[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