The Acute Effects of the Atypical Dissociative Hallucinogen Salvinorin A on Functional Connectivity in the Human Brain

Salvinorin A, a κ-opioid receptor agonist and dissociative hallucinogen found in Salvia divinorum, alters human brain functional connectivity in ways similar to other hallucinogens. In a placebo-controlled, within-subject fMRI study, inhaled Salvinorin A tended to decrease functional connectivity within brain networks while increasing connectivity between networks, most notably attenuating the default mode network during peak effects. It reduced brainwide dynamic functional connectivity but increased brainwide entropic functional connectivity, though only the reduction survived statistical correction. Connectome-based classification models trained on dynamic connectivity accurately identified Salvinorin A scans, especially when using default mode network interactions. These findings suggest shared neural mechanisms across hallucinogen types.

Study at a glance

Abstract

Abstract Salvinorin A (SA) is a κ-opioid receptor agonist and atypical dissociative hallucinogen found in Salvia divinorum . Despite the resurgence of hallucinogen studies, the effects of κ-opioid agonists on human brain function are not well-understood. This placebo-controlled, within-subject study used functional magnetic resonance imaging for the first time to explore the effects of inhaled SA on strength, variability, and entropy of functional connectivity (static, dynamic, and entropic functional connectivity, respectively, or sFC, dFC, and eFC). SA tended to decrease within-network sFC but increase between-network sFC, with the most prominent effect being attenuation of the default mode network (DMN) during the first half of a 20-min scan (i.e., during peak effects). SA reduced brainwide dFC but increased brainwide eFC, though only the former effect survived multiple comparison corrections. Finally, using connectome-based classification, most models trained on dFC network interactions could accurately classify the first half of SA scans. In contrast, few models trained on within- or between-network sFC and eFC performed above chance. Notably, models trained on within-DMN sFC and eFC performed better than models trained on other network interactions. This pattern of SA effects on human brain function is strikingly similar to that of other hallucinogens, necessitating studies of direct comparisons.