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Home , Arylcyclohexylamine, Clonazolam, Clonitazene, Diphenidine, Etonitazene, Metonitazene

Federal Register / Vol. 86, No. 31 / Thursday, February 18, 2021 / Notices 10097

Dated: February 10, 2021. anyone else’s Social Security number, or https://www.regulations.gov. Submit Lauren K. Roth, confidential business information, such both copies to the Dockets Management Acting Principal Associate Commissioner for as a manufacturing process. Please note Staff. If you do not wish your name and Policy. that if you include your name, contact contact information to be made publicly [FR Doc. 2021–03244 Filed 2–17–21; 8:45 am] information, or other information that available, you can provide this BILLING CODE 4164–01–P identifies you in the body of your information on the cover sheet and not comments, that information will be in the body of your comments and you posted on https://www.regulations.gov. must identify this information as DEPARTMENT OF HEALTH AND • If you want to submit a comment ‘‘confidential.’’ Any information marked HUMAN SERVICES with confidential information that you as ‘‘confidential’’ will not be disclosed do not wish to be made available to the except in accordance with 21 CFR 10.20 Food and Drug Administration public, submit the comment as a and other applicable disclosure law. For [Docket No. FDA–2021–N–0165] written/paper submission and in the more information about FDA’s posting manner detailed (see ‘‘Written/Paper of comments to public dockets, see 80 International Drug Scheduling; Submissions’’ and ‘‘Instructions’’). FR 56469, September 18, 2015, or access Convention on Psychotropic Written/Paper Submissions the information at: https:// Substances; Single Convention on www.govinfo.gov/content/pkg/FR-2015- Narcotic Drugs; World Health Submit written/paper submissions as 09-18/pdf/2015-23389.pdf. Organization; Scheduling follows: • Mail/Hand Delivery/Courier (for Docket: For access to the docket to Recommendations; ; read background documents or the MDMB-4en-PINACA; CUMYL- written/paper submissions): Dockets Management Staff (HFA–305), Food and electronic and written/paper comments PEGACLONE; ; received, go to https:// Clonazolam; ; 3- Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. www.regulations.gov and insert the Methoxyphencyclidine; ; • For written/paper comments docket number, found in brackets in the Request for Comments submitted to the Dockets Management heading of this document, into the AGENCY: Food and Drug Administration, Staff, FDA will post your comment, as ‘‘Search’’ box and follow the prompts HHS. well as any attachments, except for and/or go to the Dockets Management ACTION: Notice. information submitted, marked and Staff, 5630 Fishers Lane, Rm. 1061, identified, as confidential, if submitted Rockville, MD 20852, 240–402–7500. SUMMARY: The Food and Drug as detailed in ‘‘Instructions.’’ FOR FURTHER INFORMATION CONTACT: Administration (FDA) is providing Instructions: All submissions received James R. Hunter, Center for Drug interested persons with the opportunity must include the Docket No. FDA– Evaluation and Research, Controlled to submit written comments concerning 2021–N–0165 for ‘‘International Drug Substance Staff, Food and Drug recommendations by the World Health Scheduling; Convention on Administration, 10903 New Hampshire Organization (WHO) to impose Psychotropic Substances; Single Ave., Bldg. 51, Rm. 5150, Silver Spring, international manufacturing and Convention on Narcotic Drugs; World MD 20993–0002, 301–796–3156, distributing restrictions, under Health Organization; Scheduling [email protected]. international treaties, on certain drug Recommendations; Isotonitazene; substances. The comments received in MDMB-4en-PINACA; CUMYL- SUPPLEMENTARY INFORMATION: response to this notice will be PEGACLONE; Flubromazolam; I. Background considered in preparing the United Clonazolam; Diclazepam; 3- States’ position on these proposals for a Methoxyphencyclidine; Diphenidine; The United States is a party to the meeting of the United Nations Request for Comments.’’ Received 1971 Convention on Psychotropic Commission on Narcotic Drugs (CND) in comments will be placed in the docket Substances (1971 Convention). Section Vienna, Austria, in April 2021. This and, except for those submitted as 201(d)(2)(B) of the CSA (21 U.S.C. notice is issued under the Controlled ‘‘Confidential Submissions,’’ publicly 811(d)(2)(B)) provides that when the Substances Act (CSA). viewable at https://www.regulations.gov United States is notified under Article 2 DATES: Submit either electronic or or at the Dockets Management Staff of the 1971 Convention that the CND written comments by March 22, 2021. between 9 a.m. and 4 p.m., Monday proposes to decide whether to add a ADDRESSES: You may submit comments through Friday, 240–402–7500. drug or other substance to one of the • as follows: Confidential Submissions—To schedules of the 1971 Convention, submit a comment with confidential transfer a drug or substance from one Electronic Submissions information that you do not wish to be schedule to another, or delete it from Submit electronic comments in the made publicly available, submit your the schedules, the Secretary of State following way: comments only as a written/paper must transmit notice of such • Federal eRulemaking Portal: submission. You should submit two information to the Secretary of Health https://www.regulations.gov. Follow the copies total. One copy will include the and Human Services (Secretary of HHS). instructions for submitting comments. information you claim to be confidential The Secretary of HHS must then publish Comments submitted electronically, with a heading or cover note that states a summary of such information in the including attachments, to https:// ‘‘THIS DOCUMENT CONTAINS Federal Register and provide www.regulations.gov will be posted to CONFIDENTIAL INFORMATION.’’ The opportunity for interested persons to the docket unchanged. Because your Agency will review this copy, including submit comments. The Secretary of HHS comment will be made public, you are the claimed confidential information, in must then evaluate the proposal and solely responsible for ensuring that your its consideration of comments. The furnish a recommendation to the comment does not include any second copy, which will have the Secretary of State that shall be binding confidential information that you or a claimed confidential information on the representative of the United third party may not wish to be posted, redacted/blacked out, will be available States in discussions and negotiations such as medical information, your or for public viewing and posted on relating to the proposal.

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As detailed in the following that in a letter dated 30 November 2020, the if the Government could communicate any paragraphs, the Secretary of State has Director-General of the World Health comments it considers relevant to the received notification from the Secretary- Organization (WHO), pursuant to article 3, possible scheduling of substances General of the United Nations (the paragraphs 1 and 3 of the Single Convention recommended by WHO to be placed under on Narcotic Drugs of 1961 as amended by the international control under the 1961 Secretary-General) regarding seven 1972 Protocol (1961 Convention), and article Convention, namely: substances to be considered for control 2, paragraphs 1 and 4 of the Convention on —Isotonitazene under the 1971 Convention. This Psychotropic Substances of 1971 (1971 as well as any economic, social, legal, notification reflects the Convention), notified the Secretary-General administrative or other factors that it of the following recommendations of the recommendation from the 43rd WHO considers relevant to the possible scheduling Expert Committee for Drug Dependence forty-third Meeting of the WHO’s Expert Committee on Drug Dependence (ECDD): of substances recommended by WHO to be (ECDD), which met in October 2020. In placed under international control under the the Federal Register of August 4, 2020 Substance recommended to be added to 1971 Convention, namely: Schedule I of the 1961 Convention: (85 FR 47217), FDA announced the —CUMYL-PEGACLONE WHO ECDD review and invited —Isotonitazene —MDMB-4en-PINACA interested persons to submit chemical name: N,N-diethyl-2-(2-(4- —3-Methoxyphencyclidine isopropoxybenzyl)-5-nitro-1H- —Diphenidine information for WHO’s consideration. benzo[d]imidazol-1-yl)ethan-1- The full text of the notification from —Clonazolam Substances recommended to be added to —Diclazepam the Secretary-General is provided in Schedule II of the 1971 Convention: section II. Section 201(d)(2)(B) of the —Flubromazolam —CUMYL-PEGACLONE The Secretariat of the United Nations CSA requires the Secretary of HHS, after chemical name: 5-pentyl-2-(2-phenylpropan- receiving a notification proposing avails itself of this opportunity to renew to 2-yl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1- the Permanent Mission of the United States scheduling, to publish a notice in the one of America to the United Nations (Vienna) Federal Register to provide the —MDMB-4en-PINACA the assurances of its highest consideration. chemical name: methyl 3,3-dimethyl-2-(1- opportunity for interested persons to 12 January 2012 submit information and comments on (pent-4-en-1-yl)-1H-indazole-3- the proposed scheduling action. carboxamido)butanoate Annex I The United States is also a party to —3-Methoxyphencyclidine chemical name: 1-(1-(3- Letter addressed to the Secretary-General of the 1961 Single Convention on Narcotic methoxyphenyl)cyclohexyl) the United Nations From the Director- Drugs (1961 Convention). The Secretary —Diphenidine General of the World Health Organization, of State has received a notification from chemical name: 1-(1,2- dated 30 November 2020 the Secretary-General regarding one diphenylethyl)piperidine ‘‘The Forty-third meeting of the WHO substance to be considered for control Substances recommended to be added to Expert Committee on Drug Dependence was under this convention. The CSA does Schedule IV of the 1971 Convention: convened in a virtual format from 12 to 16 not require HHS to publish a summary —Clonazolam October 2020 and was coordinated from the of such information in the Federal chemical name: 6-(2-chlorophenyl)-1-methyl- WHO headquarters in Geneva. The objective Register. Nevertheless, to provide 8-nitro-4H-benzo[f][1,2,4]triazolo[4,3- of this meeting was to carry out an in-depth a][1,4]diazepine evaluation of the abuse and dependence- interested and affected persons an producing capacity of psychoactive opportunity to submit comments —Diclazepam chemical name: 7-chloro-5-(2-chlorophenyl)- substances in order to make regarding the WHO recommendations 1- methyl-1,3-dihydro-2H- recommendations on appropriate for drugs under the 1961 Convention, benzo[e][1,4]diazepin2-one international scheduling measures. the notification regarding these —Flubromazolam The Forty-third WHO ECDD Meeting substances is also included in this chemical name: 8-bromo-6-(2-fluorophenyl)- critically reviewed eleven psychoactive Federal Register notice. The comments 1-methyl-4H-benzo[f][1,2,4]triazolo[4,3- substances, including one synthetic , will be shared with other relevant a][1,4]diazepine one , one synthetic , Agencies to assist the Secretary of State In accordance with the provisions of article two synthetic receptor , three -type drugs, and three in formulating the position of the 3, paragraph 2 of the 1961 Convention and article 2, paragraph 2 of the 1971 Convention, . These substances had not United States on the control of these previously been formally reviewed by WHO substances. The HHS recommendations the Secretary-General hereby transmits the notification as annex I to the present note. In and are currently not under international are not binding on the representative of connection with the notification, WHO also control. Information was brought to WHO’s the United States in discussions and submitted an extract of the report of the forty- attention that these substances are negotiations relating to the proposal third meeting of the WHO Expert Committee clandestinely manufactured, of especially regarding control of substances under on Drug Dependence, which provides a serious risk to public health and society, and the 1961 Convention. summary of the assessment and of no recognised therapeutic use by any recommendations made by the Expert Party. Therefore, a critical review to consider II. United Nations Notification Committee on Drug Dependence (attached as international scheduling measures was The formal notification from the annex II). undertaken for each substance. Also in accordance with the same With reference to Article 3, paragraphs 1 United Nations that identifies the drug and 3 of the Single Convention on Narcotic substances and explains the basis for the provisions, the notification from WHO will be brought to the attention of the sixty-fourth Drugs (1961), as amended by the 1972 scheduling recommendations is session of the Commission on Narcotic Drugs Protocol, and Article 2, paragraphs 1 and 4 reproduced as follows (non-relevant text (12–16 April 2021) in a pre-session document of the Convention on Psychotropic removed): that will be made available in the six official Substances (1971), WHO is pleased to submit Reference: languages of the United Nations on the recommendations of the Forty-second NAR/CL.1/2020 website of the 64th session of the CND: Meeting of ECDD as follows: WHO/ECDD43; 1961C–Art.3, 1971C–Art.2 https://www.unodc.org/unodc/en/ To be added to Schedule I of the Single CU 2021/7(A)/DTA/SGB commissions/CND/session/64_Session_ Convention on Narcotic Drugs (1961): The Secretariat of the United Nations 2021/session-64-of-the-commission-on- —Isotonitazene presents its compliments to the Permanent narcotic-drugs.html chemical name: N,N-diethyl-2-(2-(4- Mission of the United States of America and In order to assist the Commission in isopropoxybenzyl)-5-nitro-1H- has the honour to inform the Government reaching a decision, it would be appreciated benzo[d]imidazol-1-yl)ethan-1-amine

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To be added to Schedule II of the poses a risk to public health, and has no To be added to Schedule II of the Convention on Psychotropic Substances recognized therapeutic use. Convention on Psychotropic Substances (1971): Similarity to Known Substances and Effects (1971): —CUMYL-PEGACLONE on Central Nervous System CUMYL-PEGACLONE chemical name: 5-pentyl-2-(2-phenylpropan- Isotonitazene is a chemical analogue of 2-yl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1- Substance Identification and , both of which one CUMYL-PEGACLONE (Chemical name: 5- —MDMB-4en-PINACA are Schedule I compounds under the Single Convention on Narcotic Drugs, 1961. pentyl-2-(2-phenylpropan-2-yl)-2,5-dihydro- chemical name: methyl 3,3-dimethyl-2-(1- 1H-pyrido[4,3-b]indol-1-one) is a synthetic Isotonitazene is a potent opioid (pent-4-en-1-yl)-1H-indazole-3- cannabinoid. It has been found in seized with a rapid onset of action. Preclinical carboxamido)butanoate material formulated for and vaping. —3-methoxyphencyclidine studies have demonstrated that isotonitazene chemical name: 1-(1-(3- is more potent than and WHO Review History methoxyphenyl)cyclohexyl)piperidine , and substantially more CUMYL-PEGACLONE has never been —Diphenidine potent than . There is limited formally reviewed by WHO and is not chemical name: 1-(1,2- research on the effects of this compound on currently under international control. diphenylethyl)piperidine the central nervous system, but given its Information was brought to WHO’s attention To be added to Schedule IV of the demonstrated potency at the m-opioid that this substance is clandestinely Convention on Psychotropic Substances receptor, it would be expected to produce manufactured, poses a risk to public health, (1971): analgesia, respiratory depression and and has no recognized therapeutic use. —Clonazolam . Similarity to Known Substances and Effects chemical name: 6-(2-chlorophenyl)-1-methyl- Dependence Potential on Central Nervous System 8-nitro-4H-benzo[f][1,2,4]triazolo[4,3- No controlled animal or human studies CUMYL-PEGACLONE is a synthetic a][1,4]diazepine have assessed the dependence potential of cannabinoid with a —Diclazepam isotonitazene. As a potent m-opioid , it similar to that of other synthetic chemical name: 7-chloro-5-(2-chlorophenyl)- would be expected to produce dependence. . It is a potent full agonist at 1-methyl-1,3-dihydro-2H- An unverified online report described CB1 receptors. benzo[e][1,4]diazepin2-one dependent use and withdrawal symptoms, There are no controlled studies of its —Flubromazolam including flu-like symptoms and anxiety. effects, but there are online user reports chemical name: 8-bromo-6-(2-fluorophenyl)- describing , dissociation, red eyes, 1-methyl-4H-benzo[f][1,2,4]triazolo[4,3- Actual Abuse and/or Evidence of Likelihood dry mouth and appetite stimulation. These a][1,4]diazepine of Abuse effects are consistent with known The assessments and findings on which There are no controlled studies of the cannabinoid agonist effects. these recommendations are based are set out abuse potential of isotonitazene, but as a Dependence Potential in detail in the forty-third meeting report of potent m- agonist, it would be the WHO Expert Committee on Drug There are no controlled animal or human expected to produce euphoria and other studies that address the dependence Dependence. An extract of this report, effects predictive of high abuse liability. providing a summary of the assessment and potential of CUMYL-PEGACLONE. However, Due to its relatively recent appearance on CUMYL-PEGACLONE has been shown to be recommendations made by the ECDD, is the illicit drug market, there is limited contained in Annex 1 to this letter. a full and potent agonist at the CB1 receptor information on the prevalence of use of and therefore would be expected to produce I am very pleased with the ongoing isotonitazene or its associated harms. collaboration between WHO, the United dependence consistent with other CB1 Seizures have been reported in multiple receptor agonists. Nations Office on Drugs and Crime (UNODC) countries and regions. It is noted to be used Actual Abuse and/or Evidence of Likelihood and the International Narcotics Control Board via a range of routes including sublingually, of Abuse (INCB) and in particular, how this vaping and intravenously. collaboration has benefited the work of the The number of deaths involving There are no controlled animal or human WHO Expert Committee on Drug Dependence isotonitazene has increased in a short time studies that address the abuse potential of and more generally, the implementation of span. Deaths commonly occur in CUMYL-PEGACLONE. the operational recommendations of the combination with other or A number of countries across several United Nations General Assembly Special benzodiazepines. Isotonitazene deaths share regions have reported that CUMYL- Session 2016. common features with deaths, PEGACLONE is being used for its psychoactive properties. Annex II including evidence of injection, and signs There are reports of adverse effects such as consistent with opioid overdose such as Summary Assessment and Recommendations seizures and of fatalities involving CUMYL- pulmonary and/or cerebral oedema. Deaths of the 43rd Expert Committee on Drug PEGACLONE. While other drugs were are likely to be underreported due to its Dependence, 12–16 October 2020 present, CUMYL-PEGACLONE was deemed recent and rapid appearance. To be added to Schedule I of the Single to be a causal or contributory factor in a Convention on Narcotic Drugs (1961): Recommendation number of these deaths. Isotonitazene Isotonitazene (Chemical name: N,N- Therapeutic Usefulness Substance identification diethyl-2-(2-(4-isopropoxybenzyl)-5-nitro-1H- CUMYL-PEGACLONE is not known to Isotonitazene (Chemical name: N,N- benzo[d]imidazol-1-yl)ethan-1-amine) has a have any therapeutic use. mechanism of action such that it is liable to diethyl-2-(2-(4-isopropoxybenzyl)-5-nitro-1H- Recommendation benzo[d]imidazol-1-yl)ethan-1-amine) similar abuse and productive of similar ill belongs to the 2-benzylbenzimidazole group effects as other opioids which are controlled CUMYL-PEGACLONE (Chemical name: 5- of compounds, which includes the closely under Schedule I of the 1961 Single pentyl-2-(2-phenylpropan-2-yl)-2,5-dihydro- related opioids etonitazene, , Convention on Narcotic Drugs. Its use has 1H-pyrido[4,3-b]indol-1-one) is a synthetic and clonitazene. It is found in yellow, brown, been reported in a number of countries and cannabinoid receptor agonist with a mode of or off-white powder forms. has been associated with adverse effects action that suggests a likelihood of dependence and abuse, and similar ill-effects WHO Review History including deaths. It has no known therapeutic use and is likely to cause to other . Its use has Isotonitazene has never been formally substantial harm. been associated with severe adverse effects reviewed by WHO and is not currently under and fatalities. The effects of international control. Information was Therapeutic Usefulness CUMYL-PEGACLONE are similar to those of brought to WHO’s attention that this Isotonitazene is not known to have any other synthetic cannabinoids that are substance is clandestinely manufactured, therapeutic use. controlled under Schedule II of the

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Convention on Psychotropic Substances of and similar effects to a number of other controlled under Schedule II of the 1971 1971. CUMYL-PEGACLONE has no synthetic cannabinoids that are controlled Convention on Psychotropic Substances. Its therapeutic use, and its use constitutes a under Schedule II of the Convention on mode of action suggests a likelihood of abuse. substantial risk to public health. Psychotropic Substances of 1971. Use of There is evidence of use of this substance in • The committee recommended that MDMB-4en-PINACA has been associated a number of countries across different CUMYL-PEGACLONE (Chemical name: 5- with severe adverse effects, including fatal regions. 3-methoxyphencyclidine causes pentyl-2-(2-phenylpropan-2-yl)-2,5-dihydro- intoxications, and cases of impaired driving. substantial harm, including severe adverse 1H-pyrido[4,3-b]indol-1-one), be added to MDMB-4en-PINACA has no therapeutic use. events such as hallucinations, other Schedule II of the Convention on • The Committee recommended that psychotic symptoms, and fatal intoxications. Psychotropic Substances of 1971. MDMB-4en-PINACA (Chemical name: It has no therapeutic use. • The Committee recommended that 3- MDMB-4en-PINACA methyl (S)-3,3-dimethyl-2-(1-(pent-4-en-1-yl)- 1H-indazole-3-carboxamido)butanoate) be methoxyphencyclidine (Chemical name: 1-[1- Substance Identification added to Schedule II of the Convention on (3-methoxyphenyl)cyclohexyl]piperidine) be MDMB-4en-PINACA (Chemical name: Psychotropic Substances of 1971. added to Schedule II of the Convention on Psychotropic Substances of 1971. methyl (S)-3,3-dimethyl-2-(1-(pent-4-en-1-yl)- 3-methoxyphencyclidine (3-MeO-PCP) 1H-indazole-3-carboxamido)butanoate) is a Diphenidine synthetic cannabinoid. It has been identified Substance Identification Substance Identification in seized material formulated for smoking, 3-methoxyphencyclidine (3-MeO-PCP), and found as white to yellow/brown powder. (Chemical name: 1-[1-(3- Diphenidine (Chemical name: 1-(1,2- diphenylethyl)piperidine) is a dissociative WHO Review History methoxyphenyl)cyclohexyl]piperidine) is an and 3-methoxy and hallucinogenic substance of the 1,2- MDMB-4en-PINACA has never been derivative of (PCP) which is diarylethylamine class. It appears as powder formally reviewed by WHO and is not controlled under Schedule II of the and tablets. currently under international control. Convention on Psychotropic Substances of WHO Review History Information was brought to WHO’s attention 1971. It appears as powder and tablets. that this substance is clandestinely Diphenidine has never been formally manufactured, poses a risk to public health, WHO Review History reviewed by WHO and is not currently under and has no recognized therapeutic use. 3-methoxyphencyclidine has never been international control. Information was formally reviewed by WHO and is not brought to WHO’s attention that this Similarity to Known Substances and Effects substance is clandestinely manufactured, on Central Nervous System currently under international control. Information was brought to WHO’s attention poses a risk to public health, and has no MDMB-4en-PINACA is a synthetic that this substance is clandestinely recognized therapeutic use. cannabinoid that binds to CB1 cannabinoid manufactured, poses a risk to public health, Similarity to Known Substances and Effects receptors as a full and potent agonist. It is and has no recognized therapeutic use. on Central Nervous System structurally similar to 5F-MDMB-PINACA (5F-ADB) which is controlled under Similarity to Known Substances and Effects Diphenidine is known to produce Schedule II of the Convention on on Central Nervous System hallucinogenic and dissociative effects Psychotropic Substances of 1971. A report 3-methoxyphencyclidine is an N-methyl-D- through its action as an N-methyl-D-aspartate from an unpublished animal study indicates aspartate (NMDA) receptor antagonist with a (NMDA) receptor antagonist. This that MDMB-4en-PINACA can produce the similar mechanism of action and effects to mechanism of action as well as its effects are characteristic effects of CB1 cannabinoid phencyclidine. These effects include an similar to those of phencyclidine (PCP) agonists such as hypothermia and lethargy. altered mental state characterized by which is controlled under Schedule II of the Reports from online user forums describe confusion, disorientation and out of body 1971 Convention on Psychotropic -like euphoria at moderate levels of experiences as well as hallucinations and Substances. intake, with dissociation described at higher other psychotic symptoms. Dependence Potential doses. Both sedation and stimulation have Dependence Potential No animal or human studies have been reported, in addition to memory loss, determined the dependence potential for confusion and agitation. No human or animal studies have examined the dependence potential of 3- diphenidine. Dependence Potential methoxyphencyclidine. Actual Abuse and/or Evidence of Likelihood No animal or human studies were Actual Abuse and/or Evidence of Likelihood of Abuse identified that described the dependence of Abuse As an NMDA receptor antagonist, potential of MDMB-4en-PINACA. As a full diphenidine would be expected to have CB1 agonist, it would be expected to produce As an NMDA receptor antagonist, 3- methoxyphencyclidine would be expected to abuse potential similar to that of dependence similar to other CB1 receptor phencyclidine. In addition, diphenidine agonists. produce similar effects, and have abuse potential similar to that of phencyclidine. causes release, in a manner similar to, but to a lesser degree, than . This Actual Abuse and/or Evidence of Likelihood Adverse effects include cardiovascular effect may also contribute to its abuse of Abuse effects (such as hypertension and potential. No animal or human studies have been tachycardia) and cognitive effects including Cases of intoxication requiring conducted to provide an indication of the , confusion and agitation. There hospitalization are reported. Adverse effects likelihood of abuse of MDMB-4en-PINACA, may be a greater risk of psychosis in those include cardiovascular effects (such as though CB1 receptor agonists have known with a history of, or vulnerability to tachycardia and hypertension) and central abuse potential. A number of countries across psychotic illness. Cases of severe and fatal nervous system effects including intoxication are reported from several different regions have reported MDMB-4en- hallucinations, depersonalization, delusions, PINACA use. Its use has been associated with countries and regions. paranoia, dissociation, confusion, nystagmus cases of impaired driving and death. Seizures have been reported in a number and muscle rigidity. These effects have Therapeutic Usefulness of countries from several different regions. resulted in cases of acute intoxication leading MDMB-4en-PINACA is not known to have Therapeutic Usefulness to emergency department admissions. A any therapeutic use. 3-methoxyphencyclidine is not known to small number of fatal intoxications involving have any therapeutic use. diphenidine have been documented. All Recommendation deaths involved multiple drug toxicity, MDMB-4en-PINACA (Chemical name: Recommendation though cardiovascular and hallucinogenic methyl (S)-3,3-dimethyl-2-(1-(pent-4-en-1-yl)- 3-methoxyphencyclidine (Chemical name: symptoms described in the cases are 1H-indazole-3-carboxamido)butanoate) is a 1-[1-(3-methoxyphenyl)cyclohexyl] consistent with the effects of diphenidine. potent synthetic cannabinoid receptor piperidine) is an analogue of, and has similar Seizures have been reported in a number agonist with a similar mechanism of action, effects to phencyclidine (PCP), which is of countries from several different regions.

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Therapeutic Usefulness onset of withdrawal symptoms after cessation Similarity to Known Substances and Effects Diphenidine is not known to have any of use have been reported on online forums. on Central Nervous System therapeutic use. Actual Abuse and/or Evidence of Likelihood Diclazepam is an agonist at the Recommendation of Abuse site of the GABA-A receptor, acting to increase the effect of the inhibitory No human or animal studies have The available evidence indicates that neurotransmitter gamma amino butyric acid diphenidine (Chemical name: 1-(1,2- examined abuse liability. Online forums (GABA). Diclazepam has similar effects to the diphenylethyl)piperidine) has a mechanism describe its recreational use and consistently benzodiazepine , which is currently of action and effects that are similar to those report its strong effects. controlled under the Convention on of phencyclidine (PCP), which is controlled A number of published reports describe the Psychotropic Substances of 1971. It is under Schedule II of the 1971 Convention on management of cases of intoxication metabolized to the benzodiazepines Psychotropic Substances. Its mode of action involving clonazolam in emergency , and . suggests a likelihood of abuse. There is departments or intensive care. Clonazolam These metabolites are active and are also evidence of significant harm due to use has been analytically confirmed in cases pharmaceuticals that are included in diphenidine, including psychosis and of impaired driving, in combination with Schedule IV of the Convention on cardiovascular effects, which represents a other substances. Clonazolam has the Psychotropic Substances of 1971. substantial risk to public health. Diphenidine potential to increase the effects of other Diclazepam has been demonstrated to has no therapeutic use. drugs, including opioids, and on its own can cause sedation and muscle relaxation in • The Committee recommended that cause severe central nervous system animals. Central nervous systems diphenidine (Chemical name: 1-(1,2- depression, including somnolence, effects are also described in humans. diphenylethyl)piperidine) be added to confusion, sedation and unconsciousness. Dependence Potential Schedule II of the Convention on There are reports of its identification in No controlled animal or human studies Psychotropic Substances of 1971. multiple countries representing all regions, have examined the dependence potential of Substances recommended to be scheduled indicating that its use may be increasing. diclazepam. in Schedule IV of the Convention on Clonazolam is increasingly sold as falsified Online user reports describe cross- Psychotropic Substances (1971): pharmaceutical benzodiazepines. tolerance with other benzodiazepines and Clonazolam Therapeutic Usefulness use to self-manage benzodiazepine withdrawal. This evidence, along with its Substance Identification Clonazolam is not known to have any mechanism of action, suggests that Clonazolam (Chemical name: 6-(2- therapeutic use, is not listed on the WHO diclazepam has the capacity to produce chlorophenyl)-1-methyl-8-nitro-4H- Model List of Essential Medicines, and has dependence similar to other benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine) is never been marketed as a medicinal product. benzodiazepines. 1-4 similar to Recommendation Actual Abuse and/or Evidence of Likelihood , and . It is Clonazolam (Chemical name: 6-(2- of Abuse sold in powder, blotter, liquid and tablet form. chlorophenyl)-1-methyl-8-nitro-4H- No controlled animal or human studies benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine) is have examined the abuse liability of WHO Review History a 1-4 triazolobenzodiazepine that has actions diclazepam. However, based on its Clonazolam has never been formally and effects very similar to those of mechanism of action and effects, it would be reviewed by WHO and is not currently under benzodiazepines listed under Schedule IV in expected to have abuse liability similar to international control. Information was the Convention on Psychotropic Substances other benzodiazepines. brought to WHO’s attention that this of 1971. Like other benzodiazepines, Diclazepam has the potential to increase substance is clandestinely manufactured, clonazolam can produce a state of unintentional opioid overdoses. Its long half- poses a risk to public health, and has no dependence and central nervous system life may increase the risk of accumulation recognized therapeutic use. depression. There have been a number of and interactions when combined with other Similarity to Known Substances and Effects reports of abuse, impaired driving and non- drugs. Fatal intoxications with diclazepam on Central Nervous System fatal intoxications. There is sufficient have been reported. Seizures of diclazepam have been reported evidence of its abuse so as to constitute a Clonazolam enhances the effects of the from multiple countries across different public health problem, and it has no known inhibitory neurotransmitter gamma- regions. Diclazepam is increasingly sold as aminobutyric acid (GABA) through binding therapeutic use. • falsified benzodiazepines, commonly as at the benzodiazepine site of the GABA-A The Committee recommended that diazepam. receptor. This mechanism of action, as well clonazolam (Chemical name: 6-(2- Diclazepam has been implicated in cases of as its effects (sedation, muscle relaxation, chlorophenyl)-1-methyl-8-nitro-4H- impaired driving, including cases where slurred speech and loss of motor control, benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine) diclazepam was identified as the main ) are similar to those of the be added to Schedule IV of the 1971 contributor to impairment. It also has been benzodiazepines (such as diazepam, Convention on Psychotropic Substances. involved in cases of drug-facilitated sexual triazolam and alprazolam) which are Diclazepam assault. controlled under Schedule IV of the 1971 Therapeutic Usefulness Convention on Psychotropic Substances. Substance Identification In cases of clonazolam poisoning, the Diclazepam is not known to have any Diclazepam (Chemical name: 7-chloro-5-(2- effects have been reversed with the therapeutic use, is not listed on the WHO chlorophenyl)-1-methyl-1,3-dihydro-2H- benzodiazepine antagonist , Model List of Essential Medicines and has confirming that its action is mediated via the benzo[e][1,4]diazepin2-one) is a 2-chloro never been marketed as a medicinal product. derivative of the benzodiazepine diazepam. It benzodiazepine receptor in the GABA-A Recommendation receptor complex. appears as a white powder, and is commonly sold as tablets, pellets and liquid. Diclazepam (Chemical name: 7-chloro-5-(2- Dependence Potential WHO Review History chlorophenyl)-1-methyl-1,3-dihydro-2H- No controlled animal or human studies benzo[e][1,4]diazepin2-one) is a 2-chloro have examined the dependence potential of Diclazepam has never been formally analogue of the benzodiazepine diazepam clonazolam, though based on its reviewed by WHO and is not currently under that has actions and effects very similar to pharmacological effects, and similarity to international control. Information was those of benzodiazepines listed under other benzodiazepines, it would be expected brought to WHO’s attention that this Schedule IV of the Convention on to have potential to produce dependence. substance is clandestinely manufactured, Psychotropic Substances of 1971. It can The development of tolerance to the effects poses a risk to public health, and has no produce a state of dependence and central of clonazolam following repeated use and the recognized therapeutic use. nervous system depression, like other

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benzodiazepines. There have been reports of flubromazolam. Impaired driving with According to the National Forensic abuse, impaired driving and fatal and flubromazolam as the sole intoxicant is Laboratory Information System (NFLIS) nonfatal intoxications. There is sufficient reported. Non-fatal intoxications requiring database, there have been 53 encounters evidence of its abuse so as to constitute a hospital admission, and fatal intoxications of isotonitazene in the United States (as significant risk to public health, and it has no due to flubromazolam use are documented. known therapeutic use. In these cases, central nervous system of June 2020). There are no commercial • The Committee recommended that depression and severe sedation were clinical or approved medical uses for diclazepam (Chemical name: 7-chloro-5-(2- features of presentation. Flubromazolam has isotonitazene. On August 20, 2020, the chlorophenyl)-1-methyl-1,3-dihydro-2H- the potential to increase unintentional opioid Drug Enforcement Administration benzo[e][1,4]diazepin2-one) be added to overdoses. Its long half-life may increase the issued an order to temporarily control Schedule IV of the 1971 Convention on risk of accumulation and interactions when isotonitazene as a Schedule I substance Psychotropic Substances. combined with other drugs. under the CSA. As such, additional Flubromazolam Nonmedical use and seizures of permanent controls will be necessary to flubromazolam have been documented in fulfill U.S. obligations if isotonitazene is Substance Identification multiple countries across different regions. It placed in Schedule I of the 1961 Flubromazolam (Chemical name: 8-bromo- is increasingly sold as falsified pharmaceutical benzodiazepines. Convention. 6-(2-fluorophenyl)-1-methyl-4H- CUMYL-PEGACLONE is a synthetic benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine) is Therapeutic Usefulness cannabinoid that has been sold online a 1-4 triazolobenzodiazepine. Flubromazolam Flubromazolam is not known to have any and used to mimic the biological effects is a white powder, often sold as a liquid or therapeutic uses, is not listed on the WHO as tablets. of (THC), the Model List of Essential Medicines and has main psychoactive constituent in WHO Review History never been marketed as a medicinal product. marijuana. Research and clinical reports Flubromazolam has never been formally Recommendation have demonstrated that synthetic reviewed by WHO and is not currently under Flubromazolam (Chemical name: 8-bromo- cannabinoids are applied onto plant international control. Information was 6-(2-fluorophenyl)-1-methyl-4H- material so that the material may be brought to WHO’s attention that this benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine) is substance is clandestinely manufactured, smoked as users attempt to obtain a a 1-4 triazolobenzodiazepine that has actions euphoric and psychoactive ‘‘high’’. poses a risk to public health and has no and effects very similar to those of recognized therapeutic use. benzodiazepines listed under Schedule IV in Synthetic cannabinoids have been Similarity to Known Substances and Effects the Convention on Psychotropic Substances marketed under the guise of ‘‘herbal on Central Nervous System of 1971. It can produce a state of dependence incense’’, and promoted by drug and central nervous system depression, like traffickers as legal alternatives to Flubromazolam is a highly potent other benzodiazepines. There have been benzodiazepine with long lasting depressant marijuana. In vitro studies demonstrate increasing reports of abuse, impaired driving effects on the central nervous system. that CUMYL-PEGALCONE binds to and and fatal and non-fatal intoxications. There is Flubromazolam enhances the effects of the activates the cannabinoid one receptor. sufficient evidence of its abuse to constitute inhibitory neurotransmitter gamma- CUMYL-PEGALCONE has not been a significant risk to public health, and it has aminobutyric acid (GABA) through binding encountered within the United States no known therapeutic use. at the benzodiazepine site of the GABA-A The Committee recommended that according to the NFLIS database (as of receptor. This mechanism of action, as well flubromazolam (Chemical name: 8-bromo-6- January 14, 2021). There are no as its effects, are similar to those of the (2-fluorophenyl)-1-methyl-4H- commercial or approved medical uses benzodiazepines triazolam and alprazolam benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine) for CUMYL-PEGALCONE and it is not a which are controlled under Schedule IV of be added to Schedule IV of the 1971 controlled substance under the CSA. As the 1971 Convention on Psychotropic Convention on Psychotropic Substances. Substances. such, additional permanent controls A single pharmacokinetic study showed III. Discussion will be necessary to fulfill U.S. that a 0.5 mg flubromazolam dose induced obligations if CUMYL-PEGALCONE is strong effects that lasted more than Although WHO has made specific controlled under Schedule II of the 1971 10 hours, and caused partial amnesia for scheduling recommendations for each of Convention. more than 24 hours. The effects of the drug substances, the CND is not MDMB-4en-PINACA is a synthetic flubromazolam have been effectively obliged to follow the WHO cannabinoid that has been sold online reversed by the benzodiazepine antagonist recommendations. Options available to and used to mimic the biological effects flumazenil. the CND for substances considered for of THC, the main psychoactive Reports from online user forums describe control under the 1971 Convention constituent in marijuana. Research and benzodiazepine-like effects including include the following: (1) Accept the clinical reports have demonstrated that anxiolytic, euphoric and sedative effects. WHO recommendations; (2) accept the synthetic cannabinoids are applied onto Dependence Potential recommendations to control but control plant material so that the material may No controlled animal or human studies the drug substance in a schedule other be smoked as users attempt to obtain a describe the dependence potential of than that recommended; or (3) reject the euphoric and psychoactive ‘‘high’’. flubromazolam, although multiple reports recommendations entirely. Synthetic cannabinoids have been from online sources describe severe Isotonitazene (chemical name: N,N- marketed under the guise of ‘‘herbal withdrawal symptoms, such as muscle aches, diethyl-2-(2-(4-isopropoxybenzyl)-5- sleeping disorders, severe anxiety and panic incense’’, and promoted by drug attacks, dissociative symptoms, perceptual nitro-1H-benzimidazol-1-yl)ethan-1- traffickers as legal alternatives to distortions, cramping, chills, vomiting and amine) is a potent synthetic opioid that marijuana. According to the NFLIS risk of seizures. There are also descriptions is abused similar to other synthetic database, MDMB-4en-PINACA was first of loss of control over use, and rapid onset opioids. Its use has resulted in adverse encountered in the United States in of tolerance. The latter suggests that taking health effects, including positively January 2019. There have been 3,331 increased doses and developing physical identified in 49 death investigation encounters of MDMB-4en-PINACA in dependence is likely. cases in the United States between the United States (as of January 14, Actual Abuse and/or Evidence of Likelihood August 2019 and April 2020. Law 2021). MDMB-4en-PINACA has also of Abuse enforcement data indicate that been encountered mixed with opioids No controlled animal or human studies isotonitazene has appeared in the including heroin and fentanyl, with have assessed the abuse potential of United States’ illicit drug market. some incidents resulting in violent

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behaviors, tachycardia, and commonly used to treat insomnia, Dated: February 12, 2021. hypertension. There are no commercial anxiety, and seizure disorders. Lauren K. Roth, or approved medical uses for MDMB- Flubromazolam is a triazole analogue of Acting Principal Associate Commissioner for 4en-PINACA and it is not a controlled the designer benzodiazepine, Policy. substance under the CSA. As such, . Flubromazolam can be [FR Doc. 2021–03268 Filed 2–17–21; 8:45 am] additional permanent controls will be purchased on the internet and is used as necessary to fulfill U.S. obligations if a recreational substance in the United BILLING CODE 4164–01–P MDMB-4en-PINACA is controlled under States. Flubromazolam has been Schedule II of the 1971 Convention. identified in an increasing number of DEPARTMENT OF HEALTH AND 3-Methoxyphencyclidine; chemical law enforcement seizures and has been HUMAN SERVICES name: 1-(1-(3-methoxyphenyl) associated with an increasing number of cyclohexyl)piperidine) is a novel N- deaths. According to the Centers for Disease Control and methyl-D-aspartate (NMDA) receptor NFLIS database, in 2020 there were Prevention antagonist with structural and 1,446 clonazolam encounters (as of biochemical similarities to December 2020). It is abused by a broad Notice of Closed Meeting phencyclcycidine (PCP) and other range of groups including youths, young . 3- adults, and older adults. Clonazolam Pursuant to section 10(d) of the Methoxyphencyclidine is classified as has been involved in an increasing Federal Advisory Committee Act, as an arylcyclohexylamine and produces number of drug seizure events as well amended, notice is hereby given of the dissociative and as drug overdose deaths, alone and in following meeting. hallucinogenic effects. Use of this combination with . As such, the substance is associated with NFLIS database reported 249 encounters The meeting will be closed to the intoxication and published case reports in 2020 (as of December 2020). public in accordance with the of both fatal and non-fatal overdose. 3- Diclazepam is a designer provisions set forth in sections Methoxyphencyclidine is encountered benzodiazepine sold on the internet and 552b(c)(4) and 552b(c)(6), Title 5 U.S.C., by law enforcement in drug seizure most often found as a liquid solution, as amended, and the Determination of reports. 3-Methoxyphencyclidine is an but it may be sold as a powder, tablet, the Director, Strategic Business analogue of the Schedule II blotter paper, or pellet. In 2020, the Initiatives Unit, Office of the Chief hallucinogen PCP. There is no approved NFLIS database reported 113 encounters Operating Officer, CDC, pursuant to medical use for 3- of diclazepam (as of December 2020). In Public Law 92–463. The grant Methoxyphencyclidine in the United 2018, flubromazolam, clonazolam, and applications and the discussions could States and is not a controlled substance dicalazepam were all identified by law disclose confidential trade secrets or under the CSA. If intended for human enforcement in driving under the commercial property such as patentable consumption, 3-Methoxyphencyclidine influence of drugs cases in the United material, and personal information may be treated as a ‘‘controlled States. Flubromazolam, clonazolam, and concerning individuals associated with substance analogue’’ under the CSA diclazepam are not approved for the grant applications, the disclosure of pursuant to 21 U.S.C. 802(32)(A) and medical use in the United States and are which would constitute a clearly 813. As such, additional permanent not controlled substances under the unwarranted invasion of personal controls will be necessary to fulfill U.S. CSA. As such, additional permanent privacy. obligations if 3-Methoxyphencyclidine controls will be necessary to fulfill U.S. Name of Committee: Disease, is controlled under Schedule II of the obligations if flubromazolam, Disability, and Injury Prevention and 1971 Convention. clonazolam, and dicalazepam are Control Special Emphasis Panel (SEP)— Diphenidine (chemical name: 1-(1,2- controlled under Schedule IV of the SIP21–008, Examining Approaches to diphenylethyl) piperidine) is a non- 1971 Convention. Improve Care and Management of competitive NMDA receptor antagonist FDA, on behalf of the Secretary of People with Lupus. classified as a diarylethylamine and HHS, invites interested persons to produces dissociative anesthetic and submit comments on the notifications Date: May 13, 2021. hallucinogenic effects. It was originally from the United Nations concerning Time: 11:00 a.m.–6:00 p.m., EDT. synthesized in the 1920s but reports of these drug substances. FDA, in Place: Teleconference. abuse started in the last decade. Use of cooperation with the National Institute this substance is associated with on Drug Abuse, will consider the Agenda: To review and evaluate grant intoxication and published case reports comments on behalf of HHS in applications. of both fatal and non-fatal overdose evaluating the WHO scheduling FOR FURTHER INFORMATION CONTACT: Jaya outside of the United States. recommendations. Then, under section Raman, Ph.D., Scientific Review Officer, Diphenidine is encountered by law 201(d)(2)(B) of the CSA, HHS will National Center for Chronic Disease enforcement in drug seizure reports. recommend to the Secretary of State Prevention and Health Promotion, CDC, Diphenidine is not approved for what position the United States should 4770 Buford Highway, Mailstop S107–8, medical use in the United States and is take when voting on the Atlanta, Georgia 30341, Telephone (770) not a controlled substance under the recommendations for control of 488–6511, [email protected]. CSA. As such, additional permanent substances under the 1971 Convention controls will be necessary to fulfill U.S. at the CND meeting in April 2021. The Director, Strategic Business obligations if diphenidine is controlled Comments regarding the WHO Initiatives Unit, Office of the Chief under Schedule II of the 1971 recommendations for control of Operating Officer, Centers for Disease Convention. isotonitazene under the 1961 Single Control and Prevention, has been Flubromazolam, clonazolam, and Convention will also be forwarded to delegated the authority to sign Federal diclazepam belong to a class of the relevant Agencies for consideration Register notices pertaining to substances known as benzodiazepines. in developing the U.S. position announcements of meetings and other Benzodiazepines produce central regarding narcotic substances at the committee management activities, for nervous system depression and are CND meeting. both the Centers for Disease Control and

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