Notice2026-20427
Design and Safety Considerations for Clinical Trials Involving Ibogaine Drug Products; Request for Information
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Published
October 6, 2026
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA or the Agency) is describing the approaches it is considering for the design of early- phase clinical trials of ibogaine drug products and is opening a public docket to receive comments. The Department of Health and Human Services (HHS) is funding clinical development of ibogaine, and the first federally supported trials are expected to study ibogaine in adults with opioid use disorder (OUD) and adults with post-traumatic stress disorder (PTSD). FDA is building on the guidance for industry entitled "Psychedelic Drugs: Considerations for Clinical Investigations" by seeking comments, data, and information from the public on protocol elements relevant to ibogaine development--including dose selection and escalation, care setting, safety monitoring, eligibility criteria, stopping rules, and safety oversight, in part, because the Federal Government is funding work in this area. FDA will consider all information provided in response to this Request for Information (RFI) to inform whether and how these specific elements should be considered in its review of Investigational New Drug Applications (INDs) involving ibogaine.
Full Text
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<title>Federal Register, Volume 91 Issue 192 (Tuesday, October 6, 2026)</title>
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[Federal Register Volume 91, Number 192 (Tuesday, October 6, 2026)]
[Notices]
[Pages 63563-63569]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2026-20427]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2026-N-10429]
Design and Safety Considerations for Clinical Trials Involving
Ibogaine Drug Products; Request for Information
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice; request for information; establishment of a public
docket.
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SUMMARY: The Food and Drug Administration (FDA or the Agency) is
describing the approaches it is considering for the design of early-
phase clinical trials of ibogaine drug products and is opening a public
docket to receive comments. The Department of Health and Human Services
(HHS) is funding clinical development of ibogaine, and the first
federally supported trials are expected to study ibogaine in adults
with opioid use disorder (OUD) and adults with post-traumatic stress
disorder (PTSD). FDA is building on the guidance for industry entitled
``Psychedelic Drugs: Considerations for Clinical Investigations'' by
seeking comments, data, and information from the public on protocol
elements relevant to ibogaine development--including dose selection and
escalation, care setting, safety monitoring, eligibility criteria,
stopping rules, and safety oversight, in part, because the Federal
Government is funding work in this area. FDA will consider all
information provided in response to this Request for Information (RFI)
to inform whether and how these specific elements should be considered
in its review of Investigational New Drug Applications (INDs) involving
ibogaine.
DATES: Submit either electronic or written comments, data, or
information by November 20, 2026.
ADDRESSES: You may submit comments, data, and information as follows.
Please note that late, untimely filed comments will not be considered.
The <a href="https://www.regulations.gov">https://www.regulations.gov</a> electronic filing system will accept
comments until 11:59 p.m. Eastern Time at the end of November 20, 2026.
Comments received by mail/hand delivery/courier (for written/paper
submissions) will be considered timely if they are received on or
before that date.
Electronic Submissions
Submit electronic comments in the following way:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> If you want to submit a comment with confidential
information that you
[[Page 63564]]
do not wish to be made available to the public, submit the comment as a
written/paper submission and in the manner detailed (see ``Written/
Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
<bullet> Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
<bullet> For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2026-N-10429 for ``Design and Safety Considerations for Clinical
Trials Involving Ibogaine Drug Products; Request for Information.''
Received comments, those filed in a timely manner (see ADDRESSES), will
be placed in the docket and, except for those submitted as
``Confidential Submissions,'' publicly viewable at <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday, 240-402-7500.
<bullet> Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852, 240-402-7500.
FOR FURTHER INFORMATION CONTACT: Bernard Fischer, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, Rm. 4208, Silver Spring, MD 20993-0002, 855-
543-3784, <a href="/cdn-cgi/l/email-protection#b1f8d3ded6d0d8dfd4e3f7f8f1d7d5d09fd9d9c29fd6dec7"><span class="__cf_email__" data-cfemail="bbf2d9d4dcdad2d5dee9fdf2fbdddfda95d3d3c895dcd4cd">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is responsible under the Federal Food, Drug, and Cosmetic Act
(FD&C Act) (21 U.S.C. 301 et seq.) and the Public Health Service Act
for protecting and promoting the public health through the regulation
of human drugs, biological products, medical devices, foods, and other
products. FDA's oversight of drug products--including ibogaine drug
products and other psychedelic drugs--spans preclinical investigation
through the full lifecycle of an approved product. FDA remains
committed to innovation and recognizes the potential of psychedelic
drugs to treat substance use disorders and certain psychiatric and
neurologic conditions, while upholding its public health mission to
ensure that drugs are safe, effective, and of high quality.
Consistent with this commitment, FDA has taken significant steps to
support implementation of Executive Order 14401 of April 18, 2026,
``Accelerating Medical Treatments for Serious Mental Illness'' (91 FR
21709, April 22, 2026). Executive Order 14401 establishes a policy of
accelerating innovative research models and appropriate drug approvals
to help increase access to psychedelic drugs for serious mental
illness, and it specifically notes that ibogaine compounds show
potential in clinical studies to address serious mental illnesses for
patients whose conditions persist after completing standard therapy.
On July 14, 2026, FDA issued the final guidance for industry
entitled ``Psychedelic Drugs: Considerations for Clinical
Investigations'' (Psychedelics Guidance) (91 FR 43101). The guidance
provides general considerations for sponsors developing psychedelic
drugs for the treatment of certain medical conditions and discusses
recommendations for clinical investigations using psychedelic drugs.
The Agency has also allowed an early-phase clinical study of
noribogaine hydrochloride, a derivative of ibogaine, to proceed under
an IND as a potential treatment for alcohol use disorder. Consistent
with Executive Order 14401, FDA is coordinating with other components
of HHS to support the development of ibogaine drug products under
appropriate safeguards, including gathering data that bears on the
considerations described below.
Federal Support for Ibogaine Clinical Development
HHS, through the Advanced Research Projects Agency for Health
(ARPA-H), is funding a program to collect safety and efficacy data
through early-phase clinical trials. HHS, through the National
Institute on Drug Abuse (NIDA), is also funding research on ibogaine
for the potential treatment of OUD. Data collected through these
federally funded programs, which will be made available publicly to
investigators and sponsors, may support future later-stage studies to
develop ibogaine under an IND.
FDA has identified serious safety risks with ibogaine drug products
that have the potential for exposing human subjects to an unreasonable
and significant risk of illness or injury (see 21 CFR 312.42(b)(1)(i)),
including prolongation of the heart rate-corrected QT (QTc) interval
and the associated risk of life-threatening arrhythmia, neurotoxicity
in nonclinical studies, and uncertainty regarding an appropriate
starting dose for humans. The approaches under consideration in section
II are intended to address these risks to the extent possible. To
accelerate development of ibogaine drug products across development
programs, FDA is describing the approaches it is considering and
seeking comment on each before taking any additional action, such as
issuing guidance. The elements described below provide further detail
of one possible approach and are consistent with the recommendations in
Psychedelics Guidance. The Agency asks clinicians, researchers,
prospective sponsors, patients, and the public to provide feedback.
In determining whether a proposed investigation would expose
participants to an unreasonable and significant risk of illness or
injury, FDA considers the seriousness of the condition, the adequacy of
available therapy, and the safeguards built into the trial. FDA's
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review of any IND, including an IND supported by federal funds, remains
governed by the FD&C Act and FDA's regulations, and nothing in this RFI
predetermines FDA's action on any submission.
Research on Ibogaine Drug Products
While published reports suggest potential benefits of ibogaine for
treatment of substance use disorders and certain psychiatric and
neurologic conditions--including mood disorders, PTSD, and traumatic
brain injury--ibogaine also has serious known risks. Clinical data have
shown that ibogaine has serious cardiovascular risks and commonly
causes substantial QTc interval prolongation, which has been associated
with life-threatening ventricular arrhythmias and death. Commonly
reported non-cardiac adverse events include changes in perception,
impaired cognition, and impaired coordination and balance (ataxia).
Published nonclinical toxicology studies in rodent and non-rodent
species have reported dose-dependent neurotoxicity, ranging from
tremors and ataxia at lower doses to neuronal degeneration,
neuroinflammation, convulsions, and death at higher doses.
The published literature on ibogaine also has significant
limitations, particularly the detail needed to characterize the
investigational drug product adequately (e.g., dose, quality, purity,
and potency). Most studies also lack participant-level data and
reliable summary-level safety, efficacy, and pharmacokinetic data.
Uncertainty about the benefit-risk profile of ibogaine drug
products and evidence limitations of studies involving ibogaine is not
new. In 1993, FDA convened the Drug Abuse Advisory Committee to discuss
an ibogaine IND for potential treatment of cocaine dependence, focusing
specifically on whether sufficient safety data existed to allow testing
of ibogaine in human volunteers (58 FR 38773, July 20, 1993). The
discussion centered on the challenge of establishing a meaningful
therapeutic window between efficacious and toxic doses. Committee
members highlighted data on neurotoxicity, difficulties in
appropriately characterizing risks to enable informed consent, the need
for additional preclinical data, as well as the significant unmet need
for treatments for cocaine use disorder.
The questions raised at that Advisory Committee meeting remain
relevant today. However, ibogaine's association with QTc interval
prolongation and torsades de pointes (TdP) was identified after the
Advisory Committee met in 1993, so the Committee did not address
strategies to mitigate this particular life-threatening risk. FDA also
recognizes, notwithstanding the various known risks, the seriousness of
the health conditions at issue and the severity of unmet need that
patients seeking ibogaine treatments face. Given this reality, FDA
seeks information that might inform selection of populations and use
cases for clinical research with ibogaine drug products under an IND
where the potential risks may be acceptable. Through its current
research funding, and based on available data supporting potential for
a favorable benefit-risk assessment, HHS is prioritizing two initial
populations, adults with OUD and adults with PTSD, in which the
seriousness of the condition and the limits of available therapy may
justify the known risks of ibogaine in a closely monitored early-phase
trial conducted under an IND.
How FDA Evaluates Drugs That Prolong the QTc Interval
Some drugs delay cardiac repolarization, which manifests on the
surface electrocardiogram as prolongation of the QTc interval. QTc
prolongation increases the risk of TdP, a life-threatening ventricular
arrhythmia. After several drugs were withdrawn from the market because
of TdP between 1991 and 2003, the International Council for
Harmonisation of Technical Requirements for Pharmaceuticals for Human
Use (ICH) guidance ``E14 Clinical Evaluation of QT/QTc Interval
Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs''
(ICH E14 guidance) (October 2005) was developed to address this
critical safety risk. The ICH E14 guidance is applicable to chronically
administered, single-dose, and episodically administered drugs. Potent
QTc-prolonging drugs (e.g., sotalol, dofetilide) are initiated in the
hospital setting and discontinued if the QTc interval exceeds 500
milliseconds (ms), the threshold above which the overwhelming majority
of drug-induced TdP cases occur. Similarly, the 500 ms threshold
(marked QTc prolongation) is used as a stopping criterion in drug
development. This threshold for drug discontinuation is primarily
intended to prevent further drug exposure outside the hospital setting
and is therefore most applicable to chronically administered drugs.
Ibogaine, however, is typically administered as a single dosage regimen
or occasional intermittent dosing. Because TdP occurs in a minority of
patients with a QTc-interval >500 msec and can be terminated (drug
infusions, direct current cardioversion, temporary transvenous pacing,
etc.), it is conceivable that the benefit-risk balance of repeat
ibogaine exposure could still be favorable if administered in an
intensively monitored setting. Accordingly, the FDA seeks input on what
data could potentially allow for repeated dosing despite known risks of
TdP and corresponding established precedent for drug discontinuation
among patients. FDA's preliminary thinking is that an initial trial
could administer a single dose in an intensively monitored inpatient
setting, as described in section II, and that data from such a trial
could inform whether, and under what conditions, repeat dosing could be
studied.
Experience with FDA-approved drugs may inform cardiac safety
monitoring for ibogaine drug products. For example, ibutilide is an
approved antiarrhythmic drug given by brief intravenous infusion to
convert atrial fibrillation or atrial flutter to sinus rhythm, and it
causes TdP in about 1.7 percent of patients. It should be administered
by personnel trained to treat acute ventricular arrhythmias and
requires continuous electrocardiographic monitoring for at least 4-
hours (based on its short half-life) until the QTc-interval normalizes.
Thus, while ibogaine has an active metabolite and likely would require
more prolonged monitoring, the general safety monitoring approach for
administration of ibutilide could be informative.
Under section 505(d) of the FD&C Act (21 U.S.C. 355(d)), for a new
drug to be approved for marketing in the United States, FDA must
determine that the drug is safe and effective for use under the
conditions prescribed, recommended, or suggested in the product's
labeling. Demonstrating effectiveness under this standard requires
substantial evidence that the drug will have the effect it purports or
is represented to have (see section 505(d) of the FD&C Act). Because
all drugs can have adverse effects, the demonstration of safety
requires a showing that the benefits of the drug outweigh its risks.
Risks, such as substantial QTc prolongation, can be a basis for not
approving a drug, or for placing an investigation on clinical hold,
where the risk cannot feasibly be managed or outweighs the benefit,
especially where the drug offers no clear advantage over available
therapy and the available therapy appears to meet the needs of most
patients. The benefit-risk assessment may take into consideration how
serious the untreated
[[Page 63566]]
condition is and what benefit the drug has shown compared with existing
options. Whether the risk can realistically be managed through labeling
or other mechanisms is also a factor. Thus, FDA seeks input on
considerations for patient safety that could help inform the Agency's
evaluation of the overall benefit-risk profile of ibogaine drug
products.
Other Safety Considerations for Ibogaine Drug Products
As described above, published studies in animals have reported that
ibogaine can cause injury to the brain, including to the cerebellum.
The 1993 Advisory Committee focused on whether a dose exists that is
high enough to help patients, but low enough to avoid that injury. That
question remains unresolved, and its answer depends on several issues
that the published studies leave uncertain.
The most critical challenge is defining a threshold at which brain
injury would be predicted to occur in humans based upon nonclinical
data. If brain injury occurs only when drug exposure rises above a
certain threshold, the goal would be to identify a therapeutic dose
that keeps exposure below that threshold. Because neurotoxicity has
been reported in several animal species, it is critical to gather
nonclinical data on the blood concentrations that not only do not
produce brain injury but also show no adverse effects. Comparing
studies by dose alone can be misleading, because the same milligram
(mg)-per-kilogram (kg) dose can result in very different blood levels
depending on the animal species and how the drug is administered. FDA
encourages the use of new approach methodologies in place of animal
testing where appropriate.
Transient neurologic effects, particularly ataxia, are common after
ibogaine administration; in one prospective study of patients with OUD
who received a single 10 mg/kg dose, all participants experienced
severe transient ataxia (Knuijver 2022). Whether ibogaine causes
persistent neurologic or cognitive injury in humans at clinically used
doses, however, has not been systematically studied, and the available
reports generally lack the product characterization, exposure data, and
structured follow-up needed to answer that question.
II. FDA's Initial Considerations on Trial Design for Ibogaine Drug
Products
FDA welcomes INDs for ibogaine drug products and encourages
sponsors to request a pre-IND meeting to discuss a specific proposed
design. FDA has made no final determination as to the characteristics
that would allow a trial of an ibogaine drug product to proceed, and it
must evaluate whether each IND is supported by adequate scientific
justification. However, based on a thorough review of available
information, FDA has developed preliminary thinking \1\ on a design for
an initial, open-label trial in which small groups of participants each
receive a single dose of ibogaine, with the dose increasing from one
group to the next. This section describes that thinking and requests
comments, data, and information from interested parties to facilitate
the initiation of clinical trials for ibogaine drug products. This RFI
does not establish legally enforceable requirements or regulatory
expectations, nor does it represent FDA's final views.
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\1\ This includes review of published literature on ibogaine,
regulatory experience with drugs presenting similar safety profiles,
review of information regarding ibogaine administration in settings
outside the United States and other information available to the
Agency, and consultation with other components of the Department.
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Several of the elements described below apply existing requirements
and recommendations to ibogaine drug products, including the informed
consent requirements of 21 CFR part 50, the QTc evaluation principles
in the ICH E14 guidance and FDA's guidance entitled ``E14 and S7B
Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and
Proarrhythmic Potential--Questions and Answers'' (E14/S7B Q&A guidance)
(August 2022), the dose-selection principles in FDA's guidance on
estimating the maximum safe starting dose, and the monitoring
recommendations in the Psychedelics Guidance. Other elements are not
derived from existing guidance and are described here for public
comment. FDA will evaluate INDs on an individual basis and consider the
applicability of these (and other) elements in the context of each
sponsor's unique development plan. FDA will consider the comments
submitted in response to this RFI and may issue new guidance or update
existing guidance in accordance with 21 CFR 10.115, or take another
action, as appropriate.
A. Trial Design and Dose
An initial trial could assess whether ibogaine can be given safely
under close monitoring and test whether the monitoring plan works. The
main goals could be to measure how the body processes ibogaine and its
active metabolite, noribogaine, in terms of both pharmacokinetics (PK)
and pharmacodynamics (PD), how both ibogaine and noribogaine affect the
heart, and how well participants tolerate ibogaine and noribogaine.
In initial trials, participants could be enrolled in sequential
dose ascending groups, starting with an initial dose justified by the
published literature and not exceeding 10 mg/kg. Within each group,
participants could be dosed one at a time. A potential increase in dose
for the next group could be considered after appropriate review, which
may be conducted by a safety review committee (SRC), a data and safety
monitoring board (DSMB), and the FDA.
CYP2D6 is the main enzyme that converts ibogaine to noribogaine, so
participants could be genotyped for it, with only fast and intermediate
metabolizers included, and doses adjusted if needed. Sponsors could
also study whether pretreatment, such as with intravenous magnesium,
reduces the magnitude of QTc-interval prolongation. The ibogaine used
must be well characterized, with a certificate of analysis and the
chemistry, manufacturing, and controls information required under 21
CFR 312.23(a)(7).
B. Care Setting and Monitoring
In study designs FDA is contemplating, the care setting should be
an inpatient unit equipped to manage a life-threatening arrhythmia,
which would likely include continuous heart rhythm monitoring, a
physician-led team trained in advanced cardiac life support, a
defibrillator at the bedside, drugs to treat TdP, emergency cardiac
pacing, and ventilator support.
A recording before dosing (e.g., 24-hour recording) should be
considered to establish each participant's baseline heart rhythm.
Continuous monitoring should begin at dosing, ending when there are no
abnormal rhythms and the QTc interval has returned to near its pre-dose
value, which could be as long as 36 hours.
More broadly, at least two staff members should monitor each
participant during the drug's acute effects, including one that is a
licensed mental health professional (Psychedelics Guidance).
Participants should be assessed for potential adverse events, which may
include ataxia, seizures, suicidal thoughts, psychosis, and other
psychiatric symptoms. Cognitive testing at baseline and repeated at
intervals through 12 months after dosing may help distinguish short-
term effects on cognition from lasting ones.
[[Page 63567]]
C. Medications
Before dosing, participants should stop medications that prolong
the QTc-interval, slow the heart rate, interact with CYP2D6, or raise
serotonin levels. These include but are not limited to opioid agonist
medications (e.g., methadone and buprenorphine), antipsychotics,
antiemetics, and selective serotonin reuptake inhibitors (e.g.,
paroxetine, sertraline). Any medications used to treat side effects
during the trial, such as antiemetics and sleep aids, should not
prolong the QTc interval.
D. Study Stopping Rules
In the scenario FDA is considering, dosing should be paused for
appropriate review, which may be conducted by an SRC, a DSMB, and the
FDA, if any of the following occurs:
<bullet> a participant has a sustained ventricular arrhythmia or a
seizure;
<bullet> a participant's QTc prolongation above 500 ms persists
more than two days;
<bullet> a participant develops new suicidal thoughts or behavior
after the acute effects wear off, or lasting perceptual disturbances;
<bullet> a death or serious adverse event possibly related to
ibogaine occurs; or
<bullet> two or more participants in a group have severe adverse
events.
E. Safety Oversight
In the trial FDA is envisioning, the SRC should include a
cardiologist. The trial should also be overseen by an independent DSMB
that includes a cardiologist, a neurologist, a psychiatrist, and a
biostatistician. For trials enrolling participants with OUD, both
bodies should include an addiction medicine physician. FDA could also
request to review the trial data in certain circumstances, which may
include the occurrence of an adverse event meeting the study stopping
rules or prior to allowing dose escalation in a trial cohort.
F. Discharge and Follow-Up
FDA is also envisioning that the trial would have participants stay
in the telemetry monitored unit for an appropriate amount of time
(e.g., at least 36 hours after dosing). They should leave after meeting
predetermined discharge criteria, e.g., a 48-hour 12-lead ECG without
QTc prolongation. Upon physician discharge approval, the patient may be
escorted home by a trusted adult.
G. Who Can Enroll
Potential participants could be adults 18 to 55 years old who have
stopped taking psychiatric medications. Likely exclusion criteria may
include any of the following:
<bullet> structural cardiovascular disease, a baseline QTcF of 430
ms or greater, or abnormal heart rate or blood pressure;
<bullet> a personal or family history of arrhythmia or sudden
cardiac death;
<bullet> a history of seizures, psychosis, or bipolar disorder;
<bullet> recent suicidal thoughts or behavior;
<bullet> a neurodegenerative or balance disorder;
<bullet> significant liver or kidney impairment; or
<bullet> pregnancy or breastfeeding.
Low serum potassium, calcium, or magnesium levels should be
corrected before dosing.
H. Potential Study Populations
One prospective study population could include participants with
moderate-to-severe PTSD for at least 6 months. For example,
participants might have PTSD that has not responded to at least one
adequate course of a selective serotonin reuptake inhibitor and one
full course of PTSD-focused psychotherapy, with at least 12 months
since the most recent course.
A second prospective study population could include participants
with moderate or severe OUD. For example, participants might want to
stop using opioids and have not achieved sustained remission in the
years preceding study participation despite adequate treatment with an
FDA-approved medication for OUD, including opioid agonist treatment, as
well as multiple treatment attempts (outpatient, residential,
inpatient).
I. Important Study Documents
FDA guidance documents, including two guidances for industry,
``E6(R3) Good Clinical Practice'' (September 2025) and ``Informed
Consent Guidance for IRBs, Clinical Investigators, and Sponsors''
(August 2023), identify several essential documents that are
fundamental to the planning, conduct, oversight, and evaluation of
clinical trials. For this notice, the Agency highlights the following
and requests comment on how these concepts should be applied in the
context of ibogaine trials:
1. Informed consent. Participants must be given adequate
information regarding the serious, potentially life-threatening risks
of ibogaine drug products to provide informed consent for treatment.
2. Investigator's brochure. The investigator's brochure should
provide an up-to-date summary of information on the investigational
product and clinical and nonclinical data on the ibogaine drug product.
The investigator's brochure should provide sufficient information to
facilitate an understanding of the rationale for the key elements of
the protocol specific to the proposed use in the clinical trial (e.g.,
population, dosing, safety monitoring).
III. Topics for Public Input
FDA invites comment on every element described in section II.
Comments are most useful if they identify the specific element
addressed, state whether it should continue to be part of FDA's
thinking, be modified, or if FDA should change its thinking about that
element. Comments should also provide the data or clinical experience
that supports that view. In addition to the preliminary thinking
described above, FDA is particularly interested in comments on the
following questions:
(1) General Study Design Considerations
a. Are there study populations for which a strong potential for
benefit may justify the known risks of ibogaine drug products?
b. For trials enrolling participants with OUD, what approaches to
discontinuing opioid agonist medications before dosing (including
setting, duration, and measures to mitigate risks from loss of opioid
tolerance) would best manage associated risks?
(2) Dose Selection and Escalation
a. Is a maximum dose of 10 mg/kg, reached through small, stepwise
cohorts, appropriate for identifying a minimum pharmacologically active
dose and an approximate MTD? Doses ranging from 5 to 20 mg/kg have been
described in published clinical reports; however, these doses lack
adequate safety margins based on available nonclinical data. Should
dosing be based on total body weight, lean body weight, or a target
exposure? Commenters are encouraged to consider the following:
i. What animal pharmacokinetic data, if any, are available or can
be produced to correlate with no observed adverse effect levels in
animal studies from published literature in order to determine whether
adequate safety margins exist relative to anticipated human exposures
to mitigate neurotoxicity risks?
ii. What threshold for neurotoxicity can be identified from animal
studies across multiple species following both single and repeated
dosing, and what role noribogaine, the metabolite of
[[Page 63568]]
ibogaine, may be playing in contributing to or modulating such effects?
iii. Given the significant limitations of published literature on
clinical investigations with ibogaine, including inadequate
characterization of the drug product and dose, how can clinical
experience, which may include clinical neurological assessments,
cognitive testing, brain imaging, or laboratory testing, be used in
conjunction with animal study findings to inform appropriate monitoring
strategies that would help detect, and ideally mitigate, neurotoxicity
risks in clinical trials?
(3) Safety Considerations
a. Cardiac Safety Considerations. As ibogaine may have effects that
last several days, it is anticipated that a multi-day cardiac safety
monitoring period involving inpatient observation may be required.
Potential safety monitoring requirements may include but are not
limited to: (i) continuous cardiac rhythm monitoring; (ii) direct
access to cardiac resuscitation; (iii) duration of electrocardiographic
monitoring, given that ibogaine and its metabolite, noribogaine, are
cleared slowly; and (iv) managing QTc prolongation when the full dose
has already been given. Additional considerations include:
i. Given cardiac safety requirements (e.g., continuous
electrocardiogram monitoring, staff trained to provide advanced cardiac
life support interventions, resuscitation equipment), what care setting
(e.g., intensive care unit or hospital telemetry) and safeguards would
be needed to conduct an early phase trial of an ibogaine drug product
in the United States?
ii. How should QTc prolongation be managed for a drug given as a
single dose, and what potential pre-treatment to mitigate QTc
prolongation and monitoring measures might inform dosing?
iii. What study design would best quantify and distinguish the
effects on QTc interval change from baseline of ibogaine alone and
ibogaine administered with pre-treatment with magnesium or other
products intended to minimize delayed repolarization?
iv. What upper pre-treatment QTc threshold as an exclusion
criterion for enrollment (e.g., greater than 430 ms) would best
minimize the proportion of patients who experience marked QTc
prolongation of greater than 500 ms?
v. What participant-level and study-wide stopping rules would best
mitigate cardiac arrythmia risks?
vi. What enrollment criteria would best minimize risk of cardia
arrhythmia in early-stage trials based on the known risk factors for
TdP (e.g., low serum potassium, calcium, or magnesium, bradycardia,
structural heart disease, other QTc-prolonging medications, a personal
or family history suggesting congenital long QT syndrome, and
populations with known susceptibility to arrhythmia, including women)?
b. Central Nervous System Safety Considerations. Potential safety
monitoring requirements may include but are not limited to: (i)
monitoring for seizures and cerebellar abnormalities, such as ataxia;
(ii) precautions to minimize risk of falls; (iii) assessment of the
duration and persistence of neurologic and cognitive effects; and (iv)
criteria for safe discharge.
i. What clinical safety outcomes or assessments are needed to
inform acute neurologic and cognitive risks?
ii. What duration of follow-up and assessments are needed to
characterize long-term neurologic and cognitive sequelae to inform
benefit-risk assessment?
(4) Ethical and Oversight Considerations
a. What informed consent information would ensure prospective
research participants understand the serious, potentially life-
threatening risks of ibogaine drug products?
b. What factors might DSMBs and Institutional Review Boards need to
consider?
c. What would make data from treatment settings outside the United
States useful in designing a trial, including the individual-level
pharmacokinetic, electrocardiographic, and product information that
would be needed to interpret it?
FDA is not seeking comments on the following topics: (1) the safety
or effectiveness of any specific ibogaine drug product, or the merits
of any pending or anticipated application before the Agency; (2) the
scheduling status of ibogaine drug products under the Controlled
Substances Act, which is addressed through separate statutory
processes; (3) the legalization or decriminalization of psychedelic
substances, or the merits of state or local programs authorizing their
use, although FDA welcomes input on data collection from such programs
as described above; (4) religious, ceremonial, or personal (non-
medical) use of psychedelic substances; or (5) individual disputes,
enforcement matters, or complaints regarding specific practitioners or
entities. Comments addressing these topics may not be considered.
FDA will review the comments received and expects to reflect them,
as appropriate, in regulatory activities, including review of protocols
for federally supported and other clinical trials of ibogaine drug
products and future guidance on their development.
IV. References
The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (see ADDRESSES) and are available for
viewing by interested persons between 9 a.m. and 4 p.m., Monday through
Friday; they are also available electronically at <a href="https://www.regulations.gov">https://www.regulations.gov</a>. References without asterisks are not on public
display at <a href="https://www.regulations.gov">https://www.regulations.gov</a> because they have copyright
restriction. Some may be available at the website address, if listed.
References without asterisks are available for viewing only at the
Dockets Management Staff. Although FDA verified the website addresses
in this document, please note that websites are subject to change over
time.
1. Alper, K.R., Staji[cacute], M., and J.R. Gill, ``Fatalities
temporally associated with the ingestion of ibogaine,'' J. Forensic
Sci., 57(2):398-412 (2012), available at doi:10.1111/j.1556-
4029.2011.02008.x.
2. * Brunt, T.M., ``Rare but relevant: ibogaine and cardiovascular
complications--prolonged QT interval and ventricular arrhythmias,''
Addiction, 121(6):1616-1621 (2026), available at doi:10.1111/
add.70319.
3. * Knuijver, T., Schellekens, A., Belgers, M., Donders, R., van
Oosteren, T., et al., ``Safety of ibogaine administration in
detoxification of opioid-dependent individuals: a descriptive open-
label observational study,'' Addiction, 117(1):118-128 (2022),
available at doi:10.1111/add.15448.
4. * Knuijver, T., ter Heine, R., Schellekens, A.F.A., Heydari, P.,
Lucas, L., et al., ``The pharmacokinetics and pharmacodynamics of
ibogaine in opioid use disorder patients,'' J. Psychopharmacol.,
38(5):481-488 (2024), available at doi:10.1177/02698811241237873.
5. * K[ouml]ck, P., Froelich, K., Walter, M., Lang, U., and K.M.
D[uuml]rsteler, ``A systematic literature review of clinical trials
and therapeutic applications of ibogaine,'' J. Subst. Abuse Treat.,
138:108717 (2022), available at doi:10.1016/j.jsat.2021.108717.
6. Ona, G., Rocha, J.M., Bouso, J.C., Hallak, J.E.C., Borr[agrave]s,
T., et al., ``The adverse events of ibogaine in humans: an updated
systematic review of the literature (2015-2020),''
Psychopharmacology, 239(6):1977-1987 (2022), available at
doi:10.1007/s00213-021-05964-y.
7. Roden, D.M., ``Drug-induced prolongation of the QT interval,'' N.
Engl. J. Med., 350(10):1013-1022 (2004), available at doi:10.1056/
NEJMra032426.
8. Rocha, J.M., Reis, J.A.S., Bouso, J.C.,
[[Page 63569]]
Hallak, J.E.C., and R.G. Dos Santos, ``Identifying setting factors
associated with improved ibogaine safety: a systematic review of
clinical studies,'' Eur. Arch. Psychiatry Clin. Neurosci.,
273(7):1527-1542 (2023), available at doi:10.1007/s00406-023-01590-
1.
9. * U.S. Food and Drug Administration guidance for industry ``E14
and S7B Clinical and Nonclinical Evaluation of QT/QTc Interval
Prolongation and Proarrhythmic Potential--Questions and Answers''
(August 2022), available at <a href="https://www.fda.gov/media/161198/download">https://www.fda.gov/media/161198/download</a>.
10. * U.S. Food and Drug Administration guidance for industry
``Informed Consent Guidance for IRBs, Clinical Investigators, and
Sponsors'' (August 2023), available at <a href="https://www.fda.gov/media/88915/download">https://www.fda.gov/media/88915/download</a>.
11. * U.S. Food and Drug Administration guidance for industry
``E6(R3) Good Clinical Practice'' (September 2025), available at
<a href="https://www.fda.gov/media/169090/download">https://www.fda.gov/media/169090/download</a>.
12. * U.S. Food and Drug Administration guidance for industry
``Estimating the Maximum Safe Starting Dose in Initial Clinical
Trials for Therapeutics in Adult Healthy Volunteers'' (July 2005),
available at <a href="https://www.fda.gov/media/72309/download">https://www.fda.gov/media/72309/download</a>.
11. * U.S. Food and Drug Administration guidance for industry ``QTc
Information in Human Prescription Drug and Biological Product
Labeling'' (December 2025), available at <a href="https://www.fda.gov/media/170814/download">https://www.fda.gov/media/170814/download</a>.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2026-20427 Filed 10-5-26; 8:45 am]
BILLING CODE 4164-01-P
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