Psilocybin's effect on human brain synaptic plasticity

Psychedelics such as psilocybin have been linked to enhanced neuroplasticity and symptom relief in affective disorders, but the neurobiological mechanisms and impact of environmental context remain unclear. Here, we tested whether a single dose of psilocybin (0.3 mg/kg) alters synaptic density in healthy individuals and whether setting-dependent subjective experience shapes this effect. Fifteen healthy participants had a psilocybin-induced psychedelic experience either inside an MRI scanner or in a therapeutic-like room. We assessed synaptic density changes by measuring the Synaptic Vesicle glycoprotein 2A in the frontal cortex and hippocampus with [¹¹C]UCB-J PET at baseline and one-week post-dose, and assessed subjective experiences immediately afterwards and at three months. Overall, we found no statistically significant increase in SV2A density. However, participants treated in the therapeutic-like setting exhibited more intense mystical-type experiences, longer-lasting psychological benefits, and greater increases in synaptic density than those dosed in the MRI scanner. These findings indicate that psilocybin's neuroplastic effects are modulated by environmental context, with important implications for psychedelic-assisted therapies. ClinicalTrial: NCT03289949.