Altered States, Standard Rules: FDA Finalizes Guidance on Psychedelic Drug Clinical Trials

The final guidance follows the publication of a draft guidance issued in June 2023 and provides the FDA’s most detailed roadmap to date for psychedelic drug development programs.

While the guidance does not change the legal status of psychedelic drugs — a term that the FDA uses as shorthand for “classic psychedelics,” generally understood as 5‑HT2A receptor agonists such as psilocybin and lysergic acid diethylamide (LSD), as well as entactogens or empathogens such as 3,4-methylenedioxymethamphetamine (MDMA) — it nonetheless provides general considerations for sponsors engaged in evaluating the therapeutic potential of such products. 

For companies operating in the psychedelic drug sector, the message is clear: Federal policy momentum is increasing, but the FDA will apply ordinary drug approval standards while scrutinizing the features that make psychedelic therapies different, including functional unblinding, psychological support, acute vulnerability during dosing, controlled substance compliance, durability of effect, and postmarketing risk management.

Broader Federal Policy Shift

The final guidance arrives against the backdrop of the April 18 executive order (EO) on serious mental illness and psychedelic-assisted therapies, which we discussed in a prior alert. As we explained previously, the EO directed multiple federal agencies to accelerate research and expand access to psychedelic drugs as potential treatments for serious mental health conditions but did not reschedule any psychedelic substance or authorize commercial use. The new FDA guidance now supplies a clinical development framework that companies will need to navigate if they hope to convert that policy momentum into an approved drug product. 

Notably, the FDA has 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 (HRSA) issued a related request for information on training and care delivery models for potential future FDA-approved psychedelic drugs in ambulatory clinical settings. These actions underscore that the federal government is not only concerned with psychedelic drug efficacy and safety, but also contemplating practical implementation questions involving workforce capacity, clinic infrastructure, monitoring, storage, security, access, and real-world safety data.

What the Guidance Covers

The FDA guidance applies to clinical trials conducted under an investigational new drug application — including trials that are not intended to support marketing applications — and provides general considerations for sponsors developing psychedelic drugs for medical conditions such as psychiatric disorders and substance-use disorders.

• Evidentiary Standards: While the FDA acknowledges clinical studies of psychedelic drugs may present unique challenges, the agency nonetheless emphasized that psychedelic programs must meet the same evidentiary standards as other drug programs.

• Chemistry, Manufacturing, and Controls (CMC): As with all clinical trials, sponsors must provide sufficient information to ensure the identity, quality, purity, and strength of the investigational drug substance and drug product. The FDA additionally notes circumstances where the investigational product may be considered a botanical and emphasizes that all drugs must be manufactured in compliance with applicable current good manufacturing practice requirements.

• Nonclinical Programs: Nonclinical programs for psychedelic drugs should follow recommendations outlined in applicable International Conference on Harmonization guidance. The FDA provides examples of certain considerations that may be unique to psychedelic drugs, including scenarios where the substance lacks a history of adequate clinical exposure, when repeat dosing is expected, and when the drug has serotonin (5-HT) activity. 

• Clinical Pharmacology: Sponsors should ensure that they have adequately characterized the pharmacokinetics or pharmacodynamics of psychedelic drugs both in vitro and in vivo. The FDA provides examples of specific clinical pharmacology aspects that sponsors should consider, including the impact of high-fat meals, the potential for cardiac valve stiffening induced by long-term exposure to drugs that have 5‑HT2B agonism, and the extent to which potential interactions with other drug products may affect the interpretability of efficacy data and subject safety.

• Abuse Potential: While assessing abuse potential is generally conducted as part of the safety evaluation for drug products, the FDA provides specific considerations that may be uniquely applicable to the development of psychedelic drugs. 

• Trial Design: The FDA outlines numerous considerations for the design of clinical trials evaluating psychedelic drugs, including functional unblinding, approaches to minimize bias, psychological support for study subjects, durability of response for the drug product and the safety and efficacy of repeat dosing, and clinical trial population.

• Safety Considerations: Noting that study subjects receiving treatment with psychedelic drugs may remain in a vulnerable state for several hours or longer, the FDA provides an overview of the safety monitoring it expects sponsors to utilize for clinical trials, including observation by monitors during treatment sessions, on-call physicians, appropriate informed consent, documenting all central nervous system effects, addressing how adverse events and serious risks will be mitigated during the clinical trial and whether similar strategies should be utilized postmarketing, and the potential use of risk mitigation strategies to mitigate the risk of nonmedical use, accidental exposure, and overdose. 

Implications for Industry

While the FDA shied away from providing specific recommendations on clinical trial design, noting that this was an emerging area with limited examples of drug development programs that may support approval for a psychedelic drug, the foundational considerations outlined in the guidance should nonetheless improve regulatory predictability for the development of such programs. Indeed, the FDA has made clear that companies operating in this space will need development plans that connect CMC controls, nonclinical safety, clinical pharmacology, abuse-potential assessment, psychotherapy or support models, bias mitigation, and long-term safety follow-up. 

At bottom, however, commercialization remains uncertain even for products that generate positive clinical data. While there appears to be significant federal and market enthusiasm for this area, companies still must solve the scientific, clinical, controlled-substance, delivery-model, and market access challenges that will determine whether psychedelic therapies can move from policy momentum to marketable commercial products.

ArentFox Schiff will continue to monitor developments related to the federal regulatory landscape for psychedelic therapies. As this area develops further, companies that operate in the pharmaceutical, health care, and life sciences sectors should continue to assess how these policy changes may affect their product pipelines, clinical trial strategies, and compliance planning.