[Federal Register Volume 89, Number 157 (Wednesday, August 14, 2024)]
[Notices]
[Pages 66117-66119]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-18045]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2024-N-3677]


International Drug Scheduling; Single Convention on Narcotic 
Drugs; Convention on Psychotropic Substances; Hexahydrocannabinol; N-
Pyrrolidino Protonitazene (Protonitazepyne); N-Pyrrolidino Metonitazene 
(Metonitazepyne); N-Piperidinyl Etonitazene (Etonitazepipne); N-
Desethyl-isotonitazene; 3-Hydroxy-phencyclidine; N-Ethylheptedrone; 
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 23, 2024.

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 21, 2024. Comments 
received by mail/hand delivery/courier (for written/paper submissions) 
will be considered timely if they are received 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-2024-N-3677 for ``International Drug Scheduling; Single Convention 
on Narcotic Drugs; Convention on Psychotropic Substances; 
Hexahydrocannabinol (HHC); N-Pyrrolidino Protonitazene 
(Protonitazepyne); N-Pyrrolidino Metonitazene (Metonitazepyne); N-
Piperidinyl Etonitazene (Etonitazepipne); N-Desethyl-isotonitazene; 3-
Hydroxy-phencyclidine (3-OH-PCP); N-Ethylheptedrone; 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

[[Page 66118]]

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(d)(2)(A)) (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.29.2024

    The World Health Organization (WHO) presents its compliments to 
Member States and Associate Members and would like to inform that 
all recommendations made by the 46th WHO Expert Committee on Drug 
Dependence (ECDD), held in October 2023, were accepted by the 67th 
UN Commission on Narcotic Drugs.
    WHO further has the pleasure of announcing that the 47th Expert 
Committee on Drug Dependence (ECDD) will meet from 14 to 18 October 
2024 in Geneva, Switzerland. Given that WHO Expert Committee 
meetings are of a closed nature, this circular letter serves to 
notify Member States of the agenda of the 47th 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. To fulfil this mandate, WHO convenes the ECDD to advise 
on appropriate international drug control measures in view of a 
substance's ability to lead to public health harms as a result of 
their psychoactive properties, as well as its therapeutic 
applications.
    Although the meetings are of a closed nature, Member States, 
Associate Members, individuals, and representatives of public and 
private institutions and civil society who wish to present 
information to the Expert Committee on issues related to the meeting 
agenda are invited to attend a virtual information meeting (public 
consultation) on 14 October 2024. The purpose of the information 
meeting is to afford the Expert Committee the opportunity to receive 
presentations and to question representatives of interested parties 
concerning data that have been provided about substances on the ECDD 
agenda. Registration information will be made available on the ECDD 
website in due course: Forty-seventh Expert Committee on Drug 
Dependence (who.int).
    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), Member States and Associate 
Members 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 and 
Associate Members 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, 3 July 2024

Annex I

47th Expert Committee on Drug Dependence (ECDD) Substances for 
Review 14-18 October 2024

    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.

Synthetic Cannabinoids

1. Hexahydrocannabinol (HHC)

Novel Synthetic Opioids

1. N-Pyrrolidino protonitazene (protonitazepyne)
2. N-Pyrrolidino metonitazene (metonitazepyne)
3. N-Piperidinyl etonitazene (etonitazepipne)
4. N-Desethyl-isotonitazene

Dissociative-Type Substances

1. 3-Hydroxy-phencyclidine (3-OH-PCP)

Cathinone/Stimulant

1. N-Ethylheptedrone

Medicine

1. 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/ecdd/forty-seventh-ecdd-documents.

III. Substances Under WHO Review

    Hexahydrocannabinol (HHC) is a semi-synthetic cannabinoid. Several 
synthetic mechanisms for HHC have been published, which involve 
hydrogenating tetrahydrocannabinol (THC). In vitro receptor binding and 
activity studies indicate that HHC has higher affinity and agonist 
activity at the cannabinoid type 1 (CB1) receptor compared to that of 
the CB2 receptor. These data suggest that HHC produces effects similar 
to CB1 agonists, such as sedation, analgesia, mood changes, altered 
memory, psychosis, and panic. According to the National Forensic 
Laboratory Information System (NFLIS) database, HHC was first detected 
in the United States in 2022 with a total of 54 law enforcement 
seizures. There are no commercial uses or approved medical uses for HHC 
in the United States, and it is not controlled under the CSA.
    N-Pyrrolidino protonitazene (protonitazepyne) is a synthetic opioid 
of the nitazene family that is similar in structure to protonitazene. 
In vitro binding and activity data indicate that protonitazepyne is 
approximately 25-fold more potent at the mu opioid receptor than 
fentanyl. Common adverse events of opioid agonists include nausea, 
vomiting, constipation, pruritus, dizziness, sedation, and respiratory 
depression, which can lead to death. Protonitazepyne has been detected 
in 20 forensic toxicology cases in the United States and the United 
Kingdom. However, other new psychoactive substances (NPS) or other 
drugs of abuse were detected in all of these individuals and could have 
been a contributing factor to the fatality. According to the NFLIS 
database, protonitazepyne was first detected in 2023 and has been 
confirmed in 16 law enforcement seizures to date. There are no 
commercial uses or approved medical uses for protonitazepyne in the 
United States, and it is not controlled under the CSA.
    N-Pyrrolidino metonitazene (metonitazepyne) is a synthetic opioid 
of the nitazene family that is similar in structure to metonitazene. In 
vitro binding and activity data indicate that protonitazepyne is 
approximately 2-fold more potent at the mu opioid receptor than 
fentanyl. In animal behavior studies it produced subjective effects 
that were indistinguishable from morphine. As a result, it is assumed 
that metonitazepyne will have an abuse potential similar to that of 
other opioid agonists and produce adverse events that include nausea, 
vomiting,

[[Page 66119]]

constipation, pruritus, dizziness, sedation, and respiratory 
depression, which can lead to death. In the United States, 
metonitazepyne was detected in six toxicology cases; however, other NPS 
or other drugs of abuse were detected in all of these individuals and 
could have been a contributing factor to the fatality. According to the 
NFLIS database, metonitazepyne was first detected in 2023 and there 
have been seven confirmed law enforcement seizures to date. There are 
no commercial uses or approved medical uses for metonitazepyne in the 
United States, and it is not controlled under the CSA.
    N-Piperidynyl etonitazene (etonitazepipne) is a synthetic opioid of 
the nitazene family and is similar in structure to etonitazene. In 
vitro binding and activity data indicate that protonitazepyne is 
approximately 100-fold more potent at the mu opioid receptor than 
morphine. In animal behavior studies it produced subjective effects 
that were indistinguishable from morphine. As a result, it is assumed 
that etonitazepipne will have an abuse potential similar to that of 
other opioid agonists and produce adverse events that include nausea, 
vomiting, constipation, pruritus, dizziness, sedation, and respiratory 
depression, which can lead to death. According to the NFLIS database, 
etonitazepipne was first detected in 2022 and there have been 10 
confirmed law enforcement seizures to date. There are no commercial 
uses or approved medical uses for etonitazepipne in the United States. 
As of July 29, 2024, etonitazepipne is temporarily controlled in 
schedule I under the CSA.
    N-Desethyl-isotonitazene is a synthetic opioid of the nitazene 
family and is similar in structure to isotonitazene and is a known 
active metabolite of isotonitazene. In vitro binding and activity data 
indicate that N-desethyl-isotonitazene is approximately 20-fold more 
potent at the mu opioid receptor than fentanyl. In animal behavior 
studies it produced subjective effects that were indistinguishable from 
morphine. As a result, it is assumed that N-desethyl-isotonitazene will 
have an abuse potential similar to that of other opioid agonists and 
produce adverse events that include nausea, vomiting, constipation, 
pruritus, dizziness, sedation, and respiratory depression, which can 
lead to death. According to the NFLIS database, N-desethyl-
isotonitazene was first detected in 2022 and there have been 10 
confirmed law enforcement seizures to date. There are no commercial 
uses or approved medical uses for N-desethyl-isotonitazene in the 
United States. As of July 29, 2024, N-desethyl-isotonitazene is 
temporarily controlled in schedule I under the CSA.
    3-Hydroxy-phencyclidine (3-OH-PCP) is a dissociative hallucinogen 
of the arylcyclohexylamine class that has a structure similar to that 
of phencyclidine (PCP). In vitro binding and activity data indicate 
that 3-OH-PCP functions as a high affinity antagonist of the N-methyl-
D-aspartate receptor. Unlike PCP, 3-OH-PCP was also found to have high 
agonist activity at opioid receptors. In animal behavior studies it 
produced subjective effects that were indistinguishable from PCP. As a 
result, it is assumed that it will have a potential of abuse similar to 
that of PCP and produce effects such as hallucinations, audio and 
visual distortions, analgesia, and convulsions at high doses. According 
to the NFLIS database, 3-OH-PCP was first detected in the United States 
in 2020 with 45 law enforcement seizures. The following years saw a 
dramatic increase in law enforcement detections with 598 in 2021, 335 
in 2022, and 42 in 2023.\1\ Since 2020 there have been 34 fatalities in 
which 3-OH-PCP was determined to be a contributing factor by the 
medical examiner. There are no commercial uses or approved medical uses 
for 3-OH-PCP in the United States, and it is not controlled under the 
CSA.
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    \1\ The data from 2023 are still being accumulated as of the 
time of these data were collected (May 2024). As a result, the 2023 
data will likely increase.
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    N-Ethylheptedrone is a stimulant from the substituted cathinone 
class of drugs that has been used for recreational use. As a stimulant, 
N-ethylheptedrone, would be expected to produce adverse effects 
consistent with other stimulants such as decreased appetite, anxiety, 
headaches, weight loss, insomnia, and psychosis. It was first detected 
in 2019 in Hungry and has since been detected in New Zealand. There are 
no commercial uses or approved medical uses for N-ethylheptedrone in 
the United States, and it is not controlled under the CSA.
    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 was approved for medical use in 
the United States in 1959 as a muscle relaxant and is typically 
prescribed in combination with analgesics to treat muscle pain. FDA's 
Adverse Event Reporting System reported a total of 6,426 adverse events 
involving carisoprodol since 1969, and 18 of those being reported as 
drug abuse (data retrieved July 2024). Only 5 of the 18 were reported 
as abuse of carisoprodol alone. According to the NFLIS database, there 
were 405 law enforcement seizures of carisoprodol in 2022 alone. 
Scientific studies indicated that carisoprodol demonstrated abuse 
potential similar to that of benzodiazepines, resulting in it being 
controlled in schedule IV under the CSA on January 11, 2012 (76 FR 
77330).

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 identified in this document. Any comments received by 
the deadline 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 
2024. 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 8, 2024.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2024-18045 Filed 8-13-24; 8:45 am]
BILLING CODE 4164-01-P