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

This article (2021) explores the methodological challenges faced in psychedelic clinical trials and recommendations for future research. Several sources of potential bias exist; difficulties blinding, inflated expectations as well as placebo and nocebo effects, amongst others. Recommendations to avoid these biases include; 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.

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.”

Authors: Jacob Aday, Boris D. Heifets, Steven D. Pratscher, Ellen Bradley, Raymond Rosen & Joshua D. Woolley

Notes

The therapeutic potential of psychedelics is garnering significant attention from academics, elected officials and the public alike. Thanks to solid clinical research, the narrative surrounding these psychoactive substances is changing for the better. The medicalization of psychedelics like psilocybin, MDMA and ketamine is slowly becoming a reality. If therapeutic models using these substances are truly going mainstream, they must withstand the scrutiny of the clinical trial process and address the inherent methodological issues which often occur conducting such trials.

For example, the proliferation of news articles regarding the promise of psychedelic-assisted therapies is paradoxically leading to expectancy effects among clinical trial participants i.e overwhelmingly positive news articles are leading people to believe that psychedelic-assisted therapy will ‘cure’ any mental health problem they may be experiencing. In reality, psychedelics will not work for everyone and are by no means a silver bullet aimed at global mental health.

A recent preprint article explores some of the major methodological issues faced when conducting clinical trials with psychedelics. As well as the issues surrounding expectancy effects, the researchers identified several unique sources of potential bias when conducting such trials:

• 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.
• Participant unmasking and treatment expectations can interact in such a way that makes psychedelic therapy highly susceptible to large placebo and nocebo effects.

The researchers in the present study recommend a number of design elements for future research in order to minimize the risk of bias:

• Study development and design; a 3-arm study is best to test for substance efficacy (psychedelic vs. active placebo vs. inactive placebo) & a single administration session of a psychedelic is recommended.
• Participant recruitment and selection; recruit psychedelic-naïve participants in order to prioritize effective condition masking.
• Expectation bias; investigators should emphasize the uncertainty regarding treatment efficacy & use established measures of expectancy e.g the Stanford Expectations of Treatment Scale.
• It is critically important to distinguish “incomplete exposure” from “deception.”
• Anticipating the placebo effect, measuring the contribution of expectancies, assessing the effectiveness of masking, and systematically reporting these data will set standards and lead to iterative improvements in trial design.

The present study seeks to improve the clinical trial process involving psychedelics. Legitimatizing psychedelic research is no mean feat. However, addressing the issues identified in this study and taking the authors recommendations into account will help to bring psychedelic-assisted therapies to the masses.