Acute psilocybin and ketanserin effects on cerebral blood flow: 5-HT2AR neuromodulation in healthy humans
Journal of Cerebral Blood Flow & Metabolism – February 26, 2025
Source: OpenAlex
Summary
Psilocybin, a potent hallucinogen, drastically reduces cerebral blood flow and constricts major arteries, a novel finding for medicine. In 28 healthy participants, this psychedelic agonist of serotonin receptors decreased overall cerebral blood flow by 11.6% and narrowed the internal carotid artery by 10.5%. Ketanserin, a serotonin antagonist, showed negligible effects. This pharmacology insight into psilocybin's action, relevant to cardiology and internal medicine, reveals how neurotransmitter receptor influence on behavior unfolds, impacting psychology and future drug studies.
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 (p FWER < 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.