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In the new era of psychedelic assisted therapy: A systematic review of study methodology in randomized controlled trials

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Abstract

Recent years have seen a resurgence in randomized, placebo controlled trials (RCTs) utilizing non-classical psychedelics (e.g. 3,4-methyl enedioxy methamphetamine [MDMA]), and classical psychedelics (e.g. psilocybin, lysergic acid diethylamide [LSD], and N,N-dimethyltryptamine [DMT/ayahuasca]) in conjunction with assisted therapy (AT) for psychiatric disorders. A notable methodological challenge in psychedelic AT, however, is the complexity of blinding procedures. The lack of efficacious blinding can introduce considerable response bias, reduce internal validity, and compromise participant retention. This systematic review examines design and blinding techniques in RCTs utilizing psychedelics and placebo for the treatment of psychiatric disorders. The aim of this work is to identify factors that may inform future RTC design for conducting psychedelics research. We conducted a systematic review of PubMed, MEDLINE, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), Psycinfo, Embase, and Web of Science Core Collection to examine: (1) placebo selection, (2) study design, and (3) integrity of blinding measures. Sixteen publications were identified as meeting the criteria for a systematic review. Our findings suggest that traditional placebo administration is insufficient to control for expectancy confounds. Consequently, experimental methodology that limits personnel unblinding and the use of an active placebo are important considerations when designing prospective clinical studies involving psychedelics.

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Funding

PSS was supported by the Brown University UTRA and the ROYCE Fellowship. DEC was supported by the National Institute on Alcohol Abuse and Alcoholism (R01 AA027760 and Research Supplements to Promote Diversity in Health-Related Research). CLH-K is supported by the National Institute on Alcohol Abuse and Alcoholism (R01 AA026589; R01 AA027760; R21 AA027614). CLH-K, EE and CC are also supported by the National Institute of General Medical Sciences (NIGMS), Center of Biomedical Research Excellence (COBRE, P20 GM130414) and the Brown University Office of the Vice President for Research (OVPR).

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Author notes

  1. Paul S. Soliman and Dallece E. Curley contributed equally.

Authors and Affiliations

  1. Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA

    Paul S. Soliman, Dallece E. Curley, Christy Capone, Erica Eaton & Carolina L. Haass-Koffler

  2. Department of Neuroscience, Brown University, Providence, RI, USA

    Paul S. Soliman

  3. Department of Neuroscience, Neuroscience Graduate Program, Brown University, Providence, RI, USA

    Dallece E. Curley

  4. Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, Providence, RI, USA

    Christy Capone, Erica Eaton & Carolina L. Haass-Koffler

  5. Providence Veteran Administration Medical Center, Providence, RI, USA

    Christy Capone & Erica Eaton

  6. Department of Behavioral and Social Sciences, School of Public Health, Brown University, Providence, RI, USA

    Carolina L. Haass-Koffler

  7. Carney Institute for Brain Science, Brown University, Providence, RI, USA

    Carolina L. Haass-Koffler

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  1. Paul S. Soliman
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  2. Dallece E. Curley
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  5. Carolina L. Haass-Koffler
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Correspondence to Carolina L. Haass-Koffler.

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Conflicts of interest

CLH-K received mifepristone and matching placebo for another trial and travel support to CA to present the data at the Corcept Therapeutic Conference (September 2022), holds two patents for the development of negative allosteric modulators targeting the stress system and one patent application on the development of a compound for noradrenergic blockade. All is unrelated to this work. The other authors declare no competing interests.

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Soliman, P.S., Curley, D.E., Capone, C. et al. In the new era of psychedelic assisted therapy: A systematic review of study methodology in randomized controlled trials. Psychopharmacology (2024). https://doi.org/10.1007/s00213-024-06598-6

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