Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial

This single-blind, placebo-controlled study (n=19) of psilocybin (21mg/70kg) in combination with therapy (ACT, 8x) finds an improvement in depression scores. However, the difference between the psilocybin and placebo groups was insignificant. Though the study tried to control for expectancy (placebo) effects, participants (80%) correctly guessed if they received psilocybin.

Abstract of Psilocybin-assisted therapy for major depressive disorder

Background: Several early phase studies have demonstrated that psilocybin-assisted therapy has rapid-acting and persisting antidepressant effects from just one or two doses. However, methodological limitations (e.g., placebo-control, blinding) limit interpretability of the existing literature.

Methods: In an exploratory placebo-controlled, within-subject, fixed-order study, individuals with moderate to severe major depressive disorder were administered placebo (n = 19) followed by psilocybin (0.3 mg/kg) (n = 15) 4 weeks later. Dosing sessions were embedded within an manualized course of psychotherapy. Enhanced blinding procedures were used. Depression, anxiety, and quality of life were measured over a 16-week study period.

Results: Depression and anxiety significantly improved following both placebo and psilocybin with no significant difference in the degree of change between the two conditions. However, antidepressant effect sizes were larger after psilocybin (d′ = 1.02–2.27) than after placebo (d′ = 0.65–0.99) and there were high rates of response (66.7%) and remission (46.7%) following psilocybin administration. Antidepressant effects following psilocybin persisted, on average, for 2 months and there were persisting improvements in mood-related quality of life domains. The strength of mystical-type experience during psilocybin dosing was not correlated with subsequent antidepressant effects.

Conclusions: The results of this exploratory study highlight the complex interplay between expectancy, therapy effects, and drug/placebo effects in psychedelic-assisted psychotherapy studies. Nonetheless, the acute and persisting clinical improvements observed following psilocybin support further study of its potential in the treatment of major depression. Future studies should more explicitly mitigate and measure expectancy effects and assess the impact of repeated dosing and different forms of psychotherapeutic support.”

Authors: Jordan Sloshower, Patrick D. Skosnik, Hamideh Safi-Aghdam, Surbhi Pathania, Shariful Syed, Brian Pittman & Deepak C. D’Souza

Summary of Psilocybin-assisted therapy for major depressive disorder

Psilocybin, a naturally occurring alkaloid found in the Psilocybe genus of mushrooms, is categorized as a “classical psychedelic” compound and produces a range of acute perceptual and mood alterations in humans.

Several early-phase trials have suggested that psilocybin-assisted psychotherapy may have rapid-acting and long-lasting therapeutic effects in depressive disorders. These trials include two randomized controlled trials (RCTs) in cancer patients with depression and anxiety, and two open-label studies investigating psilocybin with psychological support as a treatment for major depression.

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Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial

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Cite this paper (APA)

Sloshower, J., Skosnik, P. D., Safi-Aghdam, H., Pathania, S., Syed, S., Pittman, B., & D’Souza, D. C. (2023). Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial. Journal of Psychopharmacology, 02698811231154852.

Study details

Compounds studied
Psilocybin Placebo

Topics studied
Depression Treatment-Resistant Depression

Study characteristics
Original Placebo-Controlled Single-Blind Within-Subject

19 Humans


Authors associated with this publication with profiles on Blossom

Jordan Sloshower
Jordan Sloshower is a research fellow in addiction psychiatry at Yale University. His research and clinical interests focus on therapeutic applications of psychedelic substances and he is currently an investigator and therapist in two clinical trials of psilocybin-assisted therapy in the treatment of major depressive disorder (MDD).


Institutes associated with this publication

Yale University
The Yale Psychedelic Science Group was established in 2016.

Compound Details

The psychedelics given at which dose and how many times

Psilocybin 21 mg | 1x

Linked Research Papers

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