Schedules of Controlled Substances: Placement of Cipepofol in Schedule IV

Issuing agencies

Abstract

On May 29, 2026, the United States Food and Drug Administration (FDA) approved a new drug application for Cypsedo (cipepofol) for induction of general anesthesia in adults undergoing surgery. The Department of Health and Human Services provided the Drug Enforcement Administration (DEA) with a scheduling recommendation to place cipepofol, chemically known as 2-[(1R)-1-cyclopropylethyl]-6- isopropylphenol, in schedule IV of the Controlled Substances Act (CSA). In accordance with the CSA, as amended by the Improving Regulatory Transparency for New Medical Therapies Act, DEA is hereby issuing an interim final rule placing cipepofol in schedule IV of the CSA.

Full Text

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<title>Federal Register, Volume 91 Issue 165 (Thursday, August 27, 2026)</title>
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[Federal Register Volume 91, Number 165 (Thursday, August 27, 2026)]
[Rules and Regulations]
[Pages 55259-55265]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2026-17536]



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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA 1713]


Schedules of Controlled Substances: Placement of Cipepofol in 
Schedule IV

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Interim final rule; request for comments.

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SUMMARY: On May 29, 2026, the United States Food and Drug 
Administration (FDA) approved a new drug application for Cypsedo 
(cipepofol) for induction of general anesthesia in adults undergoing 
surgery. The Department of Health and Human Services provided the Drug 
Enforcement Administration (DEA) with a scheduling recommendation to 
place cipepofol, chemically known as 2-[(1R)-1-cyclopropylethyl]-6-
isopropylphenol, in schedule IV of the Controlled Substances Act (CSA). 
In accordance with the CSA, as amended by the Improving Regulatory 
Transparency for New Medical Therapies Act, DEA is hereby issuing an 
interim final rule placing cipepofol in schedule IV of the CSA.

DATES: This rule is effective August 27, 2026. Comments must be 
submitted electronically or postmarked on or before September 28, 2026. 
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.
    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 September 28, 2026.

ADDRESSES: Interested persons may file written comments on this 
rulemaking in accordance with 21 U.S.C. 811(j)(3) and 21 CFR 
1308.43(g). To ensure proper handling of comments, please reference 
``Docket No. DEA1713'' on all correspondence, including any 
attachments.
    <bullet> Electronic comments: The Drug Enforcement Administration 
(DEA) encourages commenters to submit comments electronically through 
the Federal eRulemaking Portal, which provides the ability to type 
short comments directly into the comment field on the web page or 
attach a file for lengthier comments. Please go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> and follow the online instructions at that site for 
submitting comments. Upon completion of your submission, you will 
receive a Comment Tracking Number for your comment. If you have 
received a Comment Tracking Number, your comment has been successfully 
submitted and there is no need to resubmit the same comment. Commenters 
should be aware that the electronic Federal Docket Management System 
will not accept comments after 11:59 p.m. Eastern Time on the last day 
of the comment period.
    <bullet> Paper comments: Paper comments that duplicate electronic 
submissions are not necessary and are discouraged. Should you wish to 
mail a paper comment in lieu of an electronic comment, it should be 
sent via regular or express mail to: Drug Enforcement Administration, 
Attn: DEA Federal Register Representative/DPW, 8701 Morrissette Drive, 
Springfield, VA 22152.
    <bullet> Hearing requests: All requests for 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 filed with the 
DEA Administrator, who will make the determination of whether a hearing 
will be needed to address such matters of fact and law in the 
rulemaking. Such requests must be sent to: Drug Enforcement 
Administration, Attn: Administrator, 8701 Morrissette Drive, 
Springfield, Virginia 22152. For informational purposes, a courtesy 
copy of requests for hearing and waivers of participation should also 
be sent to: (1) Drug Enforcement Administration, Attn: Hearing Clerk/
OALJ, 8701 Morrissette Drive, Springfield, Virginia 22152; and (2) Drug 
Enforcement Administration, Attn: DEA Federal Register Representative/
DPW, 8701 Morrissette Drive, Springfield, Virginia 22152.
    <bullet> Paperwork Reduction Act Comments: All comments concerning 
collections of information under the Paperwork Reduction Act must be 
submitted to the Office of Information and Regulatory Affairs, OMB, 
Attention: Desk Officer for DOJ, Washington, DC 20503. Please state 
that your comment refers to Docket No. DEA1713.

FOR FURTHER INFORMATION CONTACT: Dr. Terrence L. Boos, Drug & Chemical 
Evaluation Section, Diversion Control Division, Drug Enforcement 
Administration; Telephone: (571) 362-3249.

SUPPLEMENTARY INFORMATION: In this interim final rule (IFR), Drug 
Enforcement Administration (DEA) is adding cipepofol to schedule IV of 
the Controlled Substances Act (CSA).

Posting of Public Comments

    All comments received in response to this docket are considered 
part of the public record. DEA will make comments available for public 
inspection online at <a href="https://www.regulations.gov">https://www.regulations.gov</a>, unless reasonable 
cause is given. Such information includes personal or business 
identifying information (such as name, address, State or Federal 
identifiers, etc.) voluntarily submitted by the commenter.
    Commenters submitting comments which include personal identifying 
information (PII), confidential, or proprietary business information 
that the commenter does not want made publicly available should submit 
two copies of the comment. One copy must be marked ``CONTAINS 
CONFIDENTIAL INFORMATION'' and should clearly identify all PII or 
business information the commenter does not want to be made publicly 
available, including any supplemental materials. DEA will review this 
copy, including the claimed PII and confidential business information, 
in its consideration of comments. The second copy should be marked ``TO 
BE PUBLICLY POSTED'' and must have all claimed confidential PII and 
business information already redacted. DEA will post only the redacted 
comment on <a href="https://www.regulations.gov">https://www.regulations.gov</a> for public inspection. DEA 
generally will not redact additional information contained in the 
comment marked ``TO BE PUBLICLY POSTED.'' The Freedom of Information 
Act applies to all comments received.
    For easy reference, an electronic copy of this document and 
supplemental information to this IFR are available at <a href="http://www.regulations.gov">http://www.regulations.gov</a>.

Request for Hearing or Appearance; Waiver

    Pursuant to 21 U.S.C. 811(j)(3), an interested person may ``request 
a hearing.'' Such proceedings are conducted pursuant to the provisions 
of the Administrative Procedure Act (APA), 5 U.S.C. 551-559.\1\ 
Interested persons, as defined in 21 CFR 1300.01(b), may file requests 
for a hearing in conformity with the requirements of 21 CFR 1308.44(a) 
and 1316.47(a), and such requests must:
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    \1\ 21 CFR 1308.41-1308.45; 21 CFR part 1316, subpart D.
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    (1) state with particularity the interest of the person in the 
proceeding;
    (2) state with particularity the objections or issues concerning 
which the person desires to be heard; and

[[Page 55260]]

    (3) state briefly the position of the person with regard to the 
objections or issues.
    Any interested person may file a waiver of an opportunity for a 
hearing or to participate in a hearing in conformity with the 
requirements of 21 CFR 1308.44(c), together with a written statement of 
position on the matters of fact and law involved in any hearing.\2\
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    \2\ 21 CFR 1316.49.
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    All requests for hearings 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. The decision whether a hearing will be 
needed to address such matters of fact and law in the rulemaking will 
be made by the Administrator. If a hearing is needed, DEA will publish 
a notice of hearing on the interim final rule in the Federal 
Register.\3\ Further, once the Administrator determines a hearing is 
needed to address such matters of fact and law in rulemaking, he will 
then designate an Administrative Law Judge (ALJ) to preside over the 
hearing. The ALJ's functions shall commence upon designation, as 
provided in 21 CFR 1316.52.
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    \3\ 21 CFR 1308.44(b), 1316.53.
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    In accordance with 21 U.S.C. 811 and 812, the purpose of a hearing 
would be to determine whether cipepofol meets the statutory criteria 
for placement in schedule IV.

Legal Authority

    Under the CSA, as amended in 2015 by the Improving Regulatory 
Transparency for New Medical Therapies Act (section 2(b) of Pub. Law 
114-89), DEA is required to commence an expedited scheduling action 
with respect to certain new drugs approved by the Food and Drug 
Administration (FDA). As provided in 21 U.S.C. 811(j), this expedited 
scheduling is required where both of the following conditions apply: 
(1) The Secretary of the Department of Health and Human Services (HHS) 
has advised DEA that a New Drug Application (NDA) has been submitted 
for a drug that has a stimulant, depressant, or hallucinogenic effect 
on the central nervous system (CNS), and that it appears that such drug 
has an abuse potential; and (2) the Secretary of HHS recommends that 
DEA control the drug in schedule II, III, IV, or V pursuant to 21 
U.S.C. 811(a) and (b). In these circumstances, DEA is required to issue 
an IFR controlling the drug within 90 days.
    Subsection 811(j)(2) states that the 90-day timeframe starts the 
later of (1) the date DEA receives HHS's scientific and medical 
evaluation/scheduling recommendation, or (2) the date DEA receives 
notice of the NDA approval by HHS. Subsection 811(j)(3) specifies that 
the rulemaking shall become immediately effective as an IFR without 
requiring DEA to demonstrate good cause therefore. Thus, the purpose of 
subsection 811(j) is to speed the process by which DEA schedules newly 
approved drugs that are currently either in schedule I or not 
controlled (but which have sufficient abuse potential to warrant 
control) so that such drugs may be marketed without undue delay 
following FDA approval.\4\
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    \4\ Given the parameters of subsection 811(j), in DEA's view, it 
would not apply to a reformulation of a drug containing a substance 
currently in schedules II through V for which an NDA has recently 
been approved.
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    Subsection 811(j)(3) further provides that the IFR shall give 
interested persons the opportunity to comment and to request a hearing. 
After the conclusion of such proceedings, DEA must issue a final rule 
in accordance with the scheduling criteria of 21 U.S.C. 811(b) through 
(d), and 812(b).

Background

    Cipepofol is a new molecular entity with CNS activity, acting as a 
positive allosteric modulator and agonist at the gamma-aminobutyric 
acid A (GABA<INF>A</INF>) receptor, inducing chloride ion influx and 
reversing action potential generation in neuronal tissue. The chemical 
structure and mechanism of action of cipepofol are similar to those of 
the FDA-approved drugs propofol and fospropofol. Also, the mechanism of 
action of cipepofol is similar to certain FDA-approved neuroactive 
steroid products, which are controlled in schedule IV (i.e., 
alfaxalone, brexanolone, and zuranolone) or schedule V (i.e., 
ganaxolone).

Determination To Schedule Cipepofol

    On May 6, 2026, DEA received from HHS a scientific and medical 
evaluation entitled ``Basis for the Recommendation to Control Cipepofol 
in Schedule IV of the Controlled Substances Act'' and a scheduling 
recommendation. Pursuant to 21 U.S.C. 811(b) and (c), this document 
contained an eight-factor analysis of the abuse potential, legitimate 
medical use, and dependence liability of cipepofol, along with HHS's 
recommendation to control cipepofol under schedule IV of the CSA.
    In response, DEA reviewed the scientific and medical evaluation and 
scheduling recommendation provided by HHS, along with all other 
relevant data, and completed its own eight-factor review pursuant to 21 
U.S.C. 811(c). DEA concluded that cipepofol meets the 21 U.S.C. 
812(b)(4) criteria for placement in schedule IV of the CSA.
    Pursuant to subsection 811(j), and based on HHS's scheduling 
recommendation, the approval of the NDA by HHS/FDA, and DEA's 
determination, DEA is issuing this IFR to schedule cipepofol as a 
schedule IV controlled substance under the CSA.
    Included below is a brief summary of each factor as analyzed by HHS 
and DEA, and as considered by DEA in its scheduling action. Please note 
that both DEA and HHS analyses are available in their entirety under 
``Supporting Documents'' in the public docket for this IFR at <a href="https://www.regulations.gov">https://www.regulations.gov</a>, under Docket Number ``DEA1713.'' Full analysis of, 
and citations to, the information referenced in the summary may also be 
found in the supporting and related material.

1. Its Actual or Relative Potential for Abuse

    Cipepofol is currently legally marketed in China, where data shows 
zero abuse or misuse cases. According to HHS, because cipepofol has not 
been legally marketed in the United States, the legitimate drug 
channels for cipepofol are limited to the research conducted with the 
drug, and to manufacturing facilities and the supply chain to produce 
cipepofol for legitimate drug research. HHS further notes because 
cipepofol has not been legally marketed in the United States, abuse of 
cipepofol in the United States would be limited to incidents following 
diversion of supplies from research or manufacturing activities of 
cipepofol. Both DEA and FDA are not aware of any such incidents of 
diversion or abuse related to cipepofol. Accordingly, DEA's National 
Forensic Laboratory Information System (NFLIS)-Drug \5\ data confirms 
there is no report of law enforcement encounters of cipepofol in the 
United States. Cipepofol targets GABA<INF>A</INF> receptors and shares 
a similar mechanism of action with both propofol (which has proposed 
schedule IV status due to its potential for abuse and

[[Page 55261]]

dependence liability) and its prodrug, fospropofol (a schedule IV 
substance that can induce euphoria). It also shares a similar mechanism 
of action with certain controlled neuroactive steroids, including 
alfaxalone, brexanolone, and zuranolone (schedule IV), and ganaxolone 
(schedule V). Accordingly, both FDA and DEA concluded that cipepofol 
poses safety hazards and has an abuse potential similar to schedule IV 
substances.
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    \5\ NFLIS-Drug represents an important resource in monitoring 
illicit drug trafficking, including the diversion of legally 
manufactured pharmaceuticals into illegal markets. NFLIS-Drug is a 
national forensic laboratory reporting system that systematically 
collects results from drug chemistry analyses conducted by Federal, 
State and local forensic laboratories in the United States. While 
NFLIS-Drug data is not direct evidence of abuse, it can lead to an 
inference that a drug has been diverted and abused. See Schedules of 
Controlled Substances: Placement of Carisoprodol Into Schedule IV, 
76 FR 77330, 77332 (Dec. 12, 2011). NFLIS-Drug data was queried on 
May 11, 2026.
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2. Scientific Evidence of Its Pharmacological Effects, if Known

    Based on in vitro binding and functional reports, HHS noted that 
cipepofol acts as a selective GABA<INF>A</INF> receptor positive 
modulator and agonist that induces chloride ion influx to cause 
neuronal hyperpolarization and thus achieve CNS depression.

Preclinical Behavioral Studies

    Functional Studies: Single intravenous doses of cipepofol (up to 6 
mg/kg) in rats produced dose-dependent increase in duration and level 
of anesthesia with effect declining within 45 minutes. Neurobehavioral 
tests at 2 and 24 hours post-dose showed no residual treatment-related 
effects.\6\
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    \6\ HHS eight-factor analysis document. Page 6. 2026.
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    Conditioned Place Preference (CPP): A 6-day CPP study in rats 
compared cipepofol (1, 2, or 4 mg/kg) against vehicle and propofol. 
Data from the study showed that neither propofol nor cipepofol produced 
environmental preference or evidence of CPP. However, because 
literature shows propofol can induce CPP under different parameters, 
this negative result does not completely rule out the reward potential 
of cipepofol. HHS concluded these findings must be interpreted 
alongside broader abuse liability data.
    Self-Administration: In rats trained to self-administer propofol 
(1.7 mg/kg/injection), substituting cipepofol (0.2, 0.4, and 0.8 mg/kg/
injection) successfully maintained lever-pressing behavior. Higher 
doses caused a decrease in injection frequency but an increase in total 
drug intake. Response rates also likely fell due to the drug's sedative 
effects. HHS concluded that these data confirm cipepofol has rewarding 
and reinforcing properties.
    Physical Dependence and Withdrawal: A 30-day study evaluated 
dependence in rats using titrated doses of cipepofol, propofol, 
morphine, or vehicle, followed by a 14-day abrupt withdrawal phase. The 
high dose of cipepofol (5.4 mg/kg/day) replicated human therapeutic 
exposure levels. Higher doses were omitted because profound sedation 
would impair the animals. Abruptly stopping cipepofol caused mild, 
intermittent withdrawal symptoms like temporary chewing and body 
shakes, mirroring the mild withdrawal profile of propofol. These 
findings indicate that cipepofol carries a low risk for physical 
dependence at therapeutic doses.

Pharmacological and Behavioral Studies in Human

    Human Abuse Potential (HAP) studies assess a drug's abuse liability 
by comparing a test drug to active controls and placebos. As described 
in HHS's scientific and medical evaluation, an intravenous HAP study 
was conducted by the drug sponsor to assess the abuse potential of 
cipepofol in participants who were non-dependent, recreational drug 
users. High scores on specific visual analog scales (VAS), such as 
``Drug Liking'' and ``High,'' indicate abuse potential. Propofol served 
as the active control because both drugs share a similar mechanism of 
action. The dose selection phase (part 1) used 43 subjects to select 
safe doses, establishing cipepofol doses at 0.175 mg/kg and 0.2 mg/kg, 
and propofol at 0.725 mg/kg. The main study was a randomized, double-
blind- and active-controlled, four-way crossover trial (part 2) with 42 
participants, though 2 were excluded from the final analysis due to 
oversedation and invariant responses. Ultimately, 40 participants 
completed the entire trial.
    Regarding the pharmacodynamic (PD) results, cipepofol showed an 
abuse potential similar to propofol. Both active drugs scored 
significantly higher than the placebo, but participants liked both 
active drugs equally. These comparable liking scores demonstrate a 
similar liability for misuse. Cipepofol demonstrated a statistically 
significant increase in drug-liking over placebo, establishing its 
abuse potential, though it did not surpass that of propofol. Its 
psychological profile mirrors the standard anesthetic control. 
Regarding the pharmacokinetic (PK) results, cipepofol plasma levels 
peaked rapidly at 2 minutes, reaching 226 ng/mL for the 0.175 mg/kg 
dose and 257 ng/mL for the 0.2 mg/kg dose. The drug clearance was 
rapid, with levels falling below the 5 ng/mL lower limit of 
quantification by 8 hours post-dose. Total drug exposure was similar 
between both doses. Half-life and peak times showed no meaningful 
differences, matching the drug's rapid-onset and short-duration 
profile.
    For safety and adverse events (AEs), abuse-related side effects 
were rare. In Part 1 of the clinical trial, propofol users reported 
euphoria and sleepiness, while cipepofol users reported one instance of 
depressed mood. The Part 2 qualification phase saw one instance of 
euphoria from propofol. During the Part 2 treatment phase, one 
oversedation event occurred from cipepofol, but no other abuse-related 
adverse events were observed.
    The analysis of pooled Phase 1 data across 13 healthy volunteer 
studies highlights the value of subtherapeutic dosing for evaluating 
abuse potential, as therapeutic doses induce too much sedation. Out of 
322 cipepofol recipients, 69 received subtherapeutic doses (<0.4 mg/kg) 
and 253 received therapeutic doses (>=0.4 mg/kg), while 46 received 
propofol. Dizziness was the top CNS adverse event, hitting 15% of the 
propofol group but only 4% of the therapeutic cipepofol group. 
Restlessness and disorientation occurred at 2% or less, solely in the 
therapeutic cipepofol cohort.
    An HHS safety review of pooled Phase 2 and 3 studies showed minimal 
abuse-related adverse events, with comparable safety profiles between 
cipepofol and propofol across multiple clinical settings. Across open-
label sedation trials (219 patients), procedural sedation and non-
endotracheal surgical procedures (848 patients), and general anesthesia 
induction trials (1,365 patients), dizziness was consistently the most 
common central nervous system event, occurring at nearly identical 
rates between the two drugs (4% to 6% for cipepofol vs. 6% to 7% for 
propofol). Other abuse-related adverse events including excessive 
talking, somnolence, anxiety, restlessness, agitation, confusion, 
disorientation, and emotional disorder were rarely observed, affecting 
1% or less of participants in both cohorts.
    Another HHS review of United States and European Union Phase 3 data 
covering 723 cipepofol and 357 propofol recipients found dizziness was 
the most common CNS event. Other abuse-related events--specifically 
anxiety, restlessness, agitation, confusion, disorientation, and 
somnolence--occurred at low rates (<=1%) in both groups, with further 
details on physical dependence assessments found in Factor 7.
    In summary, HHS concluded that no adverse events involving actual 
abuse, misuse, diversion, intentional overdose, or physical dependence 
occurred during the cipepofol clinical trials. Abuse-related events 
were rare and balanced between the cipepofol and propofol groups. 
Frequent reports of dizziness in both cohorts were distinct from

[[Page 55262]]

euphoria-related symptoms like elevated mood or feeling drunk, with the 
only instance of euphoric mood linked to cipepofol being a single 
report (verbatim term ``agitated'') during procedural sedation. Based 
on this comprehensive review, intravenous cipepofol demonstrates 
reinforcing effects similar to propofol, indicative of its abuse 
potential.

3. The State of Current Scientific Knowledge Regarding the Drug or 
Other Substance

    Cipepofol, chemically known as 2-[(1R)-1-cyclopropylethyl]-6-
isopropylphenol, is a new molecular entity. The final cipepofol product 
is distributed as a 2.5 mg/mL oil-in-water emulsion for injection, 
provided in 20 mL single-use vials. An HHS review indicates intravenous 
cipepofol distributes rapidly, peaking within 1 to 2 minutes. Cipepofol 
exhibits extensive tissue distribution and is 99% protein-bound in 
serum. The major metabolite of cipepofol was identified as M4 
metabolite, which was found to be pharmacologically inactive and thus 
poses a negligible abuse risk. At a 0.4 mg/kg dose, plasma half-life of 
cipepofol is 1 to 5 hours. Kidneys clear 85% of the dose of cipepofol, 
mainly as metabolites M4 and M5-1. As discussed in the background 
section, cipepofol has an accepted medical use in treatment in the 
United States.

4. Its History and Current Pattern of Abuse

    Because cipepofol is not marketed in the United States, domestic 
abuse data remains unavailable. Based on available postmarket data from 
China provided in the NDA submission, it is estimated that 14.5 million 
patients in China have received the drug and postmarket adverse event 
surveillance data shows no reports of abuse or misuse. Spontaneous 
reports in the Drug Adverse Event Reporting System (DAERS) noted side 
effects like dizziness, agitation, and hallucinations, but some 
published literature show no evidence of misuse. Furthermore, HHS noted 
that recent epidemiological data shows no documented instances of 
abuse. Population-level analyses from America's Poison Centers National 
Poison Data System (NPDS) and the National Electronic Injury 
Surveillance System-Cooperative Adverse Drug Event Surveillance (NEISS-
CADES) confirm this absence, suggesting that it is likely cipepofol 
currently shows no cases of abuse or misuse due to its lack of U.S. 
approval. Data from preclinical and clinical studies indicate that the 
abuse potential of cipepofol is similar to that of propofol. HHS notes 
that consistent with the recommendation made in 2010 to place propofol 
in schedule IV of the CSA, there continue to be reports of propofol 
abuse and misuse, primarily in healthcare professionals with 
occupational access to the drug. Although there is currently no 
available data on the abuse or misuse of cipepofol, the information on 
propofol, a closely related drug, may provide some evidence supporting 
the abuse potential of cipepofol.
    In summary, pharmacological data on cipepofol shows that it 
produces abuse-related effects and has an abuse potential similar to 
that of propofol and other schedule IV CNS depressants.

5. The Scope, Duration, and Significance of Abuse

    Cipepofol has been marketed exclusively in China since 2021 and 
remains unavailable in the United States, resulting in limited domestic 
abuse data. Current HHS reviews indicate no documented instances of 
abuse, misuse, or diversion, though this finding is restricted by the 
drug's brief clinical history. Consequently, potential extra-medical 
use is projected to remain confined to healthcare professionals with 
direct occupational exposure. Nonclinical and clinical data demonstrate 
an abuse potential comparable to propofol, a substance recommended for 
schedule IV designation. Furthermore, DEA's NFLIS-Drug database 
confirms that cipepofol is entirely absent from the illicit United 
States drug market. Because preclinical and clinical studies showed 
that cipepofol has an abuse potential that is similar to that of 
propofol, it is likely that upon its availability in the market, 
cipepofol may be abused.

6. What, if Any, Risk There Is to the Public Health

    A drug's abuse potential is a key indicator of its overall risk to 
public health risk. Thus, HHS started that because cipepofol possesses 
an abuse potential comparable to propofol, it is anticipated that 
cipepofol will exhibit a similar abuse profile and present a comparable 
public health risk to that of propofol.
    To evaluate cipepofol's public health risk, HHS analyzed clinical 
trials and overdose data for cipepofol across diverse patient 
populations. In patients receiving cipepofol for general anesthesia 
induction, the most frequent common side effects included hypotension, 
nausea, and procedural pain, with dizziness being the top CNS effect. 
Furthermore, HHS noted that cipepofol overdose may lead to potentially 
fatal cardiovascular and respiratory depression if not promptly and 
adequately managed.
    HHS recommends advising patients against driving or operating heavy 
machinery after receiving cipepofol, as its anesthetic effects, 
including drowsiness, and impair mental alertness. In summary, data 
from nonclinical and clinical studies indicate that cipepofol's abuse 
potential and public health risks are comparable to propofol, 
suggesting a risk profile consistent with schedule IV substances.

7. Its Psychic or Physiological Dependence Liability

    Psychic (or psychological) dependence is a state similar to 
addiction and can be measured through animal self-administration 
studies, HAP studies, case reports, and epidemiological data. Rodent 
animal data shows that cipepofol is self-administered, providing 
evidence of cipepofol's reinforcing and rewarding properties. In 
propofol-trained rats, cipepofol maintained stable self-administration. 
Higher doses of cipepofol decreased injection counts but raised total 
drug intake. The response rate also decreased with higher doses of 
cipepofol, likely due to sedative effects. Similarly, HAP studies show 
cipepofol carries abuse potential that is comparable to propofol. Like 
propofol, cipepofol scored higher than placebo on the Drug Liking VAS 
E<INF>max</INF> scale. In addition, sedative doses of cipepofol exhibit 
clear reinforcing effects in humans. The secondary endpoints (i.e., VAS 
E<INF>max</INF> for Overall Drug Liking and Take Drug Again) also 
support a risk for psychological dependence. Collectively, these 
findings show it is likely that cipepofol can produce psychological 
dependence.
    Physical dependence develops from physiological adaptation to 
repeated drug use and manifests as withdrawal symptoms after abrupt 
drug discontinuation or reduction of a drug. HHS assessed the physical 
dependence liability of cipepofol in rats after repeated administration 
of cipepofol for 30 days followed by a 14-day abrupt discontinuation 
phase. In this study, cipepofol was compared to vehicle, morphine, and 
propofol. Morphine as the positive control was associated with a 
significant increase in withdrawal symptoms (e.g., significant decrease 
in body weight, increased wet dog shakes, writhing, teeth chattering, 
chewing, and ptosis) following abrupt discontinuation of morphine. 
Abrupt cipepofol discontinuation was associated with limited, 
intermittent behavioral changes including withdrawal symptoms like

[[Page 55263]]

weight loss and teeth chattering. Likewise, propofol discontinuation 
after 30 days of repeated administration showed a similar minimal 
withdrawal profile.
    HHS noted that clinical trials did not systematically evaluate 
cipepofol's physical dependence. However, a limited subset of 
participants in some clinical trials were assessed for discontinuation-
emergent adverse events (DEAEs). DEAEs occurred more than four hours 
after stopping cipepofol. Reported DEAEs included nausea, vomiting, 
insomnia, and palpitations, but these events occurred with low 
frequency.
    Published literature notes withdrawal syndromes following 
continuous propofol infusions. Because cipepofol shares a similar 
chemical structure, mechanism, and abuse potential with propofol, it is 
anticipated that cipepofol, like propofol, may also experience physical 
dependence. Therefore, the overall data suggests that chronic 
administration of cipepofol may result in physiologic dependence.

8. Whether the Substance Is an Immediate Precursor of a Substance 
Already Controlled Under the CSA

    Cipepofol is not an immediate precursor of any controlled 
substance, as defined by 21 U.S.C. 802(23).
    Conclusion: After considering the scientific and medical evaluation 
and scheduling recommendation provided by HHS, and its own eight-factor 
analysis, DEA has determined that these facts and all relevant data 
constitute substantial evidence of potential for abuse of cipepofol. As 
such, DEA hereby schedules cipepofol as a controlled substance under 
the CSA.

Determination of Appropriate Schedule

    The CSA lists the findings required to place a drug or other 
substance in any particular schedule (I, II, III, IV, or V).\7\ 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)(4), finds that:
---------------------------------------------------------------------------

    \7\ 21 U.S.C. 812(b).
---------------------------------------------------------------------------

    (1) Cipepofol has a low potential for abuse relative to the drugs 
or other substances in schedule III.
    Cipepofol is an intravenous anesthetic for adults that modulates 
GABAA receptors to inhibit neurons. The drug produces dose-dependent 
anesthesia and shows reinforcing properties by maintaining self-
administration in propofol-trained rats. In human abuse potential 
studies, subtherapeutic doses mimicked propofol's positive subjective 
effects. However, clinical trials showed a low (< 2%) incidence of 
abuse-related adverse events, matching propofol rates except for higher 
dizziness. Consequently, due to its similarities to propofol (schedule 
IV), cipepofol has a low abuse potential relative to Schedule III 
substances under the CSA.
    (2) Cipepofol has a currently accepted medical use in treatment in 
the United States.
    Cipepofol was approved by FDA for the induction of general 
anesthesia in adults undergoing surgery. Thus, cipepofol has a 
currently accepted medical use in treatment in the United States.
    (3) Abuse of cipepofol may lead to limited physical dependence or 
psychological dependence relative to the drugs or other substances in 
schedule III.
    A rat study showed limited behavioral changes upon abrupt cipepofol 
discontinuation, while clinical trials found that most post-
discontinuation events mirrored common treatment effects, with rare 
instances of insomnia or palpitations. Research indicated that 
cipepofol's reinforcing properties in animal models are comparable to 
propofol. Furthermore, human abuse potential studies at subtherapeutic 
doses showed that subjective responses to cipepofol were statistically 
indistinguishable from those of propofol. Consequently, cipepofol is 
associated with a low risk of physical or psychological dependence 
relative to schedule III substances.
    Based on these findings, the Administrator concludes that cipepofol 
warrants control in schedule IV of the CSA.\8\
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    \8\ 21 U.S.C. 812(b)(4).
---------------------------------------------------------------------------

Requirements for Handling Cipepofol

    Cipepofol is subject to the CSA's schedule IV regulatory controls 
and administrative, civil, and criminal sanctions applicable to the 
manufacture, distributing, dispensing, importing, exporting, research, 
and conduct of instructional activities, including the following:
    1. Registration. Any person who handles (manufactures, distributes, 
reverse distributes, dispenses, imports, exports, engages in research, 
or conducts instructional activities or chemical analysis with, or 
possesses) cipepofol must 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. These registration 
requirements, however, are not applicable to patients (end users) who 
possess cipepofol pursuant to a lawful prescription.
    2. Disposal of Stocks. Any person unwilling or unable to obtain a 
DEA registration must surrender all quantities of currently held 
cipepofol, or may transfer all quantities of currently held cipepofol 
to a person registered with DEA. Cipepofol is 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. Cipepofol is subject to schedule III-V security 
requirements for DEA registrants and must be handled and stored in 
accordance with 21 CFR 1301.71-1301.77, pursuant to 21 U.S.C. 821, 823, 
and 871(b). Non-practitioners handling cipepofol must also comply with 
the employee screening requirements of 21 CFR 1301.90-1301.93. These 
requirements, however, are not applicable to patients (end users) who 
possess cipepofol pursuant to a lawful prescription.
    4. Labeling and Packaging. All labels and packaging for commercial 
containers of cipepofol must comply with 21 U.S.C. 825 and 958(e) and 
be in accordance with 21 CFR part 1302.
    5. Inventory. Every DEA registrant who possesses any quantity of 
cipepofol must have an initial inventory of all stocks of controlled 
substances (including cipepofol) 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.
    Any person who registers with DEA to handle cipepofol must take an 
initial inventory of all stocks of controlled substances (including 
cipepofol) on hand on the date the registrant first engages in the 
handling of controlled substances, pursuant to 21 U.S.C. 827 and 
958(e), and in accordance with 21 CFR 1304.03, 1304.04, and 1304.11(a) 
and (b).
    After the initial inventory, every DEA registrant must take 
inventory of all controlled substances (including cipepofol) 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. These requirements, however, are not 
applicable to patients (end users) who possess Cipepofol pursuant to a 
lawful prescription.
    6. Records and Reports. DEA registrants must maintain records and 
submit reports for cipepofol, pursuant to 21 U.S.C. 827, 832(a), and 
958(e), and in accordance with 21 CFR 1301.74(b) and (c) and parts 
1304, 1312, and in

[[Page 55264]]

accordance with 21 CFR 1301.74(b) and (c) and parts 1304, 1312, and 
1317.
    7. Prescriptions. All prescriptions for cipepofol, or products 
containing cipepofol, must comply with 21 U.S.C. 829, and be issued in 
accordance with 21 CFR parts 1306 and 1311, subpart C.
    8. Manufacturing and Distributing. In addition to the general 
requirements of the CSA and DEA regulations that are applicable to 
manufacturers and distributors of schedule IV controlled substances, 
such registrants should be advised that (consistent with the foregoing 
considerations) any manufacturing or distribution of cipepofol may only 
be for the legitimate purposes consistent with the drug's labeling, or 
for research activities authorized by the Federal Food, Drug, and 
Cosmetic Act, as applicable, and the CSA.
    9. Importation and Exportation. All importation and exportation of 
cipepofol must be in compliance with 21 U.S.C. 952, 953, 957, and 958, 
and in accordance with 21 CFR part 1312.
    10. Liability. Any activity involving cipepofol not authorized by, 
or in violation of, the CSA or its implementing regulations, is 
unlawful, and may subject the person to administrative, civil, and/or 
criminal sanctions.

Regulatory Analyses

Administrative Procedure Act

    The APA (5 U.S.C. 553) generally requires notice and comment for 
rulemakings. However, 21 U.S.C. 811(j) provides that in cases where a 
certain new drug is (1) approved by HHS, under section 505(c) of the 
FDCA, and (2) HHS recommends control in CSA schedule II-V, DEA shall 
issue an IFR scheduling the drug within 90 days. As stated in the legal 
authority section, the 90-day time frame is the later of: (1) the date 
DEA receives HHS's scientific and medical evaluation/scheduling 
recommendation, or (2) the date DEA receives notice of the NDA approval 
by HHS. Additionally, subsection 811(j) specifies that the rulemaking 
shall become immediately effective as an IFR without requiring DEA to 
demonstrate good cause.

Executive Orders 12866, 14192, and 14294

    This rule has been determined to be not significant for purposes of 
E.O. 12866 and accordingly has received a waiver under E.O. 14192.
    DEA scheduling actions are not subject to E.O. 14294, Fighting 
Overcriminalization in Federal Regulations.

Executive Order 12988, Civil Justice Reform

    This rulemaking 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 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 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

    This rule would require compliance with the following existing OMB 
collections: 1117-0003, 1117-0004, 1117-0006, 1117-0008, 1117-0009, 
1117-0010, 1117-0012, 1117-0014, 1117-0021, and 1117-0056. An agency 
may not conduct or sponsor, and a person is not required to respond to, 
a collection of information unless it displays a currently valid OMB 
control number.

Regulatory Flexibility Act

    The Regulatory Flexibility Act (RFA), 5 U.S.C. 601-612, applies to 
rules that are subject to the notice-and-comment requirements the APA 
at 5 U.S.C. 553. The RFA's requirements for the preparation of an 
initial regulatory flexibility analysis in 5 U.S.C. 603(a) are not 
applicable where, as here, DEA is not required by the APA or any other 
law to publish a general notice of proposed rulemaking. As noted in the 
above discussion regarding the applicability of the APA, DEA is not 
required to publish a general notice of proposed rulemaking. 
Consequently, the RFA does not apply to this IFR.

Unfunded Mandates Reform Act of 1995

    In accordance with the Unfunded Mandates Reform Act (UMRA) of 1995, 
2 U.S.C. 1501 et seq., DEA has determined and certifies that this 
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.

Congressional Review Act

    This rule is not a major rule as defined by the Congressional 
Review Act (CRA), 5 U.S.C. 804. However, pursuant to the CRA, DEA is 
submitting a copy of this IFR to both Houses of Congress and to the 
Comptroller General.

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, DEA amends 21 CFR part 1308 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.  1308.14:
0
a. Redesignate paragraphs (c)(11) through (60) as paragraphs (c)(12) 
through (61);
0
b. Add a new paragraph (c)(11) to read as follows:


Sec.  1308.14  Schedule IV.

* * * * *
    (c) * * *

 
                                * * * * *
(11) Cipepofol...............................................       2139
 
                                * * * * *
------------------------------------------------------------------------

* * * * *

Signing Authority

    This document of the Drug Enforcement Administration was signed on 
August 25, 2026, by DEA Administrator Terrance C. Cole. That document 
with the original signature and date is maintained by DEA. For 
administrative purposes only, and in compliance with requirements of 
the Office of the Federal Register, the undersigned DEA Federal 
Register Liaison Officer has been authorized to sign and submit the 
document in electronic format for publication, as an official document 
of DEA. This administrative process in no way alters

[[Page 55265]]

the legal effect of this document upon publication in the Federal 
Register.

Heather Achbach,
Federal Register Liaison Officer, Drug Enforcement Administration.
[FR Doc. 2026-17536 Filed 8-25-26; 4:15 pm]
BILLING CODE 4410-09-P


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