Opioid Receptors in Psychedelia: Indirect Serotonergic Modulation of Direct KOR Activation by Salvinorin A
Biomedicines February 21, 2026 Maximiliano Ganado, Carmen Rubio, Javier Pérez-villavicencio et al.
Psychedelic effects are not solely driven by serotonin receptors. The compound salvinorin A, from Salvia divinorum, produces altered consciousness by directly activating kappa opioid receptors (KORs), bypassing serotonin entirely. This review synthesizes evidence from lab studies, animal models, and human brain imaging. Salvinorin A triggers a specific signaling pathway (β-arrestin bias) that causes rapid receptor desensitization, disrupts thalamocortical communication, suppresses dopamine activity in reward circuits, and fragments large-scale brain networks. Despite being a potent opioid agonist, it has low abuse potential because its aversive effects and dopamine suppression prevent positive reinforcement. Understanding opioid receptor mechanisms expands psychedelic neuroscience beyond serotonin-focused models and may guide development of treatments for depression, addiction, and chronic pain.