[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 [www.gpo.gov]
[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.
     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 https://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. Submitted 
comments are not instantaneously available for public view on 
regulations.gov. If you have received a Comment Tracking Number, you 
have submitted your comment successfully 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, 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 https://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 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 https://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 confidential as directed above.
    An electronic copy of this document and supplemental information to 
this proposed rule are available at https://www.regulations.gov 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 https://www.regulations.gov 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

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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 
C15H21NO2. 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.
---------------------------------------------------------------------------

    \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\
---------------------------------------------------------------------------

    \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