Proposed Rule2024-07694
Schedules of Controlled Substances: Placement of Butonitazene, Flunitazene, and Metodesnitazene Substances in Schedule I
Primary source
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Published
April 11, 2024
Issuing agencies
Justice DepartmentDrug Enforcement Administration
Abstract
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.
Full Text
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<title>Federal Register, Volume 89 Issue 71 (Thursday, April 11, 2024)</title>
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[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 [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[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.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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.
<bullet> 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.
<bullet> 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.
<bullet> 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:
<bullet> butonitazene (2-(2-(4-butoxybenzyl)-5-nitro-1H-
benzimidazol-1-yl)-N,N-diethylethan-1-amine),
<bullet> flunitazene (N,N-diethyl-2-(2-(4-fluorobenzyl)-5-nitro-1H-
benzimidazol-1-yl)ethan-1-amine),
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>, 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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.<SUP>12 13</SUP>
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
(<a href="http://cfsre.org">cfsre.org</a>).
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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:
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\23\ 21 U.S.C. 812(b).
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(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).
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(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).
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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
</pre></body>
</html>Indexed from Federal Register on April 11, 2024.
This is legal information, not legal advice. Laws vary by jurisdiction and change frequently. Always verify current law with official sources and consult a licensed attorney in your jurisdiction for advice on your specific situation.