FDA Finalizes Psychedelic Clinical Trial Guidance; States Move on Ibogaine Research

The U.S. Food and Drug Administration (FDA) on July 14 announced final guidance for clinical investigations of psychedelic drugs, providing the agency's most detailed roadmap to date for psychedelic drug development programs. The guidance applies to clinical trials conducted under an investigational new drug application and reiterates that psychedelic programs must meet the same evidentiary standards as other drug programs. It does not change the legal status of psychedelic drugs, which the FDA defines as classic psychedelics such as psilocybin and LSD, as well as entactogens such as MDMA.

The guidance follows a draft issued in June 2023 and outlines considerations for chemistry, manufacturing and controls; nonclinical programs; clinical pharmacology, including the impact of high-fat meals and the potential for cardiac valve stiffening from long-term exposure to drugs with 5-HT2B agonism; abuse potential; and trial design. The FDA also scheduled a September 14 public hearing on the potential future therapeutic use of psychedelic drugs in supervised and supportive settings, and the Health Resources and Services Administration issued a request for information on training and care delivery models for potential future FDA-approved psychedelic drugs.

The final guidance arrives against the backdrop of an April 18 executive order directing multiple federal agencies to accelerate research and expand access to psychedelic drugs. The FDA granted breakthrough therapy designation to several psilocybin-based treatments in 2018 and 2019, and more than 120 clinical trials are now underway. The New England Journal of Medicine recently published results of the largest-ever clinical trial for psilocybin-based medicine, reporting that a single dose led to significant improvement in depressive symptoms in three weeks. Nearly a quarter of U.S. adults suffer from a mental illness, and depression affects one in five adults; at least 30% of patients with major depressive disorder do not respond to multiple courses of antidepressant treatment.

In parallel federal actions, the Department of Health and Human Services and the Department of Veterans Affairs entered into a five-year memorandum of understanding to strengthen collaboration on research, clinical development, and deployment to veterans of potential future rapid-acting psychedelic drug products if approved by the FDA. The FDA and VA also entered into a second MOU covering information-sharing and scientific collaboration. The National Institute on Drug Abuse has awarded funding to a multi-phase ibogaine research project working toward investigational new drug clearance, and has also revived and validated data from earlier ibogaine studies. The Advanced Research Projects Agency for Health has invited bids for funding to study ibogaine for opioid use disorder.

Several states have moved to support psychedelic research. Texas committed $50 million in state funds to support FDA-directed clinical trials of ibogaine, a compound being studied for opioid use disorder, PTSD, and traumatic brain injury. Louisiana enacted Senate Bill 43, now Act 956, establishing a Psychedelic-Assisted Therapy Initiative within the Department of Health's Office of Behavioral Health to support research using psilocybin, ibogaine, and MDMA; the program is to be funded in significant part by the state's $600 million opioid settlement fund. Mississippi has advanced legislation authorizing ibogaine clinical trials. Colorado passed a bill creating an ibogaine research pilot program under the Behavioral Health Administration, which may approve up to five pilot sites; the program requires compliance with FDA's investigational new drug process and includes a benefit-sharing plan with Indigenous communities. Georgia signed a law directing the Georgia Composite Medical Board to issue rules for clinics administering psychedelic-assisted therapies by December 31, 2026, with licensure required by July 1, 2027. In Michigan, legislation would create an ibogaine grant program with a proposed $50 million appropriation from the state's opioid healing and recovery fund.

In the private sector, Eli Lilly announced the acquisition of AtaiBeckley for $2.8 billion upfront, with up to $1 billion more in contingent value rights tied to FDA approval and DEA rescheduling of BPL-003, a synthetic 5-MeO-DMT delivered intranasally that has Breakthrough Therapy Designation and is in Phase 3 for treatment-resistant depression. Compass Pathways has completed its pivotal psilocybin program and is targeting an FDA filing for COMP360 in the fourth quarter of this year. Definium reported positive Phase 3 results for a novel LSD formulation in major depressive disorder. AbbVie acquired Gilgamesh's bretisilocin for up to $1.2 billion, Otsuka acquired Transcend Therapeutics for up to $1.2 billion, and Reunion Neuroscience earned Breakthrough Therapy Designation for postpartum depression.

According to experts, ibogaine carries heavy cardiovascular risks and requires attentive medical monitoring in a clinical setting; early observational studies are promising, but no randomized controlled trials have been conducted. The FDA has allowed an early phase clinical study of noribogaine hydrochloride, a derivative of ibogaine, as a potential treatment for alcohol use disorder — the first time the agency has permitted a clinical study of an ibogaine derivative.