Psilocybin May Not Be Safe or Offer a Long-term Benefit for Treatment-resistant Depression

EBM Focus - Volume 17, Issue 38

Reference: N Engl J Med. 2022 Nov 3;387(18):1637-1648

Practice Point: A treatment that offers a small, short-term benefit but that comes with a significant risk of (self-)harm is unlikely to take flight.

EBM Pearl: Minimally important clinical difference (MCID) is an important factor for interpreting scaled outcomes like depression scores.

With the relaxation of cultural and political pressures, the therapeutic potential of psychedelics is being reexamined. A recent phase 2 double-blind randomized trial published in NEJM explores the role of psilocybin, a hallucinogenic alkaloid found in magic mushrooms, in the management of treatment-resistant depression.

Investigators randomized 233 adults with treatment-resistant depression (mean age 39) to a single dose of a synthetic psilocybin at 25 mg, 10 mg, or 1 mg (control) during a 6-8 hour session accompanied by support from 2 trained therapists. At baseline, 68% had severe depression (MADRS scale total score ≥ 31 points) and 30% had moderate depression (MADRS total score 20-30 points). Prior to administration of psilocybin, participants completed a run-in period for 3-6 weeks in which antidepressants were tapered and discontinued. Participants were encouraged to stay off antidepressants for at least 3 weeks after taking psilocybin (though this was not required) and were followed for a total of 12 weeks.

Three weeks after psilocybin administration, an intention-to-treat analysis demonstrated a statistically significant decrease in MADRS scores in those randomized to 25 mg compared to 1 mg (-6.6 points, 95% CI -10.2 to -2.9 points), but not in those randomized to 10 mg. Response ( ≥ 50% reduction in baseline score) was not sustained in any group at 12 weeks. No minimally important clinical difference (MCID) in the primary outcome was identified by the authors, although an MCID of 6 points could be inferred as the study was powered to detect a difference of 6 points on the MADRS scale. In evaluation of harms, suicidal ideation or serious self-injury in the first 3 weeks occurred in 5% of the 25 mg group and in 4% of the 10 mg group. No such serious events occurred in the 1-mg group.

This study got a few things right which other studies of psilocybin have gotten wrong: multi-site recruitment, no confounding from concomitant psychotherapy, and a good-enough attempt at blinding, made possible by the choice of an active control and lack of previous exposure to psychedelics by most of the participants. However, we still don’t know whether the benefit seen with the higher-dose psilocybin is sustained past 3 weeks. We are left weighing the small, short-term benefit against the pretty clear safety concerns. In most cases, we would never consider using a treatment which could provide only a small short-term benefit at the risk of significant harm. However, in the management of depression, patients and clinicians seemingly have more tolerance for possible harms if it comes with hope for improvement.

For more information, see the topic Depression Alternative Treatments in DynaMed.

DynaMed EBM Focus Editorial Team

This EBM Focus was written by Nicole Jensen, MD, Family Physician at WholeHealth Medical. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Dan Randall, MD, Deputy Editor at DynaMed; Vincent Lemaitre, PhD, Senior Medical Writer at DynaMed; and Sarah Hill, MSc, Associate Editor at DynaMed.