Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder

This randomized open-label study (n=24) found that two sessions with psilocybin (20 and 30mg/70kg) significantly improved depression scores for a population with major depressive disorder (MDD) up to 8 weeks later.

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 = 2.2; 95% CI, 1.4-3.0; P < .001) and week 8 (Cohen d = 2.6; 95% CI, 1.7-3.6; 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 = 3.0; 95% CI, 1.9-4.0; P < .001), which remained statistically significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d = 3.1; 95% CI, 1.9-4.2; 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.“

Authors: Alan K. Davis, Frederick S. Barrett, Darrick G. May, Mary P. Cosimano, Nathan D. Sepeda, Matthew W. Johnson, Patrick H. Finan & Roland R. Griffiths

Notes

This paper is included in our ‘Top 10 Articles on Psychedelics in the Treatment of Depression‘ and ‘Top 10 Articles on Psychedelics in the Year 2020‘

The significance of this paper is that its the first to use psilocybin for major depressive disorder (MDD), a much broader category than treatment resistant depression (TRD).

“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…”

This paper was also reported on in New Atlas, Hopkins Medicine, Futurity, Scimex, NPR, Bezinga, Healthline,

From the Hopkins publication: “In a small study of adults with major depression, Johns Hopkins Medicine researchers report that two doses of the psychedelic substance psilocybin, given with supportive psychotherapy, produced rapid and large reductions in depressive symptoms, with most participants showing improvement and half of study participants achieving remission through the four-week follow-up.“

You can find a talk by Alan Davis here, an interview with Roland Griffiths here, and that of a participant here.

In the first video, Roland Griffiths does note that much larger trials are needed and will take up to four years to be completed.

*There was a small correction to this study published that stated that this number should have been 71% (instead of the originally reported 67%, or 17 versus 16 of the participants).

Summary

Depression is a major public health concern, affecting more than 300 million individuals worldwide, and is estimated to be responsible for $210 billion in economic burden.

Although many patients with depression showed reduced symptoms after treatment with existing pharmacotherapies, 30% to 50% of patients did not respond fully, and 10% to 30% were considered treatment-resistant.

Most current pharmacotherapies for MDD increase levels of brain monoamine neurotransmitters such as serotonin and norepinephrine, but newer ketamine-like medications exert therapeutic efficacy through effects on glutamate neurotransmission. Ketamine has high abuse liability and requires medical monitoring.

MDD has a negative public health impact and current pharmacotherapies have variable efficacy and unwanted adverse effects. Psilocybin therapy may improve or save lives.

Study Design and Participants

Participants with moderate or severe MDD episodes were eligible for this trial of psilocybin therapy. They were required to self-report no current pharmacotherapy for depression at trial screening, and to refrain from using antidepressants for at least 5 half-lives before the screening and up to 4 months after enrollment.

We recruited 870 participants using flyers, print advertisements, internet forums, social media, and the study website. 27 participants were randomized to either an immediate treatment group or a delayed treatment group, and the 4-week primary outcome assessments were completed in July 2019.

Immediate Treatment Condition

A group of 20 participants underwent 2 daylong psilocybin administration sessions at the Center for Psychedelic and Consciousness Research. The sessions were conducted 1.6 weeks apart and involved preparatory meetings with 2 session facilitators.

Psilocybin was administered in opaque gelatin capsules with approximately 100 mL water. Participants were instructed to lie on a couch in a living room-like environment and focus their attention inward.

Delayed Treatment Condition

During the 8-week delay period, participants were monitored weekly by in-person assessment or brief telephone calls. They completed the same intervention as the participants in the immediate treatment group.

Outcome Assessments

The primary outcome measure was the GRID-HAMD, which was administered by blinded clinician raters at baseline, postrandomization weeks 5 and 8 and at weeks 1 and 4 postsession 2 follow-up visits for both groups.

GRID-HAMD indicates GRID Hamilton Depression Rating Scale.

Severity of depression was assessed using the total GRID-HAMD score, and a clinically significant response was defined as 50% or greater decrease from baseline. Interrater reliability for all depression assessments was 85%.

The Beck Depression Inventory II and the 9-item Patient Health Questionnaire were used to measure depressive symptoms, and the Columbia-Suicide Severity Rating Scale was used to measure anxiety symptoms. Blood pressure and heart rate were examined before and during the psilocybin sessions.

Statistical Analysis

A previous study of psilocybin found a large effect of a high psilocybin dose on reducing GRID-HAMD scores. A repeated-measures analysis of variance was used to examine changes in the primary depression outcome (GRID-HAMD score).

The primary outcomes included a descriptive analysis of the percentage of participants who met the criterion for clinically significant response and remission in the sample, and a comparison of week 1 with week 4 GRID-HAMD scores in the immediate treatment condition group.

Results

A total of 27 participants were randomized, of whom 24 completed the intervention as well as the postsession assessments at weeks 1 and 4. There were no statistically significant differences between conditions in terms of demographic characteristics or baseline GRID-HAMD scores.

The immediate treatment condition showed significantly lower depression scores at weeks 1 and 4 postsession-2 follow-up compared with the delayed treatment condition at weeks 5 and 8. The effect sizes were large at weeks 5 and 8.

After the psilocybin session, 16 participants at week 1 and 17 participants at week 4 had a clinically significant response to the intervention, and 14 participants at week 1 and 13 participants at week 4 met the criteria for remission of depression.

All secondary depression and anxiety outcomes showed statistically significant differences between conditions and across both conditions after entry into the active intervention period.

Participants reported challenging emotional and physical experiences, including feeling body shake or tremble, after completing at least one-half of the psilocybin sessions. Mild to moderate transient headache was reported during 16 of 48 sessions (33%) and after the subjective psilocybin effects had subsided after 14 of 48 sessions (29%).

Discussion

This randomized clinical trial showed that psilocybin-assisted therapy produced substantial rapid and enduring antidepressant effects among patients with MDD, and that the therapeutic effects persisted for at least 4 weeks. Furthermore, psilocybin was found to have low potential for addiction and a minimal adverse event profile.

Psilocybin is being used to treat a variety of psychiatric conditions, and mystical-type and psychologically insightful experiences are associated with favorable outcomes. Furthermore, psilocybin may decrease negative affect and the neural correlates of negative affect, which may be a mechanism underlying transdiagnostic efficacy.

The present trial showed that psilocybin administered in the context of supportive psychotherapy produced large, rapid, and sustained antidepressant effects. Psilocybin was associated with nonserious adverse effects, and may be more acceptable to patients than widely prescribed antidepressant medications.

Strengths and Limitations

This study had some strengths, such as a randomized design, blinded clinician raters, and controlled for the possible effects of having been accepted into the trial. However, it had some limitations.

This study has some limitations, including a short-term follow-up, a small sample, and a predominantly White non-Hispanic population. Further research is needed to better assess the safety and efficacy of psilocybin therapy among patients with MDD.

Conclusions

Psilocybin-assisted therapy produced large, rapid, and sustained antidepressant effects among patients with MDD. Further studies are needed in larger and diverse populations.