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Acute psilocybin and ketanserin effects on cerebral blood flow: 5-HT2AR neuromodulation in healthy humans.

Kristian Larsen, Ulrich Lindberg, Brice Ozenne, Drummond E. Mcculloch, Sophia Armand, Martin K Madsen, Annette Johansen, Dea S Stenbæk, Gitte M. Knudsen, Patrick M. Fisher

Journal of Cerebral Blood Flow & Metabolism February 26, 2025 DOI: 10.1177/0271678x251323364 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Single-blind, cross-over study Peer reviewed
Sample size 28
Population Healthy participants
Interventions Psilocybin Ketanserin
Topics Psilocybin Serotonin
Keywords Psychedelics hallucinogens Entheogens Psychedelic drugs Brain imaging neuroimaging MRI Brain scanning Arterial spin labelling Brain circulation V Cerebral blood flow Internal carotid artery Ketanserin
Citations 9
Key points Psilocybin significantly decreased cerebral blood flow and constricted the internal carotid artery, while ketanserin had no such effects, indicating a serotonin 2A receptor-mediated mechanism.

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.

Comparable studies

Other randomized controlled trials on serotonin, most cited first.

Study Year Design Participants
Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose?effect study Healthy human subjects 2004 Randomized controlled trial n = 8
Dose-Response Study of N,N-Dimethyltryptamine in Humans Experienced hallucinogen users 1994 Double-blind, saline placebo-controlled, randomized study n = 12
Acute Effects of Lysergic Acid Diethylamide in Healthy Subjects Healthy subjects (8 women, 8 men) 2014 Double-blind, randomized, placebo-controlled, crossover study n = 16
Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor Healthy human participants 2018 Double-blind, randomized, counterbalanced, cross-over study n = 24
Activation of Serotonin 2A Receptors Underlies the Psilocybin-Induced Effects on Oscillations, N170 Visual-Evoked Potentials, and Visual Hallucinations Healthy human subjects 2013 Randomized controlled trial

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