Differential contributions of serotonergic and dopaminergic functional connectivity to the phenomenology of LSD

RATIONALE: LSD is the prototypical psychedelic. Despite a clear central role of the 5HT(2a) receptor in its mechanism of action, the contributions of additional receptors for which it shows affinity and agonist activity remain unclear. OBJECTIVES: We employed receptor-enriched analysis of functional connectivity by targets (REACT) to explore differences in functional connectivity (FC) associated with the distributions of the primary targets of LSD—the 5HT(1a), 5HT(1b), 5HT(2a), D1 and D2 receptors. METHODS: We performed secondary analyses of an openly available dataset (N = 15) to estimate the LSD-induced alterations in receptor-enriched FC maps associated with these systems. Principal component analysis (PCA) was employed as a dimension reduction strategy for subjective experiences associated with LSD captured by the Altered States of Consciousness (ASC) questionnaire. Correlations between these principal components as well as VAS ratings of subjective effects with receptor-enriched FC were explored. RESULTS: Compared to placebo, LSD produced differences in FC when the analysis was enriched with each of the primary serotonergic and dopaminergic receptors. Altered receptor-enriched FC showed relationships with the subjective effects of LSD on conscious experience, with serotonergic and dopaminergic systems being predominantly associated with perceptual effects and perceived selfhood as well as cognition respectively. These relationships were dissociable, with different receptors showing the same relationships within, but not between, the serotonergic and dopaminergic systems. CONCLUSIONS: These exploratory findings provide new insights into the pharmacology of LSD and highlight the need for additional investigation of non-5HT(2a)-mediated mechanisms. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00213-022-06117-5.