Acute psilocybin and ketanserin effects on cerebral blood flow: 5-HT2AR neuromodulation in healthy humans
In a single‑blind cross‑over study of 28 healthy volunteers, acute psilocybin — but not the 5‑HT2A antagonist ketanserin — produced significant global and regional reductions in cerebral blood flow that correlated with plasma psilocin and subjective drug intensity (approximately 11.6% at peak). Psilocybin also caused a 10.5% constriction of the internal carotid artery, providing the first in vivo human evidence of asymmetric 5‑HT2A receptor modulation of cerebral haemodynamics.
Authors
- Gitte Knudsen
- Patrick Fisher
- Dea Stenbæk
Published
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.
Research Summary of 'Acute psilocybin and ketanserin effects on cerebral blood flow: 5-HT2AR neuromodulation in healthy humans'
Introduction
Psilocybin, via its active metabolite psilocin, is a serotonergic psychedelic that shows rapid and sustained therapeutic effects in disorders such as major depression and anxiety. Prior work indicates that stimulation of the serotonin 2A receptor (5-HT2AR) underlies the acute subjective effects of classical psychedelics, and that 5-HT2ARs are expressed both on cortical neurons and on vascular smooth muscle where they can mediate vasoconstriction. Functional neuroimaging studies using BOLD fMRI and EEG have reported large changes in functional connectivity during acute psychedelic experiences, while a small number of arterial spin labelling (ASL) studies have reported reductions in cerebral blood flow (CBF) after psilocybin. However, inconsistencies remain across those reports with respect to regional patterns and possible vascular vs neuronal mechanisms, and no in vivo human studies have directly contrasted a 5-HT2AR agonist and antagonist to dissociate receptor-specific vascular and neurophysiological effects.
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Study Details
- Study Typeindividual
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- APA Citation
Larsen, K., Lindberg, U., Ozenne, B., McCulloch, D. E., Armand, S., Madsen, M. K., Johansen, A., Stenbæk, D. S., Knudsen, G. M., & Fisher, P. M. (2025). Acute psilocybin and ketanserin effects on cerebral blood flow: 5-HT2AR neuromodulation in healthy humans. Journal of Cerebral Blood Flow & Metabolism, 45(7), 1385-1401. https://doi.org/10.1177/0271678x251323364
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