Psychedelics disrupt hierarchical cortical propagations in the default mode network of humans and mice

Jun 8, 2026Proceedings of the National Academy of Sciences of the United States of America

Psychedelics disturb the flow of activity in the brain's default mode system in humans and mice

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Abstract

All psychedelics tested reduce the magnitude and bottom-up directionality of activity in the brain's default mode network (DMN).

Psychedelics may modulate brain activity by affecting hierarchical processing within the DMN.
Four independent datasets were analyzed, including data from both humans and mice.
Signal flow magnitude and bottom-up directionality in the DMN are attenuated across all tested psychedelics.
This attenuation is not linked to data quality or known effects of psychedelics.
Self-reported outcomes are uniquely associated with the observed propagation attenuation.

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Psychedelic drugs are poised to become mainstream treatments, yet we lack a circuit-level account of how they reshape brain activity. Emerging evidence suggests that multiple psychedelic compounds modulate activity in the brain's default mode network (DMN), often interpreted as either increased or decreased bottom-up hierarchical processing. Most imaging studies, however, quantify activity as if it were stationary, remaining agnostic to the ascending or descending movements of activity that defines hierarchical processing. Here, we adapt optical flow analyses to track frame-to-frame trajectories of DMN activity across four independent datasets (humans and mice; methylenedioxymethamphetamine, psilocybin, and lysergic acid diethylamide; nine drug-vs.-control contrasts). In functional magnetic resonance and calcium imaging, all psychedelics attenuate signal flow magnitude and bottom-up directionality within the DMN. Propagation attenuation is not attributable to data quality or previously documented effects of psychedelics and is uniquely associated with self-reported outcomes. This replicable and generalizable attenuation of bottom-up cortical propagations provides fundamental clarification of the effects of psychedelics on macroscale hierarchical processing.

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Psychedelic ScienceIssue #41

Psychedelics disrupt brain signal flow in both humans and mice across LSD, psilocybin, and MDMA

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Psychedelics disrupt hierarchical cortical propagations in the default mode network of humans and mice

Abstract

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