Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial

Abstract

Background: Psilocybin has been suggested as a novel, rapid-acting treatment for depression. Two consecutive doses have been shown to markedly decrease symptom severity in an open-label setting or when compared to a waiting list group. To date, to our knowledge, no other trial compared a single, moderate dose of psilocybin to a placebo condition.

Methods: In this double-blind, randomised clinical trial, 52 participants diagnosed with major depressive disorder and no unstable somatic conditions were allocated to receive either a single, moderate dose (0.215 mg/kg body weight) of psilocybin or placebo in conjunction with psychological support. MADRS and BDI scores were assessed to estimate depression severity, while changes from baseline to 14 days after the intervention were defined as primary endpoints. The trial took place between April 11th, 2019 and October 12th, 2021 at the psychiatric university hospital in Zürich, Switzerland and was registered with clinicaltrials.gov (NCT03715127).

Findings: The psilocybin condition showed an absolute decrease in symptom severity of -13.0 points compared to baseline and were significantly larger than those in the placebo condition (95% CI -15.0 to -1.3; Cohens' d = 0.97; P = 0.0011; MADRS) and -13.2 points (95% CI; -13.4 to -1.3; Cohens' d = 0.67; P = 0.019; BDI) 14 days after the intervention. 14/26 (54%) participants met the MADRS remission criteria in the psilocybin condition.

Interpretation: These results suggest that a single, moderate dose of psilocybin significantly reduces depressive symptoms compared to a placebo condition for at least two weeks. No serious adverse events were recorded. Larger, multi-centric trials with longer follow-up periods are needed to inform further optimisation of this novel treatment paradigm.

Funding: The study was funded by the Swiss National Science Foundation, Crowdfunding, the Swiss Neuromatrix Foundation, and the Heffter Research Institute.

Keywords: Depression; Efficacy; Major depressive disorder; Placebo-controlled; Psilocybin; Psychedelic-assisted therapy; RCT.

Fig. 1

CONSORT flow diagram and study design. After enrolment, all participants underwent two preparation sessions (4–6 days and 1 day prior to administration) before being randomised to either the placebo or the psilocybin condition. Drug administration took place on the administration day at 9 a.m. and participants were discharged between 3 a.m. and 5 p.m. on the same day after acute drug effects had completely worn off. Integration of the experience was conducted 2 days, 8 days and 14 days after administration.

Fig. 2

Mean trajectories of MADRS and BDI at every study visit for both treatment conditions. a: mean scores of clinician-rated primary endpoint (MADRS); b: mean scores of self-reported primary endpoint (BDI). The grey bar depicts the time of substance administration. The endpoints reported for the administration day were assessed after all subjective effects had worn off (around 6 h after administration). The dotted line depicts thresholds defined for the remission of symptoms. Differences between treatment conditions (blue = psilocybin; yellow = placebo) at each time point were calculated using independent two-samples Welch's t-tests rejecting the null-hypothesis at significance levels of ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001. Error bars represent standard errors of means (se).

Fig. 3

Association of treatment response with subjective effects. a: Mean values and standard errors of the mean (error bars) on the 5 dimensions altered states of consciousness questionnaire (ASC) in the psilocybin and placebo groups. Treatment groups (blue) differed significantly from Placebo (yellow) on all dimensions. OBN = oceanic boundlessness; AED = anxious ego dissolution; VRS = visual restructuralization; AUA = auditory alterations; VIR = vigilance reduction. 11 dimensions: EXU = experience of unity; SPE = spiritual experiences; BLS = blissfulness; ISF = insightfulness; DEB = disembodiment; ICC = impaired cognition and control; ANX = anxiety; EIM = elementary imagery; CIM = complex imagery; AVS = audio-visual synesthesia; CMP = changed meaning of percepts. b: ASC global intensity scores for responders and non-responders in the psilocybin and placebo groups. Responder and non-responders were defined according to the MADRS response criterion (−50% symptom reduction and/or decrease below the remission threshold) for changes between visit 2 (−5d) and visit 7 (+14d). Distributions were obtained using a gaussian density estimator kernel.