Molecular, haemodynamic, and functional effects of LSD in the human brain

In this study, we provide the first study to integrate molecular and functional neuroimaging during psychedelic drug effects in humans. Using simultaneous PET-MRI technology, we describe multiple brain actions of lysergic acid diethylamide (LSD) in healthy volunteers. We quantify the occupancy of LSD at cerebral serotonin 2A receptors and show that LSD increases global cerebral blood flow and internal carotid artery flow without affecting the diameter of the internal carotid artery, opposite effects to those observed following psilocybin. Functional connectivity analyses showed widespread decreases in global connectivity, particularly in visual networks, alongside increases in network-wise sample entropy and spatial complexity. We observed an anticlockwise hysteresis loop between plasma drug levels and subjective effects, suggesting atypical pharmacodynamic mechanisms. By establishing the dose-occupancy relation of LSD in humans, our findings provide critical insights for the clinical development of psychedelic compounds and demonstrate unique neurophysiological effects that distinguish LSD from related psychedelics. Our findings challenge the leading hypotheses of psychedelic brain-action, until now thought to be instrumental for therapeutic efficacy.Competing Interest StatementDEM salary is supported by an unrestricted grant from COMPASS Pathways Ltd, which had no input on study design or manuscript preparation. The authors declare that the research was conducted in the absence of any commercial, non-financial, or financial relationships that could be construed as a potential conflict of interest.Clinical TrialNCT05953038Clinical Protocols https://aspredicted.org/gn3un.pdf Funding StatementThis project was funded by Savvaerksejerfonden and Novo Nordisk Fonden (NNF23OC0082288). DEMs salary was supported by an unrestricted grant from COMPASS Pathways PLC, which had no input in the study design or manuscript preparation. KLs salary was supported by Rigshospitalet Research Fund (R259-A11532). KHRJs salary was funded by The Lundbeck Foundation as part of the BrainDrugs study (R279-2018-1145). FH was supported by the Swiss National Science Foundation (grant no. P500PM_210867)Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe 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 Denmark(H-21060056) and the Danish Medicines Agency (EudraCT no.: 2021-002633-42; CTIS: 2024-519564-41-00).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.YesI 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).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesData from this study are available through the Center for Integrated Molecular Brain Imaging (Cimbi) Database and Biobank at Rigshospitalet, Copenhagen (96). Researchers can request access to the dataset by completing a standardised application form available at the Cimbi website (https://nru.dk/index.php/research-menu/research-groups/115-the-cimbi-database-and-biobank) (96)