International Drug Scheduling; Convention on Psychotropic Substances; Single Convention on Narcotic Drugs; World Health Organization; Scheduling Recommendations; Brorphine; Metonitazene; Eutylone; Request for Comments, 8586-8592 [2022-03229]
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[FR Doc. 2022–03225 Filed 2–14–22; 8:45 am]
BILLING CODE 4164–01–P
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.
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.
SUMMARY:
Electronic Submissions
Submit electronic comments in the
following way:
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• 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
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Federal Register / Vol. 87, No. 31 / Tuesday, February 15, 2022 / Notices
information you claim to be confidential
with a heading or cover note that states
‘‘THIS DOCUMENT CONTAINS
CONFIDENTIAL INFORMATION.’’ The
Agency will review this copy, including
the claimed confidential information, in
its consideration of comments. The
second copy, which will have the
claimed confidential information
redacted/blacked out, will be available
for public viewing and posted on
https://www.regulations.gov. Submit
both copies to the Dockets Management
Staff. If you do not wish your name and
contact information to be made publicly
available, you can provide this
information on the cover sheet and not
in the body of your comments and you
must identify this information as
‘‘confidential.’’ Any information marked
as ‘‘confidential’’ will not be disclosed
except in accordance with 21 CFR 10.20
and other applicable disclosure law. For
more information about FDA’s posting
of comments to public dockets, see 80
FR 56469, September 18, 2015, or access
the information at: https://
www.govinfo.gov/content/pkg/FR-201509-18/pdf/2015-23389.pdf.
Docket: For access to the docket to
read background documents or the
electronic and written/paper comments
received, go to https://
www.regulations.gov and insert the
docket number, found in brackets in the
heading of this document, into the
‘‘Search’’ box and follow the prompts
and/or go to the Dockets Management
Staff, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852, 240–402–7500.
FOR FURTHER INFORMATION CONTACT:
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,
james.hunter@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
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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
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a summary of such information in the
Federal Register and provide
opportunity for interested persons to
submit comments. The Secretary of HHS
must then evaluate the proposal and
furnish a recommendation to the
Secretary of State that shall be binding
on the representative of the United
States in discussions and negotiations
relating to the proposal.
As detailed in the following
paragraphs, the Secretary of State has
received notification from the SecretaryGeneral of the United Nations (the
Secretary-General) regarding 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
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8587
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-(4Bromophenyl)ethyl]-piperidin-4-yl]-1,3dihydro-2H-imidazol-2-one
—Metonitazene
IUPAC name: N,N-Diethyl-2-(2-(4methoxybenzyl)-5-nitro-1Hbenzo[d]imidazol-1-yl)ethan-1-amine
Substances recommended to be added to
Schedule II of the 1971 Convention:
—Eutylone (alternate name: 3,4methylenedioxy-alpha-ethylamino
butiophenone)
IUPAC names: 1-(Benzo[d][1,3]dioxol-5-yl)-2(ethylamino)butan-1-one 1-(1,3Benzodioxol-5-yl)-2-(ethylamino)butan-1one
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}amino)-3,3dimethylbutanoate; Methyl 2-(1-(4fluorobutyl)-1H-indole-3-carbaxamido)-3,3dimethylbutanoate
—Benzylone (alternate name: 3,4Methylenedioxy-N-benzylcathinone)
IUPAC name: 1-(Benzo[d][1,3]dioxol-5-yl)-2(benzylamino)propan-1-one
—Kratom, mitragynine, and 7hydroxymitragynine
—Phenibut (alternate name: 4-amino-3phenyl-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
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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: 3,4methylenedioxy-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 DirectorGeneral 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
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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-(4Bromophenyl)ethyl]- piperidin-4-yl]-1,3dihydro-2H- imidazol-2- one
—Metonitazene
IUPAC name: N,N-Diethyl-2-(2-(4methoxybenzyl)-5-nitro-1Hbenzo[d]imidazol-1-yl)ethan-1-amine
To be added to Schedule II of the
Convention on Psychotropic Substances
(1971):
—Eutylone (alternate name: 3,4methylenedioxy-alpha-ethylamino
butiophenone)
IUPAC names: 1-(Benzo[d][1,3]dioxol-5-yl)-2(ethylamino)butan-1-one; 1-(1,3Benzodioxol-5-yl)-2-(ethylamino)butan-1one
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}amino)-3,3dimethylbutanoate; Methyl 2-(1-(4fluorobutyl)-1H-indole-3- carbaxamido)3,3- dimethylbutanoate
—Benzylone (alternate name: 3,4Methylenedioxy-N-benzylcathinone)
IUPAC name: 1-(Benzo[d][1,3]dioxol-5-yl)-2(benzylamino)propan-1-one
—Kratom, mitragynine, 7hydroxymitragynine
—Phenibut (alternate name: 4-amino-3phenyl-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
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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]-1,3dihydro-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 m-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 m-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
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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 nonfatal 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-(4bromophenyl)ethyl]-piperidin-4-yl]-1,3dihydro-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,NDiethyl-2-(2-(4-methoxybenzyl)-5-nitro-1Hbenzo[d]imidazol-1-yl)ethan-1-amine)
belongs to the series of 2benzylbenzimidazole 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
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and has potent m-opioid agonist effects. No
controlled human studies have reported on
the dependence potential of metonitazene,
but as a potent m-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 m-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-(4methoxybenzyl)-5-nitro-1Hbenzo[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-alphaethylamino 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
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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-3yl]carbonyl}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, offwhite, 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.
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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-(4fluorobutyl)-1H-indol-3-yl]carbonyl}amino)3,3-dimethylbutanoate) be kept under
surveillance by the WHO Secretariat.
Benzylone (3,4-Methylenedioxy-Nbenzylcathinone)
Substance Identification
Benzylone (IUPAC chemical name: 1(Benzo[d][1,3]dioxol-5-yl)-2(benzylamino)propan-1-one) is a ringsubstituted synthetic cathinone. Benzylone is
a white powder. The hydrochloride salt of
benzylone is a crystalline solid.
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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 7hydroxymitragynine
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
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components of kratom are mitragynine and 7hydroxymitragynine, 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 7hydroxymitragynine have effects indicative
of abuse liability in some animal models but
not in others. Mitragynine is not selfadministered by animals, while 7hydroxymitragynine has been shown to be
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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.
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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 7hydroxymitragynine.
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: 4Amino-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,
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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 a2-d 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
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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-(4bromophenyl)ethyl)piperidin-4-yl)-1,3dihydro-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,Ndiethyl-2-(2-(4-methoxybenzyl)-5-nitro1H-benzo[d]imidazol-1-yl)ethan-1amine) belongs to the series of 2benzylbenzimidazole 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
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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-(1,3benzodioxol-5-yl)-2-(ethylamino)butan1-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 3,4methylenedioxymethamphetamine,
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.
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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
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket Nos. FDA–2010–D–0575 and FDA–
2021–N–0764]
Compliance Policy Guide Sec. 510.800
Beverages—Serving Size Labeling;
Compliance Policy Guide Sec. 540.420
Raw Breaded Shrimp—Microbiological
Criteria for Evaluating Compliance
With Current Good Manufacturing
Practice Regulations; and Compliance
Policy Guide Sec. 562.800 Vending
Machine Food—Labeling; Withdrawal
of Guidances
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice; withdrawal.
The Food and Drug
Administration (FDA or we) is
announcing the withdrawal of three
compliance policy guides (CPG) entitled
‘‘Compliance Policy Guide Sec. 510.800
Beverages—Serving Size Labeling,’’
‘‘Compliance Policy Guide Sec. 540.420
Raw Breaded Shrimp—Microbiological
Criteria for Evaluating Compliance with
Current Good Manufacturing Practice
Regulations,’’ and ‘‘Compliance Policy
Guide Sec. 562.800 Vending Machine
Food—Labeling.’’ We are withdrawing
these CPGs because they have become
outdated or have been superseded by
subsequent FDA actions.
DATES: The withdrawal is applicable
February 15, 2022.
ADDRESSES: For access to the docket, go
to https://www.regulations.gov and
insert docket number FDA–2010–D–
0575 for ‘‘Compliance Policy Guide Sec.
510.800 Beverages—Serving Size
Labeling’’ or FDA–2021–N–0764 for
‘‘Compliance Policy Guide Sec. 540.420
Raw Breaded Shrimp—Microbiological
Criteria for Evaluating Compliance with
Current Good Manufacturing Practice
Regulations’’ and ‘‘Compliance Policy
Guide Sec. 562.800 Vending Machine
Food—Labeling’’ 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:
Kevin Kwon, Office of Compliance
SUMMARY:
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(HFS–605), Center for Food Safety and
Applied Nutrition, Food and Drug
Administration, 5001 Campus Dr.,
College Park, MD 20740, 240–402–4597;
or Alexandra Jurewitz, Office of
Regulations and Policy (HFS–024),
Center for Food Safety and Applied
Nutrition, Food and Drug
Administration, 5001 Campus Dr.,
College Park, MD 20740, 240–402–2378.
SUPPLEMENTARY INFORMATION:
I. Background
We are announcing the withdrawal of
three CPGs entitled ‘‘Compliance Policy
Guide Sec. 510.800 Beverages—Serving
Size Labeling,’’ ‘‘Compliance Policy
Guide Sec. 540.420 Raw Breaded
Shrimp—Microbiological Criteria for
Evaluating Compliance with Current
Good Manufacturing Practice
Regulations,’’ and ‘‘Compliance Policy
Guide Sec. 562.800 Vending Machine
Food—Labeling.’’
CPG Sec. 510.800 entitled
‘‘Beverages—Serving Size Labeling’’ was
first issued in December 2010. This CPG
provided guidance for FDA staff and
industry as to when we would typically
consider not taking enforcement action
in connection to a ‘‘12 [fluid ounce]
(360 [milliliter])’’ labeled serving size on
specific types of beverages larger than
20 fluid ounces. On May 27, 2016, FDA
issued a final rule entitled ‘‘Food
Labeling: Serving Sizes of Foods That
Can Reasonably Be Consumed at One
Eating Occasion; Dual-Column Labeling;
Updating, Modifying, and Establishing
Certain Reference Amounts Customarily
Consumed; Serving Size for Breath
Mints; and Technical Amendments’’ (81
FR 34000). The final rule amended the
Reference Amounts Customarily
Consumed (RACCs) that are used by
manufacturers to determine serving
sizes for certain foods, including certain
beverages. Our regulations, at 21 CFR
101.12(b), table 2, lists the categories for
each type of food product and each
category’s current RACC. Due to the
updated RACCs for certain beverages,
CPG Sec. 510.800 is now obsolete, and
the enforcement discretion provided in
this CPG is no longer applicable.
Therefore, CPG Sec. 510.800 is being
withdrawn.
CPG Sec. 540.420 entitled ‘‘Raw
Breaded Shrimp—Microbiological
Criteria for Evaluating Compliance with
Current Good Manufacturing Practice
Regulations’’ was first issued in August
1983. This CPG used data collected in
fiscal year 1978 and listed an outdated
sampling and compliance structure. The
compliance criteria and the
methodology used in the CPG have
become outdated and are no longer
useful. This CPG is superseded by the
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]]>Agencies
[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
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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
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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
