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.
Abstract of Single-Dose Psilocybin for Depression With Severe Treatment Resistance
“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.”
Authors: Scott T. Aaronson, Andrew van der Vaart, Tammy Miller, Jeffrey LaPratt, Kimberly Swartz, Audrey Shoultz, Margo Lauterbach, Trisha Suppes & Harold A. Sackeim
Summary of Single-Dose Psilocybin for Depression With Severe Treatment Resistance
The study addresses the challenge of severe treatment-resistant depression (TRD), a condition characterised by the failure to respond to multiple standard treatments. Traditional approaches, such as successive antidepressant trials and neurostimulation techniques like vagus nerve stimulation (VNS) or deep brain stimulation (DBS), yield limited success and carry significant risks. Previous studies have shown psilocybin’s potential in alleviating depressive symptoms, but research specifically targeting severe TRD, defined as failure to respond to at least five adequate treatments, is scarce.
The authors aimed to investigate the safety and efficacy of a single dose of synthetic psilocybin in patients with severe TRD. The study included patients with comorbidities like post-traumatic stress disorder (PTSD) and generalised anxiety disorder (GAD) to evaluate interactions that could influence outcomes.
From the same trial, another study was published earlier that focussed on veterans.
Methods
Study Design and Participants
Find this paper
Single-Dose Psilocybin for Depression With Severe Treatment Resistance: An Open-Label Trial
https://doi.org/10.1176/appi.ajp.20231063
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Cite this paper (APA)
Aaronson, S. T., van der Vaart, A., Miller, T., LaPratt, J., Swartz, K., Shoultz, A., ... & 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.
Study details
Compounds studied
Psilocybin
Topics studied
Depression
Treatment-Resistant Depression
Study characteristics
Original
Open-Label
Participants
12
Humans
Compound Details
The psychedelics given at which dose and how many times
Psilocybin 25 mg | 1xLinked Research Papers
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