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

LSD alters functional connectivity in the brain in ways that depend on its interactions with multiple serotonin and dopamine receptors, not only the 5-HT2A receptor. By analyzing brain scans from 15 participants, researchers found that LSD-induced changes in connectivity linked to different receptors corresponded to different subjective effects: serotonin-related receptors were predominantly associated with perceptual changes, while dopamine-related receptors were more tied to alterations in selfhood and cognition. These patterns were distinct, with similar relationships appearing within each receptor family but not between them. The findings suggest that LSD's full effects involve a broader set of receptors than previously emphasized.

Study at a glance

Abstract

Abstract 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.