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What should constitute a control condition in psychedelic drug trials?

Nature Mental Health volume 2, pages 1152–1160 (2024)Cite this article

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Abstract

Over the past decade there has been a surge in interest in placebo-controlled trials using non-classical 3,4-methylenedioxymethamphetamine (MDMA) and classical psychedelics such as psilocybin, lysergic acid diethylamide (LSD) and N,N-dimethyltryptamine (DMT) to treat neuropsychiatric disorders. However, the success and reliability of these trials depend on the design of the trials, the choice of control conditions, and the ability to blind both participants and researchers. When appropriate control conditions are lacking, it becomes difficult to disentangle placebo and expectation effects from medication effects. Here we explore the neurobiology of placebo and expectation effects, alongside the methodological considerations for selecting suitable control conditions in psychedelic trials. This includes examining the advantages and disadvantages of various control conditions and proposing new directions to enhance the validity of these trials and their regulatory science. By addressing these factors, we aim to improve the reliability of psychedelic research in uncovering the therapeutic benefits of psychedelics beyond placebo and expectation effects.

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Fig. 1: Preliminary evaluation of expectation of benefit in a phase 3 trial of MDMA plus assisted therapy versus placebo plus assisted therapy in participants with moderate to severe PTSD.

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Acknowledgements

Some of research described in this Perspective is supported by the US National Institutes of Health National Center for Complementary and Integrative Health (R01AT01033 and R01AT011347).

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  1. Department of Pain and Translational Symptom Science, Placebo Beyond Opinions Center, University of Maryland School of Nursing, Baltimore, MD, USA

    Luana Colloca

  2. Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    Maurizio Fava

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  1. Luana Colloca
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  2. Maurizio Fava
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L.C. and M.F. drafted the first synopsis. L.C. prepared the first draft. L.C. and M.F. finalized the manuscript. L.C. and M.F. confirm sole responsibility for the content.

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Correspondence to Luana Colloca.

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L.C. declares no competing interests. M.F.'s disclosures are available at https://mghcme.org/maurizio-fava-bio-disclosure/.

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Colloca, L., Fava, M. What should constitute a control condition in psychedelic drug trials?. Nat. Mental Health 2, 1152–1160 (2024). https://doi.org/10.1038/s44220-024-00321-2

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