Psilocybin May Not Be More Efficacious Than a Common Antidepressant

March 2022

The first-line treatment for major depressive disorder is a selective serotonin reuptake inhibitor, but not all patients respond to this treatment. Psilocybin, a psychedelic made by certain mushrooms, is one alternative that is receiving renewed interest. The mechanistic rationale for psilocybin in treating depression comes from its metabolite psilocin, a serotonin receptor agonist. Previous trials have suggested that psilocybin reduces symptoms of depression. In this phase 2 randomized trial, investigators examined whether psilocybin would be more efficacious than a widely used selective serotonin reuptake inhibitor for long-standing major depressive disorder.

Participants had a moderate-to-severe major depressive disorder. Participants were excluded if they or a family member had a history of psychosis, a previous suicide attempt, or previous use of escitalopram. The 30 patients in the psilocybin group received a 25-mg dose during a supervised visit to the trial site. The 29 patients in the escitalopram group received a 1-mg dose of psilocybin, a presumed ineffective concentration. At home, patients took a placebo (the psilocybin group) or escitalopram daily. The process was repeated in 3 weeks, after which the escitalopram dose was increased. All patients received psychological support from 2 mental health professionals during the psilocybin dosing. The primary outcome was the change from baseline in the Quick Inventory of Depressive Symptomatology–Self-Report with 16 items at 6 weeks.

Both groups had an improvement in scores from baseline, but the difference between groups was not statistically significant. Although secondary outcomes for other measures of depression, anxiety, and well-being were improved more with psilocybin than escitalopram, the investigators did not believe that any conclusion could be drawn.

Although patients were randomized, the groups differed in several respects before the start of the trial, which may have influenced the results. Escitalopram does not reduce symptoms rapidly, so a head-to-head comparison in a longer trial may favor escitalopram over psilocybin.

The investigators experienced some difficulties conducting a trial with a psychedelic that potentially induces different psychological effects in different people. They noted that the “content and subjective quality of the psychedelic experience is influenced by a person’s memories, perceptions, and degree to which the environment is supportive at the time of administration of the agent.” In this trial, patients with certain coexisting psychiatric conditions were excluded because of the risk of reactions that were too severe for the level of psychological support offered during psilocybin administration. This may have favored patients who could take psilocybin without serious adverse events.

Furthermore, many of the recruited patients said that they hoped to be in the psilocybin group. This desire raises the concern of biasing as some patients admitted to guessing their group assignment and changing their daily oral placebo or escitalopram doses. In fact, while 5 patients in the escitalopram group stopped or reduced their medication, none in the psilocybin group refused the second dose.

The investigators suggested that longer head-to-head trials with greater numbers of participants are necessary to determine whether psilocybin is comparable to current treatments.


Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of psilocybin versus escitalopram for depression. N Engl J Med. 2021;384:1402-1411.

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