[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]


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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.

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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.

[[Page 10351]]

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-

[[Page 10352]]

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


