Psychedelics like psilocybin and DOI alter the brain's hemodynamic response, potentially disrupting the normal coupling between neuronal activity and blood flow. In human fMRI scans, psilocybin induced changes in hemodynamic response functions. In awake mice, DOI differentially affected the relationship between cortical excitatory neuronal activity and hemodynamic signals, both during whisker stimulation and at rest, leading to discordant changes in functional connectivity measures depending on whether they were based on neuronal or hemodynamic data. A selective serotonin-2A receptor antagonist reversed many of these effects. The findings indicate that the vasoactive effects of psychedelics must be considered when interpreting blood-based measures of brain function.
Psychedelics show promise for treating mood disorders, but their effects on brain blood vessels have been overlooked. Psilocybin altered hemodynamic response functions in humans, suggesting changes in neurovascular coupling (NVC). Using wide-field optical imaging in awake mice, the psychedelic DOI (a serotonin-2A receptor agonist) partially altered task-based NVC but caused more pronounced NVC changes during rest, especially in association brain regions. Calcium and hemodynamic signals gave different accounts of resting-state functional connectivity under DOI. Co-administration with a 5-HT2A antagonist reversed many effects. The dissociation between neuronal and hemodynamic signals highlights the need to consider neurovascular effects when interpreting fMRI measures in psychedelic studies.