[Federal Register Volume 84, Number 41 (Friday, March 1, 2019)]
[Notices]
[Pages 7070-7082]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-03663]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2019-N-0671]


International Drug Scheduling; Convention on Psychotropic 
Substances; Single Convention on Narcotic Drugs; World Health 
Organization; Scheduling Recommendations; Cyclopropyl Fentanyl; 
Methoxyacetyl Fentanyl; Ortho-Fluorofentanyl; Para-Fluorobutyrfentanyl; 
N-Ethylnorpentylone; and Four Additional Substances; Request for 
Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of comment.

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SUMMARY: The Food and Drug Administration (FDA) is providing interested 
persons with the opportunity to submit written comments concerning 
recommendations by the World Health Organization (WHO) to impose 
international manufacturing and distributing restrictions, under 
international treaties, on certain drug substances. The comments 
received in response to this notice will be considered in preparing the 
United States' position on these proposals for a meeting of the United 
Nations Commission on Narcotic Drugs (CND) in Vienna, Austria, in March 
18-22, 2019. This notice is issued under the Controlled Substances Act 
(CSA).

DATES: Submit either electronic or written comments by March 14, 2019.

[[Page 7071]]

The short time period for the submission of comments is needed to 
ensure that the Department of Health and Human Services (HHS) may, in a 
timely fashion, carry out the required action and be responsive to the 
United Nations.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be considered. Electronic comments 
must be submitted on or before March 14, 2019. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of March 14, 2019. Comments received 
by mail/hand delivery/courier (for written/paper submissions) will be 
considered timely if they are postmarked or the delivery service 
acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2019-N-0671 for ``International Drug Scheduling; Convention on 
Psychotropic Substances; Single Convention on Narcotic Drugs; World 
Health Organization; Scheduling Recommendations; Cyclopropyl Fentanyl; 
Methoxyacetyl Fentanyl; Ortho-Fluorofentanyl; Para-Fluorobutyrfentanyl; 
N-Ethylnorpentylone; ADB-FUBINACA; FUB-AMB(MMB-FUBINACA_AMB-FUBINACA); 
ADB-CHMINACA; CUMYL-4CN-BINACA; Request for Comments.'' Received 
comments, those filed in a timely manner (see ADDRESSES), will be 
placed in the docket and, except for those submitted as ``Confidential 
Submissions,'' publicly viewable at https://www.regulations.gov or at 
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through 
Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: http://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: James R. Hunter, Center for Drug 
Evaluation and Research, Controlled Substance Staff, Food and Drug 
Administration, 10903 New Hampshire Ave. Bldg. 51, Rm. 5150, Silver 
Spring, MD 20993-0002, 301-796-3156, [email protected].

SUPPLEMENTARY INFORMATION: 

I. Background

    The United States is a party to the 1971 Convention on Psychotropic 
Substances (Psychotropic Convention). Section 201(d)(2)(B) of the CSA 
(21 U.S.C. 811(d)(2)(B)) provides that when the United States is 
notified under Article 2 of the Psychotropic Convention that the CND 
proposes to decide whether to add a drug or other substance to one of 
the schedules of the Psychotropic Convention, transfer a drug or 
substance from one schedule to another, or delete it from the 
schedules, the Secretary of State must transmit notice of such 
information to the Secretary of HHS. The Secretary of HHS must then 
publish a summary of such information in the Federal Register and 
provide opportunity for interested persons to submit comments. The 
Secretary of HHS must then evaluate the proposal and furnish a 
recommendation to the Secretary of State that shall be binding on the 
representative of the United States in discussions and negotiations 
relating to the proposal.
    As detailed in the following paragraphs, the Secretary of State has 
received notification from the Secretary-General of the United Nations 
(the Secretary-General) regarding five substances to be considered for 
control under the Psychotropic Convention. This notification reflects 
the recommendation from the 41st WHO Expert Committee for Drug 
Dependence (ECDD), which met in November 2018. In the Federal Register 
of October 10, 2018 (83 FR 50938), FDA announced the WHO ECDD review 
and invited interested persons to submit information for WHO's 
consideration.
    The full text of the notification from the Secretary-General is 
provided in section II of this document. Section 201(d)(2)(B) of the 
CSA requires the Secretary of HHS, after receiving a notification 
proposing scheduling, to publish a notice in the Federal Register to 
provide the opportunity for interested persons to submit information 
and comments on the proposed scheduling action.

[[Page 7072]]

    The United States is also a party to the 1961 Single Convention on 
Narcotic Drugs (1961 Single Convention). The Secretary of State has 
received a notification from the Secretary-General regarding four 
substances to be considered for control under this convention. The CSA 
does not require HHS to publish a summary of such information in the 
Federal Register. Nevertheless, to provide interested and affected 
persons an opportunity to submit comments regarding the WHO 
recommendations for narcotic drugs, the notification regarding these 
substances is also included in this Federal Register notice. The 
comments will be shared with other relevant agencies to assist the 
Secretary of State in formulating the position of the United States on 
the control of these substances. The HHS recommendations are not 
binding on the representative of the United States in discussions and 
negotiations relating to the proposal regarding control of substances 
under the 1961 Single Convention.

II. United Nations Notification

    The formal notification from the United Nations that identifies the 
drug substances and explains the basis for the recommendations is 
reproduced as follows (non-relevant text removed):

Reference: NAR/CL.2/2019
    WHO/ECDD41; 1961C-Art.3, 1971C-Art.2 CU
    2019/35/DTA/SGB (A)

    The Secretary-General of the United Nations presents his 
compliments to the Secretary of State of the United States of America 
and has the honour to inform the Government that on 28 January 2019, he 
received a notification from the Director-General of the World Health 
Organization (WHO), pursuant to article 3, paragraphs 1 and 3 of the 
Single Convention on Narcotic Drugs of 1961 as amended by the 1972 
Protocol (1961 Convention), and article 2, paragraphs 1 and 4 of the 
Convention on Psychotropic Substances of 1971 (1971 Convention) with 
the following recommendations regarding ten New Psychoactive Substances 
(NPS):
    Substances recommended to be added to Schedule I of the 1961 
Convention:
    --Parafluorobutyrylfentanyl
    chemical name: N-(4-fluorophenyl)-N-[1-(2-phenylethyl)piperidin-4-
yl]butanamide
    --Ortho-fluorofentanyl
    chemical name: N-(2-fluorophenyl)-N-[1-(2-phenylethyl)piperidin-4-
yl]propanamide
    --Methoxyacetyl fentanyl
    chemical name: 2-methoxy-N-phenyl-N-[1-(2-phenylethyl)piperidin-4-
yl]acetamide
    --Cyclopropylfentanyl
    chemical name: N-Phenyl-N-[1-(2-phenylethyl)piperidin-4-
yl]cyclopropanecarboxamide
    Substances recommended to be added to Schedule II of the 1971 
Convention:
    --ADB-FUBINACA
    chemical name: N-[(2S)-1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[(4-
fluorophenyl)methyl]-1H-indazole-3-carboxamide
    --FUB-AMB (MMB-FUBINACA, AMB-FUBINACA)
    chemical name: methyl (2S)-2-({1-[(4-fluorophenyl)methyl]-1H-
indazole-3-carbonyl{time} amino)-3-methylbutanoate
    --CUMYL-4CN-BINACA
    chemical name: 1-(4-cyanobutyl)-N-(2-phenylpropan-2-yl)-1H-
indazole-3-carboxamide
    --ADB-CHMINACA (MAB-CHMINACA)
    chemical name: N-[(2S)-1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-
(cyclohexylmethyl)-1H-indazole-3-carboxamide
    --N-Ethylnorpentylone (ephylone)
    chemical name: 1-(2H-1,3-benzodioxol-5-yl)-2-(ethylamino)pentan-1-
one
    In the letter from the Director-General of the World Health 
Organization to the Secretary-General, reference is also made to the 
recommendation by the forty-first meeting of the WHO Expert Committee 
on Drug Dependence (ECDD) to keep the following New Psychoactive 
Substance under surveillance:
    --Paramethoxybutyrylfentanyl
    chemical name: N-(4-methoxyphenyl)-N-[1-(2-phenylethyl)piperidin-4-
yl]butanamide
    In addition, in the letter from the Director-General of the World 
Health Organization to the Secretary-General, reference is made to the 
recommendations by the forty-first meeting of the WHO ECDD to keep the 
following two pain-relieving medicines under surveillance:
    --Pregabalin
    chemical name: (3S)-3-(aminomethyl)-5-methylhexanoic acid
    --Tramadol
    chemical name: (1R*,2R*)-2-[(dimethylamino)methyl]-1-
(3methoxyphenyl)cyclohexan-1-ol
    In accordance with the provisions of article 3, paragraph 2 of the 
1961 Convention and article 2, paragraph 2 of the 1971 Convention, the 
Secretary-General hereby transmits the notification as annex I to the 
present note. In connection with the notification, WHO has also 
submitted the relevant extract from the report of the forty-first 
meeting of the WHO ECDD which is hereby transmitted as annex II. For 
time reasons, this notification and its annexes I and II are 
transmitted in English only. The notification will be transmitted in 
French and Spanish as soon as it becomes available.
    Also in accordance with the same provisions, the notification from 
WHO will be brought to the attention of the sixty-second session of the 
Commission on Narcotic Drugs (from 14 to 22 March 2019) in document E/
CN.7/2019/8 which will be made available on the website of the 62nd 
session of the CND:
    http://www.unodc.org/unodc/en/commissions/CND/session/62_Session_2019/session-62-of-the-commission-on-narcotic-drugs.html.
    In order to assist the Commission in reaching a decision, it would 
be appreciated if the Government could communicate any comments it 
considers relevant to the possible scheduling of New Psychoactive 
Substances recommended by WHO to be placed under international control 
under the 1961 Convention, namely:
    --Parafluorobutyrylfentanyl; Ortho-fluorofentanyl; Methoxyacetyl 
fentanyl; Cyclopropylfentanyl
    as well as any economic, social, legal, administrative or other 
factors that it considers relevant to the possible scheduling of New 
Psychoactive Substances recommended by WHO to be placed under 
international control under the 1971 Convention, namely:
    --ADB-FUBINACA, FUB-AMB (MMB-FUBINACA, AMB-FUBINACA), CUMYL-4CN-
BINACA, ADB-CHMINACA (MAB-CHMINACA), N-Ethylnorpentylone (ephylone).
    Communications should be sent to the Executive Director of the 
United Nations Office on Drugs and Crime, c/o Secretary, Commission on 
Narcotic Drugs, P.O. Box 500, 1400 Vienna, Austria, email: [email protected] (fax: +43-1-26060-5885), at the latest by 28 February 2019.

1 February 2019

His Excellency

Mr. Michael Pompeo

Secretary of State of the United States of America
Annex I
Letter addressed to the Secretary-General of the United Nations from 
the Director-General of the World Health Organization, dated 24 January 
2019
    ``The forty-first meeting of the WHO Expert Committee on Drug 
Dependence (ECDD) convened from 12 to 16 November 2018 at WHO 
headquarters in Geneva. The objective of this meeting was to carry out 
an in-depth evaluation of psychoactive substances in order to determine 
whether the World Health

[[Page 7073]]

Organization (WHO) should recommend if these substances should be 
placed under international control or if their level of control should 
be changed.
    The forty-first WHO ECDD reviewed ten New Psychoactive Substances 
(NPS), five of which are synthetic opioids and two pain-relieving 
medicines; pregabalin and tramadol. The ECDD scheduling recommendations 
for these substances are detailed below.
    In addition, the forty-first WHO ECDD critically reviewed cannabis 
and cannabis-related substances. The recommendations regarding cannabis 
and cannabis-related substances are communicated to you through a 
separate letter under the same date as this letter.
    With reference to Article 3, paragraphs 1 and 3 of the Single 
Convention on Narcotic Drugs (1961), as amended by the 1972 Protocol, 
and Article 2, paragraphs 1 and 4 of the Convention on Psychotropic 
Substances (1971), I am pleased to submit recommendations of the forty-
first meeting of the ECDD regarding NPS and two pain-relieving 
medicines, tramadol and pregabalin, as follows:

New Psychoactive Substances

    To be added to Schedule I of the Single Convention on Narcotic 
Drugs (1961):

--Parafluorobutyrylfentanyl
chemical name: N-(4-fluorophenyl)-N-[1-(2-phenylethyl)piperidin-4-
yl]butanamide
--Ortho-fluorofentanyl
chemical name: N-(2-fluorophenyl)-N-[1-(2-phenylethyl)piperidin-4-
yl]propanamide
--Methoxyacetyl fentanyl
chemical name: 2-methoxy-N-phenyl-N-[1-(2-phenylethyl)piperidin-4-
yl]acetamide
--Cyclopropylfentanyl
chemical name: N-Phenyl-N-[1-(2-phenylethyl)piperidin-4- 
yl]cyclopropanecarboxamide

    To be added to Schedule II of the Convention on Psychotropic 
Substances (1971):

--ADB-FUBINACA
chemical name: N-[(2S)-1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[(4- 
fluorophenyl)methyl]-1H-indazole-3-carboxamide
--FUB-AMB (MMB-FUBINACA, AMB-FUBINACA)
chemical name: methyl (2S)-2-({1-[(4-fluorophenyl)methyl]-1H- indazole-
3-carbonyl{time} amino)-3-methylbutanoate
--CUMYL-4CN-BINACA
chemical name: 1-(4-cyanobutyl)-N-(2-phenylpropan-2-yl)-1H- indazole-3-
carboxamide
--ADB-CHMINACA (MAB-CHMINACA)
chemical name: N-[(2S)-1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1- 
(cyclohexylmethyl)-1H-indazole-3-carboxamide
--N-Ethylnorpentylone (ephylone)
chemical name: 1-(2H-1,3-benzodioxol-5-yl)-2-(ethylamino)pentan-1-one

    To be kept under surveillance:

--Paramethoxybutyrylfentanyl
chemical name: N-(4-methoxyphenyl)-N-[1-(2-phenylethyl)piperidin-4- 
yl]butanamide

Medicines

    To be kept under surveillance:

--Pregabalin
chemical name: (3S)-3-(aminomethyl)-5-methylhexanoic acid
--Tramadol
chemical name: (1R*,2R*)-2-[(dimethylamino)methyl]-1-
(3methoxyphenyl)cyclohexan-1-ol

    The assessments and findings on which they are based are set out in 
detail in the forty-first report of the WHO Expert Committee on Drug 
Dependence. An extract of the report is attached in Annex II of this 
letter.
    I am very pleased with the ongoing collaboration between WHO, the 
United Nations Office on Drugs and Crime (UNODC) and the International 
Narcotics Control Board (INCB), and in particular, how this 
collaboration has benefited the work of the WHO Expert Committee on 
Drug Dependence (including through the participation of UNODC and INCB 
in the forty-first meeting of the ECDD), and more generally, the 
implementation of the operational recommendations of the United Nations 
General Assembly Special Session (UNGASS) 2016.

[signed]
Annex II
Extract from the Report of the 41st Expert Committee on Drug 
Dependence: Fentanyl analogues, synthetic cannabinoids, cathinones, and 
medicines: pregabalin and tramadol

1. Fentanyl Analogues

1.1 Para-fluoro-butyrylfentanyl

Substance identification
    Para-fluoro-butyrylfentanyl (N-(4-fluorophenyl)-N-[1-(2-
phenylethyl)piperidin-4-yl]butanamide) is a synthetic analogue of the 
opioid analgesic fentanyl. Samples obtained from seizures and from 
other collections suggest that para-fluoro-butyrylfentanyl appears in 
powder, tablet, nasal spray and vaping form.
WHO review history
    Para-fluoro-butyrylfentanyl has not been previously pre-reviewed or 
critically reviewed by the WHO Expert Committee on Drug Dependence 
(ECDD) [the Committee]. A direct critical review was proposed based on 
information brought to WHO's attention that para-fluoro-butyrylfentanyl 
poses serious risk to public health and has no recognised therapeutic 
use.
Similarity to known substances and effects on the central nervous 
system
    Para-fluoro-butyrylfentanyl binds to [mu]-opioid receptors with 
high selectivity over [kappa]- and [delta]-opioid receptors and has 
been shown to act as a partial agonist at the [mu]-opioid receptor. In 
animals, it produces typical opioid effects including analgesia, with a 
potency between that of morphine and fentanyl. In cases of non-fatal 
intoxication in humans, para-fluoro-butyrylfentanyl has produced signs 
and symptoms such as disorientation, slurred speech, unsteady gait, 
hypotension and pupil constriction that are consistent with an opioid 
mechanism of action.
    Para-fluoro-butyrylfentanyl can be readily converted to its isomer 
p-fluoro-isobutyrylfentanyl (N-(4-fluorophenyl)-2-methyl-N-[1-(2-
phenylethyl)piperidin-4-yl]propanamide), which is an opioid listed in 
Schedule I of the 1961 Single Convention on Narcotic Drugs.
Dependence potential
    There are no studies of the dependence potential of this substance 
in humans or laboratory animals. However, based on its mechanism of 
action, para-fluoro-butyrylfentanyl would be expected to produce 
dependence similar to other opioid drugs.
Actual abuse and/or evidence of likelihood of abuse
    There are no controlled studies of the abuse potential of para-
fluoro-butyrylfentanyl and there is very little information on the 
extent of abuse. The substance has been detected in biological samples 
obtained from cases of fatal and non-fatal intoxication. Fatalities 
have been reported in some countries where the compound has been 
identified in biological fluids in combination with other drugs, 
including cases where death has been attributed to the effects of para-
fluoro-butyrylfentanyl.
Therapeutic applications/usefulness
    Para-fluoro-butyrylfentanyl is not known to have any therapeutic 
uses.
Recommendation
    Para-fluoro-butyrylfentanyl is an opioid receptor agonist that has 
significant potential for dependence and

[[Page 7074]]

likelihood of abuse. The limited available evidence indicates that it 
has typical opioid adverse effects that include the potential for death 
due to respiratory depression. Para-fluoro-butyrylfentanyl has caused 
substantial harm and has no therapeutic usefulness. As it is liable to 
similar abuse and produces similar ill-effects as many other opioids 
placed in Schedule I of the 1961 Single Convention on Narcotic Drugs:
     Recommendation 1.1: The Committee recommended that Para-
fluoro-butyryl fentanyl (N-(4-fluorophenyl)-N-[1-(2-
phenylethyl)piperidin-4-yl]butanamide) be added to Schedule I of the 
1961 Single Convention on Narcotic Drugs.

1.2 Para-methoxy-butyryl fentanyl

Substance identification
    Para-methoxy-butyrylfentanyl (N-(4-methoxyphenyl)-N-[1-(2-
phenylethyl)piperidin-4-yl]butanamide) is a synthetic analogue of the 
opioid analgesic fentanyl. Samples obtained from seizures and from 
other collections suggest that para-methoxy-butyrylfentanyl occurs in 
powder, tablet, and nasal spray forms.
WHO review history
    Para-methoxy-butyrylfentanyl has not been previously pre-reviewed 
or critically reviewed by the WHO ECDD. A critical review was proposed 
based on information brought to WHO's attention that para-methoxy-
butyrylfentanyl poses serious risk to public health and has no 
recognised therapeutic use.
Similarity to known substances and effects on the central nervous 
system
    Para-methoxy-butyrylfentanyl binds to [mu]-opioid receptors with 
high selectivity over [kappa]- and [delta]-opioid receptors and has 
been shown to act as a partial agonist at the [mu]-opioid receptor. In 
animals, it produces typical opioid effects, including analgesia, and 
in some tests it has a potency higher than morphine and close to that 
of fentanyl.
    Reported clinical features of intoxication in which para-methoxy-
butyrylfentanyl is involved included the typical opioid effects of 
reduced level of consciousness, respiratory depression and pupil 
constriction. In some cases, treatment with the opioid antagonist 
naloxone was shown to reverse the drug-induced respiratory depression. 
While this is consistent with an opioid mechanism of action, it should 
be noted that in all such cases at least one other opioid was present.
Dependence potential
    There are no studies of the dependence potential of this substance 
in humans or laboratory animals. However, based on its mechanism of 
action, Para-methoxy-butyrylfentanyl would be expected to produce 
dependence similar to other opioid drugs.
Abuse potential and/or evidence of likelihood of abuse
    There are no controlled studies of the abuse potential of Para-
methoxy-butyrylfentanyl and very little information on the extent of 
abuse. Para-methoxy-butyrylfentanyl has been detected in biological 
samples obtained from a limited number of acute intoxication cases. 
Reported clinical features are consistent with opioid effects and 
including respiratory depression. However, in all of the documented 
cases of severe adverse events associated with use of para-methoxy-
butyrylfentanyl, other fentanyl derivatives were detected and hence the 
role of para-methoxy-butyrylfentanyl is not clear.
Therapeutic applications/usefulness
    Para-methoxy-butyrylfentanyl is not known to have any therapeutic 
uses.
Recommendation
    The limited available information indicates that para-methoxy-
butyrylfentanyl is an opioid drug, and an analogue of the opioid 
analgesic fentanyl. There is evidence of its use in a limited number of 
countries with few reports of intoxication and no reports of deaths. In 
the intoxication cases, the role of para-methoxy-butyrylfentanyl was 
not clear due to the presence of other opioids. It has no therapeutic 
usefulness. At this time, there is little evidence of the impact of 
para-methoxy-butyrylfentanyl in causing substantial harm that would 
warrant its placement under international control.
     Recommendation 1.2: The Committee recommended that para-
methoxy-butyrylfentanyl (N-(4-methoxyphenyl)-N-[1-(2-
phenylethyl)piperidin-4-yl]butanamide) be kept under surveillance by 
the WHO Secretariat.

1.3 Ortho-fluorofentanyl

Substance identification
    Ortho-fluorofentanyl (N-(2-fluorophenyl)-N-[1-(2-
phenylethyl)piperidin-4-yl]propanamide) is a synthetic analogue of the 
opioid analgesic fentanyl. It has two positional isomers (para-
fluorofentanyl and meta-fluorofentanyl).
WHO review history
    Ortho-fluorofentanyl has not been previously pre-reviewed or 
critically reviewed by the WHO ECDD. A direct critical review was 
proposed based on information brought to WHO's attention that ortho-
fluorofentanyl poses a serious risk to public health and has no 
recognised therapeutic use.
Similarity to known substances and effects on the central nervous 
system
    Receptor binding data show that ortho-fluorofentanyl binds to [mu]-
opioid receptors with high selectivity over [kappa]- and [delta]-opioid 
receptors. There were no preclinical or clinical studies available in 
the scientific literature. However, the clinical features present in 
non-fatal intoxication cases include characteristic opioid effects such 
as loss of consciousness, pupil constriction and respiratory 
depression. The effects of ortho-fluorofentanyl are responsive to the 
administration of the opioid antagonist naloxone, further confirming 
its opioid agonist mechanism of action.
Dependence potential
    There are no studies of the dependence potential of ortho-
fluorofentanyl in humans or laboratory animals. However, based on its 
mechanism of action, it would be expected to produce dependence similar 
to other opioid drugs.
Actual abuse and/or evidence of likelihood of abuse
    There are no available preclinical or clinical studies to assess 
the abuse liability of ortho-fluorofentanyl. There is evidence of use 
from several countries, including seizures in Europe and the United 
States. A number of confirmed fatalities associated with the compound 
have been reported. Ortho-fluorofentanyl is being sold as heroin or an 
adulterant in heroin. A number of fatalities have been associated with 
this substance (1 in Europe and 16 in the United States since 2016). As 
a consequence of ortho-fluorofentanyl cross-reacting with standard 
fentanyl immunoassays, it is possible that deaths due to ortho-
fluorofentanyl have been attributed to fentanyl and hence the number of 
recorded ortho-fluorofentanyl deaths may be an underestimate. Several 
countries in different parts of the world have controlled ortho-
fluorofentanyl.
Therapeutic applications/usefulness
    Ortho-fluorofentanyl is not known to have any therapeutic uses.

[[Page 7075]]

Recommendation
    Ortho-fluorofentanyl is an opioid receptor agonist that has 
potential for dependence and likelihood of abuse. The limited available 
evidence indicates that it has typical opioid adverse effects that 
include the potential for death due to respiratory depression. Ortho-
fluorofentanyl has caused substantial harm and has no therapeutic 
usefulness. As it is liable to similar abuse and produces similar ill-
effects as many other opioids placed in Schedule I of the 1961 Single 
Convention on Narcotic Drugs:
     Recommendation 1.3: The Committee recommended that ortho-
fluorofentanyl (N-(2-fluorophenyl)-N-[1-(2-phenylethyl)piperidin-4-
yl]propanamide) be added to Schedule I of the 1961 Single Convention on 
Narcotic Drugs.

1.4 Methoxyacetylfentanyl

Substance identification
    Methoxyacetylfentanyl (2-methoxy-N-phenyl-N-[1-(2-
phenylethyl)piperidin-4-yl] acetamide) is a synthetic analogue of the 
opioid fentanyl. Samples obtained from seizures and from other 
collections suggest that methoxyacetylfentanyl has appeared in powders, 
liquids, and tablets.
WHO review history
    Methoxyacetylfentanyl has not been previously pre-reviewed or 
critically reviewed by the WHO ECDD. A critical review was proposed 
based on information brought to WHO's attention that 
methoxyacetylfentanyl poses serious risk to public health and has no 
recognised therapeutic use.
Similarity to known substances and effects on the central nervous 
system
    Methoxyacetylfentanyl binds to [mu]-opioid receptors with high 
selectivity over [kappa]- and [delta]-opioid receptors and has been 
shown to act as an agonist at the [mu]-opioid receptor. In animals, it 
produces analgesia with a potency higher than morphine and close to 
that of fentanyl. The analgesia was blocked by the opioid antagonist 
naltrexone, confirming its opioid mechanism of action.
    In people using methoxyacetylfentanyl the most serious acute health 
risk is respiratory depression, which in overdose can lead to 
respiratory arrest and death. This is consistent with its opioid 
mechanism of action.
Dependence potential
    There are no studies of the dependence potential of this substance 
in humans or laboratory animals. However, based on its mechanism of 
action, methoxyacetylfentanyl would be expected to produce dependence 
similar to other opioid drugs.
Actual abuse and/or evidence of likelihood of abuse
    In the animal drug discrimination model of subjective drug effects, 
methoxyacetylfentanyl produced effects similar to those of morphine. It 
also decreased activity levels and both the discriminative and rate-
decreasing effects were blocked by the opioid antagonist naltrexone. 
Based on its receptor action and these effects in animal models, it 
would be expected that methoxyacetylfentanyl would be subject to abuse 
in a manner comparable to other opioids.
    There is evidence that methoxyacetyl- fentanyl has been used by 
injection and by nasal insufflation of powder. A large number of 
seizures of this substance have been reported in Europe and the United 
States. A number of deaths have been reported in Europe and the United 
States in which methoxyacetylfentanyl was detected in post-mortem 
samples. While other drugs were present in most of these cases, 
methoxyacetylfentanyl was deemed the cause of death or a major 
contributor to death in a significant proportion of these. Several 
countries have controlled methoxyacetylfentanyl in their national 
legislation.
Therapeutic applications/usefulness
    Methoxyacetylfentanyl is not known to have any therapeutic uses.
    The committee considered that methoxyacetylfentanyl is a substance 
with high abuse liability and dependence potential. It is an opioid 
agonist that is more potent than morphine and its use has contributed 
to a large number of deaths in different regions. It has no therapeutic 
usefulness and it poses a significant risk to public health. The 
Committee considered that the evidence of its abuse warrants placement 
under international control.
    Recommendation 1.4: The Committee recommended that 
methoxyacetylfentanyl (2-methoxy-N-phenyl-N-[1-(2-
phenylethyl)piperidin-4-yl] acetamide) be added to Schedule I of the 
Single Convention on Narcotic Drugs of 1961.

1.5 Cyclopropylfentanyl

Substance identification
    Cyclopropylfentanyl ((N-phenyl-N-1-(2-phenylethyl)-4-piperidyl) 
cyclopropanecarboxamide) is a synthetic analogue of the opioid 
fentanyl. Samples obtained from seizures and from other collections 
suggest that cyclopropylfentanyl has appeared in powders, liquids, and 
tablets.
WHO review history
    Cyclopropylfentanyl has not been previously pre-reviewed or 
critically reviewed by the WHO ECDD. A critical review was proposed 
based on information brought to WHO's attention that 
cyclopropylfentanyl poses a serious risk to public health and has no 
recognised therapeutic use.
Similarity to known substances and effects on the central nervous 
system
    Cyclopropylfentanyl binds selectively to the [mu] opioid receptors 
compared to [delta] and [kappa] opioid receptors. There is no further 
information on the actions and effects of cyclopropylfentanyl from 
controlled studies. Based on its role in numerous deaths, as described 
below, it is reasonable to consider that cyclopropylfentanyl acts as a 
[mu] opioid receptor agonist similar to morphine and fentanyl.
Dependence potential
    There are no preclinical or clinical studies published in the 
scientific literature concerning dependence on cyclopropylfentanyl. 
However, based on its mechanism of action, cyclopropylfentanyl would be 
expected to produce dependence similar to other opioid drugs.
Actual abuse and/or evidence of likelihood of abuse
    A large number of seizures of cyclopropylfentanyl have been 
reported from countries in different regions. In some countries, this 
substance has been among the most common fentanyl analogues detected in 
post-mortem samples. In almost all of these deaths, cyclopropylfentanyl 
was determined to either have caused or contributed to death, even in 
presence of other substances.
Therapeutic applications/usefulness
    Cyclopropylfentanyl is not known to have any therapeutic uses.
Recommendation
    The available evidence indicates that cyclopropylfentanyl has 
opioid actions and effects. It has been extensively trafficked and has 
been used by several different routes of administration. Its use has 
been associated with a large number of documented deaths, and for most 
of these it has been the principal cause of death. Cyclopropylfentanyl 
has

[[Page 7076]]

no known therapeutic use and has been associated with substantial harm.
     Recommendation 1.5: The Committee recommended that 
cyclopropylfentanyl (N-Phenyl-N-[1-(2-phenylethyl)piperidin-4-
yl]cyclopropanecarboxamide) be added to Schedule I of the 1961 Single 
Convention on Narcotic Drugs.

2. Synthetic cannabinoids

2.1 ADB-FUBINACA

Substance identification
    ADB-FUBINACA (N-[(2S)-1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[(4-
fluorophenyl)methyl]-1H-indazole-3-carboxamide) is encountered as a 
powder, in solution or sprayed on herbal material that mimics the 
appearance of cannabis. It is sold as herbal incense or branded 
products with a variety of different names.
WHO review history
    ADB-FUBINACA has not been previously pre-reviewed or critically 
reviewed by the WHO Expert Committee on Drug Dependence (ECDD). A 
critical review was proposed based on information brought to WHO's 
attention that ADB-FUBINACA poses serious risk to public health and has 
no recognised therapeutic use.
Similarity to known substances/effects on the central nervous system
    ADB-FUBINACA is similar to other synthetic cannabinoid receptor 
agonists that are currently scheduled under the Convention on 
Psychotropic Substances of 1971. It binds to both the CB1 
and CB2 cannabinoid receptors with full agonist activity as 
demonstrated by in vitro studies. The efficacy and potency of ADB-
FUBINACA is substantially greater when compared to [Delta]\9\-THC. 
Reported clinical features of intoxication include confusion, 
agitation, somnolence, hypertension and tachycardia, similar to other 
synthetic cannabinoid receptor agonists.
Dependence potential
    No controlled experimental studies examining the dependence 
potential of ADB-FUBINACA in humans or animals were available. However, 
based on its central nervous system action as a full CB1 
agonist, ADB-FUBINACA would be expected to produce dependence in a 
manner similar to or more pronounced than cannabis.
Actual abuse and/or evidence of likelihood of abuse
    ADB-FUBINACA is sold and used as a substitute for cannabis. It is 
invariably smoked or vaped (i.e. using an e-cigarette) but due to the 
nature of synthetic cannabinoid products (whereby drug components are 
introduced onto herbal material), users are unaware of which synthetic 
cannabinoid may be contained within such products. Evidence from case 
reports in which ADB-FUBINACA has been detected in biological samples 
has demonstrated that use of this substance has contributed to severe 
adverse reactions in humans including death. However, it was also noted 
that other substances, including other synthetic cannabinoids, were 
also present in the urine or blood following non-fatal and fatal 
intoxications and/or in the product used. Evidence of use has been 
reported in Europe, the United States and Asia. In recognition of its 
abuse and associated harm, ADB-FUBINACA has been placed under national 
control in a number of countries in several different regions.
Therapeutic applications/usefulness
    There are currently no approved medical or veterinary uses of ADB-
FUBINACA.
Recommendation
    ADB-FUBINACA is a synthetic cannabinoid receptor agonist that is 
used by smoking plant material sprayed with the substance or inhaling 
vapour after heating. Its mode of action suggests the potential for 
dependence and likelihood of abuse. Its use has been associated with a 
range of severe adverse effects including death. These effects are 
similar to those produced by other synthetic cannabinoids which have a 
mechanism of action the same as that of ADB-FUBINACA and which are 
placed in Schedule II of the Convention on Psychotropic Substances of 
1971. ADB-FUBINACA has no therapeutic usefulness.
     Recommendation 2.1: The Committee recommended that ADB-
FUBINACA (N-[(2S)-1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-[(4-
fluorophenyl)methyl]-1H-indazole-3-carboxamide) be added to Schedule II 
of the Convention on Psychotropic Substances of 1971.

2.2 FUB-AMB

Substance identification
    FUB-AMB (chemical name: methyl (2S)-2-({1-[(4-fluorophenyl)methyl]-
1H-indazole-3- carbonyl{time} amino)-3-methylbutanoate) is a synthetic 
cannabinoid that is also referred to as MMB-FUBINACA and AMB-FUBINACA. 
FUB-AMB is encountered as a powder, in solution or sprayed on herbal 
material that mimics the appearance of cannabis. It is sold as herbal 
incense or branded products with a variety of different names.
WHO review history
    FUB-AMB has not been previously pre-reviewed or critically reviewed 
by the WHO ECDD. A critical review was proposed based on information 
brought to WHO's attention that FUB-AMB poses serious risk to public 
health and has no recognised therapeutic use.
Similarity to known substances/effects on the central nervous system
    FUB-AMB is similar to other synthetic cannabinoid receptor agonists 
that are currently scheduled under the Convention on Psychotropic 
Substances of 1971. It binds to both the CB1 and 
CB2 cannabinoid receptors with full agonist activity as 
demonstrated by in vitro studies. The efficacy and potency of FUB-AMB 
is substantially greater than [Delta] \9\-THC and it shares effects 
with other synthetic cannabinoids including severe central nervous 
system depression, resulting in slowed behaviour and speech.
Dependence potential
    No controlled experimental studies examining the dependence 
potential of FUB-AMB in humans or animals were available. However, 
based on its central nervous system action as a full CB1 
agonist, FUB-AMB would be expected to produce dependence in a manner 
similar to or more pronounced than cannabis.
Actual abuse and/or evidence of likelihood of abuse
    Consistent with its CB1 cannabinoid receptor agonist 
activity, FUB-AMB produces complete dose-dependent substitution for the 
discriminative stimulus effects of [Delta]\9\-THC in mice by various 
routes of administration. This suggests that it has abuse potential at 
least as great as that of [Delta]\9\-THC.
    Evidence of the use of FUB-AMB has been reported in Europe, the 
United States and New Zealand. It is usually smoked or vaped (i.e. 
using an e-cigarette) but due to the nature of synthetic cannabinoid 
products (whereby drug components are introduced onto herbal material), 
users are unaware of which synthetic cannabinoid may be contained 
within such products.
    FUB-AMB use was confirmed in case reports of a mass intoxication in 
the United States with the predominant symptom being severe central 
nervous system depression, resulting in slowed behaviour and speech. It 
was reported that in New Zealand there were at least

[[Page 7077]]

20 deaths related to the use of FUB-AMB. It was noted that the amounts 
of FUB-AMB in confiscated products were 2 to 25 times greater than 
those reported in the incidents in the United States.
Therapeutic applications/usefulness
    There are currently no approved medical or veterinary uses of FUB-
AMB.
Recommendation
    FUB-AMB is a synthetic cannabinoid receptor agonist that is used by 
smoking plant material sprayed with the substance or inhaling vapour 
after heating. Its mode of action suggests the potential for dependence 
and likelihood of abuse. Its use has been associated with a range of 
severe adverse effects including a number of deaths. Its mechanism of 
action and manner of use are similar to other synthetic cannabinoids 
placed in Schedule II of the Convention on Psychotropic Substances of 
1971. FUB-AMB has no therapeutic usefulness.
     Recommendation 2.2: The Committee recommended that FUB-AMB 
(chemical name: methyl (2S)-2-({1-[(4-fluorophenyl)methyl]-1H-indazole-
3-carbonyl{time} amino)-3-methylbutanoate) be added to Schedule II of 
the Convention on Psychotropic Substances of 1971.

2.3 ADB-CHMINACA

Substance identification
    ADB-CHMINACA (N-[(2S)-1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-
(cyclohexylmethyl)indazole-3-carboxamide) is a synthetic cannabinoid 
that is also referred to as MAB-CHMINACA. ADB-CHMINACA is encountered 
as a powder, in solution or sprayed on herbal material that mimics the 
appearance of cannabis. It is sold as herbal incense or branded 
products with a variety of different names.
WHO review history
    ADB-CHMINACA has not been previously pre-reviewed or critically 
reviewed by the WHO ECDD. A critical review was proposed based on 
information brought to WHO's attention that ADB-CHMINACA poses a 
serious risk to public health and has no recognised therapeutic use.
Similarity to known substances/effects on the central nervous system
    ADB-CHMINACA is similar to other synthetic cannabinoid receptor 
agonists that are currently scheduled under the Convention on 
Psychotropic Substances of 1971. It binds to both the CB1 
and CB2 cannabinoid receptors with full agonist activity as 
demonstrated by in vitro studies. The efficacy and potency of ADB-
CHMINACA is substantially greater than [Delta]\9\-THC and it is among 
the most potent synthetic cannabinoids studied to date. It shares a 
profile of central nervous system mediated effects with other synthetic 
cannabinoids. ADB-CHMINACA demonstrates decreased locomotor activity in 
mice in a time and dose dependent fashion with a rapid onset of action 
and long-lasting effects.
    Signs and symptoms of intoxication arising from use of ADB-CHMINACA 
have included tachycardia, unresponsiveness, agitation, combativeness, 
seizures, hyperemesis, slurred speech, delirium and sudden death. These 
are consistent with the effects of other synthetic cannabinoids.
Dependence potential
    No controlled experimental studies examining the dependence 
potential of ADB-CHMINACA in humans or animals were available. However, 
based on its central nervous system action as a full CB1 
agonist, ADB-CHMINACA would be expected to produce dependence in a 
manner similar to or more pronounced than cannabis.
Actual abuse and/or evidence of likelihood of abuse
    Consistent with its CB1 cannabinoid receptor agonist 
activity, ADB-CHMINACA fully substituted for [Delta]\9\-THC in drug 
discrimination tests. This suggests that it has abuse potential at 
least as great as that of [Delta]\9\-THC.
    Evidence of the use of ADB-CHMINACA has been reported in Europe, 
the United States and Japan, including cases of driving under the 
influence. It is invariably smoked or vaped (i.e. using an e-cigarette) 
but due to the nature of synthetic cannabinoid products (whereby drug 
components are introduced onto herbal material), users are unaware of 
which synthetic cannabinoid may be contained within such products.
    ADB-CHMINACA use was analytically confirmed in case reports of 
several drug-induced clusters of severe illness and death in the United 
States. In Europe, 13 deaths with analytically confirmed use of ADB-
CHMINACA were reported between 2014 and 2016, and another death 
occurred in Japan.
Therapeutic applications/usefulness
    There are currently no approved medical or veterinary uses of ADB-
CHMINACA.
Recommendation
    ADB-CHMINACA is a synthetic cannabinoid receptor agonist that is 
used by smoking plant material sprayed with the substance or inhaling 
vapour after heating. It has effects that are similar to other 
synthetic cannabinoid receptor agonists placed in Schedule II of the 
Convention on Psychotropic Substances of 1971. Its mode of action 
suggests the potential for dependence and likelihood of abuse. Its use 
has resulted in numerous cases of severe intoxication and death. There 
is evidence that ADB-CHMINACA has been associated with fatal and non-
fatal intoxications in a number of countries. The substance causes 
substantial harm and has no therapeutic usefulness.
    Recommendation 2.3: The Committee recommended that ADB-CHMINACA 
(chemical name: N-[(2S)-1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-
(cyclohexylmethyl)-1H-indazole-3-carboxamide) be added to Schedule II 
of the Convention on Psychotropic Substances of 1971.

2.4 CUMYL-4CN-BINACA

Substance identification
    CUMYL-4CN-BINACA (chemical name: 1-(4-cyanobutyl)-N-(2-
phenylpropan-2-yl)-1H-indazole-3-carboxamide) is a synthetic 
cannabinoid. It is encountered as a powder, in solution or sprayed on 
herbal material that mimics the appearance of cannabis. It is sold as 
herbal incense or branded products with a variety of different names.
WHO review history
    CUMYL-4CN-BINACA has not been previously pre-reviewed or critically 
reviewed by the WHO ECDD. A critical review was proposed based on 
information brought to WHO's attention that CUMYL-4CN-BINACA poses 
serious risk to public health and has no recognised therapeutic use.
Similarity to known substances/effects on the central nervous system
    CUMYL-4CN-BINACA is similar to other synthetic cannabinoid receptor 
agonists that are currently scheduled under the Convention on 
Psychotropic Substances of 1971. It binds to both the CB1 
and CB2 cannabinoid receptors with full agonist activity as 
demonstrated by in vitro studies. The efficacy and potency of CUMYL-
4CN-BINACA is substantially greater than [Delta]\9\-THC and it shares a 
profile of central nervous system mediated effects with other synthetic 
cannabinoids. Data have shown that it produced hypothermia in mice in 
common with other CB1 cannabinoid receptor agonists.

[[Page 7078]]

Dependence potential
    No controlled experimental studies examining the dependence 
potential of CUMYL-4CN-BINACA in humans or animals were available. 
However, based on its central nervous system action as a full 
CB1 agonist, CUMYL-4CN-BINACA would be expected to produce 
dependence in a manner similar to or more pronounced than cannabis.
Actual abuse and/or evidence of likelihood of abuse
    Consistent with its CB1 cannabinoid receptor agonist 
activity, CUMYL-4CN-BINACA fully substituted for [Delta]\9\-THC in drug 
discrimination tests. This suggests that it has abuse potential at 
least as great as that of [Delta]\9\-THC.
    Evidence of the use of CUMYL-4CN-BINACA has been currently reported 
only from Europe but this may be due to under-reporting including 
through lack of detection in other countries. In Europe, CUMYL-4CN-
BINACA has been among the most frequently seized synthetic 
cannabinoids. It is invariably smoked or vaped (i.e. using an e-
cigarette) but due to the nature of synthetic cannabinoid products 
(whereby drug components are introduced onto herbal material), users 
are unaware of which synthetic cannabinoid may be contained within such 
products.
    A number of non-fatal intoxications involving CUMYL-4CN-BINACA have 
been reported. CUMYL-4CN-BINACA has been analytically confirmed as 
being present in 11 fatalities and 5 non-fatal intoxications in Europe. 
In 2 deaths, CUMYL-4CN-BINACA was the only drug present.
Therapeutic applications/usefulness
    There are currently no approved medical or veterinary uses of 
CUMYL-4CN-BINACA.
Recommendation
    CUMYL-4CN-BINACA is a synthetic cannabinoid receptor agonist that 
is used by smoking plant material sprayed with the substance or 
inhaling vapour after heating and is sold under a variety of brand 
names. It has effects that are similar to other synthetic cannabinoid 
receptor agonists placed in Schedule II of the Convention on 
Psychotropic Substances of 1971. Its mode of action suggests the 
potential for dependence and likelihood of abuse. There is evidence 
that CUMYL-4CN-BINACA has been associated with fatal and non-fatal 
intoxications in a number of countries. The substance causes 
substantial harm and has no therapeutic usefulness.
     Recommendation 2.4: The Committee recommended that CUMYL-
4CN-BINACA (chemical name: 1-(4-cyanobutyl)-N-(2-phenylpropan-2-yl)-1H-
indazole-3-carboxamide) be added to Schedule II of the Convention on 
Psychotropic Substances of 1971.

3. Cathinone

3.1 N-ethylnorpentylone

Substance identification
    N-Ethylnorpentylone (chemical name: 1-(2H-1,3-benzodioxol-5-yl)-2-
(ethylamino)pentan-1-one) is a ring-substituted synthetic cathinone 
analogue that originally emerged in the 1960s during pharmaceutical 
drug development efforts. It is also known as ephylone and incorrectly 
referred to as N-ethylpentylone. In its pure form, N-Ethylnorpentylone 
exists as a racemic mixture in form of a powder or crystalline solid. 
However, the substance is usually available as a capsule, powered 
tablet, pill and powder often sold as ``Ecstasy'' or MDMA. N-
Ethylnorpentylone is also available in its own right and is advertised 
for sale by internet retailers.
WHO review history
    N-Ethylnorpentylone has not been previously pre-reviewed or 
critically reviewed by the WHO Expert Committee on Drug Dependence 
(ECDD). A critical review was proposed based on information brought to 
WHO's attention that N-Ethylnorpentylone poses serious risk to public 
health and has no recognised therapeutic use.
Similarity to known substances/effects on the central nervous system
    The information currently available suggests that N-
Ethylnorpentylone is a psychomotor stimulant. N-Ethylnorpentylone users 
exhibit psychomotor stimulant effects including agitation, paranoia, 
tachycardia and sweating which are consistent with other substituted 
cathinone and central nervous system stimulant drugs. Not all reported 
adverse effects could be causally linked to N-Ethylnorpentylone alone, 
but there are indications that the observed effects are consistent with 
those seen with other psychomotor stimulants, with some instances 
involving cardiac arrest.
    Its molecular mechanism of action is similar to the synthetic 
cathinones MDPV and [alpha]-PVP which are both listed in Schedule II of 
the Convention on Psychotropic Substances of 1971. In vitro 
investigations showed that N-Ethylnorpentylone inhibited the reuptake 
of dopamine, noradrenaline and, to a lesser extent, serotonin, which is 
consistent with closely related other substituted cathinones with known 
abuse liability and with cocaine.
    There is no specific information available to indicate that N-
Ethylnorpentylone may be converted into a substance currently 
controlled under the U.N. Conventions.
Dependence potential
    No controlled experimental studies examining the dependence 
potential of N-Ethylnorpentylone in humans or animals were available. 
However, based on its action in the central nervous system, it would be 
expected that N-Ethylnorpentylone would have the capacity to produce a 
state of dependence similar to that of other stimulants such as the 
ones listed in Schedule II of the Convention on Psychotropic Drugs of 
1971.
Actual abuse and/or evidence of likelihood of abuse
    In rodent drug discrimination studies, N-Ethylnorpentylone fully 
substituted for methamphetamine and cocaine, and it was also shown to 
increase activity levels, suggesting it has potential for abuse similar 
to other psychomotor stimulants.
    N-Ethylnorpentylone has been detected in biological fluids 
collected from a number of cases involving adverse effects including 
deaths. It is frequently used in combination with other drugs. Users 
may be unaware of the additional risks of harm associated with the 
consumption of N-Ethylnorpentylone either alone or in combination with 
other drugs. Users may also be unaware of the exact dose or compound 
being ingested.
    A number of countries in various regions have reported use or 
detection of this compound in either seized materials or biological 
samples of individuals, including in cases of driving under the 
influence of drugs. Increased seizures of N-Ethylnorpentylone were 
reported by the United States over the last 2 years. N-
Ethylnorpentylone has been detected in biological fluids collected from 
fatal and non-fatal cases of intoxication with a total of 125 
toxicological reports associated with N-Ethynorpentylone between 2016 
and 2018 having been documented.
    The current available data therefore suggest that N-
Ethylnorpentylone is liable to abuse.
Therapeutic applications/usefulness
    N-Ethylnorpentylone is not known to have any therapeutic uses.

[[Page 7079]]

Recommendation
    N-Ethylnorpentylone is a synthetic cathinone with effects that are 
similar to other synthetic cathinones listed as Schedule II substances 
in the Convention on Psychotropic Substances of 1971. Its mode of 
action and effects are consistent with those of other central nervous 
system stimulants such as cocaine, indicating that it has significant 
potential for dependence and likelihood of abuse. There is evidence of 
use of N-Ethylnorpentylone in a number of countries in various regions 
and this use has resulted in fatal and non-fatal intoxications. The 
substance causes substantial harm and has no therapeutic usefulness. 
Accordingly:
     Recommendation 3.1: The Committee recommended that N-
Ethylnorpentylone (chemical name: 1-(2H-1,3-benzodioxol-5-yl)-2-
(ethylamino)pentan-1-one) be added to Schedule II of the 1971 
Convention on Psychotropic Substances.

4. Medicines

4.1 Pregabalin

Substance identification
    Chemically, pregabalin is (3S)-3-(aminomethyl)-5-methylhexanoic 
acid.
WHO review history
    Pregabalin was previewed by the 39th ECDD in November 2017.
Similarity to known substances/effects on the central nervous system
    Pregabalin is an inhibitor of alpha-2-delta subunit containing 
voltage-gated calcium channels (VGCCs). Through this mechanism it 
decreases the release of neurotransmitters such as glutamate, 
noradrenaline and substance P. It has been suggested that pregabalin 
exerts its therapeutic effects by reducing the neuronal activation of 
hyper-excited neurons while leaving normal activation unaffected. The 
mechanism(s) by which pregabalin produces euphoric effects or induces 
physical dependence is unknown.
    Despite being a chemical analogue of the neurotransmitter gamma 
aminobutyric acid (GABA), pregabalin does not influence GABA activity 
via either GABA receptors or benzodiazepine receptors. However, 
pregabalin has been found to produce effects that are similar to those 
produced by controlled substances, such as benzodiazepines, that 
increase GABA activity.
Dependence potential
    Tolerance has been shown to develop to the effects of pregabalin, 
particularly the euphoric effects. A number of published reports have 
described physical dependence associated with pregabalin use in humans. 
The withdrawal symptoms that occur following abrupt discontinuation of 
pregabalin include insomnia, nausea, headache, anxiety, sweating, and 
diarrhoea. Current evidence suggests that the incidence and severity of 
withdrawal symptoms may be dose-related and hence those taking doses 
above the normal therapeutic range are most at risk of withdrawal. At 
therapeutic doses, withdrawal may be minimized by gradual dose 
tapering.
Actual abuse and/or evidence of likelihood to produce abuse
    While some preclinical research using self-administration and 
conditioned place preference models has shown reinforcing effects of 
pregabalin, taken as a whole, the results from such research are 
contradictory and inconclusive.
    In clinical trials, patients have reported euphoria, although 
tolerance develops rapidly to this effect. Human laboratory research is 
very limited and only a relatively low dose of pregabalin has been 
tested in a general population sample; the results indicated low abuse 
liability. However, a higher dose of pregabalin administered to users 
of alcohol or sedative/hypnotic drugs was rated similar to diazepam, 
indicative of abuse liability.
    Pregabalin is more likely to be abused by individuals who are using 
other psychoactive drugs (especially opioids) with significant 
potential of adverse effects among these subpopulations. The adverse 
effects of pregabalin include dizziness, blurred vision, impaired 
coordination, impaired attention, somnolence, confusion and impaired 
thinking. Other reported harms associated with non-medical use of 
pregabalin include suicidal ideation and impaired driving. Users of 
pregabalin in a number of countries have sought treatment for 
dependence on the drug. Whilst pregabalin has been cited as the main 
cause of death in over 30 documented overdose fatalities, there are 
very few cases of fatal intoxications resulting from pregabalin use 
alone and the vast majority of instances involve other central nervous 
system depressants such as opioids and benzodiazepines.
    There is only limited information regarding the scope and magnitude 
of the illicit trade in pregabalin, but there is evidence of illicit 
marketing through online pharmacies.
    Pregabalin is under national control in many countries across 
different regions of the world.
Therapeutic applications/usefulness
    Pregabalin is used for the treatment of neuropathic pain, including 
painful diabetic peripheral neuropathy and postherpetic neuralgia, 
fibromyalgia, anxiety and the adjunctive treatment of partial seizures. 
The exact indications for which pregabalin has received approval vary 
across countries. Pregabalin has also been used for conditions such as 
substance use disorders, alcohol withdrawal syndrome, restless legs 
syndrome and migraine.
Recommendation
    The Committee noted that there has been increasing concern in many 
countries regarding the abuse of pregabalin. A number of cases of 
dependence have been reported and there are increasing reports of 
adverse effects. While these problems are concentrated in certain drug 
using populations, there is presently limited data on the extent of the 
problems related to pregabalin abuse in the general population. The 
Committee also noted that pregabalin has approved therapeutic uses for 
a range of medical conditions, including some for which there are few 
therapeutic options. Given the limitations in the available information 
regarding the abuse of pregabalin:
     Recommendation 4.1: The Committee recommended that 
pregabalin (chemical name: (3S)-3-(aminomethyl)-5-methylhexanoic acid) 
should not be scheduled but be kept under surveillance by the WHO 
Secretariat.

4.2 Tramadol

Substance identification
    Tramadol (chemical name: (1R*,2R*)-2-[(dimethylamino)methyl]-1-(3-
methoxyphenyl)cyclohexan-1-ol) is a white, bitter, crystalline and 
odourless powder soluble in water and ethanol. Tramadol is marketed as 
the hydrochloride salt and is available in a variety of pharmaceutical 
formulations for oral (tablets, capsules), sublingual (drops), 
intranasal, rectal (suppositories), intravenous, subcutaneous, and 
intramuscular administration. It is also available in combination with 
acetaminophen (paracetamol). Preparations of tramadol are available as 
immediate- and extended-release formulations.
WHO review history
    Tramadol has been considered for critical review by the ECDD five 
times: in 1992, 2000, 2002, 2006 and 2014. Tramadol was pre-reviewed at 
the 39th

[[Page 7080]]

ECDD meeting in November 2017 and it was recommended that tramadol be 
subject to a critical review at a subsequent ECDD meeting. The 
Committee requested the WHO Secretariat to collect additional data for 
the critical review, including information on the extent of problems 
associated with tramadol misuse in countries. Also, the Committee asked 
for information on the medical use of tramadol including the extent to 
which low income countries, and aid and relief agencies, use and 
possibly rely on tramadol for provision of analgesia. In response to 
these requests, the WHO Secretariat collected data from Member States 
and relief agencies on the extent of medical use of tramadol, its 
misuse and on the level of control implemented in countries.
Similarity to known substances/effects on the central nervous system
    Tramadol is a weak opioid analgesic that produces opioid-like 
effects primarily due to its metabolite, O-desmethyltramadol (M1). The 
analgesic effect of tramadol is also believed to involve its actions on 
noradrenergic and serotonergic receptor systems. The adverse effects of 
tramadol are consistent with its dual opioid and non-opioid mechanisms 
of action and they include dizziness, nausea, constipation and 
headache. In overdose, symptoms such as lethargy, nausea, agitation, 
hostility, aggression, tachycardia, hypertension and other cardiac 
complications, renal complications, seizures, respiratory depression 
and coma have been reported. Serotonin syndrome (a group of symptoms 
associated with high concentrations of the neurotransmitter serotonin 
that include elevated body temperature, agitation, confusion, enhanced 
reflexes, and tremor and might result in seizures and respiratory 
arrest) is a potential complication of the use of tramadol in 
combination with other serotonergic drugs. Tramadol has been detected 
in a number of deaths. It is often present along with other drugs, 
including opioids, benzodiazepines and antidepressants, but fatalities 
have also been reported due to tramadol alone.
Dependence potential
    Evidence suggests that the development of physical dependence to 
tramadol is dose-related, and administration of supra-therapeutic doses 
leads to a similar dependence profile to morphine and other opioids 
such as oxycodone and methadone. There are reports of considerable 
number of people with tramadol dependence seeking help. Withdrawal 
symptoms include those typical of opioids such as pain, sweating, 
diarrhoea and insomnia as well as symptoms not normally seen with 
opioids and related to noradrenergic and serotonergic activity, such as 
hallucinations, paranoia, confusion and sensory abnormalities. Low dose 
tramadol use over extended periods is associated with a lower risk of 
dependence.
Actual abuse and/or evidence of likelihood of abuse
    Consistent with its opioid mechanism of action, human brain imaging 
has shown that tramadol activates brain reward pathways associated with 
abuse. While reports from people administered tramadol in controlled 
settings have shown that it is identified as opioid-like and tramadol 
has reinforcing effects in experienced opioid users, these effects may 
be weaker than those produced by opioids such as morphine and may be 
partially offset by unpleasant effects of tramadol such as sweating, 
tremor, agitation, anxiety and insomnia.
    Abuse, dependence and overdose from tramadol have emerged as 
serious public health concerns in countries across several regions. 
Epidemiological studies in the past have reported a lower tendency for 
tramadol misuse when compared to other opioids, but more recent 
information indicates a growing number of people abusing tramadol, 
particularly in a number of Middle Eastern and African countries. The 
sources of tramadol include diverted medicines as well as falsified 
medicines containing high doses of tramadol. Seizures of illicitly 
trafficked tramadol, particularly in African countries, have risen 
dramatically in recent years.
    The oral route of administration has been the predominant mode of 
tramadol abuse as it results in a greater opioid effect compared to 
other routes. It is unlikely that tramadol will be injected to any 
significant extent. Abuse of tramadol is likely to be influenced by 
genetic factors such that some people will experience a much stronger 
opioid effect following tramadol administration compared to others. The 
genotype associated with a stronger opioid effect following tramadol 
administration occurs at different rates in populations across 
different parts of the world.
    Many countries have placed tramadol under national control.
Therapeutic applications/usefulness
    Tramadol is used to treat both acute and chronic pain of moderate 
to severe intensity. The conditions for which tramadol has been used 
include osteoarthritis, neuropathic pain, chronic low back pain, cancer 
pain and postoperative pain. It has also been used for treatment of 
restless leg syndrome and opioid withdrawal management. As is the case 
with abuse potential, the analgesic efficacy and the nature of adverse 
effects experienced are strongly influenced by genetic factors. 
Systematic reviews have reported that the ability of tramadol to 
control chronic pain such as cancer pain is less than optimal, and its 
use is associated with a relatively high prevalence of adverse effects.
    Tramadol is listed on the national essential medicines lists of 
many countries across diverse regions, but it is not listed on the WHO 
Lists of Essential Medicines.
    As an opioid analgesic available in generic forms which is not 
under international control, tramadol is widely used in many countries 
where access to other opioids for the management of pain is limited. It 
is also used extensively by international aid organisations in 
emergency and crisis situations for the same reasons.
Recommendations
    The Committee was concerned by the increasing evidence for tramadol 
abuse in a number of countries in diverse regions, in particular the 
widespread abuse of tramadol in many low to middle income countries. 
Equally concerning was the clear lack of alternative analgesics for 
moderate to severe pain for which tramadol is used. The Committee was 
strongly of the view that the extent of abuse and evidence of public 
health risks associated with tramadol warranted consideration of 
scheduling, but the Committee recommended that tramadol not be 
scheduled at this time in order that access to this medication not be 
adversely impacted, especially in countries where tramadol may be the 
only available opioid analgesic or in crisis situations where there is 
very limited or no access at all to other opioids.
    The Committee also strongly urged the WHO and its partners to 
address, as a high priority, the grossly inadequate access and 
availability of opioid pain medication in low income countries. WHO and 
its partners are also strongly encouraged to update and disseminate WHO 
pain management guidelines and to support both country-specific 
capacity building needs and prevention and treatment initiatives in 
order to address the tramadol crisis in low income countries. The 
Committee also recommended that WHO and its partners support countries 
in strengthening their regulatory capacity

[[Page 7081]]

and mechanisms for preventing the supply and use of falsified and 
substandard tramadol.
    Recommendation 4.2: The Committee recommended that the WHO 
Secretariat continues to keep tramadol under surveillance, collect 
information on the extent of problems associated with tramadol misuse 
in countries and on its medical use, and that it be considered for 
review at a subsequent meeting.

III. Discussion

    Although WHO has made specific scheduling recommendations for each 
of the drug substances, the CND is not obliged to follow the WHO 
recommendations. Options available to the CND for substances considered 
for control under the Psychotropic Convention include the following: 
(1) Accept the WHO recommendations; (2) accept the recommendations to 
control, but control the drug substance in a schedule other than that 
recommended; or (3) reject the recommendations entirely.
    ADB-FUBINACA (chemical name: N-[1-(aminocarbonyl)-2,2-
dimethylpropyl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide) 
is an indazole-based synthetic cannabinoid that is a potent, full 
agonist at CB1 receptors. This substance functionally 
(biologically) mimics the effects of the structurally unrelated delta-
9-tetrahydrocannabinol (THC), a Schedule I substance, and the main 
psychoactive chemical constituent in the cannabis (marijuana) plant. 
Synthetic cannabinoids have been marketed under the guise of ``herbal 
incense,'' and promoted by drug traffickers as legal alternatives to 
marijuana. ADB-FUBINACA use has been associated with serious adverse 
events including death in the United States. There are no commercial or 
approved medical uses for ADB-FUBINACA. On April 10, 2017, ADB-FUBINACA 
was temporarily controlled as a Schedule I substance under the CSA. As 
such, additional permanent controls will be necessary to fulfill U.S. 
obligations if ADB-FUBINACA is controlled under Schedule II of the 1971 
Convention on Psychotropic Substances.
    FUB-AMB (other names: MMB-FUBINACA; AMB-FUBINACA; chemical name: 
methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3-
methylbutanoate) is an indazole-based synthetic cannabinoid that is a 
potent full agonist at CB1 receptors. This substance 
functionally (biologically) mimics the effects of the structurally 
unrelated THC, a Schedule I substance, and the main psychoactive 
chemical constituent in marijuana. Synthetic cannabinoids have been 
marketed under the guise of ``herbal incense,'' and promoted by drug 
traffickers as legal alternatives to marijuana. FUB-AMB use has been 
associated with serious adverse events including death in the United 
States. There are no commercial or approved medical uses for FUB-AMB. 
On November 3, 2017, FUB-AMB was temporarily controlled as a Schedule I 
substance under the CSA. As such, additional permanent controls will be 
necessary to fulfill U.S. obligations if FUB-AMB is controlled under 
Schedule II of the 1971 Convention on Psychotropic Substances.
    ADB-CHMINACA (other name: MAB-CHMINACA; chemical name: N-(1-amino-
3,3-dimethyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-1H-indole-3-
carboxamide) is an indazole-based synthetic cannabinoid that is a 
potent full agonist at CB1 receptors. This substance 
functionally (biologically) mimics the effects of the structurally THC, 
a Schedule I substance, and the main psychoactive chemical constituent 
in marijuana. Synthetic cannabinoids have been marketed under the guise 
of ``herbal incense,'' and promoted by drug traffickers as legal 
alternatives to marijuana. ADB-CHMINACA use has been associated with 
serious adverse events including death in the United States. There are 
no commercial or approved medical uses for ADB-CHMINACA. On January 29, 
2019, ADB-CHMINACA was permanently controlled as a Schedule I substance 
under the CSA. As such, additional permanent controls will not be 
necessary to fulfill U.S. obligations if ADB-CHMINACA is controlled 
under Schedule II of the 1971 Convention on Psychotropic Substances.
    CUMYL-4CN-BINACA (chemical name: 1-(4-cyanobutyl)-N-(2-
phenylpropan-2-yl)-1H-indazole-3-carboxamide) is a clandestinely 
produced indazole-3-carboxamide based synthetic cannabinoid that has 
been sold online and used to mimic the biological effects of THC, the 
main psychoactive chemical constituent in marijuana. Synthetic 
cannabinoids have been marketed under the guise of ``herbal incense,'' 
and promoted by drug traffickers as legal alternatives to marijuana. 
Hospital, scientific publications and law enforcement reports show that 
CUMYL-4CN-BUTINACA is abused for its psychoactive properties. CUMYL-
4CN-BUTINACA has been associated with serious adverse events in the 
United States, in addition to multiple deaths in Europe. CUMYL-4CN-
BUTINACA has no commercial or medical uses. On July 10, 2018, CUMYL-
4CN-BUTINACA was temporarily controlled as a Schedule I substance under 
the CSA. As such, additional permanent controls will be necessary to 
fulfill U.S. obligations if CUMYL-4CN-BUTINACA is controlled under 
Schedule II of the 1971 Convention on Psychotropic Substances.
    Cyclopropyl fentanyl is a synthetic opioid that has a 
pharmacological profile similar to other Schedule I and II controlled 
opioid substances such as acetyl fentanyl, fentanyl, and other related 
[micro]-opioid receptor agonist substances. This clandestinely produced 
analog of fentanyl is associated with adverse events typically 
associated with opioid use such as respiratory depression, anxiety, 
constipation, tiredness, hallucinations, and withdrawal. Cyclopropyl 
fentanyl has been associated with numerous fatalities. At least 115 
confirmed overdose deaths involving cyclopropyl fentanyl abuse have 
been reported in the United States. Cyclopropyl fentanyl has no 
commercial or currently accepted medical uses in the United States. On 
January 4, 2018, cyclopropyl fentanyl was temporarily placed into 
Schedule I of the CSA. As such, additional permanent controls will be 
necessary to fulfill U.S. obligations if Cyclopropyl fentanyl is 
controlled under Schedule I of the 1961 Single Convention.
    Methoxyacetyl fentanyl has a pharmacological profile similar to 
other Schedule I and II opioid substances such as acetyl fentanyl, 
fentanyl, and other related [micro]-opioid receptor agonist substances. 
Evidence suggests that the pattern of abuse of fentanyl analogues, 
including methoxyacetyl fentanyl is similar to heroin and prescription 
opioid analgesics. Law enforcement and public health reports 
demonstrate that methoxyacetyl fentanyl is being illicitly distributed 
and abused. The Drug Enforcement Administration (DEA) is aware of at 
least two overdose deaths associated with the abuse of methoxyacetyl 
fentanyl in the United States. Methoxyacetyl fentanyl has no currently 
accepted medical use in treatment in the United States. On October 26, 
2017, methoxyacetyl fentanyl was temporarily placed into Schedule I of 
the CSA. As such, additional permanent controls will be necessary to 
fulfill U.S. obligations if methoxyacetyl fentanyl is controlled under 
Schedule I of the 1961 Single Convention.
    Para-fluorobutyrfentanyl shares pharmacological profile with other 
Schedule I (e.g. butyryl fentanyl) and II

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(e.g., fentanyl) opioid substances. Para-fluorobutyrfentanyl has no 
currently accepted medical use in treatment in the United States. The 
abuse of para-fluorobutyrfentanyl carries public health risks similar 
to that of heroin, fentanyl, and prescription opioid analgesics. On 
February 1, 2018, para-fluorobutyrfentanyl was temporarily placed into 
Schedule I of the CSA. As such, additional permanent controls will be 
necessary to fulfill U.S. obligations if Para-fluorobutyrfentanyl is 
controlled under Schedule I of the 1961 Single Convention.
    Ortho-fluorofentanyl has a pharmacological profile similar to 
fentanyl and other related [micro]-opioid receptor agonist. Ortho-
fluorofentanyl has no currently accepted medical use in treatment in 
the United States. Ortho-fluorofentanyl has been encountered by law 
enforcement and public health officials. The DEA has received reports 
for at least 13 confirmed overdose deaths involving ortho-
fluorofentanyl abuse in the United States. On October 26, 2017, ortho-
fluorofentanyl was temporarily placed into Schedule I of the CSA. As 
such, additional permanent controls will be necessary to fulfill U.S. 
obligations if Ortho-fluorofentanyl is controlled under Schedule I of 
the 1961 Single Convention.
    N-ethylnorpentylone (other name: N-ethylpentylone) is a synthetic 
cathinone with stimulant and psychoactive properties similar to 
cathinone, a Schedule I substance. N-Ethylpentylone abuse has been 
associated with adverse health effects leading to emergency department 
admissions, and deaths. N-Ethylpentylone has no currently accepted 
medical use in treatment in the United States. On August 31, 2018, N-
ethylnorpentylone was temporarily controlled as a Schedule I substance 
under the CSA. As such, additional permanent controls will be necessary 
to fulfill U.S. obligations if N-ethylnorpentylone is controlled under 
Schedule II of the 1971 Convention on Psychotropic Substances.
    FDA, on behalf of the Secretary of HHS, invites interested persons 
to submit comments on the notifications from the United Nations 
concerning these drug substances. FDA, in cooperation with the National 
Institute on Drug Abuse, will consider the comments on behalf of HHS in 
evaluating the WHO scheduling recommendations. Then, under section 
201(d)(2)(B) of the CSA, HHS will recommend to the Secretary of State 
what position the United States should take when voting on the 
recommendations for control of substances under the Psychotropic 
Convention at the CND meeting in March 2019.
    Comments regarding the WHO recommendations for control of 
Cyclopropyl fentanyl; Methoxyacetyl fentanyl; Ortho-fluorofentanyl; 
Para-fluorobutyrfentanyl; under the 1961 Single Convention will also be 
forwarded to the relevant Agencies for consideration in developing the 
U.S. position regarding narcotic substances at the CND meeting.

    Dated: February 25, 2019.
Lowell J. Schiller,
Acting Associate Commissioner for Policy.
[FR Doc. 2019-03663 Filed 2-28-19; 8:45 am]
BILLING CODE 4164-01-P