[Federal Register Volume 89, Number 71 (Thursday, April 11, 2024)]
[Proposed Rules]
[Pages 25544-25550]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-07694]



[[Page 25544]]

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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-900N]


Schedules of Controlled Substances: Placement of Butonitazene, 
Flunitazene, and Metodesnitazene Substances in Schedule I

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Notice of proposed rulemaking.

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SUMMARY: The Drug Enforcement Administration proposes placing 
butonitazene, flunitazene, and metodesnitazene including their isomers, 
esters, ethers, salts and salts of isomers, esters and ethers in 
schedule I of the Controlled Substances Act. If finalized, this action 
would make permanent the existing regulatory controls and 
administrative, civil, and criminal sanctions applicable to schedule I 
controlled substances on persons who handle (manufacture, distribute, 
reverse distribute, import, export, engage in research, conduct 
instructional activities or chemical analysis with, or possess), or 
propose to handle these three specific controlled substances.

DATES: Comments must be submitted electronically or postmarked on or 
before May 13, 2024.
    Interested persons may file a request for a hearing or waiver of 
hearing pursuant to 21 CFR 1308.44 and in accordance with 21 CFR 
1316.47 and/or 1316.49, as applicable. Requests for a hearing, and 
waivers of an opportunity for a hearing or to participate in a hearing, 
must be received on or before May 13, 2024.

ADDRESSES: Interested persons may file written comments on this 
proposal in accordance with 21 CFR 1308.43(g). The electronic Federal 
Docket Management System will not accept comments after 11:59 p.m. 
Eastern Time on the last day of the comment period. To ensure proper 
handling of comments, please reference ``Docket No. DEA-900N'' on all 
electronic and written correspondence, including any attachments.
     Electronic comments: The Drug Enforcement Administration 
(DEA) encourages commenters to submit all comments electronically 
through the Federal eRulemaking Portal which provides the ability to 
type short comments directly into the comment field on the web page or 
to attach a file for lengthier comments. Please go to https://www.regulations.gov and follow the online instructions at that site for 
submitting comments. Upon completion of your submission, you will 
receive a Comment Tracking Number for your comment. If you have 
received a Comment Tracking Number, your comment has been successfully 
submitted and there is no need to resubmit the same comment. Commenters 
should be aware that the electronic Federal Docket Management System 
will not accept comments after 11:59 p.m. Eastern Time on the last day 
of the comment period.
     Paper comments: Paper comments that duplicate electronic 
submissions are not necessary and are discouraged. Should you wish to 
mail a paper comment in lieu of an electronic comment, it should be 
sent via regular or express mail to: Drug Enforcement Administration, 
Attn: DEA Federal Register Representative/DPW, 8701 Morrissette Drive, 
Springfield, Virginia 22152.
     Hearing requests: All requests for a hearing and waivers 
of participation, together with a written statement of position on the 
matters of fact and law asserted in the hearing, must be filed with the 
DEA Administrator, who will make the determination of whether a hearing 
will be needed to address such matters of fact and law in the 
rulemaking. Such requests must be sent to: Drug Enforcement 
Administration, Attn: Administrator, 8701 Morrissette Drive, 
Springfield, Virginia 22152. For informational purposes, a courtesy 
copy of requests for hearing and waivers of participation should also 
be sent to: (1) Drug Enforcement Administration, Attn: Hearing Clerk/
OALJ, 8701 Morrissette Drive, Springfield, Virginia 22152; and (2) Drug 
Enforcement Administration, Attn: DEA Federal Register Representative/
DPW, 8701 Morrissette Drive, Springfield, Virginia 22152.
     Paperwork Reduction Act Comments: All comments concerning 
collections of information under the Paperwork Reduction Act must be 
submitted to the Office of Information and Regulatory Affairs, OMB, 
Attention: Desk Officer for DOJ, Washington, DC 20503. Please state 
that your comment refers to Docket No. DEA-900N.

FOR FURTHER INFORMATION CONTACT: Dr. Terrence L. Boos, Drug and 
Chemical Evaluation Section, Diversion Control Division, Drug 
Enforcement Administration; Telephone: (571) 362-3249.

SUPPLEMENTARY INFORMATION: In this proposed rule, the Drug Enforcement 
Administration (DEA) proposes to permanently schedule the following 
three controlled substances in schedule I of the Controlled Substances 
Act (CSA), including their isomers, esters, ethers, salts, and salts of 
isomers, esters, and ethers whenever the existence of such isomers, 
esters, ethers, and salts is possible within the specific chemical 
designation:
     butonitazene (2-(2-(4-butoxybenzyl)-5-nitro-1H-
benzimidazol-1-yl)-N,N-diethylethan-1-amine),
     flunitazene (N,N-diethyl-2-(2-(4-fluorobenzyl)-5-nitro-1H-
benzimidazol-1-yl)ethan-1-amine),
     metodesnitazene (N,N-diethyl-2-(2-(4-methoxybenzyl)-1H-
benzimidazol-1-yl)ethan-1-amine).

Posting of Public Comments

    All comments received in response to this docket are considered 
part of the public record. DEA will make comments available for public 
inspection online at https://www.regulations.gov, unless reasonable 
cause is given. Such information includes personal or business 
identifiers (such as name, address, state of federal identifiers, etc.) 
voluntarily submitted by the commenter.
    Commenters submitting comments which include personal identifying 
information (PII), confidential, or proprietary business information 
that the commenter does not want made publicly available should submit 
two copies of the comment. One copy must be marked ``CONTAINS 
CONFIDENTIAL INFORMATION'' and should clearly identify all PII or 
business information the commenter does not want to be made publicly 
available, including any supplemental materials. DEA will review this 
copy, including the claimed PII and confidential business information, 
in its consideration of comments. The second copy should be marked ``TO 
BE PUBLICLY POSTED'' and must have all claimed confidential PII and 
business information already redacted. DEA will post only the redacted 
comment on https://www.regulations.gov for public inspection. DEA 
generally will not redact additional information contained in the 
comment marked ``TO BE PUBLICLY POSTED.'' The Freedom of Information 
Act applies to all comments received.
    For easy reference, an electronic copy of this document and 
supplemental information to this proposed scheduling action are 
available at https://www.regulations.gov.

Request for Hearing or Appearance; Waiver

    Pursuant to 21 U.S.C. 811(a), this action is a formal rulemaking 
``on the

[[Page 25545]]

record after opportunity for a hearing.'' Such proceedings are 
conducted pursuant to the provisions of the Administrative Procedure 
Act (APA), 5 U.S.C. 551-559.\1\ Interested persons, as defined in 21 
CFR 1300.01(b), may file requests for a hearing in conformity with the 
requirements of 21 CFR 1308.44(a) and 1316.47(a), and such requests 
must:
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    \1\ 21 CFR 1308.41 through 1308.45; 21 CFR part 1316, subpart D.
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    (1) state with particularity the interest of the person in the 
proceeding;
    (2) state with particularity the objections or issues concerning 
which the person desires to be heard; and
    (3) state briefly the position of the person with regarding to the 
objections or issues.
    Any interested person may file a waiver of an opportunity for a 
hearing or to participate in a hearing in conformity with the 
requirements of 21 CFR 1308.44(c), together with a written statement of 
position on the matters of fact and law involved in any hearing.\2\
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    \2\ 21 CFR 1316.49.
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    All requests for a hearing and waivers of participation, together 
with a written statement of position on the matters of fact and law 
involved in such hearing, must be sent to DEA using the address 
information provided above. The decision whether a hearing will be 
needed to address such matters of fact and law in the rulemaking will 
be made by the Administrator. If a hearing is needed, DEA will publish 
a notice of hearing on the proposed rulemaking in the Federal 
Register.\3\ Further, once the Administrator determines a hearing is 
needed to address such matters of fact and law in rulemaking, she will 
then designate an Administrative Law Judge (ALJ) to preside over the 
hearing. The ALJ's functions shall commence upon designation, as 
provided in 21 CFR 1316.52.
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    \3\ 21 CFR 1308.44(b), 1316.53.
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    In accordance with 21 U.S.C. 811 and 812, the purpose of a hearing 
would be to determine whether butonitazene, flunitazene, and 
metodesnitazene meet the statutory criteria for placement in schedule 
I, as proposed in this rule.

Legal Authority

    The CSA provides that proceedings for the issuance, amendment, or 
repeal of the scheduling of any drug or other substance may be 
initiated by the Attorney General (delegated to the Administrator of 
DEA pursuant to 28 CFR 0.100) on his own motion, at the request of the 
Secretary of Health and Human Services (HHS), or on the petition of any 
interested party.\4\ This proposed action is supported by a 
recommendation from the Assistant Secretary for Health of HHS 
(Assistant Secretary for HHS or Assistant Secretary) and an evaluation 
of all other relevant data by DEA. If finalized, this action would make 
permanent the existing temporary regulatory controls and 
administrative, civil, and criminal sanctions of schedule I controlled 
substances on any person who handles or proposes to handle these three 
substances.
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    \4\ 21 U.S.C. 811(a).
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Background

    On April 12, 2022, pursuant to 21 U.S.C. 811(h)(1), DEA published 
an order in the Federal Register temporarily placing butonitazene, 
flunitazene, metodesnitazene, and four additional benzimidazole-opioids 
in schedule I of the Controlled Substances Act (CSA) based upon a 
finding that these substances pose an imminent hazard to the public 
safety.\5\ That temporary order was effective upon the date of 
publication. Under 21 U.S.C. 811(h)(2), the temporary scheduling of a 
substance expires at the end of two years from the date of issuance of 
the scheduling order, except that DEA may extend temporary scheduling 
of that substance for up to one year during the pendency of permanent 
scheduling proceedings under 21 U.S.C. 811(a)(1) with respect to the 
substance. Pursuant to 21 U.S.C. 811(h)(2), the temporary scheduling of 
butonitazene, flunitazene, and metodesnitazene expires on April 12, 
2024, unless extended. An extension of the temporary order is being 
ordered by the DEA Administrator in a separate action, published 
elsewhere in this issue of the Federal Register.
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    \5\ See Schedules of Controlled Substances: Temporary Placement 
of Butonitazene, Etodesnitazene, Flunitazene, Metodesnitazene, 
Metonitazene, N-Pyrrolidino etonitazene, and Protonitazene in 
Schedule I, 87 FR 21556 (Apr. 12, 2022). The four additional 
benzimidazole-opioids were etodesnitazene, metonitazene, N-
pyrrolidino etonitazene, and protonitazene. DEA pursued separate 
scheduling actions for metonitazene, see 88 FR 56466 (Aug. 18, 2023) 
and for etodesnitazene, N-pyrrolidino etonitazene, and 
protonitazene, to remain as a schedule I substances under the CSA in 
order to meet the United States' obligations under the United 
Nations Single Convention on Narcotic Drugs, Mar. 30, 1961, 18 
U.S.T. 1407, 520 U.N.T.S. 151 (Single Convention), as amended by the 
1972 Protocol.
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    As described in the temporary order published on April 12, 2022, 
butonitazene, flunitazene, and metodesnitazene belong to the class of 
substances known as benzimidazole-opioids and are synthetic opioids. 
The Assistant Secretary for HHS has advised DEA that there are no 
exemptions or approvals in effect for butonitazene, flunitazene, and 
metodesnitazene under section 505 of the Federal Food, Drug and 
Cosmetic Act, 21 U.S.C. 335. According to HHS, and also by DEA's 
findings in this proposed rule, butonitazene, flunitazene, and 
metodesnitazene have no known accepted medical use. These substances 
are not the subject of any approved new drug application (NDA) or 
investigational new drug application (IND), and are not currently 
marketed as approved drug products.
    The Administrator, on her own motion pursuant to 21 U.S.C. 811(a), 
is initiating proceedings to permanently schedule butonitazene, 
flunitazene, and metodesnitazene. DEA gathered the necessary data and 
reviewed the available information regarding the pharmacology, 
chemistry, trafficking, actual abuse, pattern of abuse, and the 
relative potential for abuse for these substances. On July 13, 2022, in 
accordance with 21 U.S.C. 811(b), the Administrator then submitted a 
request to the Assistant Secretary to provide DEA with a scientific and 
medical evaluation of available information and a scheduling 
recommendation for six benzimidazole substances.
    On November 15, 2023, the Assistant Secretary submitted HHS's 
scientific and medical evaluation and scheduling recommendation for 
butonitazene, flunitazene, metodesnitazene, and three other 
benzimidazole-opioids and their salts to the Administrator,\6\ which 
recommended placing butonitazene, flunitazene, and metodesnitazene and 
their salts in schedule I of the CSA. In accordance with 21 U.S.C. 
811(c), upon receipt of the scientific and medical evaluation and 
scheduling recommendation from HHS, DEA reviewed the documents and all 
other relevant data, and conducted its own eight-factor analysis of the 
abuse potential of these three substances.
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    \6\ The three other benzimidazole-opioids (etodesnitazene, N-
pyrrolidino etonitazene, and protonitazene) will not be discussed 
further in this proposed rule.
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Proposed Determination to Permanently Schedule Butonitazene, 
Flunitazene, and Metodesnitazene

    As discussed in the background section, the Administrator is 
initiating proceedings, pursuant to 21 U.S.C. 811(a), to permanently 
add butonitazene, flunitazene, and metodesnitazene to schedule I. DEA 
reviewed the scientific and medical evaluation and scheduling 
recommendation received from HHS, and all other relevant data, and it 
conducted its own eight-factor analysis of the abuse potential of these 
three

[[Page 25546]]

substances pursuant to 21 U.S.C. 811(c). Included below is a brief 
summary of each factor as analyzed by HHS and DEA, and as considered by 
DEA in its proposed scheduling action. Please note that both the DEA 
and HHS analyses are available in their entirety under ``Supporting 
Documents'' of the public docket for this proposed rule at https://www.regulations.gov under Docket Number ``DEA-900N.''

1. The Drug's Actual or Relative Potential for Abuse

    In addition to considering the information HHS provided in its 
scientific and medical evaluation document for butonitazene, 
flunitazene, and metodesnitazene, DEA also considered all other 
relevant data regarding actual or relative potential for abuse of these 
three substances. The term ``abuse'' is not defined in the CSA; 
however, the legislative history of the CSA suggests that DEA consider 
the following criteria when determining whether a particular drug or 
substance has a potential for abuse: \7\
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    \7\ Comprehensive Drug Abuse Prevention and Control Act of 1970, 
H.R. Rep. No. 91-1444, 91st Cong., Sess. 1 (1970); reprinted in 1970 
U.S.C.C.A.N. 4566, 4603.

    a. There is evidence that individuals are taking the drug or 
drugs containing such a substance in amounts sufficient to create a 
hazard to their health or to the safety of other individuals or of 
the community; or
    b. There is a significant diversion of the drug or substance 
from legitimate drug channels; or
    c. Individuals are taking the drug or drugs containing such a 
substance on their own initiative rather than on the basis of 
medical advice from a practitioner licensed by law to administer 
such drugs in the course of his professional practice; or
    d. The drug or drugs containing such a substance are new drugs 
so related in their action to a drug or drugs already listed as 
having a potential for abuse to make it likely that the drug will 
have the same potentiality for abuse as such drugs, thus making it 
reasonable to assume that there may be significant diversions from 
legitimate channels, significant use contrary to or without medical 
advice, or that it has a substantial capability of creating hazards 
to the health of the user or to the safety of the community.

    Both DEA and HHS eight-factor analyses found that butonitazene, 
flunitazene, and metodesnitazene have pharmacological profiles similar 
to those of the synthetic opioids etonitazene and isotonitazene, which 
are both schedule I controlled substances and have high potential for 
abuse. According to HHS, butonitazene, flunitazene, and metodesnitazene 
have no approved medical uses in the United States, and they have been 
encountered on the illicit drug market with adverse outcomes on the 
public health and safety. Because there are no Food and Drug 
Administration (FDA)-approved or FDA-exempted products for 
butonitazene, flunitazene, and metodesnitazene in the United States or 
in any other country, a practitioner may not legally prescribe them, 
and they cannot be dispensed to an individual. However, these 
benzimidazole-opioids substances are available for purchase from 
legitimate chemical companies because they can be used in scientific 
research. There is no known diversion from research activities for 
these substances.
    Because butonitazene, flunitazene, and metodesnitazene are not 
formulated or available for clinical use as approved medicinal 
products, it is inferred that all current use of these substances by 
individuals are based on their own initiative, rather than on the basis 
of medical advice from a practitioner licensed by law to administer 
such drugs. According to drug seizure data from 2020 and 2023 from the 
National Forensic Laboratory Information System (NFLIS-Drug) \8\ 
database, which collects drug identification results from drug cases 
submitted to and analyzed by Federal, State, and local forensic 
laboratories, there have been a total of 130 reports for butonitazene, 
flunitazene, or metodesnitazene. Evidence from law enforcement seizures 
\9\ indicate that individuals are taking these benzimidazole-opioids 
with no accepted medical use, on their own initiative rather than on 
the medical advice of a licensed practitioner. Individuals may be using 
these benzimidazole-opioids on their own initiative because of their 
opioidergic effects similar to other schedule I or II opioid 
substances. Consequently, law enforcement encounters of butonitazene, 
flunitazene, and metodesnitazene demonstrate that these substances are 
being abused, and thus pose safety hazards to the health of users or 
the community.
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    \8\ NFLIS-Drug represents an important resource in monitoring 
illicit drug trafficking, including the diversion of legally 
manufactured pharmaceuticals into illegal markets. NFLIS-Drug is a 
comprehensive information system that includes data from forensic 
laboratories that handle the nation's drug analysis cases. NFLIS-
Drug participation rate, defined as the percentage of the national 
drug caseload represented by laboratories that have joined NFLIS, is 
currently 98.5 percent. NFLIS includes drug chemistry results from 
completed analyses only. NFLIS-Drug data was queried on November 21, 
2023.
    \9\ While law enforcement data is not direct evidence of abuse, 
it can lead to an inference that a drug has been diverted and 
abused. See Schedules of Controlled Substances: Placement of 
Carisoprodol Into Schedule IV, 76 FR 77330, 77332 (Dec. 12, 2011).
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2. Scientific Evidence of the Drug's Pharmacological Effects, if Known

    According to DEA and HHS, the pharmacological activity of 
butonitazene, flunitazene, and metodesnitazene in humans is unknown. 
Preclinical studies show that these benzimidazole-opioids exhibit a 
pharmacological profile similar to that of morphine and fentanyl. As 
explained in detail in both DEA and HHS eight-factor analyses, data 
from binding studies show that these substances, similar to morphine 
and fentanyl, selectively bound to mu-opioid receptors.\10\ In opioid 
receptor functional assays, butonitazene, flunitazene, and 
metodesnitazene, similar to fentanyl and morphine, acted as mu-opioid 
receptor agonists.\11\ Further, data from preclinical studies using 
rodents showed that butonitazene, flunitazene, and metodesnitazene, 
similar to morphine and fentanyl, produced analgesic effects that can 
be attenuated by an opioid antagonist pre-treatment.12 13 
HHS concluded that, similar to morphine and fentanyl, butonitazene, 
flunitazene, and metodesnitazene produced analgesic effects via 
activation of mu-opioid receptors.
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    \10\ DEA-VA Interagency Agreement. ``In Vitro Receptor and 
Transporter Assays for Abuse Liability Testing for the DEA by the 
VA''. Binding and Functional Activity at Delta, Kappa and Mu Opioid 
Receptors. 2020. Unpublished data.
    \11\ DEA-VA Interagency Agreement. ``In Vitro Receptor and 
Transporter Assays for Abuse Liability Testing for the DEA by the 
VA''. Binding and Functional Activity at Delta, Kappa and Mu Opioid 
Receptors. 2021. Unpublished data.
    \12\ Gatch MB. Evaluation of Abuse Potential of Synthetic 
Opioids Using in Vivo Pharmacological Studies. Test of analgesic 
effects alone and in combination with naltrexone. Unpublished Data. 
2022.
    \13\ Paronis C. Evaluation of Synthetic Opioid Substances using 
Analgesia and Drug Discrimination Assays. Test of antinociceptive 
effects. Unpublished Data. 2021a.
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    Additionally, behavioral effects of butonitazene, flunitazene, and 
metodesnitazene were assessed using the drug discrimination model. Drug 
discrimination studies can be used to determine whether a test drug 
produces pharmacological effects (i.e., interoceptive stimulus effects) 
similar to those produced by a known drug of abuse. Drugs that produce 
stimulus effects similar to known drugs of abuse in animals are also 
likely to be abused by humans. As explained in detail in both DEA and 
HHS eight-factor analyses, data from drug discrimination

[[Page 25547]]

studies demonstrate that butonitazene,\14\ flunitazene,\15\ and 
metodesnitazene \16\ have stimulus properties that are similar to both 
morphine and fentanyl, schedule II drugs. Taken together, data from 
preclinical studies demonstrate that butonitazene, flunitazene, and 
metodesnitazene share similarities in their pharmacological effects and 
mechanism of action to the schedule II opioid drugs morphine and 
fentanyl.
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    \14\ Gatch, M. Butonitazene: Test of substitution for the 
discriminative stimulus effects of morphine (15DDHQ21F00000340, 
2021. Unpublished Data).
    \15\ Paronis, C. Flunitazene: Test of morphine-like 
discriminative stimulus effects (15DDHQ20P00000709, 2021b. 
Unpublished Data).
    \16\ Paronis, C. Metodesnitazene: Test of morphine-like 
discriminative stimulus effects (15DDHQ20P00000709, 2021c. 
Unpublished Data).
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3. The State of Current Scientific Knowledge Regarding the Drug or 
Other Substance

    Butonitazene, flunitazene, and metodesnitazene belong to the 2-
benzylbenzimidazole structural class. The chemical structures of these 
2-benzylbenzimidazoles contain a benzimidazole ring and a benzyl group 
at the benzimidazole 2-position. These benzimidazole-opioids are 
structurally related to several schedule I substances, including 
etonitazene. There are no FDA-approved marketing applications for drug 
products containing butonitazene, flunitazene, and metodesnitazene for 
any therapeutic indication in the United States or medical use in any 
other country. Further, there are no well-controlled clinical studies 
that have demonstrated the safety or efficacy for these substances. 
According to HHS, FDA concluded that butonitazene, flunitazene, and 
metodesnitazene have no currently accepted medical use in the United 
States. Similarly, DEA concludes that butonitazene, flunitazene, and 
metodesnitazene have no currently accepted medical use according to 
established DEA procedure and case law.

4. Its History and Current Pattern of Abuse

    In the late 1950s, the Swiss chemical company CIBA 
Aktiengesellschaft synthesized a group of benzimidazole derivatives 
with analgesic properties; \17\ however, the research did not lead to 
any medically approved analgesic products. These benzimidazole 
derivatives include schedule I substances, such as the synthetic 
opioids clonitazene, etonitazene, and isotonitazene. In 2019, 
isotonitazene emerged on the illicit drug market and was involved in 
numerous fatal overdose events; in August 2020, it was temporarily 
controlled as a schedule I substance under the CSA.\18\ Subsequently, 
additional six benzimidazole-opioids emerged on the illicit opioid drug 
market. In April 2022, DEA temporarily controlled these six 
benzimidazole-opioids as schedule I substances due, in part, to their 
involvement in numerous postmortem and toxicology cases.\19\ Law 
enforcement agencies have encountered butonitazene, flunitazene, and 
metodesnitazene in several solid (e.g., powder, rock, and tablet) 
forms. These substances are not approved for medical use anywhere in 
the world.
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    \17\ Hunger, A., Kebrle, J., Rossi, A., & Hoffmann, K. 
[Synthesis of analgesically active benzimidazole derivatives with 
basic substitutions]. Experientia, 1957 Oct 15;13(10), 400-401.
    \18\ 85 FR 51342 (Aug. 20, 2020).
    \19\ 87 FR 21556 (Apr. 12, 2022).
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    According to HHS, there are no FDA-approved drug products for 
butonitazene, flunitazene, and metodesnitazene in the United 
States.\20\ The appearance of these benzimidazole-opioids on the 
illicit drug market is similar to other synthetic opioids that are 
trafficked for their psychoactive effects. These three benzimidazole-
opioid substances are likely to be abused in the same manner as 
schedule I opioids, such as etonitazene, isotonitazene, and heroin. 
These substances have been identified as powders or tablets, typically 
of unknown purity or concentration. Between 2020 and 2021, 
butonitazene, flunitazene, and metodesnitazene emerged on the illicit 
synthetic drug market as evidenced by their identification in forensic 
drug seizures and in biological samples. Based on NFLIS-Drug data, law 
enforcement encounters of butonitazene, flunitazene, and 
metodesnitazene often included mixtures. Substances found in 
combination with some of these benzimidazole-opioids include other 
substances of abuse, such as heroin, fentanyl, fentanyl analogues, 
designer benzodiazepines, and cocaine.
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    \20\ Department of Health and Human Services. Basis for the 
Recommendation to Control Butonitazene, Etodesnitazene, Flunitazene, 
Metodesnitazene, N-Pyrrolidino Etonitazene, and Protonitazene and 
Their Salts in Schedule I of the Controlled Substances Act (November 
2023).
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5. The Scope, Duration, and Significance of Abuse

    Butonitazene, flunitazene, and metodesnitazene, similar to schedule 
I substances, such as etonitazene and isotonitazene, are synthetic 
opioids, and evidence suggests they are abused for their opioidergic 
effects. The abuse of these benzimidazole-opioids, similar to other 
synthetic opioids, has resulted in their identification in toxicology, 
post-mortem cases, and law enforcement encounters. Data from the 
toxicology analysis showed that butonitazene has been positively 
identified in three postmortem cases, flunitazene in four post mortem 
cases,\21\ and metodesnitazene in one case.\22\
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    \21\ Walton SE, Krotulski AJ, Logan BK. A Forward-Thinking 
Approach to Addressing the New Synthetic Opioid 2-
Benzylbenzimidazole Nitazene Analogs by Liquid Chromatography--
Tandem Quadrupole Mass Spectrometry (LC-QQQ-MS). J Anal Toxicol. 
2022 Mar 21;46(3):221-231.
    \22\ Metodesnitazene_092221_ToxicologyAnalyticalReport.pdf 
(cfsre.org).
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    Data from law enforcement suggest that butonitazene, flunitazene, 
and metodesnitazene are being abused in the United States as 
recreational drugs. The law enforcement encounters of these 
benzimidazole-opioids, as reported to NFLIS-Drug, included 130 exhibits 
since 2020. NFLIS-Drug registered 66 encounters of butonitazene from 7 
states, 60 encounters of flunitazene from 11 states, and 4 encounters 
of metodesnitazene from 3 states. Of the 66 reports involving 
butonitazene, fentanyl was co-identified in 24 cases. Flunitazene was 
commonly co-identified with metonitazene (n = 30) in fifty percent of 
the cases. Metodesnitazene was co-reported with diphenhydramine (n = 
2), fentanyl (n = 2), and heroin (n = 2).
    The identification of these benzimidazole-opioids in forensic and 
toxicology cases suggests they may be presented as a substitute for 
heroin or fentanyl and likely abused in the same manner as either of 
those substances. The population likely to be harmed by these 
benzimidazole-opioids appears to be the same as that harmed by other 
opioid substances, such as heroin, tramadol, fentanyl, and other 
synthetic opioid substances. This is evidenced by the types of other 
drugs co-identified in biological samples and law enforcement 
encounters. Law enforcement and toxicology reports demonstrate that 
butonitazene, flunitazene, and metodesnitazene are being abused, and 
that their use can produce serious adverse events that can lead to 
death. Because users of butonitazene, flunitazene, and metodesnitazene 
are likely to obtain these substances through unregulated sources, the 
identity, purity, and quantity of these substances are uncertain and 
likely to be inconsistent, thus posing significant adverse health risks 
to the end user. Individuals who initiate use of one or more of these 
benzimidazole-opioids are likely to be at risk of developing a 
substance use disorder, fatal or non-fatal

[[Page 25548]]

overdose, similar to that of other opioid analgesics (e.g., fentanyl, 
morphine, etc.).

6. What, if Any, Risk There Is to the Public Health

    The increase in opioid overdose deaths in the United States has 
been exacerbated recently by the availability of potent synthetic 
opioids on the illicit drug market. It is well established that 
substances that act as mu-opioid receptor agonists have a high 
potential for abuse and addiction and can induce dose-dependent 
respiratory depression. As with any mu-opioid receptor agonist, the 
potential health and safety risks for users of butonitazene, 
flunitazene, and metodesnitazene are high. Consistently, these three 
benzimidazole-opioids have been positively identified in toxicology 
cases. The public health risks associated with the abuse of mu-opioid 
receptor agonists are well established.
    The introduction of synthetic opioids, such as butonitazene, 
flunitazene, and metodesnitazene, into the illicit drug market may 
serve as a portal to problematic opioid use for those seeking these 
opioids. Evidence from toxicology reports show that poly-substance 
abuse remains common in fatalities associated with the abuse of some of 
these benzimidazole-opioids.

7. Its Psychic or Physiological Dependence Liability

    Butonitazene, flunitazene, and metodesnitazene have pharmacological 
effects similar to those of schedule I benzimidazole-opioids such as 
clonitazene, etonitazene, and isotonitazene. According to HHS, 
analgesic studies conducted on these benzimidazole-opioids show that 
they produce effects similar to that of either morphine or fentanyl, 
both schedule II narcotic drugs. Although there are no clinical studies 
that have evaluated the dependence potential of these substances, they 
are mu-opioid receptor agonists, and it is well known that the 
discontinuation of the use of mu-opioid receptor agonists, such as 
fentanyl and morphine, causes withdrawal symptoms indicative of 
physical dependence. The similarities in the pharmacological profile 
and pattern of abuse of these benzimidazole-opioids, heroin, and 
fentanyl are indicative of their similar potential to have psychic and 
physiological dependence liability.

8. Whether the Substance Is an Immediate Precursor of a Substance 
Already Controlled Under the CSA

    Butonitazene, flunitazene, and metodesnitazene are not immediate 
precursors of a substance controlled under the CSA, as defined by 21 
U.S.C. 802(23).
    Conclusion:
    After considering the scientific and medical evaluation and 
accompanying scheduling recommendation of HHS, and DEA's own eight-
factor analysis, DEA finds that these facts and all relevant data 
constitute substantial evidence of potential for abuse of butonitazene, 
flunitazene, and metodesnitazene. As such, DEA proposes to permanently 
schedule these three benzimidazole-opioids as schedule I controlled 
substances under the CSA.

Proposed Determination of Appropriate Schedule

    The CSA establishes five schedules of controlled substances known 
as schedules I, II, III, IV, and V. The CSA also outlines the findings 
required to place a drug or other substance in any particular 
schedule.\23\ After consideration of the analysis and recommendation of 
the Assistant Secretary for HHS and review of all other available data, 
the Administrator of DEA, pursuant to 21 U.S.C. 811(a) and 812(b)(1), 
finds that:
---------------------------------------------------------------------------

    \23\ 21 U.S.C. 812(b).
---------------------------------------------------------------------------

    (1) Butonitazene, flunitazene, and metodesnitazene have a high 
potential for abuse. Butonitazene, flunitazene, and metodesnitazene, 
similar to etonitazene and fentanyl, are mu-opioid receptor agonists. 
These three benzimidazole-opioids have analgesic effects and these 
effects are mediated by mu-opioid receptor agonism. HHS states that 
substances that produce mu-opioid receptor agonist effects in the 
central nervous system are considered as having a high potential for 
abuse (e.g. morphine and fentanyl). Data obtained from drug 
discrimination studies indicate that butonitazene, flunitazene, and 
metodesnitazene fully substituted for the discriminative stimulus 
effects of morphine.
    (2) Butonitazene, flunitazene, and metodesnitazene have no 
currently accepted medical use in the United States. There are no FDA-
approved drug products for butonitazene, flunitazene, and 
metodesnitazene in the United States. There are no known therapeutic 
applications for these benzimidazole-opioids and DEA is not aware of 
any currently accepted medical uses for these substances in the United 
States.\24\
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    \24\ HHS and DEA both applied a five-part test for currently 
accepted medical use as part of this scheduling action. Under that 
test, with respect to a drug that has not been approved by the Food 
and Drug Administration, to have a currently accepted medical use in 
treatment in the United States, all of the following must be 
demonstrated: i. The drug's chemistry must be known and 
reproducible; ii. there must be adequate safety studies; iii. there 
must be adequate and well-controlled studies proving efficacy; iv. 
the drug must be accepted by qualified experts; and v. the 
scientific evidence must be widely available. Marijuana Scheduling 
Petition; Denial of Petition; Remand, 57 FR 10499 (Mar. 26, 1992), 
pet. for rev. denied, Alliance for Cannabis Therapeutics v. Drug 
Enforcement Admin., 15 F.3d 1131, 1135 (D.C. Cir. 1994).
---------------------------------------------------------------------------

    (3) There is a lack of accepted safety for use of butonitazene, 
flunitazene, and metodesnitazene under medical supervision. Because 
these substances have no FDA-approved medical use and have not been 
investigated as new drugs, their safety for use under medical 
supervision is not determined.
    Based on these findings, the Administrator of DEA concludes that 
butonitazene, flunitazene, and metodesnitazene, including their 
isomers, esters, ethers, salts, and salts of isomers, esters, and 
ethers whenever the existence of such isomers, esters, ethers, and 
salts is possible within the specific chemical designation, warrant 
continued control in schedule I of the CSA.\25\
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    \25\ 21 U.S.C. 812(b)(1).
---------------------------------------------------------------------------

Requirements for Handling Butonitazene, Flunitazene, and 
Metodesnitazene

    As discussed above, these three substances are currently subject to 
a temporary scheduling order, which added them to schedule I. If this 
rule is finalized as proposed, butonitazene, flunitazene, and 
metodesnitazene would be subject, on a permanent basis, to the CSA's 
schedule I regulatory controls and administrative, civil, and criminal 
sanctions applicable to the manufacture, distribution, reverse 
distribution, dispensing, importation, exportation, engagement in 
research, and conduct of instructional activities or chemical analysis 
with, and possession of schedule I substances, including the following:
    1. Registration. Any person who handles (manufactures, distributes, 
reverse distributes, dispenses, imports, exports, engages in research, 
or conducts instructional activities or chemical analysis with, or 
possesses) butonitazene, flunitazene, and metodesnitazene must be 
registered with DEA to conduct such activities pursuant to 21 U.S.C. 
822, 823, 957, and 958, and in accordance with 21 CFR parts 1301 and 
1312. Security. Butonitazene, flunitazene, and metodesnitazene are 
subject to schedule I security requirements and must be handled and 
stored pursuant to 21 U.S.C. 821, 823, and 871(b), and in accordance 
with 21 CFR 1301.71 through 1301.76. Non-practitioners

[[Page 25549]]

handling these three substances also must comply with the screening 
requirements of 21 CFR 1301.90 through 1301.93.
    3. Labeling and Packaging. All labels and labeling for commercial 
containers of butonitazene, flunitazene, and metodesnitazene must 
comply with 21 U.S.C. 825 and 958(e), and be in accordance with 21 CFR 
part 1302.
    4. Quota. Only registered manufacturers are permitted to 
manufacture butonitazene, flunitazene, and metodesnitazene in 
accordance with a quota assigned pursuant to 21 U.S.C. 826, and in 
accordance with 21 CFR part 1303.
    5. Inventory. Any person registered with DEA to handle 
butonitazene, flunitazene, and metodesnitazene must have an initial 
inventory of all stocks of controlled substances (including these 
substances) on hand on the date the registrant first engages in the 
handling of controlled substances pursuant to 21 U.S.C. 827 and 958, 
and in accordance with 21 CFR 1304.03, 1304.04, and 1304.11.
    After the initial inventory, every DEA registrant must take a new 
inventory of all stocks of controlled substances (including 
butonitazene, flunitazene, and metodesnitazene) on hand every two years 
pursuant to 21 U.S.C. 827 and 958, and in accordance with 21 CFR 
1304.03, 1304.04, and 1304.11.
    6. Records and Reports. Every DEA registrant must maintain records 
and submit reports with respect to butonitazene, flunitazene, and 
metodesnitazene, pursuant to 21 U.S.C. 827, 832(a), and 958(e), and in 
accordance with 21 CFR 1301.74(b) and (c) and 1301.76(b) and 21 CFR 
parts 1304, 1312, and 1317. Manufacturers and distributors would be 
required to submit reports regarding butonitazene, flunitazene, and 
metodesnitazene to the Automation of Reports and Consolidated Order 
System pursuant to 21 U.S.C. 827, and in accordance with 21 CFR parts 
1304 and 1312.
    7. Order Forms. Every DEA registrant who distributes butonitazene, 
flunitazene, and metodesnitazene must comply with the order form 
requirements, pursuant to 21 U.S.C. 828 and 21 CFR part 1305.
    8. Importation and Exportation. All importation and exportation of 
butonitazene, flunitazene, and metodesnitazene must comply with 21 
U.S.C. 952, 953, 957, and 958, and in accordance with 21 CFR part 1312.
    9. Liability. Any activity involving butonitazene, flunitazene, and 
metodesnitazene not authorized by, or in violation of, the CSA or its 
implementing regulations is unlawful, and may subject the person to 
administrative, civil, and/or criminal sanctions.

Regulatory Analyses

Executive Orders 12866 (Regulatory Planning and Review), 13563 
(Improving Regulation and Regulatory Review), and 14094 (Modernizing 
Regulatory Review)

    In accordance with 21 U.S.C. 811(a), this proposed scheduling 
action is subject to formal rulemaking procedures done ``on the record 
after opportunity for a hearing,'' which are conducted pursuant to the 
provisions of 5 U.S.C. 556 and 557. The CSA sets forth the criteria for 
scheduling a drug or other substance. Such actions are exempt from 
review by the Office of Management and Budget (OMB) pursuant to section 
3(d)(1) of Executive Order (E.O.) 12866 and the principles reaffirmed 
in E.O. 13563. E.O. 14094 modernizes the regulatory review process to 
advance policies that promote the public interest and address national 
priorities.

Executive Order 12988, Civil Justice Reform

    This proposed regulation meets the applicable standards set forth 
in sections 3(a) and 3(b)(2) of E.O. 12988 to eliminate drafting errors 
and ambiguity, minimize litigation, provide a clear legal standard for 
affected conduct, and promote simplification and burden reduction.

Executive Order 13132, Federalism

    This proposed rulemaking does not have federalism implications 
warranting the application of E.O. 13132. The proposed rule does not 
have substantial direct effects on the states, on the relationship 
between the National Government and the States, or the distribution of 
power and responsibilities among the various levels of government.

Executive Order 13175, Consultation and Coordination With Indian Tribal 
Governments

    This proposed rule does not have tribal implications warranting the 
application of E.O. 13175. It does not have substantial direct effects 
on one or more Indian tribes, on the relationship between the Federal 
Government and Indian tribes, or on the distribution of power and 
responsibilities between the Federal Government and Indian tribes.

Regulatory Flexibility Act

    The Administrator, in accordance with the Regulatory Flexibility 
Act, 5 U.S.C. 601-612, has reviewed this rule and, by approving it, 
certifies that it will not have a significant economic impact on a 
substantial number of small entities.
    On April 12, 2022, DEA published an order to temporarily place 
seven benzimidazole-opioids in schedule I of the CSA pursuant to the 
temporary scheduling provisions of 21 U.S.C. 811(h). DEA estimates that 
all entities handling or planning to handle butonitazene, flunitazene, 
and metodesnitazene have already established and implemented systems 
and processes required to handle these substances.
    There are currently 45 registrations authorized to specifically 
handle butonitazene, flunitazene, or metodesnitazene, as well as 1,239 
registered analytical labs and 861 researchers that are authorized to 
handle schedule I controlled substances generally. These 45 
registrations represent 31 entities. A review of the 45 registrations 
indicates that all entities that currently handle butonitazene, 
flunitazene, and metodesnitazene also handle other schedule I 
controlled substances and have established and implemented (or 
maintained) systems and processes required to handle these substances. 
Therefore, DEA anticipates this proposed rule will impose minimal or no 
economic impact on any affected entities; and thus, will not have a 
significant economic impact on any affected small entity. Therefore, 
DEA has concluded that this proposed rule will not have a significant 
economic impact on a substantial number of small entities.

Unfunded Mandates Reform Act of 1995

    In accordance with the Unfunded Mandates Reform Act (UMRA) of 1995, 
2 U.S.C. 1501 et seq., DEA has determined and certifies that this 
action would not result in any Federal mandate that may result ``in the 
expenditure by State, local, and tribal governments, in the aggregate, 
or by the private sector, of $100,000,000 or more (adjusted annually 
for inflation) in any 1 year. . . .'' Therefore, neither a Small 
Government Agency Plan nor any other action is required under UMRA of 
1995.

Paperwork Reduction Act of 1995

    This proposed rule would not impose a new collection or modify an 
existing collection of information under the Paperwork Reduction Act of 
1995.\26\ Also, this proposed rule would not impose new or modify 
existing recordkeeping or reporting requirements on state or local 
governments,

[[Page 25550]]

individuals, businesses, or organizations. However, this proposed rule 
would require compliance with the following existing OMB collections: 
1117-0003, 1117-0004, 1117-0006, 1117-0008, 1117-0009, 1117-0010, 1117-
0012, 1117-0014, 1117-0021, 1117-0023, 1117-0029, and 1117-0056. An 
agency may not conduct or sponsor, and a person is not required to 
respond to, a collection of information unless it displays a currently 
valid OMB control number.
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    \26\ 44 U.S.C. 3501-3521.
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List of Subjects in 21 CFR Part 1308

    Administrative practice and procedure, Drug traffic control, 
Reporting and recordkeeping requirements.

Signing Authority

    This document of the Drug Enforcement Administration was signed on 
April 5, 2024, by Administrator Anne Milgram. That document with the 
original signature and date is maintained by DEA. For administrative 
purposes only, and in compliance with requirements of the Office of the 
Federal Register, the undersigned DEA Federal Register Liaison Officer 
has been authorized to sign and submit the document in electronic 
format for publication, as an official document of DEA. This 
administrative process in no way alters the legal effect of this 
document upon publication in the Federal Register.

Scott Brinks,
Federal Register Liaison Officer, Drug Enforcement Administration.

    For the reasons set out above, DEA proposes to amend 21 CFR part 
1308 as follows:

PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES

0
1. The authority citation for 21 CFR part 1308 continues to read as 
follows:

    Authority: 21 U.S.C. 811, 812, 871(b), 956(b), unless otherwise 
noted.

0
2. In Sec.  1308.11:
0
a. Redesignate paragraphs (b)(62) through (107) as paragraphs (b)(66) 
through (110);
0
b. Redesignate paragraphs (b)(44) through (62) as paragraphs (b)(46) 
through (64);
0
c. Redesignate paragraphs (b)(24) through (43) as paragraphs (b)(25) 
through (44);
0
d. Add new paragraphs (b)(24), (45), and (65); and
0
e. Remove and reserve paragraphs (h)(50), (52), and (53).
    The additions to read as follows:


Sec.  1308.11   Schedule I.

* * * * *
    (b) * * *

 
                              * * * * * * *
(24) Butonitazene (2-(2-(4-butoxybenzyl)-5-nitro-1H-benzimidazol-   9751
 1-yl)-N,N-diethylethan-1-amine)................................
 
                              * * * * * * *
(45) Flunitazene (N,N-diethyl-2-(2-(4-fluorobenzyl)-5-nitro-1H-     9756
 benzimidazol-1-yl)ethan-1-amine)...............................
 
                              * * * * * * *
(65) Metodesnitazene (N,N-diethyl-2-(2-(4-methoxybenzyl)-1H-        9764
 benzimidazol-1-yl)ethan-1-amine)...............................
 

* * * * *
[FR Doc. 2024-07694 Filed 4-10-24; 8:45 am]
BILLING CODE 4410-09-P