[Federal Register Volume 86, Number 31 (Thursday, February 18, 2021)]
[Notices]
[Pages 10097-10103]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-03268]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2021-N-0165]


International Drug Scheduling; Convention on Psychotropic 
Substances; Single Convention on Narcotic Drugs; World Health 
Organization; Scheduling Recommendations; Isotonitazene; MDMB-4en-
PINACA; CUMYL-PEGACLONE; Flubromazolam; Clonazolam; Diclazepam; 3-
Methoxyphencyclidine; Diphenidine; 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 April 
2021. This notice is issued under the Controlled Substances Act (CSA).

DATES: Submit either electronic or written comments by March 22, 2021.

ADDRESSES: You may submit comments as follows:

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-2021-N-0165 for ``International Drug Scheduling; Convention on 
Psychotropic Substances; Single Convention on Narcotic Drugs; World 
Health Organization; Scheduling Recommendations; Isotonitazene; MDMB-
4en-PINACA; CUMYL-PEGACLONE; Flubromazolam; Clonazolam; Diclazepam; 3-
Methoxyphencyclidine; Diphenidine; Request for Comments.'' Received 
comments will be placed in the docket and, except for those submitted 
as ``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: James R. Hunter, Center for Drug 
Evaluation and Research, Controlled Substance Staff, Food and Drug 
Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 5150, Silver 
Spring, MD 20993-0002, 301-796-3156, james.hunter@fda.hhs.gov.

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.

[[Page 10098]]

    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 seven substances to be considered for 
control under the 1971 Convention. This notification reflects the 
recommendation from the 43rd WHO Expert Committee for Drug Dependence 
(ECDD), which met in October 2020. In the Federal Register of August 4, 
2020 (85 FR 47217), 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 one substance 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.1/2020
WHO/ECDD43; 1961C-Art.3, 1971C-Art.2
CU 2021/7(A)/DTA/SGB

    The Secretariat of the United Nations presents its compliments 
to the Permanent Mission of the United States of America and has the 
honour to inform the Government that in a letter dated 30 November 
2020, the Director-General of the World Health Organization (WHO), 
pursuant to article 3, paragraphs 1 and 3 of the Single Convention 
on Narcotic Drugs of 1961 as amended by the 1972 Protocol (1961 
Convention), and article 2, paragraphs 1 and 4 of the Convention on 
Psychotropic Substances of 1971 (1971 Convention), notified the 
Secretary-General of the following recommendations of the forty-
third Meeting of the WHO's Expert Committee on Drug Dependence 
(ECDD):

    Substance recommended to be added to Schedule I of the 1961 
Convention:

--Isotonitazene
chemical name: N,N-diethyl-2-(2-(4-isopropoxybenzyl)-5-nitro-1H-
benzo[d]imidazol-1-yl)ethan-1-amine

    Substances recommended to be added to Schedule II of the 1971 
Convention:

--CUMYL-PEGACLONE
chemical name: 5-pentyl-2-(2-phenylpropan-2-yl)-2,5-dihydro-1H-
pyrido[4,3-b]indol-1-one
--MDMB-4en-PINACA
chemical name: methyl 3,3-dimethyl-2-(1-(pent-4-en-1-yl)-1H-
indazole-3-carboxamido)butanoate
--3-Methoxyphencyclidine
chemical name: 1-(1-(3-methoxyphenyl)cyclohexyl)piperidine
--Diphenidine
chemical name: 1-(1,2-diphenylethyl)piperidine

    Substances recommended to be added to Schedule IV of the 1971 
Convention:

--Clonazolam
chemical name: 6-(2-chlorophenyl)-1-methyl-8-nitro-4H-
benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine
--Diclazepam
chemical name: 7-chloro-5-(2-chlorophenyl)-1- methyl-1,3-dihydro-2H-
benzo[e][1,4]diazepin2-one
--Flubromazolam
chemical name: 8-bromo-6-(2-fluorophenyl)-1-methyl-4H-
benzo[f][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 an extract of the report of the forty-third 
meeting of the WHO Expert Committee on Drug Dependence, which 
provides a summary of the assessment and recommendations made by the 
Expert Committee on Drug Dependence (attached as annex II).
    Also in accordance with the same provisions, the notification 
from WHO will be brought to the attention of the sixty-fourth 
session of the Commission on Narcotic Drugs (12-16 April 2021) in a 
pre-session document that will be made available in the six official 
languages of the United Nations on the website of the 64th session 
of the CND:

https://www.unodc.org/unodc/en/commissions/CND/session/64_Session_2021/session-64-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:

--Isotonitazene

    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:

--CUMYL-PEGACLONE
--MDMB-4en-PINACA
--3-Methoxyphencyclidine
--Diphenidine
--Clonazolam
--Diclazepam
--Flubromazolam

    The Secretariat of the United Nations avails itself of this 
opportunity to renew to the Permanent Mission of the United States 
of America to the United Nations (Vienna) the assurances of its 
highest consideration.

12 January 2012

Annex I

Letter addressed to the Secretary-General of the United Nations 
From the Director-General of the World Health Organization, dated 
30 November 2020

    ``The Forty-third meeting of the WHO Expert Committee on Drug 
Dependence was convened in a virtual format from 12 to 16 October 
2020 and was coordinated from the WHO headquarters in Geneva. The 
objective of this meeting was to carry out an in-depth evaluation of 
the abuse and dependence-producing capacity of psychoactive 
substances in order to make recommendations on appropriate 
international scheduling measures.
    The Forty-third WHO ECDD Meeting critically reviewed eleven 
psychoactive substances, including one synthetic opioid, one 
hallucinogen, one synthetic stimulant, two synthetic cannabinoid 
receptor agonists, three dissociative-type drugs, and three 
benzodiazepines. These substances had not previously been formally 
reviewed by WHO and are currently not under international control. 
Information was brought to WHO's attention that these substances are 
clandestinely manufactured, of especially serious risk to public 
health and society, and of no recognised therapeutic use by any 
Party. Therefore, a critical review to consider international 
scheduling measures was undertaken for each substance.
    With reference to Article 3, paragraphs 1 and 3 of the Single 
Convention on Narcotic Drugs (1961), as amended by the 1972 
Protocol, and Article 2, paragraphs 1 and 4 of the Convention on 
Psychotropic Substances (1971), WHO is pleased to 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):

--Isotonitazene
chemical name: N,N-diethyl-2-(2-(4-isopropoxybenzyl)-5-nitro-1H-
benzo[d]imidazol-1-yl)ethan-1-amine


[[Page 10099]]


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

--CUMYL-PEGACLONE
chemical name: 5-pentyl-2-(2-phenylpropan-2-yl)-2,5-dihydro-1H-
pyrido[4,3-b]indol-1-one
--MDMB-4en-PINACA
chemical name: methyl 3,3-dimethyl-2-(1-(pent-4-en-1-yl)-1H-
indazole-3-carboxamido)butanoate
--3-methoxyphencyclidine
chemical name: 1-(1-(3-methoxyphenyl)cyclohexyl)piperidine
--Diphenidine
chemical name: 1-(1,2-diphenylethyl)piperidine

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

--Clonazolam
chemical name: 6-(2-chlorophenyl)-1-methyl-8-nitro-4H-
benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine
--Diclazepam
chemical name: 7-chloro-5-(2-chlorophenyl)-1-methyl-1,3-dihydro-2H-
benzo[e][1,4]diazepin2-one
--Flubromazolam
chemical name: 8-bromo-6-(2-fluorophenyl)-1-methyl-4H-
benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

    The assessments and findings on which these recommendations are 
based are set out in detail in the forty-third meeting report of the 
WHO Expert Committee on Drug Dependence. An extract of this report, 
providing a summary of the assessment and recommendations made by 
the ECDD, is contained in Annex 1 to this letter.
    I am very pleased with the ongoing collaboration between WHO, 
the United Nations Office on Drugs and Crime (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 2016.

Annex II

Summary Assessment and Recommendations of the 43rd Expert Committee 
on Drug Dependence, 12-16 October 2020

    To be added to Schedule I of the Single Convention on Narcotic 
Drugs (1961):

Isotonitazene
Substance identification
    Isotonitazene (Chemical name: N,N-diethyl-2-(2-(4-
isopropoxybenzyl)-5-nitro-1H-benzo[d]imidazol-1-yl)ethan-1-amine) 
belongs to the 2-benzylbenzimidazole group of compounds, which 
includes the closely related opioids etonitazene, metonitazene, and 
clonitazene. It is found in yellow, brown, or off-white powder 
forms.

WHO Review History

    Isotonitazene has never been formally reviewed by WHO and is not 
currently under international control. Information was brought to 
WHO's attention that this substance is clandestinely manufactured, 
poses a risk to public health, and has no recognized therapeutic 
use.

Similarity to Known Substances and Effects on Central Nervous System

    Isotonitazene is a chemical analogue of etonitazene and 
clonitazene, both of which are Schedule I compounds under the Single 
Convention on Narcotic Drugs, 1961. Isotonitazene is a potent opioid 
analgesic with a rapid onset of action. Preclinical studies have 
demonstrated that isotonitazene is more potent than fentanyl and 
hydromorphone, and substantially more potent than morphine. There is 
limited research on the effects of this compound on the central 
nervous system, but given its demonstrated potency at the [mu]-
opioid receptor, it would be expected to produce analgesia, 
respiratory depression and sedation.

Dependence Potential

    No controlled animal or human studies have assessed the 
dependence potential of isotonitazene. As a potent [mu]-opioid 
agonist, it would be expected to produce dependence. An unverified 
online report described dependent use and withdrawal symptoms, 
including flu-like symptoms and anxiety.

Actual Abuse and/or Evidence of Likelihood of Abuse

    There are no controlled studies of the abuse potential of 
isotonitazene, but as a potent [mu]-opioid receptor agonist, it 
would be expected to produce euphoria and other effects predictive 
of high abuse liability.
    Due to its relatively recent appearance on the illicit drug 
market, there is limited information on the prevalence of use of 
isotonitazene or its associated harms. Seizures have been reported 
in multiple countries and regions. It is noted to be used via a 
range of routes including sublingually, vaping and intravenously.
    The number of deaths involving isotonitazene has increased in a 
short time span. Deaths commonly occur in combination with other 
opioids or benzodiazepines. Isotonitazene deaths share common 
features with heroin deaths, including evidence of injection, and 
signs consistent with opioid overdose such as pulmonary and/or 
cerebral oedema. Deaths are likely to be underreported due to its 
recent and rapid appearance.

Recommendation

    Isotonitazene (Chemical name: N,N-diethyl-2-(2-(4-
isopropoxybenzyl)-5-nitro-1H-benzo[d]imidazol-1-yl)ethan-1-amine) 
has a mechanism of action such that it is liable to similar abuse 
and productive of similar ill effects as other opioids which are 
controlled under Schedule I of the 1961 Single Convention on 
Narcotic Drugs. Its use has been reported in a number of countries 
and has been associated with adverse effects including deaths. It 
has no known therapeutic use and is likely to cause substantial 
harm.

Therapeutic Usefulness

    Isotonitazene is not known to have any therapeutic use.

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

CUMYL-PEGACLONE

Substance Identification

    CUMYL[hyphen]PEGACLONE (Chemical name: 5-pentyl-2-(2-
phenylpropan-2-yl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one) is a 
synthetic cannabinoid. It has been found in seized material 
formulated for smoking and vaping.

WHO Review History

    CUMYL-PEGACLONE has never been formally reviewed by WHO and is 
not currently under international control. Information was brought 
to WHO's attention that this substance is clandestinely 
manufactured, poses a risk to public health, and has no recognized 
therapeutic use.

Similarity to Known Substances and Effects on Central Nervous System

    CUMYL-PEGACLONE is a synthetic cannabinoid with a mechanism of 
action similar to that of other synthetic cannabinoids. It is a 
potent full agonist at CB1 receptors.
    There are no controlled studies of its effects, but there are 
online user reports describing euphoria, dissociation, red eyes, dry 
mouth and appetite stimulation. These effects are consistent with 
known cannabinoid agonist effects.

Dependence Potential

    There are no controlled animal or human studies that address the 
dependence potential of CUMYL-PEGACLONE. However, CUMYL-PEGACLONE 
has been shown to be a full and potent agonist at the CB1 receptor 
and therefore would be expected to produce dependence consistent 
with other CB1 receptor agonists.

Actual Abuse and/or Evidence of Likelihood of Abuse

    There are no controlled animal or human studies that address the 
abuse potential of CUMYL-PEGACLONE.
    A number of countries across several regions have reported that 
CUMYL-PEGACLONE is being used for its psychoactive properties.
    There are reports of adverse effects such as seizures and of 
fatalities involving CUMYL-PEGACLONE. While other drugs were 
present, CUMYL-PEGACLONE was deemed to be a causal or contributory 
factor in a number of these deaths.

Therapeutic Usefulness

    CUMYL-PEGACLONE is not known to have any therapeutic use.

Recommendation

    CUMYL[hyphen]PEGACLONE (Chemical name: 5-pentyl-2-(2-
phenylpropan-2-yl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one) is a 
synthetic cannabinoid receptor agonist with a mode of action that 
suggests a likelihood of dependence and abuse, and similar ill-
effects to other synthetic cannabinoids. Its use has been associated 
with severe adverse effects and fatalities. The effects of 
CUMYL[hyphen]PEGACLONE are similar to those of other synthetic 
cannabinoids that are controlled under Schedule II of the

[[Page 10100]]

Convention on Psychotropic Substances of 1971. 
CUMYL[hyphen]PEGACLONE has no therapeutic use, and its use 
constitutes a substantial risk to public health.
     The committee recommended that CUMYL[hyphen]PEGACLONE 
(Chemical name: 5-pentyl-2-(2-phenylpropan-2-yl)-2,5-dihydro-1H-
pyrido[4,3-b]indol-1-one), be added to Schedule II of the Convention 
on Psychotropic Substances of 1971.

MDMB-4en-PINACA

Substance Identification

    MDMB-4en-PINACA (Chemical name: methyl (S)-3,3-dimethyl-2-(1-
(pent-4-en-1-yl)-1H-indazole-3-carboxamido)butanoate) is a synthetic 
cannabinoid. It has been identified in seized material formulated 
for smoking, and found as white to yellow/brown powder.

WHO Review History

    MDMB-4en-PINACA has never been formally reviewed by WHO and is 
not currently under international control. Information was brought 
to WHO's attention that this substance is clandestinely 
manufactured, poses a risk to public health, and has no recognized 
therapeutic use.

Similarity to Known Substances and Effects on Central Nervous System

    MDMB-4en-PINACA is a synthetic cannabinoid that binds to CB1 
cannabinoid receptors as a full and potent agonist. It is 
structurally similar to 5F-MDMB-PINACA (5F-ADB) which is controlled 
under Schedule II of the Convention on Psychotropic Substances of 
1971. A report from an unpublished animal study indicates that MDMB-
4en-PINACA can produce the characteristic effects of CB1 cannabinoid 
agonists such as hypothermia and lethargy. Reports from online user 
forums describe cannabis-like euphoria at moderate levels of intake, 
with dissociation described at higher doses. Both sedation and 
stimulation have been reported, in addition to memory loss, 
confusion and agitation.

Dependence Potential

    No animal or human studies were identified that described the 
dependence potential of MDMB-4en-PINACA. As a full CB1 agonist, it 
would be expected to produce dependence similar to other CB1 
receptor agonists.

Actual Abuse and/or Evidence of Likelihood of Abuse

    No animal or human studies have been conducted to provide an 
indication of the likelihood of abuse of MDMB-4en-PINACA, though CB1 
receptor agonists have known abuse potential. A number of countries 
across different regions have reported MDMB-4en-PINACA use. Its use 
has been associated with cases of impaired driving and death.

Therapeutic Usefulness

    MDMB-4en-PINACA is not known to have any therapeutic use.

Recommendation

    MDMB-4en-PINACA (Chemical name: methyl (S)-3,3-dimethyl-2-(1-
(pent-4-en-1-yl)-1H-indazole-3-carboxamido)butanoate) is a potent 
synthetic cannabinoid receptor agonist with a similar mechanism of 
action, and similar effects to a number of other synthetic 
cannabinoids that are controlled under Schedule II of the Convention 
on Psychotropic Substances of 1971. Use of MDMB-4en-PINACA has been 
associated with severe adverse effects, including fatal 
intoxications, and cases of impaired driving. MDMB-4en-PINACA has no 
therapeutic use.
     The Committee recommended that MDMB-4en-PINACA 
(Chemical name: methyl (S)-3,3-dimethyl-2-(1-(pent-4-en-1-yl)-1H-
indazole-3-carboxamido)butanoate) be added to Schedule II of the 
Convention on Psychotropic Substances of 1971.

3-methoxyphencyclidine (3-MeO-PCP)

Substance Identification

    3-methoxyphencyclidine (3-MeO-PCP), (Chemical name: 1-[1-(3-
methoxyphenyl)cyclohexyl]piperidine) is an arylcyclohexylamine and 
3-methoxy derivative of phencyclidine (PCP) which is controlled 
under Schedule II of the Convention on Psychotropic Substances of 
1971. It appears as powder and tablets.

WHO Review History

    3-methoxyphencyclidine has never been formally reviewed by WHO 
and is not currently under international control. Information was 
brought to WHO's attention that this substance is clandestinely 
manufactured, poses a risk to public health, and has no recognized 
therapeutic use.

Similarity to Known Substances and Effects on Central Nervous System

    3-methoxyphencyclidine is an N-methyl-D-aspartate (NMDA) 
receptor antagonist with a similar mechanism of action and effects 
to phencyclidine. These effects include an altered mental state 
characterized by confusion, disorientation and out of body 
experiences as well as hallucinations and other psychotic symptoms.

Dependence Potential

    No human or animal studies have examined the dependence 
potential of 3-methoxyphencyclidine.

Actual Abuse and/or Evidence of Likelihood of Abuse

    As an NMDA receptor antagonist, 3-methoxyphencyclidine would be 
expected to produce similar effects, and have abuse potential 
similar to that of phencyclidine.
    Adverse effects include cardiovascular effects (such as 
hypertension and tachycardia) and cognitive effects including 
psychosis, confusion and agitation. There may be a greater risk of 
psychosis in those with a history of, or vulnerability to psychotic 
illness. Cases of severe and fatal intoxication are reported from 
several countries and regions.
    Seizures have been reported in a number of countries from 
several different regions.

Therapeutic Usefulness

    3-methoxyphencyclidine is not known to have any therapeutic use.

Recommendation

    3-methoxyphencyclidine (Chemical name: 1-[1-(3-
methoxyphenyl)cyclohexyl] piperidine) is an analogue of, and has 
similar effects to phencyclidine (PCP), which is controlled under 
Schedule II of the 1971 Convention on Psychotropic Substances. Its 
mode of action suggests a likelihood of abuse. There is evidence of 
use of this substance in a number of countries across different 
regions. 3-methoxyphencyclidine causes substantial harm, including 
severe adverse events such as hallucinations, other psychotic 
symptoms, and fatal intoxications. It has no therapeutic use.
     The Committee recommended that 3-methoxyphencyclidine 
(Chemical name: 1-[1-(3-methoxyphenyl)cyclohexyl]piperidine) be 
added to Schedule II of the Convention on Psychotropic Substances of 
1971.

Diphenidine

Substance Identification

    Diphenidine (Chemical name: 1-(1,2-diphenylethyl)piperidine) is 
a dissociative and hallucinogenic substance of the 1,2-
diarylethylamine class. It appears as powder and tablets.

WHO Review History

    Diphenidine has never been formally reviewed by WHO and is not 
currently under international control. Information was brought to 
WHO's attention that this substance is clandestinely manufactured, 
poses a risk to public health, and has no recognized therapeutic 
use.

Similarity to Known Substances and Effects on Central Nervous System

    Diphenidine is known to produce hallucinogenic and dissociative 
effects through its action as an N-methyl-D-aspartate (NMDA) 
receptor antagonist. This mechanism of action as well as its effects 
are similar to those of phencyclidine (PCP) which is controlled 
under Schedule II of the 1971 Convention on Psychotropic Substances.

Dependence Potential

    No animal or human studies have determined the dependence 
potential for diphenidine.

Actual Abuse and/or Evidence of Likelihood of Abuse

    As an NMDA receptor antagonist, diphenidine would be expected to 
have abuse potential similar to that of phencyclidine. In addition, 
diphenidine causes dopamine release, in a manner similar to, but to 
a lesser degree, than cocaine. This effect may also contribute to 
its abuse potential.
    Cases of intoxication requiring hospitalization are reported. 
Adverse effects include cardiovascular effects (such as tachycardia 
and hypertension) and central nervous system effects including 
hallucinations, depersonalization, delusions, paranoia, 
dissociation, confusion, nystagmus and muscle rigidity. These 
effects have resulted in cases of acute intoxication leading to 
emergency department admissions. A small number of fatal 
intoxications involving diphenidine have been documented. All deaths 
involved multiple drug toxicity, though cardiovascular and 
hallucinogenic symptoms described in the cases are consistent with 
the effects of diphenidine.
    Seizures have been reported in a number of countries from 
several different regions.

[[Page 10101]]

Therapeutic Usefulness

    Diphenidine is not known to have any therapeutic use.

Recommendation

    The available evidence indicates that diphenidine (Chemical 
name: 1-(1,2-diphenylethyl)piperidine) has a mechanism of action and 
effects that are similar to those of phencyclidine (PCP), which is 
controlled under Schedule II of the 1971 Convention on Psychotropic 
Substances. Its mode of action suggests a likelihood of abuse. There 
is evidence of significant harm due to diphenidine, including 
psychosis and cardiovascular effects, which represents a substantial 
risk to public health. Diphenidine has no therapeutic use.
     The Committee recommended that diphenidine (Chemical 
name: 1-(1,2-diphenylethyl)piperidine) be added to Schedule II of 
the Convention on Psychotropic Substances of 1971.

    Substances recommended to be scheduled in Schedule IV of the 
Convention on Psychotropic Substances (1971):

Clonazolam

Substance Identification

    Clonazolam (Chemical name: 6-(2-chlorophenyl)-1-methyl-8-nitro-
4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine) is 1-4 
triazolobenzodiazepine similar to clonazepam, triazolam and 
alprazolam. It is sold in powder, blotter, liquid and tablet form.

WHO Review History

    Clonazolam has never been formally reviewed by WHO and is not 
currently under international control. Information was brought to 
WHO's attention that this substance is clandestinely manufactured, 
poses a risk to public health, and has no recognized therapeutic 
use.

Similarity to Known Substances and Effects on Central Nervous System

    Clonazolam enhances the effects of the inhibitory 
neurotransmitter gamma-aminobutyric acid (GABA) through binding at 
the benzodiazepine site of the GABA-A receptor. This mechanism of 
action, as well as its effects (sedation, muscle relaxation, slurred 
speech and loss of motor control, amnesia) are similar to those of 
the benzodiazepines (such as diazepam, triazolam and alprazolam) 
which are controlled under Schedule IV of the 1971 Convention on 
Psychotropic Substances.
    In cases of clonazolam poisoning, the effects have been reversed 
with the benzodiazepine antagonist flumazenil, confirming that its 
action is mediated via the benzodiazepine receptor in the GABA-A 
receptor complex.

Dependence Potential

    No controlled animal or human studies have examined the 
dependence potential of clonazolam, though based on its 
pharmacological effects, and similarity to other benzodiazepines, it 
would be expected to have potential to produce dependence.
    The development of tolerance to the effects of clonazolam 
following repeated use and the onset of withdrawal symptoms after 
cessation of use have been reported on online forums.

Actual Abuse and/or Evidence of Likelihood of Abuse

    No human or animal studies have examined abuse liability. Online 
forums describe its recreational use and consistently report its 
strong anxiolytic effects.
    A number of published reports describe the management of cases 
of intoxication involving clonazolam in emergency departments or 
intensive care. Clonazolam use has been analytically confirmed in 
cases of impaired driving, in combination with other substances. 
Clonazolam has the potential to increase the effects of other drugs, 
including opioids, and on its own can cause severe central nervous 
system depression, including somnolence, confusion, sedation and 
unconsciousness.
    There are reports of its identification in multiple countries 
representing all regions, indicating that its use may be increasing. 
Clonazolam is increasingly sold as falsified pharmaceutical 
benzodiazepines.

Therapeutic Usefulness

    Clonazolam is not known to have any therapeutic use, is not 
listed on the WHO Model List of Essential Medicines, and has never 
been marketed as a medicinal product.

Recommendation

    Clonazolam (Chemical name: 6-(2-chlorophenyl)-1-methyl-8-nitro-
4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine) is a 1-4 
triazolobenzodiazepine that has actions and effects very similar to 
those of benzodiazepines listed under Schedule IV in the Convention 
on Psychotropic Substances of 1971. Like other benzodiazepines, 
clonazolam can produce a state of dependence and central nervous 
system depression. There have been a number of reports of abuse, 
impaired driving and non-fatal intoxications. There is sufficient 
evidence of its abuse so as to constitute a public health problem, 
and it has no known therapeutic use.
     The Committee recommended that clonazolam (Chemical 
name: 6-(2-chlorophenyl)-1-methyl-8-nitro-4H-
benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine) be added to Schedule 
IV of the 1971 Convention on Psychotropic Substances.

Diclazepam

Substance Identification

    Diclazepam (Chemical name: 7-chloro-5-(2-chlorophenyl)-1-methyl-
1,3-dihydro-2H-benzo[e][1,4]diazepin2-one) is a 2-chloro derivative 
of the benzodiazepine diazepam. It appears as a white powder, and is 
commonly sold as tablets, pellets and liquid.

WHO Review History

    Diclazepam has never been formally reviewed by WHO and is not 
currently under international control. Information was brought to 
WHO's attention that this substance is clandestinely manufactured, 
poses a risk to public health, and has no recognized therapeutic 
use.

Similarity to Known Substances and Effects on Central Nervous System

    Diclazepam is an agonist at the benzodiazepine site of the GABA-
A receptor, acting to increase the effect of the inhibitory 
neurotransmitter gamma amino butyric acid (GABA). Diclazepam has 
similar effects to the benzodiazepine diazepam, which is currently 
controlled under the Convention on Psychotropic Substances of 1971. 
It is metabolized to the benzodiazepines delorazepam, lorazepam and 
lormetazepam. These metabolites are active and are also 
pharmaceuticals that are included in Schedule IV of the Convention 
on Psychotropic Substances of 1971.
    Diclazepam has been demonstrated to cause sedation and muscle 
relaxation in animals. Central nervous systems depressant effects 
are also described in humans.

Dependence Potential

    No controlled animal or human studies have examined the 
dependence potential of diclazepam.
    Online user reports describe cross-tolerance with other 
benzodiazepines and use to self-manage benzodiazepine withdrawal. 
This evidence, along with its mechanism of action, suggests that 
diclazepam has the capacity to produce dependence similar to other 
benzodiazepines.

Actual Abuse and/or Evidence of Likelihood of Abuse

    No controlled animal or human studies have examined the abuse 
liability of diclazepam. However, based on its mechanism of action 
and effects, it would be expected to have abuse liability similar to 
other benzodiazepines.
    Diclazepam has the potential to increase unintentional opioid 
overdoses. Its long half-life may increase the risk of accumulation 
and interactions when combined with other drugs. Fatal intoxications 
with diclazepam have been reported.
    Seizures of diclazepam have been reported from multiple 
countries across different regions. Diclazepam is increasingly sold 
as falsified benzodiazepines, commonly as diazepam.
    Diclazepam has been implicated in cases of impaired driving, 
including cases where diclazepam was identified as the main 
contributor to impairment. It also has been involved in cases of 
drug-facilitated sexual assault.

Therapeutic Usefulness

    Diclazepam is not known to have any therapeutic use, is not 
listed on the WHO Model List of Essential Medicines and has never 
been marketed as a medicinal product.

Recommendation

    Diclazepam (Chemical name: 7-chloro-5-(2-chlorophenyl)-1-methyl-
1,3-dihydro-2H-benzo[e][1,4]diazepin2-one) is a 2-chloro analogue of 
the benzodiazepine diazepam that has actions and effects very 
similar to those of benzodiazepines listed under Schedule IV of the 
Convention on Psychotropic Substances of 1971. It can produce a 
state of dependence and central nervous system depression, like 
other

[[Page 10102]]

benzodiazepines. There have been reports of abuse, impaired driving 
and fatal and nonfatal intoxications. There is sufficient evidence 
of its abuse so as to constitute a significant risk to public 
health, and it has no known therapeutic use.
     The Committee recommended that diclazepam (Chemical 
name: 7-chloro-5-(2-chlorophenyl)-1-methyl-1,3-dihydro-2H-
benzo[e][1,4]diazepin2-one) be added to Schedule IV of the 1971 
Convention on Psychotropic Substances.

Flubromazolam

Substance Identification

    Flubromazolam (Chemical name: 8-bromo-6-(2-fluorophenyl)-1-
methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine) is a 1-4 
triazolobenzodiazepine. Flubromazolam is a white powder, often sold 
as a liquid or as tablets.

WHO Review History

    Flubromazolam has never been formally reviewed by WHO and is not 
currently under international control. Information was brought to 
WHO's attention that this substance is clandestinely manufactured, 
poses a risk to public health and has no recognized therapeutic use.

Similarity to Known Substances and Effects on Central Nervous System

    Flubromazolam is a highly potent benzodiazepine with long 
lasting depressant effects on the central nervous system. 
Flubromazolam enhances the effects of the inhibitory 
neurotransmitter gamma-aminobutyric acid (GABA) through binding at 
the benzodiazepine site of the GABA-A receptor. This mechanism of 
action, as well as its effects, are similar to those of the 
benzodiazepines triazolam and alprazolam which are controlled under 
Schedule IV of the 1971 Convention on Psychotropic Substances.
    A single pharmacokinetic study showed that a 0.5 mg 
flubromazolam dose induced strong sedative effects that lasted more 
than 10 hours, and caused partial amnesia for more than 24 hours. 
The effects of flubromazolam have been effectively reversed by the 
benzodiazepine antagonist flumazenil.
    Reports from online user forums describe benzodiazepine-like 
effects including anxiolytic, euphoric and sedative effects.

Dependence Potential

    No controlled animal or human studies describe the dependence 
potential of flubromazolam, although multiple reports from online 
sources describe severe withdrawal symptoms, such as muscle aches, 
sleeping disorders, severe anxiety and panic attacks, dissociative 
symptoms, perceptual distortions, cramping, chills, vomiting and 
risk of seizures. There are also descriptions of loss of control 
over use, and rapid onset of tolerance. The latter suggests that 
taking increased doses and developing physical dependence is likely.

Actual Abuse and/or Evidence of Likelihood of Abuse

    No controlled animal or human studies have assessed the abuse 
potential of flubromazolam. Impaired driving with flubromazolam as 
the sole intoxicant is reported. Non-fatal intoxications requiring 
hospital admission, and fatal intoxications due to flubromazolam use 
are documented. In these cases, central nervous system depression 
and severe sedation were clinical features of presentation. 
Flubromazolam has the potential to increase unintentional opioid 
overdoses. Its long half-life may increase the risk of accumulation 
and interactions when combined with other drugs.
    Nonmedical use and seizures of flubromazolam have been 
documented in multiple countries across different regions. It is 
increasingly sold as falsified pharmaceutical benzodiazepines.

Therapeutic Usefulness

    Flubromazolam is not known to have any therapeutic uses, is not 
listed on the WHO Model List of Essential Medicines and has never 
been marketed as a medicinal product.

Recommendation

    Flubromazolam (Chemical name: 8-bromo-6-(2-fluorophenyl)-1-
methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine) is a 1-4 
triazolobenzodiazepine that has actions and effects very similar to 
those of benzodiazepines listed under Schedule IV in the Convention 
on Psychotropic Substances of 1971. It can produce a state of 
dependence and central nervous system depression, like other 
benzodiazepines. There have been increasing reports of abuse, 
impaired driving and fatal and non-fatal intoxications. There is 
sufficient evidence of its abuse to constitute a significant risk to 
public health, and it has no known therapeutic use.
    The Committee recommended that flubromazolam (Chemical name: 8-
bromo-6-(2-fluorophenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-
a][1,4]diazepine) be added to Schedule IV of the 1971 Convention on 
Psychotropic Substances.

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.
    Isotonitazene (chemical name: N,N-diethyl-2-(2-(4-
isopropoxybenzyl)-5-nitro-1H-benzimidazol-1-yl)ethan-1-amine) is a 
potent synthetic opioid that is abused similar to other synthetic 
opioids. Its use has resulted in adverse health effects, including 
positively identified in 49 death investigation cases in the United 
States between August 2019 and April 2020. Law enforcement data 
indicate that isotonitazene has appeared in the United States' illicit 
drug market.
    According to the National Forensic Laboratory Information System 
(NFLIS) database, there have been 53 encounters of isotonitazene in the 
United States (as of June 2020). There are no commercial or approved 
medical uses for isotonitazene. On August 20, 2020, the Drug 
Enforcement Administration issued an order to temporarily control 
isotonitazene as a Schedule I substance under the CSA. As such, 
additional permanent controls will be necessary to fulfill U.S. 
obligations if isotonitazene is placed in Schedule I of the 1961 
Convention.
    CUMYL-PEGACLONE is a synthetic cannabinoid that has been sold 
online and used to mimic the biological effects of tetrahydrocannabinol 
(THC), the main psychoactive constituent in marijuana. 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 marijuana. In 
vitro studies demonstrate that CUMYL-PEGALCONE binds to and activates 
the cannabinoid one receptor. CUMYL-PEGALCONE has not been encountered 
within the United States according to the NFLIS database (as of January 
14, 2021). There are no commercial or approved medical uses for CUMYL-
PEGALCONE and it is not a controlled substance under the CSA. As such, 
additional permanent controls will be necessary to fulfill U.S. 
obligations if CUMYL-PEGALCONE is controlled under Schedule II of the 
1971 Convention.
    MDMB-4en-PINACA is a synthetic cannabinoid that has been sold 
online and used to mimic the biological effects of THC, the main 
psychoactive constituent in marijuana. 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 marijuana. According to the NFLIS 
database, MDMB-4en-PINACA was first encountered in the United States in 
January 2019. There have been 3,331 encounters of MDMB-4en-PINACA in 
the United States (as of January 14, 2021). MDMB-4en-PINACA has also 
been encountered mixed with opioids including heroin and fentanyl, with 
some incidents resulting in violent

[[Page 10103]]

behaviors, tachycardia, and hypertension. There are no commercial or 
approved medical uses for MDMB-4en-PINACA and it is not a controlled 
substance under the CSA. As such, additional permanent controls will be 
necessary to fulfill U.S. obligations if MDMB-4en-PINACA is controlled 
under Schedule II of the 1971 Convention.
    3-Methoxyphencyclidine; chemical name: 1-(1-(3-
methoxyphenyl)cyclohexyl)piperidine) is a novel N-methyl-D-aspartate 
(NMDA) receptor antagonist with structural and biochemical similarities 
to phencyclcycidine (PCP) and other arylcyclohexylamines. 3-
Methoxyphencyclidine is classified as an arylcyclohexylamine and 
produces dissociative anesthetic and hallucinogenic effects. Use of 
this substance is associated with intoxication and published case 
reports of both fatal and non-fatal overdose. 3-Methoxyphencyclidine is 
encountered by law enforcement in drug seizure reports. 3-
Methoxyphencyclidine is an analogue of the Schedule II hallucinogen 
PCP. There is no approved medical use for 3-Methoxyphencyclidine in the 
United States and is not a controlled substance under the CSA. If 
intended for human consumption, 3-Methoxyphencyclidine may be treated 
as a ``controlled substance analogue'' under the CSA pursuant to 21 
U.S.C. 802(32)(A) and 813. As such, additional permanent controls will 
be necessary to fulfill U.S. obligations if 3-Methoxyphencyclidine is 
controlled under Schedule II of the 1971 Convention.
    Diphenidine (chemical name: 1-(1,2-diphenylethyl) piperidine) is a 
non-competitive NMDA receptor antagonist classified as a 
diarylethylamine and produces dissociative anesthetic and 
hallucinogenic effects. It was originally synthesized in the 1920s but 
reports of abuse started in the last decade. Use of this substance is 
associated with intoxication and published case reports of both fatal 
and non-fatal overdose outside of the United States. Diphenidine is 
encountered by law enforcement in drug seizure reports. Diphenidine is 
not approved for medical use in the United States and is not a 
controlled substance under the CSA. As such, additional permanent 
controls will be necessary to fulfill U.S. obligations if diphenidine 
is controlled under Schedule II of the 1971 Convention.
    Flubromazolam, clonazolam, and diclazepam 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. Flubromazolam is a triazole analogue of 
the designer benzodiazepine, flubromazepam. Flubromazolam can be 
purchased on the internet and is used as a recreational substance in 
the United States. Flubromazolam has been identified in an increasing 
number of law enforcement seizures and has been associated with an 
increasing number of drug overdose deaths. According to the NFLIS 
database, in 2020 there were 1,446 clonazolam encounters (as of 
December 2020). It is abused by a broad range of groups including 
youths, young adults, and older adults. Clonazolam has been involved in 
an increasing number of drug seizure events as well as drug overdose 
deaths, alone and in combination with alcohol. As such, the NFLIS 
database reported 249 encounters in 2020 (as of December 2020). 
Diclazepam is a designer benzodiazepine sold on the internet and most 
often found as a liquid solution, but it may be sold as a powder, 
tablet, blotter paper, or pellet. In 2020, the NFLIS database reported 
113 encounters of diclazepam (as of December 2020). In 2018, 
flubromazolam, clonazolam, and dicalazepam were all identified by law 
enforcement in driving under the influence of drugs cases in the United 
States. Flubromazolam, clonazolam, and diclazepam are not approved for 
medical use in the United States and are not controlled substances 
under the CSA. As such, additional permanent controls will be necessary 
to fulfill U.S. obligations if flubromazolam, clonazolam, and 
dicalazepam 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 April 2021.
    Comments regarding the WHO recommendations for control of 
isotonitazene under the 1961 Single Convention will also be forwarded 
to the relevant Agencies for consideration in developing the U.S. 
position regarding narcotic substances at the CND meeting.

    Dated: February 12, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2021-03268 Filed 2-17-21; 8:45 am]
BILLING CODE 4164-01-P


