SN_26_158_ASCENT_IBO.pdf

Special Notice (SN) ARPA-H-SN-26-158 Accelerating Safe Clinical Evaluation of Novel Treatments: Ibogaine for Better outcomes in OUD (ASCENT-IBO) Related to Implementation of Executive Order 14401: Accelerating Medical Treatments for

Serious Mental Illness

I. INTRODUCTION

ARPA-H Innovative Solutions Opening (ISO) ARPA-H-SOL-24-106 is an open solicitation that allows the Proactive Health Office (PHO) to accept revolutionary Solutions that fall outside of the scope of a current ARPA-H program. Solutions are accepted and reviewed on an ongoing basis in accordance with the terms and conditions of the ISO.

Special Notice (SN) ARPA-H-SN-26-158, ASCENT-IBO, builds upon SN ARPA-H-SN-26-156, which introduced a PHO area of interest (AOI) tied to recent Executive Order (EO) 14401:

Accelerating Medical Treatments for Serious Mental Illness. Interested entities are encouraged to take actions as outlined below to support development of ibogaine for high-risk populations with opioid use disorder (OUD) with accelerated Phase I and II clinical trials.

This SN is supplementary to the ISO and does not amend it in any way. Unless explicitly stated in this SN, all submissions should be submitted to, and comply with, ISO ARPA-H-

SOL-24-106.

Key Dates:

• Registration opens for Proposers’ Day: 05 August 2026

• Registration deadline for Proposers’ Day: 7 September 2026 at 5 PM ET

• Proposers’ Day: 15 September 2026 (DC Metro Area)

• ASCENT-IBO Solution Summary submissions requested by: 15 October 2026 at 5 PM

ET

II. AREA OF INTEREST (AOI)

EO 14401 notes the Administration’s policy to accelerate innovative research models and appropriate drug approvals to increase access to psychedelic and other rapid-acting neuroplastogen-based interventions (referred to herein as “neuroplastogens”), such as ibogaine, that could save lives and reverse the crisis of serious mental illness in America.

The EO directs ARPA-H to allocate funds to support and partner with state governments that have enacted or are developing programs to advance neuroplastogen for serious mental illnesses.

Substance Use Disorders (SUD) are chronic, relapsing conditions that affect ~49 million

Americans and 2.8 million Veterans [1]. OUD is a type of SUD which is estimated to affect >5 million people in the US [1]. Despite widespread efforts to address and reduce the rates of opioid overdose fatalities, the opioid epidemic remains one of the most severe public health crises in US history [2]. The current standard-of-care for treating OUD involves medications for OUD (MOUD), such as naltrexone or buprenorphine, coupled with concurrent psychotherapy to reduce overall mortality. At present, >75% of individuals with OUD go completely untreated, highlighting a major gap in access to evidence-based care [1].

Although current treatments reduce risks of negative health outcomes and overdose deaths, they are far from complete solutions. In many cases, even with MOUD, treatment discontinuation and relapse rates remain high, leaving patients at increased risk of overdose and death [3-6]. The need for improved treatment strategies is further underscored by the elevated risk of death following treatment discontinuation or a nonfatal overdose which represents a critical but frequently missed period for intervention [7, 8].

For these reasons, novel approaches for OUD care are critical for improving patient outcomes and preventable overdose deaths.

Emerging evidence suggests neuroplastogens (such as ibogaine) may have potential for treating serious mental illnesses and OUD [9-11]. In recent years, anecdotal reports from unregulated medical clinics point towards ibogaine’s potential in improving OUD outcomes. To date, there are no active trials with an open investigational new drug (IND) application to study ibogaine’s safety and efficacy in OUD. Given the significant unmet need, ARPA-H is seeking to accelerate the next generation of highly effective treatment approaches by supporting the early clinical development of ibogaine for OUD.

III. NEXT STEPS

Given the urgency of the national opioid crisis and the Administration’s directive, this SN encourages action on a translational component of the larger ibogaine development program: clinical evaluation of ibogaine’s safety and efficacy in early-stage trials.

A. ARPA-H invites submission of Solution Summaries (≤6 pages; see Appendix A in the PHO ISO ARPA-H-SOL-24-106) to the PHO ISO that are responsive to all of the following tasks:

1. Combined Phase I/II clinical trial design: The ideal study design will simultaneously evaluate safety and efficacy of ibogaine in patient cohorts with OUD at increased risk of mortality. Solutions should describe trial designs at a high-level and address:

i. Dosing Strategy: Ibogaine dosing approaches that achieve clinically relevant, psychoactive exposure levels associated with therapeutic efficacy;

ii. Set and Setting: Plans for the therapeutic environment and psychological support framework used during and after ibogaine administration to maximize therapeutic potential;

iii. Placebo Strategy: An appropriate placebo or active comparator to minimize patient bias and preserve blinding to the extent feasible given ibogaine’s psychoactive profile, including measurements of patient unblinding to contextualize potential effects on outcomes; and

iv. Safety Assessments & Risk Mitigation Strategies: Rigorous safety monitoring aligned with gold-standard scientific and regulatory principles for neuroplastogen drug development. Solutions should identify known and anticipated risks in ibogaine and OUD patient cohorts

– including drug-related cardiotoxicity, drug-drug interactions, and detoxification/opioid withdrawal management. In addition to the above, Solutions should describe safety strategies to manage potential toxicity such as dose de-escalation or step-back actions to prioritize patient safety.

2. Operational Plans for Trial Execution: Solutions should outline high-level plans for clinical trial implementation, including staff training, plans for Integration, patient education, and scalable, ethically sound patient recruitment strategies.

3. Future Development Plans: Solutions should include high-level plans to prepare for accelerated entry into Phase III trials and plans for developing a Risk Evaluation and Mitigation Strategy (REMS).

Note: While not required, Solutions that consider opportunities to leverage the FDA’s Expanded Access program or Right-to-Try Act to broaden access for eligible patients are highly encouraged.

Entities interested in submitting Solutions are advised of the following:

• In line with the urgency to accelerate patient access to ibogaine treatment, Solutions led by a commercial entity who will be responsible for all activities related to the clinical trial execution may be most advantageous for rapid clinical advancement and eventual market entry.

• Interested entities are responsible for accomplishing all elements of the statement of work (SOW). Interested entities should ensure adequate personnel coverage, including regulatory consultants with neuroplastogen drug development expertise.

• Entities with existing relationships or state-level support for ibogaine or neuroplastogen-based therapeutic clinical development should clearly describe those partnerships and commitments as part of their Solution.

• ARPA-H aims to increase patient access to effective treatments; therefore, the most competitive Solutions will include initial concepts for affordability, price transparency, and public health benefit models following advanced clinical development.

• To achieve accelerated trials for ibogaine, Solutions will be prioritized that use combined Phase I and II trials, have well defined safety strategies, and have either an IND application submitted or imminent plans to submit to the FDA.

• Solutions that propose the use of ibogaine-derived derivates or analogues, other neuroplastogen-based compounds (to include but not limited to psilocybin and ketamine), and neuromodulation-based treatments do not align with the objectives of this SN.

Submissions should be submitted to, and comply with, ISO ARPA-H-SOL-24-106 (see Section 5 and Appendix A). Following review of Solution Summaries, proposers will be contacted with further guidance.

B. Proposers’ Day

ARPA-H is hosting a Proposers’ Day (PD) in support of ASCENT-IBO in the DC Metro Area.

ARPA-H invites interested entities to join us to develop accelerated clinical trial designs and approaches for ibogaine as a next generation treatment to prevent the excess morbidity and mortality caused by OUD.

1. What to Expect?

i. AOI Overview: The PD will include overview presentations by government personnel and other stakeholders.

ii. Lightning Talks: Interested entities are invited to present their work in person. Participants will be granted 3 minutes to present 1 slide.

Lightning talk submissions (no more than one per organization) will be accepted on a first-come, first-served basis, until the maximum possible number of submissions (given time constraints) is reached. Interested attendees must identify their intention to submit the lightning talk during registration. Further instructions will be provided via email to interested entities. Due to limited availability, ARPA-H does not guarantee that these requests will be fulfilled and will not accept pre-recorded presentations from attendees unable to attend onsite.

iii. Panel on Federal Considerations for Development of Neuroplastogen-based Treatments: Learn directly from federal agencies about regulatory considerations, clinical guidance, and anticipated challenges to inform proposal development.

2. Registration Information

i. Participants must register in advance through the registration website no later than 7 September 2026. Due to capacity limitations, in-person registration may be limited. Participation is not intended for patients, patient advocates, or a general interest audience. There is no registration fee for the PD. Note that there will be no same-day registration. An online registration form and various other meeting details can be found at: https://solutions.arpa-h.gov/events.

ii. All in-person attendees will be required to present valid, government issued photo identification. Individuals who are unable to register because the deadline has passed, or capacity has been reached for the PD, will be added to a waitlist.

3. Virtual Attendance Information

i. Virtual attendees will receive the link to the PD once they are verified and registration is confirmed.

4. Teaming

i. Developing a quality Solution will likely require combining relevant expertise, facilities, and capabilities to achieve the tasks outlined in ASCENT-IBO. Interested entities are encouraged to submit a teaming profile to engage with potential collaborators at: https://solutions.arpa-h.gov/teaming.

IV. DISCLAIMER

This SN is issued solely for information purposes and does not constitute a formal solicitation for Proposals or Solution Summaries. Responses to this notice are not offers and cannot be accepted by the government to form a binding award. Interested parties should submit Solution Summaries in accordance with solicitation ARPA-H-SOL-24-106, which is the formal solicitation for this AOI.

Submission of any information in response to this SN is voluntary and is not required to propose to subsequent ARPA-H ISOs or research solicitations on this or any other topic. ARPA- H will not provide reimbursement for costs incurred in responding to this SN, participation in any collaborative efforts or Proposers’ Day, and/or for any formal submissions to the PHO ISO.

Respondents are advised that ARPA-H is under no obligation to acknowledge receipt of the information received or provide feedback to respondents with respect to any information received related to this SN. Finally, ARPA-H is under no obligation to pursue any further action directly or indirectly related to this SN.

1. Substance Abuse and Mental Health Services Administration. (2025). Key substance use and mental health indicators in the United States: Results from the 2024 National Survey on Drug Use and Health (HHS Publication No. PEP25-07-007, NSDUH Series H-60). Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration.

https://www.samhsa.gov/data/data-we-collect/nsduh-national-surveydrug-use-and-health/national-releases

2. U.S. Department of Health and Human Services (HHS), Office of the Surgeon General, Facing

Addiction in America: The Surgeon General’s Spotlight on Opioids. Washington, DC: HHS, September 2018.

3. Glanz, J.M., et al., The association between buprenorphine treatment duration and mortality: a multi-site cohort study of people who discontinued treatment. Addiction, 2023. 118(1): p. 97–107.

4. Chhatwal, J., et al., Estimated Reductions in Opioid Overdose Deaths With Sustainment of Public Health Interventions in 4 US States. JAMA Network Open, 2023. 6(6): p. e2314925–e2314925.

5. Ware, O.D., et al., Risk of Relapse Following Discharge from Non-Hospital Residential Opioid Use Disorder Treatment: A Systematic Review of Studies Published from 2018 to 2022. Subst Abuse Rehabil, 2025. 16: p. 105–118.

6. Shulman, M., et al., Optimizing retention strategies for opioid use disorder pharmacotherapy: The retention phase of the CTN-0100 trial (RDD). Contemp Clin Trials, 2025. 150: p. 107816.

7. Olfson, M., et al., Causes of Death After Nonfatal Opioid Overdose. JAMA Psychiatry, 2018. 75(8): p.

820–827.

8. Weiner, S.G., et al., One-Year Mortality of Patients After Emergency Department Treatment for Nonfatal Opioid Overdose. Ann Emerg Med, 2020. 75(1): p. 13–17.

9. Davis, A.K., et al., Subjective effectiveness of ibogaine treatment for problematic opioid consumption:

Short- and long-term outcomes and current psychological functioning. J Psychedelic Stud, 2017. 1(2):

p. 65–73.

10. Zafar, R.R., et al., High hopes? Precision psychedelic addiction medicine. Front Psychiatry, 2025. 16:

p. 1681795.

11. Vollenweider, F.X. and K.H. Preller, Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders. Nat Rev Neurosci, 2020. 21(11): p. 611–624.