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

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.

Lasting effects of a single psilocybin dose on resting-state functional connectivity in healthy individuals

“…Although we do not see a persistent effect on DMN connectivity, acute disruption of the DMN may still be therapeutically relevant (Carhart-Harris and Friston, 2019;Mason et al, 2020). Intake of both Salvinorin-A, a 5-HT2AR-independent hallucinogen, and MDMA, which has a subjective effect profile distinct from serotonergic psychedelics (Doss et al, 2020;Müller et al, 2020;Roseman et al, 2014), leads to a reduction in DMN connectivity. Reduced DMN connectivity is not associated with ego-dissolution in response to psilocybin (Lebedev et al, 2015).…”

An Encounter With the Other: A Thematic and Content Analysis of DMT Experiences From a Naturalistic Field Study

“…Alternatively, similarities may be owing to converging downstream mechanisms, such as default-mode network (DMN) disintegration (e.g., Winkelman, 2017 ), considered the gross neural correlate of psychedelic action by 5HT-2A agonism. For example, salvia divinorum , a Mexican shamanic herb and atypical psychedelic generative of disconnection of consciousness to immersive spaces, though stimulating the kappa-opioid receptor it similarly reduces static functional connectivity in the DMN ( Doss et al, 2020 ). Neurophysiologically, such radical perceptual restructuring and ‘world building’ may be owing to collapse of alpha-beta wave, and dominance of delta-theta wave ( Timmermann et al, 2019 ; Pallavicini et al, 2020 ) and forward travelling wave activity across the cortex ( Alamia et al, 2020 ; Gallimore, 2020 ), evidenced at least by DMT.…”

Classical Psychedelics as Therapeutics in Psychiatry – Current Clinical Evidence and Potential Therapeutic Mechanisms in Substance Use and Mood Disorders

“…Interestingly, acute subjective effects induced by other hallucinogenic drugs with weak or no affinity for 5-HT2A receptors (e. g., ketamine, salvinorin A, ibogaine) share some similarities with those induced by classical psychedelics. It has recently been shown that, in particular, changes in subjective experience and brain connectivity evoked by savinorin A (a kappa opioid receptor) resemble those induced by LSD or psilocybin, highlighting a potential involvement of the opioid receptor system [94,95].…”