[Federal Register Volume 89, Number 27 (Thursday, February 8, 2024)]
[Notices]
[Pages 8683-8689]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-02573]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2022-N-0105]


International Drug Scheduling; Convention on Psychotropic 
Substances; Single Convention on Narcotic Drugs; World Health 
Organization; Scheduling Recommendations; Butonitazene; 3-
Chloromethcathinone; Dipentylone; 2-Fluorodeschloroketamine; 
Bromazolam; 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 Commission on Narcotic Drugs (CND) in Vienna, Austria, in March 
2024. This notice is issued under the Controlled Substances Act (CSA).

DATES: Submit either electronic or written comments by February 27, 
2024.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be considered. Electronic comments 
must be submitted on or before February 27, 2024. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of February 27, 2024. 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-2022-N-0105 for ``International Drug Scheduling; Convention on 
Psychotropic Substances; Single Convention on Narcotic Drugs; World 
Health Organization; Scheduling Recommendations; Butonitazene; 3-
Chloromethcathinone; Dipentylone; 2-Fluorodeschloroketamine; 
Bromazolam; 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. 5110, Silver 
Spring, MD 20993-0002, 301-796-0727, [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

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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 four substances to be considered for 
control under the 1971 Convention. This notification reflects the 
recommendation from the 46th WHO Expert Committee for Drug Dependence 
(ECDD), which met in October 2023. In the Federal Register of August 
24, 2023 (88 FR 52179), 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 one substance to be 
considered for control under this convention. The CSA does not require 
HHS to publish a summary 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.18/2023
WHO/ECDD46; 1961C-Art.3, 1971C-Art.2
CU 2023/403/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 Permanent 
Mission that, in a letter dated 15 November 2023, 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-sixth Meeting of the WHO's 
Expert Committee on Drug Dependence (ECDD):
    Substance recommended to be added to Schedule I of the 1961 
Convention:

--Butonitazene
    IUPAC (International Union of Pure and Applied Chemistry) name: 
N,N-diethyl-2-[(4-butoxyphenyl)methyl]-5-nitro-1H-benzimidazole-1-
ethanamine

    Substances recommended to be added to Schedule II of the 1971 
Convention:

--3-chloromethcathinone or 3-CMC
    IUPAC name: 1-(3-chlorophenyl)-2-(methylamino)propan-1-one
--Dipentylone
    IUPAC name: 1-(1,3-benzodioxol-5-yl)-2-(dimethylamino)pentan-1-
one
--2-fluorodeschloroketamine
    IUPAC name: 2-(2-fluorophenyl)-2-(methylamino)cyclohexan-1-one

    Substance recommended to be added to Schedule IV of the 1971 
Convention:
--Bromazolam
    IUPAC name: 8-bromo-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-
a][1,4]benzodiazepine

    Substance recommended to proceed to critical review at a future 
ECDD meeting:
    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-sixth 
meeting, to conduct a critical review of the following substance:

--Carisoprodol
    IUPAC name: 2-[(carbamoyloxy)methyl]-2-methylpentyl(1-
methylethyl)carbamate

    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-sixth 
meeting, to keep the following substances under surveillance:

--Flubromazepam
    IUPAC name: 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-
benzodiazepin-2-one
--Nitrous oxide
    IUPAC name: nitrous oxide

    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 NAR/CL.18/
2023--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, hereby transmitted in NAR/CL.18/
2023--Annex II.
    Also, in accordance with the same provisions, the notification 
from WHO will be brought to the attention of the sixty-seventh 
session of the Commission on Narcotic Drugs (14-22 March 2024) in a 
pre-session document that will be made available in the six official 
languages of the United Nations on the website of the sixty-seventh 
session of the Commission on Narcotic Drugs: https://www.unodc.org/unodc/en/commissions/CND/session/67_Session_2024/67CND_Main.html.
    In order to assist the Commission in reaching a decision, it 
would be appreciated if the Permanent 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:

--Butonitazene
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:

--3-chloromethcathinone or 3-CMC
--Dipentylone
--2-fluorodeschloroketamine
--Bromazolam

    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.

12 December 2023

Annex I

Letter Addressed to the Secretary-General of the United Nations 
From the Director-General of the World Health Organization, Dated 
15 November 2023

    I have the honour to refer to the Forty-sixth Meeting of the 
World Health Organization (WHO) Expert Committee on Drug Dependence 
(ECDD), which was convened in Geneva, Switzerland, from 16 to 19 
October 2023.
    WHO is mandated by the 1961 and 1971 International Drug Control 
Conventions to make recommendations to the Secretary-General of the 
United Nations 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-sixth WHO ECDD Meeting critically reviewed six new 
psychoactive substances: one novel synthetic opioid (butonitazene), 
two cathinones/stimulants (3-chloromethcathinone or 3-CMC, 
dipentylone), one dissociative substance (2-fluorodeschloroketamine) 
and two benzodiazepines (bromazolam, flubromazepam). These 
substances, with the exception of bromazolam, had previously not

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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-sixth ECDD carried out pre-reviews of the 
medications nitrous oxide and carisoprodol 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-sixth Meeting of ECDD:
    Substance recommended to be added to Schedule I of the 1961 
Convention:

--Butonitazene
    IUPAC (International Union of Pure and Applied Chemistry) name: 
N,N-diethyl-2-[(4-butoxyphenyl)methyl]-5-nitro-1H-benzimidazole-1-
ethanamine

    Substances recommended to be added to Schedule II of the 1971 
Convention:

--3-chloromethcathinone or 3-CMC
    IUPAC name: 1-(3-chlorophenyl)-2-(methylamino)propan-1-one
--Dipentylone
    IUPAC name: 1-(1,3-benzodioxol-5-yl)-2-(dimethylamino)pentan-1-
one
--2-fluorodeschloroketamine
    IUPAC name: 2-(2-fluorophenyl)-2-(methylamino)cyclohexan-1-one

    Substance recommended to be added to Schedule IV of the 1971 
Convention:

--Bromazolam
    IUPAC name: 8-bromo-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-
a][1,4]benzodiazepine

    Substance recommended to proceed to critical review at a future 
ECDD meeting:

--Carisoprodol
    IUPAC name: 2-[(carbamoyloxy)methyl]-2-methylpentyl(1-
methylethyl)carbamate

    Substances to be kept under surveillance:

--Flubromazepam
    IUPAC name: 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-
benzodiazepin-2-one
--Nitrous oxide
    IUPAC name: nitrous oxide

    The assessments and findings on which these recommendations are 
based are set out in detail in the forty-sixth meeting report of the 
WHO Expert Committee on Drug Dependence. A summary of the assessment 
and recommendations made by the Forty-sixth ECDD is contained in 
Annex I 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

Summary Assessment and Recommendations of the 46th Expert Committee 
on Drug Dependence, 16-19 October 2023

    Substance to be added to Schedule I of the Single Convention on 
Narcotic Drugs (1961):

Butonitazene

Substance Identification

    Butonitazene (IUPAC name: N,N-diethyl-2-[(4-
butoxyphenyl)methyl]-5-nitro-1H-benzimidazole-1-ethanamine), also 
known as butoxynitazene, is a benzimidazole-derived synthetic 
opioid. Butonitazene is found as a crystalline solid and a white or 
yellow-brown powder.

WHO Review History

    Butonitazene has not been reviewed formally by WHO and is not 
currently under international control. Information was brought to 
WHO's attention 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

    The chemical structure and pharmacological effects of 
butonitazene are similar to those of opioid drugs such as 
etonitazene and isotonitazene that are controlled under Schedule I 
of the United Nations Conventions on Narcotic Drugs of 1961. 
Butonitazene is an agonist at [mu]-opioid receptors and has similar 
analgesic effects as morphine and fentanyl.

Dependence Potential

    No studies in experimental animal or humans were found on the 
dependence potential of butonitazene; however, as it is a [mu]-
opioid receptor agonist, it would be expected to produce dependence.

Actual Abuse and/or Evidence of Likelihood of Abuse

    No studies on the abuse potential of butonitazene in humans were 
found. In an animal model predictive of abuse potential, 
butonitazene had morphine-like effects, which were blocked by the 
opioid antagonist naltrexone. As it is a [mu]-opioid receptor 
agonist, it would be expected to produce euphoria and other effects 
predictive of high abuse liability. Butonitazene is reported to be 
administered by various routes, including smoking, intranasally and 
by injection. Non-fatal intoxications that involved butonitazene and 
required hospitalization have been reported. Seizures of 
butonitazene have been reported in multiple countries in two 
regions.

Therapeutic Use

    Butonitazene is not known to have any therapeutic use and has 
never been marketed as a medicinal product.

Rationale and Recommendation

    Butonitazene, also known as butoxynitazene, is a synthetic 
opioid that is liable to abuse and to production of ill effects 
similar to those of other opioids that are controlled under Schedule 
I of the Single Convention on Narcotic Drugs, 1961. Its use has been 
reported in a number of countries. It has no known therapeutic use 
and is likely to cause substantial harm. The Committee recommended 
that butonitazene (IUPAC name: N,N-diethyl-2-[(4-
butoxyphenyl)methyl]-5-nitro-1H-benzimidazole-1-ethanamine), also 
known as butoxynitazene, be added to Schedule I of the Single 
Convention on Narcotic Drugs, 1961.

    Substances to be added to Schedule II of the Convention on 
Psychotropic Substance (1971):

3-Chloromethcathinone (3-CMC)

Substance Identification

    3-Chloromethcathinone or 3-CMC (IUPAC name: 1-(3-chlorophenyl)-
2-(methylamino)propan-1- one), is a synthetic cathinone. 3-CMC has 
been described as a grey or white solid and as a white powder. It 
has been identified in capsule, tablet, and liquid forms.

WHO Review History

    3-CMC has not been reviewed formally by WHO and is not currently 
under international control. Information was brought to WHO's 
attention 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

    3-CMC is a chemical analogue of methcathinone, which is 
controlled under Schedule I of the United Nations Convention on 
Psychotropic Substances of 1971. Its structural isomer, 4-CMC, is 
controlled under Schedule II of the United Nations Convention on 
Psychotropic Substances of 1971. In common with other cathinone 
psychostimulants, 3-CMC has been shown to act via dopamine, 
serotonin and norepinephrine transporters in the central nervous 
system to increase the concentrations of these neurotransmitters.

Dependence Potential

    No controlled experimental studies of the dependence potential 
of 3-CMC in experimental animals or humans were available; however, 
clinical admissions associated with dependence to 3-CMC have been 
reported. Given its action in the central nervous system, 3-CMC 
would be expected to produce a state of dependence similar to that 
produced by amphetamine and other psychostimulants.

Actual Abuse and/or Evidence of Likelihood of Abuse

    No controlled studies of the abuse potential of 3-CMC in 
experimental animals or humans were available. In experimental 
animals, 3-CMC produced locomotor effects consistent with a 
psychostimulant. Cases of intoxication with 3-CMC alone and with 
other drugs requiring hospitalization have been reported. The 
adverse effects included

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agitation, restlessness, seizures, high blood pressure, sweating, 
and chest pain. These adverse effects are similar to those of other 
psychostimulants, such as amphetamine and various cathinones. Fatal 
intoxications involving 3-CMC have been documented, including in 
cases in which 3-CMC was the only substance identified. It is 
reported to be administered by various routes, including smoking, 
intranasally and by injection. 3-CMC has been detected in an 
increasing number of countries in most regions of the world. 
Seizures of 3-CMC have been reported in multiple countries and 
regions, with recent increases coinciding with international control 
of 4-CMC.

Therapeutic Use

    3-CMC is not known to have any therapeutic uses and has never 
been marketed as a medicinal product.

Rationale and Recommendation

    3-Chloromethcathinone or 3-CMC is a synthetic cathinone with 
effects similar to those of other synthetic cathinones, such as 
mephedrone and 4-CMC, which are listed as Schedule II substances 
under the Convention on Psychotropic Substances of 1971. Its mode of 
action and effects are similar to those of other cathinones. There 
is evidence of use of 3-CMC in a number of countries and regions, 
where it has resulted in fatal and non-fatal intoxications. The 
substance causes substantial harm, constitutes a substantial risk to 
public health and has no therapeutic use. The Committee recommended 
that 3-chloromethcathinone or 3-CMC (IUPAC name: 1(3-chlorophenyl)-
2-(methylamino)propan-1-one) be added to Schedule II of the 
Convention on Psychotropic Substances of 1971.

Dipentylone

Substance Identification

    Dipentylone or N-methylpentylone (IUPAC name: 1-(1,3-
benzodioxol-5-yl)-2-(dimethylamino)pentan-1-one, also known as N,N-
dimethylpentylone, dimethylpentylone or bk-DMBDP) is a synthetic 
cathinone. It is distributed mainly as crystals or tablets.

WHO Review History

    Dipentylone has not been reviewed formally by WHO and is not 
currently under international control. Information was brought to 
WHO's attention 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

    In common with other cathinone psychostimulants, dipentylone has 
been shown to act via dopamine, serotonin, and norepinephrine 
transporters in the central nervous system to increase the 
concentrations of these neurotransmitters. Online self-reports 
describe insomnia, hallucinations, paranoia and confusion after its 
use. Adverse effects documented in clinical presentations include 
agitation and tachycardia. These effects are consistent with a 
psychostimulant mechanism of action.

Dependence Potential

    No controlled experimental studies of the dependence potential 
of dipentylone in experimental animals or humans were available. In 
view of its action in the central nervous system, however, 
dipentylone would be expected to produce a state of dependence 
similar to that produced by amphetamine and other psychostimulants.

Actual Abuse and/or Evidence of Likelihood of Abuse

    Studies in experimental animals demonstrate that dipentylone has 
an abuse potential similar to that of methamphetamine, which is 
listed under Schedule II of the Convention on Psychotropic 
Substances of 1971, and cocaine, which is listed under Schedule I of 
the Convention on Narcotic Drugs of 1961. Dipentylone has been shown 
to produce locomotor stimulant effects in animal models. No 
controlled studies on the abuse potential of dipentylone in humans 
were identified. Non-fatal intoxication involving dipentylone that 
required hospitalization has been reported, and fatal intoxications 
have been reported by a number of countries, in which no other 
substance was involved in at least one case. Cases of driving under 
the influence of dipentylone have reported by some countries. 
Seizures of dipentylone have been reported in a number of countries 
and regions. Dipentylone appears to be commonly sold as cocaine or 
MDMA.

Therapeutic Use

    Dipentylone is not known to have any therapeutic uses and has 
never been marketed as a medicinal product.

Rationale and Recommendation

    Dipentylone or N-methylpentylone 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. 
Its mode of action suggests the likelihood of abuse, and it poses a 
substantial risk to public health. It has no known therapeutic use. 
The Committee recommended that dipentylone or N-methylpentylone 
(IUPAC name: 1-(1,3- benzodioxol-5-yl)-2-(dimethylamino)pentan-1-
one) be added to Schedule II of the Convention on Psychotropic 
Substances of 1971.

2-Fluorodeschloroketamine

Substance Identification

    2-Fluorodeschloroketamine (IUPAC name: 2-(2-fluorophenyl)-2-
(methylamino)cyclohexan-1-one) is an arylcyclohexylamine that is 
chemically related to the dissociative anaesthetic ketamine. It has 
been described as a brown oil in its free base form or as a 
crystalline solid or white powder as a salt. It has been identified 
in some food products (chocolates).

WHO Review History

    2-Fluorodeschloroketamine has not been reviewed formally by WHO 
and is not currently under international control. Information was 
brought to WHO's attention 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

    The mechanism of action of 2-fluorodeschloroketamine is 
uncertain, but it has effects similar to those of N-methyl-D-
aspartate receptor antagonists such as phencyclidine, which are 
controlled under Schedule II of the Convention on Psychotropic 
Substances of 1971. Effects documented during clinical admissions 
due to 2-fluorodeschloroketamine intoxication include dissociation, 
confusion, agitation, tachycardia and hypertension. Unverified 
reports from people who use 2-fluorodeschloroketamine describe 
hallucinogenic and dissociative effects. The clinical and self-
reported effects of 2-fluorodeschloroketamine are consistent with 
the effects of phencyclidine.

Dependence Potential

    No controlled studies in experimental animal or humans were 
found on the dependence potential of 2-fluorodeschloroketamine; 
however, clinical admissions for dependence on 2-
fluorodeschloroketamine have been reported in various countries and 
regions.

Actual Abuse and/or Evidence of Likelihood of Abuse

    Studies in experimental animals indicate that 2-
fluorodeschloroketamine has behavioural (locomotor) effects 
consistent with central nervous system stimulation. Such studies 
confirm that it has rewarding properties and effects predictive of 
abuse liability. Cases of intoxication that involved 2-
fluorodeschloroketamine and required hospitalization have been 
reported. The adverse effects included central nervous system 
effects such as dissociation, confusion, agitation, combativeness, 
nystagmus, hallucinations and impaired consciousness, loss of 
consciousness and cardiovascular effects such as tachycardia and 
hypertension. Fatal intoxications involving 2-
fluorodeschloroketamine have been documented, including at least one 
case in which no other substance was involved. 2-
Fluorodeschloroketamine has been analytically confirmed in people 
driving under the influence of drugs and in clinical admissions due 
to drug intoxication. It is reported to be administered by various 
routes including orally, intranasally and by injection. Seizures 
have been reported in a number of countries in several regions.

Therapeutic Use

    2-Fluorodeschloroketamine is not known to have any therapeutic 
use, is not listed on the WHO Model Lists of Essential Medicines and 
has never been marketed as a medicinal product.

Rationale and Recommendation

    2-Fluorodeschloroketamine has effects similar to those of 
dissociative substances such as phencyclidine, which are controlled 
under Schedule II of the Convention on Psychotropic Substances of 
1971. The results of studies in experimental animals indicate a high 
likelihood of abuse. There is evidence

[[Page 8687]]

that this substance is used in a number of countries in several 
regions. 2-Fluorodeschloroketamine causes substantial harm, 
including impaired driving, emergency department presentations and 
deaths. It has no known therapeutic use. The Committee recommended 
that 2-fluorodeschloroketamine (IUPAC name: 2-(2-fluorophenyl)-2-
(methylamino)cyclohexan-1-one) be added to Schedule II of the 
Convention on Psychotropic Substances of 1971.
    Substance to be added to Schedule IV of the Convention on 
Psychotropic Substances (1971):

Bromazolam

Substance Identification

    Bromazolam (IUPAC name: 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 chewable candy products (``gummies''). 
Bromazolam has been identified in falsified pharmaceutical 
benzodiazepine products.

WHO Review History

    Bromazolam was critically reviewed at the 45th ECDD meeting. 
Because of lack of information on its pharmacological effects, it 
was not recommended for international control but was placed under 
surveillance. New information on such effects was brought to WHO's 
attention, in addition to ongoing evidence 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

    Bromazolam is a benzodiazepine with relatively high potency and 
a short-intermediate duration of action. It is structurally related 
to alprazolam. Like other benzodiazepines, bromazolam binds to 
[gamma]-aminobutyric acid (GABAA) receptors, and its 
effects can be reversed by administration of the benzodiazepine 
receptor antagonist flumazenil. Unconfirmed online reports by people 
who use bromazolam describe benzodiazepine-like effects, including 
hypnotic, sedative, muscle relaxant and euphoric effects.

Dependence Potential

    No controlled studies in experimental animals or in humans have 
examined the dependence potential of bromazolam. In view of its 
pharmacological effects and similarity to other benzodiazepines, 
however, it would be expected to produce dependence. Online self-
reports describe withdrawal symptoms after cessation of chronic use.

Actual Abuse and/or Evidence of Likelihood of Abuse

    No studies in humans were found of the abuse liability of 
bromazolam. In an animal model predictive of abuse liability, 
bromazolam had effects similar to those of midazolam and diazepam, 
which are controlled under Schedule IV of the Convention on 
Psychotropic Substances of 1971. The effects were attenuated by pre-
administration of the benzodiazepine receptor antagonist flumazenil, 
confirming bromazolam's action as a benzodiazepine. Seizures of 
bromazolam have been reported increasingly in many countries in 
various regions. Bromazolam has been analytically confirmed as a 
causal or contributory agent in several deaths and non-fatal 
intoxications, and its presence has been confirmed in instances of 
driving under the influence of drugs. These harms have been reported 
in multiple countries and regions.

Therapeutic Use

    Bromazolam is not known to have any therapeutic use, is not 
listed on the WHO Model Lists of Essential Medicines and has never 
been marketed as a medicinal product.

Rationale and Recommendation

    The mechanism of action and ill effects of bromazolam are 
similar to those of other benzodiazepines, such as alprazolam and 
diazepam, that are listed under Schedule IV of the Convention on 
Psychotropic Substances of 1971. Reports of seizures and detection 
in fatal and non-fatal intoxications have increased over time. There 
is sufficient evidence of its abuse to conclude that it constitutes 
a significant risk to public health and has no known therapeutic 
use. The Committee recommended that bromazolam (IUPAC name: 8-bromo-
1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine) be 
added to Schedule IV of the Convention on Psychotropic Substances of 
1971.
    Substances to be recommended for critical review:

Carisoprodol

Substance Identification

    Carisoprodol (IUPAC name: 2-[(carbamoyloxy)methyl]-2-
methylpentyl(1-ethylethyl)carbamate) is a centrally-acting skeletal 
muscle relaxant sold as a single-ingredient preparation and in 
combination products. Carisoprodol is available as a pharmaceutical 
product in tablet form, has been detected in falsified 
pharmaceuticals and is also found as a white powder.

WHO Review History

    Carisoprodol was pre-reviewed at the 32nd ECDD meeting in 2000. 
The Committee did not recommend critical review of carisoprodol at 
that time, noting that sporadic nonmedical use of carisoprodol was 
not a new phenomenon and there was no indication of significantly 
increasing nonmedical use. A new pre-review was initiated in 2023 
after information received from an international agency that 
suggested a significant increase in the reported number of 
trafficking cases and seizures involving carisoprodol.

Similarity to Known Substances and Effects on the Central Nervous 
System

    Carisoprodol is an analogue of meprobamate and has effects 
similar to those of other central nervous system depressants such as 
meprobamate, pentobarbital, diazepam and chlordiazepoxide that are 
listed under schedules III and IV of the Convention on Psychotropic 
Substances of 1971. Meprobamate is also a metabolite of 
carisoprodol. Although its exact mechanism of action is not known, 
the therapeutic effects of carisoprodol appear to be due to 
modulation of GABAA receptors similar to the action of 
barbiturates. The sedative effects of carisoprodol can be 
potentiated when it is combined with benzodiazepines, opioids or 
alcohol.

Dependence Potential

    Tolerance and withdrawal have been documented in experimental 
animals, and the potential for dependence on carisoprodol is 
considered to be similar to that of barbiturates and 
benzodiazepines. Tolerance, withdrawal and craving have been 
documented in humans, and increasing numbers of cases of 
carisoprodol dependence have been documented in pharmacovigilance 
reporting systems.

Actual Abuse and/or Evidence of Likelihood of Abuse

    In animal models indicative of abuse liability, the effects of 
carisoprodol were similar to those of pentobarbital, 
chlordiazepoxide and meprobamate in a dose-dependent manner. In 
humans, carisoprodol produces central nervous system depressant 
effects, including drowsiness, sedation, confusion and coma. Public 
health harm associated with use of carisoprodol has included cases 
of driving under the influence of the drug. Nonmedical use of 
carisoprodol is widely documented in multiple countries and regions, 
including in combination with opioids and/or benzodiazepines. The 
incidence of poisoning and other public health harm has been 
reported to have decreased in some countries after increased 
restrictions on carisoprodol prescription or removal of the drug 
from the market.

Therapeutic Use

    Carisoprodol is a centrally acting muscle relaxant used in some 
countries in the short term as an adjunct in symptomatic treatment 
of acute musculoskeletal disorders associated with painful muscle 
spasms. It is not on the 2023 WHO Essential Medicines List or the 
WHO Essential Medicines List for Children. It has been withdrawn 
from use in some countries because of concern about increased rates 
of diversion, nonmedical use, dependence, intoxication and 
psychomotor impairment.

Rationale and Recommendation

    The increasing evidence of misuse and abuse of carisoprodol in a 
number of countries is a growing cause for concern. Carisoprodol has 
been shown to produce a state of dependence and central nervous 
system depression. It has only limited medical use. The Committee 
recommended that carisoprodol be subject to a future critical 
review.
    Substances to be kept under surveillance:

Flubromazepam

Substance Identification

    Flubromazepam (IUPAC name: 7-bromo-5-(2-fluorophenyl)-1,3-
dihydro-2H-1,4-benzodiazepin-2-one) is a 1,4-benzodiazepine. 
Flubromazepam is described as a white powder or a crystalline solid 
and has been found in infused paper forms.

[[Page 8688]]

WHO Review History

    Flubromazepam has not been formally reviewed by WHO and is not 
currently under international control. Information was brought to 
WHO's attention 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

    The chemical structure of flubromazepam is similar to that of 
other benzodiazepines, including phenazepam. Currently, there is 
insufficient information on the pharmacological profile of 
flubromazepam from controlled studies in experimental animals or 
humans to conclude that it has effects that are similar to those of 
benzodiazepines that are controlled under the Convention on 
Psychotropic Substances of 1971. Online self-reports by people who 
claim to have used flubromazepam describe sedative, muscle relaxant 
and euphoric effects and its use to self-manage benzodiazepine 
withdrawal. There are, however, no clinical reports to confirm such 
effects.

Dependence Potential

    No controlled study in experimental animals or humans have 
addressed the dependence potential of flubromazepam.

Actual Abuse and/or Evidence of Likelihood of Abuse

    No studies in humans were found of the abuse liability of 
flubromazepam. People who self-report flubromazepam use describe 
euphoric effects and other benzodiazepine-like effects that would 
suggest it has a similar likelihood of abuse, but their use of 
flubromazepam cannot be confirmed. Results from limited studies in 
experimental animals suggest abuse liability. Seizures have been 
reported in multiple countries across a number of regions. Although 
flubromazepam has been detected in several deaths and cases of 
driving under the influence of drugs, other drugs were also 
detected, and the contribution of flubromazepam was unclear.

Therapeutic Use

    Flubromazepam is not known to have any therapeutic use, is not 
listed on the WHO Model Lists of Essential Medicines and has never 
been marketed as a medicinal product.

Rationale and Recommendation

    Flubromazepam is a 1,4-benzodiazepine. Although it is chemically 
similar to other benzodiazepines listed under Schedule IV of the 
Convention on Psychotropic Substances of 1971, little information is 
available on its effects. Few studies in experimental animals and no 
studies in humans were found on its effects or abuse potential. The 
limited information on its effects provides insufficient evidence to 
justify the placement of flubromazepam under international control. 
The Committee recommended that flubromazepam (IUPAC name: 7-bromo-5-
(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one) be kept 
under surveillance by the WHO ECDD secretariat.

Nitrous Oxide

Substance Identification

    Nitrous oxide (IUPAC name: Nitrous oxide, N2O) is an 
inhalational anaesthetic marketed under a range of trade names as 
both a single ingredient gas and in multi-ingredient preparations. 
It is also manufactured for industrial use, including in food 
production, as small metal canisters, bulbs and larger cylinders. It 
is described as a colourless gas.

WHO Review History

    Nitrous oxide is not currently under international control and 
has never been reviewed by the ECDD. Information was brought to 
WHO's attention by a Member State of increased nonmedical use, such 
that it presented a risk to public health.

Similarity to Known Substances and Effects on the Central Nervous 
System

    Nitrous oxide appears to have multiple mechanisms of action that 
are not entirely understood. There is some evidence for effects on 
opioid, GABAergic, glutamatergic and other neurotransmitter systems. 
Nitrous oxide produces anaesthesia, analgesia and, in laboratory 
studies with humans, subjective effects such as perceptual 
distortion, paranoia, delusions, anhedonia and cognitive 
disorganization.

Dependence Potential

    Acute and chronic tolerance to the effects of nitrous oxide have 
been documented in experimental animals, with signs of withdrawal 
when exposure was ended abruptly. Animals that were tolerant to 
nitrous oxide were partially cross-tolerant to ethanol but not to 
barbiturates or morphine. Laboratory studies in humans provide 
evidence of tolerance to some effects of nitrous oxide, but the 
degree of tolerance varied according to the effect and between 
individuals. Epidemiological and clinical studies provide evidence 
of dependence.

Actual Abuse and/or Evidence of Likelihood of Abuse

    The evidence from studies in experimental animals on the 
likelihood of abuse of nitrous oxide is inconsistent. The abuse 
potential of nitrous oxide has been reported since the 19th century, 
including its euphoric effects and ability to cause auditory and 
visual distortions. Nitrous oxide was originally promoted for 
recreational use as ``laughing gas''; however, laboratory studies 
with humans have produced inconsistent results on abuse liability. 
The global prevalence of non-medical use of nitrous oxide is 
unknown. Reports from several countries indicate that nonmedical use 
is highest among adolescents and young adults, and evidence from 
some countries indicates an increase in use in recent years. Nitrous 
oxide used nonmedically is typically obtained from legal 
manufacturers, with no evidence of illicit manufacture and minimal 
evidence of cross-border trading. Nitrous oxide use has been 
implicated in cases of impaired driving. Deaths directly related to 
nonmedical use of nitrous oxide appear to be rare and to be due to 
intended or unintended asphyxia. Long-term exposure can result in 
neurological and haematological toxicity.

Therapeutic Use

    Nitrous oxide is widely used globally for analgesia and sedation 
during childbirth and in painful short procedures in dentistry and 
emergency medicine. It is used commonly as a supplementary agent in 
anaesthesia. Nitrous oxide is listed on the 2023 WHO Model List of 
Essential Medicines and the Essential Medicines List for Children as 
an inhalational anaesthetic. Clinical trials of nitrous oxide are 
being conducted to explore its value as a medication for other 
indications such as treatment-resistant depression and management of 
alcohol withdrawal symptoms.

Rationale and Recommendation

    Nitrous oxide is a widely used inhalation anaesthetic and is 
listed on the 2023 WHO Model List of Essential Medicines and 
Essential Medicines List for Children. While the Committee 
acknowledged the concerns raised by some countries, it recommended 
that nitrous oxide not proceed to critical review because of the 
absence of evidence of illicit manufacture and of common trading 
across borders, and in recognition of its global therapeutic value. 
The Committee recommended that nitrous oxide 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.
    Butonitazene (chemical name: N,N-diethyl-2-[(4-
butoxyphenyl)methyl]-5-nitro-1H-benzimidazole-1-ethanamine) is a 
benzimidazole synthetic opioid that functions as an agonist of the 
[micro]-opioid receptor and has similar psychoactive effects as 
morphine and fentanyl. Butonitazene is reported to produce euphoria 
after administration through various routes including smoking, oral, 
intranasal, and injection. It was first identified in law enforcement 
seizures in the United States in 2021 and has since (i.e., 2021 to 
2023) been identified in 63 different drug seizures. Butonitazene has 
also been identified in drug toxicology screens and is confirmed to 
have been responsible for at least one fatality in the United States. 
There are no commercial or approved medical uses for butonitazene. 
Butonitazene is controlled in schedule I of the CSA and will not 
require additional permanent controls if it is placed in Schedule I of 
the 1961 Single Convention.

[[Page 8689]]

    3-Chloromethcathinone (3-CMC) (chemical name: 1-(3-chlorophenyl)-2-
(methylamino)propan-1-one) is a synthetic cathinone that functions to 
inhibit reuptake of the dopamine, serotonin, and norepinephrine 
transporters in the central nervous system. Functionally this increases 
the concentration of these neurotransmitters which leads to 
psychostimulatory effects. Humans and animals have demonstrated 
clinical signs of agitation, restlessness, seizures, high blood 
pressure, and increased locomotor activity. The appearance of 3-CMC on 
the illicit drug market is similar to other designer drugs trafficked 
for their psychoactive effects. There are no commercial or approved 
medical uses for 3-CMC in the United States. Methcathinone was 
controlled in Schedule I of the CSA on October 15, 1993. As a 
positional isomer of methcathinone, 3-CMC is controlled in Schedule I 
of the CSA. As such, additional permanent controls will not be needed 
if 3-CMC is placed in Schedule II of the Convention on Psychotropic 
Substances, 1971.
    Dipentylone (chemical name: 1-(1,3-benzodioxol-5-yl)-2-
(dimethylamino)pentan-1-one, also known as N,N-dimethylpentylone, 
dimethylpentylone or bk-DMBDP) is a synthetic cathinone that produces 
psychostimulant effects similar to cathinone. Dipentylone functions by 
increasing the concentration of dopamine, serotonin, and norepinephrine 
in the central nervous system similar to amphetamines. Anecdotal 
reports indicate that dipentylone produces clinical effects of 
insomnia, hallucinations, paranoia, and confusion. As of 2021, 
dipentylone was identified in 8,368 drug seizures, and was confirmed as 
the cause of death in at least nine fatalities in 2023. There are no 
commercial or approved medical uses for dipentylone in the United 
States. Pentylone was controlled in Schedule I of the CSA on March 4, 
2016. As a positional isomer of pentylone, dipentylone is controlled in 
Schedule I of the CSA. As such, additional permanent controls will not 
be needed if dipentylone is placed in Schedule II of the Convention on 
Psychotropic Substances, 1971.
    2-Fluorodeschloroketamine (chemical name: 2-(2-fluorophenyl)-2-
(methylamino)cyclohexan-1-one), fluoroketamine, or 2-FDCK) is an 
arylcyclohexylamine that is related to ketamine and phencyclidine 
(PCP). 2-FDCK is thought to function as an N-methyl-D-aspartate 
receptor antagonist and produce effects similar to other dissociative 
anesthetics (e.g., ketamine). According to anecdotal reports, these 
effects include dissociation, hallucination, confusion, agitation, 
stimulation, and tachycardia and hypertension. Studies in animals 
indicate that 2-FDCK was self-administered (i.e., produced reinforcing 
effects) and produced a drug cue similar to that of ketamine. As a 
result, animal data suggests that 2-FDCK has an abuse potential similar 
to ketamine. 2-FDCK has not been detected in law enforcement seizures, 
or in toxicology screens in the United States. There are no commercial 
or approved medical uses for 2-FDCK, and it is not a controlled 
substance under the CSA. As such, additional permanent controls will be 
necessary to fulfill U.S. obligations if 2-FDCK is controlled under 
Schedule II of the Convention on Psychotropic Substances, 1971.
    Bromazolam (chemical name: 8-bromo-1-methyl-6-phenyl-4H-
[1,2,4]triazolo[4,3-a][1,4]benzodiazepine) is a triazolobenzodiazepine 
that functions as a positive allosteric modulator of [gamma]-
aminobutyric acid A (GABAA) channels thereby decreasing 
neuronal activity. Similar to other benzodiazepines, such as 
alprazolam, it produces sedative and anxiolytic effects typically taken 
after oral administration or through injection. Unconfirmed anecdotal 
reports indicate that it can also produce hypnotic, muscle relaxant, 
and euphoric effects as well as physical dependence demonstrated 
through a withdrawal syndrome. Since 2021, bromazolam has been detected 
in 637 law enforcement seizures and has been implicated in 53 
fatalities. There are no commercial or approved medical uses for 
bromazolam in the United States, and it is not a controlled substance 
under the CSA. As such, additional permanent controls will be necessary 
to fulfill U.S. obligations if bromazolam is controlled under Schedule 
IV of the Convention on Psychotropic Substances, 1971.
    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 2024.
    Comments regarding the WHO recommendations for control of 
butonitazene 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 5, 2024.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2024-02573 Filed 2-7-24; 8:45 am]
BILLING CODE 4164-01-P