Response to emotional stimuli weaker in SSRI users compared with psilocybin

In a randomized double-blind trial, adults with moderate to severe depression received either the SSRI escitalopram or a placebo over six weeks, with both groups also receiving one high dose (25 mg) and one low dose (1 mg) of psilocybin at different points. Brain imaging showed that emotional responses to fearful, happy, and neutral faces were reduced in the escitalopram group but remained stable or increased slightly in the psilocybin group. Depressive symptoms improved more in the psilocybin group, and greater emotional responsiveness was linked to better symptom relief. The authors concluded that psilocybin therapy and SSRIs likely work through distinct therapeutic mechanisms.

Study at a glance

Abstract

Use of selective serotonin reuptake inhibitor (SSRI) antidepressants has been associated with reduced intensity of emotional experience. Conversely, some research has shown that use of psilocybin in patients with depression leads to an increase in responsiveness to emotional face stimuli, suggesting that the psychedelic generates a transient elevation in mood. Investigators conducted a randomized, double-blind trial comparing the effects of psilocybin and escitalopram on brain responsiveness in patients with depression. Participants, adults aged 18 to 80 with moderate to severe depression, were randomized into two groups. In the first, participants received escitalopram 10 mg/day for 3 weeks, which was then increased to 20 mg/day for another 3 weeks. In the second group, participants received placebo for 6 weeks. Prior to initiating escitalopram or placebo, the escitalopram group was administered a dose of psilocybin 1 mg (a sham dosage) and the placebo group received psilocybin 25 mg. The same psilocybin doses were administered to each group 3 weeks later. Both groups received psychological support during the study period. The primary clinical outcome was the score on the Quick Inventory of Depressive Symptomatology. Participants also underwent functional magnetic resonance imaging (fMRI) at baseline and after 6 weeks of escitalopram/placebo treatment, with testing of their responses to facial expressions depicting fear, happiness and a neutral emotion. A total of 45 participants completed the fMRI screenings. Clinical findings indicated a greater reduction in depressive symptoms in the psilocybin group, based on scores on the Beck Depression Inventory. Participant responses to emotional faces were significantly reduced in the escitalopram group, but remained stable or increased slightly in the psilocybin group. Results suggested that higher emotional function after psilocybin therapy was associated with greater improvement in depressive symptoms. “This study's findings lend support to the view that psilocybin therapy and SSRIs have distinct therapeutic mechanisms of action,” the authors wrote. [Wall, W., et al. (2025). American Journal of Psychiatry. https://doi.org/10.1176/appi.ajp.20230751]