[Federal Register Volume 87, Number 31 (Tuesday, February 15, 2022)]
[Notices]
[Pages 8586-8592]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-03229]


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

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; Brorphine; Metonitazene; 
Eutylone; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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

SUMMARY: The Food and Drug Administration (FDA) is providing interested 
persons with the opportunity to submit written comments concerning 
recommendations by the World Health Organization (WHO) to impose 
international manufacturing and distributing restrictions, under 
international treaties, on certain drug substances. The comments 
received in response to this notice will be considered in preparing the 
United States' position on these proposals for a meeting of the United 
Nations Commission on Narcotic Drugs (CND) in Vienna, Austria, in March 
2022. This notice is issued under the Controlled Substances Act (CSA).

DATES: Submit either electronic or written comments by February 28, 
2022.

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 28, 2022. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of February 28, 2022. 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; Brorphine; 
Metonitazene; Eutylone; 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

[[Page 8587]]

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: James R. Hunter, 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, 301-796-3156, [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 one substance to be considered for 
control under the 1971 Convention. This notification reflects the 
recommendation from the 44th WHO Expert Committee for Drug Dependence 
(ECDD), which met in October 2021. In the Federal Register of July 23, 
2021 (86 FR 39038), 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 two substances 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.13/2021
WHO/ECDD44; 1961C-Art.3, 1971C-Art.2
CU 2021/453/DTA/SGB

    The Secretariat of the United Nations presents its compliments 
to the Permanent Mission of the United States of America and has the 
honour to inform the Government that in a letter dated 18 November 
2021, 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-
third Meeting of the WHO's Expert Committee on Drug Dependence 
(ECDD):
    Substance recommended to be added to Schedule I of the 1961 
Convention:
--Brorphine
IUPAC (International Union of Pure and Applied Chemistry) name: 1-
[1-[1-(4-Bromophenyl)ethyl]-piperidin-4-yl]-1,3-dihydro-2H-imidazol-
2-one
--Metonitazene
IUPAC name: N,N-Diethyl-2-(2-(4-methoxybenzyl)-5-nitro-1H-
benzo[d]imidazol-1-yl)ethan-1-amine
    Substances recommended to be added to Schedule II of the 1971 
Convention:
--Eutylone (alternate name: 3,4-methylenedioxy-alpha-ethylamino 
butiophenone)
IUPAC names: 1-(Benzo[d][1,3]dioxol-5-yl)-2-(ethylamino)butan-1-one 
1-(1,3-Benzodioxol-5-yl)-2-(ethylamino)butan-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-fourth 
meeting, to keep the following substances under surveillance:

--4F-MDMB-BICA (alternate name: 4F-MDMB-BUTICA)
IUPAC names: Methyl 2-({[1-(4-fluorobutyl)-1H-indol-3-
yl]carbonyl{time} amino)-3,3-dimethylbutanoate; Methyl 2-(1-(4-
fluorobutyl)-1H-indole-3-carbaxamido)-3,3-dimethylbutanoate
--Benzylone (alternate name: 3,4-Methylenedioxy-N-benzylcathinone)
IUPAC name: 1-(Benzo[d][1,3]dioxol-5-yl)-2-(benzylamino)propan-1-one
--Kratom, mitragynine, and 7-hydroxymitragynine
--Phenibut (alternate name: 4-amino-3-phenyl-butyric acid)
IUPAC name: 4-Amino-3-phenylbutanoic acid

    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

[[Page 8588]]

findings for these recommendations made by ECDD, which is 
transmitted as annex II.
    Also, in accordance with the same provisions, the notification 
from WHO will be brought to the attention of the sixty-fifth session 
of the Commission on Narcotic Drugs (14-18 March 2022, tent.) in a 
pre-session document that will be made available in the six official 
languages of the United Nations on the website of the 65th session 
of the Commission on Narcotic Drugs: https://www.unodc.org/unodc/en/commissions/CND/session/65_Session_2022/65CND_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:

--Brorphine
--Metonitazene; 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:
--Eutylone (alternate name: 3,4-methylenedioxy-alpha-ethylamino 
butiophenone).
    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.

8 December 2021

Annex I

    Letter addressed to the Secretary-General of the United Nations 
from the Director-General of the World Health Organization, dated 18 
November 2021
    ``The Forty-fourth Meeting of the World Health Organization 
(WHO)'s Expert Committee on Drug Dependence (ECDD) was convened in a 
virtual format from 11 to 15 October 2021 and was coordinated from 
the WHO headquarters in Geneva.
    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, and level of, international control of 
psychoactive substances based on the advice of its independent 
scientific advisory body, the ECDD. In order to recommend if a 
psychoactive substance should be placed under international control 
or if its level of control should be changed, the WHO convenes the 
ECDD annually to thoroughly review the potential for abuse, 
dependence, and harm to health of a psychoactive substance, as well 
as any therapeutic applications.
    The Forty-fourth WHO ECDD Meeting critically reviewed five new 
psychoactive substances, including one synthetic cannabinoid 
receptor agonist (4F-MDMB-BICA), two novel synthetic opioids 
(brorphine; metonitazene), and two cathinones/stimulants (eutylone; 
benzylone). 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 especially serious risk to public 
health and society, and of no recognised 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 available about 
these substances may justify the scheduling or a change in 
scheduling of a substance in the 1961 or 1971 Conventions.
    In addition, the Forty-fourth ECDD Meeting carried out pre-
reviews of kratom, mitragynine, and 7-hydroxymitragynine; and 
phenibut 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-fourth Meeting of the 
ECDD:
    To be added to Schedule I of the Single Convention on Narcotic 
Drugs (1961):

--Brorphine
IUPAC (International Union of Pure and Applied Chemistry) name: 1-
[1-[1-(4-Bromophenyl)ethyl]- piperidin-4-yl]-1,3-dihydro-2H- 
imidazol-2- one
--Metonitazene
IUPAC name: N,N-Diethyl-2-(2-(4- methoxybenzyl)-5-nitro-1H-
benzo[d]imidazol-1-yl)ethan-1-amine

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

--Eutylone (alternate name: 3,4-methylenedioxy-alpha-ethylamino 
butiophenone)
IUPAC names: 1-(Benzo[d][1,3]dioxol-5-yl)-2-(ethylamino)butan-1-one; 
1-(1,3-Benzodioxol-5-yl)-2-(ethylamino)butan-1-one

    To be kept under surveillance:

--4F-MDMB-BICA (alternate name: 4F-MDMB-BUTICA)
IUPAC names: Methyl 2-({[1-(4-fluorobutyl)-1H-indol-3-
yl]carbonyl{time} amino)-3,3- dimethylbutanoate; Methyl 2-(1-(4-
fluorobutyl)-1H-indole-3- carbaxamido)-3,3- dimethylbutanoate
--Benzylone (alternate name: 3,4-Methylenedioxy-N-benzylcathinone)
IUPAC name: 1-(Benzo[d][1,3]dioxol-5-yl)-2- (benzylamino)propan-1-
one
--Kratom, mitragynine, 7-hydroxymitragynine
--Phenibut (alternate name: 4-amino-3-phenyl-butyric acid)
IUPAC name: 4-Amino-3-phenylbutanoic acid

    The assessments and findings on which these recommendations are 
based are set out in detail in the Forty-fourth ECDD Meeting Report 
of the WHO Expert Committee on Drug Dependence. A summary of the 
assessments and findings for these recommendations made by the ECDD 
is contained in Annex 1 to this letter.
    I am very 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 44th Expert 
Committee on Drug Dependence, 11-15 October 2021
    Substances to be added to Schedule I of the Single Convention on 
Narcotic Drugs (1961):

Brorphine

Substance Identification

    Brorphine (IUPAC chemical name: 1-[1-[1-(4-bromophenyl)ethyl]-
piperidin-4-yl]-1,3-dihydro-2H-imidazol-2-one) has a chemical 
structure similar to bezitramide, an opioid listed in Schedule I of 
the 1961 Convention. Brorphine freebase has been described as a 
white or off-white solid, and the hydrochloride salt as a neat 
solid, with seized samples described as white, yellowish, gray, 
purple, or white powder, or in crystal form. It is also found in 
tablets and capsules as falsified opioid medicines. It is reported 
to be used by the oral, inhalation, and intravenous routes of 
administration.

WHO Review History

    Brorphine 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 is of no recognized therapeutic 
use.

Similarity to Known Substances and Effects on Central Nervous System

    Brorphine is a full agonist at the [mu]-opioid receptor, with 
greater potency than morphine, and less potency than fentanyl. It 
has analgesic effects that are reversed by an opioid antagonist and, 
based on its mechanism of action, it would be expected to produce 
other typical opioid effects such as respiratory depression and 
sedation. Brorphine may be convertible to bezitramide, which is an 
opioid listed in Schedule I of the 1961 Single Convention on 
Narcotic Drugs.

Dependence Potential

    No controlled animal or human studies have examined the 
dependence potential of brorphine. As a potent [micro]-opioid 
agonist, it would be expected to produce dependence similar to other 
opioid substances. Unverified online reports describe tolerance and 
withdrawal following repeated brorphine use.

Actual Abuse and/or Evidence of Likelihood of Abuse

    In an animal model predictive of abuse potential, brorphine was 
shown to produce effects similar to morphine and fentanyl.
    Deaths involving brorphine have been reported in several 
countries. Deaths commonly occur after use of brorphine in

[[Page 8589]]

combination with other opioids or with benzodiazepines such as 
flualprazolam. Brorphine has been identified in falsified opioid 
medicines, suggesting that sometimes its use may be unintentional. 
Fatal and non-fatal intoxications due to brorphine share features 
with intoxications due to other opioids, such as pulmonary oedema. 
Brorphine has been detected with other substances in biological 
fluids in cases of driving under the influence.
    Seizures have been reported in multiple countries and regions.

Therapeutic Usefulness

    Brorphine is not known to have any therapeutic use.

Recommendation

    The mechanism of action of brorphine indicates that it is liable 
to have similar abuse potential and ill effects as 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 brorphine (IUPAC 
chemical name: 1-[1-[1-(4-bromophenyl)ethyl]-piperidin-4-yl]-1,3-
dihydro-2H-imidazol-2-one) be added to Schedule I of the 1961 Single 
Convention on Narcotic Drugs.

Metonitazene

Substance Identification

    Metonitazene (IUPAC chemical name: N,N-Diethyl-2-(2-(4-
methoxybenzyl)-5-nitro-1H-benzo[d]imidazol-1-yl)ethan-1-amine) 
belongs to the series of 2-benzylbenzimidazole opioid compounds. It 
is a white or off-white/beige or coloured powder, and is sometimes 
crystalline in consistency. Reports suggest that it is used 
intranasally and by intravenous injection.

WHO Review History

    Metonitazene 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 Central Nervous System

    Metonitazene is a chemical analogue of etonitazene and 
isotonitazene, both of which are Schedule I compounds under the 
Single Convention on Narcotic Drugs, 1961. Metonitazene is a potent 
opioid analgesic with a rapid onset of action and greater potency 
than fentanyl and hydromorphone. Limited early clinical research 
demonstrated that metonitazene produces analgesia and typical opioid 
adverse effects including sedation, respiratory depression, nausea, 
and vomiting. The effects of metonitazene have been shown to be 
reversed by an opioid antagonist.

Dependence Potential

    Animal studies have demonstrated that metonitazene suppresses 
opioid withdrawal and has potent [mu]-opioid agonist effects. No 
controlled human studies have reported on the dependence potential 
of metonitazene, but as a potent [mu]-opioid agonist, it would be 
expected to produce dependence similar to other opioids.

Actual Abuse and/or Evidence of Likelihood of Abuse

    No controlled studies have been reported on the abuse potential 
of metonitazene, but as it is a potent [mu]-opioid receptor agonist, 
it would be expected to have high abuse liability. Online reports 
from people who report use of metonitazene describe its euphoric and 
opioid-like effects.
    A number of deaths have been reported in association with use of 
metonitazene. In many of these cases metonitazene has been used in 
combination with other opioids or benzodiazepines. However, in some 
fatalities, metonitazene was the sole substance identified in the 
analyzed biological samples.
    Trafficking and use of metonitazene have been reported from a 
number of countries across several regions.

Therapeutic Usefulness

    Metonitazene is not known to have any therapeutic use.

Recommendation

    The mechanism of action and effects of metonitazene indicate 
that it is liable to have similar abuse potential and ill effects as 
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 been associated with adverse effects, including 
death. Metonitazene has no known therapeutic use and is likely to 
cause substantial harm.
    Recommendation: The Committee recommended that metonitazene 
(IUPAC chemical name: N,N-Diethyl-2-(2-(4-methoxybenzyl)-5-nitro-1H-
benzo[d]imidazol-1-yl)ethan-1-amine) 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):

Eutylone (3,4-methylenedioxy-alpha-ethylamino butiophenone)

Substance Identification

    Eutylone (IUPAC chemical name: 1-(Benzo[d][1,3]dioxol-5-yl)-2-
(ethylamino)butan-1-one) is a synthetic cathinone of the 
phenethylamine class. The hydrochloride salt of eutylone has been 
described as a crystalline solid. Eutylone is mostly found as 
tablets, capsules, and crystals. It is used orally and intranasally.

WHO Review History

    Eutylone 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 Central Nervous System

    Eutylone is a synthetic cathinone with a mechanism of action and 
effects similar to other cathinones and to stimulants such as 
methamphetamine. Related cathinones, such as methylone and N-
ethylnorpentylone, are listed under Schedule II of the Convention on 
Psychotropic Substances of 1971. The clinical features described are 
similar to other cathinones, including sympathomimetic effects and 
psychostimulant effects such as euphoria, insomnia, tachycardia, 
agitation, anxiety, delirium and psychosis.

Dependence Potential

    No animal or human studies have been conducted on the dependence 
potential of eutylone. Based on its overall profile of effects, 
eutylone would be expected to produce dependence similar to other 
psychostimulants.

Actual Abuse and/or Evidence of Likelihood of Abuse

    In an animal model predictive of abuse potential, eutylone has 
been shown to produce effects similar to those of methamphetamine. 
Online reports from people reporting use of eutylone suggest that it 
has high abuse potential.
    Eutylone has been detected in biological samples from forensic, 
post-mortem, and driving under the influence cases. Published case 
reports describe fatalities as a result of eutylone use. In addition 
to the effects described above, reported adverse events in these 
cases have included rhabdomyolysis, hyperthermia, hypertension, and 
seizures.
    Eutylone has been detected in seized materials in multiple 
countries across several regions.

Therapeutic Usefulness

    Eutylone is not known to have any therapeutic use.

Recommendation

    Eutylone has effects similar to those of related cathinones 
listed under Schedule II of the Convention on Psychotropic 
Substances of 1971.
    There is evidence that this substance is used in multiple 
countries in various regions. Eutylone causes substantial harm, 
including severe adverse events and fatal intoxications. Its mode of 
action suggests a likelihood of abuse and it poses a substantial 
risk to public health. It has no known therapeutic usefulness.
    Recommendation: The Committee recommended that eutylone (IUPAC 
chemical name: 1-(Benzo[d][1,3]dioxol-5-yl)-2-(ethylamino)butan-1-
one) be added to Schedule II of the Convention on Psychotropic 
Substances of 1971.
    Substances to be kept under surveillance:

4F-MDMB-BICA (4F-MDMB-BUTICA)

Substance Identification

    4F-MDMB-BICA (IUPAC chemical name: Methyl 2-({[1-(4-
fluorobutyl)-1H-indol-3-yl]carbonyl{time} amino)-3,3-
dimethylbutanoate) has a chemical structure similar to a number of 
synthetic cannabinoids. It has been identified in seized materials 
as a white, off-white, brown or orange powder, and has been 
identified in herbal blends, vaping solutions, and infused onto 
paper. It is also available as a reference material as crystalline 
solid.

[[Page 8590]]

WHO Review History

    4F-MDMB-BICA 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 Central Nervous System

    4F-MDMB-BICA is a synthetic cannabinoid, structurally related to 
5F-MDMB-PICA, a synthetic cannabinoid, which is included in Schedule 
II of the United Nations Single Convention on Psychotropic 
Substances of 1971. Some data suggest that 4F-MDMB-BICA has activity 
at the cannabinoid CB1 receptor, but this action may not be 
identical to that exerted by other CB1 agonists. No animal or human 
studies have evaluated the effects of 4F-MDMB-BICA, and there is 
insufficient data on 4F-MDMB-BICA overdose cases to confirm that it 
has typical cannabinoid effects.

Dependence Potential

    No studies have been reported in animals or humans on the 
dependence potential of 4F-MDMB-BICA.

Actual Abuse and/or Evidence of Likelihood of Abuse

    No studies have been reported in animals or humans to indicate 
the likelihood of abuse of 4F-MDMB-BICA. A number of countries in 
various regions have reported use of 4F-MDMB-BICA. Its use has been 
associated with multiple deaths and Emergency Department visits, 
although multiple substances have been present in analysed 
biological samples, and the relationship between 4F-MDMB-BICA 
exposure and cause of death is not established.

Theraputic Usefulness

    4F-MDMB-BICA is not known to have any therapeutic use.

Recommendation

    4F-MDMB-BICA has a structure similar to other synthetic 
cannabinoids, but its mechanism of action has yet to be confirmed. 
The magnitude of harm due to 4F-MDMB-BICA alone is unclear, and no 
animal or human studies have examined the effects or abuse potential 
of 4F-MDMB-BICA. Based on the limited information available 
concerning abuse, dependence and risks to public health, there is 
insufficient evidence to justify placing 4F-MDMB-BICA under 
international control.
    Recommendation: The Committee recommended that 4F-MDMB-BICA 
(IUPAC chemical name: Methyl 2-({[1-(4-fluorobutyl)-1H-indol-3-
yl]carbonyl{time} amino)-3,3-dimethylbutanoate) be kept under 
surveillance by the WHO Secretariat.

Benzylone (3,4-Methylenedioxy-N-benzylcathinone)

Substance Identification

    Benzylone (IUPAC chemical name: 1-(Benzo[d][1,3]dioxol-5-yl)-2-
(benzylamino)propan-1-one) is a ring-substituted synthetic 
cathinone. Benzylone is a white powder. The hydrochloride salt of 
benzylone is a crystalline solid.

WHO Review History

    Benzylone 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 Central Nervous System

    Benzylone has a mode of action suggestive of stimulant effects 
similar to other cathinones. However, these effects are relatively 
weak and it fails to produce stimulant effects in animal models.
    Limited information is available on its effects in humans.

Dependence Potential

    There is no information available on the dependence potential of 
benzylone in animals or humans

Actual Abuse and/or Evidence of Likelihood of Abuse

    In an animal model predictive of abuse potential, benzylone did 
not produce effects similar to MDMA, and its similarity to 
methamphetamine is unclear. No human studies have been conducted to 
assess abuse liability.
    Benzylone has been detected in seized materials in multiple 
countries across several regions.
    There is little information concerning the adverse effects of 
benzylone. Although it has been detected in postmortem samples along 
with other substances, there is no significant evidence of benzylone 
playing a causative role in deaths.

Therapeutic Usefulness

    Benzylone is not known to have any therapeutic use.

Recommendation

    Benzylone is a synthetic cathinone that has some effects in 
common with substances listed under Schedule II of the Convention on 
Psychotropic Substances of 1971. However, its effects are relatively 
weak and there is no consistent evidence supporting the likelihood 
of abuse or dependence. In addition, there is no consistent evidence 
of the extent of public health and social problems related to use of 
benzylone.
    Recommendation: The Committee recommended that benzylone (IUPAC 
chemical name: 1-(Benzo[d][1,3]dioxol-5-yl)-2-(benzylamino)propan-1-
one) be kept under surveillance by the WHO Secretariat.

Kratom, mitragynine, and 7-hydroxymitragynine

Substance Identification

    Kratom is the common term for Mitragyna speciosa, a tree native 
to Southeast Asia. Kratom use is almost exclusively oral, typically 
by chewing the leaves, ingesting powdered leaf, or drinking a kratom 
infusion or decoction, or by ingesting powdered leaf as a capsule or 
pill or dissolved in a beverage. Other forms such as extracts and 
resins are also used.
    Several alkaloids have been detected in kratom plants. The main 
known psychoactive components of kratom are mitragynine and 7-
hydroxymitragynine, both of which are found in the leaves of 
Mitragyna speciosa. Mitragynine is the most abundant alkaloid in 
kratom.
    Whilst 7-hydroxymitragynine is a minor alkaloid, it is also a 
metabolite of mitragynine.

WHO Review History

    Kratom has been under ECDD surveillance since 2020 due to a 
country level report indicating the potential for abuse, dependence, 
and harm to public health from mitragynine and 7-hydroxymitragynine, 
and a report from an international organization regarding documented 
fatalities associated with kratom use. A pre-review on kratom, 
mitragynine, and 7-hydroxymitragynine was initiated following 
consideration of these reports.

Similarity to Known Substances and Effects on Central Nervous System

    Mitragynine and 7-hydroxymitragynine are partial agonists at the 
mu-opioid receptor. Human studies demonstrate the analgesic effects 
of kratom, while kratom extract, mitragynine and 7-
hydroxymitragynine have been shown to be antinociceptive in animal 
models. The antinociceptive effects are reversed by an opioid 
antagonist.
    Mitragynine also binds to adrenergic receptors, serotonergic and 
dopamine receptors. Although there is limited information regarding 
its effects at these receptors, kratom extracts and mitragynine have 
been reported in animal studies to have a variety of non-opioid-like 
behavioural effects, including antidepressant and antipsychotic 
effects.
    Reported adverse effects as a result of kratom intoxication have 
included neuropsychiatric (agitation, confusion, sedation, 
hallucinations, tremor, seizure, coma), cardiovascular (tachycardia, 
hypertension), gastrointestinal (abdominal pain, nausea, vomiting) 
and respiratory (respiratory depression) symptoms. A number of cases 
of kratom-associated liver toxicity have been documented.

Dependence Potential

    In animal models, repeated dosing with mitragynine produced 
dependence, evidenced by naloxone-precipitated withdrawal. The 
withdrawal syndrome from kratom appears to be less severe than 
withdrawal from morphine.
    In humans, opioid-like withdrawal symptoms have been reported 
following cessation of kratom use. Limited epidemiological evidence 
indicates that withdrawal is usually mild. There are a small number 
of cases of neonatal opioid withdrawal symptoms in neonates born to 
mothers who used kratom regularly.

Actual Abuse and/or Evidence of Likelihood of Abuse

    Animal studies with kratom extracts have not shown abuse 
liability in one animal model. Mitragynine and 7-hydroxymitragynine 
have effects indicative of abuse liability in some animal models but 
not in others. Mitragynine is not self-administered by animals, 
while 7-hydroxymitragynine has been shown to be

[[Page 8591]]

self-administered, supporting a likely abuse liability.
    Kratom can produce serious toxicity in people who use high 
doses, but the number of cases is probably low as a proportion of 
the total number of people who use kratom. Although mitragynine has 
been analytically confirmed in a number of deaths, almost all 
involve use of other substances, so the degree to which kratom use 
has been a contributory factor to fatalities is unclear.
    Kratom and mitragynine have been associated with cases of 
driving under the influence, but their role in driving impairment 
could not be established in most instances.
    Multiple countries across various regions report nonmedical use 
of kratom. Seizures of kratom and related products have been 
reported in several countries.

Therapeutic Usefulness

    People report using kratom to self-medicate a variety of 
disorders and conditions, including pain, opioid withdrawal, opioid 
use disorder, anxiety, and depression. Kratom is being used as a 
part of traditional medicine in some countries.
    Research is ongoing to determine the basic pharmacology and the 
potential therapeutic value of kratom, mitragynine, and 7-
hydroxymitragynine.

Recommendation

    Kratom contains multiple alkaloids. The two main known 
psychoactive alkaloids, mitragynine and 7-hydroxymitragynine, 
produce at least some effects similar to opioids under international 
control.
    Mitragynine, the most abundant of these alkaloids, also has non-
opioid actions, the significance of which is unclear. There is mixed 
evidence on the abuse liability of mitragynine in animal models. 
Kratom is used for self-medication for a variety of disorders but 
there is limited evidence of abuse liability in humans.
    Cessation of regular use of kratom may lead to withdrawal 
symptoms.
    The Committee considered information regarding the traditional 
use and investigation into possible medical applications of kratom.
    The Committee concluded that there is insufficient evidence to 
recommend a critical review of kratom. With respect to mitragynine 
and 7-hydroxymitragynine, the Committee, except for one member, also 
concluded that there is insufficient evidence to recommend a 
critical review at this time.
    Recommendation: The Committee recommended that kratom, 
mitragynine, and 7-hydroxymitragynine be kept under surveillance by 
the WHO Secretariat.

Phenibut (4-amino-3-phenyl-butyric acid)

Substance Identification

    Phenibut (IUPAC chemical name: 4-Amino-3-phenylbutanoic acid) is 
a structural analogue of baclofen and gabapentin. It is produced in 
various formulations including tablets and powder for oral use, and 
crystalline form. Phenibut is a registered pharmaceutical in some 
countries and is also marketed online for a number of uses including 
as a sleep aid, mood enhancer, treatment for anxiety and a cognitive 
enhancer.

WHO Review History

    Phenibut has not been formally reviewed by WHO and is not 
currently under international control. Phenibut has been under ECDD 
surveillance since 2017 due to reports from Member States of its 
abuse and dependence potential. A pre-review was initiated following 
consideration of these reports.

Similarity to Known Substances and Effects on Central Nervous System

    Phenibut acts primarily as an agonist at the GABAB 
receptor, similar to baclofen, and at the [alpha]2-[delta] subunit 
of voltage dependent calcium channels, similar to gabapentin.
    Animal studies show that phenibut has dose-dependent analgesic, 
antidepressant, and anxiolytic effects, which are mediated both by 
its GABAB agonist effects and actions at voltage 
dependent calcium channels.
    Phenibut intoxication has presented with central nervous system 
depressive symptoms including decreased level of consciousness, 
muscle tone, stupor, depressed respiration, temperature 
dysregulation, hyper- or hypotension, and coma. However, in other 
cases individuals have presented with agitation, hallucinations, 
seizures, and delirium.

Dependence Potential

    There are no studies conducted in animals examining the 
dependence potential of phenibut. People who use phenibut describe 
escalating dosing suggestive of tolerance and difficulty in 
cessation.
    There are a limited number of case reports of withdrawal 
symptoms following abrupt discontinuation of high dose phenibut use. 
Reported symptoms have included insomnia, psychomotor agitation, 
delusions, psychosis, disorganized thought patterns, auditory/visual 
hallucinations, anxiety, depression, fatigue, dizziness, seizures, 
decreased appetite, nausea and vomiting, palpitations, and 
tachycardia. However, in most cases the use of phenibut was not 
verified analytically, and the clinical picture was complicated by 
the use of other drugs.

Actual Abuse and/or Evidence of Likelihood of Abuse

    No controlled animal or human studies have examined the abuse 
potential of phenibut.
    There are reports from different countries of adverse effects 
due to nonmedical use of phenibut. Medically unsupervised use of 
phenibut obtained via the internet is often at doses much higher 
than those used clinically. However, many cases involve multiple 
drugs, and the role of phenibut in these cases remains unclear.
    Multiple countries over several regions report seizures of 
phenibut. However, the extent of non-medical use is unknown.

Therapeutic Usefulness

    Phenibut is approved in a few countries as a medicine for a 
range of psychiatric and neurological conditions.

Recommendation

    The Committee noted that there has been concern in several 
countries regarding the nonmedical use of phenibut. While there are 
reports of adverse effects and of a withdrawal syndrome following 
cessation of use, the information on these cases is very limited. In 
addition, there is very little information on the abuse liability of 
phenibut, on the magnitude of its misuse or abuse, and on its 
similarity to currently internationally controlled substances.
    The Committee also noted that phenibut is used therapeutically 
in a small number of countries.
    Recommendation: The Committee recommended that phenibut (IUPAC 
chemical name: 4-Amino-3-phenylbutanoic acid) should not proceed to 
critical review but should 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.
    Brorphine (chemical name: 1-(1-(1-(4-bromophenyl)ethyl)piperidin-4-
yl)-1,3- dihydro-2H-benzo[d]imidazol-2-one) is a potent synthetic 
opioid encountered as both a single substance of abuse and in 
combination with other opioid substances, such as heroin and fentanyl. 
The appearance of brorphine on the illicit drug market is similar to 
other designer drugs trafficked for their psychoactive effects. 
Beginning in June 2019, brorphine emerged in the United States illicit, 
synthetic drug market as evidenced by its identification in drug 
seizures. The use of brorphine has been associated with at least seven 
fatalities between June and July 2020 in the United States. Brorphine 
is not approved for medical use in the United States. On March 1, 2021, 
the U.S. Drug Enforcement Administration (DEA) issued a temporary order 
to control brorphine as a Schedule I substance under the CSA, therefore 
additional permanent controls may be needed if brorphine is placed in 
Schedule I of the 1961 Convention.
    Metonitazene (chemical name: N,N-diethyl-2-(2-(4-methoxybenzyl)-5-
nitro-1H-benzo[d]imidazol-1-yl)ethan-1-amine) belongs to the series of 
2-benzylbenzimidazole opioid compounds and is classified as a potent 
opioid structurally resembling etonitazene and dissimilar in structure 
to other synthetic opioids such as fentanyl analogues. Novel opioids 
such as metonitazene have been reported to

[[Page 8592]]

cause psychoactive effects and adverse events, including deaths similar 
to heroin, fentanyl, and other opioids. As of January 2021, 
metonitazene has been identified in eight blood specimens associated 
with postmortem death investigations in the United States. There are no 
commercial or approved medical uses for metonitazene. On December 7, 
2021, the DEA issued a temporary order (86 FR 69182) to control 
metonitazene as a Schedule I substance under the CSA, therefore 
additional permanent controls may be needed if metonitazene is placed 
in Schedule I of the 1961 Convention.
    Eutylone (chemical name: 1-(1,3-benzodioxol-5-yl)-2-
(ethylamino)butan-1-one) is a designer drug of the phenethylamine 
class. Eutylone is a synthetic cathinone with chemical structural and 
pharmacological similarities to Schedule I and II amphetamines and 
cathinones, such as to 3,4-methylenedioxymethamphetamine, methylone, 
and pentylone. Eutylone emerged in the United States illicit, synthetic 
drug market in 2014 as evidenced by its identification in drug 
seizures. Other evidence indicates that eutylone, like other Schedule I 
synthetic cathinones, is abused for its psychoactive effects. Adverse 
effects associated with synthetic cathinones abuse include agitation, 
hypertension, tachycardia, and death. Eutylone is not approved for 
medical use in the United States. As a positional isomer of pentylone, 
eutylone is controlled in Schedule I of the CSA. As such, additional 
permanent controls will not be needed if eutylone 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 2022.
    Comments regarding the WHO recommendations for control of brorphine 
and metonitazene 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 9, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-03229 Filed 2-14-22; 8:45 am]
BILLING CODE 4164-01-P


