Reference: JAMA. 2023 Sep 5;330(9):843-853
Practice Point: Single-dose psilocybin 25 mg appears safe and effective for moderate to severe MDD, with results lasting at least 6 weeks.
EBM Pearl: Patients lost to follow-up in trials are often sicker, less adherent, or both, which predisposes them to worse outcomes. ITT analysis is essential to moderate the impact of differential loss-to-follow up on results.
Depression can be hard to treat, and harder to watch as patients suffer. Patients are often at an all-time low, feeling unmotivated to get out of bed with little energy to do basic day-to-day obligations. Yet, most treatments require them to remember to take a pill every day which doesn’t make them feel any better for weeks (if it ever does), and may give them side effects that make them feel worse in the meantime. If patients are even willing to try therapy, they are required to jump through many hoops just to get an appointment, then have to show up for weekly visits and do the emotionally exhausting work that often is therapy. You can see why a magic pill is in order.
A recent randomized trial of 104 adults with moderate-to-severe depression evaluated a single dose of psilocybin 25 mg versus niacin 100 mg, an active control that results in flushing symptoms. Each drug was administered as a one-time dose during an 8- hour “set and setting” protocol that involved guiding them through the experience and monitoring for side effects. Patients were evaluated at 8 and 43 days using the 60-point MADRS questionnaire administered by a blinded outcome assessor. Results were impressive, showing an improvement of 19.1 vs 6.8 points at 6 weeks in the psilocybin group compared to niacin. Significant improvements were seen in the psilocybin group at as early as 2 days, with sustained depressive symptom response (≥ 50% reduction in MADRS score) at each visit up to 6 weeks in 41.7% vs. 11.4% (p = 0.002, NNT 4). There were no severe adverse effects related to treatment in either group, but more minor ones (headache, nausea) with psilocybin.
This study is important for several reasons. First, previous trials of psilocybin have been criticized for functional unblinding due to lack of side effects with inactive or mildly active placebo, with the implication being that the magnitude of effect seen with psilocybin could have been exaggerated. In this trial, the use of niacin allowed for better blinding of the intervention. The differential loss to follow up, 21% in the niacin group compared to 2% in the psilocybin group, could suggest that patients might still have known the difference to some extent. It could also mean, however, that the psilocybin worked better, and more patients in the niacin group were still too depressed to come back for follow-up. Second, the fact that the improvements persisted at 6 weeks is very promising, as previous studies mostly evaluated much shorter-term outcomes.
As somewhat of an aside, from time to time we talk about how per protocol (PP) analyses tend to overestimate the magnitude of effect compared to intention-to-treat (ITT) analyses in superiority trials. This phenomenon is demonstrated in this trial, with a higher magnitude of effect seen in the PP analysis compared to the ITT, in the setting of a higher dropout rate in the control group. In addition, sustained remission rates were not significantly improved in the ITT analysis, but the differences were significant with PP. Patients drop out for a variety of reasons, but are often sicker or less compliant, both of which we know to be associated with worse outcomes in general. So if you compare a group where people with worse outcomes were removed to one where they are included (as is done with PP), the treatment effect may appear better than it truly is.
While psilocybin is obviously not really a magic pill, and it does still involve some amount of effort on the patient’s part to show up to the day-long therapy session, the magnitude of benefit compared to other available treatments and the relative lack of adverse effects suggests that this treatment might be about ready for prime time.
For more information, see the topic Depression Alternative Treatments in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Dan Randall, MD, Deputy Editor at DynaMed; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Medical Editor at DynaMed; Elham Razmpoosh, PhD, Postdoctoral fellow at McMaster University; and Sarah Hill, MSc, Senior Associate Editor at DynaMed.