[Federal Register Volume 86, Number 139 (Friday, July 23, 2021)]
[Notices]
[Pages 39038-39040]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-15685]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2021-N-0739]


International Drug Scheduling; Convention on Psychotropic 
Substances; Single Convention on Narcotic Drugs; 4F-MDMB-BICA (4F-MDMB-
BUTICA); Brorphine; Metonitazene; Eutylone (bk-EBDB); BMDP (3,4-
Methylenedioxy-N-benzylcathinone); Kratom (mitragynine, 7-
hydroxymitragynine); Phenibut; 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 Agency) is inviting 
interested persons to submit comments concerning abuse potential, 
actual abuse, medical usefulness, trafficking, and impact of scheduling 
changes on availability for medical use of seven 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 9, 2021.

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 9, 2021. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of August 9, 2021. 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:
    <bullet> 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.
    <bullet> 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:
    <bullet> 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.
    <bullet> 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-0739 for ``International Drug Scheduling; Convention on 
Psychotropic Substances; Single Convention on Narcotic Drugs; 4F-MDMB-
BICA (4F-MDMB-BUTICA); Brorphine; Metonitazene; Eutylone (bk-EBDB); 
BMDP (3,4-Methylenedioxy-N-benzylcathinone); Kratom (mitragynine, 7-
hydroxymitragynine); Phenibut; 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.
    <bullet> 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, <a href="/cdn-cgi/l/email-protection#254f444840560b4d504b514057654341440b4d4d560b424a53"><span class="__cf_email__" data-cfemail="771d161a1204591f021903120537111316591f1f0459101801">[email protected]</span></a>.

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

[[Page 39039]]

may require international control or change in such control, it shall 
so notify the Secretary-General of the United Nations (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 
(nonrelevant text removed):

Ref.: C.L.20.2021

    The World Health Organization (WHO) presents its compliments to 
Member States and Associate Members and has the pleasure of 
announcing that the 44th Expert Committee on Drug Dependence (ECDD) 
will meet from 11 to 15 October 2021, coordinated from Geneva, 
Switzerland. Given that WHO Expert Committee meetings are of a 
closed nature, this letter serves to notify Member States of the 
substances under review at the 44th ECDD, which are in the Annex I, 
attached 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 44th 
ECDD Open Session on 11 October 2021. The Open Session will allow 
interested parties to learn about present and future activities of 
the ECDD Secretariat, and 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 44th 
ECDD by emailing <a href="/cdn-cgi/l/email-protection#6d080e09091e080e1f08190c1f040c192d1a050243040319"><span class="__cf_email__" data-cfemail="c5a0a6a1a1b6a0a6b7a0b1a4b7aca4b185b2adaaebacabb1">[email protected]</span></a> with the subject ``Ref: 
C.L.20.2021''.
    The World Health Organization takes this opportunity to renew to 
Member States and Associate Members the assurance of its highest 
consideration.

GENEVA, 10 June 2021

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

Annex I

44th Expert Committee on Drug Dependence (ECDD) 11-15 October 2021, 
Substances For Review

    Critical reviews: 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. The Expert Committee will consider whether 
information presented during a critical review may justify the 
scheduling or a change in the scheduling of the substance in the 
1961 or 1971 Conventions.
Synthetic cannabinoid receptor agonists
    1. 4F-MDMB-BICA (4F-MDMB-BUTICA)
Novel synthetic opioids
    2. Brorphine
    3. Metonitazene
Cathinones/stimulants
    4. Eutylone (bk-EBDB)
    5. BMDP (3,4-Methylenedioxy-N-benzylcathinone), benzylone
    Pre-reviews: The substances listed below have been proposed for 
a pre-review. The purpose of a pre-review is to determine whether 
current information justifies an Expert Committee critical review. A 
pre-review is a preliminary analysis and findings at this stage 
should not determine whether the control status of a substance 
should be changed.
Herbal drugs
    6. Kratom, mitragynine, 7-hydroxymitragynine
Medicines
    7. Phenibut

    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/groups/who-expert-committee-on-drug-dependence/forty-fourth-ecdd-documents.

III. Substances Under WHO Review

    4F-MDMB-BICA (4F-MDMB-BUTICA) is a synthetic cannabinoid that has 
been sold online and used to mimic the biological effects of 
tetrahydrocannabinol, 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 National Forensic 
Laboratory Information System database, 4F-MDMB-BICA emerged in the 
United States in May 2020 through identification in drug seizures. Per 
NPS Discovery,\1\ 4F-MDMB-BICA has been identified in at least 26 
toxicology cases associated with postmortem and driving under the 
influence of drugs investigations in the United States. There are no 
commercial or approved medical uses for 4F-MDMB-BICA, and it is not a 
controlled substance under the CSA but may be considered an analogue of 
other Schedule I substances.
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    \1\ https://www.npsdiscovery.org/positivity-of-new-synthetic-cannabinoid-4f-mdmb-bica-increasing-in-u-s-as-prevalence-of-5f-mdmb-pica-wanes/.
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    Brorphine (chemical name: 1-(1-(1-(4-bromophenyl)ethyl)piperidin-4-
yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one) is a potent synthetic opioid 
encountered as both a single substance of abuse and in combination with 
other opioid substances, such as heroin and fentanyl. The appearance of 
brorphine on the illicit drug market is similar to other designer drugs 
trafficked for their psychoactive effects. Beginning in June 2019, 
brorphine emerged in the United States illicit, synthetic drug market 
as evidenced by its identification in drug seizures. The use of 
brorphine has been associated with at least seven fatalities between 
June and July 2020 in the United States. Brorphine is not approved for 
medical use in the United States. On March 1, 2021, the U.S. Drug 
Enforcement Administration issued a

[[Page 39040]]

temporary order to control brorphine as a Schedule I substance under 
the CSA.
    Eutylone (bk-EBDB) (chemical name: 1-(1,3-benzodioxol-5-yl)-2-
(ethylamino)butan-1-one) is a designer drug of the phenethylamine 
class. Eutylone is a synthetic cathinone with chemical structural and 
pharmacological similarities to Schedule I and II amphetamines and 
cathinones, such as to 3,4-Methylenedioxymethamphetamine, methylone, 
and pentylone. Eutylone emerged in the United States illicit, synthetic 
drug market in 2014 as evidenced by its identification in drug 
seizures. Other evidence indicates that eutylone, like other Schedule I 
synthetic cathinones, is abused for its psychoactive effects. Adverse 
effects associated with synthetic cathinones abuse include agitation, 
hypertension, tachycardia, and death. Eutylone is not approved for 
medical use in the United States. As a positional isomer of pentylone, 
eutylone is controlled in Schedule I of the CSA.
    BMDP (chemical name: 3,4-Methylenedioxy-N-benzylcathinone) is a 
designer drug of the phenethylamine class. BMDP is a synthetic 
cathinone with chemical structural and pharmacological similarities to 
Schedule I and II amphetamines (e.g., methamphetamine and 3,4- 
methylenedioxymethamphetamine) and cathinones (e.g., methylone). Law 
enforcement has seen an increase in the encounters of BMDP in 2019 in 
the United States illicit, synthetic drug market as evidenced by its 
identification in drug seizures. BMDP has no commercial or approved 
medical uses, and it is not controlled under the CSA. However, if BMDP 
is found to meet the criteria outlined in Title 21 of the United States 
Code, section 802(32) (21 U.S.C. 802(32)), and it is intended for human 
consumption, it may be treated as a Schedule I controlled substance 
analogue for the purpose of Federal law pursuant to 21 U.S.C. 813.
    Mitragynine and 7-hydroxymitragynine are the main active 
constituents of the plant Mitragyna speciosa, commonly known as kratom, 
an indigenous plant of Southeast Asia. Kratom is abused for its ability 
to produce opioid-like effects. Kratom is available in several 
different forms to include dried/crushed leaves, powder, capsules, 
tablets, liquids, and gum/resin. Kratom is an increasingly popular drug 
of abuse and readily available on the recreational drug market in the 
United States. Evidence suggests that kratom is abused individually and 
with other psychoactive substances. Kratom does not have an approved 
medical use in the United States and has not been studied as a 
treatment agent in the United States. Kratom has a history of being 
used as an opium substitute in Southeast Asia. In the United States, 
kratom is misused to self-treat chronic pain and opioid withdrawal 
symptoms. Consumption of kratom can lead to a number of health impacts, 
including, among others, respiratory depression, vomiting, nervousness, 
weight loss, and constipation. Kratom has been reported to have both 
narcotic and stimulant-like effects, and withdrawal symptoms may 
include hostility, aggression, excessive tearing, aching of muscles and 
bones, and jerky limb movements. Kratom is not a controlled substance 
under the CSA.
    Phenibut (chemical name: Beta-phenyl-gamma-aminobutyric acid HCl) 
is a neuropsychotropic drug that is used in Russia to treat alcohol 
withdrawal, anxiety, insomnia, and vestibular disorders. It has 
anxiolytic and nootropic (cognition enhancing) effects. Phenibut acts 
as a gamma-aminobutyric acid (GABA)-mimetic, primarily at GABA(B) and, 
to some extent, at GABA(A) receptors. Phenibut is sold online as a 
supplement to improve cognitive function, memory, creativity in healthy 
persons, and used to self-medicate anxiety, insomnia, and alcohol 
cravings. There are reports of people taking phenibut arriving to 
emergency departments with agitation, intoxication, altered mental 
status, and withdrawal, and also reports of phenibut in toxicology 
urinalysis reports from a prison facility, where inmates were abusing 
multiple drugs, including phenibut. There is no approved medical use 
for phenibut in the United States, and phenibut 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 
2021. 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 19, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2021-15685 Filed 7-22-21; 8:45 am]
BILLING CODE 4164-01-P


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