Multi-metric evaluations of acute psychedelic effects on fMRI brain entropy
Drummond E-Wen Mcculloch, Anders S. Olsen, Brice Ozenne, Kristian Larsen, Dea Siggaard Stenbæk, Sophia Armand, M. Madsen, Gitte M. Knudsen, Patrick M. Fisher
Nature Communications June 24, 2026 DOI: 10.1038/s41467-026-74215-5 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Sample size | 28 |
| Population | Healthy adults |
| Intervention | Psilocybin |
| Keywords | Sample entropy Voxel Neuroimaging Pattern recognition psychology Brain mapping Artificial intelligence Cognitive psychology |
| Key findings | Psychedelic effects on brain entropy are nuanced: only some entropy metrics consistently increase, while others show no effect, and the metrics are poorly correlated. |
Abstract
A prominent theory of psychedelics is that they increase brain entropy. Thirteen studies have evaluated psychedelic effects on fMRI brain entropy, each applying a distinct measure. Here we evaluated these metrics in an independent 28-participant healthy cohort with 121 pre- and post-psilocybin fMRI scans. We assessed relations between brain entropy and objective and subjective psychedelic drug effects using linear mixed-effects models. All metrics were evaluated using two parcellation strategies and 7 denoising pipelines. We observed consistent significant positive associations for Shannon entropy of the spatial eigendistribution of the time by voxel matrix, path-length, instantaneous correlations, brain-state switching, and sample entropy at short time-scales. We consistently did not observe significant effects for 8 of 14 entropy metrics and observe inconsistent positive effects for Lempel-Ziv complexity of the BOLD signal. Brain entropy quantifications showed limited inter-measure correlations. Our observations support a nuanced acute psychedelic effect on brain entropy, empirically demonstrating that these metrics do not reflect a singular construct.