A lasting impact of serotonergic psychedelics on visual processing and behavior

Serotonergic psychedelics (e.g., psilocybin) have shown potential for treating psychiatric disorders, with therapeutic effects lasting weeks after a single dose. Predictive processing theories posit that psychedelics work by loosening priors or high-level beliefs, including ingrained biases that have become pathological, leading to shifts in bottom-up vs top-down information processing that reconfigure perception, cognition, and mood. Because 5-HT2A receptors, the primary target of psychedelics, are enriched in visual cortices, we investigated whether psychedelics alter visual processing in a manner consistent with predictive processing theories. People who recently (<3 weeks) used 5-HT2A-agonist psychedelics (psilocybin, LSD) exhibited slowed response latencies and increased cortical involvement in generating saccades to targets in predictable locations, along with a generalization of sensory prediction errors (i.e., deviance detection) during passive visual processing. Individuals who recently used a 5-HT1A- selective psychedelic (5-MeO-DMT) displayed similar changes in saccade production, but unaltered deviance detection, suggesting circuit-specific effects. Mice administered DOI (5- HT2A-agonist) exhibited altered deviance detection within primary visual cortex (V1), along with weakened top-down feedback to V1 from higher cortical area ACa. These results concord with the hypothesis that psychedelics shift the balance from top-down to bottom-up in sensory cortical circuits - an effect that persists beyond the acute exposure period.