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.