Salvinorin A: pharmacology, therapeutic potential and structural considerations of a unique non-nitrogenous selective k-opioid receptor agonist, and active component of the sage Salvia divinorum.

Abstract

Salvia divinorum is a plant indigenous of Oaxaca, Mexico. Traditionally, the plant is used for healing and divinatory purposes. At present, S. divinorum is also used recreationally by teenagers and young adults around the world. The main active component is salvinorin A, a unique non-nitrogenous kappa-opioid receptor agonist with hallucinogenic properties. Scientific interest is high, due to two facts: 1) salvinorin A was the first non-nitrogenous opioid-receptor ligand, 2) it elicits hallucinogenic effects without binding at serotonin receptors, as classical hallucinogens (LSD, psilocin, mescaline) do. Structural modifications of salvinorin A led to the discovery of herkinorin and other non-nitrogenous opioid receptors ligands, which are a powerful tool for elucidating the complex biological mechanisms of opioid receptors and for drug discovery of new therapeutic agents for pain treatment, drug dependence and mental disorders. The pharmacological profile of salvinorin A suggests several clinical applications related to the regulation of gastrointestinal functions, mood and drug-seeking behavior. The fast metabolism and pharmacokinetics of salvinorin A hinder clinical development, however it has been shown that some analogs have improved metabolic and pharmacokinetic profile. The first psychopharmacological studies on humans reported intense and unique psychedelic effects and positive after-effects on mood, well-being and awareness which may outweigh negative effects. Moreover, the drug exhibits low toxicity, few reported adverse effects and low abuse potential, making it suitable for further clinical studies. Taking in account the traditional use of the plant, the overall safe pharmacological profile, and the positive results on mood and general well-being obtained so far, it would be interesting and potentially beneficial to investigate further on the psychopharmacology of this unique molecule in respect of drug-assisted psychotherapy and treatment of depression, besides the clinical applications of salvinorin A and analogs for gastrointestinal disorders, pain treatment, drug dependence and mental problems.