Salvinorin A, a kappa-opioid receptor agonist hallucinogen: pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders

Salvinorin A, a hallucinogen from the plant Salvia divinorum, selectively activates kappa-opioid receptors (KOPr) in the brain, which are normally stimulated by endogenous dynorphins. This activation counterbalances dopamine-driven reward and mood systems, producing aversion and anhedonia in animal models. Unlike other opioid ligands, salvinorin A is a non-nitrogenous neoclerodane, offering a novel chemical scaffold for drug development. Ongoing research aims to create semi-synthetic analogs with partial or biased KOPr agonism to achieve therapeutic effects—such as for pain or mood disorders—while reducing the undesirable effects seen with salvinorin A itself.

Study at a glance

Abstract

Salvinorin A is a potent hallucinogen, isolated from the ethnomedical plant Salvia divinorum. Salvinorin A is a selective high efficacy kappa-opioid receptor (KOPr) agonist, and thus implicates the KOPr system and its endogenous agonist ligands (the dynorphins) in higher functions, including cognition and perceptual effects. Salvinorin A is the only selective KOPr ligand to be widely available outside research or medical settings, and salvinorin A-containing products have undergone frequent non-medical use. KOPr/dynorphin systems in the brain are known to be powerful counter-modulatory mechanisms to dopaminergic function, which is important in mood and reward engendered by natural and chemical reinforcers (including drugs of abuse). KOPr activation (including by salvinorin A) can thus cause aversion and anhedonia in preclinical models. Salvinorin A is also a completely new scaffold for medicinal chemistry approaches, since it is a non-nitrogenous neoclerodane, unlike other known opioid ligands. Ongoing efforts have the goal of discovering novel semi-synthetic salvinorin analogs with potential KOPr-mediated pharmacotherapeutic effects (including partial agonist or biased agonist effects), with a reduced burden of undesirable effects associated with salvinorin A.