[Federal Register Volume 84, Number 250 (Tuesday, December 31, 2019)]
[Notices]
[Pages 72370-72377]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-28269]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2019-N-5955]
International Drug Scheduling; Convention on Psychotropic
Substances; Single Convention on Narcotic Drugs; World Health
Organization; Scheduling Recommendations; AB-FUBINACA; 5F-AMB-PINACA;
5F-MDMB-PICA; 4-F-MDMB-BINACA; 4-CMC; N-ethylhexedrone; alpha-PHP; DOC;
Crotonyl Fentanyl; Valeryl Fentanyl; Flualprazolam and Etizolam;
Request for Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is providing interested
persons with the opportunity to submit written comments concerning
recommendations by the World Health Organization (WHO) to impose
international manufacturing and distributing restrictions, under
international treaties, on certain drug substances. The comments
received in response to this notice will be considered in preparing the
United States' position on these proposals for a meeting of the United
Nations Commission on Narcotic Drugs (CND) in Vienna, Austria, in March
2020. This notice is issued under the Controlled Substances Act (CSA).
DATES: Submit either electronic or written comments by January 30,
2020. The short time period for the submission of comments is needed to
ensure that Health and Human Services (HHS) may, in a timely fashion,
carry out the required action and be responsive to the United Nations.
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 January 30, 2020. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of January 30, 2020. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are postmarked or the delivery
service acceptance receipt is 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-2019-N-5955 for ``International Drug Scheduling; Convention on
Psychotropic Substances; Single Convention on Narcotic Drugs; World
Health Organization; Scheduling Recommendations; AB-FUBINACA; 5F-AMB-
PINACA; 5F-MDMB-PICA; 4-F-MDMB-BINACA; 4-CMC; N-ethylhexedrone; alpha-
PHP; DOC; Crotonyl Fentanyl; Valeryl Fentanyl; Flualprazolam and
Etizolam; 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.
Confidential Submissions--To submit a comment with
confidential
[[Page 72371]]
information that you do not wish to be made publicly available, submit
your comments only as a written/paper submission. You should submit two
copies total. One copy will include the information you claim to be
confidential with a heading or cover note that states ``THIS DOCUMENT
CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will review this copy,
including the claimed confidential information, in its consideration of
comments. The second copy, which will have the claimed confidential
information redacted/blacked out, will be available for public viewing
and posted on https://www.regulations.gov. Submit both copies to the
Dockets Management Staff. If you do not wish your name and contact
information to be made publicly available, you can provide this
information on the cover sheet and not in the body of your comments and
you must identify this information as ``confidential.'' Any information
marked as ``confidential'' will not be disclosed except in accordance
with 21 CFR 10.20 and other applicable disclosure law. For more
information about FDA's posting of comments to public dockets, see 80
FR 56469, September 18, 2015, or access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.
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 ten substances to be considered for
control under the 1971 Convention. This notification reflects the
recommendation from the 42nd WHO Expert Committee for Drug Dependence
(ECDD), which met in October 2019. In the Federal Register of September
10, 2019 (84 FR 47521), 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. 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.10/2019
WHO/ECDD42; 1961C-Art.3, 1971C-Art.2 CU 2019/462/DTA/SGB (A)
The Secretary-General of the United Nations presents his
compliments to the Secretary of State of the United States of America
and has the honour to inform the Government that in a letter dated 15
November 2019 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:
Substances recommended to be added to Schedule I of the 1961
Convention:
Crotonyl fentanyl
chemical name: (2E)-N-phenyl-N-[1-(2-phenylethyl)piperidin-4-
yl]but-2-enamide
Valeryl fentanyl
chemical name: N-phenyl-N-[1-(2-phenylethyl)piperidin-4-
yl]pentanamide
Substance recommended to be added to Schedule I of the 1971
Convention:
DOC
chemical name: 1-(4-chloro-2,5-dimethoxyphenyl)propan-2-amine
Substances recommended to be added to Schedule II of the 1971
Convention:
AB-FUBINACA
chemical name: N-[1-amino-3-methyl-1-oxobutan-2-yl]-1-[(4-
fluorophenyl)methyl]-1H-indazole-3-carboxamide
5F-AMB-PINACA (5F-AMB, 5F-MMB-PINACA)
chemical name: methyl 2-{[1-(5-fluoropentyl)-1H-indazole-3-
carbonyl]amino{time} -3-methylbutanoate
5F-MDMB-PICA (5F-MDMB-2201)
chemical name: methyl 2-{[1-(5-fluoropentyl)-1H-indole-3-
carbonyl]amino{time} -3,3-dimethylbutanoate
4F-MDMB-BINACA
chemical name: methyl 2-{[1-(4-fluorobutyl)-1H-indazole-3-
carbonyl]amino{time} -3,3-dimethylbutanoate
4-CMC (4-chloromethcathinone; clephedrone)
chemical name: 1-(4-chlorophenyl)-2-(methylamino)propan-1-one
[[Page 72372]]
N-Ethylhexedrone
chemical name: 2-(ethylamino)-1-phenylhexan-1-one
Alpha-PHP
chemical name: 1-phenyl-2-(pyrrolidine-1-yl)hexan-1-one
Substances recommended to be added to Schedule IV of the 1971
Convention:
Flualprazolam
chemical name: 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-
benzo[f][1,2,4]triazolo[4,3-a][1,4] diazepine
Etizolam
chemical name: 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-
thieno[3,2f][1,2,4]triazolo[4,3 a][1,4]diazepine
In accordance with the provisions of article 3, paragraph 2 of the
1961 Convention and article 2, paragraph 2 of the 1971 Convention, the
Secretary-General hereby transmits the notification as annex I to the
present note. In connection with the notification, WHO also submitted a
summary of the rationale of the recommendations which is hereby
transmitted as annex II. For time reasons, this notification and its
annexes I and II are transmitted in English only. The notification and
its annexes will be transmitted in French and Spanish as soon as
available.
Also in accordance with the same provisions, the notification from
WHO will be brought to the attention of the 63rd session of the
Commission on Narcotic Drugs (2-6 March 2020) in a pre-session document
that will be made available in the six official languages of the United
Nations on the website of the 63rd session of the CND: https://www.unodc.org/unodc/en/commissions/CND/session/63_Session_2020/session-63-of-the-commission-on-narcotic-drugs.html.
In order to assist the Commission in reaching a decision, it would
be appreciated if the Government 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: Crotonyl fentanyl, Valeryl fentanyl, 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: DOC, AB-FUBINACA, 5F-AMB-PINACA (5F-AMB, 5F-MMB-
PINACA), 5F-MDMB-PICA (5F-MDMB-2201), 4F-MDMB-BINACA, 4-CMC (4-
chloromethcathinone; clephedrone), N-Ethylhexedrone, Alpha-PHP,
Flualprazolam, Etizolam.
Communications should be sent to the Executive Director of the
United Nations Office on Drugs and Crime, c/o Secretary, Commission on
Narcotic Drugs, P.O. Box 500, 1400 Vienna, Austria, email: [email protected] (fax: +43-1-26060-5885), no later than by 31 January 2020.
2 December 2019
His Excellency,
Mr. Rex Tillerson,
Secretary of State of the United States of America
Annex I
Letter Addressed to the Secretary-General of the United Nations From
the Director-General of the World Health Organization
``The Forty-second meeting of the WHO Expert Committee on Drug
Dependence was convened from 21 to 25 October 2019 at WHO headquarters
in Geneva. The objective of this meeting was to carry out an in-depth
evaluation of psychoactive substances in order to determine whether WHO
should recommend these substances to be placed under international
control or if their level of control should be changed.
The Forty-second Meeting reviewed thirteen psychoactive substances,
five of which are synthetic cannabinoids, four synthetic stimulants,
two fentanyl analogues, and two benzodiazepines. In addition, the
Meeting carried out a pre- review of preparations of
acetyldihydrocodeine, codeine, dihydrocodeine, ethylmorphine,
nicocodine, nicodicodine, norcodeine and pholcodine that are listed in
Schedule III of the 1961 Convention on Narcotic Drugs.
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), I am pleased to submit recommendations of the Forty-
second Meeting of ECDD as follows:
To be added to Schedule I of the Single Convention on Narcotic
Drugs (1961):
Crotonyl fentanyl
chemical name: (2E)-N-phenyl-N-[1-(2-phenylethyl)piperidin-4-
yl]but-2-enamide
Valeryl fentanyl
chemical name: N-phenyl-N-[1-(2-phenylethyl)piperidin-4-
yl]pentanamide
To be added to Schedule I of the Convention on Psychotropic
Substances (1971):
DOC
chemical name: 1-(4-chloro-2,5-dimethoxyphenyl)propan-2-amine
To be added to Schedule II of the Convention on Psychotropic
Substances (1971):
AB-FUBINACA
chemical name: N-[1-amino-3-methyl-1-oxobutan-2-yl]-1-[(4-
fluorophenyl)methyl]-1H-indazole-3-carboxamide
5F-AMB-PINACA (5F-AMB, 5F-MMB-PINACA)
chemical name: methyl 2-{[1-(5-fluoropentyl)-1H-indazole-3-
carbonyl]amino{time} -3-methylbutanoate
5F-MDMB-PICA (5F-MDMB-2201)
chemical name: methyl 2-{[1-(5-fluoropentyl)-1H-indole-3-
carbonyl]amino{time} -3,3-dimethylbutanoate
4-F-MDMB-BINACA
chemical name: methyl 2-{[1-(4-fluorobutyl)-1H-indazole-3-
carbonyl]amino{time} -3,3-dimethylbutanoate
4-CMC (4-chloromethcathinone; clephedrone)
chemical name: 1-(4-chlorophenyl)-2-(methylamino)propan-1-one
N-ethylhexedrone
chemical name: 2-(ethylamino)-1-phenylhexan-1-one
Alpha-PHP
chemical name: 1-phenyl-2-(pyrrolidine-1-yl)hexan-1-one
To be added to Schedule IV of the Convention on Psychotropic
Substances (1971):
Flualprazolam
chemical name: 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-
benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine
Etizolam
chemical name: 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-
thieno[3,2f][1,2,4]triazolo [4,3-a][1,4]diazepine
To be kept under surveillance:
APINACA (AKB-48)
chemical name: N-(adamantan-1-yl)-1-pentyl-1H-indazole-3-
carboxamide
To proceed to critical review:
--Preparations of acetyldihydrocodeine, codeine, dihydrocodeine,
ethylmorphine, nicocodine, nicodicodine, norcodeine and pholcodine
listed in Schedule III of the 1961 Single Convention on Narcotic Drugs
The assessments and findings on which these recommendations are
based are set out in detail in the report of the Forty-second Meeting
of the WHO Expert Committee on Drug Dependence.
[[Page 72373]]
A summary of the rationale of these recommendations is attached in
Annex 1 of this letter.
I am very pleased with the ongoing collaboration between WHO, the
United Nations Office on Drugs and Crime (UNODC) and the International
Narcotics Control Board (INCB) 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 (UNGASS) 2016.''
Annex II
Summary of the Rationale for the Recommendations of the 42nd Expert
Committee on Drug Dependence
Substances recommended to be added to Schedule I of the Single
Convention on Narcotic Drugs (1961), as amended by the 1972 Protocol:
Crotonyl fentanyl
The chemical name for crotonyl fentanyl is (2E)-N-phenyl-N-[1-(2-
phenylethyl)piperidin-4-yl]but-2-enamide.
Crotonyl fentanyl binds to mu opioid receptors and acts as an
opioid agonist. In animal models, crotonyl fentanyl produces
antinociception, actions predictive of oxycodone-like subjective
effects and both central nervous system stimulation and depression. The
opioid antagonist naltrexone blocks the effects of crotonyl fentanyl.
This pharmacological profile indicates that crotonyl fentanyl is an
opioid and comparative studies suggest that it has a potency
intermediate between oxycodone and fentanyl.
Consistent with the results from animal studies, the effects of
crotonyl fentanyl were reversed by an opioid antagonist in a clinical
admission due to overdose. Due to its opioid mechanism of action,
crotonyl fentanyl has the potential to be associated with substantial
harm.
Crotonyl fentanyl has been found in seized material from countries
across several regions. It has no veterinary or medical use.
Based on its opioid mechanism of action and similarity to drugs
such as oxycodone and fentanyl that are controlled under Schedule I of
the Single Convention on Narcotic Drugs, it is recommended that
crotonyl fentanyl also be controlled under Schedule I of the Single
Convention on Narcotic Drugs (1961).
Valeryl fentanyl
The chemical name for valeryl fentanyl is N-phenyl-N-[1-(2-
phenylethyl)piperidin-4-yl]pentanamide.
Valeryl fentanyl binds to mu opioid receptors and acts as an opioid
agonist. In animal models, valeryl fentanyl suppresses opioid
withdrawal symptoms, produces antinociception and has actions
predictive of oxycodone-like subjective effects. The opioid antagonist
naltrexone blocks the effects of valeryl fentanyl. This pharmacological
profile indicates that valeryl fentanyl is an opioid and comparative
studies suggest that it has a potency less than that of fentanyl.
Valeryl fentanyl has been detected in biological samples from a
small number of deaths and cases of driving under the influence of
drugs.
Valeryl fentanyl has been detected in seizures from countries
across several regions. It has no veterinary or medical use.
Based on the evidence of its opioid mechanism of action and
similarity to drugs such as fentanyl that are controlled under Schedule
I of the Single Convention on Narcotic Drugs, it is recommended that
valeryl fentanyl also be controlled under Schedule I of the Single
Convention on Narcotic Drugs (1961).
Substance recommended to be added to Schedule I of the Convention
on Psychotropic Substances (1971):
DOC
DOC is also known as 4-chloro-2,5-DMA or 2,5-dimethoxy-4-
chloroamphetamine. Its chemical name is 1-(4-chloro-2,5-
dimethoxyphenyl)propan-2-amine.
DOC is an agonist at the serotonergic 5-HT2A receptor, a mechanism
it shares with hallucinogens such as LSD.
In animal models, DOC has actions predictive of hallucinogenic
subjective effects (similar to LSD and DOM) and shows evidence of
rewarding effects. It can produce both central nervous system
stimulation and depression.
Based on clinical admissions due to overdose, the adverse effects
associated with use of DOC include agitation, aggression,
hallucinations, tachycardia, hyperthermia and seizures.
DOC has been detected in 40 countries. It has no veterinary or
medical use.
Based on its similarity in mechanism of action and effects to
currently scheduled hallucinogens such as LSD and DOM, and the evidence
that it is abused so as to constitute a public health and social
problem, it is recommended that DOC be controlled under the 1971
Convention on Psychotropic Substances. As it has no medical use and its
use constitutes a serious risk to public health, it is recommended that
it be controlled under Schedule I of 1971 Convention on Psychotropic
Substances.
Substances recommended to be scheduled in Schedule II of the
Convention on Psychotropic Substances (1971):
AB-FUBINACA
The chemical name for AB-FUBINACA is N-[1-amino-3-methyl-1-
oxobutan-2-yl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide.
In common with other synthetic cannabinoids, AB-FUBINACA is a full
agonist at the cannabinoid CB1 receptor that mediates the psychoactive
effects of cannabinoids. In animal studies, it produced central nervous
system depression and other typical cannabinoid behavioural effects and
had actions predictive of cannabinoid subjective effects.
AB-FUBINACA produces neurological signs in animals that are
indicative of toxicity, including seizures, hyperreflexia and
aggression. Based on its mechanism of action, it would be expected to
produce a range of adverse effects in human users that include
tachycardia, nausea, vomiting, confusion and hallucinations. There are
a large number of cases of intoxication resulting from AB-FUBINACA,
often in combination with other drugs, and at least one death has been
reported that is attributable to the effects of AB-FUBINACA.
AB-FUBINACA use has been reported in over 30 countries across
different regions. It has no veterinary or medical use.
Based on its capacity to produce a state of dependence, its ability
to produce central nervous system depression and the evidence that it
is abused so as to constitute a public health and social problem, it is
recommended that AB-FUBINACA be controlled under the 1971 Convention on
Psychotropic Substances. As it has no medical use and its use
constitutes a substantial risk to public health, it is recommended that
it be controlled under Schedule II of 1971 Convention on Psychotropic
Substances.
5F-AMB-PINACA
5F-AMB-PINACA is also known as 5F-AMB and 5F-MMB-PINACA. Its
chemical name is methyl 2-{[1-(5-fluoropentyl)-1H-indazole-3-
carbonyl]amino{time} -3-methylbutanoate.
In common with other synthetic cannabinoids, 5F-AMB-PINACA is a
full agonist at the cannabinoid CB1 receptor that mediates the
psychoactive effects of cannabinoids. In animal studies it
[[Page 72374]]
produced central nervous system depression and had actions predictive
of cannabinoid-like subjective effects. 5F-AMB-PINACA produces
impairment of memory and seizures in animals.
5F-AMB-PINACA use has been associated with a number of cases of
fatal and non-fatal intoxication often in combination with other drugs.
In a case of non-fatal intoxication due to 5F-AMB-PINACA alone, the
effects included cognitive impairment, slowed movement, slurred speech
and poor coordination. Based on its mechanism of action, it would also
be expected to produce a range of other effects in human users that
include tachycardia, nausea, vomiting, confusion and hallucinations.
5F-AMB-PINACA has been identified as a causal factor in motor vehicle
accidents, some of which were fatal.
5F-AMB-PINACA use has been reported in over 30 countries across
different regions. It has no veterinary or medical use.
Based on its capacity to produce a state of dependence, its ability
to produce central nervous system depression and the evidence that it
is abused so as to constitute a public health and social problem, it is
recommended that 5F-AMB-PINACA be controlled under the 1971 Convention
on Psychotropic Substances. As it has no medical use and its use
constitutes a substantial risk to public health, it is recommended that
it be controlled under Schedule II of the 1971 Convention on
Psychotropic Substances.
5F-MDMB-PICA
5F-MDMB-PICA is also known as 5F-MDMB-2201. Its chemical name is
methyl 2-{[1-(5-fluoropentyl)-1H-indole-3-carbonyl]amino{time} -3,3-
dimethylbutanoate.
In common with other synthetic cannabinoids, 5F-MDMB-PICA is a full
agonist at the cannabinoid CB1 receptor that mediates the psychoactive
effects of cannabinoids.
Its use has been associated with a number of fatal and non-fatal
intoxications that have been characterised by effects such as decreased
mental status, agitated delirium and seizures. While 5F-MDMB-PICA has
been present in biological samples mostly in combination with other
drugs, in at least some of these cases 5F-MDMB-PICA has been assessed
as having a high contribution to the effects produced. It has been used
by victims of three apparent mass overdose events, but at least one
other synthetic cannabinoid was also detected in biological fluids from
the victims.
5F-MDMB-PICA has been detected in 20 countries. It has no
veterinary or medical use.
Based on its mechanism of action, 5F-MDMB-PICA has the ability to
produce a state of dependence and central nervous system depression.
There is evidence that it is abused so as to constitute a public health
and social problem. It is therefore recommended that 5F-MDMB-PICA be
controlled under the 1971 Convention on Psychotropic Substances. As it
has no medical use and its use constitutes a substantial risk to public
health, it is recommended that it be controlled under Schedule II of
the 1971 Convention on Psychotropic Substances.
4F-MDMB-BINACA
4F-MDMB-BINACA is also known as 4F-MDMB-BUTINACA. Its chemical name
is methyl 2-{[1-(4-fluorobutyl)-1H-indazole-3-carbonyl]amino{time} -
3,3-dimethylbutanoate.
In common with other synthetic cannabinoids, 4F-MDMB-BINACA is a
full agonist at the CB1 receptor that mediates the psychoactive effects
of cannabinoids.
Self-reported effects provided by individuals who had used
cannabinoid products that included 4F-MDMB-BINACA as the major
constituent, included auditory and visual hallucinations, vomiting,
paranoia, euphoria, relaxation, irregular heartbeat, agitation,
confusion, insomnia, and chest pain. These effects are consistent with
the cannabinoid full agonist mechanism of action of 4F-MDMB-BINACA. Its
use has been associated with a number of fatal and non-fatal
intoxications and of cases of driving under the influence of drugs.
However, other synthetic cannabinoids have been detected in most of
these cases.
4F-MDMB-BINACA has been detected in a small number of countries to
date, but its use may be increasing. It has no veterinary or medical
use.
Based on its mechanism of action, 4F-MDMB-BINACA has the ability to
produce a state of dependence and central nervous system depression.
There is evidence that it is abused so as to constitute a public health
and social problem. It is therefore recommended that 4F-MDMB-BINACA be
controlled under the 1971 Convention on Psychotropic Substances. As it
has no medical use and its use constitutes a substantial risk to public
health, it is recommended that it be controlled under Schedule II of
the 1971 Convention on Psychotropic Substances.
4-CMC
4-CMC is also known as 4-chloromethcathinone and clephedrone. Its
chemical name is 1-(4-chlorophenyl)-2-(methylamino)propan-1-one.
In common with other stimulants used non-medically, 4-CMC increases
neuronal concentrations of the neurotransmitter dopamine. It also has
effects on serotonin and, to a lesser extent, noradrenaline.
In animal models, 4-CMC has effects predictive of abuse potential,
including actions predictive of MDMA-like subjective effects and
stimulation of brain reward centres. It also produces central nervous
system stimulation. Users of the drug report effects similar to other
stimulants, particularly MDMA-like effects, including increased energy,
mood elevation and increased sociability.
4-CMC use has been associated with adverse effects typical of
stimulant drugs, including tachycardia, agitation and impaired
movement. Based on these effects and its mechanism of action, major
risks associated with use of this drug will include cardiac failure and
psychosis. In association with other drugs, 4-CMC has been involved in
fatalities due to overdose, suicide and traffic accidents. It has been
detected in used syringes, indicating the potential for injection
related health problems in association with its use.
4-CMC has been detected in many countries across different regions.
It has no veterinary or medical use.
Based on its mechanism of action and effects, 4-CMC has the ability
to produce a state of dependence and central nervous system
stimulation. There is evidence that it is abused so as to constitute a
public health and social problem. It is therefore recommended that 4-
CMC be controlled under the 1971 Convention on Psychotropic Substances.
As it has no medical use and its use constitutes a substantial risk to
public health, it is recommended that it be controlled under Schedule
II of the 1971 Convention on Psychotropic Substances.
N-Ethylhexedrone
The chemical name for N-ethylhexedrone is 2-(ethylamino)-1-
phenylhexan-1-one.
In common with other stimulants used non-medically, N-
ethylhexedrone increases neuronal concentrations of the
neurotransmitter dopamine. It also has effects on noradrenaline.
In preclinical models, N-ethylhexedrone has actions predictive of
methamphetamine-like subjective effects and produces central nervous
system stimulation. Users of the drug
[[Page 72375]]
report effects similar to other stimulants, including increased energy,
mood elevation, perceptual changes and increased sociability.
Information on the adverse effects is limited, but the effects
reported are consistent with the effects of stimulant drugs and include
tachycardia, tremor, seizures and hyperthermia. N-ethylhexedrone has
been implicated as the cause of at least one fatality and of cases of
impaired driving. It has been detected in used syringes, indicating the
potential for injection related health problems in association with its
use.
N-ethylhexedrone has been detected in 30 countries across different
regions. It has no veterinary or medical use.
Based on its mechanism of action and effects, N-ethylhexedrone has
the ability to produce a state of dependence and central nervous system
stimulation. There is evidence that it is abused so as to constitute a
public health and social problem. It is therefore recommended that N-
ethylhexedrone be controlled under the 1971 Convention on Psychotropic
Substances. As it has no medical use and its use constitutes a
substantial risk to public health, it is recommended that it be
controlled under Schedule II of the 1971 Convention on Psychotropic
Substances.
Alpha-PHP
Alpha-PHP is also known as alpha-pyrrolidinohexanophenone. Its
chemical name is 1-phenyl-2-(pyrrolidine-1-yl)hexan-1-one.
In common with other stimulants used non-medically, alpha-PHP
increases neuronal concentrations of the neurotransmitter dopamine. It
also has effects on noradrenaline.
In animal models, alpha-PHP has effects predictive of abuse and
dependence potential, including actions predictive of methamphetamine-
like subjective effects and reinforcing properties. It produces central
nervous system stimulation in animals. Users of the drug report effects
similar to other stimulants, including increased energy, mood
elevation, perceptual changes and appetite suppression.
The adverse effects of the drug include tachycardia, paranoia and
hallucinations. It has been identified as the cause of multiple deaths
and clinical admissions.
Alpha-PHP has been detected in over 20 countries across different
regions. It has no veterinary or medical use.
Based on its mechanism of action and effects, alpha-PHP has the
ability to produce a state of dependence and central nervous system
stimulation. There is evidence that it is abused so as to constitute a
public health and social problem. It is therefore recommended that
alpha-PHP be controlled under the 1971 Convention on Psychotropic
Substances. As it has no medical use and its use constitutes a
substantial risk to public health, it is recommended that it be
controlled under Schedule II of the 1971 Convention on Psychotropic
Substances.
Substances recommended to be scheduled in Schedule IV of the
Convention on Psychotropic Substances (1971):
Flualprazolam
The chemical name for flualprazolam is 8-chloro-6-(2-fluorophenyl)-
1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4] diazepine.
Flualprazolam is chemically similar to the benzodiazepines
alprazolam and triazolam and in animal models it produces the typical
benzodiazepine effects of sedation, muscle relaxation and
anticonvulsant actions. Users have reported effects such as sedation,
disinhibition and memory impairment that are common with
benzodiazepines and have described it as similar to alprazolam and
clonazepam.
In toxicology reports, flualprazolam has been documented as
contributing to forensic and clinical events, including fatal and non-
fatal intoxications and cases of driving under the influence. It has no
medical use.
There is limited information on the extent of global use of
flualprazolam with most reported identifications coming from two
countries. There are numerous reports of its use on internet forums.
Based on its capacity to produce a state of dependence and central
nervous system depression similar to the controlled benzodiazepine
alprazolam, which is controlled under Schedule IV of the1971 Convention
on Psychotropic Substances, as well as evidence that it is likely to be
abused so as to constitute a public health and social problem, it is
recommended that flualprazolam be controlled under Schedule IV of the
1971 Convention on Psychotropic Substances.
Etizolam
The chemical name for etizolam is 4-(2-chlorophenyl)-2-ethyl-9-
methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine. It has
been previously reviewed by the ECDD, most recently at its 39th meeting
in 2017.
Etizolam is an agonist at the benzodiazepine site on the GABAA
receptor, inducing central nervous system depression. It has typical
benzodiazepine effects that include sedation and muscle relaxation as
well as anxiolytic and anticonvulsant actions. Adverse effects include
drowsiness, ataxia, slurred speech, cognitive impairment and loss of
consciousness.
Etizolam use has been associated with a large number of deaths,
generally along with another drug or drugs. Benzodiazepines such as
etizolam pose a significant risk when combined with opioids as they can
potentiate the respiratory depressant effects of opioids.
Etizolam has been used in a number of countries and in some of
these countries has been associated with reports of fatal and no-fatal
intoxication as well as cases of driving under the influence. It has
marketing authorization for medical use in three countries.
Based on its capacity to produce a state of dependence and central
nervous system depression similar to other controlled benzodiazepines,
as well as evidence that it is abused so as to constitute a public
health and social problem, it is recommended that etizolam be
controlled under Schedule IV of the 1971 Convention on Psychotropic
Substances.
Substance recommended for surveillance:
APINACA
The chemical name for APINACA (also known as AKB-48) is N-
(adamantan-1-yl)-1-pentyl-1H-indazole-3-carboxamide. It was previously
reviewed at the 36th meeting of the WHO Expert Committee on Drug
Dependence in 2014 but was not recommended for control at that time.
In common with other synthetic cannabinoids, APINACA is an agonist
at the CB1 receptor that mediates the psychoactive effects of
cannabinoids. In animal studies it produced central nervous system
depression and had actions predictive of cannabinoid-like subjective
effects.
APINACA produces neurological signs in animals that include
seizures, hyperreflexia and aggression. However, there are no studies
of the adverse effects of APINACA in human users of the drug and no
available information regarding fatal or non-fatal intoxications.
APINACA use has been reported in a number of countries but its use
has been declining since 2015 and it is now detected very infrequently
if at all.
Owing to the lack of significantly more information since the
review conducted by the 36th ECDD in 2014, and considering the current
insufficiency of data regarding dependence, abuse and risks to public
health (including risks to the
[[Page 72376]]
individual), the Committee recommended that APINACA be kept under
surveillance.
Preparations recommended for critical review:
--Preparations of acetyldihydrocodeine, codeine, dihydrocodeine,
ethylmorphine, nicocodine, nicodicodine, norcodeine and pholcodine
listed in Schedule III of the 1961 Single Convention on Narcotic Drugs
The Committee considered a pre-review of the following preparations
listed in Schedule III of the 1961 Single Convention on Narcotic Drugs:
acetyldihydrocodeine, codeine, dihydrocodeine, ethylmorphine,
nicocodine, nicodicodine, norcodeine and pholcodine, when compounded
with one or more other ingredients and containing not more than 100
milligrams of the drug per dosage unit and with a concentration of not
more than 2.5 per cent in undivided preparations.
These preparations have not been previously reviewed. The ECDD
Secretariat commissioned a pre-review of these preparations, on the
basis of concerns regarding abuse and harm of preparations of codeine
that were conveyed to the Secretariat. As many of the substances listed
in the first entry of Schedule III of the 1961 Single Convention are
chemically and pharmacologically similar to codeine, the eight
preparations were considered together.
These preparations have been marketed and used as antitussive
medicines and analgesics for mild to moderate pain. In many countries
these preparations are available without medical prescription. The
active substances in the preparations are opioids and all substances
themselves are controlled under Schedule II of the 1961 Single
Convention on Narcotic Drugs. Misuse of and dependence on preparations
of codeine and dihydrocodeine have been well described. The pre-review
suggested that there may be less evidence regarding the other
preparations. The Committee also noted evidence of separation of the
opioid drug such as codeine from the other ingredients in these
preparations by people misusing these preparations.
Based on the evidence available regarding dependence, abuse and
risks to public health, the Committee recommended a critical review of
the following preparations included in Schedule III of the 1961
Convention at a future meeting: acetyldihydrocodeine, codeine,
dihydrocodeine, ethylmorphine, nicocodine, nicodicodine, norcodeine,
and pholcodine when compounded with one or more other ingredients and
containing not more than 100 milligrams of the drug per dosage unit and
with a concentration of not more than 2.5 per cent in undivided
preparations.
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.
Crotonyl fentanyl (chemical name: N-(1-phenethylpiperidin-4-yl)-N-
phenylbut-2-enamide) and valeryl fentanyl (chemical name: N-(1-
phenethylpiperidin-4-yl)-N-phenylpentanamide) are synthetic opioids
that have a pharmacological profile similar to other Schedule I and II
opioid substances controlled under the CSA such as cyclopropyl
fentanyl, fentanyl, and other related mu-opioid receptor agonist
substances. They are clandestinely produced and associated with adverse
events typically associated with opioid use such as respiratory
depression, anxiety, constipation, tiredness, hallucinations, and
withdrawal. Crotonyl fentanyl and valeryl fentanyl have been
encountered by law enforcement and/or reported in the scientific
literature by public health officials as being illicitly distributed
and abused. Crotonyl fentanyl and valeryl fentanyl have no commercial
or currently accepted medical uses in the United States. On February 1,
2018, valeryl fentanyl was temporarily placed into Schedule I of the
CSA. The chemical structure of crotonyl fentanyl defines it as a
fentanyl-related substance, as defined in 21 CFR 1308.11(h)(30);
therefore, crotonyl fentanyl was temporarily controlled as a Schedule I
controlled substance under the CSA as of February 6, 2018. As such,
additional controls will be necessary to fulfill United States
obligations if crotonyl fentanyl and valeryl fentanyl are placed in
Schedules I of the Single Convention on Narcotic Drugs (1961).
DOC (chemical names: 2,5-Dimethoxy-4-chloroamfetamine; 2,5-
dimethoxy-4-chloroamphetamine; 1-(4-chloro-2,5-dimethoxyphenyl)propan-
2-amine) is a hallucinogenic substance with psychedelic effects. Law
enforcement has encountered DOC in tablet, capsule, powder, liquid, and
blotter paper forms. Its use has been associated with at least one
death. DOC has no currently accepted medical use in treatment in the
United States. DOC is not controlled under the CSA but is a Schedule I
controlled substance in the state of Florida. As such, additional
permanent controls will be necessary to fulfill United States
obligations if DOC is controlled under Schedule I of the 1971
Convention.
AB-FUBINACA (chemical name: N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-
(4-fluorobenzyl)-1H-indazole-3-carboxamide) is a synthetic cannabinoid
that is a potent full agonist at CB1 receptors. This substance
functionally (biologically) mimics the effects of structurally
unrelated THC, a Schedule I substance under the CSA, and the main
psychoactive chemical constituent in cannabis. Synthetic cannabinoids
have been marketed under the guise of ``herbal incense,'' and promoted
by drug traffickers as legal alternatives to cannabis. AB-FUBINACA use
has been associated with serious adverse events including death in the
United States. There are no commercial or approved medical uses for AB-
FUBINACA. On September 6, 2016, AB-FUBINACA was permanently placed as a
Schedule I controlled substance under the CSA. As such, additional
permanent controls will not be necessary to fulfill United States
obligations if AB-FUBINACA is controlled under Schedule II of the 1971
Convention.
5F-AMB (5F-AMB-PINACA, 5F-MMB-PINACA) (chemical name: methyl 2-(1-
(5-fluoropentyl)-1H-indazole-3-carboxamido)-3-methylbutanoate) is a
synthetic cannabinoid that is a potent full agonist at CB1 receptors.
This substance functionally (biologically) mimics the effects of THC, a
Schedule I substance under the CSA, and the main psychoactive chemical
constituent in cannabis. Synthetic cannabinoids have been marketed
under the guise of ``herbal incense,'' and promoted by drug traffickers
as legal alternatives to cannabis. The use of synthetic cannabinoids,
including, 5F-AMB has been associated with nausea and vomiting,
shortness of breath or depressed breathing, hypertension, tachycardia,
chest pain, muscle twitching, acute renal failure, anxiety, agitation,
psychosis, suicidal ideation, and/or cognitive impairment. There are no
commercial or approved medical uses for 5F-AMB. On April 8, 2019, a
Drug Enforcement Administration Notice of Proposed Rulemaking proposed
permanently placing 5F-AMB
[[Page 72377]]
into Schedule I of the CSA. As such, additional permanent controls will
not be necessary to fulfill United States obligations if 5F-AMB is
controlled under Schedule II of the 1971 Convention.
5F-MDMB-PICA (5F-MDMB-2201) (chemical name: methyl 2-(1-(5-
fluoropentyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate) is a
synthetic cannabinoid that has been sold online and used to mimic the
biological effects of THC, the main psychoactive chemical constituent
in cannabis. Research and clinical reports have demonstrated that
synthetic cannabinoids are applied onto plant material so that the
material may be smoked as users attempt to obtain a euphoric and
psychoactive ``high.'' Synthetic cannabinoids have been marketed under
the guise of ``herbal incense,'' and promoted by drug traffickers as
legal alternatives to cannabis. 5F-MDMB-PICA has been associated with
law enforcement seizures and overdoses requiring emergency medical
intervention. On April 16, 2019, 5F-MDMB-PICA was temporarily
controlled as a Schedule I substance under the CSA. As such, additional
permanent controls will be necessary to fulfill United States
obligations if 5F-MDMB-PICA is controlled under Schedule II of the 1971
Convention.
4F-MDMB-BINACA (4F-ADB) (chemical name: methyl 2-(1-(4-
fluorobutyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate) is a
synthetic cannabinoid that is a potent full agonist at CB1 receptors.
This substance functionally (biologically) mimics the effects of THC, a
Schedule I substance, and the main psychoactive constituent in
cannabis. 4F-MDMB-BINACA has been encountered in numerous synthetic
cannabinoid products that are smoked for their psychoactive effects.
Multiple law enforcement encounters of 4F-MDMB-BINACA have been
reported involving overdose deaths, illicit use, and seizures of drug
evidence between December 2018 and February 2019. There are no
commercial or approved medical uses for 4F-MDMB-BINACA. 4F-MDMB-BINACA
is a positional isomer of 5F-AMB (chemical name: methyl 2-(1-(5-
fluoropentyl)-1H-indazole-3-carboxamido)-3-methylbutanoate), as defined
by 21 CFR 1300.01, and has been a Schedule I controlled substance under
the CSA since April 10, 2017. As such, additional permanent controls
will not be necessary to fulfill United States obligations if 4F-MDMB-
BINACA is controlled under Schedule II of the 1971 Convention.
4-CMC (4-chloromethcathinone; clefedrone, clephedrone) (chemical
name: 1-(4-chlorophenyl)-2-(methylamino)propan-1-one) is a synthetic
cathinone. 4-CMC produces central nervous system stimulant effects and
is abused for its psychoactive properties. 4-CMC abuse has been
associated with adverse health effects. 4-CMC has no currently accepted
medical use in treatment in the United States. 4-CMC is not controlled
under the CSA, but it is considered a Schedule I controlled substance
by a number of states in the United States. As such, additional
permanent controls will be necessary to fulfill United States
obligations if 4-CMC is controlled under Schedule II of the 1971
Convention.
N-Ethylhexedrone (chemical name: 2-(ethylamino)-1-phenylhexan-1-
one; NEH, hexen, Ethyl-Hex) and alpha-PHP (chemical name: 1-phenyl-2-
(pyrrolidin-1-yl)hexan-1-one; PV-7, [alpha]-pyrrolidinohexanophenone)
are synthetic cathinones. N-Ethylhexedrone and alpha-PHP produce
central nervous system stimulant effects and are abused for their
psychoactive properties. N-Ethylhexedrone and alpha-PHP have been
associated with adverse health effects leading to emergency department
admissions, and deaths. N-Ethylhexedrone and alpha-PHP have no
currently accepted medical use in treatment in the United States. On
July 18, 2019, N-Ethylhexedrone and alpha-PHP were temporarily
controlled as a Schedule I substance under the CSA. As such, additional
permanent controls will be necessary to fulfill United States
obligations if N-Ethylhexedrone and alpha-PHP are controlled under
Schedule II of the 1971 Convention.
Flualprazolam and etizolam belong to a class of substances known as
benzodiazepines. Benzodiazepines produce central nervous system
depression and are commonly used to treat insomnia, anxiety, and
seizure disorders. Etizolam is currently prescribed in some countries;
however, neither drug substance is approved for medical use in the
United States. Currently, flualprazolam and etizolam are not controlled
under the CSA, but are controlled in a number of states in the United
States. As such, additional permanent controls will be necessary to
fulfill United States obligations if flualprazolam and etizolam are
controlled under Schedule IV of the 1971 Convention.
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 2020.
Comments regarding the WHO recommendations for control of crotonyl
fentanyl and valeryl fentanyl; under the 1961 Single Convention will
also be forwarded to the relevant Agencies for consideration in
developing the United States position regarding narcotic substances at
the CND meeting.
Dated: December 23, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-28269 Filed 12-30-19; 8:45 am]
BILLING CODE 4164-01-P