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Simple question: Is psilocybin a potential treatment for major depression? There’s certainly been a lot of press coverage, but, to date, the reports are largely open trials in a variety of conditions, including OCD, substance use, PTSD, and patients with cancer and psychological distress. Against that backdrop, a randomized trial of psilocybin for major depressive disorder is an exciting new step.
Hi! Jim Phelps for the Psychopharmacology Institute. You’re thinking that the results of this randomized trial must be positive, and sure enough, they are. What’s interesting are, who did they study, and, of course, is this a big enough sample to have some confidence in the results? So, let’s get into the results.
A delayed treatment group did get psilocybin but not until 2 months after the treatment group. These were the controls, and they didn’t really improve at all. At baseline, 5, and 8 weeks, their Hamilton Depression Scale scores were 22, 23, and 23. The treatment group got psilocybin shortly after study entry, and their HAM-D scores at baseline, 5, and 8 weeks were 23, 8, and 8. The difference between treatment and control amounts to an effect size of 2.2 at Week 5 and 2.6 at Week 8. An effect size of 2.5—that’s huge. But then come all the caveats.
First, think about the design. Take a bunch of people willing to get psilocybin for their depression in a country such as the United States, where it’s not easy to get psilocybin for depression outside such a study, then make these enthusiasts wait for 2 months. Well, of course, that control group wouldn’t get better even with some mood assessments at Weeks 5 and 8. And you’d expect a huge placebo response in a group that presumably comes into a study with high hopes. For the treatment group, intervention also included hours with 2 trained facilitators, select music, and a couch. Well, even if you cut the effect size in half, it’s still big.
So, who were these 27 participants? Wait a minute—27? That’s the sample size? Right. Of 870 people assessed for eligibility, 800 were excluded. Red flags going up here. The sample may have been so highly selected so that even though the results were amazing, they may not be very generalizable.
What were the exclusion criteria? Half of the 800 excluded simply lived too far away, as the study was conducted at Johns Hopkins in Baltimore, or they were already on an antidepressant, or they couldn’t have the MRIs that were part of this study. The MRI data are not published yet and may be coming later. But most of the remaining half of those excluded had reasons that directly relate to your patients, such as an overweight BMI, significant prior suicide attempt, prior hallucinogen experience, some other psychiatric diagnosis besides major depression, other psychiatric medications, or failure to respond to ECT during the current episode.
So, you can see that there was some selection for favorable participants here. Moreover, after an in-person interview, another 60% were excluded because they did not have confirmable major depression, had a history of significant substance use, were at risk of developing suicidal ideation, or were—get this—“judged to be incompatible with the establishment of rapport or safe exposure to psilocybin.” That latter group accounted for a quarter of these after-interview exclusions.
So, we can conclude that the stunning effect sizes are in a population selected to be relatively ideal for psilocybin and treated by one of the world’s most experienced treatment teams. As the advertising phrase goes, your results may vary. Nevertheless, this study strongly suggests that psilocybin has antidepressant effects in select patients. Which patients? Well, the treatment protocol includes an assessment of prior antidepressant response, but it doesn’t appear to select for treatment-resistant patients. In any case, before we endorse psilocybin, let alone recommend it for patients with major depression, we should await further insight into what centers like Johns Hopkins are selecting for. In that subgroup, they have demonstrated striking results.
If you’re interested, there is more on this paper, which is linked here at the Psychopharmacology Institute. Details of their treatment protocol are found in Supplement 1. The 5 half-lives antidepressant taper for some participants is also worth investigating in terms of generalizing the results.
Abstract
Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial
Alan K Davis, Frederick S Barrett, Darrick G May, Mary P Cosimano, Nathan D Sepeda, Matthew W Johnson, Patrick H Finan, Roland R Griffiths
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, 16 participants (67%) 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.
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Reference
Davis, A. K., Barrett, F. S., May, D. G., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., Finan, P. H., & Griffiths, R. R. (2020). Effects of psilocybin-assisted therapy on major depressive disorder. JAMA Psychiatry. e203285.
