[Federal Register Volume 88, Number 150 (Monday, August 7, 2023)]
[Notices]
[Pages 52179-52182]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-16812]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2023-N-3032]


International Drug Scheduling; Convention on Psychotropic 
Substances; Single Convention on Narcotic Drugs; Bromazolam; 
Flubromazepam; Butonitazene; 3-Chloromethcathinone (3-CMC); 
Dipentylone; 2-Fluorodeschloroketamine (2-FDCK); Nitrous Oxide (N2O); 
Carisoprodol; 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 eight 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: Either electronic or written comments must be submitted by 
August 24, 2023.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of August 24, 2023. Comments 
received by mail/hand delivery/courier (for written/paper submissions) 
will be considered timely if they are received on or before that date.

[[Page 52180]]

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-2023-N-3032 for ``International Drug Scheduling; Convention on 
Psychotropic Substances; Single Convention on Narcotic Drugs; 
Bromazolam; Flubromazepam; Butonitazene; 3-Chloromethcathinone (3-CMC); 
Dipentylone; 2-Fluorodeschloroketamine (2-FDCK); Nitrous oxide 
(N2O); Carisoprodol; 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: Edward (Greg) Hawkins, Center for Drug 
Evaluation and Research, Controlled Substance Staff, Food and Drug 
Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 5110, Silver 
Spring, MD 20993-0002, 301-796-0727, [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 (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.22.2023

    The World Health Organization (WHO) presents its compliments to 
Member States and Associate Members and has the pleasure of 
announcing that the 46th Expert Committee on Drug Dependence (ECDD) 
will meet from 16 to 20 October 2023, in 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 46th ECDD, which are in the Annex I file, 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 whether or not a psychoactive 
substance should be placed under international control, 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 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 46th 
ECDD Information Session on 16 October 2023. The Information Session 
will be held virtually and allow interested parties to learn about 
present and future activities of the ECDD Secretariat, and to 
present information concerning substances under review to the 46th 
Expert Committee

[[Page 52181]]

for consideration in its deliberations. Registration information 
will be made available on the ECDD website in due course: https://www.who.int/news-room/events/detail/2023/10/16/default-calendar/forty-sixth-expert-committee-on-drug-dependence.
    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 up to date and 
accurate information concerning the substances under review in 
advance of the meeting. For this purpose, and as per previous 
practice, 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.
    The World Health Organization takes this opportunity to renew to 
Member States and Associate Members the assurance of its highest 
consideration.

GENEVA, 27 June 2023

    \1\ https://apps.who.int/gb/ebwha/pdf_files/EB126-REC1/B126_REC1-en.pdf#page=90.

Annex I

46th Expert Committee on Drug Dependence (ECDD) Substances for 
Review 16-20 October 2023

    Critical reviews: The substances listed below have been proposed 
by WHO for critical review 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.

Benzodiazepines
    1. Bromazolam
    2. Flubromazepam
Novel Synthetic Opioids
    3. Butonitazene
    Cathinones/stimulants
    4. 3-Chloromethcathinone (3-CMC)
    5. Dipentylone
Dissociative-type substances
    6. 2-fluorodeschloroketamine (2-FDCK)

    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.

Medicines
    7. Nitrous oxide
    8. Carisoprodol

    FDA has verified the website addresses contained in the WHO notice 
as of the date this document publishes in the Federal Register; 
however, 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/46th-ecdd-documents.

III. Substances Under WHO Review

    Bromazolam is a triazolobenzodiazepine that produces agonist 
effects on gamma-aminobutyric acid (GABA) type-A channels through the 
benzodiazepine site. Through this mechanism of action, bromazolam can 
produce sedative and anxiolytic effects similar to other drugs of the 
benzodiazepine class. According to the National Forensic Laboratory 
Information System (NFLIS) database, there were 2,881 drug seizures of 
bromazolam in the United States from 2016 to May of 2023; however, some 
case reports are still pending for 2022 and 2023, so this number is 
increasing. Toxicology data indicate that bromazolam is typically 
detected in samples that include other drugs such as stimulants and 
opioids. This polydrug combination has led to the determination that 
bromazolam has played at least a contributory role in 152 confirmed 
deaths associated with the use of bromazolam. There are no commercial 
or approved medical uses for bromazolam in the United States, and it is 
not controlled under the CSA.
    Flubromazepam is a compound of the benzodiazepine class that 
produces agonist effects on GABAA channels and can produce 
sedative and anxiolytic effects similar to other drugs of the class. 
Law enforcement data indicate that flubromazepam has been detected in 
169 biological samples from 2019 through 2022. In 2022, 87 percent of 
those samples also contained fentanyl. There are no commercial or 
approved medical uses for flubromazepam in the United States and it is 
not controlled under the CSA.
    Butonitazene is a novel synthetic mu-opioid receptor agonist of the 
benzimidazole structural class. Law enforcement data indicates that 
butonitazene appeared on the U.S. illicit markets as evidenced by their 
identification in forensic drug seizures and biological samples. The 
abuse liability of benzimidazole opioids is similar to other synthetic 
opioids. Butonitazene has been identified in toxicological samples from 
post-mortem cases. The public health risks attendant to the abuse of 
mu-opioid receptor agonists are well established and can result in 
drowsiness, nausea, vomiting, and respiratory depression leading to 
death. Butonitazene has no approved medical uses in the United States 
and is a schedule I substance under the CSA.
    3-Chloromethcathinone (3-CMC) and dipentylone are synthetic 
stimulant designer drugs structurally similar to schedule I synthetic 
cathinones and schedule II stimulants like methamphetamine. Like other 
schedule I synthetic cathinones, 3-MMC and dipentylone are abused for 
their psychoactive effects. Adverse effects associated with the abuse 
of synthetic cathinones include agitation, hypertension, tachycardia, 
and death. According to NFLIS, dipentylone was first detected in the 
United States in 2014, and in 2022 there were 4,901 law enforcement 
seizures of the drug. Both 3-CMC and dipentylone have been detected in 
biological samples from toxicological drug tests and from postmortem 
samples. 3-CMC and dipentylone have no approved medical uses in the 
United States and both are schedule I substances under the CSA.
    2-Fluorodeschloroketamine (2-FDCK) is a dissociative anesthetic 
related to ketamine. 2-FDCK is a novel psychoactive substance (NPS) 
that is used as a research chemical and is sometimes marketed as a 
legal high. In animals, 2-FDCK demonstrated a similar potential for 
abuse as ketamine in studies that compare measurements of reinforcing 
effects (e.g., self-administration) and discriminative stimulus effects 
(e.g., drug discrimination and conditioned place preference). As a 
result, 2-FDCK is presumed to produce psychoactive effects similar to 
ketamine such as sensory dissociation, derealization, analgesia, 
hallucinations, mania, and amnesia. 2-FDCK has been detected in 
biological samples from toxicological drug tests and from postmortem 
samples. 2-FDCK has no approved medical uses in the United States and 
is not a controlled substance under the CSA, although it is controlled 
in many European countries.
    Nitrous oxide (N2O) is an inhalable gas that is also 
known by the common names, laughing gas, nitrous, whippets, NOS, or 
hippy-crack. It is part of the dissociative class of hallucinogens and 
is thought to function through modulation of GABA and N-methyl-D-
aspartate (NMDA) receptors. N2O was first used in the late 
1700s as an analgesic for dental and surgical operations. It is 
approved by FDA as a medical gas but has seen increasing use around the 
world for its subjective effects. These effects include, but are not 
limited to, dizziness, loss of motor control, euphoria, perceptual 
changes, numbness, amnesia, derealization, and altered acuity. 
N2O is not controlled under the CSA.

[[Page 52182]]

    Carisoprodol is a sedative-hypnotic that is used as a centrally 
acting muscle relaxant and hypnotic. Carisoprodol is a prodrug that is 
metabolized in the liver to form meprobamate which functions similarly 
to benzodiazepines and barbiturates. It is approved for medical use in 
the United States as a muscle relaxant and is typically prescribed in 
combination with analgesics to treat muscle pain. Scientific studies 
indicate that carisoprodol has a demonstrated abuse potential similar 
to benzodiazepines, and it is controlled under schedule IV 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 eight 
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 
2023. 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 (21 U.S.C. 811).

    Dated: August 2, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-16812 Filed 8-4-23; 8:45 am]
BILLING CODE 4164-01-P