Single-Dose Psilocybin for Depression With Severe Treatment Resistance: An Open-Label Trial
This open-label trial (n=12) conducted at Sheppard Pratt Hospital finds that psilocybin (25mg) significantly decreases depressive symptoms in patients with severe treatment-resistant depression (TRD) at 3 weeks (MADRS −15.8) and 12 weeks (MADRS −17.2) post-treatment. Exploratory analyses suggest the Oceanic Boundlessness dimension correlates with antidepressant responses, while patients with comorbid PTSD show reduced antidepressant effects.
Authors
- Trisha Suppes
- Scott Tyler Aaronson
Published
Abstract
Objective
Depression varies along a difficulty-to-treat spectrum. Patients whose illness fails to respond to at least five treatments may be considered to have severely treatment-resistant depression (TRD). The objective of this study was to document the safety and efficacy of psilocybin in patients with severe TRD.
Methods
This was a 12-week, open-label trial conducted at Sheppard Pratt Hospital. Participants were 18-65 years of age, in a major depressive episode with documented insufficient benefit from at least five treatments during the current episode. A single dose of synthetic psilocybin (25 mg) was administered. Psychotropic medications were discontinued at least 2 weeks prior to dosing through at least 3 weeks post-dosing. Therapists met with patients for three sessions during pretreatment, during the 8-hour dosing day, and for three integration sessions posttreatment. The primary outcome measure was change in Montgomery-Åsberg Depression Rating scale (MADRS) at 3 weeks posttreatment. Secondary measures including MADRS scores up to 12 weeks posttreatment, and subject-rated scales capturing depression and level of function were completed at baseline and all subsequent visits.
Results
Twelve participants (six male, six female; mean age=40.6 years [SD=9.6]) with severe TRD were followed over the study period. Depressive symptoms were significantly decreased at week 3 (MADRS least-squares mean change=−15.8, 95% CI=−25.4 to −6.3) and Week 12 (MADRS least-squares mean change=−17.2, 95% CI=−25.2 to −9.1). In exploratory analyses, the Oceanic Boundlessness (OB) dimension of the psychedelic experience correlated with post-dosing antidepressant responses. Patients with comorbid PTSD (N=5) showed significantly less antidepressant effect of psilocybin.
Conclusions
This open-label study suggests efficacy and safety of psilocybin in severe TRD and supports further study of psychedelics in this population, including consideration of PTSD interaction effects.
Research Summary of 'Single-Dose Psilocybin for Depression With Severe Treatment Resistance: An Open-Label Trial'
Introduction
Earlier research has shown that psilocybin can produce rapid antidepressant effects in people with major depressive disorder and in samples with treatment-resistant depression (TRD), but most previous trials enrolled patients with no more than four prior treatment failures and often excluded common psychiatric comorbidities. Patients whose current episode has failed to respond to at least five adequate treatments represent a more severe TRD phenotype for which outcomes with usual care are very poor and for which invasive neuromodulation approaches have been tested but carry surgical risks. Aaronson and colleagues set out to document the safety and preliminary efficacy of a single 25 mg oral dose of synthetic psilocybin (COMP360) in patients meeting criteria for severe TRD (≥5 prior treatment failures in the current episode). The trial also aimed to characterise subjective aspects of the psychedelic experience, to explore whether those experience dimensions predict antidepressant response, and to examine whether common comorbidities such as post-traumatic stress disorder (PTSD) influence outcomes.
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Study Details
- Study Typeindividual
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- APA Citation
Aaronson, S. T., van der Vaart, A., Miller, T., LaPratt, J., Swartz, K., Shoultz, A., Lauterbach, M., Suppes, T., & Sackeim, H. A. (2025). Single-Dose Psilocybin for Depression With Severe Treatment Resistance: An Open-Label Trial. American Journal of Psychiatry, 182(1), 104-113. https://doi.org/10.1176/appi.ajp.20231063
References (5)
Papers cited by this study that are also in Blossom
Raison, C. L., Sanacora, G., Woolley, J. D. et al. · JAMA (2023)
Goodwin, G. M., Aaronson, S. T., Alvarez, O. et al. · New England Journal of Medicine (2022)
Barrett, F. S., Bradstreet, M. P., Leoutsakos, J. M. S. et al. · Journal of Psychopharmacology (2016)
MacLean, K. A., Leoutsakos, J. S., Johnson, M. W. et al. · Journal for the Scientific Study of Religion (2012)
Roseman, L., Nutt, D. J., Carhart-Harris, R. L. · Frontiers in Pharmacology (2018)
Cited By (1)
Papers in Blossom that reference this study
Ellis, S., Bostian, C., Donnelly, A. et al. · Journal of Affective Disorders (2025)
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