Psychedelics disrupt hierarchical cortical propagations in the default mode network of humans and mice.
Adam R Pines, Xue Zhang, John Kochalka, Sam S Vesuna, Isaac V Kauvar, Divya Rajasekharan, T Rick Reneau, Teddy J Akiki, Laura M Hack, Joshua S Siegel, Leanne M Williams
Proceedings of the National Academy of Sciences of the United States of America June 16, 2026 Peer reviewed DOI: 10.1073/pnas.2522000123 via PubMed
Summary
Psychedelic drugs reduce the flow of neural signals and bottom-up processing within the brain's default mode network (DMN). An analysis of data from humans and mice showed that all tested psychedelics, including methylenedioxymethamphetamine, psilocybin, and lysergic acid diethylamide, led to an attenuation of signal flow magnitude and directionality in the DMN. This effect is associated with self-reported outcomes and is not due to data quality or known psychedelic effects.
Study at a glance
| Population | humans and mice |
|---|---|
| Key finding | All psychedelics tested attenuate signal flow magnitude and bottom-up directionality within the default mode network. |
Abstract
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.