Psilocybin therapy performed no better than open-label antidepressants for depression

Key Findings

🧠 Psychedelics don't simply increase brain excitability

• A systematic review of 49 electrophysiological studies reveals psychedelics have complex, heterogeneous effects on brain activity—not the simple "increased excitability" often assumed

• Psychedelics modulate both excitatory and inhibitory brain processes in cell-type and location-specific ways, with effects that can be biphasic and dose-dependent

• The compounds appear to work by fine-tuning calcium signaling and NMDA receptors rather than broadly ramping up neural activity

🔬 High-dose psilocybin trial misses primary endpoint despite promising signals

• 25mg psilocybin achieved a 17% response rate compared to 10.6% for placebo in 142 patients with treatment-resistant depression—not statistically significant

• Despite missing the primary outcome, exploratory analyses suggested clinically meaningful improvements on depression scales

• Safety concerns emerged: 4% of high-dose patients reported suicidal thoughts on dosing days versus 1-2% in comparison groups, plus one case of persistent visual disturbances

💊 Chronic antidepressant use dampens psychedelic effects in mice

• Mice given fluoxetine (Prozac) for 14 days showed reduced behavioral responses to psychedelics compared to acute treatment

• The effect was compound-specific: acute fluoxetine reduced psilocybin's efficacy but had no effect on DOI (another psychedelic)

• Stopping antidepressants for 14 days reversed the dampened response, suggesting the interaction is temporary but significant

🏪 Canada's gray-market psilocybin stores expanded 33% despite federal prohibition

• The number of brick-and-mortar psilocybin retailers grew from 57 to 75 stores between 2024 and 2025, despite high turnover (53% of 2024 stores closed)

• Two large chains now operate 44% of all Canadian psilocybin stores, with 97% located in Ontario and British Columbia

• 69% of online retailers sell products designed to mimic popular snack brands like Scooby-Doo Fruit Snacks and Arizona Iced Tea

💰 Psilocybin therapy could save healthcare systems money

• Economic modeling suggests psilocybin-assisted therapy would save approximately $7,000 per patient and provide 0.10 additional quality-adjusted life-years compared to standard depression care

• Over 30 years, the cumulative savings could reach $215,900 per patient with 9.87 additional quality-adjusted life-years

• The cost-effectiveness held up across different dosing strategies, retreatment assumptions, and psilocybin prices

🏃 Most psychedelic clinical trials actually qualify as psychotherapy

• Analysis of 29 clinical trials (449 patients) found 69% met all four criteria for psychotherapy using a standard framework

• Among trials explicitly labeled as "psychotherapy," 84% met all criteria, while 40% of "non-psychotherapy" studies still included psychotherapeutic elements

• This suggests the psychological support in psychedelic trials is more structured and therapeutic than often acknowledged