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.