[Federal Register Volume 85, Number 67 (Tuesday, April 7, 2020)]
[Proposed Rules]
[Pages 19401-19408]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-07095]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-498]


Schedules of Controlled Substances: Placement of 4,4'-DMAR in 
Schedule I

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Notice of proposed rulemaking.

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SUMMARY: The Drug Enforcement Administration proposes placing the 
substance 4,4'-DMAR (Chemical name: 4,4'-dimethylaminorex), including 
its salts, isomers, and salts of isomers, in schedule I of the 
Controlled Substances Act. This action is being taken to enable the 
United States to meet its obligations under the 1971 Convention on 
Psychotropic Substances. If finalized, this action would impose the 
regulatory controls and administrative, civil, and criminal sanctions 
applicable to schedule I controlled substances on persons who handle 
(manufacture, distribute, reverse distribute, import, export, engage in 
research, conduct instructional activities or chemical analysis with, 
or possess), or propose to handle 4,4'-DMAR.

DATES: Comments must be submitted electronically or postmarked on or 
before June 8, 2020.
    Interested persons may file a request for hearing or waiver of 
hearing pursuant to 21 CFR 1308.44 and in accordance with 21 CFR 
1316.45 and/or 1316.47, as applicable. Requests for hearing and waivers 
of an opportunity for a hearing or to participate in a hearing must be 
received on or before May 7, 2020.

ADDRESSES: Interested persons may file written comments on this 
proposal in accordance with 21 CFR 1308.43(g). Commenters should be 
aware that the electronic Federal Docket Management System will not 
accept comments after 11:59 p.m. Eastern Time on the last day of the 
comment period. To ensure proper handling of comments, please reference 
``Docket No. DEA-498'' on all electronic and written correspondence, 
including any attachments.
     Electronic comments: The Drug Enforcement Administration 
encourages that all comments be submitted electronically through the 
Federal eRulemaking Portal, which provides the ability to type short 
comments directly into the comment field on the web page or attach a 
file for lengthier comments. Please go to http://www.regulations.gov 
and follow the on-line instructions at that site for submitting 
comments. Upon completion of your submission you will receive a Comment 
Tracking Number for your comment. Please be aware that submitted 
comments are not instantaneously available for public view on 
regulations.gov. If you have received a Comment Tracking Number, your 
comment has been successfully submitted and there is no need to 
resubmit the same comment.
     Paper comments: Paper comments that duplicate electronic 
submissions are not necessary and are discouraged. Should you wish to 
mail a paper comment in lieu of an electronic comment, it should be 
sent via regular or express mail to: Drug Enforcement Administration, 
Attn: DEA Federal Register Representative/DPW, 8701 Morrissette Drive, 
Springfield, Virginia 22152.
     Hearing requests: All requests for a hearing and waivers 
of participation must be sent to: Drug Enforcement Administration, 
Attn: Administrator, 8701 Morrissette Drive, Springfield, Virginia 
22152. All requests for hearing and waivers of participation should 
also be sent to: (1) Drug Enforcement Administration, Attn: Hearing 
Clerk/LJ, 8701 Morrissette Drive, Springfield, Virginia 22152; and (2) 
Drug Enforcement Administration, Attn: DEA Federal Register 
Representative/DPW, 8701 Morrissette Drive, Springfield, Virginia 
22152.

FOR FURTHER INFORMATION CONTACT: Scott A. Brinks, Regulatory Drafting 
and

[[Page 19402]]

Policy Section, Diversion Control Division, Drug Enforcement 
Administration; Mailing Address: 8701 Morrissette Drive, Springfield, 
Virginia 22152; Telephone: (202) 598-6812.

SUPPLEMENTARY INFORMATION:

Posting of Public Comments

    Please note that all comments received in response to this docket 
are considered part of the public record. They will, unless reasonable 
cause is given, be made available by the Drug Enforcement 
Administration (DEA) for public inspection online at http://www.regulations.gov. Such information includes personal identifying 
information (such as your name, address, etc.) voluntarily submitted by 
the commenter. The Freedom of Information Act (FOIA) applies to all 
comments received. If you want to submit personal identifying 
information (such as your name, address, etc.) as part of your comment, 
but do not want it to be made publicly available, you must include the 
phrase ``PERSONAL IDENTIFYING INFORMATION'' in the first paragraph of 
your comment. You must also place all of the personal identifying 
information you do not want made publicly available in the first 
paragraph of your comment and identify what information you want 
redacted.
    If you want to submit confidential business information as part of 
your comment, but do not want it to be made publicly available, you 
must include the phrase ``CONFIDENTIAL BUSINESS INFORMATION'' in the 
first paragraph of your comment. You must also prominently identify the 
confidential business information to be redacted within the comment.
    Comments containing personal identifying information and 
confidential business information identified, as directed above, will 
generally be made publicly available in redacted form. If a comment has 
so much confidential business information that it cannot be effectively 
redacted, all or part of that comment may not be made publicly 
available. Comments posted to http://www.regulations.gov may include 
any personal identifying information (such as name, address, and phone 
number) included in the text of your electronic submission that is not 
identified as directed above as confidential.
    An electronic copy of this document and supplemental information to 
this proposed rule are available at http://www.regulations.gov for easy 
reference.

Request for Hearing or Waiver of Participation in Hearing

    Pursuant to 21 U.S.C. 811(a), this action is a formal rulemaking 
``on the record after opportunity for a hearing.'' Such proceedings are 
conducted pursuant to the provisions of the Administrative Procedure 
Act (APA), 5 U.S.C. 551-559. 21 CFR 1308.41-1308.45; 21 CFR part 1316, 
subpart D. Interested persons may file requests for a hearing or 
notices of intent to participate in a hearing in conformity with the 
requirements of 21 CFR 1308.44(a) or (b), and include a statement of 
interest in the proceeding and the objections or issues, if any, 
concerning which the person desires to be heard. Any interested person 
may file a waiver of an opportunity for a hearing or to participate in 
a hearing together with a written statement regarding the interested 
person's position on the matters of fact and law involved in any 
hearing as set forth in 21 CFR 1308.44(c). All requests for hearing and 
waivers of participation must be sent to DEA using the address 
information provided above.

Legal Authority

    The United States is a party to the 1971 United Nations Convention 
on Psychotropic Substances (``1971 Convention''), February 21, 1971, 32 
U.S.T. 543, 1019 U.N.T.S. 175, as amended. Procedures respecting 
changes in drug schedules under the 1971 Convention are governed 
domestically by 21 U.S.C. 811(d). When the United States receives 
notification of a scheduling decision pursuant to Article 2 of the 1971 
Convention that a drug or other substance has been added or transferred 
to a schedule specified in the notification, the Secretary of the 
Department Health and Human Services (HHS),\1\ after consultation with 
the Attorney General, shall first determine whether existing legal 
controls under subchapter I of the Controlled Substances Act (CSA) and 
the Federal Food, Drug, and Cosmetic Act (FDCA) meet the requirements 
of the schedule specified in the notification with respect to the 
specific drug or substance. 21 U.S.C. 811(d)(3). If such requirements 
are not met by such existing controls and the Secretary of HHS concurs 
in the scheduling decision, the Secretary shall recommend to the 
Attorney General that he initiate proceedings for scheduling the drug 
or substance under the appropriate schedule pursuant to 21 U.S.C. 
811(a) and (b). 21 U.S.C. 811(d)(3)(B). Pursuant to 21 U.S.C. 
811(a)(1), the Attorney General may, by rule, add to such a schedule or 
transfer between such schedules any drug or other substance, if he 
finds that such drug or other substance has a potential for abuse, and 
makes with respect to such drug or other substance the findings 
prescribed by 21 U.S.C. 812(b) for the schedule in which such drug or 
other substance is to be placed. The Attorney General has delegated 
this scheduling authority to the Administrator of DEA (Administrator). 
28 CFR 0.100.
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    \1\ As discussed in a memorandum of understanding entered into 
by the Food and Drug Administration (FDA) and the National Institute 
on Drug Abuse (NIDA), the FDA acts as the lead agency within HHS in 
carrying out the Secretary's scheduling responsibilities under the 
Controlled Substances Act, with the concurrence of NIDA. 50 FR 9518 
(March 8, 1985). The Secretary of HHS has delegated to the Assistant 
Secretary for Health of HHS the authority to make domestic drug 
scheduling recommendations. 58 FR 35460 (July 1, 1993).
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Background

    4,4'-dimethylaminorex (4,4'-DMAR) is a synthetic stimulant drug 
that is structurally related to 4-methylaminorex (4-MAR), a schedule I 
substance in the United States and listed as a schedule I substance in 
the 1971 Convention. 4,4'-DMAR first emerged on the illicit drug market 
in December 2012 in the Netherlands. 4,4'-DMAR can be purchased through 
websites selling ``research chemicals'' and is typically sold as a 
powder or tablet. Based on drug user forum information presented in the 
scientific literature and through the European Monitoring Centre for 
Drugs and Drug Addiction (EMCDDA) and World Health Organization (WHO) 
reviews, it appears that the most common routes of administration for 
4,4'-DMAR are via nasal insufflation and oral ingestion. There is 
limited information with respect to the pharmacological properties of 
4,4'-DMAR. In vitro studies have reported that exposure to 4,4'-DMAR 
results in dopamine, norepinephrine, and serotonin release at dopamine, 
norepinephrine, and serotonin transporters, respectively, and the dose 
levels are comparable to other known stimulant drugs. There are no 
animal or human studies that have examined dependence potential 
associated with 4,4'-DMAR. Due to the large number of known fatalities 
(46 known fatalities in several European countries since 2013) 
associated with 4,4'-DMAR, the United Kingdom's Advisory Council on the 
Misuse of Drugs (ACMD), EMCDDA, and the WHO stated that 4,4'-DMAR 
carries a substantial risk to the public health. Adverse symptoms such 
as agitation, increased body temperature, respiratory distress, and 
cardiac arrest have been reported in 4,4'-DMAR-related drug overdoses 
and deaths. In most of these deaths and overdoses, other drugs were 
also detected.

[[Page 19403]]

    In November 2015, the Director-General of the WHO recommended to 
the Secretary-General of the United Nations that 4,4'-DMAR be placed in 
schedule II of the 1971 Convention, as 4,4'-DMAR produces a spectrum of 
pharmacological effects similar to that of psychomotor stimulants in 
schedule II of the 1971 Convention, and has dependence and abuse 
potential. On May 17, 2016, the Secretary-General of the United Nations 
advised the Secretary of State of the United States that during its 
59th Session on March 2016, the Commission on Narcotic Drugs (CND) 
voted to place 4,4'-dimethylaminorex (4,4'-DMAR) in schedule II of the 
1971 Convention on Psychotropic Substances (CND Dec/59/5).
    Article 2, paragraph 7(b), of the 1971 Convention sets forth the 
minimum requirements that the United States must meet when a substance 
has been added to schedule II of the 1971 Convention. Pursuant to the 
1971 Convention, the United States must require licenses for the 
manufacture, export and import, and distribution of 4,4'-DMAR. This 
license requirement is accomplished by the CSA's registration 
requirement as set forth in 21 U.S.C. 822, 823, 957, 958, and in 
accordance with 21 CFR parts 1301 and 1312. In addition, the United 
States must adhere to specific export and import provisions that are 
provided in the 1971 Convention. This requirement is accomplished by 
the CSA's export and import provisions established in 21 U.S.C. 952, 
953, 957, 958, and in accordance with 21 CFR part 1312. Likewise, under 
Article 13, paragraphs 1 and 2, of the 1971 Convention, a party to the 
1971 Convention may notify another party, through the Secretary-General 
of the United Nations, that it prohibits the importation of a substance 
in schedule II, III, or IV of the Convention. If such notice is 
presented to the United States, the United States shall take measures 
to ensure that the named substance is not exported to the notifying 
country. This requirement is also accomplished by the CSA's export 
provisions mentioned above. Under Article 16, paragraph 4, of the 1971 
Convention, the United States is required to provide annual statistical 
reports to the International Narcotics Control Board (INCB). Using INCB 
Form P, the United States shall provide the following information: (1) 
In regard to each substance in schedule I and II of the 1971 
Convention, quantities manufactured, exported to and imported from each 
country or region as well as stocks held by manufacturers; (2) in 
regard to each substance in schedule III and IV of the 1971 Convention, 
quantities manufactured, as well as quantities exported and imported; 
(3) in regard to each substance in schedule II and III of the 1971 
Convention, quantities used in the manufacture of exempt preparations; 
and (4) in regard to each substance in schedule II-IV of the 1971 
Convention, quantities used for the manufacture of non-psychotropic 
substances or products. Lastly, under Article 2 of the 1971 Convention, 
the United States must adopt measures in accordance with Article 22 to 
address violations of any statutes or regulations that are adopted 
pursuant to its obligations under the 1971 Convention. The United 
States complies with this provision as persons acting outside the legal 
framework established by the CSA are subject to administrative, civil, 
and/or criminal action.

Proposed Determination to Schedule 4,4'-DMAR

    Pursuant to 21 U.S.C. 811(b), DEA gathered the necessary data on 
4,4'-DMAR and on March 21, 2017, submitted it to the Assistant 
Secretary for Health of HHS with a request for a scientific and medical 
evaluation of available information and a scheduling recommendation for 
4,4'-DMAR. On October 12, 2018, HHS provided to DEA a scientific and 
medical evaluation entitled ``Basis for the Recommendation to Place 
4,4'-Dimethylaminorex (4,4'-DMAR) and its salts in schedule I of the 
Controlled Substances Act'' and a scheduling recommendation. Following 
consideration of the eight-factors and findings related to the 
substance's abuse potential, legitimate medical use, and dependence 
liability, HHS recommended that 4,4'-DMAR be controlled in schedule I 
of the CSA under 21 U.S.C. 812(b). In response, DEA reviewed the 
scientific and medical evaluation and scheduling recommendation 
provided by HHS and all other relevant data, and completed its own 
eight-factor review document pursuant to 21 U.S.C. 811(c). Included 
below is a brief summary of each factor as analyzed by HHS and DEA in 
their respective eight-factor analyses, and as considered by DEA in 
this proposed scheduling determination. Please note that both DEA and 
HHS analyses are available in their entirety under ``Supporting 
Documents'' of the public docket for this proposed rule at http://www.regulations.gov under docket number ``DEA-498.''
    1. The Drug's Actual or Relative Potential for Abuse:
    In addition to considering the information HHS provided in its 
scientific and medical evaluation document for 4,4'-DMAR, DEA also 
considered all other relevant data regarding 4,4'-DMAR's actual or 
relative potential for abuse. The term ``abuse'' is not defined in the 
CSA, however, the legislative history of the CSA suggests the following 
be considered when determining whether a particular drug or substance 
has a potential for abuse: \2\
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    \2\ Comprehensive Drug Abuse Prevention and Control Act of 1970, 
H.R. Rep. No. 91-1444, 91st Cong., 2nd Sess. (1970) reprinted in 
1970 U.S.C.C.A.N. 4566, 4603.
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    a. Individuals are taking the drug or other substance in amounts 
sufficient to create a hazard to their health or to the safety of other 
individuals or to the community; or
    b. There is a significant diversion of the drug or other substance 
from legitimate drug channels; or
    c. Individuals are taking the drug or other substance on their own 
initiative rather than on the basis of medical advice from a 
practitioner licensed by law to administer such drugs; or
    d. The drug is so related in its action to a drug or other 
substance already listed as having a potential for abuse to make it 
likely that it will have the same potential for abuse as such 
substance, thus making it reasonable to assume that there may be 
significant diversions from legitimate channels, significant use 
contrary to or without medical advice, or that it has a substantial 
capability of creating hazards to the health of the user or to the 
safety of the community.
    DEA reviewed the scientific and medical evaluation provided by HHS 
and all other data relevant to the abuse potential of 4,4'-DMAR. These 
data as presented below demonstrate that 4,4'-DMAR has a high potential 
for abuse.
    a. Individuals are taking the substance in amounts sufficient to 
create a hazard to their health or to the safety of other individuals 
or to the community.
    4,4'-DMAR is not currently approved for medical use in the United 
States. There are currently no data regarding 4,4'-DMAR abuse in the 
United States. Since 2013, 46 fatalities in which 4,4'-DMAR was 
detected were reported in several European countries including Hungary, 
Poland, and the United Kingdom (UK). As noted by HHS, all but one of 
these fatalities involved the concomitant use of other drugs, typically 
stimulants. Regardless, 4,4'-DMAR was still determined to be a 
contributing factor to their deaths (Factor 6).
    DEA further gathered and evaluated available information from its 
forensic laboratory databases such as

[[Page 19404]]

STARLiMS,\3\ System to Retrieve Information from Drug Evidence 
(STRIDE),\4\ and the National Forensic Laboratory Information System 
(NFLIS).\5\ According to these databases, there are no known reports of 
4,4'-DMAR related drug seizures in the United States.
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    \3\ STARLiMS is a laboratory information management system that 
systematically collects results from drug chemistry analyses 
conducted by DEA laboratories. On October 1, 2014, STARLiMS replaced 
System to Retrieve Information from Drug Evidence (STRIDE) as the 
DEA laboratory drug evidence data system of record.
    \4\ STRIDE is a database of drug exhibits sent to DEA 
laboratories for analysis. Exhibits from the database are from DEA, 
other federal agencies, and some local law enforcement agencies.
    \5\ The National Forensic Laboratory Information System (NFLIS) 
is a national forensic laboratory reporting system that 
systematically collects results from drug chemistry analyses 
conducted by State and local forensic laboratories in the United 
States.
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    Although 4,4'-DMAR has not been seized in the United States, there 
have been numerous reports of seizures of the substance in Europe. 
4,4'-DMAR was first encountered in a customs seizure in the Netherlands 
in December 2012. The EMCDDA reported in 2014 that there was one 
internet site that offered 4,4'-DMAR for sale. Since the initial report 
of the 4,4'-DMAR seizure in the Netherlands, there have been reports of 
seizures in other European nations including Denmark, Finland, Hungary, 
the Netherlands, Romania, Sweden, and the UK in 2014. Furthermore, it 
was reported that organized crime groups in Hungary are involved in the 
trafficking and distribution of 4,4'-DMAR.
    b. There is a significant diversion of the substance from 
legitimate drug channels.
    According to HHS, 4,4'-DMAR is not an FDA-approved drug product for 
treatment in the United States and there appear to be no legitimate 
sources for 4,4'-DMAR as a marketed drug.
    The NFLIS, STRIDE, and STARLiMS databases did not contain any 
reports of 4,4'-DMAR when queried in March 2019. This suggests that 
4,4'-DMAR is not trafficked in the United States. Because 4,4'-DMAR is 
not approved as a drug for medical use in the United States, there 
appear to be no legitimate drug channels from which 4,4'-DMAR can be 
diverted.
    According to HHS, 4,4'-DMAR can be purchased from several internet 
sources as a research chemical. Although it is likely that some 
individuals with abuse-related disorders obtained 4,4'-DMAR from these 
internet sources, findings have indicated that the majority of the 
fatalities associated with 4,4'-DMAR were the result of the user being 
sold what they thought was 3, 4-methylenedioxy-methamphetamine (MDMA) 
from their illicit source as opposed to users obtaining 4,4'-DMAR 
directly from these websites.
    c. Individuals are taking the substance on their own initiative 
rather than on the basis of medical advice from a practitioner licensed 
by law to administer such drugs.
    4,4'-DMAR is not approved for medical use in the United States and 
is not formulated or available for clinical use. As noted by HHS, law 
enforcement seizures and anecdotal internet user experience posts 
(drugs-forum.com and bluelight.org) indicate that individuals are 
taking 4,4'-DMAR without medical advice from a licensed practitioner.
    d. The substance is so related in its action to a drug or other 
substance already listed as having a potential for abuse to make it 
likely that it will have the same potential for abuse as such 
substance, thus making it reasonable to assume that there may be 
significant diversion from legitimate channels, significant use 
contrary to or without medical advice, or that it has a substantial 
capability of creating hazards to the health of the user or to the 
safety of the community.
    As stated by HHS, 4,4'-DMAR is a derivative of substances that are 
in schedule I of the 1971 Convention and substances that are in 
schedule I of the CSA. HHS further states that the substances in 
schedule I of the 1971 Convention and of the CSA are known to have high 
potential for abuse. 4,4'-DMAR is similar in both its mechanism of 
action and its high potential for abuse to other scheduled compounds 
including 4-MAR (schedule I of the 1971 Convention and schedule I of 
the CSA) and aminorex (schedule I of the CSA). 4,4'-DMAR, 4-MAR, and 
aminorex have all been shown to increase neurotransmitter levels within 
the central nervous system resulting in a stimulant effect. Although 
there are no clinical studies on 4,4'-DMAR, extrapolated animal studies 
indicate its abuse and dependence potential. HHS concluded that 4,4'-
DMAR has a similar potential for abuse as substances already controlled 
internationally and federally in the United States.
    2. Scientific Evidence of the Drug's Pharmacological Effects, If 
Known:
    There are few pharmacological studies conducted on 4,4'-DMAR and no 
abuse related or clinical studies in human subjects have been conducted 
on this substance. 4,4'-DMAR is structurally similar to aminorex and 
both share a similar mechanism of pharmacological action. The abuse 
potential of aminorex was evaluated in monkeys using drug self-
administration or drug discrimination assays. The results showed that 
monkeys self-administered aminorex more than saline and similar to 
methohexital, a positive control agent. In drug discrimination assays 
in animals trained to distinguish d-amphetamine or pentobarbital from 
saline, aminorex fully substituted for the discriminative stimulus 
effects of damphetamine but produced little pentobarbital appropriate 
responding. Furthermore, aminorex can stimulate locomotor activity and 
increased the physiological dependence of rats taking pentobarbital. 
These data suggest that aminorex has dependence liability similar to 
that of amphetamine. 4-MAR with structural similarity to aminorex and 
4,4'-DMAR has also been reported to be self-administered by monkeys. 
The structural and pharmacological similarities of 4,4'-DMAR with 
substances known to have high abuse potential suggest that 4,4'-DMAR 
itself has high abuse potential.
    As described by HHS, in vitro studies showed that 4,4'-DMAR, 
similar to other controlled substances such as amphetamine, aminorex 
and MDMA, affects the functions of monoamine transporters. An in vitro 
study in isolated brain synaptosomes from Sprague-Dawley rats evaluated 
the functional activity of 4,4'-DMAR and several other stimulant drugs 
including d-amphetamine, aminorex, ()-cis-4-MAR, 
and ()-cis-4,4'-DMAR. All tested drugs evoked release of 
monoamines through the three monoamine transporters, namely dopamine 
transporter (DAT), norepinephrine transporter (NET), and serotonin 
transporter (SERT). They are also potent at DAT and NET, indicating 
their potential to release dopamine and norepinephrine in the central 
nervous system (CNS). But, their potencies at the SERT transport are 
different and varied by more than 100-fold. ()-cis-4,4'-
DMAR was the most potent drug at SERT, with an EC50 value of 
18.5 nM, similar to its potencies at DAT (8.6 nM) and NET (26.9 nM). 
The data from these studies revealed that ()-cis-4,4'-DMAR 
is a non-selective releaser of dopamine, norepinephrine, and serotonin 
and that it is more potent in releasing serotonin than amphetamine. 
Another in vitro study compared the potencies of cis and trans isomers 
of 4,4'-DMAR against 3,4-methylenedioxymethamphetamine (MDMA or 
ecstasy) in releasing monoamines in rat brain synaptosomal 
preparations. It showed that cis-4,4'-DMAR is 2- to 3-fold more potent 
than trans-4,4'-DMAR in releasing dopamine or norepinephrine. The study 
also revealed that both isomers of 4,4'-DMAR are about 4- to 10-fold 
more potent than

[[Page 19405]]

(+)-MDMA in releasing dopamine, norepinephrine, or serotonin.
    Based on the review of both DEA and HHS, no clinical studies have 
been performed to evaluate the effects of 4,4'-DMAR in human subjects. 
Anecdotal reports of 4,4'-DMAR use reveal that insufflation and oral 
consumption of tablets are the major methods of administration. Reports 
of injection were also noted. According to the user reports from 
websites (e.g., bluelight.org and drug-forum.com), oral and 
insufflation doses range from 10 to 200 mg and from 10 to 65 mg, 
respectively. Euphoria, stimulation, happiness, and increased 
sociability were reported to be the desired effects of 4,4'-DMAR. Drug 
use discussion forums report the desired effects begin within 8-60 
minutes and the peak was in approximately 3 hours. 4,4'-DMAR at higher 
doses produced adverse effects including nausea, dysphoria, agitation, 
psychosis, tachycardia, hypertension, breathing problems, convulsions, 
and cardiac arrest. Although there are indications of 4,4'-DMAR's 
potential to cause serotonin syndrome, poly-drug use with substances 
that produce serotonergic effects confound these reports.
    3. The State of Current Scientific Knowledge Regarding the Drug or 
Other Substance:

Chemistry

    The molecular formula of 4,4'-DMAR is 
C11H14N2O and it has a molecular 
weight of 190.24 g/mol. 4,4'-DMAR is a synthetic substituted oxazoline 
derivative. The oxazoline structure consists of a five-membered ring 
containing an oxygen (O) atom at the 1-position and a nitrogen (N) atom 
at the 3-position. The structure of 4,4'-DMAR has two chiral centers, 
C4 and C5, in the oxazoline ring. Therefore, it may exist as four 
stereoisomers known as (4S,5S), (4S,5R), (4R,5S), and (4R, 5R). 4,4'-
DMAR is structurally related to cis 4-methylaminorex (cis 4-MAR) which 
is a psychostimulant. 4-MAR is currently a schedule I substance in the 
United States and is listed as a schedule I substance under the 1971 
Convention.
    The synthesis of 4,4'-DMAR is a complex process requiring many 
steps. Both ()-cis 4,4'-DMAR and ()-trans 4,4'-
DMAR are synthesized by the cyclization of 2-amino-1-(4-methylphenyl) 
propan-1-ol (also known as 4'-methylnorepinephrine). The agent used for 
cyclization determines the synthesis of one isomer over the other. The 
synthetic process of the ()-cis-4,4'-DMAR isomers requires 
the use of anhydrous sodium acetate, methanol, and sodium carbonate in 
the final step, whereas the synthesis of the ( )-trans-
4,4'-DMAR isomers requires 2-amino-1-(4-methylphenyl)propan-1-ol, 
potassium cyanate, water, hydrochloric acid, sodium carbonate, 
dichloromethane, and methanol. These substances are available for 
purchase through internet sources; however, the equipment and knowledge 
required make it difficult for an average individual to synthesize this 
substance.

Toxicology and Pharmacokinetics

    Based on the evaluation of both DEA and HHS, there have been no 
non-clinical or clinical studies to directly evaluate the toxicology of 
4,4'DMAR. The toxicological data are from anecdotal reports or from 
fatalities in which 4,4'-DMAR was implicated as a contributory factor. 
Emergency Room visits and death reports revealed that 4,4'-DMAR 
consumption produces adverse health effects including agitation, 
tachycardia, hypertension, breathing problems, convulsions, and cardiac 
arrest. 4,4'-DMAR is believed to be a contributing factor in several 
deaths in Europe. Since 2013, at least 46 known fatalities have been 
associated with the use of 4,4'-DMAR in several European nations 
including Hungary, Poland, and the UK. The reported mean blood 
concentration of 4,4'-DMAR in 27 fatalities was 2.04 mg/L, while the 
range of urine concentrations in three of the fatalities ranged from 
5.93 to 43.49 mg/L.
    As mentioned by HHS, there are no human pharmacokinetic data for 
4,4'-DMAR. A preliminary study in rats showed that cis-4,4'-DMAR 
administered intravenously (1 mg/kg) rapidly enters the brain after 5 
minutes.
    4. Its History and Current Pattern of Abuse:
    HHS and DEA's review indicates that several European countries have 
reported drug seizures in which 4,4'-DMAR was detected in either powder 
or tablet form. As mentioned in the HHS review, customs authorities 
first detected 4,4'-DMAR in the Netherlands in 2012, in a seized drug 
powder that came from India. In 2013, Hungarian authorities reported at 
least 78 seizures of 4,4'-DMAR alone or mixed with other stimulants 
(mainly cathinones), both in powder and tablet form, which originated 
from China. Romania, Sweden, Denmark, and Finland also reported 
multiple drug seizures containing various amounts of 4,4'-DMAR since 
2013. According to HHS, two published studies in 2015 examined the 
availability of 4,4'-DMAR using internet search engines and reported 
that there was one internet site that sold 4,4'-DMAR, which is 
currently still available.
    There have been no published studies addressing the prevalence and 
pattern of abuse of 4,4'DMAR. 4,4'-DMAR is a fine white powder that can 
be pressed into tablets. The most common routes of administration for 
4,4'-DMAR are oral ingestion and nasal insufflation. According to user 
reports, doses of 4,4'-DMAR range from 10 to 200 mg and 10 to 65 mg for 
oral administration and insufflation, respectively.
    5. The Scope, Duration, and Significance of Abuse:
    There are no studies directly monitoring the scope and duration of 
use or abuse of 4,4'-DMAR. However, some internet websites contain 
anecdotal reports indicating that users can purchase 4,4'-DMAR from 
online sources as a research chemical. Fatalities reports reveal that 
most users believed they used another drug, such as MDMA, which is 
typically obtained illicitly from drug dealers. A published paper in 
2015 reported at least one online retailer selling 4,4'-DMAR at a 
minimum amount of 500 mg for [euro]36.08/g. The EMCDDA report also 
identified two internet sources for 4,4'-DMAR.
    HHS stated that no specific epidemiological reports regarding the 
significance of abuse of 4,4'-DMAR are available. The reported cases of 
4,4'-DMAR-associated deaths suggest that many of these drug users 
assumed that they were using MDMA. Thus, the majority of instances of 
abuse appear to be unintentional (see Factor 6).
    Additionally, based on DEA's review, there is no evidence of 4,4'-
DMAR abuse in the United States. DEA's STRIDE/STARLiMS and the NFLIS 
databases as queried in March 2019 had no reports of 4,4'-DMAR, 
suggesting that it is not trafficked in the United States. The first 
seizure of 4,4'-DMAR (500 grams of white powder) occurred in the 
Netherlands in 2012; subsequently a small seizure was made in Finland 
in 2013. Hungary reported 41 seizures totaling 1,852 tablets and 37 
seizures totaling 377 grams of powder between June and October of 2013. 
In twenty percent of these seizures (both powder and tablets), 4,4'-
DMAR was mixed with other illicit substances such as synthetic 
cathinones and synthetic cannabinoids. In the subsequent years, 4,4'-
DMAR was reported in Denmark, Finland, France, Hungary, the 
Netherlands, Poland, Romania, Sweden, and the UK. These seizures in 
Europe have been small in size. Because synthetic cathinones and 
synthetic cannabinoids are being widely abused in the United States, it 
is possible that the abuse of 4,4'-DMAR mixed with these substances may 
occur domestically if 4,4'-DMAR were to be

[[Page 19406]]

trafficked and abused in the United States.
    6. What, If Any, Risk There Is to the Public Health:
    Based on the review of both HHS and DEA, use of 4,4'-DMAR has been 
associated with at least 31 serious adverse events and 46 fatalities 
throughout Europe since 2013. These serious adverse events and 
fatalities are the result of unintentional consumption of 4,4'-DMAR. 
These individuals bought what they thought to be another substance such 
as MDMA, cocaine, or mephedrone from websites. According to HHS, the so 
called ``psychonauts'' who purchase substances for exploratory purposes 
appear to be buying 4,4'-DMAR from research chemical websites.
    According to the medical examiner reports mentioned in 2014 EMCDDA 
Risk Assessment, of the 23 fatalities, one was the result of 4,4'DMAR 
alone; in two fatalities, 4,4'-DMAR had a major role, and in the 
remaining 20 cases, 4,4'-DMAR mixed with other drugs likely contributed 
to deaths. Prior to their deaths, many of these individuals showed 
symptoms similar to sympathomimetic toxicity, which included agitation, 
aggression, seizures, and hyperthermia. Another study further analyzed 
the EMCDDA and ACMD's epidemiological data and revealed that in 31 
fatalities associated with 4,4'-DMAR, 22 were male, 8 were female, and 
1 was unknown. Many of these individuals also had ingested multiple 
drugs. Combining 4,4'-DMAR with other drugs may contribute to fatal 
overdoses and pose a risk to the public health.
    7. Its Psychic or Physiological Dependence Liability:
    There are no non-clinical or clinical studies examining the psychic 
or physiological dependence liability of 4,4'-DMAR. Drug abuse-
associated internet forums or drug treatment facilities had no mentions 
of dependence liability associated with 4,4'-DMAR. Although direct 
evidence regarding the psychic and physiologic dependence liability of 
4,4'-DMAR is lacking, information on substances that have a 
pharmacological mechanism of action similar to that of 4,4'-DMAR can be 
used to infer the dependence potential of this substance. As stated in 
Factor 2, 4,4'-DMAR shares a mechanism of action with aminorex, a 
structurally related substance. Aminorex increases locomotor activity 
and the physiological dependence of rats taking pentobarbital. Aminorex 
has dependence liability similar to the stimulant amphetamine. Because 
of similarities in structure and pharmacology between aminorex and 
4,4'-DMAR, it can be inferred that 4,4'-DMAR will have high psychic and 
physiological dependence liability similar to that of d-amphetamine.
    8. Whether the Substance is an Immediate Precursor of a Substance 
Already Controlled Under the CSA:
    DEA and HHS find that 4,4'-DMAR is not an immediate precursor of a 
substance already controlled under the CSA.

Conclusion

    Based on consideration of the scientific and medical evaluation and 
accompanying recommendation of HHS, and based on DEA's consideration of 
its own eight-factor analysis, DEA finds that these facts and all 
relevant data constitute substantial evidence of potential for abuse of 
4,4'-DMAR. As such, DEA hereby proposes to schedule 4,4'-DMAR as a 
schedule I controlled substance under the CSA.

Proposed Determination of Appropriate Schedule

    The CSA establishes five schedules of controlled substances known 
as schedule I, II, III, IV, and V. The CSA also outlines the findings 
required to place a drug or other substance in any particular schedule. 
21 U.S.C. 812(b). After consideration of the analysis and 
recommendation of the Assistant Secretary for Health of HHS and review 
of all available data, the Acting Administrator of DEA (Acting 
Administrator), pursuant to 21 U.S.C. 812(b)(1), finds that:
    (1) 4,4'-DMAR has a high potential for abuse. There are no non-
clinical or clinical studies directly evaluating the abuse potential of 
4,4'-DMAR. However, 4,4'-DMAR is chemically similar to aminorex 
(schedule I) and in vitro activity assays using brain synaptosomes 
indicate that 4,4'-DMAR has similar pharmacological activity to d-
amphetamine (schedule II), aminorex (schedule I), and MDMA (schedule 
I). More specifically, 4,4'-DMAR acts as a more potent releaser of 
dopamine, norepinephrine, and serotonin than substances that are listed 
in schedules I and II of the CSA. 4,4'-DMAR has been detected in 
several drug seizures in several European countries. These reports 
correlate with 46 deaths in which 4,4'-DMAR played a contributory role. 
The data provides supportive evidence that 4,4'-DMAR has a high 
potential for abuse that is similar to substances in schedule I or II 
of the CSA
    (2) 4,4'-DMAR has no currently accepted medical use in treatment in 
the United States. There are no approved New Drug Applications for 
4,4'-DMAR and no known therapeutic applications for 4,4'-DMAR in the 
United States. Therefore, 4,4'-DMAR has no currently accepted medical 
use in treatment in the United States.\6\
---------------------------------------------------------------------------

    \6\ Although there is no evidence suggesting that 4,4'-DMAR has 
a currently accepted medical use in treatment in the United States, 
it bears noting that a drug cannot be found to have such medical use 
unless DEA concludes that it satisfies a five-part test. 
Specifically, with respect to a drug that has not been approved by 
the FDA, to have a currently accepted medical use in treatment in 
the United States, all of the following must be demonstrated:
     i. The drug's chemistry must be known and reproducible;
     ii. there must be adequate safety studies;
     iii. there must be adequate and well-controlled studies proving 
efficacy;
     iv. the drug must be accepted by qualified experts; and
     v. the scientific evidence must be widely available.
    57 FR 10499 (1992).
---------------------------------------------------------------------------

    (3) There is a lack of accepted safety for use of 4,4'-DMAR under 
medical supervision. Because 4,4'-DMAR has no approved medical use and 
has not been investigated as a new drug, its safety for use under 
medical supervision has not been determined. Therefore, there is a lack 
of accepted safety for use of 4,4'-DMAR under medical supervision.
    Based on these findings, the Acting Administrator concludes that 
4,4'-DMAR warrants control in schedule I of the CSA. 21 U.S.C. 
812(b)(1). More precisely, because of its stimulant effects, and 
because it may produce stimulant-like tolerance and dependence in 
humans, DEA is proposing to place 4,4'-DMAR in 21 CFR 1308.11(f) (the 
stimulants category of schedule I). As such, the proposed control of 
4,4'-DMAR includes the substance as well as its salts, isomers, and 
salts of isomers.

Requirements for Handling 4,4'-DMAR

    If this rule is finalized as proposed, 4,4'-DMAR would be subject 
to the CSA's schedule I regulatory controls and administrative, civil, 
and criminal sanctions applicable to the manufacture, distribution, 
reverse distribution, import, export, engagement in research, conduct 
of instructional activities or chemical analysis with, and possession 
of schedule I controlled substances, including the following:
    1. Registration. Any person who handles (manufactures, distributes, 
reverse distributes, imports, exports, engages in research, or conducts 
instructional activities or chemical analysis with, or possesses) 4,4'-
DMAR, or who desires to handle 4,4'-DMAR, would need to be registered 
with DEA to conduct such activities pursuant to 21 U.S.C. 822, 823, 
957, 958, and in accordance with 21 CFR parts 1301 and

[[Page 19407]]

1312 as of the effective date of a final scheduling action. Any person 
who currently handles 4,4'-DMAR, and is not registered with DEA, would 
need to submit an application for registration and may not continue to 
handle 4,4'-DMAR after the effective date of a final scheduling action 
unless DEA has approved that application for registration pursuant to 
21 U.S.C. 822, 823, 957, 958, and in accordance with 21 CFR parts 1301 
and 1312.
    2. Disposal of stocks. Any person who does not desire or is not 
able to obtain a schedule I registration would be required to surrender 
all quantities of currently held 4,4'-DMAR, or transfer all quantities 
of currently held 4,4'-DMAR to a person registered with DEA before the 
effective date of a final scheduling action, in accordance with all 
applicable federal, state, local, and tribal laws. As of the effective 
date of a final scheduling action, 4,4'-DMAR would be required to be 
disposed of in accordance with 21 CFR part 1317, in addition to all 
other applicable federal, state, local, and tribal laws.
    3. Security. 4,4'-DMAR would be subject to schedule I security 
requirements and would need to be handled and stored in accordance with 
21 CFR 1301.71-1301.93 as of the effective date of a final scheduling 
action.
    4. Labeling and Packaging. All labels, labeling, and packaging for 
commercial containers of 4,4'-DMAR would need to be in compliance with 
21 U.S.C. 825 and 958(e), and be in accordance with 21 CFR part 1302, 
as of the effective date of a final scheduling action.
    5. Quota. Only registered manufacturers would be permitted to 
manufacture 4,4'-DMAR in accordance with a quota assigned, pursuant to 
21 U.S.C. 826 and in accordance with 21 CFR part 1303, as of the 
effective date of a final scheduling action.
    6. Inventory. Every DEA registrant who possesses any quantity of 
4,4'-DMAR on the effective date of a final scheduling action would be 
required to take an inventory of 4,4'-DMAR on hand at that time, 
pursuant to 21 U.S.C. 827 and 958, and in accordance with 21 CFR 
1304.03, 1304.04, and 1304.11(a) and (d).
    Any person who becomes registered with DEA on or after the 
effective date of the final scheduling action would be required to take 
an initial inventory of all stocks of controlled substances (including 
4,4'-DMAR) on hand on the date the registrant first engages in the 
handling of controlled substances, pursuant to 21 U.S.C. 827 and 958, 
and in accordance with 21 CFR 1304.03, 1304.04, and 1304.11(a) and (b).
    After the initial inventory, every DEA registrant would be required 
to take an inventory of all controlled substances (including 4,4'-DMAR) 
on hand every two years, pursuant to 21 U.S.C. 827 and 958, and in 
accordance with 21 CFR 1304.03, 1304.04, and 1304.11.
    7. Records and Reports. Every DEA registrant would be required to 
maintain records and submit reports pursuant to 21 U.S.C. 827 and 958, 
and in accordance with 21 CFR parts 1304, 1312, and 1317, as of the 
effective date of a final scheduling action. Manufacturers and 
distributors would be required to submit reports regarding 4,4'-DMAR to 
the Automation of Reports and Consolidated Order System (ARCOS) 
pursuant to 21 U.S.C. 827 and in accordance with 21 CFR parts 1304 and 
1312, as of the effective date of a final scheduling action.
    8. Order Forms. Every DEA registrant who distributes 4,4'-DMAR 
would be required to comply with order form requirements, pursuant to 
21 U.S.C. 828, and in accordance with 21 CFR part 1305, as of the 
effective date of a final scheduling action.
    9. Importation and Exportation. All importation and exportation of 
4,4'-DMAR would need to be in compliance with 21 U.S.C. 952, 953, 957, 
and 958, and in accordance with 21 CFR part 1312, as of the effective 
date of a final scheduling action.
    10. Liability. Any activity involving 4,4'-DMAR not authorized by, 
or in violation of, the CSA or its implementing regulations, would be 
unlawful, and may subject the person to administrative, civil, and/or 
criminal sanctions.

Regulatory Analyses

Executive Orders 12866, 13563, and 13771, Regulatory Planning and 
Review, Improving Regulation and Regulatory Review, and Reducing 
Regulation and Controlling Regulatory Costs

    In accordance with 21 U.S.C. 811(a), this proposed scheduling 
action is subject to formal rulemaking procedures performed ``on the 
record after opportunity for a hearing,'' which are conducted pursuant 
to the provisions of 5 U.S.C. 556 and 557. The CSA sets forth the 
procedures and criteria for scheduling a drug or other substance. Such 
actions are exempt from review by the Office of Management and Budget 
(OMB) pursuant to section 3(d)(1) of Executive Order 12866 and the 
principles reaffirmed in Executive Order 13563.
    This rulemaking is not an Executive Order 13771 regulatory action 
because this rule is not significant under Executive Order 12866.

Executive Order 12988, Civil Justice Reform

    This proposed regulation meets the applicable standards set forth 
in sections 3(a) and 3(b)(2) of Executive Order 12988, Civil Justice 
Reform, to eliminate drafting errors and ambiguity, minimize 
litigation, provide a clear legal standard for affected conduct, and 
promote simplification and burden reduction.

Executive Order 13132, Federalism

    This proposed rulemaking does not have federalism implications 
warranting the application of Executive Order 13132. The proposed rule 
does not have substantial direct effects on the States, on the 
relationship between the national government and the States, or the 
distribution of power and responsibilities among the various levels of 
government.

Executive Order 13175, Consultation and Coordination With Indian Tribal 
Governments

    This proposed rule does not have tribal implications warranting the 
application of Executive Order 13175. It does not have substantial 
direct effects on one or more Indian tribes, on the relationship 
between the Federal Government and Indian tribes, or on the 
distribution of power and responsibilities between the Federal 
Government and Indian tribes.

Regulatory Flexibility Act

    The Acting Administrator, in accordance with the Regulatory 
Flexibility Act (RFA), 5 U.S.C. 601-602, has reviewed this proposed 
rule, and by approving it, certifies that it will not have a 
significant economic impact on a substantial number of small entities.
    DEA proposes placing the substance 4,4'-DMAR (Chemical name: 4-
methyl-5-(4-methylphenyl)-4,5-dihydro-l,3-oxazol-2-amine), including 
its salts, isomers, and salts of isomers, whenever the existence of 
such salts, isomers, and salts of isomers is possible, in schedule I of 
the CSA. This action is being taken to enable the United States to meet 
its obligations under the 1971 Convention on Psychotropic Substances. 
If finalized, this action would impose the regulatory controls and 
administrative, civil, and criminal sanctions applicable to schedule I 
controlled substances on persons who handle (manufacture, distribute, 
reverse distribute, import, export, engage in research, conduct 
instructional activities or chemical

[[Page 19408]]

analysis with, or possess), or propose to handle 4,4'-DMAR.
    According to HHS, 4,4'-DMAR has a high potential for abuse, has no 
currently accepted medical use in treatment in the United States, and 
lacks accepted safety for use under medical supervision. DEA's research 
confirms that there is no commercial market for 4,4'-DMAR in the United 
States. Additionally, queries of DEA's STRIDE/STARLiMS and the NFLIS 
databases in February, 2020, did not generate any reports of 4,4'-DMAR, 
suggesting that it is not trafficked in the United States. Therefore, 
DEA estimates that no U.S. entity currently handles 4,4'-DMAR and does 
not expect any U.S. entity to handle 4,4'-DMAR in the foreseeable 
future. DEA concludes that no U.S. entity would be affected by this 
rule if finalized. As such, the proposed rule will not have a 
significant effect on a substantial number of small entities.

Duplicative, Overlapping, and Conflicting Rules

    DEA is the only agency with authority to schedule drugs under the 
CSA. DEA has not identified any duplicative, overlapping, or 
conflicting rules with the proposed rule.

Unfunded Mandates Reform Act of 1995

    In accordance with the Unfunded Mandates Reform Act (UMRA) of 1995, 
2 U.S.C. 1501 et seq., DEA has determined and certifies that this 
action would not result in any Federal mandate that may result ``in the 
expenditure by State, local, and tribal governments, in the aggregate, 
or by the private sector, of $100,000,000 or more (adjusted for 
inflation) in any 1 year * * *.'' Therefore, neither a Small Government 
Agency Plan nor any other action is required under UMRA of 1995.

Paperwork Reduction Act

    This action does not impose a new collection of information 
requirement under the Paperwork Reduction Act, 44 U.S.C. 3501-3521. 
This action would not impose recordkeeping or reporting requirements on 
State or local governments, individuals, businesses, or organizations. 
An agency may not conduct or sponsor, and a person is not required to 
respond to, a collection of information unless it displays a currently 
valid OMB control number.

Congressional Review Act

    This rule is not a major rule as defined by section 804 of the 
Small Business Regulatory Enforcement Fairness Act of 1996 
(Congressional Review Act (CRA)). This rule will not result in: An 
annual effect on the economy of $100,000,000 or more; a major increase 
in costs or prices for consumers, individual industries, Federal, 
State, or local government agencies, or geographic regions; or 
significant adverse effects on competition, employment, investment, 
productivity, innovation, or on the ability of U.S.-based companies to 
compete with foreign-based companies in domestic and export markets.

List of Subjects in 21 CFR Part 1308

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

    For the reasons set out above, 21 CFR part 1308 is proposed to be 
amended to read as follows:

PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES

0
1. The authority citation for 21 CFR part 1308 continues to read as 
follows:

    Authority:  21 U.S.C. 811, 812, 871(b), unless otherwise noted.

0
2. In Sec.  1308.11, redesignate paragraphs (f)(4) through (f)(8) as 
paragraphs (f)(5) through (f)(9) and add a new paragraph (f)(4) to read 
as follows:


Sec.  1308.11  Schedule I.

* * * * *
    (f) * * *
    (4) 4,4'-Dimethylaminorex (4,4'-DMAR; 4,5-dihydro-4-methyl-5-(4-
methylphenyl)-2-oxazolamine; 4-methyl-5-(4-methylphenyl)-4,5-dihydro-
1,3-oxazol-2-amine). ........................................... 1595
* * * * *

Uttam Dhillon,
Acting Administrator.
[FR Doc. 2020-07095 Filed 4-6-20; 8:45 am]
BILLING CODE 4410-09-P