Acute Effects of Hallucinogens on Functional Connectivity: Psilocybin and Salvinorin-A

Introduction

Hallucinogens are experiencing renewed research interest for potential therapeutic applications in psychiatric disorders, pain and addiction. Most contemporary work focuses on classical serotonergic psychedelics that act at the serotonin 2A receptor (5-HT2A R), such as psilocybin, which has shown promise in models of depression and addiction. Other hallucinogenic drugs with distinct pharmacology, including kappa-opioid receptor (KOR) agonists like salvinorin-A, produce dissociative subjective effects and have different clinical profiles (for example, reported pro‑depressive or dysphoric effects). Functional connectivity (FC) MRI studies of serotonergic psychedelics commonly report reduced intra-network FC in the Default Mode Network (DMN) and altered thalamo-cortical coupling, but comparable imaging data for non‑serotonergic hallucinogens are scarce; only a single FC study of salvinorin-A in humans was noted by the authors. This study, conducted in rhesus macaques, set out to compare acute effects of a serotonergic hallucinogen (psilocybin) and a non‑serotonergic KOR agonist (salvinorin-A) on resting‑state functional connectivity within and between regions implicated in hallucinogenic states. Targets included the claustrum, thalamus, prefrontal cortex (PFC), the DMN and its subcomponents (anterior and posterior cingulate cortices, precuneus, angular gyrus). Bagdasarian and colleagues hypothesised that both drugs would dissociate DMN connectivity but would exert distinct modulatory effects on claustral‑cortical and thalamo‑cortical circuits owing to their differing receptor pharmacology.