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The extrapolation fallacy in unblinded psychedelic trials

Nature Mental Health (2026)Cite this article

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The tension between gold-standard double-blind randomized controlled trials and the overt psychoactive effects of psychedelics increases the risk of extrapolation fallacy, with potentially harmful downstream consequences.

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References

  1. Robison, R. et al. JAMA 334, 1358–1372 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Muthukumaraswamy, S. D., Forsyth, A. & Lumley, T. Expert Rev. Clin. Pharmacol. 14, 1133–1152 (2021).

    Article  PubMed  Google Scholar 

  3. Schenberg, E. E. Expert Rev. Clin. Pharmacol. 14, 1317–1319 (2021).

    Article  PubMed  Google Scholar 

  4. Aday, J. S. et al. Psychopharmacology 239, 1989–2010 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  5. European Medicines Agency. Guideline on Clinical Investigation of Medicinal Products in the Treatment of Depression. EMA/CHMP/185423/2010 Rev.3 (EMA, 2025).

  6. Browne, K. et al. ACS Pharmacol. Transl. Sci. 8, 2830–2838 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Hopewell, S. et al. JAMA 333, 1998–2005 (2025).

    Article  PubMed  Google Scholar 

  8. Schulz, K. F., Altman, D. G., Moher, D. & Fergusson, D. Lancet 375, 1144–1146 (2010).

    Article  PubMed  Google Scholar 

  9. Worrall, J. in Current Trends in Philosophy of Science (ed. Gonzalez, W. J.) 15–43 (Springer, 2022).

  10. Huneke, N. T. M., Fusetto Veronesi, G., Garner, M., Baldwin, D. S. & Cortese, S. JAMA Psychiatry 82, 531–538 (2025).

    Article  PubMed  Google Scholar 

  11. Schenberg, E. E., Hauskeller, C., Schwarz, C. G. & King, F. Nat. Ment. Health 2, 1265–1267 (2024).

    Article  Google Scholar 

  12. Schenberg, E. E. Pharmacol. Res. Perspect. 13, e70097 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  13. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the Guideline on Statistical Principles for Clinical Trials. ICH E9(R1) (ICH, 2019).

  14. Parnas, J., Sass, L. A. & Zahavi, D. Schizophr. Bull. 39, 270–277 (2013).

    Article  PubMed  Google Scholar 

  15. Soares, C. N. JAMA 334, 1333–1335 (2025).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Disclaimer: The views expressed in this Comment are the personal views of the author (M.H.) and may not be understood or quoted as being made on behalf of or reflecting the position of the regulatory agency/agencies with which the author is employed/affiliated, including the Federal Institute for Drugs and Medical Devices (BfArM).

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Authors and Affiliations

  1. Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal

    Eduardo Ekman Schenberg

  2. The Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School, Cambridge, MA, USA

    Eduardo Ekman Schenberg

  3. Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Franklin King IV

  4. Harvard Medical School, Boston, MA, USA

    Franklin King IV

  5. Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn, Germany

    Marion Haberkamp

Authors
  1. Eduardo Ekman Schenberg
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  2. Franklin King IV
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  3. Marion Haberkamp
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Corresponding author

Correspondence to Franklin King IV.

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Competing interests

E.E.S. was scientific advisor to Ocama Partners between August 2021 and July 2023. F.K. declares Cybin and Compass personal stock, serving as Apex Labs scientific advisor and receiving research support from Tryp Therapeutics, Unlikely Collaborators and the David Borsook Project. M.H. declares no competing interests.

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Ekman Schenberg, E., King IV, F. & Haberkamp, M. The extrapolation fallacy in unblinded psychedelic trials. Nat. Mental Health (2026). https://doi.org/10.1038/s44220-026-00596-7

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