Neurocognitive effects of psilocybin: A systematic and comprehensive review of neuroimaging studies in humans

Psilocybin is a psychedelic serotonergic compound that is renowned for its potent psychoactive effects. Over the past 15 years, an increasing number of controlled clinical trials showed that it has a fast-acting and sustainable efficacy in treating various psychiatric disorders. Neuroimaging studies have been conducted with the objective of elucidating the neurobiological mechanisms underlying the subjective and therapeutic effects of psilocybin. However, the diversity of neuroimaging techniques, tasks, and analytical approaches makes it difficult to gain a comprehensive overview of psilocybin's effects on the brain. To address this gap in the literature, we conducted a systematic review in the Medline, Psychinfo and Cochrane databases between January 1, 1990, and May 9, 2025, following PRISMA recommendations. A total of 81 articles met the inclusion criteria. A variety of neuroimaging techniques were employed in small samples of healthy volunteers and patients with medical conditions. The studies investigated the effects of psilocybin on brain activity and connectivity, both at rest and during cognitive tasks. They revealed that psilocybin reproducibly impacted neuronal networks such as the default mode network. However, other findings were more inconsistent. Psilocybin effects on the brain were associated with acute alterations in self-experience, sensory and emotional processing, and sustained effects on mood, personality, and social functioning. In patients with depression, clinical outcomes correlated with brain changes. This review indicates that psilocybin induces acute and long-lasting functional brain changes. While these neuroimaging data require confirmation and further expansion, they shed light on the mechanisms of psilocybin's acute subjective and therapeutic effects in humans.