PS01a – Placebo Controls in Psychedelic Research: A Systematic Review and Qualitative Analysis of Clinical Trials

PS01a – Placebo Controls in Psychedelic Research: A Systematic Review and Qualitative Analysis of Clinical Trials

Thursday, Oct. 19
14:30 – 15:30 (N/A)
Meeting Room: Finback (3rd floor – B Tower)
Nikhita Singhal*, MD; Cory Weissman, MD; Alexander Wen, BSc; Brett Jones, MD; Richard Zeifman, PhD

CanMEDS Roles:

  1. Medical Expert
  2. Scholar
  3. Professional

At the end of this session, participants will be able to: 1) Appreciate the methodological challenges associated with conducting clinical trials involving psychedelic substances; 2) Consider the role of placebo controls and the potential contribution of placebo mechanisms to psychedelic therapy outcomes; and 3) Identify ways in which future psychedelic clinical trials can address blinding challenges and mitigate the risk of bias.

The use of classic psychedelics as potent mental health treatments is gaining traction, yet significant challenges remain in conducting trials with these substances. Both the role of placebo control subjects and the importance of placebo mechanisms in explaining the efficacy of psychedelic therapy remain understudied. We thus conducted a systematic review of placebo use in clinical trials involving classic psychedelic administration to enhance understanding of this complex area. The characteristics and findings of included studies are presented as a systematic narrative synthesis including qualitative outcomes and summarized in tabular format. Of 1,053 studies retrieved through our search, 55 were eligible for inclusion, with publication dates ranging from 1963 to 2020. The most common forms of placebo used were empty capsules, niacin, and IV saline. Clinical outcomes included subjective mental states, physiological measures, creative imagination and mental imagery tests, BDNF and cortisol levels, eyeblink responses, and formal measures of clinical depression and anxiety. Our review suggests that most placebo-controlled psychedelic therapy studies involve healthy participants; there is a limited number of placebo-controlled studies among psychiatric populations, and the quality of placebo control subjects has been questionable. The use of adequate placebo controls, as well as assessment and balancing of expectancy, is severely lacking in existing trials. Future psychedelic clinical trials should include adequate assessment of blinding, more appropriate control subjects, and randomization of treatment arms and treatment expectancy. Active psychopharmacological controls (such as other rapid acting agents), in addition to head-to-head comparison with active treatments, should be considered as alternatives.


  1. Burke MJ, Blumberger DM. Caution at psychiatry’s psychedelic frontier. Nat Med 2021;27(10):1687–1688.
  2. Muthukumaraswamy SD, Forsyth A, Lumley T. Blinding and expectancy confounds in psychedelic randomized controlled trials. Expert Rev Clin Pharmacol 2021;14(9):1133–1152.