Knocking at the Doors of Perception: Relating LSD Effects on Low‐Frequency Fluctuations and Regional Homogeneity to...

Despite a renewed scientific interest in lysergic acid diethylamide (LSD), its local neural effects remain underexplored. This functional magnetic resonance imaging (fMRI) study explored and compared LSD-induced changes in local activity (amplitude of low-frequency fluctuations: ALFF) and local connectivity (regional homogeneity: ReHo), assessing their relationship to regional receptor density. Imaging data of 15 healthy adults from an open dataset were analyzed. For each participant, two pairs of resting-state runs were available (rest1 and rest2), one performed under placebo and one following the intravenous administration of 75-μg LSD. Voxel-wise paired t-tests compared ALFF and ReHo in the LSD versus placebo conditions. Rest1*rest2 test-retest reliability and ALFF*ReHo cross-modal associations were assessed with conjunction maps and vertex-wise correlations. Finally, neurochemical enrichment analyses related LSD-induced ALFF and ReHo changes to cortical density maps of LSD-related neurotransmitter receptors and transporters. Both ALFF and ReHo decreased in somatosensory/visual cortices under LSD compared to placebo. Specific decreases were observed for ALFF in associative regions belonging to the default mode and frontoparietal networks, and for ReHo in subcortical regions (cluster-based corrected p < 0.05). Test-retest reliability was high for ALFF (rho = 0.80, p = 0.001) and moderate for ReHo (rho = 0.46, p = 0.001). ALFF*ReHo LSD-induced changes were moderately associated (rest1: rho = 0.36, p = 0.001; rest2: rho = 0.56, p = 0.001). Neurochemical enrichment analysis showed that LSD-induced ALFF/ReHo alterations were reliably and negatively correlated with the density of D2 and 5-HT1A receptors (FDR-corrected p < 0.05). These preliminary findings suggest that LSD may engage complex and dynamic neurochemical processes beyond its known 5-HT2A receptor target, warranting further investigation.