[Federal Register Volume 85, Number 150 (Tuesday, August 4, 2020)]
[Notices]
[Pages 47217-47220]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-16905]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2020-N-1680]


International Drug Scheduling; Convention on Psychotropic 
Substances; Single Convention on Narcotic Drugs; Isotonitazene; MDMB-
4en-PINACA; CUMYL-PEGACLONE; Flubromazolam; Clonazolam; Diclazepam; 3-
MeO-PCP; DIPHENIDINE; 2-MEO-DIPHENIDINE; 5-MEO-DALT; and 3-
FLUOROPHENMETRAZINE (3-FPM); Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; request for comments.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
requesting interested persons to submit comments concerning abuse 
potential, actual abuse, medical usefulness, trafficking, and impact of 
scheduling

[[Page 47218]]

changes on availability for medical use of 11 drug substances. These 
comments will be considered in preparing a response from the United 
States to the World Health Organization (WHO) regarding the abuse 
liability and diversion of these drugs. WHO will use this information 
to consider whether to recommend that certain international 
restrictions be placed on these drug substances. This notice requesting 
comments is required by the Controlled Substances Act (CSA).

DATES: Submit either electronic or written comments by August 28, 2020.

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 August 28, 2020. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of August 28, 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-2020-N-1680 for ``International Drug Scheduling; Convention on 
Psychotropic Substances; Single Convention on Narcotic Drugs; 
Isotonitazene; MDMB-4en-PINACA; CUMYL-PEGACLONE; Flubromazolam; 
Clonazolam; Diclazepam; 3-MeO-PCP; DIPHENIDINE; 2-MEO-DIPHENIDINE; 5-
MEO-DALT; and 3-FLUOROPHENMETRAZINE (3-FPM); Request for Comments.'' 
Received comments, those filed in a timely manner (see ADDRESSES), will 
be placed in the docket and, except for those submitted as 
``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: James R. Hunter, Center for Drug 
Evaluation and Research, Controlled Substance Staff, Food and Drug 
Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 5150, Silver 
Spring, MD 20993-0002, 301-796-3156, [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    The United States is a party to the 1971 Convention on Psychotropic 
Substances (Psychotropic Convention). Article 2 of the Psychotropic 
Convention provides that if a party to the convention or WHO has 
information about a substance, which in its opinion may require 
international control or change in such control, it shall so notify the 
Secretary-General of the United Nations (the U.N. Secretary-General) 
and provide the U.N. Secretary-General with information in support of 
its opinion.
    Paragraph (d)(2)(A) of the CSA (21 U.S.C. 811) (Title II of the 
Comprehensive Drug Abuse Prevention and Control Act of 1970) provides 
that when WHO notifies the United States under Article 2 of the 
Psychotropic Convention that it has information that may justify adding 
a drug or other substances to one of the schedules of the Psychotropic 
Convention, transferring a drug or substance from one schedule to 
another, or deleting it from the schedules, the Secretary of State must 
transmit the notice to the Secretary of Health and Human Services 
(Secretary of HHS). The Secretary of HHS must then publish the notice 
in the Federal Register and provide opportunity for interested persons 
to submit comments that will be considered by HHS in its preparation of 
the scientific and medical evaluations of the drug or substance.

II. WHO Notification

    The Secretary of HHS received the following notice from WHO (non-
relevant text removed):
Ref.: C.L.22.2020

    The World Health Organization (WHO) presents its compliments to 
Member States and Associate Members and in reference to C.L.14.2019 
has the pleasure of informing

[[Page 47219]]

that the 43rd Expert Committee on Drug Dependence (ECDD) will meet 
from 12 to 16 October 2020 in Geneva, Switzerland. In the event that 
the meeting should be held virtually due to exceptional 
circumstances, corresponding arrangements will be made. Given that 
ECDD meetings are of a closed nature, this letter serves to notify 
Member States of the substances under review at the 43rd ECDD, which 
are in the Annex I for reference.
    WHO is mandated by the 1961 and 1971 International Drug Control 
Conventions to make recommendations to the UN Secretary-General on 
the need for and level of international control of psychoactive 
substances based on the advice of its independent scientific 
advisory body, the ECDD. To assess the appropriate control of a 
psychoactive substance, the ECDD convenes annually to review the 
potential of this substance to cause dependence, abuse and harm to 
health, as well as any therapeutic applications. In order to perform 
this review and make scientific and evidence-based decisions, the 
ECDD conducts medical, scientific, and public health evaluations of 
the selected psychoactive substances using the best available 
information.
    Although the meetings are of a closed nature, Member States are 
invited to contribute to the ECDD review process by joining the 43rd 
ECDD Open Session on 12 October 2020. The Open Session will allow 
interested parties to present information concerning substances 
under review to the Expert Committee. Registration information will 
be made available on the ECDD website: https://www.who.int/medicines/access/controlled-substances/en/.
    As in the past and in line with the publication ``Guidance on 
the WHO review of psychoactive substances for international 
control'' (EB126/2010/REC1, Annex 6),\1\ Member States can also 
contribute to the ECDD review process by providing accurate 
information concerning the substances under review in advance of the 
meeting. For this purpose, a questionnaire will be sent to Member 
States to gather country information on the legitimate use, harmful 
use, status of national control and potential impact of 
international control for each substance under evaluation.
    In addition to the questionnaire, Member States are also 
encouraged to provide any additional relevant information 
(unpublished or published) on substances to be reviewed by the 43rd 
ECDD by emailing [email protected] with the subject ``Ref: 
C.L.22.2020''.
    The World Health Organization takes this opportunity to renew to 
Member States and Associate Members the assurance of its highest 
consideration.

GENEVA, 23 June 2020

\1\ https://apps.who.int/gb/ebwha/pdf_files/EB126-REC1/B126_REC1-en.pdf#page=58.

Annex I

43nd Expert Committee on Drug Dependence (ECDD), 12-16 October 2020, 
Substances for Review

    The substances listed below have never been formally reviewed by 
WHO and are not currently 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 recognized therapeutic use by any Party.

                             Critical Review
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Synthetic Opioids.........................  1. Isotonitazene
Synthetic Cannabinoid Receptor Agonists...  2. MDMB-4en-PINACA
                                            3. CUMYL-PEGALONE
Benzodiazepines...........................  4. Flubromazolam
                                            5. Clonazolam
                                            6. Diclazepam
Dissociative-type substances..............  7. 3-MeO-PCP
                                            8. DIPHENIDINE
                                            9. 2-MEO-DIPHENIDINE
Hallucinogen..............................  10. 5-MEO-SALT
Synthetic Stimulant.......................  11. 3-FLUROPHENMETRAZINE (3-
                                             FPM)
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    FDA has verified the website addresses contained in the WHO notice, 
as of the date this document publishes in the Federal Register, but 
websites are subject to change over time. Access to view the WHO 
questionnaire can be found at https://www.who.int/teams/health-product-and-policy-standards/controlled-substances/ecdd-member-state-questionnaire.

III. Substances Under WHO Review

    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 June 18, 2020, the Drug 
Enforcement Administration issued a notice of intent to temporarily 
control isotonitazene as a schedule I substance under the CSA.
    MDMB-4en-PINACA 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. 
According to the NFLIS database, MDMB-4en-PINACA was first encountered 
in the United States in January 2019. There have been 1,436 encounters 
of MDMB-4en-PINACA in the United States (as of July 6, 2020). MDMB-4en-
PINACA has also been encountered mixed with opioids including heroin 
and fentanyl, with some incidents resulting in violent behaviors, 
tachycardia, and hypertension. There are no commercial or approved 
medical uses for MDMB-4en-PINACA and MDMB-4en-PINACA is not a 
controlled substance under the CSA.
    CUMYL-PEGACLONE 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. 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 July 6, 2020). 
There are no commercial or approved medical uses for CUMYL-PEGALCONE 
and is not a controlled substance under the CSA.
    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. 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. Diclazepam is a designer benzodiazepine sold on the internet 
and

[[Page 47220]]

most often found as a liquid solution, but it may be sold as a powder, 
tablet, blotter paper, or pellet. 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.
    3-MeO-PCP (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-MeO-PCP 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-MeO-PCP is encountered by law enforcement in 
drug seizure reports. 3-MeO-PCP is an analogue of the Schedule II 
hallucinogen PCP. There is no approved medical use for 3-MeO-PCP in the 
United States. 3-MeO-PCP is not a controlled substance under the CSA. 
If intended for human consumption, 3-MeO-PCP may be treated as a 
``controlled substance analogue'' under the CSA pursuant to 21 U.S.C 
802(32) (A) and 813.
    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.
    2-MeO-DIPHENIDINE (2-methoxy-diphenidine, methoxphenidine) is a 
non-competitive NMDA receptor antagonist classified as a 
diarylethylamine and produces dissociative anesthetic and 
hallucinogenic effects that may produce effects similar to high doses 
of dextromethorphan. Use of this substance is associated with 
intoxication and non-fatal overdose in published case reports outside 
the United States. 2-MeO-DIPHENIDINE is encountered by law enforcement 
in drug seizure reports. There is no approved medical use for 2-MeO-
DIPHENIDINE in the United States and 2-MeO-DIPHENIDINE is not a 
controlled substance under the CSA.
    5-MeO-DALT (chemical name: N,N-Diallyl-5-methoxytryptamine) is a 
tryptamine hallucinogen and is an agonist of the serotonin (5-HT) 5-
HT2A receptor. 5-MeO-DALT appears to produce hallucinogenic 
effects similar to other tryptamine hallucinogens and fully substituted 
for 2,5-dimethoxy-4-methylamphetamine (DOM) in DOM-trained rats. 5-MeO-
DALT is an analogue of the Schedule I controlled substance 5methoxy-
N,N-diisopropyltryptamine (5-MeO-DiPT). 5-MeO-DALT has been encountered 
by law enforcement in drug seizure reports. 5-MeO-DALT is not approved 
for medical use in the United States and is not controlled under the 
CSA.
    3-FLUOROPHENMETRAZINE (3-FPM) (chemical name: 1-(3-fluorophenyl)-2-
(methylamino)propan-1-one) shares substantial chemical structural 
similarity to phenmetrazine, a Schedule II controlled substance that 
was prescribed as an appetite suppressant before being withdrawn from 
the pharmaceutical drug market in the United States because of its 
abuse potential. 3-FPM, which is similar to phenmetrazine and other 
stimulant drugs of abuse, increases extracellular concentrations of the 
neurotransmitter dopamine by inhibiting the uptake of this 
neurotransmitter at the dopamine transporter. Elevated extracellular 
dopamine concentrations have been implicated in the mechanism of action 
of stimulant drugs of abuse. There is no approved medical use for 3-FPM 
in the United States and 3-FPM is not a controlled substance under the 
CSA.

IV. Opportunity To Submit Domestic Information

    As required by paragraph (d)(2)(A) of the CSA, FDA, on behalf of 
HHS, invites interested persons to submit comments regarding the 11 
drug substances. Any comments received will be considered by HHS when 
it prepares a scientific and medical evaluation for drug substances 
that is responsive to the WHO Questionnaire for these drug substances. 
HHS will forward such evaluation of these drug substances to WHO, for 
WHO's consideration in deciding whether to recommend international 
control/decontrol of any of these drug substances. Such control could 
limit, among other things, the manufacture and distribution (import/
export) of these drug substances and could impose certain recordkeeping 
requirements on them.
    Although FDA is, through this notice, requesting comments from 
interested persons, which will be considered by HHS when it prepares an 
evaluation of these drug substances, HHS will not now make any 
recommendations to WHO regarding whether any of these drugs should be 
subjected to international controls. Instead, HHS will defer such 
consideration until WHO has made official recommendations to the 
Commission on Narcotic Drugs, which are expected to be made in late-
2020. Any HHS position regarding international control of these drug 
substances will be preceded by another Federal Register notice 
soliciting public comments, as required by paragraph (d)(2)(B) of the 
CSA.

    Dated: July 29, 2020.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2020-16905 Filed 8-3-20; 8:45 am]
BILLING CODE 4164-01-P