Navigating the chaos of psychedelic neuroimaging: A multi-metric evaluation of acute psilocybin effects on brain entropy

Abstract

AbstractInvestigations into the acute effects of psychedelics on brain imaging have emphasised increased ‘brain entropy’ as a potential neural correlate. To date, 12 previous studies have reported brain entropy effects, each reporting a single and unique metric, none of which have been examined in an independent cohort. Here we evaluated acute psilocybin effects on these 12 brain entropy metrics in an independent cohort of 28 healthy participants. Following a single psilocybin dose, participants completed pre/post resting-state BOLD fMRI scans (28 pre-drug, 93 post-drug scans during the acute drug effects). Each scan was accompanied by a plasma sample to quantify plasma drug levels and estimate brain serotonin 2A receptor occupancy, as well as a rating of subjective drug intensity. We assessed relations between brain entropy and these measures with linear mixed-effects models. There was a significantly positive association for Shannon entropy of path-length and instantaneous correlation distributions and divergent associations of network-wise sample entropy at varying time-scales. We did not observe significant psilocybin effects for seven of 12 brain-entropy metrics. Whole-brain entropy metrics showed limited correlations between each other. Our observations suggest a nuanced acute effect of psychedelics on brain entropy, underscoring the need for reproducing effects. The variable effects and limited inter-metric correlation undermines the generalisability of ‘brain entropy’ as a singular construct. Future studies in clinical cohorts are crucial to elucidate the link between these metrics and therapeutic effects of psychedelics.