Psychedelic drugs that activate the 5-HT2A receptor, such as psilocybin and DMT, produce dose-related psychological effects including hallucinations, out-of-body experiences, emotional breakthroughs, and mystical-type experiences. When combined with psychological support, these substances can rapidly improve mood in people with depression, with benefits lasting months. The therapeutic effects may stem from increased brain entropy that disrupts fixed negative thinking, enhanced cognitive flexibility after treatment, and changes in self-referential psychological processes. The brain mechanisms underlying serotonergic psychedelics likely differ from those of classical serotonin reuptake-blocking antidepressants.
A single high dose of psilocybin (25 mg) in 28 healthy, psychedelic-naive participants produced anatomical and functional brain changes lasting from one hour to one month. At one month, participants showed increased cognitive flexibility, psychological insight, and well-being. Diffusion tensor imaging revealed decreased axial diffusivity in prefrontal-subcortical tracts, correlating with reduced brain network modularity. Decreased modularity negatively correlated with increased well-being, consistent with depression findings. Increased cortical signal entropy one to two hours after dosing predicted improved well-being at one month, mediated by next-day psychological insight. No effects occurred with a 1 mg placebo dose.