Psilocybin Depression Treatment Shows Shared Brain Mechanisms with Standard Antidepressants

Too long to read? Go for the highlights below.

• Psilocybin and escitalopram both reduced negative emotional bias in depressed patients, suggesting overlapping mechanisms despite different chemical pathways

• Both treatments improved facial emotion recognition equally after six weeks, though long-term correlations with symptom improvement differed between drugs

• The findings reveal how psychedelic therapy may work through similar brain changes as traditional antidepressants, despite requiring only two doses versus six weeks of daily medication

---

A clinical trial comparing psilocybin (the active compound in magic mushrooms) with a standard antidepressant has revealed unexpected similarities in how both treatments alter emotional processing in the brain. The research, published in Translational Psychiatry, examined 59 patients with long-standing moderate-to-severe depression and found that both interventions produced comparable shifts in how people interpret emotional information.

Credits: Britanica

The study design placed participants into two groups: one received two 25-milligram doses of psilocybin three weeks apart, whilst the other took daily escitalopram for six weeks alongside two low doses of psilocybin. All participants received identical psychological support. Researchers measured changes in emotional cognition using the Facial Expression Recognition Task, an established method for detecting how antidepressants influence brain function.

Negative Bias Reduction Across Both Treatments

Depression characteristically distorts emotional perception: patients tend to interpret neutral or ambiguous facial expressions as more negative than they actually are. This negative bias plays a fundamental role in maintaining depressive symptoms. The trial demonstrated that both psilocybin and escitalopram reduced this distortion to statistically comparable levels.

Credits: The Guardian

Specifically, participants showed decreased accuracy in recognising negative facial expressions after treatment, along with fewer misclassifications of other faces as negative. In practical terms, patients stopped seeing negativity where none existed: a shift that represents more balanced emotional processing rather than artificially inflated positivity.

The magnitude of improvement proved substantial. Across both groups, negative bias reduction showed an effect size of 0.85 for accuracy and 0.37 for misclassifications. Response times also improved, with participants becoming quicker at processing both negative and positive emotions after treatment.

Divergent Pathways to Similar Outcomes

The parallel outcomes appear particularly noteworthy given the distinct pharmacological mechanisms involved. Escitalopram, a selective serotonin reuptake inhibitor, works by gradually increasing serotonin availability in neural synapses over several weeks. Psilocybin acts as a direct serotonin 5-HT2A receptor agonist (binding to specific serotonin receptors rather than modulating overall serotonin levels) and produces therapeutic effects within days rather than weeks.

Previous neuroimaging work from the same trial revealed that escitalopram reduced brain activity in the amygdala (the region processing emotional responses) when viewing emotional faces, whilst psilocybin showed no such dampening effect. Yet both treatments produced similar behavioural outcomes in emotional processing tasks. This suggests that different neural routes may converge on shared psychological mechanisms.

Credits: Business Insider

The cognitive neuropsychological model of antidepressant action proposes that successful treatments work by acutely shifting the balance of negative versus positive emotional processing, with clinical mood improvements following later as patients interact with their environment. The current findings support this framework, though with important caveats.

Temporal Patterns and Predictive Value

When researchers examined whether changes in emotional bias predicted subsequent depression improvement, they found divergent patterns. For escitalopram, reduced negative bias at six weeks correlated with lower depression scores at the ten-week follow-up—consistent with the model that bias changes require time to translate into mood improvements through environmental interaction.

Surprisingly, this correlation did not hold for psilocybin, where bias reduction showed no statistical relationship with later symptom improvement. The correlation coefficients actually pointed in opposite directions between the two groups. This suggests that whilst both treatments may alter emotional processing similarly, the mechanisms linking those changes to therapeutic benefit might differ.

Several explanations warrant consideration. Psilocybin's rapid onset of therapeutic effects may involve additional mechanisms beyond emotional bias shifts, perhaps through increased neural plasticity or altered processing of established negative memories. Alternatively, the timing of measurements may have missed earlier bias changes that drive psilocybin's therapeutic effects.

Methodological Considerations and Future Directions

The study's design presents both strengths and limitations. The facial recognition task has proven sensitive to antidepressant effects across multiple trials, and behavioural measures prove less susceptible to placebo effects than subjective symptom reports: a particular concern in psychedelic research where blinding proves difficult due to obvious drug effects.

However, the absence of a placebo control group limits definitive conclusions about treatment efficacy. Both groups showed numerical improvements in depression scores, but without an inert comparison, separating drug effects from natural improvement or placebo responses remains impossible. The trial also measured emotional processing only at baseline and six weeks, potentially missing earlier changes that might clarify mechanistic differences.

Future research should incorporate placebo controls and measure emotional processing at multiple timepoints, particularly in the days immediately following treatment. This would help determine whether psilocybin produces earlier bias shifts than conventional antidepressants, and whether those early changes predict later clinical response.

The findings nonetheless advance understanding of psychedelic therapy's mechanisms. Demonstrating that psilocybin and conventional antidepressants produce similar changes in emotional processing, despite different pharmacology and dosing schedules, suggests at least partial overlap in how disparate treatments address depression. Whether this represents convergent evolution in therapeutic approaches or fundamentally shared mechanisms remains an open question deserving further investigation.