Great Expectations: Recommendations for improving the methodological rigor of psychedelic clinical trials

Clinical trials of psychedelic therapy face unique methodological challenges that threaten the interpretability of results. The intense subjective effects of high-dose psychedelics make it difficult to mask participants to their treatment condition, and widespread positive media coverage inflates participants' expectations for benefit. Participant unmasking and treatment expectations can interact, making psychedelic therapy highly susceptible to large placebo and nocebo effects. Recommendations to improve rigor include careful study development, participant recruitment and selection, incomplete disclosure of the study design, choice of active placebo condition, and measurement of participant expectations and masking efficacy. Incorporating these design elements is intended to reduce bias and increase the ability to discern treatment-specific effects.

Study at a glance

Abstract

Rationale: Psychedelic research continues to garner significant public and scientific interest with a growing number of clinical studies examining a wide range of conditions and disorders. However, expectancy effects and effective condition masking have been raised as critical limitations to the interpretability of the research.Objective: In this article, we review the many methodological challenges of conducting psychedelic clinical trials and provide recommendations for improving the rigor of future research.Results: We found that although some challenges are shared with psychotherapy and pharmacology trials more broadly, psychedelic clinical trials have to contend with several unique sources of potential bias. The subjective effects of a high-dose psychedelic are often so pronounced that it is difficult to mask participants to their treatment condition; the significant hype from positive media coverage on the clinical potential of psychedelics influences participants’ expectations for treatment benefit; and participant unmasking and treatment expectations can interact in such a way that makes psychedelic therapy highly susceptible to large placebo and nocebo effects. Specific recommendations to increase the success of masking procedures and reduce the influence of participant expectancies concern study development, participant recruitment and selection, incomplete disclosure of the study design, choice of active placebo condition, as well as the measurement of participant expectations and masking efficacy.Conclusion: Incorporating these design elements is intended to reduce the risk of bias in psychedelic clinical trials and thereby increase the ability to discern treatment-specific effects of psychedelic therapy