Schedules of Controlled Substances: Placement of 2-Methyl AP-237 in Schedule I

<RULE> DEPARTMENT OF JUSTICE <SUBAGY>Drug Enforcement Administration</SUBAGY> <CFR>21 CFR Part 1308</CFR> <DEPDOC>[Docket No. DEA-1245]</DEPDOC> <SUBJECT>Schedules of Controlled Substances: Placement of 2-Methyl AP-237 in Schedule I</SUBJECT> <HD SOURCE="HED">AGENCY:</HD> Drug Enforcement Administration, Department of Justice. <HD SOURCE="HED">ACTION:</HD> Final amendment; final order. <SUM> <HD SOURCE="HED">SUMMARY:</HD> With the issuance of this final order, the Administrator of the Drug Enforcement Administration is permanently placing 1-(2-methyl-4-(3-phenylprop-2-en-1-yl)piperazin-1-yl)butan-1-one (commonly known as 2-methyl AP-237), including its optical and geometric 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, in schedule I of the Controlled Substances Act. This scheduling action discharges the United States' obligations under the Single Convention on Narcotic Drugs (1961). This action imposes the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances on persons who handle (manufacture, distribute, import, export, engage in research or conduct instructional activities with, or possess), or propose to handle 2-methyl AP-237. </SUM> <EFFDATE> <HD SOURCE="HED">DATES:</HD> Effective April 15, 2024. </EFFDATE> <FURINF> <HD SOURCE="HED">FOR FURTHER INFORMATION CONTACT:</HD> Dr. Terrence L. Boos, Drug and Chemical Evaluation Section, Diversion Control Division, Drug Enforcement Administration; Telephone: (571) 362-3249. </FURINF> <SUPLINF> <HD SOURCE="HED">SUPPLEMENTARY INFORMATION:</HD> <HD SOURCE="HD1">Legal Authority</HD> The United States is a party to the 1961 United Nations Single Convention on Narcotic Drugs, March 30, 1961, 18 U.S.T. 1407, 570 U.N.T.S. 151 (Single Convention), as amended by the 1972 Protocol. Article 3, paragraph 7 of the Single Convention requires that if the Commission on Narcotic Drugs (Commission) adds a substance to one of the schedules of such Convention, and the United States receives notification of such scheduling decision from the Secretary-General of the United Nations (Secretary-General), the United States, as a signatory Member State, is obligated to control the substance under its national drug control legislation. Under 21 U.S.C. 811(d)(1) of the Controlled Substances Act (CSA), if control of a substance is required “by United States obligations under international treaties, conventions, or protocols in effect on October 27, 1970,” the Attorney General must issue an order controlling such drug under the schedule he deems most appropriate to carry out such obligations, without regard to the findings required by 21 U.S.C. 811(a) or 812(b), and without regard to the procedures prescribed by 21 U.S.C. 811(a) and (b). The Attorney General has delegated scheduling authority under 21 U.S.C. 811 to the Administrator of the Drug Enforcement Administration (Administrator of DEA or Administrator). 28 CFR 0.100. <HD SOURCE="HD1">Background</HD> In a letter dated November 24, 2022, the Director-General of the World Health Organization recommended to the Secretary-General of the United Nations that 2-methyl AP-237 be placed in Schedule I of the Single Convention, as this substance has an opioid mechanism of action and similarity to drugs that are controlled in Schedule I of the Single Convention ( <E T="03">i.e.,</E> 2-methyl AP-237 is similar to drugs such as isotonitazene) and has dependence and abuse potential. On May 17, 2023, the United States Government was informed by the Secretariat of the United Nations, by letter, that during its 66th session in March 2023, the Commission voted to place 2-methyl AP-237 in Schedule I of the Single Convention (CND Mar/66/1). <HD SOURCE="HD1">2-Methyl AP-237</HD> 2-Methyl AP-237 has a pharmacological profile similar to other classical opioids such as fentanyl (schedule II), morphine (schedule II) and heroin (schedule I), which act as mu-opioid receptor agonists. Because of the pharmacological similarities of 2-methyl AP-237 to the aforementioned opioids, 2-methyl AP-237 presents a high risk of abuse and has negatively affected users and communities. According to the DEA Toxicology Testing Program (DEA TOX)  <SU>1</SU> <FTREF/> and a recent publication, <SU>2</SU> <FTREF/> the abuse of 2-methyl AP-237 has been associated with at least seven fatalities in the United States between February 2020 and July 2023. The identification of this substance in post-mortem cases is a serious concern to public safety. <FTNT> <SU>1</SU>  The DEA Toxicology Testing Program (DEA TOX) was initiated in response to the ongoing novel synthetic drug abuse epidemic. This program provides toxicology data on synthetic drugs from biological samples that may not be routinely identified, which are generated from drug overdose victims. Data queried on 8/7/2023. </FTNT> <FTNT> <SU>2</SU>  Fogarty, MF, Vandeputte, MM, Krotulski, AJ, Walton, SE, Stove, CP, and Logan, BK (2022). Toxicological and pharmacological characterization of novel cinnamylpiperazine synthetic opioids in humans and in vitro including 2-methyl AP-237 and AP-238. Archives of Toxicology 96:1701-1710. </FTNT> In June 2019, 2-methyl AP-237 emerged on the United States illicit drug market as evidenced by its identification in drug seizures. <SU>3</SU> <FTREF/> Law enforcement reports demonstrate that 2-methyl AP-237 is being illicitly distributed and abused. The illicit use and distribution of this substance is similar to that of heroin (schedule I) and prescription opioid analgesics. According to the National Forensic Laboratory Information System (NFLIS-Drug) database, which collects drug identification results from drug cases submitted to and analyzed by Federal, State, and local forensic laboratories, there have been 92 reports of 2-methyl AP-237 in the United States since 2019 (data queried July 17, 2023). <FTNT> <SU>3</SU>  NFLIS 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. While NFLIS data is not direct evidence of abuse, it can lead to an inference that a drug has been diverted and abused. <E T="03">See</E> Schedules of Controlled Substances: Placement of Carisoprodol Into Schedule IV; 76 FR 77330, 77332, December 12, 2011. NFLIS data was queried on July 17, 2023. Reports to NFLIS-Drug are still pending for 2023. </FTNT> DEA is not aware of any claims or any medical or scientific literature suggesting that 2-methyl AP-237 has a currently accepted medical use in treatment in the United States. In addition, the Assistant Secretary for Health of the U.S. Department of Health and Human Services, by a letter to DEA dated December 22, 2022, stated that there are no investigational new drug applications or approved new drug applications for 2-methyl AP-237 in the United States; hence, there are no legitimate channels for this substance as a marketed drug product in the United States. Because 2-methyl AP-237 is not formulated or available for clinical use as an approved medicinal product, all current use of this substance by individuals is based on their own initiative, rather than on the basis of medical advice from a practitioner licensed by law to administer such a drug. Therefore, consistent with 21 U.S.C. 811(d)(1), DEA concludes that 2-methyl AP-237 has no currently accepted medical use in treatment in the United States  <SU>4</SU> <FTREF/> and is most appropriately placed in schedule I of the CSA. Because control is required under the Single Convention, DEA will not be initiating regular rulemaking proceedings to permanently schedule 2-methyl AP-237 pursuant to 21 U.S.C. 811(a). <FTNT> <SU>4</SU>  Although, as discussed above, there is no evidence suggesting that 2-methyl AP-237 has a currently accepted medical use in treatment in the United States, it bears noting that a drug cannot be found to have such medical use unless DEA concludes that it satisfies a five-part test. Specifically, 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. 57 FR 10499 (Mar 26,1992), <E T="03">pet. for rev. denied, Alliance for Cannabis Therapeutics</E> v. <E T="03">Drug Enforcement Admin.,</E> 15 F.3d 1131, 1135 (D.C. Cir. 1994). </FTNT> <HD SOURCE="HD1">Conclusion</HD> In order to meet the United States' obligations under the Single Convention and because 2-methyl AP-237 has no currently accepted medical use in treatment in the United States, the Administrator has determined that 2-methyl AP-237, including its optical and geometric 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, should be placed in schedule I of the CSA. <HD SOURCE="HD1">Requirements for Handling</HD> Upon the effective date of the final order contained in this doc ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Preview showing 10k of 21k characters. Full document text is stored and available for version comparison. ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━