Cross-species mapping of psychedelic gene expression reveals links to the 5HT2A receptor, cortical layers, and human accelerated regions

Psychedelic drugs exert rapid and profound effects on human consciousness and are increasingly explored for their clinical potential. Yet, the genetic programs through which psychedelics reshape brain function and structure remain incompletely understood, in part because most studies have been conducted in preclinical models and cell cultures. We conducted a systematic literature search of transcriptomic studies in animal models and cell cultures to identify genes changing expression within 5 hours from the administration of a classical psychedelic. By cross-referencing with the Allen Human Brain Atlas, we identified a set of high-confidence psychedelic-responsive genes expressed in the human brain. These genes showed selective enrichment in cortical pyramidal neurons (layers 5 and 6) and were associated with Gene Ontology categories linked to neuron projection and neuronal spine morphology. Strikingly, psychedelic-responsive genes were overrepresented among human accelerated genes, suggesting an evolutionary dimension to their regulation. Spatial expression of the gene set was selectively correlated with the cortical distribution of the 5HT2A receptor, the canonical target of classical psychedelic compounds. Clustering analysis further revealed three distinct cortical gene expression modules, potentially reflecting separable biological pathways engaged by psychedelic action in the human brain. Together, these findings delineate a convergent molecular architecture through which psychedelics may shape cortical circuits and provide a translational framework to link cellular gene expression changes with macroscale neurobiology in humans.