Navigating the chaos of psychedelic fMRI brain-entropy via multi-metric evaluations of acute psilocybin effects

A prominent theory of psychedelics is that they increase brain entropy. Thirteen studies have evaluated psychedelic effects on fMRI brain entropy; no findings have been replicated. 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.