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

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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.


In this article, we review the many methodological challenges of conducting psychedelic clinical trials and provide recommendations for improving the rigor of future research.


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 are discussed in the context of 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.


Incorporating the recommended design elements is intended to reduce the risk of bias in psychedelic clinical trials and thereby increases the ability to discern treatment-specific effects of psychedelic therapy.

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  1. In recent years, the term “masking” has been used in place of “blinding”; here, we have opted to use the term “masking” but consider the terms synonymous

  2. Notably, there is significant debate about the proper terminology for the people who provide the preparation and integration and who monitor participants during the dosing session. “Guide,” “sitter,” “facilitator,” “therapist,” “monitor,” and other terms have been proposed and have their advocates and detractors. The intensity of these debates highlights the truth of the old joke that “Scientists would rather use each other’s toothbrushes than use each other’s terminology.” We use the term “facilitator” throughout this manuscript without taking a strong stance on which term is the most correct

  3. These strategies are complementary to existing mechanisms for patients to try unapproved therapies, instituted as the Right to Try Act in the USA, as well as expanded access clinical programs (Holbein et al. 2015)


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We would like to thank members of the Translational Psychedelic Research (TrPR) Program at the University of California, San Francisco (UCSF) for providing comments on this manuscript.

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Correspondence to Jacob S. Aday.

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JDW was a paid consultant for Silo Pharma and Filament Health last in June 2021. BDH is a paid consultant for Clairvoyant Therapeutics. None of the other co-authors have any conflicts of interest to declare.

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Boris D. Heifets is co-first author

This article belongs to a Special Issue on Psychopharmacology on Psychedelic Drugs

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Aday, J.S., Heifets, B.D., Pratscher, S.D. et al. Great Expectations: recommendations for improving the methodological rigor of psychedelic clinical trials. Psychopharmacology 239, 1989–2010 (2022).

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