Psilocybin and escitalopram produce antidepressant effects via distinct brain mechanisms, study suggests

A new study published in the American Journal of Psychiatry sheds light on how psilocybin and the antidepressant escitalopram affect brain responses to emotional stimuli in people with major depressive disorder. While both treatments led to improvements in mood, only escitalopram was linked to a reduction in brain activity in response to emotional faces. Psilocybin, on the other hand, appeared to preserve or slightly enhance emotional responsiveness, especially to neutral expressions.

Psilocybin is a naturally occurring psychedelic compound found in certain mushrooms. In recent years, it has attracted growing attention as a potential treatment for depression, particularly for individuals who do not respond to standard antidepressants. Unlike traditional medications, which typically take several weeks to show results, psilocybin often leads to rapid and lasting improvements after just one or two sessions, especially when paired with psychological support.

Traditional antidepressants like escitalopram work by increasing levels of serotonin, a brain chemical involved in mood regulation. However, these drugs are often only moderately effective and may come with side effects such as emotional blunting and sexual dysfunction. Emotional blunting refers to a general reduction in emotional intensity or responsiveness and has been reported by nearly half of patients taking selective serotonin reuptake inhibitors (SSRIs).

The researchers behind this study wanted to find out whether these two treatments—psilocybin and escitalopram—have different effects on how the brain responds to emotional information, especially facial expressions, which are central to social and emotional communication.

“This is part of a long program of research at Imperial College London, which I’ve been very lucky and honored to be a part of, which is investigating the effects of psychedelic therapy. The inspiration for this particular study was to compare psychedelic therapy with a standard depression treatment (escitalopram) and investigate the possible mechanisms behind both,” explained study author Matt Wall, the director of translational MRI at Perceptive Inc. and a honorary senior lecturer at Imperial College London.

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To investigate this, the researchers conducted a randomized, double-blind clinical trial comparing psilocybin-assisted therapy with a standard course of escitalopram. The study included 46 individuals with moderate to severe depression. Twenty-five participants received two high-dose psilocybin sessions spaced three weeks apart, along with daily placebo capsules. Twenty-one others received daily escitalopram, beginning with 10 milligrams per day for the first three weeks and increasing to 20 milligrams for the final three weeks, along with two placebo psilocybin sessions involving a nonpsychoactive 1-milligram dose. All participants received the same psychological support throughout the trial.

Before starting treatment and again six weeks later, participants underwent functional MRI scans while viewing emotional facial expressions—fearful, happy, and neutral. This allowed the researchers to observe how the brain’s response to emotional information changed over time and differed between the two treatment groups.

The results showed clear differences between the groups. In the escitalopram group, brain activity in response to emotional faces decreased across a wide range of cortical regions after treatment. The amygdala, a brain structure involved in processing emotions like fear, also showed reduced responses to fearful faces in this group. These findings are consistent with earlier studies linking SSRIs to dampened emotional responses, which may help patients feel less overwhelmed by negative emotions but can also blunt positive feelings.

In contrast, psilocybin did not lead to the same kind of neural dampening. In fact, responses to emotional faces were mostly unchanged or slightly increased, especially in response to neutral expressions. Activity in the amygdala showed minimal change following psilocybin treatment. The differences in brain responses between the two groups were significant and involved areas linked to attention, emotion, and social understanding.

One possible reason for the absence of strong neural changes in the psilocybin group may be the timing of the post-treatment scans. “Some of our previous work actually showed an increase in emotional brain function after psychedelic therapy, which we didn’t see this time; we think this is probably due to the timings of the after-treatment scans in this study which was quite a long time after the psychedelic therapy sessions (three weeks),” Wall told PsyPost. “These effects we saw before may have worn off by then.”

Despite these neural differences, both treatments were effective in reducing depressive symptoms. Participants in the psilocybin group reported larger improvements in well-being, pleasure, and emotional intensity compared to those in the escitalopram group. Notably, those treated with escitalopram showed greater reductions in emotional intensity, consistent with emotional blunting. Sexual function scores also declined more in the escitalopram group.

Additional analyses explored how changes in brain activity and emotional function were related to clinical outcomes. In the escitalopram group, reductions in brain responses to emotional stimuli were associated with improved mood—particularly among participants who also experienced emotional blunting. In contrast, in the psilocybin group, improvements in depression were more closely tied to increases in emotional intensity rather than changes in brain activation. This suggests that while SSRIs may work by dampening emotional reactivity, psilocybin may help people reconnect with their emotions.

These findings indicate “that psychedelic therapy and escitalopram were both effective treatments for depression, but the mechanisms behind how they produce these clinical effects may be quite different,” Wall said. “Escitalopram seems to reduce brain responses to all emotions, and we think this may relate to a common side effect of standard antidepressants called emotional blunting where patients report that they feel emotionally flat or numb. On the other hand, psychedelic therapy was as good as (or perhaps even better) at treating depression symptoms, but without the change in emotional brain function. Psychedelic therapy may be a good antidepressant treatment for patients who find the emotional blunting side-effects of standard antidepressants problematic.”

But there are some caveats to consider. Although the study was randomized and blinded, the strong effects of psilocybin likely made it easy for participants to guess their treatment group.

“It’s still a pretty small study with roughly 20 subjects in each group, so bigger studies of this type would be useful,” Wall noted. “Also, there are the standard issues with psychedelic research where it’s very difficult to keep subjects blinded to which treatment they’re having; it’s usually very clear to the patient if they’re in the psychedelic treatment group!”

Future research with larger samples and different timing may help clarify how psilocybin influences emotional brain function over time. Studies that include more diverse populations, varied imaging tasks, and direct measures of brain plasticity could also offer new clues about how this therapy works.

“Long-term the aim is really to have psychedelic therapy available as a mainstream treatment in a range of possible psychiatric disorders, but unfortunately we’re still quite a long way from that goal, and there a huge number of scientific, legal, and political hurdles to get over on the way,” Wall said.

The study, “Reduced Brain Responsiveness to Emotional Stimuli With Escitalopram But Not Psilocybin Therapy for Depression,” was authored by Matthew B. Wall, Lysia Demetriou, Bruna Giribaldi, Leor Roseman, Natalie Ertl, David Erritzoe, David J. Nutt, and Robin L. Carhart-Harris.