710. The neuropsychopharmacology of LSD

Abstract Background LSD has recently entered phase 3 clinical trials for anxiety and depressive disorders, yet understanding of its mechanisms of action in the human brain remains incomplete. The serotonin 2A receptor (5-HT2AR) is the critical target for psychedelic effects, but no investigations to date have evaluated the relation between target engagement and systems-level brain function. Additionally, the role of cerebral vasculature has been largely neglected despite rich expression of 5-HT2AR on vascular smooth muscle cells. This study provides the first integration of molecular and functional neuroimaging during psychedelic drug effects in humans. Aims & Objectives We aimed to: (1) quantify LSD occupancy at cerebral 5-HT2AR and establish the dose-occupancy relation; (2) comprehensively evaluate psychedelic effects on brain haemodynamics including cerebral blood flow and internal carotid artery flow; (3) characterize LSD effects on functional brain connectivity; (4) assess relations between receptor occupancy, plasma drug levels, subjective effects, and neural changes; and (5) contrast findings with an independent psilocybin cohort to identify key consistencies and differences.

Method: Eleven healthy volunteers underwent baseline multimodal imaging. Seven participants completed simultaneous PET-MRI scans during peak effects following oral LSD administration (25-200 μg). We acquired [11C]Cimbi-36 PET to quantify 5-HT2AR occupancy, multi-band multi-echo fMRI to assess brain activity, pseudo-continuous arterial spin labelling for cerebral blood flow, and phase contrast mapping for internal carotid artery flow. Plasma LSD levels and subjective drug intensity were measured throughout. Receptor occupancy was modeled using Hill-Langmuir equations. We analyzed global connectivity (GCOR) and correlations between occupancy, cerebral blood flow, and functional changes.

Results: LSD showed high-affinity binding with IC50 of 1.93 nM (0.62 ng/ml) and maximum occupancy of 97.4%. An anticlockwise hysteresis loop emerged between plasma levels and subjective effects, with peak intensity occurring 30 minutes after peak plasma levels. LSD substantially increased global cerebral blood flow (19.3%) and internal carotid artery flow (28%) without affecting artery diameter. GCOR decreased across most of the neocortex, particularly in visual and posterior default-mode regions. Change in GCOR was negatively correlated with change in cerebral blood flow. This negative relation was also observed in an independent psilocybin cohort despite opposite directional effects. Discussion & Conclusions We provide the first in vivo dose-occupancy relation for LSD in humans, with estimates aligning well with ex vivo data. The observed hysteresis between plasma levels and subjective effects may reflect LSD's unique binding kinetics at 5-HT2AR. LSD produced widespread increases in cerebral blood flow—opposite effects to those observed with psilocybin—suggesting distinct downstream or off-target mechanisms despite shared 5-HT2AR agonism. The consistent negative relation between GCOR and cerebral blood flow changes across both psychedelics suggests potential alterations in neurovascular coupling that warrant further investigation. These findings establish a framework for evaluating target engagement of emerging psychedelic compounds and demonstrate unique neurophysiological effects that distinguish LSD from related psychedelics.