FDA Issues Guidance for Clinical Trials that Research Psychedelics

Last month, the U.S. Food and Drug Administration published new draft guidance for researchers investigating the use of psychedelic drugs for potential treatment of medical conditions, including psychiatric or substance use disorders. The guidance outlines best practices in clinical trial design for psychedelic drugs — including psilocybin, lysergic acid diethylamide (LSD), and methylenedioxymethamphetamine (MDMA).

The use of psychedelics in clinical settings has gained increasing attention over the last five years. The research community has come a long way since the days of Richard Alpert, also known as Ram Dass, and his research on LSD at Harvard University in the 1960s. Fifty years later, however, it is still considered an emerging area of clinical drug development.

There is growing evidence that these substances can help alleviate symptoms of PTSD, depression, substance-use disorders, and anxiety. Research studies are underway to examine the impact of psychedelics for treatments of neurological conditions, as well, such as migraines.

Tiffany Farchione, M.D., director of the Division of Psychiatry in the FDA’s Center for Drug Evaluation and Research, said, “By publishing this draft guidance, the FDA hopes to outline the challenges inherent in designing psychedelic drug development programs and provide information on how to address these challenges. The goal is to help researchers design studies that will yield interpretable results that will be capable of supporting future drug applications.”

Because of the potential for abuse of these drugs, the agency stresses the need for careful consideration and putting sufficient safety measures in place for preventing misuse throughout clinical development. The draft guidance also addresses the role of psychotherapy in psychedelic drug development, considerations for safety monitoring and the importance of characterizing dose-response and the durability of any treatment effect.

The guidance does not provide specific recommendations for study design, only fundamental considerations for sponsors, including academic sponsor-investigators. The guidance reflects some of the unique characteristics of research on these substances.

Nonclinical Data

Submission of the IND without previous animal toxicology studies may be appropriate when there is extensive information on human exposure from other clinical trials. The agency does not clarify what would be considered “extensive.” Psychedelic drugs without a history of adequate clinical exposure should not be tested in humans until safety has been established in nonclinical studies.


Some studies have suggested statistically significant results after a single dose, while other research has used intermittent dose treatment models. Due to the chronic nature of many of the mental health indications being evaluated, sponsors must evaluate safety and durability in determining dosing paradigms.

Clinical Pharmacology

The guidance recommends including in the protocol the evaluation of the impact of diet and drug-drug interactions. Because of the known cardiac risks associated with the use of psychedelics, researchers must closely monitor pharmacodynamic interactions with selective serotonin reuptake inhibitors (SSRIs) and other antidepressants. Sponsors should also outline plans to monitor patients for valve and pulmonary artery functions.

Risk of Abuse

The assessment of the abuse potential of a drug is generally part of its safety evaluation. Because psychedelics act on the central nervous system and can produce mood and cognitive changes, including hallucinations, sponsors must evaluate the potential for drug abuse.

Because many of the drugs are Schedule I substances, the IND must comply with the applicable Drug Enforcement Administration (DEA) regulations for research, manufacturing, importation/exportation, handling, and storage requirements.

Use of Placebos

The guidance acknowledges the challenge of designing an adequate and well-controlled study, considering the intense perceptual effects of active ingredients versus placebo. The agency offers several recommendations to address this, including the use of video for observation by ‘raters’ who are blinded to treatment allocation.

Adjunct Psychotherapy

Many of the psychedelic drug development programs involve administering the investigational drug and then engaging in psychological support or psychotherapy either while the subject is experiencing the acute effects of the drug or in a subsequent session. This additional variable both complicates the assessment of effectiveness and presents a challenge for any future product labeling.

Sponsors should justify the inclusion of a psychotherapy component and describe any trial design elements intended to reduce potential bias or to quantify the contribution of psychotherapy to the overall treatment effect.

Monitoring Patients

One aspect that has garnered pharmaceutical trade media attention is the recommendation that subjects of psychedelic clinical trials should be observed by two monitors for the full duration of the treatment, which can last up to 12 hours.

The lead monitor should be healthcare providers with graduate-level professional training and clinical experience in psychotherapy, licensed to practice independently. This includes a clinical or counseling psychologist (PhD/PsyD), a psychiatrist or other physician (MD/DO), a master of social work (MSW), or a psychiatric nurse practitioner.

Besides the usual safety monitoring of patients enrolled in the studies, the FDA says it will also consider public health concerns in evaluating risk-benefits for the use of psychedelics. Public health risks include nonmedical use, substance use disorder, accidental exposure, and overdose for patients and nonpatients.

Interest in the therapeutic potential of psychedelic drugs has been increasing among the medical community as well as the general public. While psychedelic drug development programs are subject to the same regulations and the same evidentiary standards for approval as other drug development programs, clinical studies to evaluate the safety and effectiveness of these compounds present a number of unique challenges.

The FDA is accepting comments until August 25, 2023.