FDA Issues First Draft Guidance on Clinical Trials with Psychedelic Drugs

The U.S. Food and Drug Administration (FDA) issued a new guidance to provide general considerations to sponsors developing psychedelic drugs. This is the first kind of FDA guidance that presents considerations for designing clinical trials for these substances. According to the agency, there has been growing interest in the therapeutic potential of psychedelic drugs such as the use for depression, post-traumatic stress disorder, substance use disorders and other conditions. However, "designing clinical studies to evaluate the safety and effectiveness of these substances presents a number of unique challenges that require careful consideration", the agency says.

Within the draft guidance, the term psychedelics refers to "classic psychedelics", typically understood to be drugs such as psilocybin and lysergic acid diethylamide (LSD) that act on the brain's serotonin system (5-HT2 agonists), as well as "entactogens" or "empathogens" such as methylenedioxymethamphetamine (MDMA). Comments can be submitted to the FDA by 25 August 2023.

Safety Measures

The draft guidance describes basic considerations including trial conduct, data collection, patient safety and new drug application requirements. Psychedelic drugs may produce psychoactive effects such as mood and cognitive changes, as well as hallucinations. As a result, there is the potential for drug abuse, which is a drug safety issue that requires sufficient safety measures in place for preventing misuse. For substances that are currently Schedule I controlled (i.e. narcotics), activities also must comply with applicable Drug Enforcement Administration (DEA) requirements. The regulations for establishing effectiveness of psychedelic drugs are in principle the same as for all other drugs. However, "there are unique factors investigators may need to consider when designing their clinical trials if those trials are to be considered adequate and well-controlled", the agency states. 

Chemistry, Manufacturing and Controls (CMCs)

  • For all phases of clinical trials sponsors must provide sufficient CMC information to ensure proper identification, quality, purity, and strength of the investigational drug substance and the IMP (investigational medicinal product).
  • If using plant material, algae, macroscopic fungi, or a combination of these, the IMP may be considered a botanical (see FDA´s guidance for industry on Botanical Drug Development from December 2016).
  • IMPs that are genetically modified; produced by fermentation of yeast, bacteria, or plant cells; or highly purified substances from naturally occurring sources are not considered botanicals.
  • Medicinal Products must be manufactured in compliance with current Good Manufacturing Practice (cGMP). However, for most IMPs manufactured in support of phase 1 studies, manufacturers should follow the recommendations in FDA´s guidance for industry, cGMP for Phase 1 Investigational Drugs (July 2008). Certain IMPs manufactured in support of phase 1 studies and IMPs manufactured in support of phase 2 studies and beyond must comply with applicable cGMP regulations (studies in which patients are enrolled to measure the effectiveness of a drug for a particular indication are generally considered phase 2 studies). Investigators and sponsors should refer to FDA´s guidance for industry INDs for Phase 2 and 3 Studies; Chemistry, Manufacturing and Controls Information (May 2003) and the guidance for industry Content and Format of INDs for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products (October 2000).

More information is available in FDA´s draft guidance Psychedelic Drugs: Considerations for Clinical Investigations.

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