Is psilocybin-assisted therapy efficacious among patients with major depressive disorder?
In this randomized clinical trial of 24 participants with major depressive disorder, participants who received immediate psilocybin-assisted therapy compared with delayed treatment showed improvement in blinded clinician rater–assessed depression severity and in self-reported secondary outcomes through the 1-month follow-up.
This randomized clinical trial found that psilocybin-assisted therapy was efficacious in producing large, rapid, and sustained antidepressant effects in patients with major depressive disorder.
Major depressive disorder (MDD) is a substantial public health burden, but current treatments have limited effectiveness and adherence. Recent evidence suggests that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression.
To investigate the effect of psilocybin therapy in patients with MDD.
Design, Setting, and Participants
This randomized, waiting list–controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. Adults aged 21 to 75 years with an MDD diagnosis, not currently using antidepressant medications, and without histories of psychotic disorder, serious suicide attempt, or hospitalization were eligible to participate. Enrollment occurred between August 2017 and April 2019, and the 4-week primary outcome assessments were completed in July 2019. A total of 27 participants were randomized to an immediate treatment condition group (n = 15) or delayed treatment condition group (waiting list control condition; n = 12). Data analysis was conducted from July 1, 2019, to July 31, 2020, and included participants who completed the intervention (evaluable population).
Two psilocybin sessions (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg) were given (administered in opaque gelatin capsules with approximately 100 mL of water) in the context of supportive psychotherapy (approximately 11 hours). Participants were randomized to begin treatment immediately or after an 8-week delay.
Main Outcomes and Measures
The primary outcome, depression severity was assessed with the GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at baseline (score of ≥17 required for enrollment) and weeks 5 and 8 after enrollment for the delayed treatment group, which corresponded to weeks 1 and 4 after the intervention for the immediate treatment group. Secondary outcomes included the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR).
Of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 postsession assessments. This population had a mean (SD) age of 39.8 (12.2) years, was composed of 16 women (67%), and had a mean (SD) baseline GRID-HAMD score of 22.8 (3.9). The mean (SD) GRID-HAMD scores at weeks 1 and 4 (8.0 [7.1] and 8.5 [5.7]) in the immediate treatment group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed treatment group. The effect sizes were large at week 5 (Cohen d = 2.5; 95% CI, 1.4-3.5; P < .001) and week 8 (Cohen d = 2.6; 95% CI, 1.5-3.7; P < .001). The QIDS-SR documented a rapid decrease in mean (SD) depression score from baseline to day 1 after session 1 (16.7 [3.5] vs 6.3 [4.4]; Cohen d = 2.6; 95% CI, 1.8-3.5; P < .001), which remained statistically significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d = 2.3; 95% CI, 1.5-3.0; P < .001). In the overall sample, 17 participants (71%) at week 1 and 17 (71%) at week 4 had a clinically significant response to the intervention (≥50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (≤7 GRID-HAMD score).
Conclusions and Relevance
Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression.
ClinicalTrials.gov Identifier: NCT03181529
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Accepted for Publication: July 31, 2020.
Published Online: November 4, 2020. doi:10.1001/jamapsychiatry.2020.3285
Correction: This article was corrected on February 10, 2021, to fix errors in the Abstract Results and Results section.
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Davis AK et al. JAMA Psychiatry.
Corresponding Authors: Alan K. Davis, PhD (email@example.com), and Roland R. Griffiths, PhD (firstname.lastname@example.org), Center for Psychedelic and Consciousness Research, Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, 5510 Nathan Shock Drive, Baltimore, MD 21224.
Author Contributions: Drs Davis and Griffiths had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Davis, Barrett, May, Cosimano, Johnson, Griffiths.
Acquisition, analysis, or interpretation of data: Davis, Barrett, May, Sepeda, Johnson, Finan, Griffiths.
Drafting of the manuscript: Davis, Barrett, May, Cosimano, Sepeda, Griffiths.
Critical revision of the manuscript for important intellectual content: Davis, Barrett, May, Sepeda, Johnson, Finan, Griffiths.
Statistical analysis: Davis, Griffiths.
Obtained funding: Barrett, Griffiths.
Administrative, technical, or material support: Davis, Barrett, May, Cosimano, Sepeda, Finan, Griffiths.
Supervision: Davis, Barrett, May, Cosimano, Johnson, Griffiths.
Conflict of Interest Disclosures: Dr Davis reported being a board member at Source Research Foundation. Dr Johnson reported receiving grants from Heffter Research Institute outside the submitted work and personal fees as a consultant and/or advisory board member from Beckley Psychedelics Ltd, Entheogen Biomedical Corp, Field Trip Psychedelics Inc, Mind Medicine Inc, and Otsuka Pharmaceutical Development & Commercialization Inc. Dr Griffiths reported being a board member at Heffter Research Institute and receiving grants from Heffter Research Institute outside the submitted work. No other disclosures were reported.
Funding/Support: This study was funded in part by a crowd-sourced funding campaign organized by Tim Ferriss; a grant from the Riverstyx Foundation; and grants from Tim Ferriss, Matt Mullenweg, Craig Nerenberg, Blake Mycoskie, and the Steven and Alexandra Cohen Foundation. Drs Davis and May were supported by postdoctoral training grant T32DA07209 from NIDA. Dr Finan was supported by grant K23DA035915 from NIDA. Drs Griffiths and Johnson were partially supported by grant R01DA03889 from NIDA. The Center for Psychedelic and Consciousness Research is funded by the Steven and Alexandra Cohen Foundation and has received support from Tim Ferriss, Matt Mullenweg, Craig Nerenberg, and Blake Mycoskie.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: Annie Umbricht, MD, and Eric Strain, MD, provided medical oversight during the study sessions. Jessiy Salwen, PhD, and Mary Bailes, LCPC, served as blinded clinician raters. Natalie Gukasyan, MD; Laura Doyle, BA; John Clifton, BS; Kasey Cox, MS; and Rhiannon Mayhugh, PhD, facilitated the intervention sessions. These individuals, from Johns Hopkins University, received no additional compensation, outside of their usual salary, for their contributions.
Data Sharing Statement: See Supplement 3.
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