REVIEW OF: Carhart-Harris R et al, New Engl J Med 2021;384(15):1402–1411

STUDY TYPE: Randomized controlled trial

Psilocybin is, among other things, a serotonin 2A agonist responsible for the psychedelic properties of magic mushrooms. Back in 1960, Sandoz (now Novartis) began marketing psilocybin to enhance the effects of psychotherapy, but production was stopped soon after due to concerns about its abuse liability and potential to induce psychosis. Now, over a half-century later, the FDA has granted psilocybin breakthrough status and fast-tracked research to explore its potential antidepressant effects. Those effects have been associated with psilocybin’s ability to induce transcendent spiritual states. Similar to how it was used in the 1960s, modern-day psilocybin is delivered along with supportive psychotherapy to enhance those beneficial effects while maintaining close oversight in case patients experience a “bad trip.”

In this double-blind study, investigators randomized 59 patients with moderate to severe depression to receive either psilocybin 25 mg (given twice: on day 1 and on day 21) or escitalopram 10–20 mg/day over the course of six weeks. Importantly, most patients included in the trial were not treatment resistant, having taken on average only two psychotropic medications in the past. Although there was no placebo group, the escitalopram group received a microdose of psilocybin so all patients could be informed that they were receiving it—a clever maneuver that aimed to standardize expectations.

The primary outcome of interest was reduction in scores on the 16-item Quick Inventory of Depression Symptomatology-Self Report (QIDS). Both groups improved, with overall scores favoring psilocybin over escitalopram: 8- versus 6-point reduction in depression scores on the QIDS and response rates of 70% versus 48%. However, these differences were not statistically significant.

On questioning, patients receiving psilocybin reported greater perceived improvements “in the ability to cry and feel compassion, intense emotions, and pleasure.” Adverse effects were similar between the two groups, and there were no reports of perceptual changes, psychosis, or other serious problems with psilocybin.

TCPR’S TAKE
The study ostensibly shows that psilocybin is as effective as escitalopram for depression. However, the research suffers from two major flaws. First, the researchers failed to assess the integrity of the blind. Given that patients were mostly self-referred and highly motivated, and that 72% had used psilocybin in the past, they could very possibly have guessed whether they were receiving a therapeutic dose of psilocybin. Second, lacking a placebo group, we can’t know whether psilocybin even worked. Nearly 50% of SSRI trials fail to separate from placebo, and that’s with sample sizes 10 times larger than the ones used in this study. It’s possible that neither psilocybin nor escitalopram were effective.

The New England Journal of Medicine rarely publishes psychiatric research, and with the level of interest surrounding psilocybin, you will no doubt hear more about this pilot study. Unfortunately, the study fails to move the needle much, and it would be premature to recommend psilocybin to your patients until larger, placebo-controlled studies are conducted.

Related content: When Psilocybin was a Psych Med