Staff, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852, 240–402–7500.
You may submit comments on any
guidance at any time (see 21 CFR
10.115(g)(5)).
Submit written requests for single
copies of the draft guidance to the
Division of Drug Information, Center for
Drug Evaluation and Research, Food
and Drug Administration, 10001 New
Hampshire Ave., Hillandale Building,
4th Floor, Silver Spring, MD 20993–
0002. Send one self-addressed adhesive
label to assist that office in processing
your requests. See the SUPPLEMENTARY
INFORMATION section for electronic
access to the draft guidance document.
FOR FURTHER INFORMATION CONTACT:
Christine Le, Center for Drug Evaluation
and Research, Food and Drug
Administration, 301–796–2398, PSGQuestions@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
E:\FR\FM\17FEN1.SGM
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]]>Agencies
[Federal Register Volume 88, Number 33 (Friday, February 17, 2023)]
[Notices]
[Pages 10344-10352]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-03375]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2023-N-0438]
International Drug Scheduling; Convention on Psychotropic
Substances; Single Convention on Narcotic Drugs; World Health
Organization; Scheduling Recommendations; ADB-BUTINACA; Alpha-PiHP; 3-
Methylmethcathinone; Request for Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is providing interested
persons with the opportunity to submit written comments concerning
recommendations by the World Health Organization (WHO) to impose
international manufacturing and distributing restrictions, under
international treaties, on certain drug substances. The comments
received in response to this notice will be considered in preparing the
United States' position on these proposals for a meeting of the United
Nations
[[Page 10345]]
Commission on Narcotic Drugs (CND) in Vienna, Austria, in March 2023.
This notice is issued under the Controlled Substances Act (CSA).
DATES: Submit either electronic or written comments by February 28,
2023.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of February 28, 2023. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are received on or before that date.
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2023-N-0438 for ``International Drug Scheduling; Convention on
Psychotropic Substances; Single Convention on Narcotic Drugs; World
Health Organization; Scheduling Recommendations; ADB-BUTINACA; alpha-
PiHP; 3-Methylmethcathinone; Request for Comments.'' Received comments,
those filed in a timely manner (see ADDRESSES), will be placed in the
docket and, except for those submitted as ``Confidential Submissions,''
publicly viewable at https://www.regulations.gov or at the Dockets
Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-
402-7500.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852, 240-402-7500.
FOR FURTHER INFORMATION CONTACT: Edward (Greg) Hawkins, Center for Drug
Evaluation and Research, Controlled Substance Staff, Food and Drug
Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 5150, Silver
Spring, MD 20993-0002, 202-713-8981, [email protected].
SUPPLEMENTARY INFORMATION:
I. Background
The United States is a party to the 1971 Convention on Psychotropic
Substances (1971 Convention). Section 201(d)(2)(B) of the CSA (21
U.S.C. 811(d)(2)(B)) provides that when the United States is notified
under Article 2 of the 1971 Convention that the CND proposes to decide
whether to add a drug or other substance to one of the schedules of the
1971 Convention, transfer a drug or substance from one schedule to
another, or delete it from the schedules, the Secretary of State must
transmit notice of such information to the Secretary of Health and
Human Services (Secretary of HHS). The Secretary of HHS must then
publish a summary of such information in the Federal Register and
provide opportunity for interested persons to submit comments. The
Secretary of HHS must then evaluate the proposal and furnish a
recommendation to the Secretary of State that shall be binding on the
representative of the United States in discussions and negotiations
relating to the proposal.
As detailed in the following paragraphs, the Secretary of State has
received notification from the Secretary-General of the United Nations
(the Secretary-General) regarding three substances to be considered for
control under the 1971 Convention. This notification reflects the
recommendation from the 45th WHO Expert Committee for Drug Dependence
(ECDD), which met in October 2022. In the Federal Register of August 3,
2022 (87 FR 47428), FDA announced the WHO ECDD review and invited
interested persons to submit information for WHO's consideration.
The full text of the notification from the Secretary-General is
provided in section II of this document. Section 201(d)(2)(B) of the
CSA requires the Secretary of HHS, after receiving a notification
proposing scheduling, to publish a notice in the Federal Register to
provide the opportunity for interested persons to submit information
and comments on the proposed scheduling action.
The United States is also a party to the 1961 Single Convention on
Narcotic Drugs (1961 Convention). The Secretary of State has received a
notification from the Secretary-General regarding four substances to be
considered for control under this convention. The CSA does not require
HHS to publish a summary
[[Page 10346]]
of such information in the Federal Register. Nevertheless, to provide
interested and affected persons an opportunity to submit comments
regarding the WHO recommendations for drugs under the 1961 Convention,
the notification regarding these substances is also included in this
Federal Register notice. The comments will be shared with other
relevant Agencies to assist the Secretary of State in formulating the
position of the United States on the control of these substances. The
HHS recommendations are not binding on the representative of the United
States in discussions and negotiations relating to the proposal
regarding control of substances under the 1961 Convention.
II. United Nations Notification
The formal notification from the United Nations that identifies the
drug substances and explains the basis for the scheduling
recommendations is reproduced as follows (non-relevant text removed):
Reference:
NAR/CL.6/2022
WHO/ECDD45; 1961C-Art.3, 1971C-Art.2
CU 2022/386/DTA/SGB
The Secretariat of the United Nations presents its compliments
to the Permanent Mission of the United States of America to the
United Nations (Vienna) and has the honour to inform the Mission
that, in a letter dated 24 November 2022, the Director-General of
the World Health Organization (WHO), pursuant to article 3,
paragraphs 1 and 3 of the Single Convention on Narcotic Drugs of
1961 as amended by the 1972 Protocol (1961 Convention), and article
2, paragraphs 1 and 4 of the Convention on Psychotropic Substances
of 1971 (1971 Convention), notified the Secretary-General of the
following recommendations of the Forty-fifth Meeting of the WHO's
Expert Committee on Drug Dependence (ECDD):
Substances recommended to be added to Schedule I of the 1961
Convention:
--2-Methyl-AP-237
IUPAC (International Union of Pure and Applied Chemistry) name: 1-
[2-Methyl-4-(3-phenyl-2-propen-1-yl)-1-piperazinyl]-1-butanone
--Etazene
IUPAC name: 2-[(4-Ethoxyphenyl)methyl]-N,N-diethyl-1H-benzimidazole-
1-ethanamine
--Etonitazepyne
IUPAC name: 2-[(4-Ethoxyphenyl)methyl]-5-nitro-1-(2-pyrrolidin-1-
ylethyl)-1H-benzoimidazole
--Protonitazene
IUPAC name: N,N-Diethyl-5-nitro-2-[(4-propoxyphenyl)methyl]-1H-
benzimidazole-1-ethanamine
Substance recommended to be added to Schedule II of the 1971
Convention:
--ADB-BUTINACA
IUPAC name: N-[1-(Aminocarbonyl)-2,2-dimethylpropyl]-1-butyl-1H-
indazole-3-carboxamide
--alpha-PiHP
IUPAC name: 4-Methyl-1-phenyl-2-(pyrrolidin-1-yl)pentan-1-one
--3-Methylmethcathinone
IUPAC name: 2-(Methylamino)-1-(3-methylphenyl)propan-1-one
Substances to be kept under surveillance:
In the letter from the Director-General of WHO to the Secretary-
General, reference is also made to the recommendation made by the
WHO Expert Committee on Drug Dependence (ECDD), at its forty-fifth
meeting, to keep the following substances under surveillance:
--Adinazolam
IUPAC name: 8-Chloro-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-
a][1,4]benzodiazepine-1-methanamine
--Bromazolam
IUPAC name: 8-Bromo-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-
a][1,4]benzodiazepine
--Zopiclone
IUPAC name: 6-(5-Chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-
pyrrolo[3,4-b]pyrazin-5-yl 4-methylpiperazine-1-Carboxylate
In accordance with the provisions of article 3, paragraph 2, of
the 1961 Convention and article 2, paragraph 2, of the 1971
Convention, the notification is hereby transmitted as Annex I to the
present note. In connection with the notification, WHO also
submitted a summary of the assessments and findings for these
recommendations made by ECDD in Annex 1 to the letter to the
Secretary-General, which is transmitted herewith in Annex II.
Also, in accordance with the same provisions, the notification
from WHO will be brought to the attention of the sixty-sixth session
of the Commission on Narcotic Drugs (13-17 March 2023) in a pre-
session document that will be made available in the six official
languages of the United Nations on the website of the 66th session
of the Commission on Narcotic Drugs: https://www.unodc.org/unodc/en/commissions/CND/session/66_Session_2023/66CND_Main.html.
In order to assist the Commission in reaching a decision, it
would be appreciated if the Mission could communicate any comments
it considers relevant to the possible scheduling of substances
recommended by WHO to be placed under international control under
the 1961 Convention, namely:
--2-Methyl-AP-237
--Etazene
--Etonitazepyne
--Protonitazene;
as well as any economic, social, legal, administrative, or other
factors that it considers relevant to the possible scheduling of
substances recommended by WHO to be placed under international
control under the 1971 Convention, namely:
--ADB-BUTINACA
--alpha-PiHP
--3-Methylmethcathinone
The Secretariat of the United Nations avails itself of this
opportunity to renew to the Permanent Mission of the United States
of America to the United Nations (Vienna) the assurances of its
highest consideration.
Annex I
Letter addressed to the Secretary-General of the United Nations
from the Director-General of the World Health Organization, dated 24
November 2022:
``I have the honour to refer to the Forty-fifth Meeting of the
World Health Organization (WHO) Expert Committee on Drug Dependence
(ECDD) that was convened in Geneva, Switzerland from 10 to 13
October 2022.
WHO is mandated by the 1961 and 1971 International Drug Control
Conventions to make recommendations to the United Nations Secretary-
General on the need for a level of international control of
psychoactive substances based on the advice of its independent
scientific advisory body, the ECDD. To assess the appropriate
control of a psychoactive substance, WHO convenes ECDD annually to
review the potential of a substance to cause dependence, abuse and
harm to health, as well as any therapeutic applications.
The Forty-fifth WHO ECDD Meeting critically reviewed nine new
psychoactive substances: one synthetic cannabinoid receptor agonist
(ADB-BUTINACA), four novel synthetic opioids (2-Methyl-AP-237,
etazene, etonitazepyne, and protonitazene), two cathinones/
stimulants (alpha-PiHP, 3-methylmethcathinone), and two
benzodiazepines (adinozolam, bromazolam). These substances had not
previously been formally reviewed by WHO and are currently not under
international control.
Information was brought to WHO's attention that these substances
are clandestinely manufactured, of risk to public health and
society, and of no recognized therapeutic use by any party.
Therefore, a critical review to consider international scheduling
measures was undertaken for each substance so that the Expert
Committee could consider whether information about these substances
may justify the scheduling of a substance in the 1961 or 1971
Conventions. In addition, the Forty-fifth ECDD carried out a pre-
review of zopiclone to consider whether current information
justified a critical review.
With reference to Article 3, paragraphs 1 and 3 of the Single
Convention on Narcotic Drugs (1961), as amended by the 1972
Protocol, and Article 2, paragraphs 1 and 4 of the Convention on
Psychotropic Substances (1971), WHO is pleased to endorse and submit
the following recommendations of the Forty-fifth Meeting of the
ECDD:
To be added to Schedule I of the Single Convention on Narcotic
Drugs (1961):
--2-Methyl-AP-237
IUPAC (International Union of Pure and Applied Chemistry) name: 1-
[2-Methyl-4-(3-phenyl-2-propen-1-yl)-1-piperazinyl]-1-butanone
--Etazene
IUPAC name: 2-[(4-Ethoxyphenyl)methyl]-N,N-diethyl-1H-benzimidazole-
1-ethanamine
--Etonitazepyne
[[Page 10347]]
IUPAC name: 2-[(4-Ethoxyphenyl)methyl]-5-nitro-1-(2-pyrrolidin-1-
ylethyl)-1H-benzoimidazole
--Protonitazene
IUPAC name: N,N-Diethyl-5-nitro-2-[(4-propoxyphenyl)methyl]-1H-
benzimidazole-1-ethanamine
To be added to Schedule II of the Convention on Psychotropic
Substances (1971):
--ADB-BUTINACA
IUPAC name: N-[1-(Aminocarbonyl)-2,2-dimethylpropyl]-1-butyl-1H-
indazole-3-carboxamide
--alpha-PiHP
IUPAC name: 4-Methyl-1-phenyl-2-(pyrrolidin-1-yl)pentan-1-one
--3-Methylmethcathinone
IUPAC name: 2-(Methylamino)-1-(3-methylphenyl)propan-1-one
To be kept under surveillance:
--Adinazolam
IUPAC name: 8-Chloro-N,N-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-
a][1,4]benzodiazepine-1-methanamine
--Bromazolam
IUPAC name: 8-Bromo-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-
a][1,4]benzodiazepine
--Zopiclone
IUPAC name: 6-(5-Chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-
pyrrolo[3,4-b]pyrazin-5-yl 4-methylpiperazine-1-Carboxylate
The assessments and findings on which these recommendations are
based are set out in detail in the Forty-fifth Meeting report of the
WHO Expert Committee on Drug Dependence. A summary of the assessment
and recommendations made by the ECDD is contained in Annex 1 to this
letter.
I am pleased with the ongoing collaboration between WHO, the
United Nations Office on Drugs and Crime, and the International
Narcotics Control Board, and in particular, how this collaboration
has benefited the work of the WHO Expert Committee on Drug
Dependence and more generally, the implementation of the operational
recommendations of the United Nations General Assembly Special
Session 2016.''
Annex II
45th WHO ECDD Summary Assessments, Findings and Recommendations, 10-13
October 2022
Substances to be added to Schedule I of the Single Convention on
Narcotic Drugs (1961).
2-Methyl-AP-237
Substance Identification
2-Methyl-AP-237 (IUPAC chemical name: 1-[2-Methyl-4-(3-phenyl-2-
propen-1-yl)-1-piperazinyl]-1-butanone) is a methyl derivative of
the opioid analgesic AP-237 (or bucinnazine). 2-Methyl-AP-237 has
been described as a white crystalline powder, a crystalline solid,
and a white solid.
WHO Review History
2-Methyl-AP-237 has been under WHO surveillance but has not been
formally reviewed by WHO, and is not currently under international
control. Information was brought to the attention of WHO that this
substance is manufactured clandestinely, poses a risk to public
health and has no recognized therapeutic use.
Similarity to Known Substances and Effects on the Central Nervous
System
2-Methyl-AP-237 is an opioid analgesic with a rapid onset of
action and a potency and analgesic effects similar to those of
fentanyl, which is listed under Schedule I of the Single Convention
on Narcotic Drugs, 1961. In animals, it produces acute toxic effects
typical of opioids, including respiratory depression. Limited
research has been reported on the effects of 2-methyl-AP-237 in
humans, although its respiratory depressant effects have been
observed, which can be reversed by the opioid antagonist, naloxone.
Dependence Potential
No controlled studies of the dependence potential of 2-methyl-
AP-237 have been reported in animals or humans. As it is a [mu]-
opioid receptor agonist, it would be expected to produce dependence
similar to that induced by other opioids, such as morphine and
fentanyl. Online self-reports described tolerance and withdrawal.
Actual Abuse and/or Evidence of Likelihood of Abuse
In an animal model predictive of abuse potential, 2-methyl-AP-
237 was shown to produce opioid-like effects with a potency between
those of morphine and fentanyl. These effects were blocked by the
opioid antagonist, naltrexone.
No controlled studies on the abuse potential of 2-methyl-AP-237
in humans have been reported, but, as it is a [mu]-opioid receptor
agonist, it would be expected to produce euphoria and other effects
predictive of high abuse liability. Online self-reports support its
euphoric and other opioid effects.
Seizures of 2-methyl-AP-237 have been reported in multiple
countries in two regions. A number of deaths in which 2-methyl-AP-
237 has been found have been reported, often with multiple
substances involved. The deaths occurred in a number of countries
and regions.
Therapeutic Usefulness
2-Methyl-AP-237 is not known to have any therapeutic use.
Recommendation
2-Methyl-AP-237 (IUPAC chemical name: 1-[2-Methyl-4-(3-phenyl-2-
propen-1-yl)-1-piperazinyl]-1-butanone) is a synthetic opioid that
is liable to abuse and to have ill effects similar to those of other
opioids that are controlled under Schedule I of the 1961 Single
Convention on Narcotic Drugs. Its use has been reported in a number
of countries and has been associated with adverse effects, including
death. It has no known therapeutic use and is likely to cause
substantial harm.
Recommendation: The Committee recommended that 2-methyl-AP-237
(IUPAC chemical name: 1-[2-Methyl-4-(3-phenyl-2-propen-1-yl)-1-
piperazinyl]-1-butanone) be added to Schedule I of the 1961 Single
Convention on Narcotic Drugs.
Etazene
Substance Identification
Etazene (IUPAC chemical name: 2-[(4-ethoxyphenyl)methyl]-N,N-
diethyl-1H-benzimidazole-1-ethanamine), also known as
etodesnitazene, is a benzimidazole-derived synthetic opioid. Etazene
has been described as a grey crystalline, light-yellow, white, or
beige powder. It has also been identified in liquid form and in
falsified pharmaceutical opioids.
WHO Review History
Etazene has not been formally reviewed by WHO and is not
currently under international control. Information was brought to
the attention of WHO that this substance is manufactured
clandestinely, poses a risk to public health and has no recognized
therapeutic use.
Similarity to Known Substances and Effects on the Central Nervous
System
Etazene binds to the [mu]-opioid receptor with a potency greater
than that of morphine. In studies of analgesia in animals, etazene
had full agonist effects, with a potency between those of morphine
and fentanyl, which are both controlled under Schedule I of the
Single Convention on Narcotic Drugs, 1961. The effects of etazene
are reversed by the opioid antagonist, naltrexone.
Dependence Potential
No controlled studies of the dependence potential of etazene in
animals or in humans have been reported. As it is a potent [mu]-
opioid receptor agonist, it would be expected to produce dependence
similar to other opioids, such as morphine and fentanyl. Online
self-reports described tolerance with repeated use of etazene.
Actual Abuse and/or Evidence of Likelihood of Abuse
In an animal model predictive of abuse potential, etazene had
effects similar to those of morphine. No controlled studies have
been conducted of the abuse potential of etazene in humans, but, as
it is a potent [mu]-opioid receptor agonist, it would be expected to
produce euphoria and other effects predictive of high abuse
liability. Online self-reports support its euphoric and other opioid
effects.
Seizures of etazene have been reported in multiple countries in
two regions.
A number of deaths have occurred in which the presence of
etazene was confirmed analytically and in which it was considered to
have contributed to death, although other substances were also
identified in these cases.
Therapeutic Usefulness
Etazene is not known to have any therapeutic use.
Recommendation
Etazene (IUPAC chemical name: 2-[(4-ethoxyphenyl)methyl]-N,N-
diethyl-1H-benzimidazole-1-ethanamine), also known as
etodesnitazene, is a synthetic opioid that is liable to abuse and
produces ill effects similar to other opioids that are controlled
under Schedule I of the 1961 Single Convention on Narcotic Drugs.
Its use has been reported in a number of countries and
[[Page 10348]]
has been associated with adverse effects, including death. It has no
known therapeutic use and poses a significant risk to public health.
Recommendation: The Committee recommended that etazene (IUPAC
chemical name: 2-[(4-ethoxyphenyl)methyl]-N,N-diethyl-1H-
benzimidazole-1-ethanamine), also known as etodesnitazene, be added
to Schedule I of the 1961 Single Convention on Narcotic Drugs.
Etonitazepyne
Substance Identification
Etonitazepyne (IUPAC chemical name: 2-[(4-ethoxyphenyl)methyl]-
5-nitro-1-(2-pyrrolidin-1-ylethyl)-1H-benzoimidazole), also known as
N-pyrrolidino etonitazene, is a benzimidazole-derived synthetic
opioid. Etonitazepyne is found as a yellow powder and crystalline
solid and has been identified in falsified pharmaceutical opioid
tablets.
WHO Review History
Etonitazepyne has not been formally reviewed by WHO and is not
currently under international control. Information was brought to
the attention of WHO that this substance is manufactured
clandestinely, poses a risk to public health, and has no recognized
therapeutic use.
Similarity to Known Substances and Effects on the Central Nervous
System
Studies in animals have demonstrated that etonitazepyne is a
potent, full agonist at [mu]-opioid receptors. In animals, it
produces effects similar to those of opioids such as morphine,
fentanyl, and isotonitazene but with greater potency. There is
limited information about the effects of etonitazepyne alone in
humans.
Dependence Potential
No controlled studies of the dependence potential of
etonitazepyne in animals or humans have been reported. As it is a
potent [mu]-opioid receptor agonist, it would be expected to produce
dependence similarly to other opioids, such as morphine and
fentanyl. Online self-reports describe tolerance and withdrawal
after repeated etonitazepyne use.
Actual Abuse and/or Evidence of Likelihood of Abuse
In an animal model predictive of abuse potential, etonitazepyne
was shown to produce effects that indicated greater potency compared
to morphine and fentanyl, and these effects were reversed by the
opioid antagonist, naltrexone.
Seizures of etonitazepyne have been reported in multiple
countries in two regions. It is reported to be administered by
various routes, including snorting, sniffing, and oral
administration. Etonitazepyne has been identified in falsified
medicines, suggesting that its use may sometimes be unintentional.
Etonitazepyne is a relatively new drug on the illicit market,
and there is limited information on the prevalence of its use and of
its harm, although non-fatal and fatal intoxications have been
documented in a number of countries. The number of deaths involving
etonitazepyne has increased over a relatively short time but may be
underreported because of its recent, rapid appearance.
Therapeutic Usefulness
Etonitazepyne is not known to have any therapeutic use.
Recommendation
Etonitazepyne (IUPAC chemical name: 2-[(4-ethoxyphenyl)methyl]-
5-nitro-1-(2-pyrrolidin-1-ylethyl)-1H-benzoimidazole), also known as
N-pyrrolidino etonitazene, is a synthetic opioid that is liable to
abuse and to produce ill effects similar to other opioids that are
controlled under Schedule I of the 1961 Single Convention on
Narcotic Drugs. Its use has been reported in a number of countries
and has been associated with adverse effects, including death. It
has no known therapeutic use and poses a significant risk to public
health.
Recommendation: The Committee recommended that etonitazepyne
(IUPAC chemical name: 2-[(4-ethoxyphenyl)methyl]-5-nitro-1-(2-
pyrrolidin-1-ylethyl)-1H-benzoimidazole), also known as N-
pyrrolidino etonitazene, be added to Schedule I of the 1961 Single
Convention on Narcotic Drugs.
Protonitazene
Substance Identification
Protonitazene (IUPAC chemical name: N,N-Diethyl-5-nitro-2-[(4-
propoxyphenyl)methyl]-1H-benzimidazole-1-ethanamine), also known as
propoxynitazene, is a 5-nitro-2-benzylbenzimidazole synthetic
opioid. Protonitazene has been described as a white, yellow, or
brown powder and as a crystalline solid.
WHO Review History
Protonitazene has not been formally reviewed by WHO and is not
currently under international control. Information was brought to
the attention of WHO that this substance is manufactured
clandestinely, poses a risk to public health and has no recognized
therapeutic use.
Similarity to Known Substances and Effects on the Central Nervous
System
Protonitazene is a chemical analogue of metonitazene and
etonitazene, which are controlled under Schedule I of the Single
Convention on Narcotic Drugs of 1961. Studies in animals have
demonstrated that protonitazene is a full agonist at [mu]-opioid
receptors, with greater potency than morphine and similar potency to
fentanyl. Its effects are blocked by the opioid antagonist,
naltrexone.
Dependence Potential
No controlled studies of the dependence potential of
protonitazene in animals or humans have been reported. As it is a
potent [mu]-opioid receptor agonist, it would be expected to produce
dependence similar to other opioids such as morphine and fentanyl.
Actual Abuse and/or Evidence of Likelihood of Abuse
In animals, protonitazene showed potent opioid effects and abuse
potential, similar to those of morphine and fentanyl. Its abuse
potential has not been studied in humans; however, online self-
reports indicate typical opioid effects, including sedation and
euphoria.
Protonitazene is relatively new on the illicit drug market, and
there is limited information on the prevalence of its use or of its
harm. The only available information is that several fatalities have
occurred in which the presence of protonitazene was confirmed,
usually with other substances. The number of deaths may be
underreported because of limitations in testing, including
difficulty in differentiating this substance from isotonitazene.
Protonitazene is reported to be administered through various
routes, including intranasally and intravenously.
Seizures of protonitazene have been reported in multiple
countries in two regions.
Therapeutic Usefulness
Protonitazene is not known to have any therapeutic use.
Recommendation
Protonitazene (IUPAC chemical name: N,N-Diethyl-5-nitro-2-[(4-
propoxyphenyl)methyl]-1H-benzimidazole-1-ethanamine), also known as
propoxynitazene, is a synthetic opioid that is liable to abuse and
to produce ill effects similar to other opioids that are controlled
under Schedule I of the 1961 Single Convention on Narcotic Drugs.
Its use has been reported in a number of countries and has been
associated with adverse effects, including death. It has no known
therapeutic use and is likely to cause substantial harm.
Recommendation: The Committee recommended that protonitazene
(IUPAC chemical name: N,N-Diethyl-5-nitro-2-[(4-
propoxyphenyl)methyl]-1H-benzimidazole-1-ethanamine), also known as
propoxynitazene, be added to Schedule I of the 1961 Single
Convention on Narcotic Drugs.
Substances to be added to Schedule II of the Convention on
Psychotropic Substances (1971).
ADB-BUTINACA
Substance Identification
ADB-BUTINACA (IUPAC chemical name: N-[1-(aminocarbonyl)-2,2-
dimethylpropyl]-1-butyl-1H-indazole-3-carboxamide) is an indazole-
derived synthetic cannabinoid. It is described as a crystalline
solid or a beige or yellowish powder and has also been found sprayed
onto plant material and paper. It is commonly smoked or vaped,
although isolated cases of oral use have also been reported.
WHO Review History
ADB-BUTINACA has not been formally reviewed by WHO and is not
currently under international control. Information was brought to
the attention of WHO that this substance is manufactured
clandestinely, poses a risk to public health, and has no recognized
therapeutic use.
Similarity to Known Substances and Effects on the Central Nervous
System
ADB-BUTINACA is a synthetic cannabinoid that binds to CB1 and
CB2 receptors with high affinity and is a potent
[[Page 10349]]
full agonist at both receptors. Its effects are similar to those of
other potent CB1 agonists that are currently controlled under
Schedule II of the Convention on Psychotropic Substances of 1971.
No controlled studies of the effects of ADB-BUTINACA have been
reported. Online self-reports describe euphoria, appetite
stimulation, sedation, and paranoia after its use. These effects are
consistent with the known effects of cannabinoid agonists.
Dependence Potential
No controlled studies of the dependence potential of ADB-
BUTINACA in animals or humans have been reported. However, its
effects at the CB1 receptor suggest that it would be expected to
produce dependence similar to other synthetic cannabinoids.
Actual Abuse and/or Evidence of Likelihood of Abuse
In an animal model predictive of abuse potential, ADB-BUTINACA
had effects similar to the CB1 receptor agonist delta-9-
tetrahydrocannabinol. No studies have been conducted to determine
the likelihood of abuse of ADB-BUTINACA in humans; however, CB1
receptor agonists have known abuse potential.
A number of countries in various regions have reported use of
ADB-BUTINACA and harm related to its use, including multiple deaths
and presentations of patients to emergency departments with altered
consciousness and loss of consciousness. Other substances were
usually also involved in these cases, although a number of deaths
involved only ADB-BUTINACA.
Therapeutic Usefulness
ADB-BUTINACA is not known to have any therapeutic use.
Recommendation
ADB-BUTINACA (N-[1-(aminocarbonyl)-2,2-dimethylpropyl]-1-butyl-
1H-indazole-3-carboxamide) is a potent synthetic cannabinoid
receptor agonist with a mechanism of action and effects similar to
those of a number of other synthetic cannabinoids that are
controlled under Schedule II of the Convention on Psychotropic
Substances of 1971. Its mode of action suggests the likelihood of
abuse and potential for dependence. Use of ADB-BUTINACA has been
associated with severe adverse effects, including fatal
intoxications. ADB-BUTINACA has no known therapeutic use.
Recommendation: The Committee recommended that ADB-BUTINACA (N-
[1-(aminocarbonyl)-2,2-dimethylpropyl]-1-butyl-1H-indazole-3-
carboxamide) be added to Schedule II of the Convention on
Psychotropic Substances of 1971.
Alpha-PiHP
Substance Identification
Alpha-pyrrolidinoisohexanophenone (IUPAC chemical name: 4-
Methyl-1-phenyl-2-(pyrrolidin-1-yl)pentan-1-one), also known as
alpha-PiHP, is a synthetic cathinone. It has been described as an
off-white solid, a white powder, and a crystalline solid.
WHO Review History
Alpha-PiHP has been under WHO surveillance but has not been
formally reviewed by WHO and is not currently under international
control. Information was brought to the attention of WHO that this
substance is manufactured clandestinely, poses a risk to public
health, and has no recognized therapeutic use.
Similarity to Known Substances and Effects on the Central Nervous
System
Alpha-PiHP is an isomer of alpha-PHP, which is controlled under
Schedule II of the Convention on Psychotropic Substances of 1971.
Laboratory studies suggest that alpha-PiHP can inhibit the uptake of
dopamine and norepinephrine more potently than substances with known
abuse potential, including methcathinone, cocaine, and
methamphetamine. Studies in animals have shown that alpha-PiHP is a
psychomotor stimulant, with effects comparable to those of cocaine
and methamphetamine.
Online self-reports by people who use alpha-PiHP describe
stimulant effects similar to those of alpha-PVP and alpha-PHP.
Dependence Potential
No controlled studies of the dependence potential of alpha-PiHP
in animals or humans have been reported. In view of its actions and
effects on the central nervous system, it would be expected to
produce dependence similarly to other psychostimulants such as
methamphetamine.
Actual Abuse and/or Evidence of Likelihood of Abuse
Studies in animals predictive of abuse liability indicate that
alpha-PiHP produces effects similar to those of methamphetamine and
cocaine. No controlled studies of the abuse potential of alpha-PiHP
in humans have been reported.
Seizures of alpha-PiHP have been described in multiple countries
in three regions.
Alpha-PiHP has been identified in a number of serious adverse
events and drug-related deaths. As it is usually detected with other
substances, including opioids and benzodiazepines, the role of
alpha-PiHP is unclear in some instances.
Therapeutic Usefulness
Alpha-PiHP is not known to have any therapeutic use.
Recommendation
Alpha-pyrrolidinoisohexanophenone (IUPAC chemical name: 4-
Methyl-1-phenyl-2-(pyrrolidin-1-yl)pentan-1-one), also known as
alpha-PiHP, is a synthetic cathinone with effects similar to those
of other synthetic cathinones and other psychostimulants, such as
methamphetamine, that are listed under Schedule II of the Convention
on Psychotropic Substances of 1971. There is evidence that its abuse
is likely to constitute a substantial public health and social
problem. It has no known therapeutic use.
Recommendation: The Committee recommended that alpha-
pyrrolidinoisohexanophenone (IUPAC chemical name: 4-Methyl-1-phenyl-
2-(pyrrolidin-1-yl)pentan-1-one), also known as alpha-PiHP, be added
to Schedule II of the 1971 Convention on Psychotropic Substances.
3-Methylmethcathinone
Substance Identification
3-Methylmethcathinone (IUPAC chemical name: 2-(methylamino)-1-
(3-methylphenyl)propan-1-one), also known as 3-MMC, is a synthetic
cathinone. 3-Methylmethcathinone has been found as a white or off-
white powder, a white, yellow, or orange solid, and a crystalline
solid. It has been detected in tablet, capsule, and liquid forms.
WHO Review History
3-Methylmethcathinone was critically reviewed by the Committee
at its 38th meeting, in 2016, when it decided to request a further
critical review once more information became available and to
consider it at a subsequent meeting. Information was brought to the
attention of WHO that this substance is manufactured clandestinely,
poses a risk to public health, and has no recognized therapeutic
use. Information from international agencies suggests that there has
been a significant increase in the availability of and harm due to
3-methylmethcathinone in recent years.
Similarity to Known Substances and Effects on the Central Nervous
System
3-Methylmethcathinone is an isomer of 4-methylmethcathinone
(mephedrone), which is a synthetic cathinone listed under Schedule
II of the Convention on Psychotropic Substances of 1971.
3-Methylmethcathinone has a typical psychostimulant profile,
similar to that of 4-methylmethcathinone, including inhibition of
the reuptake of dopamine, norepinephrine, and serotonin, and
increased release of dopamine and serotonin.
Clinical features of 3-methylmethcathinone intoxication are
consistent with those produced by other stimulants and include
tachycardia, hypertension, agitation, aggression, hallucinations,
rhabdomyolysis, and kidney failure.
Dependence Potential
No controlled studies of the dependence potential of 3-
methylmethcathinone in animals or humans have been reported.
Withdrawal symptoms indicative of physical dependence have been
documented in people who use 3-methylmethcathinone. In view of its
actions and effects on the central nervous system, 3-
methylmethcathinone would be expected to produce dependence similar
to other psychostimulants, such as methamphetamine.
Actual Abuse and/or Evidence of Likelihood of Abuse
In animal models predictive of rewarding effects, 3-
methylmethcathinone produced effects that were similar to those of
methamphetamine. 3-Methylmethcathinone also produced behavioural
(stimulant) effects similar to methamphetamine. No controlled
studies in humans have examined the abuse potential of 3-
methylmethcathinone.
3-Methylmethcathinone has been seized in multiple countries in
several regions. Many fatal and non-fatal intoxications involving 3-
[[Page 10350]]
methylmethcathinone have been reported. Other substances were
commonly involved in these cases, although severe intoxication and
death have been reported in cases in which 3-methylmethcathinone was
the only substance identified.
Therapeutic Usefulness
3-Methylmethcathinone is not known to have any therapeutic use.
Recommendation
3-Methylmethcathinone (IUPAC chemical name: 2-(methylamino)-1-
(3-methylphenyl)propan-1-one), also known as 3-MMC, is a synthetic
cathinone with effects similar to those of other synthetic
cathinones and other psychostimulants such as methamphetamine that
are listed under Schedule II of the Convention on Psychotropic
Substances of 1971. There is evidence that its abuse is likely to
constitute a substantial public health and social problem. It has no
known therapeutic use.
Recommendation: The Committee recommended that 3-
Methylmethcathinone (IUPAC chemical name: 2-(methylamino)-1-(3-
methylphenyl)propan-1-one), also known as 3-MMC, be added to
Schedule II of the Convention on Psychotropic Substances of 1971.
Substances to be kept under surveillance:
Adinazolam
Substance Identification
Adinazolam (IUPAC chemical name: 8-Chloro-N,N-dimethyl-6-phenyl-
4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-methanamine) is a
triazolobenzodiazepine. Adinazolam appears as a white or yellow
powder and is also sold as tablets and capsules, including as
falsified pharmaceuticals.
WHO Review History
Adinazolam has not been formally reviewed by WHO and is not
currently under international control. Information was brought to
the attention of WHO that this substance is manufactured
clandestinely, poses a risk to public health, and has no recognized
therapeutic use.
Similarity to Known Substances and Effects on the Central Nervous
System
Adinazolam is a short-acting benzodiazepine with moderate
affinity for the benzodiazepine receptor. It is a chemical analogue
of alprazolam and triazolam.
Consistent with its benzodiazepine receptor action, adinazolam
showed anticonvulsant, anxiolytic and antidepressant properties in
animals. In humans, adinazolam (and its metabolite N-
desmethyladinazolam) produced a dose-dependent decrease in
psychomotor performance and increased sedation and amnesia. It also
had some subjective effects similar to those of benzodiazepines such
as diazepam and lorazepam, which are controlled under Schedule IV of
the 1971 Convention on Psychotropic Substances.
Dependence Potential
No studies have been conducted in animals or humans on the
dependence potential of adinazolam. In view of its mechanism of
action, however, it would be expected to produce typical
benzodiazepine dependence.
Actual Abuse and/or Evidence of Likelihood of Abuse
In animals, adinazolam shows behavioural effects consistent with
those of drugs with abuse liability. In controlled studies in
humans, adinazolam produced sedation, and, in one controlled study,
adinazolam produced a self-reported ``high'' feeling, with a greater
estimated street value than placebo.
While seizures of adinazolam have been reported in a few
countries in two regions, currently there is insufficient evidence
that it is being abused to such an extent as to constitute a public
health problem.
Adinazolam was identified in a few drug-related deaths in
combination with other psychoactive substances, including opioids
and other benzodiazepines; however, there was no evidence that
adinazolam played a causative role in these deaths.
Therapeutic Usefulness
Adinazolam is not known to have any therapeutic use.
Recommendation
Adinazolam (IUPAC chemical name: 8-Chloro-N,N-dimethyl-6-phenyl-
4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-methanamine) has
effects similar to those of substances listed under Schedule IV of
the Convention on Psychotropic Substances of 1971. There is,
however, insufficient evidence that its use is a public health and
social problem to justify its placement under international control.
Recommendation: The Committee recommended that adinazolam (IUPAC
chemical name: 8-Chloro-N,N-dimethyl-6-phenyl-4H-
[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-1-methanamine) be kept
under surveillance by the WHO Secretariat.
Bromazolam
Substance Identification
Bromazolam (8-Bromo-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-
a][1,4]benzodiazepine) is a triazolobenzodiazepine. Bromazolam has
been described as a white or crystalline solid and has been
identified in tablets, capsules, powders, solutions, and edible
products. Bromazolam has been identified in falsified pharmaceutical
benzodiazepine products.
WHO Review History
Bromazolam has not been formally reviewed by WHO and is not
currently under international control. Information was brought to
the attention of WHO that this substance is manufactured
clandestinely, poses a risk to public health and has no recognized
therapeutic use.
Similarity to Known Substances and Effects on the Central Nervous
System
There is currently insufficient information on the
pharmacological profile of bromazolam from controlled studies in
animals or humans to conclude that it has effects similar to those
of benzodiazepines, which are controlled under the 1971 Convention
on Psychotropic Substances.
Online self-reports by people who claim to have used bromazolam
describe benzodiazepine-like effects, including hypnotic, sedative,
muscle relaxant, and euphoric effects. There are, however, no
clinical reports or analytical confirmation of bromazolam to confirm
these effects.
Dependence Potential
No controlled studies in animals or humans have been reported on
the dependence potential of bromazolam. Online self-reports describe
withdrawal symptoms after cessation of chronic use.
Actual Abuse and/or Evidence of Likelihood of Abuse
No controlled studies in animals or humans have been reported on
the abuse liability of bromazolam. In self-reports online, people
have described using the drug for its euphoric and other
benzodiazepine-like effects; however, there is no confirmation that
that the substance used was bromazolam.
Seizures of bromazolam have been reported in multiple countries
in several regions. Bromazolam has been analytically confirmed in a
number of deaths, non-fatal intoxications, and instances of driving
under the influence of drugs. Because of the presence of other
drugs, especially other benzodiazepines; however, the contribution
of bromazolam cannot be determined.
Therapeutic Usefulness
Bromazolam is not known to have any therapeutic uses and has
never been marketed as a medicinal product.
Recommendation
While the chemical structure of bromazolam (8-Bromo-1-methyl-6-
phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine) is similar to
those of other benzodiazepines listed under the Convention on
Psychotropic Substances of 1971, its mechanism of action and effects
are yet to be confirmed. Although there is increasing evidence of
its use, no studies in animals or humans have been reported on the
effects or abuse potential of bromazolam. The limited information on
its effects provides insufficient evidence to justify placement of
bromazolam under international control.
Recommendation: The Committee recommended that bromazolam (8-
Bromo-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-
a][1,4]benzodiazepine) be kept under surveillance by the WHO
Secretariat.
Zopiclone
Substance Identification
Zopiclone (IUPAC chemical name: 6-(5-Chloropyridin-2-yl)-7-oxo-
6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-methylpiperazine-1-
carboxylate) is a sedative hypnotic drug of the cyclopyrrolone
class. Zopiclone has been reported as a white or slightly yellowish
powder. Zopiclone is available as pharmaceutical products in tablet
form for oral use. Eszopiclone (the S-enantiomer of zopiclone) is
marketed as a pharmaceutical product in some countries.
WHO Review History
Zopiclone was pre-reviewed by the Committee at its 29th meeting,
when it recommended that surveillance be continued but that a
critical review was not required.
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In view of the abuse liability of the drug and the significant
number of reports of adverse drug reactions related to zopiclone
abuse sent to the WHO international drug monitoring programme;
however, zopiclone was pre-reviewed by the Committee at its 33rd
meeting, when it recommended a critical review. Zopiclone was
critically reviewed at the 34th meeting, in 2006, when the Committee
rated its abuse liability as low and its therapeutic usefulness
considerable and recommended continued surveillance by WHO. A pre-
review was initiated after a proposal was received from an
international agency that suggested a significant increase in the
reported number of trafficking cases and seizures involving
zopiclone.
Similarity to Known Substances and Effects on the Central Nervous
System
Zopiclone binds to the benzodiazepine receptor that forms part
of the GABAA receptor complex. It may bind to different parts of the
receptor or cause different changes in the GABAA receptor complex
than benzodiazepines.
In animals, zopiclone has sedative, anxiolytic, anticonvulsant,
and muscle relaxant properties similar to those of benzodiazepines.
In studies in humans, it was less effective than benzodiazepines for
treatment of anxiety.
Dependence Potential
Studies in animals show evidence of zopiclone tolerance and
withdrawal, indicating the development of physical dependence. A
number of published reports have described physical dependence
associated with zopiclone use in humans. Withdrawal symptoms such as
increased anxiety and insomnia have been described in people who
cease zopiclone use, usually after prolonged use and dose escalation
from clinical use. Tolerance and withdrawal have also been reported
in clinical trials. Dependence is documented in databases on adverse
events associated with pharmaceutical use.
Actual Abuse and/or Evidence of Likelihood of Abuse
Studies in animals suggest that zopiclone may have abuse
liability similar to that of benzodiazepines such as midazolam,
diazepam, nitrazepam, and alprazolam. The effects indicative of
abuse liability were blocked by the benzodiazepine antagonist
flumazenil, indicating a mechanism of action involving the
benzodiazepine receptor.
No controlled studies in humans have been reported on the abuse
potential of zopiclone. Published reports describe effects
consistent with benzodiazepine-like abuse potential, its use with
alcohol and other drugs and escalation to high-dose use. The extent
of harm related to the use of zopiclone is, however, unclear.
Zopiclone is widely used therapeutically in many countries and
regions, and it is also listed in databases of adverse events
associated with pharmaceutical use. Zopiclone is most likely to be
misused by individuals to whom it is prescribed for long periods,
who are using other psychoactive drugs or in those with psychiatric
comorbidities. While seizures of zopiclone have been reported in
multiple countries in several regions, the prevalence of non-medical
use of zopiclone by the general population is unknown. Furthermore,
there is insufficient evidence that significant public health and
social problems related to abuse can be directly attributed to sole
use of zopiclone.
Therapeutic Usefulness
Zopiclone is a widely used medicine primarily indicated for the
short-term treatment of insomnia, with marketing authorisations in
many countries. It is not listed on the WHO Model List of Essential
Medicines.
Recommendation
Zopiclone (IUPAC chemical name: 6-(5-Chloropyridin-2-yl)-7-oxo-
6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-methylpiperazine-1-
carboxylate) is a sedative hypnotic drug of the cyclopyrrolone
class. The Committee noted that concern has been expressed in
several countries regarding non-prescription use of zopiclone. While
there have been reports of adverse effects, overdose, withdrawal
symptoms and an increased number of seizures of the substance, there
is still insufficient evidence that zopiclone is or is likely to be
abused to such an extent as to constitute a public health and social
problem.
The Committee also noted that zopiclone is widely used
therapeutically in many countries.
Recommendation: The Committee recommended that zopiclone (IUPAC
chemical name: 6-(5-Chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-
pyrrolo[3,4-b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate) not
proceed to critical review but be kept under surveillance by the WHO
Secretariat.
III. Discussion
Although WHO has made specific scheduling recommendations for each
of the drug substances, the CND is not obliged to follow the WHO
recommendations. Options available to the CND for substances considered
for control under the 1971 Convention include the following: (1) accept
the WHO recommendations; (2) accept the recommendations to control but
control the drug substance in a schedule other than that recommended;
or (3) reject the recommendations entirely.
ADB-BUTINACA (chemical name: N-[1-(Aminocarbonyl)-2,2-
dimethylpropyl]-1-butyl-1H-indazole-3-carboxamide) is a synthetic
cannabinoid that is a potent agonist of the cannabinoid (CB) 1 and CB2
receptors. Adverse effects associated with synthetic cannabinoids
include euphoria, appetite stimulation, sedation, loss of
consciousness, and paranoia. The use of ADB-BUTINACA has been
associated with fatalities in the United States in which other drugs
were also detected. ADB-BUTINACA is not approved for medical use in the
United States. ADB-BUTINACA has been detected in the illicit drug
market in the United States since 2020 as evidenced by drug seizures.
As a positional isomer of AB-PINACA (N-(1-amino-3-methyl-1-oxobutan-2-
yl)-1-pentyl-1H-indazole-3-carboxamide), ADB-BUTINACA is controlled
under schedule I of the CSA. As such, additional permanent controls
will not be needed if ADB-BUTINACA is placed under schedule II of the
Convention on Psychotropic Substances.
Alpha-PiHP (4-methyl-1-phenyl-2-(pyrrolidin-1-yl)pentan-1-one) is a
synthetic cathinone with chemical and pharmacological properties
similar to schedule I and II amphetamines and cathinones such as alpha-
PHP, alpha-PVP, and MDPV. Reports of intoxication indicate that alpha-
PiHP produces psychoactive effects similar to methamphetamine and
cocaine. Adverse events associated with the abuse of synthetic
cathinones include, but are not limited to, agitation, hypertension,
tachycardia, and death. Alpha-PiHP is not approved for medical use in
the United States. Alpha-PiHP has been identified in a number of drug
seizures in the United States and has been detected in mixtures with
other drugs including opioids and benzodiazepines. As a positional
isomer of alpha-PHP (1-phenyl-2-(pyrrolidin-1-yl)hexan-1-one), alpha-
PiHP is controlled under schedule I of the CSA. As such, additional
permanent controls will not be needed if alpha-PiHP is placed in
Schedule II of the Convention on Psychotropic Substances.
3-Methylmethcathinone (2-(methylamino)-1-(3-methylphenyl)propan-1-
one) is a synthetic cathinone with chemical and pharmacological
properties similar to schedule I and II amphetamines and cathinones
such as amphetamine and 4-methylmethcathinone (mephedrone, 4-MMC).
Reports of intoxication of 3-methylmethcathinone indicate that it
produces psychoactive effects similar to stimulants such as
methamphetamine. These reports also indicate that it produces adverse
events which include tachycardia, hypertension, agitation, aggression,
hallucinations, rhabdomyolysis, and kidney failure. Several fatalities
have been reported in which 3-methylmethcathinone was the only drug
detected, however, in some other cases other drugs were detected. 3-
Methylmethcathinone is not approved for medical use in the United
States. 3-Methylmethcathinone has been identified in a number of drug
seizures in the United States and has been detected in mixtures with
other drugs including opioids and benzodiazepines. As a positional
isomer of 4-
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methylmethcathinone (2-(methylamino)-1-(4-methylphenyl)propan-1-one;
mephedrone), 3-methylmethcathinone is controlled under schedule I of
the CSA. As such, additional permanent controls will not be needed if
3-methylmethcathinone is placed in Schedule II of the Convention on
Psychotropic Substances.
FDA, on behalf of the Secretary of HHS, invites interested persons
to submit comments on the notifications from the United Nations
concerning these drug substances. FDA, in cooperation with the National
Institute on Drug Abuse, will consider the comments on behalf of HHS in
evaluating the WHO scheduling recommendations. Then, under section
201(d)(2)(B) of the CSA, HHS will recommend to the Secretary of State
what position the United States should take when voting on the
recommendations for control of substances under the 1971 Convention at
the CND meeting in March 2023.
Comments regarding the WHO recommendations for control of 2-methyl-
AP-237, etazene, etonitazepyne, and protonitazene under the 1961 Single
Convention will also be forwarded to the relevant Agencies for
consideration in developing the U.S. position regarding narcotic
substances at the CND meeting.
Dated: February 13, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-03375 Filed 2-16-23; 8:45 am]
BILLING CODE 4164-01-P
