[Federal Register Volume 86, Number 138 (Thursday, July 22, 2021)]
[Proposed Rules]
[Pages 38619-38624]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-15331]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-371]


Schedules of Controlled Substances: Placement of Amineptine in 
Schedule I

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Notice of proposed rulemaking.

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SUMMARY: The Drug Enforcement Administration proposes placing the 
substance amineptine (chemical name: 7-[(10,11-dihydro-5H-
dibenzo[a,d]cyclohepten-5-yl)amino]heptanoic acid), including its 
salts, isomers, and salts of isomers, in schedule I of the Controlled 
Substances Act. This action is being taken to enable the United States 
to meet its obligations under the 1971 United Nations 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, amineptine.

DATES: Comments must be submitted electronically or postmarked, on or 
before September 20, 2021.
    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 August 
23, 2021.

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-371'' 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 http://www.regulations.gov and follow the on-line 
instructions at that site for submitting comments. Upon completion of 
your submission, you will receive a Comment Tracking Number. Submitted 
comments are not instantaneously available for public view on http://www.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.
    <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, send 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 http://www.regulations.gov. Such 
information includes personal identifying information (such as your 
name, address, etc.) voluntarily submitted by the commenter. The 
Freedom of Information Act 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 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 http://www.regulations.gov may include any 
personal identifying information (such as name, address, and phone 
number) included in the text of your electronic submission that is not 
identified as confidential as directed above.
    An electronic copy of this document and supplemental information to 
this proposed rule are available at http://www.regulations.gov for easy 
reference.

[[Page 38620]]

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 they shall 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 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 of 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 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

    Amineptine is a synthetic tricyclic antidepressant with central 
nervous system (CNS) stimulating properties that, according to HHS, has 
no approved medical use and no known therapeutic application in the 
United States. Pharmacological studies indicate that amineptine's 
primary mode of action is to increase extracellular levels of dopamine 
and norepinephrine as well as inhibit re-uptake of dopamine and 
norepinephrine within the striatum and limbic areas of the brain.
    In 1978, amineptine was approved for use in France as an 
antidepressant and subsequently marketed in 66 countries throughout 
Africa, Asia, Europe, and South America. As documented by the World 
Health Organization's (WHO) Expert Committee on Drug Dependence in its 
33rd report (2003) (WHO 2003 report), amineptine has been withdrawn 
from the market in 49 of the 66 countries. The status of current 
production of amineptine in other countries is not known, although a 
small quantity is most likely produced for research purposes.
    In April 2003, the United Nations Commission on Narcotic Drugs, on 
the advice of the Director-General of the WHO, added amineptine to 
Schedule II of the 1971 Convention, thus notifying all parties to the 
1971 Convention.\2\ Because the procedures in 21 U.S.C. 811(d)(3) and 
(4) for consultation and issuance of a temporary order for amineptine, 
discussed in the above legal authority section, were not followed, DEA 
is utilizing the procedures for permanent scheduling set forth in 21 
U.S.C. 811(a) and (b) to control amineptine. Such scheduling would 
satisfy the United States' international obligations.
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    \2\ https://www.unodc.org/unodc/en/Resolutions/resolution_2003-04-08_1.html.
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    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 amineptine. This 
license requirement is accomplished by the CSA's registration 
requirement as set forth in 21 U.S.C. 822, 823, 957, 958 and in 
accordance with 21 CFR parts 1301 and 1312. In addition, the United 
States must adhere to specific export and import provisions set forth 
in the 1971 Convention. This requirement is accomplished by the CSA's 
export and import provisions established in 21 U.S.C. 952, 953, 957, 
958 and in accordance with 21 CFR part 1312. Likewise, under Article 
13, paragraphs 1 and 2, of the 1971 Convention, a party to the 1971 
Convention may notify through the UN Secretary-General another party 
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 notifying country. This requirement is 
also accomplished by the CSA's export provisions mentioned above. Under 
Article 16, paragraph 4, of the 1971 Convention, the United States is 
required to provide annual statistical reports to the International 
Narcotics Control Board (INCB). Using INCB Form P, the United States 
shall provide the following information: (1) In regard to each 
substance in Schedule I and II of the 1971 Convention, quantities 
manufactured in, exported to, and imported from each country or region 
as well as stocks held by manufacturers; (2) in regard to each 
substance in Schedule II and III of the 1971 Convention, quantities 
used in the manufacture of exempt preparations; and (3) 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. Persons acting outside the legal 
framework established by the CSA are subject to administrative, civil, 
and/or criminal

[[Page 38621]]

action; therefore, the United States complies with this provision.
    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 Amineptine

    Pursuant to 21 U.S.C. 811(b), DEA gathered the necessary data on 
amineptine and, on August 12, 2008, submitted it to the Assistant 
Secretary for Health of HHS with a request for a scientific and medical 
evaluation of available information and a scheduling recommendation for 
amineptine. On November 8, 2011, HHS provided to DEA a written 
scientific and medical evaluation and scheduling recommendation 
entitled ``Basis for the Recommendation for Control of Amineptine in 
Schedule I of the Controlled Substances Act.'' In this recommendation, 
HHS presented its eight-factor analysis as required under 21 U.S.C. 
811(b) and recommended that amineptine be added to schedule I of the 
CSA.
    In response, DEA reviewed the scientific and medical evaluation and 
scheduling recommendation provided by HHS and all other relevant data 
and conducted its own eight-factor analysis pursuant to 21 U.S.C. 
811(c). Included below is a brief summary of each factor as analyzed by 
HHS and DEA, and as considered by DEA in the scheduling decision. Both 
DEA and HHS analyses are available in their entirety under ``Supporting 
and Related Material'' of the public docket for this rule at http://www.regulations.gov under docket number DEA-371.
    1. The Drug's Actual or Relative Potential for Abuse: As reported 
by HHS, the WHO 2003 report showed strong evidence of abuse in Europe 
and Asia, where amineptine was approved for use as an antidepressant. 
Additional HHS findings showed that due to reports of hepatotoxicity 
and abuse in Europe, Servier (a French pharmaceutical company) 
voluntarily discontinued the French marketing authorization in France 
and Spain for amineptine in 1999 (HHS, 2011; \3\ WHO, 2002 \4\). 
However, as documented by the WHO 2003 report, the medical use of 
amineptine and its abuse in developing countries still existed during 
1990 to 2003. Clinical studies used between 100--200 mg of amineptine 
(Lachatre et al., 1989; \5\ Sbarra et al., 1981 \6\); however, case 
reports from various countries (none in the United States due to its 
lack of approved medical use or known therapeutic application in the 
United States) have reported hospitalizations due to amineptine abuse 
and overdose following the ingestion of 2,000-4,300 mg and even up to 
12 g daily. However, adverse effects at prescribed doses of amineptine 
were still observed (see Factor 6).
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    \3\ Health and Human Services (HHS) (2011). Basis for the 
Recommendation for Control of Amineptine in Schedule I of the 
Controlled Substances Act.
    \4\ WHO's Critical Review of Psychoactive Substances prepared 
for evaluation by the 33rd Meeting of the WHO Expert Committee on 
Drug Dependence held in September, in Annex, 2002.1-14.
    \5\ Lachatre, G., Piva, C., Riche, C., Dumont, D., Defrance, R., 
Mocaer, E., Nicot, G. (1989). Single-dose pharmacokinetics of 
amineptine and of its main metabolite in healthy young adults. 
Fundamental and Clinical Pharmacology, 3(1):19-26.
    \6\ Sbarra, C., Castelli, M. G., Noseda, A., Fanelli, R. (1981). 
Pharmacokinetics of amineptine in man. European Journal of Drug 
Metabolism and Pharmacokinetics, 6(2), 123-126.
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    Evidence shows that amineptine produces behavioral effects in 
humans and animals that are similar to amphetamine and cocaine (both in 
schedule II). Pharmacological studies have demonstrated that amineptine 
has reinforcing effects as shown by the self-administration test and 
has locomotor stimulant effects. Studies also have shown that 
amineptine increases extracellular concentrations of dopamine in the 
brain, particularly in the striatum and nucleus accumbens, which are 
structures constituting the reward pathway and are known to be involved 
in the abuse of drugs, including amphetamine and cocaine. The above 
data indicate that amineptine has the potential for abuse similar to 
other CNS stimulants controlled under the CSA, such as cocaine and 
amphetamine.
    2. Scientific Evidence of the Drug's Pharmacological Effects, if 
Known: As stated by HHS, amineptine increases dopamine levels by 
inducing the synaptosomal release and inhibition of dopamine re-uptake 
and, to a lesser extent, increasing norepinephrine levels, a mode of 
action mechanistically similar to the known schedule II CNS stimulants 
amphetamine and cocaine. Animal behavioral studies have shown that 
amineptine, in addition to its CNS stimulant properties, has anti-
depressant, locomotor, and anti-narcoleptic activities. Human 
behavioral studies have demonstrated that amineptine works similarly to 
other antidepressants, often with an earlier onset of therapeutic 
effects. Studies have shown that amineptine administration lowers 
depression rating scales in patients and results in a positive 
subjective quality of sleep and subsequent increase in attention and 
concentration upon waking.
    3. The State of Current Scientific Knowledge Regarding the Drug or 
Other Substance: The chemical name of amineptine is 7-[(10,11-dihydro-
5H-dibenzo[a,d]cyclohepten-5-yl)amino]heptanoic acid. It is a white, 
crystalline powder and is soluble in water and in methanol. Humans 
rapidly absorb amineptine after oral administration, with mean peak 
plasma concentrations of amineptine and its main metabolite occurring 
at 1 hour and 1.5 hours, respectively. Amineptine is metabolized in the 
liver and rapidly excreted and eliminated through the kidneys with mean 
half-lives of 0.8 hours for amineptine and 2.5 hours for its 
metabolite. In humans, 70-75 percent of the administered dose of 
amineptine was excreted in the urine within 48 hours, with most of the 
elimination occurring within the first 12 hours.
    Distribution of \14\C-amineptine was also evaluated in the Macaca 
fascicularis monkey using whole body autoradiography. Results 
demonstrated high levels of radio-labeled amineptine in the liver and 
kidneys, with lower levels of activity in the blood, gastrointestinal 
tract and spleen. In the brain, radioactivity was observed in the 
cortex, putamen, caudate nucleus, globus pallidus, pulvinar, and 
geniculate bodies, with lower levels noted in the hippocampus, 
substantia nigra, and medulla.
    4. Its History and Current Pattern of Abuse: As mentioned by HHS, 
there are numerous published reports of amineptine abuse, including 186 
cases of abuse between 1978 and 1988 reported to the Regional Centers 
of Pharmacovigilance and the Laboratory Eutherapie in France, and 65 
cases of abuse between 1990 and 1998 appearing in the Observation of 
Illegal Drugs and Misuse of Psychotropic Medications database. Notably, 
amineptine has not been approved for medical use in the United States 
nor is there any

[[Page 38622]]

documented abuse in the United States of amineptine.
    At the 16th French Pharmacovigilance meeting in November 1994, the 
Fernand Widal Pharmacovigilance Centre reviewed 565 cases of amineptine 
``overconsumption'' from 1978 to 1993, and reported multiple 
characteristics of amineptine abuse including: (1) Amineptine abusers 
typically had a history of alcoholism, drug abuse, and/or eating 
disorders; (2) 28 percent of the cases of amineptine abuse resulted in 
neuropsychiatric disorders; (3) 11 percent of patients developed acne-
like lesions from amineptine use; (4) withdrawal from amineptine abuse 
was described as extremely difficult; (5) only 30 percent were 
abstinent after one month of withdrawal and long-term abstinence was 
uncommon; and (6) most patients obtained amineptine from pharmacists by 
prescription theft or by fraudulent prescriptions. Collectively, these 
three reports show that there has been a continued pattern of abuse 
from 1978 to 1998.
    DEA noted that in the WHO 2003 report, the WHO's Expert Committee 
on Drug Dependence stated that the degree of risk to public health 
associated with the abuse liability of amineptine is substantial, while 
noting several adverse effects including hepatotoxicity, severe acne, 
and anxiety. The committee also noted the limited therapeutic 
usefulness of amineptine due to the availability of safer 
antidepressants.
    Queries of DEA's System to Retrieve Information from Drug Evidence 
(STRIDE)/STARLiMS \7\ and the National Forensic Laboratory Information 
System (NFLIS) \8\ databases on November 17, 2020, did not generate any 
reports of amineptine, suggesting that it is not trafficked in the 
United States.
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    \7\ STRIDE is a database of drug exhibits sent to DEA 
laboratories for analysis. Exhibits from the database are from DEA, 
other federal agencies, and law enforcement agencies. On October 1, 
2014, STARLiMS replaced STRIDE as DEA laboratory drug evidence data 
system of record.
    \8\ NFLIS is a national drug forensic laboratory reporting 
system that systematically collects results from drug chemistry 
analyses conducted by state and local forensic laboratories across 
the country. The NFLIS participation rate, defined as the percentage 
of the national drug caseload represented by laboratories that have 
joined NFLIS, is over 97%. NFLIS includes drug chemistry results 
from completed analyses only.
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    5. The Scope, Duration, and Significance of Abuse: According to the 
published case reports from 1984 to 2001 in France, Italy, Pakistan, 
Singapore, and Spain, the majority of the reported cases of amineptine 
abuse involved patients who were prescribed amineptine for an affective 
disorder. In these cases, abuse normally began one year after 
amineptine was prescribed for the treatment of depression by patients 
independently increasing their dosage, especially in those with a 
history of alcoholism, intravenous drug abuse, and eating disorders.
    Amineptine abuse appears to be due to its psychostimulant effect. 
Indeed, reasons cited for its abuse were increased energy, joy, work 
output, alertness, and psychomotor performance. Presently, although 
internet searches result in websites with purported amineptine for 
sale, these sites do not list the formulation, purity, price, and 
quantity for this purported amineptine. In addition, the 1971 
Convention currently controls amineptine internationally as a Schedule 
II substance. Amineptine is also controlled in Belgium, Canada, the 
Czech Republic, Denmark, Estonia, Germany, Greece, Hungary, Italy, 
Latvia, Lithuania, the Netherlands, Norway, Poland, Slovenia, and 
Sweden.
    6. What, if Any, Risk There is to the Public Health: As reported by 
HHS, there are no known fatalities resulting from amineptine use or 
abuse. Some of the main public health risks of amineptine are related 
to its serious adverse effects, such as hepatotoxicity, severe acne, 
and gastrointestinal (acute pancreatitis) effects. In addition, 
neuropsychiatric symptoms including anxiety, insomnia, nervousness, 
irritability, dysarthria, acute psychosis, delusions, hallucinations, 
anorexia, agitation, psychotic disorders, and confusion have resulted 
from abuse of amineptine.
    7. Its Psychic or Physiological Dependence Liability: HHS stated 
that amineptine has been shown to produce physical and psychological 
dependence as supported by clinical evidence. While amineptine has no 
clearly defined withdrawal syndrome, reports of withdrawal symptoms 
include anxiety, dysphoria, nausea, brief psychotic episodes, tremor, 
psychomotor agitation, somatic symptoms, and sleep disturbances. In 
addition, a strong desire to take amineptine was noted in individuals 
upon withdrawal of the drug, a typical characteristic of psychological 
dependence.
    8. Whether the Substance is an Immediate Precursor of a Substance 
Already Controlled under the CSA: DEA and HHS find that amineptine is 
not an immediate precursor of a substance already controlled under the 
CSA.
    Conclusion: Based on consideration of the scientific and medical 
evaluation and accompanying recommendation of HHS, and based on DEA's 
consideration of its own eight-factor analysis, DEA finds that these 
facts and all relevant data constitute substantial evidence of 
potential for abuse of amineptine. As such, DEA hereby proposes to 
schedule amineptine 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 outlines the findings 
required to place a drug or other substance in any particular schedule. 
21 U.S.C. 812(b). After consideration of the analysis and 
recommendation of the Assistant Secretary for Health of HHS and review 
of all available data, the Administrator of DEA, pursuant to 21 U.S.C. 
812(b)(1), finds that:
    (1) Amineptine has a high potential for abuse. Amineptine has 
stimulant and euphoric effects similar to cocaine and amphetamine, 
which are both schedule II drugs. Amineptine has a high potential for 
abuse that is equivalent to cocaine and amphetamine and has been abused 
throughout Europe and Asia.
    (2) Amineptine has no currently accepted medical use in treatment 
in the United States. There are no approved New Drug Applications for 
amineptine and no known therapeutic application for amineptine in the 
United States. Therefore, amineptine has no currently accepted medical 
use in treatment in the United States.\9\
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    \9\ Although there is no evidence suggesting that amineptine 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 
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).
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    (3) There is a lack of accepted safety for use of amineptine under 
medical supervision. Clinical experience showed that patients taking 
amineptine under medical supervision for depression misused and abused 
the drug by stealing or falsifying prescriptions and taking doses that 
were 10 to 20 times higher than prescribed. As a result of taking 
higher doses, many patients developed hepatic, gastrointestinal, 
cardiovascular, and psychiatric side effects. Amineptine was once 
marketed in 66 countries throughout Europe, Africa, Asia, and

[[Page 38623]]

South America. However, amineptine was later withdrawn from the 
majority of countries due to its abuse potential and lack of safety. 
Therefore, there is a lack of accepted safety for the use of amineptine 
under medical supervision.
    Although the first finding shows amineptine to have similar effects 
to schedule II substances such as cocaine and amphetamine, it bears 
reiterating that there is only one possible schedule in the CSA--
schedule I--to place amineptine since it has no currently accepted 
medical use in treatment in the United States. See the background 
section for additional discussion.
    Based on these findings, the Administrator of DEA concludes that 
amineptine warrants control in schedule I of the CSA. 21 U.S.C. 
812(b)(1). More precisely, because of its stimulant effects, DEA 
proposes placing substance amineptine, including its salts, isomers, 
and salts of isomers, in 21 CFR 1308.11(f) (the stimulants category of 
schedule I).

Requirements for Handling Amineptine

    If this rule is finalized as proposed, amineptine would be subject 
to the CSA's schedule I regulatory controls and administrative, civil, 
and criminal sanctions applicable to the manufacture, distribution, 
reverse distribution, import, export, engagement in research, conduct 
of instructional activities or chemical analysis with, and possession 
of schedule I controlled substances, including the following:
    1. Registration. Any person who handles (manufactures, distributes, 
reverse distributes, imports, exports, engages in research, or conducts 
instructional activities or chemical analysis with, or possesses) 
amineptine, or who desires to handle amineptine, would need to be 
registered with DEA to conduct such activities pursuant to 21 U.S.C. 
822, 823, 957, 958 and in accordance with 21 CFR parts 1301 and 1312 as 
of the effective date of a final scheduling action. Any person who 
currently handles amineptine and is not registered with DEA would need 
to submit an application for registration and may not continue to 
handle amineptine 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 to transfer all quantities of currently held amineptine 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, 
amineptine 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. Amineptine would be subject to schedule I security 
requirements and would need to be handled and stored pursuant to 21 
U.S.C. 821 and 823 and in accordance with 21 CFR 1301.71-1301.93, as of 
the effective date of a final scheduling action. Non-practitioners 
handling amineptine 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 amineptine would need to be in compliance with 
21 U.S.C. 825 and 958(e) and 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 amineptine 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 
amineptine on the effective date of a final scheduling action would be 
required to take an inventory of amineptine on hand at that time, 
pursuant to 21 U.S.C. 827 and 958 and in accordance with 21 CFR 
1304.03, 1304.04, and 1304.11(a) and (d).
    Any person who becomes registered with DEA on or after the 
effective date of the final scheduling action would be required to take 
an initial inventory of all stocks of controlled substances (including 
amineptine) on hand on the date the registrant first engages in the 
handling of controlled substances, pursuant to 21 U.S.C. 827 and 958 
and in accordance with 21 CFR 1304.03, 1304.04, and 1304.11(a) and (b).
    After the initial inventory, every DEA registrant would be required 
to take a new inventory of all controlled substances (including 
amineptine) on hand every two years, pursuant to 21 U.S.C. 827 and 958 
and in accordance with 21 CFR 1304.03, 1304.04, and 1304.11.
    7. Records and Reports. Every DEA registrant would be required to 
maintain records and submit reports for amineptine, or products 
containing amineptine, pursuant to 21 U.S.C. 827 and 958 and in 
accordance with 21 CFR parts 1304, 1312, and 1317, as of the effective 
date of a final scheduling action. Manufacturers and distributors would 
be required to submit reports regarding amineptine 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 amineptine 
would be required to comply with order form requirements, pursuant to 
21 U.S.C. 828 and in accordance with 21 CFR part 1305, as of the 
effective date of a final scheduling action.
    9. Importation and Exportation. All importation and exportation of 
amineptine 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 amineptine not authorized by, 
or in violation of, the CSA or its implementing regulations, would be 
unlawful and may subject the person to administrative, civil, and/or 
criminal sanctions.

Regulatory Analyses

Executive Orders 12866 and 13563, Regulatory Planning and Review, and 
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 
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, Civil Justice Reform, to 
eliminate drafting errors and ambiguity, minimize litigation, provide a 
clear legal standard for affected conduct, and promote simplification 
and burden reduction.

Executive Order 13132, Federalism

    This proposed rulemaking does not have federalism implications 
warranting the application of E.O. 13132. The proposed rule does not 
have substantial direct effects on the States, on the

[[Page 38624]]

relationship between the national government and the States, or the 
distribution of power and responsibilities among the various levels of 
government.

Executive Order 13175, Consultation and Coordination With Indian Tribal 
Governments

    This proposed rule does not have tribal implications warranting the 
application of 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 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 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 amineptine, including its 
isomers, salts, and salts of isomers, 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, amineptine.
    According to HHS, amineptine has a high potential for abuse, has no 
currently accepted medical use in treatment in the United States, and 
lacks accepted safety for use under medical supervision. DEA's research 
confirms that there is no commercial market for amineptine in the 
United States. Additionally, queries of DEA's STRIDE/STARLiMS and the 
NFLIS databases on November 17, 2020, did not generate any reports of 
amineptine, suggesting that it is not trafficked in the United States. 
Therefore, DEA estimates that no United States entity currently handles 
amineptine and does not expect any United States entity to handle 
amineptine in the foreseeable future. DEA concludes that no United 
States entity would be affected by this rule, if finalized. As such, 
the proposed rule will not have a significant effect on a substantial 
number of small entities.

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 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 provisions of the 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 to read as follows:

PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES

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

    Authority:  21 U.S.C. 811, 812, 871(b), 956(b), unless otherwise 
noted.

0
2. Amend Sec.  1308.11 by re-designating paragraphs (f)(1) through 
(f)(9) as paragraphs (f)(2) through (f)(10), and adding a new paragraph 
(f)(1) to read as follows:


Sec.  1308.11   Schedule I.

* * * * *
    (f) * * *

(1) Amineptine (7-[(10,11-dihydro-5H-                               1219
 dibenzo[a,d]cyclohepten-5-yl)amino]heptanoic acid).....
 

* * * * *

Anne Milgram,
Administrator.
[FR Doc. 2021-15331 Filed 7-21-21; 8:45 am]
BILLING CODE 4410-09-P