Schedules of Controlled Substances: Placement of Clonazolam, Diclazepam, Etizolam, Flualprazolam, and Flubromazolam in Schedule I of the Controlled Substances Act

of this treaty.

To meet the minimum requirements of this treaty and to confront these emerging substances, DEA published an order in the Federal Register on July 26, 2023, temporarily placing clonazolam, diclazepam, etizolam, flualprazolam, and flubromazolam in schedule I of the CSA based upon a finding that these substances pose an imminent hazard to the public safety under 21 U.S.C. 811(h)(1). 8 That temporary order was effective upon the date of publication.

8 Schedules of Controlled Substances: Temporary Placement of Etizolam, Flualprazolam, Clonazolam,

Flubromazolam, and Diclazepam in Schedule I, 88 FR 48112 (July 26, 2023).

Pursuant to 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 proceedings under 21 U.S.C. 811(a)(1) with the respect to the temporarily controlled substance. The temporary control of these five substances is set to expire on July 26, 2025. DEA is publishing a temporary scheduling order to extend the temporary schedule I status of these five substances elsewhere in this issue of the Federal Register , which will extend the temporary scheduling of these substances for one year, or until the permanent scheduling action for these substances is completed, whichever occurs first.

The Acting Administrator, on his own motion pursuant to 21 U.S.C. 811(a), is initiating proceedings to permanently schedule clonazolam, diclazepam, etizolam, flualprazolam, and flubromazolam, including their salts, isomers, and salts of isomers, whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation. DEA gathered and reviewed the available information regarding the pharmacology, chemistry, trafficking, actual abuse, pattern of abuse, and the relative potential for abuse for these substances

hat individuals are taking the five designer benzodiazepines in amounts sufficient to create a hazard to their health, the safety of other individuals, or the community. The U.S. Food and Drug Administration (FDA) has not approved clonazolam, diclazepam, etizolam, flualprazolam, and flubromazolam under the FD&C Act, and thus, these five substances not legally marketed as drugs in the United States. Therefore, HHS has not identified significant diversion of these substances from legitimate drug channels in the United States and is not aware of any research or legitimate manufacturing activities in the United States from which these substances can be diverted. These substances are thus presumed to be obtained from clandestine manufacturing or diverted from international countries for nonmedical use, on an individual's own initiative, rather than on the basis of medical advice from a licensed practitioner.

In addition, law enforcement data indicate that clonazolam, diclazepam, etizolam, flualprazolam, and flubromazolam have been encountered in the U.S. illicit drug market. DEA's National Forensic Laboratory Information System (NFLIS) registered a collective total of 50,015 reports, from all 50 states and Washington, DC, pertaining to the trafficking, distribution, and abuse of the five designer benzodiazepines. 10 As such,

these data suggest that clonazolam, diclazepam, etizolam, flualprazolam, and flubromazolam are being abused and thus pose safety hazards to the health of users or the community.

10 The National Forensic Laboratory Information System (NFLIS) represents an important resource in monitoring illicit drug trafficking, including the diversion of legally manufactured pharmaceuticals into illegal markets. NFLIS is a comprehensive information system that includes data from forensic laboratories that handle more than 96% of an estimated 1.0 million distinct annual federal, state, and local drug analysis cases. NFLIS includes drug chemistry results from completed analyses only

in monitoring illicit drug trafficking, including the diversion of legally manufactured pharmaceuticals into illegal markets. NFLIS is a comprehensive information system that includes data from forensic laboratories that handle more than 96% of an estimated 1.0 million distinct annual federal, state, and local drug analysis cases. NFLIS includes drug chemistry results from completed analyses only.

While NFLIS 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). NFLIS data were queried on May 29, 2025.

Lastly, based on available data, these five designer benzodiazepines are structurally and pharmacologically related to classical benzodiazepines ( e.g., alprazolam), which are positive allosteric modulators of γ-aminobutyric acid type A (GABA A ) receptors. This allosteric modulation is thought to be responsible for the sedative-hypnotic, subjective effects commonly reported on drug user forums. According to HHS, in vitro binding data, animal behavioral data, and anecdotal reports involving human use indicate that the five designer benzodiazepines bind to GABA A receptors and produce similar drug effects, as well as adverse effects, associated with the benzodiazepine class, which have a potential for abuse. Thus, the five designer benzodiazepines have a similar potential for abuse and present a hazard to the health and safety of individuals and the community.

2. Scientific Evidence of the Drug's Pharmacological Effects, if Known

Published scientific data on the functional activity of the five designer benzodiazepines is limited; however, in vitro binding and animal behavioral studies demonstrate that the pharmacological mechanisms of action of these five substances are similar to those of the benzodiazepine drug class

individuals and the community.

2. Scientific Evidence of the Drug's Pharmacological Effects, if Known

Published scientific data on the functional activity of the five designer benzodiazepines is limited; however, in vitro binding and animal behavioral studies demonstrate that the pharmacological mechanisms of action of these five substances are similar to those of the benzodiazepine drug class. These substances bind to the GABA A receptors with high affinity; this affinity increases in the presence of GABA and is blocked by the GABA A receptor antagonist, flumazenil. 11 In addition, in drug discrimination experiments, 12 the data demonstrate that these substances fully substitute for the discriminative stimulus effects of midazolam, a schedule IV benzodiazepine. 13

11 In vitro pharmacology data was collected through the DEA-Veterans Affairs interagency agreement, “In Vitro Receptor and Transporter Assays for Abuse Liability Testing for the DEA by the VA.”

12 Drug discrimination is widely used to determine whether a new test drug or substance is pharmacologically similar to a known drug of abuse. The discriminative stimulus effects of a given drug in animals and its subjective effects in humans are strongly correlated. See Balster, R. L., & Bigelow, G. E. (2003). Guidelines and methodological reviews concerning drug abuse liability assessment. Drug and alcohol dependence, 70 (3 Suppl), S13-S40. https://doi.org/10.1016/s0376-8716(03)00097-8. See also Schuster, C. R., & Johanson, C. E. (1988). Relationship between the discriminative stimulus properties and subjective effects of drugs. Psychopharmacology series, 4, 161-175. https://doi.org/10.1007/978-3-642-73223-2_13. See also Solinas, M., Panlilio, L. V., Justinova, Z., Yasar, S., & Goldberg, S. R. (2006). Using drug-discrimination techniques to study the abuse-related effects of psychoactive drugs in rats. Nature protocols, 1 (3), 1194-1206. https://doi.org/10.1038/nprot.2006.167

the Drug or Other Substance

The five designer benzodiazepines share structural similarities with other substances of the benzodiazepine class. Benzodiazepines are named after their parent structure, which is formed from the fusion of two ring systems—the benzene ring and diazepine ring. Diclazepam contains this parent structure and is further modified with the addition of a methyl and keto group. Clonazolam, flualprazolam, and flubromazolam are considered to be part of the class of benzodiazepines known as triazolobenzodiazepines because they contain the parent structure and the addition of a triazole ring fused to the diazepine ring. Etizolam is considered to be a thienotriazolodiazepine because it contains the triazolo-diazepine fused rings, but with a thiophene ring replacing the benzene ring. Although etizolam is structurally different from a classical benzodiazepine, etizolam has similar pharmacological and chemical properties and thus considered to be an analog of benzodiazepines. 14 In addition, all five designer benzodiazepines have a pendant phenyl group that is further substituted with a halogen in the ortho position.

14 See Sanna, E., Pau, D., Tuveri, F., Massa, F., Maciocco, E., Acquas, C., Floris, C., Fontana, S.N., Maira, G., & Biggio, G. (1999). Molecular and neurochemical evaluation of the effects of etizolam on GABAA receptors under normal and stress conditions. Arzneimittel-Forschung, 49 (2), 88-95. https://doi.org/10.1055/s-0031-1300366.

4. Its History and Current Pattern of Abuse

Classical benzodiazepines have been extensively prescribed in the United States; however, these medications have also been used non-therapeutically and recreationally, with initial reports of abuse soon after pharmaceutical development (Loveridge, 1981; Woody et al., 1975). Unlike these classical benzodiazepines that have FDA approval, clonazolam, diclazepam, etizolam, flualprazolam, and flubromazolam have no legitimate channel as marketed drug products in the United States

s; however, these medications have also been used non-therapeutically and recreationally, with initial reports of abuse soon after pharmaceutical development (Loveridge, 1981; Woody et al., 1975). Unlike these classical benzodiazepines that have FDA approval, clonazolam, diclazepam, etizolam, flualprazolam, and flubromazolam have no legitimate channel as marketed drug products in the United States. Despite this, available data from user reports, toxicological cases, scientific literature, and law enforcement seizures indicate that each of these substances appear on the illicit drug market and are trafficked for their psychoactive effects. Based on these available data, the five designer benzodiazepines are often used alone or in combination with other substances, such as fentanyl, traditional and NPS benzodiazepines, NPS opioids, and stimulants. The five designer benzodiazepines substances have been encountered in various forms ( e.g., powder, tablet, liquid), are primarily reported as orally consumed (at doses less than 4 mg), and lead to toxicity and other adverse health consequences, including death.

The misuse and abuse of benzodiazepines have been demonstrated and are well-characterized. 15 According to the Substance Abuse and Mental Health Services Administration's National Survey on Drug Use and Health 2023 annual report, 16 4.7 million people reported misusing prescription tranquilizers or sedatives ( e.g., benzodiazepines) in the past year. Of the 4.7 million people who reported misusing prescription tranquilizers or sedatives in the past year in 2023, 4.0 million individuals were aged 26 years

or older and included both males and females. Drug user reports indicate that the population likely to abuse the five designer benzodiazepines appears to be the same as those abusing prescription benzodiazepines, barbiturates, and other sedative-hypnotic substances

who reported misusing prescription tranquilizers or sedatives in the past year in 2023, 4.0 million individuals were aged 26 years

or older and included both males and females. Drug user reports indicate that the population likely to abuse the five designer benzodiazepines appears to be the same as those abusing prescription benzodiazepines, barbiturates, and other sedative-hypnotic substances. This is reflected in available reports for toxicological cases involving flualprazolam; in these cases, users had an average age of 32 years and included both males and females. 17 In addition, available reports for toxicological cases involving etizolam and flubromazolam indicate that users had an average age of 39 years and included both males and females. 18 These users are likely to obtain the substances through unregulated sources and, therefore, with uncertain and inconsistent identity, purity, and quantity of these substances. Consequently, this poses significant, adverse health risks to the end user.

15 See Votaw, V.R., Geyer, R., Rieselbach, M.M., & McHugh, R.K. (2019). The epidemiology of benzodiazepine misuse: A systematic review. Drug and alcohol dependence, 200, 95-114. https://doi.org/10.1016/j.drugalcdep.2019.02.033 .

16 Key substance use and mental health indicators in the United States: Results from the 2023 National Survey on Drug Use and Health (HHS Publication No. PEP24-07-021, NSDUH Series H-59). Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. https://www.samhsa.gov/data/report/2023-nsduh-annual-national-report.

17 See Krotulski, A.J., Papsun, D.M., Homan, J.W., Nelson, L., & Logan, B.K. (2019). Flualprazolam: Potent benzodiazepine identified among death and impaired driving cases in the U.S. (December 2019 Report). Center for Forensic Science Research and Education. https://www.cfsre.org/images/content/reports/public_alerts/2019.12.05.Public-Alert_Flualprazolam_NPS-Discovery_120519.pdf

ational-report.

17 See Krotulski, A.J., Papsun, D.M., Homan, J.W., Nelson, L., & Logan, B.K. (2019). Flualprazolam: Potent benzodiazepine identified among death and impaired driving cases in the U.S. (December 2019 Report). Center for Forensic Science Research and Education. https://www.cfsre.org/images/content/reports/public_alerts/2019.12.05.Public-Alert_Flualprazolam_NPS-Discovery_120519.pdf .

18 See Aldy, K., Mustaquim, D., Campleman, S., Meyn, A., Abston, S., Krotulski, A., Logan, B., Gladden, M.R., Hughes, A., Amaducci, A., Shulman, J., Schwarz, E., Wax, P., Brent, J., Manini, A., & Toxicology Investigators Consortium Fentalog Study Group (2021). Notes from the field: Illicit benzodiazepines detected in patients evaluated in emergency departments for suspected opioid overdose—Four States, October 6, 2020-March 9, 2021. MMWR. Morbidity and mortality weekly report, 70 (34), 1177-1179. https://doi.org/10.15585/mmwr.mm7034a4 .

5. The Scope, Duration, and Significance of Abuse

Law enforcement data, including data from DEA's NFLIS, indicate that the abuse of the five designer benzodiazepines have become increasingly widespread across the United States. NFLIS-Drug 19 registered a collective total of 50,015 reports, from all 50 states and Washington, DC, pertaining to the trafficking, distribution, and abuse of the five designer benzodiazepines. Through May 2025, NFLIS-Drug reported 16,326 total encounters of clonazolam since 2015; 706 of diclazepam since 2014; 19,650 of etizolam since 2002; 10,468 of flualprazolam since 2004; and 2,865 of flubromazolam since 2015.

19 DEA's National Forensic Laboratory Information System (NFLIS) is a comprehensive information system that collects scientifically verified data on drug items and cases submitted to and analyzed by participating federal, state, and local forensic drug laboratories within the United States. NFLIS-Drug, a component of NFLIS, includes drug chemistry results from completed analyses only

since 2015.

19 DEA's National Forensic Laboratory Information System (NFLIS) is a comprehensive information system that collects scientifically verified data on drug items and cases submitted to and analyzed by participating federal, state, and local forensic drug laboratories within the United States. NFLIS-Drug, a component of NFLIS, includes drug chemistry results from completed analyses only. While NFLIS data are 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). NFLIS-Drug data were queried on May 29, 2025. NFLIS-Drug reports are still pending for 2024 and 2025 due to normal lag time.

In addition, HHS evaluated reports of human exposure to benzodiazepines to U.S. poison centers and included data over a 10-year period (2012-2021). According to HHS, among the five designer benzodiazepines, etizolam had the highest number of total exposure cases (n = 878) and total abuse cases (n = 377), followed by clonazolam (n = 343 and n = 162, respectively), flubromazolam (n = 96; n = 47), diclazepam (n = 78; n = 32), and flualprazolam (n = 67; n = 30). 20 Moreover, many toxicological cases have involved these five substances, including cases submitted to and analyzed by DEA's Toxicology Testing Program (DEA TOX). 21 Through May 2025, DEA TOX detected clonazolam in 11 cases since 2019, metabolite 8-amino clonazolam 22 in 57 cases since 2021, etizolam in 16 cases since 2019, flualprazolam in 24 cases since 2019, and flubromazolam in 6 cases since 2020. Similarly, according to HHS, the National Medical Service Labs detected clonazolam (n = 14), diclazepam (n = 40), etizolam (n = 772), and flubromazolam (n = 151) among 131,883 postmortem blood samples from January 1, 2018, through June 30, 2020

amino clonazolam 22 in 57 cases since 2021, etizolam in 16 cases since 2019, flualprazolam in 24 cases since 2019, and flubromazolam in 6 cases since 2020. Similarly, according to HHS, the National Medical Service Labs detected clonazolam (n = 14), diclazepam (n = 40), etizolam (n = 772), and flubromazolam (n = 151) among 131,883 postmortem blood samples from January 1, 2018, through June 30, 2020. 23 The Center for Forensic Science Research and Education also reported steady increases in postmortem cases and toxicology reports associated with clonazolam, etizolam, flualprazolam, and flubromazolam through June 2022. 24 Collectively, these data strongly suggest that the clonazolam, diclazepam, etizolam, flualprazolam, and flubromazolam are increasingly abused in the United States.

20 See HHS's scientific and medical evaluation, entitled “Basis for the Recommendation to Control Clonazolam, Diclazepam, Etizolam, Flualprazolam, and Flubromazolam, and Their Salts, in Schedule I of the Controlled Substances Act.”

21 DEA's Toxicology Testing Program (DEA TOX) is a surveillance program that aims to detect novel psychoactive substances (NPS) in fatal and nonfatal overdose cases within the United States. From these cases, biological samples, as well as drug paraphernalia (on limited occasions), are submitted for analysis by hospitals, medical examiners, poison centers, and law enforcement nationwide. DEA TOX data include confirmed detections of NPS through the data query date, May 27, 2025.

22 The amino metabolite of clonazolam has been noted in literature as both 7-aminoclonazolam and 8-aminoclonazolam; however, the proper nomenclature is 8-aminoclonazolam, based on the International Union of Pure and Applied Chemistry (IUPAC) rules for a triazolobenzodiazepine. See Maskell, P.D., Parks, C., Button, J., Liu, H., & McKeown, D.A. (2021). Clarification of the correct nomenclature of the amino metabolite of clonazolam: 8-Aminoclonazolam. Journal of analytical toxicology, 45 (2), e1-e2

minoclonazolam; however, the proper nomenclature is 8-aminoclonazolam, based on the International Union of Pure and Applied Chemistry (IUPAC) rules for a triazolobenzodiazepine. See Maskell, P.D., Parks, C., Button, J., Liu, H., & McKeown, D.A. (2021). Clarification of the correct nomenclature of the amino metabolite of clonazolam: 8-Aminoclonazolam. Journal of analytical toxicology, 45 (2), e1-e2. https://doi.org/10.1093/jat/bkaa169 .

23 The National Medical Service (NMS) Labs is a reference laboratory that provides clinical and postmortem toxicological testing. NMS Labs data does not include cause-of-death data. According to HHS, FDA contracted NMS Labs (U.S. Food and Drug Administration Solicitation 75F40119R00070) to receive a study report (Loperamide Postmortem Toxicology, November 6, 2020) that tabulated the number of blood specimens in which a specific substance was detected, using liquid chromatography-time-of-flight mass spectrometry, from January 1, 2018 through June 30, 2020.

24 The Center for Forensic Science Research and Education's quarterly trend reports are available online at https://www.cfsre.org/nps-discovery/trend-reports/nps-benzodiazepines/report/49?trend_type_id=1 (last accessed June 3, 2025).

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

The increase in benzodiazepine-related overdoses in the United States has been exacerbated by the availability of NPS benzodiazepines on the illicit drug market. Public health risks associated with clonazolam, diclazepam, etizolam, flualprazolam, and flubromazolam abuse relate to their pharmacological similarities with known benzodiazepines. These similarities result in similar adverse reactions in humans and expectedly include CNS depressant-like effects, such as slurred speech, ataxia, altered mental state, and respiratory depression

ific and medical evaluation and accompanying 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 clonazolam, diclazepam, etizolam, flualprazolam, and flubromazolam. As such, DEA proposes to permanently schedule these five designer benzodiazepines as 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. 25 After consideration of the analysis and recommendation of the Assistant Secretary of HHS and review of all other available data, the Acting Administrator of DEA, pursuant to 21 U.S.C. 811(a) and 812(b)(1), finds that:

25 21 U.S.C. 812(b).

(1) Clonazolam, diclazepam, etizolam, flualprazolam, and flubromazolam have a high potential for abuse. These five designer benzodiazepines are pharmacologically similar to classical benzodiazepines ( e.g., diazepam), which have been shown to produce dependence and are abused by millions of individuals in the United States. In vitro binding affinity and functional activity studies, as well as in vivo drug discrimination studies, demonstrate that these substances are highly potent positive allosteric modulators of GABA A receptors—a mechanism of action that accounts for the inhibitory effects of GABA, decreased neuronal activity, and result in the pharmacological properties of the benzodiazepine class. These pharmacological properties include CNS depressant effects, such as anxiolytic, amnesic, anticonvulsant, sedative-hypnotic, respiratory depressant, and muscle relaxant effects. This finding is consistent with drug abuse patterns and adverse outcomes from epidemiological data sources. Thus, these five substances have a high potential for abuse.

ological properties of the benzodiazepine class. These pharmacological properties include CNS depressant effects, such as anxiolytic, amnesic, anticonvulsant, sedative-hypnotic, respiratory depressant, and muscle relaxant effects. This finding is consistent with drug abuse patterns and adverse outcomes from epidemiological data sources. Thus, these five substances have a high potential for abuse.

(2) Clonazolam, diclazepam, etizolam, flualprazolam, and flubromazolam have no currently accepted medical use in treatment in the United States. According to HHS, FDA has not approved a marketing application for clonazolam, diclazepam, etizolam, flualprazolam, or flubromazolam. In addition, there are no adequate and well-controlled clinical studies for any of these substances, and there are no well-defined finished dosage forms for any of these substances. Furthermore, these five substances have no known therapeutic applications in the United States. Thus, these five substances have no currently accepted medical use in treatment in the United States. 26

26 Pursuant to 21 U.S.C. 812(b)(1)(B), when placing a drug or other substance in schedule I of the CSA, DEA must consider whether the substance has a currently accepted medical use in treatment in the United States. First, DEA looks to whether the drug or substance has FDA approval. When no FDA approval exists, DEA has traditionally applied a five-part test to determine whether a drug or substances has a currently accepted medical use: (1) the drug's chemistry must be known and reproducible; (2) there must be adequate safety studies; (3) there must be adequate and well-controlled studies proving efficacy; (4) the drug must be accepted by qualified experts; and (5) 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)

studies; (3) there must be adequate and well-controlled studies proving efficacy; (4) the drug must be accepted by qualified experts; and (5) 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). DEA and HHS applied the traditional five-part test for currently accepted medical use in this matter. In a recent published letter in a different context, HHS applied an additional two-part test to determine currently accepted medical use for substances that do not satisfy the five-part test: (1) whether there exists widespread, current experience with medical use of the substance by licensed health care practitioners operating in accordance with implemented jurisdiction-authorized programs, where medical use is recognized by entities that regulate the practice of medicine, and, if so, (2) whether there exists some credible scientific support for at least one of the medical conditions for which the part 1 is satisfied. On April 11, 2024, the Department of Justice's Office of Legal Counsel (OLC) issued an opinion, which, among other things, concluded that HHS's two-part test would be sufficient to establish that a drug has a currently accepted medical use. Office of Legal Counsel, Memorandum for Merrick B. Garland Attorney General Re: Questions Related to the Potential Rescheduling of Marijuana at 3 (Apr. 11, 2024). In its eight-factor assessment, HHS determined that clonazolam, diclazepam, etizolam, flualprazolam, and flubromazolam do not satisfy this two-part test. Therefore, since both DEA and HHS have determined that these substances do not satisfy the five-part test, and HHS has determined that the substances do not satisfy the additional two-part test, DEA concludes that clonazolam, diclazepam, etizolam, flualprazolam, and flubromazolam do not have a currently accepted medical use.

is finalized as proposed, clonazolam, diclazepam, etizolam, flualprazolam, and flubromazolam 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, dispensing, importing, exporting, research, and conduct of instructional activities, including the following:

1. Registration. Any person who handles (manufactures, distributes,

dispenses, imports, exports, engages in research, or conducts instructional activities or chemical analysis with, or possesses) clonazolam, diclazepam, etizolam, flualprazolam, or flubromazolam 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.

2. Security. Clonazolam, diclazepam, etizolam, flualprazolam, and flubromazolam are subject to schedule I security requirements and must be handled and stored pursuant to 21 U.S.C. 821 and 823 and in accordance with 21 CFR 1301.71 through 1301.76. Non-practitioners handling these five 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 clonazolam, diclazepam, etizolam, flualprazolam, or flubromazolam must comply with 21 U.S.C. 825 and be in accordance with 21 CFR part 1302.

4. Quota. Only registered manufacturers are permitted to manufacture clonazolam, diclazepam, etizolam, flualprazolam, and flubromazolam 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 clonazolam, diclazepam, etizolam, flualprazolam, or flubromazolam 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

estimates that all entities handling or planning to handle clonazolam, diclazepam, etizolam, flualprazolam, or flubromazolam have already established and implemented systems and processes required to handle these substances. DEA proposes placing clonazolam, diclazepam, etizolam, flualprazolam, and flubromazolam, including its salts, isomers, and salts of isomers, in schedule I on a permanent basis.

According to HHS, these five designer benzodiazepines have a high potential for abuse, have no currently accepted medical use in treatment in the United States, and lack accepted safety for use under medical supervision. There appear to be no legitimate sources for clonazolam, diclazepam, etizolam, flualprazolam, or flubromazolam as a marketed drug in the United States, but DEA notes that these substances are available for purchase from legitimate suppliers for scientific research. There is no evidence of significant diversion of these five substances from legitimate suppliers. Therefore, DEA has concluded that this proposed rule, if finalized, will not have a significant economic impact on a substantial number of small entities.

If finalized, this action would impose the 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 clonazolam, diclazepam, etizolam, flualprazolam, or flubromazolam, including its salts, isomers, and salts of isomers, or any combination thereof. DEA determines the industries that best represent these business activities using the North American Industry Classification System (NAICS). 28 From Statistics of U.S

instructional activities or chemical analysis with, or possess), or propose to handle clonazolam, diclazepam, etizolam, flualprazolam, or flubromazolam, including its salts, isomers, and salts of isomers, or any combination thereof. DEA determines the industries that best represent these business activities using the North American Industry Classification System (NAICS). 28 From Statistics of U.S. Businesses (SUSB) data, DEA determined the number of firms and small firms for each of the affected industries, and by comparing the number of affected small entities to the number of small entities for each industry, DEA determined whether a substantial number of small entities are affected in any of the industries. The following table lists the number of firms, small firms, and percent small firms in each affected industry.

28 Executive Office of the President Office of Management and Budget, North American Industry Classification System, United States, 2022, https://www.census.gov/naics/reference_files_tools/2022_NAICS_Manual.pdf (last accessed 4/2/2024).

Table 1—Business Activity and Corresponding NAICS Industries Business activity NAICS code NAICS industry description Firms 29 SBA size standard 30 Small firms 31 Percent small entities Manufacturer 325412 Pharmaceutical Preparation Manufacturing 1,179 1,300 1,099 93.2 Distributor, Importer, Exporter 424210 Drugs and Druggists' Sundries Merchant Wholesalers 7,012 250 6,760 96.4 424690 Other Chemical and Allied Products Merchant Wholesalers 5,487 175 5,197 94.7 Researcher 541715 Research and Development in the Physical, Engineering, and Life Sciences (except Nanotechnology and Biotechnology) 10,042 1,000 9,599 95.6 611310 Colleges, Universities, and Professional Schools 2,494 $34.5 1,515 60.8 Based on the American Chemical Society's SciFinder database, DEA identified ten entities supplying clonazolam, diclazepam, etizolam, flualprazolam, or flubromazolam across the industries 325412, 424210, and 424690

Physical, Engineering, and Life Sciences (except Nanotechnology and Biotechnology) 10,042 1,000 9,599 95.6 611310 Colleges, Universities, and Professional Schools 2,494 $34.5 1,515 60.8 Based on the American Chemical Society's SciFinder database, DEA identified ten entities supplying clonazolam, diclazepam, etizolam, flualprazolam, or flubromazolam across the industries 325412, 424210, and 424690. Two of these entities have already registered with DEA to handle controlled substances. Hence, DEA expects only eight entities will be impacted by this rule. Assuming that all affected suppliers were small entities and concentrated in the smallest NAICS industry, 325412, they would account for only 0.73 percent of the small entities in those industries, not a substantial number. 32

29 Statistics of U.S. Businesses, 2022 SUSB Annual Data Tables by Establishment Industry, https://www.census.gov/data/tables/2021/econ/susb/2021-susb-annual.html (last accessed 6/24/2025).

30 U.S. Small Business Administration (SBA), Table of size standards, Version March 2023, Effective: March 17, 2023, https://www.sba.gov/sites/default/files/2023-06/Table%20of%20Size%20Standards_Effective%20March%2017%2C%202023%20%282%29.pdf (last accessed 6/24/2025).

31 Based on the estimated number of firms below the SBA size standard for each industry.

32 8/1,099 = 0.73%.

Additionally, DEA expects that the number of researchers working with clonazolam, diclazepam, etizolam, flualprazolam, or flubromazolam is small, because each of these substances is not approved for medical use and has a substantial capability to be a hazard to the health of the user and to the safety of the community. Also, DEA believes that the researchers working with clonazolam, diclazepam, etizolam, flualprazolam, or flubromazolam may also work with other controlled substances; hence, these researchers are likely already registered with DEA and are qualified to handle controlled substances

e 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. 33 Also, this proposed rule would not impose new or modify existing recordkeeping or reporting requirements on state or local governments, 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.

33 44 U.S.C. 3501-3521.

List of Subjects in 21 CFR Part 1308

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

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

PART 1308—SCHEDULES OF CONTROLLED SUBSTANCES

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.

2. In § 1308.11:

a. Redesignate paragraphs (e)(1) through (3) as paragraphs (e)(6) through (8);

b. Add new paragraphs (e)(1) through (5); and

c. Remove and reserve paragraphs (h)(57) through (61).

The addition reads as follows:

§ 1308.11 Schedule I.

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 .

Heather Achbach, Federal Register Liaison Officer, Drug Enforcement Administration.

[FR Doc. 2025-14022 Filed 7-24-25; 8:45 am] BILLING CODE 4410-09-P