bioRxiv : the preprint server for biologyJun 29, 2026

Psychedelics reduce brain prediction signals after use by changing connections between thinking areas

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 30, 2026

Abstract

Recent users of serotonergic psychedelics show a disruption of predictive processing in the brain.

Users of psychedelics such as psilocybin and LSD produced fewer fast eye movements and exhibited less suppression of brain wave activity when predicting stimuli, indicating altered information processing.
These alterations in predictive processing correlated with the time elapsed since psychedelic use.
In a second group using a different psychedelic, similar disruptions in predictive processing were observed.
Mice given psilocybin exhibited a loss of predictive suppression in the primary visual cortex 24 hours after administration.
This loss of predictive processing in mice coincided with reduced top-down modulation from a specific area of the medial prefrontal cortex and an increase in neuron growth in that region.

Simplified

Serotonergic psychedelics (e.g., psilocybin, LSD) have potential to treat psychiatric disorders, with therapeutic effects lasting days to weeks after a single dose. Prominent theories suggest that psychedelics have a lasting effect on hierarchical brain circuits, reducing top-down influence on information processing to facilitate an unbiased, bottom-up reassessment of the world, but direct and concrete evidence for such an effect is lacking. Here we directly tested this hypothesis in both humans and mice, assessing predictive processing in the fronto-visual system in the days after a single psychedelic exposure. Individuals who recently (<3 weeks) used 5-HT _2A Receptor agonist psychedelics (psilocybin, LSD) were assessed via electroencephalography (EEG) and electrooculography recordings during a saccadic prediction task and compared to age- and sex-matched non-users. Compared to non-users, recent psychedelic users produced fewer fast saccades and less suppression of EEG delta/theta power to predictively presented stimuli, pointing to a disruption of predictive processing. These changes correlated with time since psychedelic use and were replicated in a second cohort taking a different serotonergic psychedelic (5-MeO-DMT). Direct recordings of primary visual cortex (V1) in mice administered psilocybin (1 mg/kg) evinced a similar loss of predictive suppression 24-hrs after the dose. This coincided with weakened top-down modulation of V1 from anterior cingulate area (ACa), a subregion of medial prefrontal cortex, along with clear spine growth in ACa neurons that project to V1. These results suggest that psychedelic-induced neural plasticity serves to reorganize feedback circuits in the cortex and relax top-down influence on bottom-up sensory processing - an effect that persists beyond the acute exposure period and may underlie a therapeutic window.