Schedules of Controlled Substances: Temporary Placement of N-Pyrrolidino Metonitazene and N-Pyrrolidino Protonitazene in Schedule I

SUPPLEMENTARY INFORMATION:

The notice of intent contained in this document is issued pursuant to the temporary scheduling provisions of 21 U.S.C. 811(h). The Drug Enforcement Administration (DEA) intends to issue a temporary scheduling order (in the form of a temporary amendment) to add the two synthetic benzimidazole-opioid substances, 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, to schedule I under the Controlled Substances Act (CSA):

• 2-(4-methoxybenzyl)-5-nitro-1-(2-(pyrrolidin-1-yl)ethyl)-1H -benzimidazole (commonly known as, N -pyrrolidino metonitazene or metonitazepyne), and
• 5-nitro-2-(4-propoxybenzyl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H -benzimidazole (commonly known as, N- pyrrolidino protonitazene or protonitazepyne).

The temporary scheduling order will be published in the Federal Register on or after October 17, 2024.

Legal Authority

Under 21 U.S.C. 811(h)(1), the CSA provides the Attorney General (as delegated to the Administrator of DEA (Administrator) pursuant to 28 CFR 0.100) has the authority to temporarily place a substance in schedule I of the CSA for two years without regard to the evaluation requirements of 21 U.S.C. 811(b), if he finds that such action is necessary to avoid an imminent hazard to the public safety. In addition, if proceedings to control a substance are initiated under 21 U.S.C. 811(a)(1) while the substance is temporarily controlled under section 811(h), the Attorney General may extend the temporary scheduling for up to one year.

Where the necessary findings are made, a substance may be temporarily scheduled if it is not listed in any other schedule under 21 U.S.C. 812, or if there is no exemption or approval in effect for the substance under section 505 of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 355.

Background

The CSA requires the Administrator to notify the Secretary of the Department of Health and Human Services (HHS) of an intent to temporarily place a substance in schedule I of the CSA ( i.e., to issue a temporary scheduling order). By letter dated December 15, 2023, the Administrator transmitted the required notice to place N -pyrrolidino metonitazene and N -pyrrolidino protonitazene in schedule I on a temporary basis to the Assistant Secretary for Health of HHS (Assistant Secretary). On December 22, 2023, the Assistant Secretary responded to this notice and advised DEA that based on a review by the Food and Drug Administration (FDA), there are currently no investigational new drug applications (IND) or approved new drug applications (NDA) for N -pyrrolidino metonitazene or N -pyrrolidino protonitazene. The Assistant Secretary also stated that HHS had no objection to the temporary placement of these substances in schedule I of the CSA. N -Pyrrolidino metonitazene and N -pyrrolidino protonitazene currently are not listed in any schedule under the CSA, and no exemptions or approvals under 21 U.S.C. 355 are in effect for these substances.

To find that temporarily placing a substance in schedule I of the CSA is necessary to avoid an imminent hazard to the public safety, the Administrator must consider three of the eight factors set forth in 21 U.S.C. 811(c): the substance's history and current pattern of abuse; the scope, duration, and significance of abuse; and what, if any, risk there is to the public health. This consideration includes any information indicating actual abuse, diversion from legitimate channels, and clandestine importation, manufacture, or distribution of N -Pyrrolidino metonitazene and N -pyrrolidino protonitazene.

Substances meeting the statutory requirements for temporary scheduling may only be placed in schedule I. Substances in schedule I have high potential for abuse, no currently accepted medical use in treatment in the United States, and a lack of accepted safety for use under medical supervision.

Two Benzimidazole-Opioids: N -pyrrolidino metonitazene and N -pyrrolidino protonitazene

The continued encounter of novel synthetic opioids on the recreational drug market poses a threat to public safety. Beginning in 2019, a new class of synthetic opioids known as benzimidazole-opioids, commonly referred to as “nitazenes,” emerged on the recreational drug market. This class of substances has a similar pharmacological profile to fentanyl, morphine, and other mu-opioid receptor agonists. Between August 2020 and March 2024, DEA temporarily controlled ten benzimidazole-opioids because they posed a threat to public safety. N -Pyrrolidino metonitazene and N -pyrrolidino protonitazene are some of the recently encountered “nitazene” synthetic opioids identified on the illicit drug market.

The continued trafficking and identification of benzimidazole-opioids in toxicology cases poses a significant threat to public health and safety. Adverse health effects associated with the misuse and abuse of synthetic opioids have led to devastating consequences including death. Preclinical pharmacology data demonstrate that N -pyrrolidino metonitazene and N -pyrrolidino protonitazene have pharmacological profiles similar to those of the potent benzimidazole-opioids metonitazene and protonitazene, schedule I opioid substances. N -Pyrrolidino metonitazene and N -pyrrolidino protonitazene have been positively identified in at least 26 toxicology cases. As the United States continues to experience a high number of opioid-involved overdoses and mortalities, the introduction of new designer opioids further exacerbates the current opioid epidemic.

Available data and information for N -pyrrolidino metonitazene and N -pyrrolidino protonitazene, summarized below, indicate that these substances have high potentials for abuse, no currently accepted medical uses in treatment in the United States, and a lack of accepted safety for use under medical supervision. DEA's three-factor analysis is available in its entirety under “Supporting and Related Material” of the public docket for this action at www.regulations.gov under Docket Number DEA-1337.

Factor 4. History and Current Pattern of Abuse

Since 2019, there has been an emergence of benzimidazole-opioid compounds on the illicit drug market, which have been positively identified in numerous cases of fatal overdose events. The benzimidazole-opioids were originally synthesized and studied in the 1950s by the pharmaceutical research laboratories of the Swiss chemical company Chemical Industries Basel. The research produced a group of structurally unique benzimidazole derivatives with analgesic properties; however, the research effort did not produce any medically approved analgesic products. These benzimidazole derivatives include schedule I substances, such as synthetic opioids clonitazene, etonitazene, and isotonitazene.

In August 2020, isotonitazene was placed in schedule I of the CSA (85 FR 51342). Subsequently, nine additional benzimidazole-opioids have been placed in schedule I of the CSA (87 FR 21556 and 89 FR 60817). Recently, N -pyrrolidino metonitazene and N -pyrrolidino protonitazene have emerged on the illicit drug market. Law enforcement officers have encountered N -pyrrolidino metonitazene and N -pyrrolidino protonitazene in several solid forms ( e.g., powder and tablets). These substances are not approved pharmaceutical products and are not approved for medical use anywhere in the world. The Assistant Secretary in a letter to DEA dated December 22, 2023, stated that there are no FDA-approved NDAs or IND applications for N -pyrrolidino metonitazene and N -pyrrolidino protonitazene in the United States; hence, there are no legitimate channels for these substances as marketed drug products.

The appearance of benzimidazole-opioids on the illicit drug market is similar to other designer opioid drugs that are trafficked for their psychoactive effects. These substances are likely to be abused in the same manner as schedule I opioids, such as etonitazene, isotonitazene, and heroin. In 2023, N -pyrrolidino metonitazene and N -pyrrolidino protonitazene 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 N -pyrrolidino metonitazene and N -pyrrolidino protonitazene were found in combination with other substances of abuse such as heroin, designer benzodiazepines, cocaine, fentanyl, methamphetamine, and xylazine.

Factor 5. Scope, Duration and Significance of Abuse

N -Pyrrolidino metonitazene and N -pyrrolidino protonitazene, similar to etonitazene, metonitazene and protonitazene (schedule I substances), have been described as potent synthetic opioids, and evidence suggests they are abused for their opioidergic effects (see Factor 6). The abuse of these benzimidazole-opioids, similar to other synthetic opioids, has resulted in serious adverse health effects. According to a public alert report published in August 2023, N -pyrrolidino protonitazene has been positively confirmed in 20 medicolegal death investigation cases in the United States (n =16) and United Kingdom (n = 4). The cases that occurred in the United States originated from seven States including California, Illinois, Maine, Massachusetts, Minnesota, Wisconsin, and Wyoming. N -Pyrrolidino metonitazene has been identified in six toxicology cases as of June 2023 in the United States. The cases occurred in at least three States including Ohio, Illinois, and West Virginia.

Data from law enforcement suggest that N -pyrrolidino metonitazene and N - pyrrolidino protonitazene are being abused in the United States as recreational drugs. Since 2023, there have been 37 exhibits reported to the NFLIS-Drug (Federal, State and local laboratories) database pertaining to the trafficking, distribution, and abuse of these substances. There were seven encounters of N -pyrrolidino metonitazene from two States in NFLIS-Drug: Missouri (n = 2) and Ohio (n = 5). N -Pyrrolidino protonitazene has been identified in 30 exhibits in NFLIS-Drug from five States: Florida (n = 4), Iowa (n = 10), Missouri (n = 1), Ohio (n = 13), and Texas (n = 2).

Because abusers of N -pyrrolidino metonitazene and N -pyrrolidino protonitazene are likely to obtain these substances through unregulated sources, the identity, purity, and quantity of these substances are uncertain and inconsistent, thus posing significant adverse health risks to the end user. The misuse and abuse of opioids have been demonstrated and are well-characterized. Individuals who initiate ( i.e., use a drug for the first time) use of these benzimidazole-opioids are likely to be at risk of developing substance use disorder, an overdose event, or death, similar to that of other opioid analgesics ( e.g., fentanyl, morphine, etc.). Law enforcement and toxicology reports demonstrate that N -pyrrolidino metonitazene and N -pyrrolidino protonitazene are being illicitly distributed and abused.

Factor 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. Data obtained from pre-clinical studies demonstrate that N -pyrrolidino metonitazene and N -pyrrolidino protonitazene exhibit pharmacological profiles similar to that of etonitazene, metonitazene, protonitazene, and other mu-opioid receptor agonists. These two benzimidazole-opioids bind to and act as agonists at the mu-opioid receptors. It is well established that substances that act as mu-opioid receptor agonists have a high potential for addiction and can induce dose-dependent respiratory depression.

Consistent with any mu-opioid receptor agonist, the potential health and safety risks for users of N -pyrrolidino metonitazene and N -pyrrolidino protonitazene are high. N -Pyrrolidino metonitazene and N -pyrrolidino protonitazene have been positively identified in forensic toxicology and post mortem cases. According to a public alert, N -pyrrolidino protonitazene has been positively identified in 20 medicolegal death investigations in the United States and United Kingdom as of August 2023. Of the cases, 16 occurred across seven States in the United States. Decedent ages ranged from mid-20s to mid-70s. N -Pyrrolidino protonitazene was co-identified with additional novel psychoactive substances (70 percent), quinine (60 percent), other benzimidazole-opioids (55 percent), methamphetamine/cocaine (55 percent), fentanyl (55 percent), xylazine (35 percent) and designer benzodiazepines (30 percent). Also, N -pyrrolidino metonitazene has been identified in six toxicology cases in the United States as of June 2023. The introduction of potent synthetic opioids such as N -pyrrolidino metonitazene and N -pyrrolidino protonitazene into the illicit market may serve as a portal to problematic opioid use for those seeking these powerful opioids. As documented by toxicology reports, polysubstance abuse remains common in fatalities associated with the abuse of some of these benzimidazole-opioids.

The United States is currently experiencing an opioid epidemic, and the presence of synthetic opioids on the illicit drug market further exacerbates the problem. The trafficking and abuse of new synthetic opioids are deadly trends which pose imminent hazard to the public safety. Adverse health effects associated with the abuse of synthetic opioids and the continued evolution and increased popularity of these substances have been a serious concern in recent years. Because of the pharmacological similarities of N- pyrrolidino metonitazene and N -pyrrolidino protonitazene to metonitazene and protonitazene, the use of these substances presents high risk of abuse and may negatively affect users and communities. The positive identification of these substances in toxicology cases is of serious concern to the public safety. Thus, N -pyrrolidino metonitazene and N -pyrrolidino protonitazene pose imminent hazard to public safety.

Finding of Necessity of Schedule I Placement To Avoid Imminent Hazard to Public Safety

In accordance with 21 U.S.C. 811(h)(3), based on the available data and information summarized above, the uncontrolled manufacture, distribution, reverse distribution, importation, exportation, conduct of research and chemical analysis, possession, and abuse of N -pyrrolidino metonitazene and N -pyrrolidino protonitazene pose imminent hazards to public safety. DEA is not aware of any currently accepted medical uses for these substances in the United States. A substance meeting the statutory requirements for temporary scheduling, found in 21 U.S.C. 811(h)(1), may only be placed in schedule I. Substances in schedule I must have a high potential for abuse, no currently accepted medical use in treatment in the United States, and a lack of accepted safety for use under medical supervision. Available data and information for N -pyrrolidino metonitazene and N -pyrrolidino protonitazene indicate that these substances meet the three statutory criteria. As required by 21 U.S.C. 811(h)(4), the Administrator transmitted to the Assistant Secretary, via letter dated December 15, 2023, notice of her intent to place N -pyrrolidino metonitazene and N -pyrrolidino protonitazene in schedule I on a temporary basis. HHS had no objection to the temporary placement of these substances in schedule I.

Conclusion

This notice of intent provides the 30-day notice pursuant to 21 U.S.C. 811(h)(1) of DEA's intent to issue a temporary scheduling order. In accordance with 21 U.S.C. 811(h)(1) and (3), the Administrator considered available data and information, herein set forth the grounds for her determination that it is necessary to temporarily schedule N -pyrrolidino metonitazene and N -pyrrolidino protonitazene in schedule I of the CSA, and finds that placement of these substances in schedule I is necessary to avoid an imminent hazard to the public safety.

The temporary placement of N -pyrrolidino metonitazene and N -pyrrolidino protonitazene in schedule I of the CSA will take effect pursuant to a temporary scheduling order, which will not be issued before October 17, 2024. Because the Administrator hereby finds this temporary scheduling order necessary to avoid an imminent hazard to the public safety, it will take effect on the date the order is published in the Federal Register and remain in effect for two years, with a possible extension of one year, pending completion of the regular (permanent) scheduling process. The Administrator intends to issue a temporary scheduling order as soon as possible after the expiration of 30 days from the date of publication of this document. Upon the temporary order's publication, N -pyrrolidino metonitazene and N -pyrrolidino protonitazene will then be subject to the CSA's schedule I regulatory controls and to administrative, civil, and criminal sanctions applicable to their manufacture, distribution, reverse distribution, importation, exportation, research, conduct of instructional activities and chemical analysis, and possession.

The CSA sets forth specific criteria for scheduling drugs or other substances. Regular scheduling actions in accordance with 21 U.S.C. 811(a) are subject to formal rulemaking procedures “on the record after opportunity for a hearing” conducted pursuant to the provisions of 5 U.S.C. 556 and 557. The regular scheduling process of formal rulemaking affords interested parties appropriate process and the government any additional relevant information needed to make a determination. Final decisions that conclude the regular scheduling process of formal rulemaking are subject to judicial review. Temporary scheduling orders are not subject to judicial review.

Regulatory Analyses

The CSA provides for expedited temporary scheduling actions where necessary to avoid an imminent hazard to the public safety. Under 21 U.S.C. 811(h)(1), the Administrator, as delegated by the Attorney General, may, by order, temporarily place substances in schedule I. Such orders may not be issued before the expiration of 30 days from: (1) The publication of a notice in the Federal Register of the intent to issue such order and the grounds upon which such order is to be issued, and (2) the date that notice of the proposed temporary scheduling order is transmitted to the Assistant Secretary, as delegated by the Secretary of HHS.

Inasmuch as section 811(h) directs that temporary scheduling actions be issued by order and sets forth the procedures by which such orders are to be issued, including the requirement to publish in the Federal Register a notice of intent, the notice-and-comment requirements of section 553 of the Administrative Procedure Act (APA), 5 U.S.C. 553, do not apply to this notice of intent. The APA expressly differentiates between orders and rules, as it defines an “order” to mean a “final disposition, whether affirmative, negative, injunctive, or declaratory in form, of an agency in a matter other than rule making. ” (Emphasis added). This contrasts with permanent scheduling actions, which are subject to formal rulemaking procedures done “on the record after opportunity for a hearing,” and final decisions that conclude the scheduling process and are subject to judicial review. 21 U.S.C. 811(a) and 877. The specific language chosen by Congress indicates its intent that DEA issue orders instead of proceeding by rulemaking when temporarily scheduling substances. Given that Congress specifically requires the Administrator (as delegated by the Attorney General) to follow rulemaking procedures for other kinds of scheduling actions, see21 U.S.C. 811(a), it is noteworthy that, in section 811(h)(1), Congress authorized the issuance of temporary scheduling actions by order rather than by rule.

Even assuming that this notice of intent is subject to section 553 of the APA, the Administrator finds that there is good cause to forgo its notice-and-comment requirements, as any further delays in the process for issuing temporary scheduling orders would be impracticable and contrary to the public interest given the manifest urgency to avoid an imminent hazard to the public safety.

Although DEA believes this notice of intent to issue a temporary scheduling order is not subject to the notice-and-comment requirements of section 553 of the APA, DEA notes that in accordance with 21 U.S.C. 811(h)(4), the Administrator took into consideration comments submitted by the Assistant Secretary in response to the notices that DEA transmitted to the Assistant Secretary pursuant to such subsection.

Further, DEA believes that this temporary scheduling action is not a “rule” as defined by 5 U.S.C. 601(2), and, accordingly, is not subject to the requirements of the Regulatory Flexibility Act (RFA). The requirements for the preparation of an initial regulatory flexibility analysis in 5 U.S.C. 603(a) are not applicable where, as here, DEA is not required by section 553 of the APA or any other law to publish a general notice of proposed rulemaking. As discussed above, DEA is issuing this notice of intent pursuant to DEA's authority to issue a temporary scheduling order. 21 U.S.C. 811(h)(1). Therefore, in this instance, since DEA believes this temporary scheduling action is not a “rule,” it is not subject to the requirements of the RFA when issuing this temporary action.

In accordance with the principles of Executive Orders (E.O.) 12866 and 13563, this action is not a significant regulatory action. E.O. 12866 directs agencies to assess all costs and benefits of available regulatory alternatives and, if regulation is necessary, to select regulatory approaches that maximize net benefits (including potential economic, environmental, public health, and safety effects; distributive impacts; and equity). E.O. 13563 is supplemental to and reaffirms the principles, structures, and definitions governing regulatory review as established in E.O. 12866. E.O. 12866, sec. 3(f), as amended by E.O. 14094, sec. 1(b), provides the definition of a “significant regulatory action,” requiring review by the Office of Management and Budget. Because this is not a rulemaking action, this is not a significant regulatory action as defined in section 3(f) of E.O. 12866.

This action will not have substantial direct effects on the States, on the relationship between the National Government and the States, or on the distribution of power and responsibilities among the various levels of government. Therefore, in accordance with E.O. 13132, it is determined that this action does not have sufficient federalism implications to warrant the preparation of a Federalism Assessment.

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

1. The authority citation for 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, add paragraphs (h)(70) and (71) to read as follows:

(h) * * *