Review of: Davis AK et al, JAMA ­Psychiatry 2020:e203285

Intravenous ketamine and intranasal esketamine (Spravato) offer hope in the search for a rapidly acting antidepressant. However, concerns regarding addiction, safety, and effect durability have prompted searches for alternative rapid-acting treatments. Psilocybin is a hallucinogen originally derived from “magic mushrooms” that, like ketamine, is a recreational drug with potential antidepressant effects. Recently, researchers published the first controlled study to explore its efficacy for depression.

Participants diagnosed with moderate to severe depression, and not taking antidepressants, were randomly assigned to a treatment group (n = 14) or a delayed-treatment/waiting-list control group (n = 13). During the initial 8 weeks, the immediate-treatment group received 3 weeks of preparatory therapy followed by two day-long sessions in which they received a lower dose of psilocybin (20 mg/70 kg) in session 1 and a higher dose (30 mg/70 kg) in session 2. During the psilocybin sessions, they received supportive therapy and were encouraged to focus their attention inward as they listened to music. Patients who were randomized to the delayed group were also provided the active 8-week psilocybin protocol after first serving as a no-treatment control for the immediate group.

How well did psilocybin work? In those first 8 weeks, the immediate group responded rapidly and significantly compared to the control group. Subjects in the control group experienced no improvement while waiting, but once treated, they responded as robustly as the immediate group on all measures. At 1 week and 4 weeks after the last drug session, 67% and 71% of pooled treated subjects, respectively, demonstrated a clinically significant response (greater than 50% drop in GRID HAM-D scores). At those same 1- and 4-week measurement points, 58% and 54% of treated subjects, respectively, experienced remission (GRID HAM-D score < 7).

Psilocybin was well tolerated. The main side effects included vague emotional symptoms (fear, sadness) and physical symptoms (such as a trembling sensation and mild, transient headaches).

CHPR’s Take
Psilocybin appears to rapidly and significantly reduce depressive symptoms. Unlike ketamine, psilocybin is not addictive, and its antidepressant efficacy seems to last longer (weeks vs days for ketamine). We’ll need larger studies to have more confidence in its efficacy.