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

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.

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

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

Fig. 3

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