Acute psilocybin and ketanserin effects on cerebral blood flow: 5-HT2AR neuromodulation in healthy humans.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism – February 26, 2025
Source: PubMed
Summary
Psilocybin reduces brain blood flow by 11.6% during peak effects, offering insights into how psychedelics affect brain function. Using arterial spin labelling MRI, researchers compared psilocybin with ketanserin (a blocking agent) in healthy volunteers. Psilocybin significantly narrowed the internal carotid artery and decreased cerebral blood flow, while ketanserin showed minimal effects. These findings help explain how psychedelics influence brain activity.
Abstract
Psilocin, the active metabolite of psilocybin, is a psychedelic and agonist at the serotonin 2A receptor (5-HT2AR) that has shown positive therapeutic effects for brain disorders such as depression. To elucidate the brain effects of psilocybin, we directly compared the acute effects of 5-HT2AR agonist (psilocybin) and antagonist (ketanserin) on cerebral blood flow (CBF) using pseudo-continuous arterial spin labeling magnetic resonance imaging (MRI) in a single-blind, cross-over study in 28 healthy participants. We evaluated associations between plasma psilocin level (PPL) or subjective drug intensity (SDI) and CBF. We also evaluated drug effects on internal carotid artery (ICA) diameter using time-of-flight MRI angiography. PPL and SDI were significantly negatively associated with regional and global CBF (∼11.6% at peak drug effect, p < 0.0001). CBF did not significantly change following ketanserin (2.3%, p = 0.35). Psilocybin induced a significantly greater decrease in CBF compared to ketanserin in the parietal cortex (pFWER < 0.0001). ICA diameter was significantly decreased following psilocybin (10.5%, p < 0.0001) but not ketanserin (-0.02%, p = 0.99). Our data support an asymmetric 5-HT2AR modulatory effect on CBF and provide the first in vivo human evidence that psilocybin constricts the ICA, which has important implications for understanding the neurophysiological mechanisms underlying its acute effects.