The DOI matches its Crossref record; 174 of the 174 references it cites were found in a registry or an index.
Great Expectations: recommendations for improving the methodological rigor of psychedelic clinical trials
Open accessPublished version of a preprint
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.
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“leading to a general call for more effective active placebo conditions and a systematic reporting of blinding efficacy [32–34].”
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“systematic unblinding has been raised as a major threat to the validity of extant findings from ‘double blind’ PAT trials due to high expectancy, presumably resulting in large placebo and nocebo effects in the experimental group and the control group, respectively [32–34].”
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“blinding efficacy (participants, therapists) and expectancy (participants) will be assessed and reported, as recommended in the literature [32–34].”
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“proposing an active placebo condition aimed at maintaining blinding, while systematically assessing and reporting blinding efficacy in participants and therapists.”
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Cites
1 retracted
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RetractedThe Cochrane Collaboration's tool for assessing risk of bias in randomised trials
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Psychosomatic medicine in Germany: more timely than ever
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Psychometric properties of the credibility/expectancy questionnaire
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Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial
Raison, C. L., Sanacora, G., Woolley, J., Heinzerling, K., Dunlop, B. W., Brown, R. T., Kakar, R., Hassman, M., Trivedi, R. P., Robison, R., et al. (2023) · JAMA · doi:10.1001/jama.2023.14530 · Cited by 545
Self-citationPharmacological, neural, and psychological mechanisms underlying psychedelics: A critical review
van Elk, M., & Yaden, D. B. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104793 · Cited by 221
Breeksema, J. J., Kuin, B. W., Kamphuis, J., van den Brink, W., Vermetten, E., & Schoevers, R. A. (2022) · Journal of Psychopharmacology · doi:10.1177/02698811221116926 · Cited by 178
Sloshower, J., Skosnik, P. D., Safi-Aghdam, H., Pathania, S., Syed, S., Pittman, B., & D’Souza, D. C. (2023) · Journal of Psychopharmacology · doi:10.1177/02698811231154852 · Cited by 165
Kumarasamy, R. V., Natarajan, P. M., Umapathy, V. R., Roy, J. R., Mironescu, M., & Palanisamy, C. P. (2024) · Frontiers in Nanotechnology · doi:10.3389/fnano.2024.1479993 · Cited by 154
Metadata
- Authors
- Aday, J. S., Heifets, B. D., Pratscher, S. D., Bradley, E., Rosen, R., & Woolley, J. D.
- Affiliations
- San Francisco VA Medical Center (US)
- Stanford Medicine (US)
- University of Florida Health (US)
- Corresponding author
- Aday, Jacob S.
- Heifets, Boris D.
- Pratscher, Steven D.
- Bradley, Ellen
- Rosen, Raymond
- Woolley, Joshua D.
- Venue
- Psychopharmacology
- Published
- 2022-04-01
- Volume
- 239
- Issue
- 6
- Pages
- 1989-2010
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- PMC
- PMC10184717
- OpenAlex
- W4226207502
- Cited by
- 237
- References
- 174
- Citations by year
- 2026: 49 · 2025: 59 · 2024: 64 · 2023: 47 · 2022: 18
- FWCI
- 7.84
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- public-domain
- www.springer.com/tdm (tdm)
- www.springer.com/tdm (vor)
- Locations
- Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- PsyArXiv (OSF Preprints) (submittedVersion)
- PsyArXiv (OSF Preprints) (submittedVersion, public-domain)
- Funders
- U.S. Department of Veterans Affairs (IK4 CX002090)
- University of California, San Francisco
- National Institute on Aging (T32AG049673)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Keywords
- placebo effect, nocebo effect, expectancy effects, active placebo, treatment expectations, bias mitigation, research design, participant recruitment
- MeSH terms
- Hallucinogens, Humans, Motivation, Psychotherapy, Research Design
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