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

Lysergic acid diethylamide (LSD) is a potent serotonergic psychedelic drug that has recently entered phase 3 clinical trials for the treatment of anxiety and depressive disorders following promising phase 1 and 2a safety and efficacy data. LSD exerts its principal effects through high-affinity agonism at the 5-HT2A receptor, but in vivo receptor occupancy data and the relationship between receptor binding, cerebrovascular physiology, and functional brain changes have not previously been characterised simultaneously in humans. Such multimodal data are critical for establishing dose-occupancy relationships that can inform rational clinical dose selection. The present study conducted the first simultaneous molecular and functional neuroimaging investigation of LSD in humans, combining positron emission tomography (PET) with the 5-HT2A receptor radioligand [11C]Cimbi-36, functional MRI, and haemodynamic measurements to characterise LSD's effects on cerebral 5-HT2AR occupancy, cerebral blood flow (CBF), and whole-brain functional activity and connectivity across a range of doses.

Eleven healthy participants (2 female; mean age 31 years) underwent a multimodal baseline imaging session comprising [11C]Cimbi-36 PET to quantify 5-HT2AR non-displaceable binding potential, multi-band multi-echo fMRI, and haemodynamic measurements using internal carotid artery (ICA) angiography, phase contrast mapping, and pseudo-continuous arterial spin labelling for CBF. On a separate day, each participant received a single oral dose of LSD across a range spanning clinically relevant doses; PET and fMRI were acquired sequentially, with haemodynamic assessment conducted 30-60 minutes post-scan onset. A pharmacokinetic-receptor occupancy model was fitted to estimate the IC50 for 5-HT2AR binding. Functional connectivity was assessed as global correlation (GCOR), thalamocortical correlation (TCOR), and network-level connectivity. Information-theoretic metrics including sample entropy, spatial complexity, Lempel-Ziv complexity, and dynamic conditional correlation entropy were computed from fMRI data. Statistical analyses used Spearman's rank correlations across participants to link occupancy to neuroimaging changes.

LSD produced dose-dependent 5-HT2AR occupancy, with an estimated IC50 of 1.9 nM — closely aligned with prior ex vivo and in vitro radioligand binding data. Global CBF increased by 19.3% (Cohen's dz = 1.20), with the largest regional effects in the occipital cortex (26.4%) and thalamus (19.4%), and more modest increases in limbic regions including the hippocampus and amygdala. ICA flow also increased under LSD without evidence of gross cerebrovascular structural changes. These CBF increases are strikingly opposite to the reductions in global CBF (approximately 12%) observed in prior psilocybin imaging studies. Functional MRI analyses revealed a widespread decrease in global connectivity (GCOR), most prominent in visual, temporal-parietal, and attention network regions, with 11 of 12 examined brain regions showing negative correlations between occupancy and connectivity change. Thalamocortical connectivity showed a more spatially restricted pattern. Information-theoretic metrics — including sample entropy, spatial complexity, and Lempel-Ziv complexity — were increased under LSD, indicating greater signal diversity and reduced structured redundancy in brain activity.

The simultaneous acquisition of molecular and functional neuroimaging data across a dose range permitted a uniquely mechanistic characterisation of LSD's brain effects. The strong negative correlation between 5-HT2AR occupancy and global functional connectivity supports a direct, on-target pharmacodynamic relationship and provides a principled basis for translating plasma LSD concentrations into estimates of receptor engagement and functional brain change. The receptor occupancy model with an IC50 of 1.9 nM converges with established in vitro binding data, validating the in vivo approach. The haemodynamic divergence from psilocybin — LSD increases CBF whilst psilocybin reduces it — is discussed in light of the two compounds' distinct pharmacological profiles beyond 5-HT2A agonism, including LSD's higher selectivity and its interactions with dopaminergic and other receptor systems. The increased information-theoretic complexity under LSD is interpreted as consistent with a state of heightened neural signal diversity and reduced modular structure — a pattern hypothesised to underlie the broadened phenomenological richness of the psychedelic state.

This first simultaneous molecular and functional neuroimaging investigation of LSD establishes in vivo receptor occupancy parameters, quantifies the cerebrovascular and functional brain effects across a clinically relevant dose range, and demonstrates that these effects are strongly coupled to 5-HT2AR occupancy. The findings provide a mechanistic foundation for clinical dose selection in ongoing phase 3 trials and highlight important haemodynamic distinctions between LSD and psilocybin that merit further investigation.