Blinding and Expectancy Confounds in Psychedelic Randomised Controlled Trials
Systematic review evidence suggests effect sizes in psychedelic randomised controlled trials are likely inflated by participant de‑blinding and high response expectancy, yet existing trials generally fail to measure or report these confounds. The authors recommend routinely measuring de‑blinding and expectancy and improving trial design and participant instructions so such biases can be estimated and removed, and they urge caution in interpreting current effect‑size estimates.
Authors
- Suresh Muthukumaraswamy
Published
Abstract
There is increasing interest in the potential for psychedelic drugs such as psilocybin, LSD and ketamine to treat a number of mental health disorders. To gain evidence for the therapeutic effectiveness of psychedelics, a number of randomised controlled trials (RCTs) have been conducted using the traditional RCT framework and these trials have generally shown promising results, with large effect sizes reported. However, in this paper we argue that estimation of treatment effect sizes in psychedelic clinical trials are likely over-estimated due to de-blinding of participants and high levels of response expectancy generated by RCT trial contingencies. The degree of over-estimation is at present difficult to estimate. We conduct systematic reviews of psychedelic RCTs and show that currently reported RCTs have failed to measure and report expectancy and malicious de-blinding. In order to overcome these confounds we argue that RCTs should routinely measure de-blinding and expectancy and that careful attention should be paid to the clinical trial design used and the instructions given to participants to allow these confounds to be estimated and removed from effect size estimates. We urge caution in interpreting effect size estimates from extant psychedelic RCTs.
Research Summary of 'Blinding and Expectancy Confounds in Psychedelic Randomised Controlled Trials'
Introduction
Over the past two decades there has been renewed clinical interest in the therapeutic potential of psychedelic drugs (for example psilocybin, LSD and ketamine) for a range of psychiatric conditions. Muthukumaraswamy and colleagues argue that standard randomised controlled trial (RCT) methods, particularly the double-masked parallel-group design, face special challenges when applied to psychedelics because the conspicuous psychoactive effects of these drugs tend to unmask participants and raters, and the trial setting and publicity surrounding psychedelics can produce strong response expectancies that bias subjective outcome measures. This paper sets out to examine how these expectancy and masking problems affect causal inference in psychedelic RCTs. Using the Rubin causal model as a conceptual frame, the researchers review the history and logic of RCTs, survey the literature on placebo responses, expectancy and therapeutic alliance, and then report systematic reviews of existing psychedelic trials (ketamine RCTs for depression and serotonergic psychedelic trials) to document current practice. Finally, they assess trial designs and statistical approaches that could reduce bias, and make recommendations for measurement and reporting to improve the reliability of treatment effect estimates.
Expert Research Summaries
Go Pro to access AI-powered section-by-section summaries, editorial takes, and the full research toolkit.
Full Text PDF
Full Paper PDF
Create a free account to open full-text PDFs.
Study Details
- Study Typemeta
- Journal
- Compounds
- Topic
- Author
- APA Citation
Muthukumaraswamy, S., Forsyth, A., & Lumley, T. (2021). Blinding and Expectancy Confounds in Psychedelic Randomised Controlled Trials. https://doi.org/10.31234/osf.io/q2hzm
References (33)
Papers cited by this study that are also in Blossom
Gukasyan, N., Nayak, S. · Preprints (2020)
Carhart-Harris, R. L., Roseman, L., Haijen, E. C. H. M. et al. · Journal of Psychopharmacology (2018)
Kaertner, L. S., Steinborn, M. B., Kettner, H. et al. · Scientific Reports (2021)
Krupitsky, E. M., Grinenko, A. Y. · Journal of Psychoactive Drugs (1997)
Murrough, J. W., Iosifescu, D. V., Chang, L. C. et al. · American Journal of Psychiatry (2013)
Mathai, D. S., Meyer, M. J., Storch, E. A. et al. · Journal of Affective Disorders (2020)
Bahji, A., Vazquez, G. H., Zarate, C. A. · Journal of Affective Disorders (2021)
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Burger, J., Capobianco, M., Lovern, R. et al. · Military Medicine (2016)
Diazgranados, N., Ibrahim, L., Brutsche, N. E. et al. · JAMA Psychiatry (2010)
Show all 33 referencesShow fewer
Grunebaum, M. F., Galfalvy, H. C., Choo, T. H. et al. · American Journal of Psychiatry (2018)
Ionescu, D. F., Bentley, K. H., Eikermann, M. et al. · Journal of Affective Disorders (2019)
Ionescu, D. F., Qiu, X., Lane, R. et al. · International Journal of Neuropsychopharmacology (2020)
Jafarinia, M., Afarideh, M., Tafakhori, A. et al. · Journal of Affective Disorders (2016)
Li, C. T., Chen, M. H., Lin, W. C. et al. · Human Brain Mapping (2016)
Nugent, A. C., Ballard, E. D., Gould, T. D. et al. · Molecular Psychiatry (2018)
Singh, J. B., Fedgchin, M., Daly, E. J. et al. · American Journal of Psychiatry (2016)
Yang, X., Yuantao, L., Xialei, H. et al. · Archives of Gynecology and Obstetrics (2017)
Gasser, P., Holstein, D., Michel, Y. et al. · Journal of Nervous and Mental Disease (2014)
Grob, C. S., Danforth, A. L., Chopra, G. S. et al. · JAMA Psychiatry (2011)
Moreno, F. A., Wiegand, C. B., Taitano, E. K. et al. · Journal of Clinical Psychiatry (2006)
Palhano-Fontes, F., Barreto, D., Onias, H. et al. · Psychological Medicine (2018)
Ross, S., Bossis, A. P., Guss, J. et al. · Journal of Psychopharmacology (2016)
Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A. et al. · Journal of Psychopharmacology (2015)
Johnson, M. W., Garcia-Romeu, A., Cosimano, M. P. et al. · Journal of Psychopharmacology (2014)
Osório, F. L., Sanches, R. F., Macedo, L. et al. · brazilian Journal of Psychiatry (2015)
Sanches, R. F., Osório, F. L., Dos Santos, R. G. et al. · Journal of Clinical Psychopharmacology (2016)
Thomas, G., Lucas, P., Rielle Capler, N. et al. · Current Drug Abuse Reviews (2013)
King, C., Nichols, D. E. · Nature Reviews Neuroscience (2013)
William Deakin, J. F., Lees, J., McKie, S. et al. · JAMA Psychiatry (2008)
Sumiyoshi, T., Kraehenmann, R., Pokorny, D. et al. · Frontiers in Pharmacology (2017)
Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F. I., Bäbler, A. et al. · NeuroReport (1998)
Holze, F., Vizeli, P., Ley, L. et al. · Neuropsychopharmacology (2020)
Cited By (21)
Papers in Blossom that reference this study
Meikle, S., Carter, O., Liknaitzky, P. et al. · Therapeutic Advances in Psychopharmacology (2025)
Aicher, H. D., Wicki, I. A., Meling, D. et al. · Journal of Psychopharmacology (2025)
Szigeti, B., Heifets, B. D. · Biological Psychiatry (2024)
Sloshower, J. A., Zeifman, R. J., Guss, J. et al. · Scientific Reports (2024)
Aday, J. S., Bloesch, E. K., Davis, A. K. et al. · Journal of Humanistic Psychology (2024)
Aicher, H. D., Mueller, M. J., Dornbierer, D. A. et al. · Frontiers in Psychiatry (2024)
Szigeti, B., Nutt, D. J., Carhart-Harris, R. L. et al. · Scientific Reports (2023)
Heifets, B. D., Olson, D. E. · Neuropsychopharmacology (2023)
Noorani, T. N., Bedi, G., Muthukumaraswamy, S. · Psychological Medicine (2023)
Muthukumaraswamy, S. · Psyarxiv (2023)
Show all 21 papersShow fewer
Bloesch, E. K., Davis, A. K., Domoff, S. E. et al. · Psyarxiv (2023)
Sloshower, J. A., Skosnik, P. D., Safi-Aghdam, H. et al. · Journal of Psychopharmacology (2023)
Kopra, E., Ferris, J. A., Winstock, A. R. et al. · Journal of Psychopharmacology (2023)
Breeksema, J. J., Kuin, B. W., Kamphuis, J. et al. · Journal of Psychopharmacology (2022)
Villiger, D. · Frontiers in Psychiatry (2022)
Muthukumaraswamy, S., Forsyth, A., Sumner, R. L. · Australian and new-zealand Journal of Psychiatry (2022)
Altman, B. R., Earleywine, M., De Leo, J. · Journal of Psychoactive Drugs (2022)
Polito, V., Liknaitzky, P. · Psyarxiv (2021)
Cavanna, F., Muller, S., de la Fuente, L. A. et al. · Translational Psychiatry (2021)
Aday, J. S., Heifets, B. D., Pratscher, S. D. et al. · Psychopharmacology (2021)
Bird, C. I. V., Modlin, N. L., Rucker, J. · International Review of Psychiatry (2021)
Your Personal Research Library
Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.