Long-term antidepressant effects of psilocybin linked to functional brain changes

Psilocybin can produce long-term antidepressant-like effects without lasting structural changes to neuron wiring, suggesting functional brain alterations may be the key mechanism. In rats, a single dose of psilocybin improved behavior in the forced swim test for at least 5 and 12 weeks. The study also used 25CN-NBOH, a synthetic compound designed to target the 5-HT2A serotonin receptor, and it produced a similar antidepressant-like effect. After 12 weeks, researchers examined the medial prefrontal cortex and found dendritic spine density and synapse-related gene expression returned to baseline, arguing against persistent structural plasticity. Electrophysiology showed lasting changes in intrinsic neuron electrical properties, including increased excitability and a state closer to firing threshold for adapting neurons. The findings point to 5-HT2A receptor activation as sufficient to trigger durable functional plasticity that may sustain antidepressant outcomes.