Serotonergic psychedelics delay resting state neurovascular coupling dynamics

Psychedelics are increasingly explored as tools to investigate consciousness and cognition, and as potential treatments for mood disorders. While neuroimaging has been central to characterizing their mechanisms of action, the interpretation of these studies may be confounded by the neurovascular effects elicited by these drugs. Here, we investigated the modulation of resting state neurovascular coupling by the serotonergic psychedelics LSD and DMT. Applying a blind deconvolution algorithm to blood-oxygen-level-dependent (BOLD) signals, we found that both drugs increased the estimated hemodynamic delays in regions overlapping with the distribution of serotonin receptors implicated in psychedelic action and vascular regulation. Deconvolution enhanced the detection of psychedelic-induced changes in whole-brain functional connectivity, suggesting that vascular effects obscure connectivity changes instead of generating spurious results. Finally, a biophysical whole-brain model linked these effects to increased flow-dependent feedback and slower dissipation of the vasoactive drive. These findings underscore the need to account for vascular effects in future psychedelic neuroimaging studies.