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

Investigations 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. ### Competing Interest Statement DEWM salary is supported by an unrestricted grant from COMPASS Pathways who have no involvement in the preparation or conception of this manuscript or related data collection. MKM has received an honorarium as a speaker for H. Lundbeck. GMK has served as a consultant for Sanos, Gilgamesh, Onsero, Pangea, Abbvie, PureHealthTech, and has received honoraria as speaker for H. Lundbeck and Sage Therapeutics. ### Clinical Trial NCT03289949 ### Clinical Protocols ### Funding Statement The work was supported by Innovation Fund Denmark (grant number 4108–00004B), Independent Research Fund Denmark (grant number 6110–00518B), and Ester M. og Konrad Kristian Sigurdssons Dyrevaernsfond (grant number 850–22–55,166–17–LNG). MKM was supported through a stipend from Rigshospitalets Research Council (grant number R130–A5324). BO has received funding from the European Unions Horizon 2020 research and innovation program under the Marie Sklodowska–Curie grant agreement No 746,850. DEM salary is supported by COMPASS Pathways Ltd. Funding agencies did not impact the study and played no role in manuscript preparation and submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was approved by the ethics committee of the capital region of Copenhagen (H-16026898) and the Danish Medicines Agency (EudraCT no.: 2016-004000-61). The study was registered at clincaltrials.gov ([NCT03289949][1]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. All functions used to derive entropy estimates from preprocessed data have been compiled into the "Copenhagen Brain Entropy Toolbox" (CopBET), a Matlab-based toolbox that can be found here: . The permutation testing code is also available here. Code for other statistical analyses and figures can be made available upon request. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03289949&atom=%2Fmedrxiv%2Fearly%2F2023%2F07%2F03%2F2023.07.03.23292164.atom