What the FDA’s groundbreaking guidance really means for psychedelic therapy clinical trials

Market Access

Mental health care is fraught with treatment-resistant conditions and ineffective or side-effect-ridden therapies.1 Psychedelic therapy, once relegated to the fringes of medical exploration, holds immense promise for addressing the limitations of existing treatments.

Recent research has revealed the remarkable capacity of a single psychedelic treatment to alleviate the burden of anxiety, depression, post-traumatic stress disorder (PTSD), and substance use disorder for months or even years when administered alongside meticulous screening and professional support.2

For example, the non-profit Multidisciplinary Association for Psychedelic Studies (MAPS) has had great success in its two Phase III MDMA-assisted therapy studies for adults with post-traumatic stress disorder (PTSD). They found that participants who underwent therapy with MDMA exhibited substantial improvements compared to those who received a placebo. This progress was not confined to the immediate aftermath of treatment; it extended to a long-term follow-up study, where participants reported enduring benefits even six months after their last therapy session.3

Nurturing groundbreaking treatments

In a historic move, the US Food and Drug Administration (FDA) issued a draft guidance for sponsors engaged in the development of psychedelic drugs for psychiatric disorders, substance use disorders, and various medical conditions.4 The FDA's interpretation of "psychedelics" in this guidance is limited to psilocybin, lysergic acid diethylamide (LSD), and methylenedioxymethamphetamine (MDMA).4 This guidance, aptly titled "Psychedelic Drugs: Considerations for Clinical Investigations Guidance for Industry", marks a pivotal moment in the journey of psychedelic therapy. It signifies the FDA's recognition of the psychedelics’ therapeutic potential and underscores the agency's willingness to collaborate with sponsors to nurture these groundbreaking treatments.

The guidance offers recommendations categorised into five main disciplines: chemistry, manufacturing, and controls (CMC); non-clinical; clinical pharmacology; abuse potential assessment; and clinical. These recommendations, however, stand as foundational concepts, rather than step-by-step instructions, leaving many stakeholders grappling with the practical implementation of these groundbreaking guidelines.

Elligo Health Research has its own team of psychedelic therapy experts and network of psychedelic research sites designed to facilitate trials. Based on our experience and understanding of psychedelic therapy, here is our perspective on what the FDA guidance really means for psychedelic therapy clinical trials’ day-to-day work in trial conduct, data collection, and patient safety.

Trial conduct

Perhaps the guidance’s main recommendation for trial conduct is the inclusion of psychological support in the form of psychotherapy.5

On-site psychotherapists should be integral parts of the psychedelic therapy journey, as they can guide patients through their complex, and oftentimes overwhelming, treatment. Also, by helping patients make sense of their psychedelic experience, psychotherapists ensure patients can integrate what they learned into their daily lives to maximise the therapy’s full effects and benefits.

However, the guidance notes that the precise contribution of the psychotherapy component to the observed efficacy of psychedelic treatment remains unclear.5 Therefore, sponsors should meticulously plan and articulate their rationale for including a psychotherapy component in their trial. Sponsors should also explain any trial design elements intended to mitigate potential bias or quantify the specific contribution of psychotherapy to the overall treatment effect.

The guidance goes a step further, advocating for a study design that bifurcates patients into two distinct groups: one receiving therapy alone and the other receiving the psychedelic drug.5 This separation ensures a clear demarcation of the therapeutic elements and allows for a more comprehensive understanding of each component’s impact. Additionally, the guidance recommends that the therapist overseeing a treatment session should not partake in post-session psychotherapy to prevent any potential bias in successive therapy sessions.5

Data collection

In the pursuit of validating the efficacy of psychedelic drugs within the confines of compliant clinical trials, the FDA’s guidance acknowledges both the universality of the substantial evidence standard and the unique characteristics of psychedelics that must be considered when designing these trials.5

Take, for example, placebos. Placebos are considered the gold standard of clinical trial controls. But, as the FDA notes in the guidance, the use of a traditional placebo could be challenging when evaluating efficacy in psychedelic research.5 In psychedelic trials, patients who are administered the substance will experience, as the FDA writes, “intense perceptual disturbances.” Because patients receiving a placebo won’t, they will be able to infer that they are in the control group, thereby negating the point of using a placebo. To mitigate this challenge, the FDA suggests the use of psychedelic microdoses or other psychoactive drugs to mimic the drug’s effects for the control group.5

The guidance also covers a few other considerations for establishing effectiveness by the substantial evidence standard, including:

  • The deployment of a blinding questionnaire for both subjects and investigators/raters, aimed at assessing the impact of functional unblinding and minimising potential bias
  • The management of trial-related adverse events and significant hazards, while also considering the feasibility of implementing analogous strategies in the post-marketing phase

Subject safety

The guidance addresses two main concerns regarding subject safety: abuse potential and the vulnerability of patients after they receive the investigational new drug (IND).

Many psychedelic drugs that are or might be studied in clinical trials are classified as Schedule I controlled substances, signifying their potential for abuse. As such, the FDA guidance suggests that every new drug application submission include an abuse potential assessment. Furthermore, sponsors are strongly encouraged to engage in early discussions with the FDA regarding their plans for these assessments. The guidance offers a pathway for sponsors to establish the abuse potential of their INDs by suggesting the use of “scientifically valid, published investigations” as supporting evidence. The FDA also directs sponsors to consult 2017’s “Assessment of Abuse Potential of Drugs” guidance for more comprehensive insights.5

Psychedelic therapy can leave individuals in a physically and mentally susceptible state for an extended duration, necessitating meticulous safety measures both during and after treatment. To this end, the guidance emphasises two strategies for ensuring subject safety before, during, and after the treatment: the presence of two monitors and heightened informed consent. The dual-monitor system ensures continuous oversight and support during the therapy sessions, as each monitor plays a distinct role. One, a fully licensed provider with clinical psychotherapy experience, serves as the lead monitor, while the other, who has at least one year of clinical experience within a licensed mental healthcare setting, assumes the role of assistant monitor. The guidance further protects subject safety by stipulating the need for comprehensive disclosure. Patients must be made fully aware that their psychedelic experience may entail changes in perception, cognition, and judgment, potentially persisting for many hours.5 This transparency empowers individuals with the knowledge needed to make informed decisions and reinforces their autonomy within the therapeutic process.

Where do we go from here?

While the guidance doesn’t provide any radical recommendations, it does represent a promising shift in attitudes toward psychedelic therapy that is sure to facilitate the expansion of this exciting field. By encouraging careful consideration of the potential for abuse, the implementation of robust safety measures throughout the clinical development process, and a focus on rigorous data collection, the guidance bestows credibility upon psychedelic therapy that will lead to an increase in interest and funding.

This support will be instrumental in fostering the field's expansion, driving further research, and ultimately delivering on the promise of creating a new world of mental healthcare that more effectively meets the complex needs of patients.


  1. Howes O., et al. Treatment resistance in psychiatry: state of the art and new directions. Mol Psychiatry. Published 2021 July 13.
  2. REPS. CORREA, BERGMAN RE-LAUNCH BIPARTISAN CAUCUS TO EXPLORE PSYCHEDELIC RESEARCH FOR MENTAL HEALTH. Representative Lou Correa for California’s 46th District. Published 2023 March 2.
  3. MAPS PBC Announces Positive Topline Results from Long-Term Observational Follow-Up Study on MDMA-Assisted Therapy for Treatment of PTSD. MAPS Public Benefit Corporation. Published 2023 April 5.
  4. FDA Issues First Draft Guidance on Clinical Trials with Psychedelic Drugs. U.S. Food & Drug Administration. Published 2023 June 23.
  5. Psychedelic Drugs: Considerations for Clinical Investigations Guidance for Industry. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Published June 2023.
Angela Terhune-Hargrove
profile mask
Angela Terhune-Hargrove