Response to emotional stimuli weaker in SSRI users compared with psilocybin
The Brown University Psychopharmacology Update August 4, 2025 DOI: 10.1002/pu.31349 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Double-blind Peer reviewed |
|---|---|
| Sample size | 45 |
| Population | Adults aged 18 to 80 with moderate to severe depression |
| Interventions | Psilocybin Escitalopram |
| Dose | psilocybin 25 mg, escitalopram 10 mg/day for 3 weeks then 20 mg/day for 3 weeks |
| Duration | 6-week intervention |
| Topics | Psilocybin |
| Keywords | Cognitive psychology Audiology Hallucinogen |
| Key findings | Emotional responsiveness to faces was reduced by escitalopram but maintained or slightly increased by psilocybin, and greater emotional responsiveness after psilocybin was associated with larger reductions in depressive symptoms. |
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]
Comparable studies
Other randomized controlled trials on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety | 2016 | Randomized controlled trial | n = 51 |
| Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Patients with cancer-related anxiety and depression | 2016 | Double-blind, placebo-controlled, crossover trial | n = 29 |
| Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance Hallucinogen-naïve adults reporting regular participation in religious or spiritual... | 2006 | Double-blind study | n = 36 |
| Trial of Psilocybin versus Escitalopram for Depression Selected group of patients with depression | 2021 | Randomized controlled trial | |
| Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder Adults aged 21 to 75 years with major depressive disorder, not currently using... | 2020 | Randomized controlled trial | n = 24 |