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

This pre-print single-blind, cross-over study (n=28) using MRI in healthy participants found that psilocybin (18.2mg/70kg) significantly decreased cerebral blood flow (CBF) and internal carotid artery (ICA) diameter. In contrast, ketanserin (20mg) had no significant effect. This finding suggests an asymmetric 5-HT2AR modulatory effect on CBF and provides the first in vivo human evidence of psilocybin-induced ICA constriction.

Abstract of Acute psilocybin and ketanserin effects on cerebral blood flow

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 labelling 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 (~11.5% 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.

Authors: Kristian Larsen, Ulrich Lindberg, Brice Ozenne, Drummond E. McCulloch, Sophia Armand, Martin K. Madsen, Annette Johansen, Dea S. Steakbæk, Gitte M. Knudsen & Patrick M. Fisher

Summary of Acute psilocybin and ketanserin effects on cerebral blood flow

The article focuses on the neuromodulatory effects of psilocybin, a psychedelic compound, and ketanserin, a serotonin 2A receptor (5-HT2AR) antagonist, on cerebral blood flow (CBF). The 5-HT2AR plays a key role in the brain’s response to psychedelics, and understanding its influence on blood flow can shed light on the neural mechanisms of psychedelic experiences. Psilocybin, after ingestion, is converted to its active metabolite psilocin, which activates the 5-HT2AR, leading to altered perception and consciousness. Ketanserin, on the other hand, blocks this receptor and is used to study the receptor’s effects in contrast to psychedelics.

Previous studies using techniques like arterial spin labelling (ASL) and functional MRI have shown that psychedelics like psilocybin can significantly alter brain function, leading to changes in functional connectivity and cerebral metabolism. This study aims to compare the effects of psilocybin and ketanserin on CBF and internal carotid artery (ICA) diameter in healthy participants, providing insights into the neurovascular effects of 5-HT2AR modulation.

Methods and Materials

Participants

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Find this paper

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

https://doi.org/10.1101/2024.09.19.24313958

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Cite this paper (APA)

Larsen, K., Lindberg, U., Ozenne, B., McCulloch, D. E., Armand, S., Madsen, M. K., ... & Fisher, P. M. (2024). Acute psilocybin and ketanserin effects on cerebral blood flow: 5-HT2AR neuromodulation in healthy humans. medRxiv, 2024-09.

Study details

Compounds studied
Psilocybin

Topics studied
Healthy Subjects Neuroscience

Study characteristics
Original Single-Blind Within-Subject Bio/Neuro

Participants
28 Humans

Compound Details

The psychedelics given at which dose and how many times

Psilocybin 18.2 mg | 1x Placebo 20 mg | 1x

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