Lysergic acid diethylamide (LSD) is a potent psychedelic with increasing therapeutic interest, yet qualification of target engagement using in vivo neuroimaging has not yet been performed. Using simultaneous positron emission tomography–magnetic resonance imaging technology, we describe multiple brain actions of LSD in seven healthy volunteers blinded to LSD dose received. Here we show that LSD occupies 5-HT2AR with a high affinity and increases both global cerebral blood flow (CBF) and internal carotid artery flow.
LSD also decreases global connectivity, which was negatively associated with changes in CBF. We observe an anticlockwise hysteresis loop between plasma drug levels and subjective effects, suggesting atypical pharmacodynamic mechanisms. We contrast our CBF and global connectivity findings and their relation in a separate cohort of 25 participants administered psilocybin, highlighting key consistencies and differences.
By establishing the dose–occupancy relation of LSD in humans, our findings provide insights for the clinical development of psychedelic compounds and demonstrate unique neurophysiological effects that distinguish LSD from psilocybin. This is a preview of subscription content, access via your institution Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription Receive 12 print issues and online access Prices may be subject to local taxes which are calculated during checkout The raw neuroimaging data generated in this study have been deposited in the Center for Integrated Molecular Brain Imaging (Cimbi database) at https://www.nru.dk/cimbidb. The data are available under restricted access due to privacy and European General Data Protection Regulation (GDPR) restrictions; access can be obtained by a Cimbi database request: https://nru.dk/index.php/research-menu/research-groups/115-the-cimbi-database-and-biobank.
Database requests may be approved based on the perceived scientific value of the proposed research project, and decisions are made within a few weeks. The subsequent legal approval process may take several months, but once granted, data will be available for as long as the proposed research project requires76. The code used for analyses is available via GitHub at https://github.com/Pneumaethylamine/dOccLS.
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Neuropsychopharmacology 47, 1180–1187 (2022). Article CAS PubMed PubMed Central Google Scholar Becker, A. Ketanserin reverses the acute response to LSD in a randomized, double-blind, placebo-controlled, crossover study in healthy participants.
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