Great Expectations: recommendations for improving the methodological rigor of psychedelic clinical trials - PubMed (original) (raw)

Review

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

Jacob S Aday et al. Psychopharmacology (Berl). 2022 Jun.

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: 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.

Conclusion: 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.

Keywords: Clinical trials; Expectancies; Masking; Placebo effect; Psychedelic therapy; Psychedelics; Recommendations; Treatment expectations.

© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest 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.

Figures

Fig. 1

Fig. 1

Treatment-nonspecific effects in clinical trials. (a) Hypothetical results of a clinical trial to delineate the sources of treatment-specific and treatment-nonspecific effects. Including placebo and no treatment control conditions allows trialists to identify treatment-specific effects (figure inspired by Wampold et al. 2016). (b) In a clear illustration of expectancy effects, Bingel et al. (2011) measured participants’ pain intensities before (i.e., Baseline) and after receiving remifentanil while manipulating participant expectancies across three groups (e.g., No expectancy, Positive expectancy, or Negative expectancy). They found that priming positive treatment expectancy doubled the analgesic effect of remifentanil when compared to no expectancy. In contrast, inducing negative treatment expectancies eliminated the analgesic effect. (c) Gold et al. (2017) demonstrated that treatment effect sizes vary as a function of the type control group utilized

Fig. 2

Fig. 2

Stages of psychedelic therapy. Psychedelic therapy typically involves preparation, dosing, and integration sessions

Fig. 3

Fig. 3

Recommendations for improving methodology in psychedelic trials. Overview of our recommendations for improving experimental methodology in future clinical trials with psychedelics

Similar articles

Cited by

References

    1. Aday JS (2021) Delineating the association between psychedelic drug use and facets of gratitude, aesthetic experience, and relationships with nature. Dissertation, Central Michigan University
    1. Aday JS, Davis AK, Mitzkovitz CM, Bloesch EK, Davoli CC (2021) Predicting reactions to psychedelic drugs: a systematic review of states and traits related to acute drug effects. ACS Pharm Trans Sci 4:424–435. 10.1021/acsptsci.1c00014 - DOI - PMC - PubMed
    1. Aday JS, Bloesch EK, Davoli CC (2020a) 2019: A year of expansion in psychedelic research, industry, and deregulation. Drug Sci Pol Law 6. 10.1177/2050324520974484 - DOI
    1. Aday JS, Mitzkovitz CM, Bloesch EK, Davoli CC, Davis AK (2020b) Long-term effects of psychedelic drugs: a systematic review. Neurosci Biobehav Rev 113:179–189. 10.1016/j.neubiorev.2020.03.017 - DOI - PubMed
    1. Atlas LY (2021) A social affective neuroscience lens on placebo analgesia. Trends Cogn Sci. 10.1016/j.tics.2021.07.016 - DOI - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources