Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial

Abstract

Importance: 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.

Objective: 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).

Interventions: 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).

Results: 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.

Trial registration: ClinicalTrials.gov Identifier: NCT03181529.

Conflict of interest statement

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.

Figures

Figure 1.. CONSORT Diagram of Participant Flow

aAfter completing the prescreening questionnaire, people were deemed ineligible if they were currently using antidepressant medication (n = 157); lived outside reasonable commuting distance (n = 161); did not meet criteria for the magnetic resonance imaging scans (n = 99); had a first- or second-degree relative with a diagnosis of schizophrenia spectrum, bipolar I or II, or other psychotic disorder ( = 77); had a recent history of substance use disorder (n = 50); opted out of in-person screening (n = 38); were not in a current depressive episode (n = 37); were more than 25% beyond the upper or lower range of recommended body weight (n = 32); had a medically significant suicide attempt (n = 30); had lifetime hallucinogen use that exceeded the exclusion threshold (n = 30); if major depressive disorder (MDD) was not primary psychiatric diagnosis (n = 18); if they had a medical exclusion (n = 11); had exclusionary use of nonserotonergic psychoactive medication (n = 11); or failed to respond to electroconvulsive therapy during current depressive episode (n = 4). Forty-five people were ineligible for other reasons. bPeople were deemed ineligible during in-person screening if they had a psychiatric condition judged to be incompatible with establishment of rapport or safe exposure to psilocybin (n = 17); did not have confirmed DSM-5 diagnosis of MDD (n = 7); had a recent history of moderate to severe substance use disorder (n = 5); were at high risk for suicidality (n = 3); disagreed with study procedures (n = 3); had a baseline GRID Hamilton Depression Rating Scale score lower than the eligibility threshold of 17 (n = 2); had cardiovascular conditions (n = 2); had lifetime hallucinogen use that exceeded the exclusion threshold (n = 2); were currently taking serotonergic medication (n = 1); or were more than 25% beyond the upper and lower range of recommended body weight (n = 1). cDropped out of the study due to anticipatory anxiety about the upcoming first psilocybin session. dDropped out of study due to sleep difficulties. Sleep difficulties were also reported at screening, and it was not clear whether sleep difficulties were exacerbated by the intervention. eParticipant showed a marked reduction in depression symptoms immediately following the first psilocybin session and chose not to proceed with the intervention.

Figure 2.. Study Timeline From Baseline Assessment and Screening to the 4-Week Postsession-2 Follow-up Visit

GRID-HAMD indicates GRID Hamilton Depression Rating Scale.

Figure 3.. Comparison of GRID Hamilton Depression Rating Scale (GRID-HAMD) Scores Between the Delayed Treatment and Immediate Treatment Groups

Data points are presented as mean (SD). In the immediate treatment group (n = 13), weeks 5 and 8 correspond to weeks 1 and 4 after the psilocybin session 2. In the delayed treatment group (n = 11), weeks 5 and 8 are prepsilocybin assessments obtained during the delay period. Effect sizes (Cohen d with 95% CI) and P values reflect the results of a 2-sample t test between the 2 groups 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).

Figure 4.. Decrease in the GRID Hamilton Depression Rating Scale (GRID-HAMD) Scores at Week 1 and Week 4 Postsession-2 Follow-up in the Overall Treatment Sample

The mean (SD) GRID-HAMD score was 22.8 (3.9) at baseline, 8.7 (7.6) at week 1, and 8.9 (7.4) at week 4. Effect sizes (Cohen d with 95% CI) and P values reflect the results of a paired sample t test that compared scores between baseline and week 1 (Cohen d = 2.3; 95% CI, 1.5-3.1; P < .001) and week 4 postsession-2 follow-up (Cohen d = 2.3; 95% CI, 1.5-3.1; P < .001).