Proposed Rule2021-26293
Schedules of Controlled Substances: Placement of Methoxetamine (MXE) in Schedule I
Primary source
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Published
December 7, 2021
Issuing agencies
Justice DepartmentDrug Enforcement Administration
Abstract
The Drug Enforcement Administration proposes placing 2- (ethylamino)-2-(3-methoxyphenyl)cyclohexan-1-one (methoxetamine, MXE), including its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation, 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, methoxetamine.
Full Text
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<title>Federal Register, Volume 86 Issue 232 (Tuesday, December 7, 2021)</title>
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[Federal Register Volume 86, Number 232 (Tuesday, December 7, 2021)]
[Proposed Rules]
[Pages 69187-69194]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2021-26293]
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DEPARTMENT OF JUSTICE
Drug Enforcement Administration
21 CFR Part 1308
[Docket No. DEA-568]
Schedules of Controlled Substances: Placement of Methoxetamine
(MXE) 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 2-
(ethylamino)-2-(3-methoxyphenyl)cyclohexan-1-one (methoxetamine, MXE),
including its salts, isomers, and salts of isomers whenever the
existence of such salts, isomers, and salts of isomers is possible
within the specific chemical designation, 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, methoxetamine.
DATES: Comments must be submitted electronically or postmarked on or
before February 7, 2022.
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,
together with a written statement of position on the matters of fact
and law asserted in the hearing, must be received on or before January
6, 2022.
ADDRESSES: Interested persons may file written comments on this
proposal in accordance with 21 CFR 1308.43(g). 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-568'' on all
electronic and written correspondence, including any attachments.
<bullet> Electronic comments: DEA encourages commenters to submit
all comments 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> and follow the on-line
instructions at that site for submitting comments. Upon completion of
your submission, you will receive a Comment Tracking Number. Submitted
comments are not instantaneously available for public view on
<a href="http://regulations.gov">regulations.gov</a>. If you have received a Comment Tracking Number, you
have submitted your comment successfully and there is no need to
resubmit the same comment.
<bullet> 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.
<bullet> Hearing requests: All requests for a hearing and waivers
of participation, together with a written statement of position on the
matters of fact and law asserted in the hearing, 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: Terrence L. Boos, Drug & Chemical
Evaluation Section, Diversion Control Division, Drug Enforcement
Administration; Telephone: (571) 362-3249.
SUPPLEMENTARY INFORMATION:
Posting of Public Comments
All comments received in response to this docket are considered
part of the public record. The Drug Enforcement Administration (DEA)
will make comments available, unless reasonable cause is given, for
public inspection online at <a href="https://www.regulations.gov">https://www.regulations.gov</a>. Such
information includes personal identifying information (such as your
name, address, etc.) voluntarily submitted by the commenter. The
Freedom of Information Act 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 DEA to make it
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 DEA to make it publicly available, you
must include the phrase ``CONFIDENTIAL BUSINESS INFORMATION'' in the
first paragraph of your comment. You must also
[[Page 69188]]
prominently identify the confidential business information to be
redacted within the comment.
DEA will generally make available in publicly redacted form
comments containing personal identifying information and confidential
business information identified, as directed above. If a comment has so
much confidential business information that DEA cannot effectively
redact it, DEA may not make available publicly all or part of that
comment. Comments posted to <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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 confidential as directed above.
An electronic copy of this document and supplemental information to
this proposed rule are available at <a href="https://www.regulations.gov">https://www.regulations.gov</a> for
easy reference.
Request for Hearing or Appearance; Waiver
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, 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 such requests must
include a statement of interest in the proceeding and the objections or
issues, if any, concerning which the person desires to be heard. 21 CFR
1316.47(a). 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 a hearing and waivers of participation, together
with a written statement of position on the matters of fact and law
involved in such hearing, 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)(2)-(4). When the United States
receives notification of a scheduling decision pursuant to Article 2 of
the 1971 Convention indicating that a drug or other substance has been
added 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 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). In the event that the Secretary
of HHS (Secretary) did not consult with the Attorney General, and the
Attorney General did not issue a temporary order, as provided under 21
U.S.C. 811(d)(4), the procedures for permanent scheduling set forth in
21 U.S.C. 811(a) and (b) control. Pursuant to 21 U.S.C. 811(a)(1), the
Attorney General may add to such a schedule any drug or other
substance, if he finds that such drug or other substance has a
potential for abuse, and makes 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. 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), 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
Methoxetamine (MXE), also known as 2-(ethylamino)-2-(3-
methoxyphenyl)cyclohexan-1-one or 2-(3-methoxyphenyl)-2-(N-
ethylamino)cyclohexanone belongs to the arylcyclohexylamine class of
drugs with dissociative anesthetic and hallucinogenic properties,
similar to phencyclidine (PCP) and ketamine. Methoxetamine has no
approved medical use in the United States.
On December 30, 2014, DEA, in accordance with the provisions of 21
U.S.C. 811(b), requested HHS provide a scientific and medical
evaluation as well as a scheduling recommendation for methoxetamine. On
April 14, 2017, DEA provided HHS additional scientific and updated
information on methoxetamine. The April 14, 2017, communication
included that on May 17, 2016, the Secretary-General of the United
Nations (UN Secretary General) advised the Secretary of State of the
United States that the Commission on Narcotic Drugs (CND), during its
59th Session in March 2016, voted to place methoxetamine in Schedule II
of the 1971 Convention (CND Dec/59/6). As a signatory to this
international treaty, the United States is required, by scheduling
under the CSA, to place appropriate controls on methoxetamine to meet
the minimum requirements of the treaty.
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 methoxetamine. This
license requirement is accomplished by the CSA with the registration
requirement as set forth in 21 U.S.C. 822, 823, 957, and 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 with the export and import provisions established in 21 U.S.C.
952, 953, 957, and 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 UN
Secretary-General, that it prohibits the importation of a substance in
Schedule II, III, or IV of the 1971 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 country of
the notifying party. This requirement is also accomplished by the
export provisions of the CSA 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
[[Page 69189]]
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.
DEA notes that there are differences between the schedules of
substances in the 1971 Convention and the CSA. The CSA has five
schedules (schedules I-V) with specific criteria set forth for each
schedule. Schedule I is the only possible schedule in which a drug or
other substance may be placed if it has high potential for abuse and no
currently accepted medical use in treatment in the United States. See
21 U.S.C. 812(b). In contrast, the 1971 Convention has four schedules
(Schedules I-IV) but does not have specific criteria for each schedule.
The 1971 Convention simply defines its four schedules, in Article 1, to
mean the correspondingly numbered lists of psychotropic substances
annexed to the Convention, and altered in accordance with Article 2.
Proposed Determination To Schedule Methoxetamine
Pursuant to 21 U.S.C. 811(b), DEA gathered the necessary data on
methoxetamine and on December 30, 2014, submitted it to the Acting
Assistant Secretary for Health of HHS (Acting Assistant Secretary) with
a request for a scientific and medical evaluation of available
information and a scheduling recommendation for methoxetamine.
Subsequently, on April 14, 2017, DEA submitted additional data on
methoxetamine to the Acting Assistant Secretary. On April 14, 2018, HHS
provided to DEA a scientific and medical evaluation entitled ``Basis
for the Recommendation to Place (2-(3-methoxyphenyl)-2-(N-ethylamino)-
cyclohexanone) Methoxetamine and its Optical Isomers and 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 methoxetamine and
its optical isomers and salts 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
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> under docket
number ``DEA-568.''
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 methoxetamine, DEA also
considered all other relevant data regarding actual or relative
potential for abuse of methoxetamine. The term ``abuse'' is not defined
in the CSA, however the legislative history of the CSA suggests the
following four prongs in 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 methoxetamine.
These data as presented below demonstrate that methoxetamine has a high
potential for abuse.
a. There Is Evidence That 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
According to HHS, individuals are taking methoxetamine in amounts
sufficient to create a hazard to their health or to the safety of other
individuals and to the community. Published case reports described non-
fatal and fatal intoxications from the United States and Europe,
including Poland, the United Kingdom, and Switzerland. The 2014
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) report
on methoxetamine mentioned 20 confirmed (by analysis of postmortem
biological samples) death reports received between 2011 and 2013 from
European Union Member States to the Early Warning System. Between 2011
and 2014, scientific publications have reported one death related to
methoxetamine from Switzerland, eight deaths from the United Kingdom,
and at least two deaths from Poland. In the United States,
methoxetamine has been reported as the cause of death in two cases; one
case was mentioned in the 2014 Annual Report of the American
Association of Poison Control Centers' National Poison Data System, and
the second case was from a 2013 news report mentioning the Medical
Examiner's findings from that death. Additionally, two case reports
suggest that some individuals use methoxetamine to self-medicate for
some clinical conditions, specifically chronic foot pain and post-
traumatic stress disorder. Further, a case report published in 2019
suggests a single injection of methoxetamine can induce prolonged
psychosis with confirmed cognitive deficits. As stated by HHS, when
abused, methoxetamine can be administered through intranasal
(insufflation or snorting), oral, sublingual, rectal, intramuscular,
and intravenous routes of administration. Abuse of methoxetamine,
similar to PCP and ketamine abuse, produces dissociative anesthetic and
hallucinogenic effects, including somatic and psychological effects
such as: Euphoria, increased empathy, sense of dissociation from the
body, vivid visual hallucinations, and pleasant intensification of
sensory experiences. Users report in online forums that methoxetamine
generally produces longer lasting effects, with a delayed
[[Page 69190]]
onset compared to PCP or ketamine. At higher doses (>40 mg), users
describe the experience as reaching the ``m-hole,'' which is similar to
the ketamine ``k-hole'' experience and characterized by extreme
dissociation from the body, comparable to an out-of-body experience.
HHS reports that commonly reported side effects of methoxetamine
include dizziness, confusion, time distortion, aphasia, psychomotor
agitation, vertigo, incoordination, nausea, and vomiting. Similar to
PCP and ketamine toxicity, signs and symptoms (toxidrome) of
methoxetamine toxicity can be grouped into three types: Dissociative/
delirious, sympathomimetic, and cerebellar symptoms. Dissociative or
delirious symptoms include depersonalization, derealization, catatonia,
audiovisual hallucinations, delusions, confusion, altered or loss of
consciousness, agitation, aggression, amnesia, and mood lability.
Sympathomimetic symptoms include rapid heart rate (tachycardia), high
blood pressure (hypertension), elevated body temperature (pyrexia),
rapid breathing (tachypnea), and pupillary dilation (mydriasis).
Cerebellar symptoms include inability to sit (truncal ataxia),
incoordination, speech impairment (dysarthria), impaired ability to
perform rapid alternating movements (dysdiadochokinesis), and rapid and
repetitive uncontrolled eye movements (nystagmus). Summarized
withdrawal symptoms reported on online forums include low mood,
depressive thoughts, and cognitive impairment for many hours in one
user followed by two days of insomnia after a single 100 mg intranasal
administration. One user reported a suicide attempt after discontinued
use of methoxetamine.
HHS states that treatment of acute toxicity caused by methoxetamine
and other drugs of the same class (e.g., PCP and ketamine) consists of
supportive treatment to control or relieve psychological complications
and side effects. This treatment may include administration of
benzodiazepines, antiemetics, intravenous fluids, and respiratory
support, if needed.
DEA notes that ketamine has been known to cause toxicities to the
bladder and renal system. When mice were given daily dose of 30 mg/kg
methoxetamine intraperitoneally (i.p.) for 90 days, significant bladder
and renal toxicity occurred. Thus, like ketamine, chronic
administration of methoxetamine is associated with bladder and renal
toxicity, including inflammatory changes with subsequent fibrosis that
could lead to bladder and kidney damage.
b. There is Significant Diversion of the Drug or Substance From
Legitimate Drug Channels
HHS states that methoxetamine is not a Food and Drug Administration
(FDA)-approved drug product for treatment in the United States and is
unaware of any country in which its use is legal. There appear to be no
legitimate sources for methoxetamine as a marketed drug. Thus, there is
no evidence of significant diversion of methoxetamine from legitimate
drug channels.
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 Substance
Methoxetamine is not approved for medical use and is not formulated
or available for clinical use. Therefore, it is assumed that
individuals are taking methoxetamine on their own initiative, rather
than based on medical advice from a properly-licensed practitioner.
This is consistent with the data from law enforcement seizures and case
reports indicating that individuals are taking methoxetamine on their
own initiative rather than on the medical advice of a licensed
practitioner.
d. The Drug is a New Drug so Related in its Action to a Drug or Other
Substance Already Listed as Having a Potential for Abuse To Make it
Likely That the Drug Substance Will Have the Same Potential for Abuse
as Such Drugs, 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
Methoxetamine is a synthetic arylcyclohexylamine and has
pharmacological properties similar to other arylcyclohexylamines such
as the ethylamine analog of phencyclidine (PCE; schedule I), the
thiophene analog of phencyclidine (TCP; schedule I), phencyclidine
(PCP, schedule II), and ketamine (schedule III). Methoxetamine, similar
to PCE, TCP, PCP, and ketamine, has been shown to produce dissociative
anesthetic and hallucinogenic effects.
As mentioned in HHS' review, the primary mechanism of action of
methoxetamine is thought to be on glutamatergic neurotransmission.
Glutamate is the major excitatory neurotransmitter system in the brain.
In vitro binding studies show that methoxetamine binds to the
glutamatergic N-methyl-D-aspartate (NMDA) receptor and acts as an
antagonist with similar potency as PCP and ketamine. HHS notes that,
similar to PCP, methoxetamine also has affinity for the serotonin
reuptake transporter and acts as a serotonin reuptake inhibitor.
Further, like many drugs of abuse, methoxetamine acutely increases the
firing rate and bursting activity of ventral tegmental area (VTA)
dopaminergic neurons projecting to the nucleus accumbens (NAc), and
inhibits the reuptake of dopamine. The VTA is an area of the brain,
rich in dopamine and serotonin neurons, which along with the NAc is
part of the brain reward pathway. The increase in the firing rate and
bursting activity of dopamine neurons produced by PCP, ketamine, and
methoxetamine that results in increased dopamine levels in the VTA may
underlie the psychotomimetic and reinforcing properties of these drugs.
Drug discrimination (an in vivo test to assess drug abuse liability
and compare drugs to known drugs of abuse) data demonstrate that
methoxetamine, similar to PCP, fully substitutes for the discriminative
stimulus effect of ketamine in rats. Additionally, conditioned place
preference (CPP) studies and self-administration studies used to assess
rewarding and reinforcing effects show that methoxetamine produces both
rewarding and reinforcing effects. Taken together, methoxetamine
produces psychopharmacological effects similar to those produced by
ketamine and PCP in animal models that are predictive of abuse
potential in humans.
As stated by HHS, users of methoxetamine experience effects similar
to those of ketamine and PCP including depersonalization, a mild to
strong sense of dissociation from the physical body, distortion of the
sense of reality, and vivid visual hallucinations. More negative or
challenging effects of methoxetamine, similar to PCP and ketamine, may
also occur and include delusions, tachycardia, hypertension, agitation,
aggression, and cerebellar toxicity. Case reports of overdose and
deaths resulting from methoxetamine abuse have been reported between
2011 and 2019 in scientific literature and by international
authorities.
As mentioned by HHS, methoxetamine is being abused for its
psychoactive effects. DEA further notes that based on concerns related
to trafficking and availability, as well as the risks to the public
health associated with its abuse, at least ten states in the United
States have controlled methoxetamine. At the international level, as of
June 2020, methoxetamine has been controlled in Russia,
[[Page 69191]]
Switzerland, Israel, Sweden, United Kingdom, Japan, Germany, France,
Brazil, China, Poland, and the European Union member states.
2. Scientific Evidence of the Drug's Pharmacological Effects, if Known
Methoxetamine is an antagonist at the glutamatergic NMDA receptors
(with moderately high affinity) and a reuptake inhibitor at the
serotonin transporter. Acute methoxetamine exposure increases the
firing rate and bursting activity of the ventral tegmental area (VTA)
dopaminergic neurons projecting to the nucleus accumbens (NAc) and
inhibits reuptake of dopamine, similarly to PCP and ketamine. The VTA
is an area of the brain that is rich in dopamine and serotonin neurons
and is a contributing part of the brain reward pathway, as is the NAc.
The net result is an increase in dopamine levels in the VTA, which may
underlie the psychomimetic and reinforcing effects of these drugs.
Animal testing data in rats show that methoxetamine, like PCP,
fully substitutes for ketamine discriminative stimulus. Additionally,
rats self-administer methoxetamine. Data from self-administration and
CPP studies show that methoxetamine has rewarding and reinforcing
effects. Thus, methoxetamine produces psychopharmacologic effects
similar to those produced by other NMDA antagonists (PCP and ketamine)
in animal models, which are predictive of its abuse in humans.
In humans, users of methoxetamine report dissociative anesthetic
and hallucinogenic effects similar to PCP and ketamine including
euphoria, increased empathy, dissociation from the body, vivid visual
hallucinations, and pleasant intensification of sensory experiences.
Delusion, tachycardia, hypertension, agitation, aggression, and
cerebellar toxicity have also been reported. Methoxetamine-associated
overdose and deaths have been reported in scientific literature and by
international authorities between 2011 and 2019.
3. The State of Current Scientific Knowledge Regarding the Drug or
Other Substance
Chemistry
Methoxetamine, also known as also known as MXE, 2-(ethylamino)-2-
(3-methoxyphenyl)cyclohexan-1-one, or 2-(3-methoxyphenyl)-2-(N-
ethylamino)cyclohexanone, has a molecular weight of 247.338 g/mol.
Methoxetamine is primarily present as a white crystalline powder and
has also been reported as being off-white, beige, or yellow in color.
The Chemical Abstract Service Registry Numbers for methoxetamine are
1239943-76-0 for methoxetamine base and 1239908-48-5 for methoxetamine
as the hydrochloride salt. Its molecular formula (as base) is
C<INF>15</INF>H<INF>21</INF>NO<INF>2</INF>. Methoxetamine hydrochloride
(salt) is soluble in organic solvents like ethanol (10 mg/mL) at 25
[deg]C, dimethyl sulfoxide (DMSO) (14 mg/mL), and dimethyl formamide (5
mg/mL). It is also soluble in aqueous solvents like a pH 7.2 phosphate
buffer (5 mg/mL). Synthesis and characterization of methoxetamine and
analytical data (nuclear magnetic resonance spectroscopy, mass
spectroscopy, and infrared spectroscopy) are reported in the scientific
literature.
Pharmacokinetics and Toxicology
Controlled pharmacokinetic clinical research studies have not been
conducted to characterize the onset of action, the plasma
concentrations after ingestion of a fixed dose of methoxetamine, or to
determine the half-life of methoxetamine. However, since methoxetamine
has been used recreationally, a summary and description of the onset
and duration of the effects of methoxetamine that come from user
reports, generally via online forums, can be found in the scientific
literature.
A summary of online user reports suggests that methoxetamine is
generally administered through intranasal (insufflation or snorting),
oral, sublingual, rectal, and intramuscular routes with additional
reports of intravenous use. Dose range administered, onset of drug
effects, and duration of drug effects vary by the route of
administration. Dose associated with intranasal use is 20 to 60 mg,
oral administration is 20 to 100 mg, and intramuscular administration
is 10 to 50 mg, with reported onset of drug effects of 30 to 90 minutes
following intranasal use, up to 90 minutes following oral
administration, and five minutes following intramuscular
administration. Drug effects can last 2.5 to 7 hours following nasal
use, 3 to 5 hours following oral ingestion, and 1 to 4 hours after
intramuscular injection. Typical doses and drug-related time effects
were not reported for other routes of administration.
As HHS reports, the metabolism of methoxetamine was investigated
using human liver microsomes in vitro and compared to toxicological
analysis of urine from individuals presenting with analytically
confirmed acute methoxetamine toxicity. Liquid chromatography high-
resolution mass spectrometry was used to identify and characterize the
metabolites of methoxetamine in vitro and in vivo. These studies
reported complex metabolism of methoxetamine including N-deethylation,
O-demethylation, hydroxylation, reduction, and dehydrogenation followed
by glucuronization (conjugation of the metabolites with glucuronic
acid). The normethoxytamine (desethylmethoxetamine) is the main
metabolite identified in both in vivo and in vitro studies.
HHS further states that kinetic studies with human hepatic CYP
isozymes have showed that N-deethylation is catalyzed by CYP2B6 and
CYP3A4, O-demethylation by CYP2B6 and CYP2C19, and hydroxylation by
CYP2B6. These studies also showed that normethoxamine is the major
metabolite in humans and rats.
The role of CYP2B6 in methoxetamine metabolism is of particular
importance. Because CYP2B6 is involved in metabolism of numerous drugs
(e.g., bupropion, methadone, propofol, sertraline), pharmacokinetic
interactions between methoxetamine and other compounds are likely to
occur. In addition, the rate of methoxetamine metabolism and toxicity
may depend on genetic polymorphism of CYP2B6. Currently, it is unknown
if any specific methoxetamine metabolites are biologically active.
4. Its History and Current Pattern of Abuse
As HHS notes, methoxetamine, similar to ketamine and PCP, is a
synthetic arylcyclohexylamine with dissociative anesthetic properties.
Typical routes of administration by drug users include oral, nasal
insufflation, intramuscular, rectal, and intravenous. Based on
available abuse data, public health risk, and drug trafficking data,
the World Health Organization (WHO) recommended to the United Nations
that methoxetamine be controlled internationally. In March 2016, the
CND voted to place methoxetamine in Schedule II of the 1971 Convention.
In 2014, WHO reported that methoxetamine has been available in
Europe since 2010. Distribution and trafficking of methoxetamine
occurred largely via the internet. According to the law enforcement
data, the first encounter in the United States occurred in mid-2011.
In 2015, WHO reported non-fatal intoxications and more than 20
deaths associated with methoxetamine. Since 2014 through 2019, there
have been reports of several other overdoses and
[[Page 69192]]
deaths in which methoxetamine was implicated in Europe. In the United
States, there have been at least two documented deaths associated with
the use of methoxetamine, one occurring in 2012 and the other in 2014.
5. The Scope, Duration, and Significance of Abuse
In the United States, evidence of abuse of methoxetamine initially
appeared in mid-2011 when a case study was published regarding an
individual who was brought to the emergency department following
methoxetamine intoxication in Massachusetts. The first reported death
in the United States from methoxetamine abuse occurred in Milwaukee
County, Wisconsin, in May 2012.
Data from the System to Retrieve Information on Drug Evidence
(STRIDE) and STARLiMS \3\ and the National Forensic Laboratory
Information System (NFLIS) \4\ indicate that methoxetamine was found in
samples starting in August 2004, in California. Specifically, there
were 114 STRIDE/STARLIMS reports from August 2004 through July 2021,
and 677 NFLIS reports from January 2011 to July 2021. Combining drug
reports and exhibits from both NFLIS and STRIDE between August 2004 and
July 2021, methoxetamine has been encountered in 45 states and the
District of Columbia. Methoxetamine drug quantities seized by United
States Customs and Border Protection (CBP) have ranged from 2 to 200
grams. Reportedly, a small percentage of the methoxetamine reports from
CBP were in combination with other drugs, such as synthetic
cannabinoids, synthetic cathinones, ketamine, caffeine, and sildenafil.
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\3\ STARLiMS is a web-based, commercial laboratory information
management system that systematically collects results from drug
chemistry analyses conducted by DEA laboratories. On October 1,
2014, STARLiMS replaced STRIDE as DEA's laboratory drug evidence
data system of record. DEA laboratory data submitted after September
30, 2014 are reposited in STARLiMS. STRIDE/STARLiMS data were
queried on August 18, 2021.
\4\ 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. NFLIS data were queried on August 18, 2021.
---------------------------------------------------------------------------
In response to abuse and safety concerns, methoxetamine has been
controlled in Virginia, Minnesota, North Dakota, Florida, Ohio,
Indiana, Louisiana, Alabama, Arizona, and Utah.
Abuse of methoxetamine has been characterized as causing acute
public health and safety issues worldwide. Methoxetamine is now
controlled in Russia, Switzerland, Israel, Sweden, United Kingdom,
Japan, Germany, France, Brazil, China, Poland and the European Union
member states. On September 25, 2014, the European Union council
decided to control methoxetamine in all European member states, and on
March 18, 2016, the CND, at its 59th Session, added methoxetamine to
Schedule II of the 1971 Convention.
6. What, if Any, Risk There Is to the Public Health
Methoxetamine shares similar mechanisms of action with and produces
similar physiological and subjective effects (see Factor 2 for more
information) as other controlled arylcyclohexylamines, such as the
ethylamine analog of phencyclidine (PCE; schedule I), the thiophene
analog of phencyclidine (TCP; schedule I), phencyclidine (PCP; schedule
II), and ketamine (schedule III). Thus, methoxetamine poses the same
risks to public health as PCE, TCP, PCP, and ketamine. Predominantly,
the risks to public health are centralized to risks of the user, but in
some cases do affect the general public, as is the case of driving
under the influence.
Users of methoxetamine describe the drug effects as being similar
to those of PCP and ketamine. Effects often include hallucinations and
dissociation of the physical body, and can produce antidepressant-like
effects. Online reports of use of methoxetamine suggest it is used via
all routes of administration (i.e., intranasal, oral, intramuscular,
rectal, and intravenous). Due to the various routes of administration,
the onset of effects can vary widely (one minute for intravenous to 90
minutes intranasal).
As HHS notes, several case reports pertaining to methoxetamine use,
toxicities, and fatal intoxications have been published in the
scientific and medical literature in several countries. In particular,
in 2014 EMCDDA reported that methoxetamine was mentioned in 20
biologically confirmed death reports from the European Union member
states Early Warning System. At least one published death related to
methoxetamine has occurred in Switzerland, eight deaths in the United
Kingdom, two deaths in Poland, and two deaths in the United States. In
2015, WHO indicated that a total of 120 nonfatal intoxications and 22
deaths related to methoxetamine had been reported, in which many but
not all had been biologically confirmed. Two case reports suggest some
individuals use methoxetamine to self-medicate to treat various
clinical conditions, specifically chronic foot pain and post-traumatic
stress disorder. In addition, DEA further notes one case report
published in 2019 suggests methoxetamine can induce prolonged psychosis
after a single injection.
7. Its Psychic or Physiological Dependence Liability
Psychological and physiological dependence are associated with
methoxetamine. The euphoric and hallucinogenic effects associated with
methoxetamine and other arylcyclohexylamine drugs serve as reinforcers
and can result in psychological dependence and are supported by case
studies with methoxetamine abusers. Several preclinical studies and
case reports examined and described physical dependence and withdrawal
effects associated with methoxetamine abuse. Signs of methoxetamine
withdrawal have included low mood and/or depressive thoughts, cognitive
impairment lasting several hours followed by two days of insomnia after
last use, and a reported suicide attempt.
8. Whether the Substance Is an Immediate Precursor of a Substance
Already Controlled Under the CSA
DEA and HHS find that methoxetamine is not an immediate precursor
of any controlled substance of the CSA.
Conclusion
Based on consideration of the scientific and medical evaluation and
accompanying recommendation of HHS, and 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
methoxetamine. As such, DEA hereby proposes to schedule methoxetamine
as a controlled substance under the CSA.
Proposed Determination of Appropriate Schedule
The CSA establishes five schedules of controlled substances known
as schedules 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 Acting Assistant Secretary for Health of HHS and
review of all other available data, the Administrator of DEA, pursuant
to 21 U.S.C. 812(b)(1), finds that:
(1) Methoxetamine has a high potential for abuse that is comparable
to other scheduled substances such as the ethylamine analog of
phencyclidine (PCE; schedule I), the thiophene analog
[[Page 69193]]
of phencyclidine (TCP; schedule I), phencyclidine (PCP; schedule II),
and ketamine (schedule III);
(2) Methoxetamine has no currently accepted medical use in
treatment in the United States. There are no approved New Drug
Applications for methoxetamine and no known therapeutic applications
for methoxetamine in the United States. Therefore, methoxetamine has no
currently accepted medical use in treatment in the United States.\5\
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\5\ Although there is no evidence suggesting that methoxetamine
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), pet. for rev. denied, Alliance for Cannabis
Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994).
---------------------------------------------------------------------------
(3) There is a lack of accepted safety for use of methoxetamine
under medical supervision. Because methoxetamine 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 methoxetamine under medical
supervision.
Based on these findings, the Acting Administrator of DEA concludes
that methoxetamine warrants control in schedule I of the CSA. More
precisely, because of its hallucinogenic effects, and because it may
produce hallucinogenic-like tolerance and dependence in humans, DEA
proposes to placing methoxetamine, including its salts, isomers, and
salts of isomers whenever the existence of such salts, isomers, and
salts of isomers is possible within the specific chemical description,
in 21 CFR 1308.11(d) (the hallucinogenic substances category of
schedule I).
Requirements for Handling Methoxetamine
If this rule is finalized as proposed, methoxetamine 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 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), or
who desires to handle, methoxetamine would be required to be registered
with DEA to conduct such activities pursuant to 21 U.S.C. 822, 823,
957, and 958, and in accordance with 21 CFR parts 1301 and 1312, as of
the effective date of a final scheduling action. Any person who
currently handles methoxetamine and is not registered with DEA would
need to submit an application for registration and may not continue to
handle methoxetamine as of 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
or transfer all quantities of currently held methoxetamine 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,
methoxetamine 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. Methoxetamine would be subject to schedule I security
requirements and would need to be handled and stored pursuant to 21
U.S.C. 823, and in accordance with 21 CFR 1301.71-1301.93, as of the
effective date of a final scheduling action. Non-practitioners handling
methoxetamine would also need to comply with the employee screening
requirements of 21 CFR 1301.90-1301.93.
4. Labeling and Packaging. All labels, labeling, and packaging for
commercial containers of methoxetamine would need to be in compliance
with 21 U.S.C. 825, 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 methoxetamine 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
methoxetamine on the effective date of the final scheduling action
would be required to take an inventory of methoxetamine on hand at that
time, pursuant to 21 U.S.C. 827, 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
methoxetamine) on hand on the date the registrant first engages in the
handling of controlled substances, pursuant to 21 U.S.C. 827 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 a new inventory of all controlled substances (including
methoxetamine) on hand every two years, pursuant to 21 U.S.C. 827 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 for methoxetamine, or products
containing methoxetamine, pursuant to 21 U.S.C. 827 and in accordance
with 21 CFR 1301.74(b) and (c) and parts 1304, 1312, and 1317, as of
the effective date of a final scheduling action. Manufacturers and
distributors would need to submit reports regarding methoxetamine to
the Automation of Reports and Consolidated Order System 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 methoxetamine
would be required to comply with the order form requirements, pursuant
to 21 U.S.C. 828, and 21 CFR part 1305, as of the effective date of a
final scheduling action.
9. Importation and Exportation. All importation and exportation of
methoxetamine 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 methoxetamine 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.
[[Page 69194]]
Regulatory Analyses
Executive Orders 12866 and 13563, Regulatory Planning and Review,
Improving Regulation and Regulatory Review
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
pursuant to section 3(d)(1) of Executive Order (E.O.) 12866 and the
principles reaffirmed in E.O. 13563.
Executive Order 12988, Civil Justice Reform
This proposed regulation meets the applicable standards set forth
in sections 3(a) and 3(b)(2) of E.O. 12988 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 E.O. 13132. The proposed rule does not
have substantial direct effects on the States, on the relationship
between the National Government and the States, or on the distribution
of power and responsibilities among the various levels of government.
Executive Order 13175, Consultation and Coordination With Indian Tribal
Governments
This proposed rule does not have tribal implications warranting the
application of E.O. 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.
Paperwork Reduction Act of 1995
This proposed action does not impose a new collection of
information requirement under the Paperwork Reduction Act of 1995 (44
U.S.C. 3501-3521).
Regulatory Flexibility Act
The Acting Administrator of DEA, in accordance with the Regulatory
Flexibility Act, 5 U.S.C. 601-612, 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 methoxetamine (chemical name: 2-
(ethylamino)-2-(3-methoxyphenyl)cyclohexan-1-one), including its salts,
isomers, and salts of isomers whenever the existence of such salts,
isomers, and salts of isomers is possible within the specific chemical
designation, in schedule I of the CSA. This action is being taken to
enable the United States to meet its obligations under the 1971
Convention. If finalized, this action would impose the regulatory
controls and administrative, civil, and/or 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 methoxetamine.
According to HHS, and also per DEA's findings in this proposed
rule, methoxetamine has 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 methoxetamine in the
United States. As such, the proposed rule will not have a significant
effect on a substantial number of small entities.
Unfunded Mandates Reform Act of 1995
On the basis of information contained in the ``Regulatory
Flexibility Act'' section above, DEA has determined pursuant to the
Unfunded Mandates Reform Act (UMRA) of 1995 (2 U.S.C. 1501 et seq.)
that this proposed 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 annually for inflation) in any 1 year *
* *.'' Therefore, neither a Small Government Agency Plan nor any other
action is required under UMRA of 1995.
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 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), 956(b), unless otherwise
noted.
0
2. In Sec. 1308.11, as proposed to be amended at 86 FR 16553 (March
30, 2021) and 86 FR 37719 (July 16, 2021), add paragraph (d)(100) to
read as follows:
Sec. 1308.11 Schedule I.
* * * * *
(d) * * *
(100) 2-(ethylamino)-2-(3-methoxyphenyl)cyclohexan-1-one 7286
(methoxetamine, MXE).......................................
* * * * *
Anne Milgram,
Administrator.
[FR Doc. 2021-26293 Filed 12-6-21; 8:45 am]
BILLING CODE 4410-09-P
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</html>Indexed from Federal Register on December 7, 2021.
This is legal information, not legal advice. Laws vary by jurisdiction and change frequently. Always verify current law with official sources and consult a licensed attorney in your jurisdiction for advice on your specific situation.