Cross-species mapping of acute psychedelic-responsive genes links HTR2A cortical expression, cell-type enrichment, and human cortical expression modules

Abstract Psychedelic drugs exert rapid and profound effects on human consciousness [1–7] and are increasingly being investigated for their therapeutic potential [8–14]. Yet the transcriptional programs through which they may reshape brain function and structure remain incompletely understood, in part because the available evidence is heterogeneous and largely preclinical [15, 16]. In a structured scoping review of transcriptomic studies in animal models and neural cell cultures, we identified genes reported in the source literature to change within 3 h of classical psychedelic administration and intersected them with the Allen Human Brain Atlas to define an acute expression set. This retained set showed cortex-centered enrichment, a marker-based deep-layer projection-neuron component, and ontology enrichment for neuron projection and related synaptic terms. A smaller subset overlapped with human accelerated region-associated genes and showed greater-than-random spatial alignment with a human cortical-expansion map. The retained cortical-expression maps showed serotonergic spatial alignment in the human cortex, most prominently with HTR2A expression. Clustering identified three cortical spatial-expression modules, including an association/limbic-weighted module enriched for plasticity and synaptic-organization terms. Together, these findings provide a human cortical framework linking acute psychedelic-responsive transcription to cortical cell-type enrichment, HTR2A spatial expression, cortical spatial-expression modules, and cortical-expansion, while leaving receptor-specific, causal, translational, and cell-type-resolved mechanisms for future work.