Psychedelic 5-HT2A receptor agonism alters neurovascular coupling and differentially affects neuronal and hemodynamic measures of brain function
Jonah A. Padawer-Curry, Oliver J. Krentzman, Chao‐cheng Kuo, Xiaodan Wang, Annie R. Bice, Ginger E. Nicol, Abraham Z. Snyder, Joshua S. Siegel, Jordan G. Mccall, Adam Q. Bauer
Nature Neuroscience October 13, 2025 DOI: 10.1038/s41593-025-02069-z (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with human neuroimaging and animal model Peer reviewed |
|---|---|
| Population | Humans and awake Thy1-jRGECO1a mice |
| Interventions | Psilocybin 2 5-dimethoxy-4-iodoamphetamine (DOI) MDL100907 |
| Topics | Serotonin |
| Keywords | Premovement neuronal activity Hemodynamics Neuroimaging Haemodynamic response Neurovascular bundle Excitatory postsynaptic potential Stimulation Thalamus Antagonist Human brain Functional imaging |
| Citations | 9 |
| Key findings | Psychedelic DOI dissociates neuronal and hemodynamic signals, indicating that neurovascular effects of psychedelics must be considered when interpreting blood-based measures of brain function. |
Abstract
Human neuroimaging studies report that psychedelics induce serotonin-2A receptor-dependent changes in functional brain reorganization, presumably reflecting neuromodulation. However, these studies often overlook the potent vasoactive effects of serotonin. Here we identified psilocybin-induced alterations in hemodynamic response functions during human functional magnetic resonance imaging, suggesting potential disruptions in neurovascular coupling. We then used wide-field optical imaging in awake Thy1-jRGECO1a mice to determine whether psychedelic-induced changes in hemodynamics arise from neuronal, vascular or neurovascular effects. Exposure to the psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) differentially altered coupling between cortical excitatory neuronal versus hemodynamic activity, both during whisker stimulation and in the resting state. Furthermore, DOI resulted in discordant changes between neuronal-based versus hemodynamic-based assessments of functional connectivity. A selective serotonin-2A receptor antagonist (MDL100907) reversed many of the effects of DOI. Our results demonstrate a dissociation between DOI-induced neuronal and hemodynamic signals, indicating a need to consider neurovascular effects of psychedelics when interpreting blood-based measures of brain function.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 14
- The entropic brain today Brain December 12, 2025
- Psilocybin shapes the slow, global propagation of brain activity over the cortical layout of 5HT2a receptors Communications Biology March 26, 2026
- LSD Reconfigures Cortical Dynamics Through Faster Brain Rhythms and Increased Fractal Dimension bioRxiv (Cold Spring Harbor Laboratory) January 29, 2026
- Current status and future prospects of research on psilocybin's regulation of neurotransmitters and their receptors related to the pathogenesis of tinnitus. Hearing research August 1, 2026
- Classic Psychedelics for Treating Chronic Pain: Mechanism and Clinical Translation Molecules July 27, 2026
and 9 more in the library
Cites 47
- The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs Frontiers in Human Neuroscience 2014
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
- Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings of the National Academy of Sciences April 11, 2016
- Homological scaffolds of brain functional networks Journal of the Royal Society, Interface October 29, 2014
- Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sciences December 17, 1984
and 42 more in the library