A new randomized controlled trial directly compared the brain effects of psilocybin-assisted therapy and escitalopram, a commonly prescribed SSRI, in patients with moderate-to-severe major depressive disorder (MDD). Using functional MRI (fMRI) to measure brain responses to emotional facial expressions, the researchers found striking differences between the two treatments, despite both yielding significant improvements in clinical symptoms.

The study involved 59 patients randomized to receive either two high-dose sessions of psilocybin (25mg each, three weeks apart) with daily placebo, or daily escitalopram (up to 20mg) with two low-dose psilocybin placebos (1mg). Both groups received equal psychological support, and fMRI scans were performed before treatment and at the six-week endpoint.

Clinically, both treatments reduced depression severity. However, the psilocybin group showed greater improvements on the Beck Depression Inventory (BDI), well-being scales, emotional responsiveness, and had significantly less sexual dysfunction compared to those on escitalopram. Importantly, patients receiving psilocybin reported increased emotional sensitivity, in contrast to the emotional blunting often associated with SSRIs.

On neuroimaging, escitalopram was associated with a significant reduction in brain activity in response to emotional stimuli, particularly in cortical regions involved in social and affective processing. The amygdala, a key region for emotional salience, also showed reduced responsiveness to fearful faces. In contrast, psilocybin therapy produced no such reductions—there was even a slight increase in responsiveness to neutral faces. These differences suggest that while escitalopram may work by dampening limbic reactivity, psilocybin therapy appears to preserve or enhance emotional processing.

Exploratory analyses revealed that clinical improvement in the escitalopram group was closely tied to reduced emotional intensity, suggesting that emotional blunting may be a therapeutic mechanism for SSRIs. Conversely, in the psilocybin group, improved emotional function—rather than reduced reactivity—was predictive of better outcomes. This highlights a mechanistic distinction: SSRIs may reduce distress by dulling emotional responses, while psilocybin may promote healing by enhancing emotional awareness and engagement.

This study underscores that psilocybin and SSRIs operate through fundamentally different pathways in the brain. Psilocybin’s mechanism—via 5-HT2A receptor agonism—may facilitate emotional reconnection and neuroplasticity, offering a new route for depression treatment that aligns more closely with psychotherapeutic models. As psilocybin therapy gains interest as a rapid-acting and well-tolerated alternative, these findings provide critical insight into how it may work differently, and perhaps more holistically, than traditional antidepressants.

Reference:
Wall MB et al. Am J Psychiatry. Epub ahead of print. Abstract.