Psilocybin’s effect on human brain synaptic plasticity

Introduction

Classical serotonergic psychedelics such as psilocybin and LSD are being investigated as potential treatments for several neuropsychiatric conditions. These compounds agonise the serotonin 2A receptor (5-HT2A R) and produce dose-dependent acute alterations in perception, emotion and cognition. One- or two-dose administrations of psilocybin have been associated with persistent positive emotional effects in healthy volunteers and symptom improvements in people with major depressive disorder and other conditions. A leading mechanistic hypothesis is that psychedelics promote neuroplasticity; preclinical work has reported rapid structural and functional synaptic changes following 5-HT2A R stimulation, including dendritic growth and upregulation of presynaptic markers such as Synaptic Vesicle glycoprotein 2A (SV2A). Johansen and colleagues set out to test whether a single oral dose of psilocybin increases synaptic density in the human brain, operationalised as SV2A binding measured with [11C]UCB-J PET. The study focused on two regions implicated in higher-order cognition and mood regulation, the frontal cortex and the hippocampus, and examined whether session setting and subjective aspects of the psychedelic experience related to any observed changes. The investigation used a single-arm, open-label design with baseline and one-week follow-up imaging to probe persisting synaptic effects after one dosing session.