Notice2022-03229
International Drug Scheduling; Convention on Psychotropic Substances; Single Convention on Narcotic Drugs; World Health Organization; Scheduling Recommendations; Brorphine; Metonitazene; Eutylone; Request for Comments
Primary source
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Published
February 15, 2022
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
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).
Full Text
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<title>Federal Register, Volume 87 Issue 31 (Tuesday, February 15, 2022)</title>
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[Federal Register Volume 87, Number 31 (Tuesday, February 15, 2022)]
[Notices]
[Pages 8586-8592]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2022-03229]
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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; Brorphine; Metonitazene;
Eutylone; 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
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> 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:
<bullet> 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.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets
Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-
402-7500.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>. 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: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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, <a href="/cdn-cgi/l/email-protection#711b101c14025f19041f051403311715105f1919025f161e07"><span class="__cf_email__" data-cfemail="a8c2c9c5cddb86c0ddc6dccddae8ceccc986c0c0db86cfc7de">[email protected]</span></a>.
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: <a href="https://www.unodc.org/unodc/en/commissions/CND/session/65_Session_2022/65CND_Main.html">https://www.unodc.org/unodc/en/commissions/CND/session/65_Session_2022/65CND_Main.html</a>.
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 GABA<INF>B</INF>
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 GABA<INF>B</INF> 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
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