Multi-metric evaluations of acute psychedelic effects on fMRI brain entropy
Drummond E-wen Mcculloch, Anders S. Olsen, Brice Ozenne, K O Larsen, Dea Siggaard Stenbæk, Sophia Armand, M. Madsen, Gitte M. Knudsen, Patrick M. Fisher
Nature Communications June 24, 2026 Peer reviewed DOI: 10.1038/s41467-026-74215-5 via OpenAlex
Summary
Psychedelics like psilocybin appear to increase brain entropy, as shown in a study of 28 healthy participants who underwent 121 fMRI scans before and after treatment. Significant positive associations were found for several measures of brain entropy, including Shannon entropy and sample entropy at short time-scales. However, no significant effects were observed for 8 of the 14 metrics analyzed, indicating that different measures of brain entropy may not represent a single concept.
Study at a glance
| Design | observational cohort |
|---|---|
| Sample size | 28 |
| Population | healthy participants |
| Key finding | The study supports a nuanced acute psychedelic effect on brain entropy, with significant associations for some metrics but not others. |
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.