Psilocybin’s acute and persistent brain effects: a precision imaging drug trial

Introduction

Psilocybin (PSIL) is a serotonin 2A (5-HT2A) agonist that has shown rapid and sometimes persistent benefits in clinical trials for conditions such as depression, end-of-life anxiety, obsessive–compulsive disorder, eating disorders, and alcohol use disorder. Previous human neuroimaging studies of psychedelics have reported acute decreases in functional connectivity within the default mode network and reduced fMRI signal power across cortex, but they have faced important limitations including inter-individual variability, head motion, autonomic changes, and potential vascular/neurovascular confounds that complicate interpretation of acute drug effects. Subramanian and colleagues aimed to address these limitations by applying a "precision imaging drug trial" (PIDT) approach, which builds on precision functional mapping (PFM) through dense repeated resting-state fMRI sampling, individualized network mapping, physiological monitoring, and advanced multi-echo acquisition and denoising. The study used a randomised cross-over design in healthy adults to compare acute and persistent brain effects of a single 25 mg oral dose of psilocybin versus an active control (40 mg methylphenidate, MTP), and included longitudinal follow-up and a replication protocol in a subset of participants. The dataset combines multi-echo resting and task fMRI, structural MRI, diffusion basis spectrum imaging, and detailed subjective and physiological measures, and is released as a resource to study individual differences and common network-level effects of psilocybin.