DARK Classics in Chemical Neuroscience: Salvinorin A.

Salvinorin A, the main psychoactive compound in the plant Salvia divinorum, is the first known nonalkaloidal opioid that acts through the kappa-opioid receptor, producing rapid and short-lived hallucinogenic effects. Its unique chemical structure lacks a protonated amine group, leading to fast metabolism and swift loss of activity. The compound has been used ancestrally in spiritual rites by the Mazatec people of Oaxaca, Mexico, but its psychotropic effects have led to misuse and bans in many countries. This review covers its history, natural isolation, total synthesis, hundreds of synthetic analogues, and pharmacological and safety profiles, highlighting its impact on neuroscience and drug development.

Study at a glance

Abstract

Salvinorin A is the main bioactive compound in Salvia divinorum, an endemic plant with ancestral use by the inhabitants of the Mazateca mountain range (Sierra Mazateca) in Oaxaca, México. The main use of la pastora, as locally known, is in spiritual rites due to its extraordinary hallucinogenic effects. Being the first known nonalkaloidal opioid-mediated psychotropic molecule, salvinorin A set new research areas in neuroscience. The absence of a protonated amine group, common to all previously known opioids, results in a fast metabolism with the concomitant fast elimination and swift loss of activity. The worldwide spread and psychotropic effects of salvinorin A account for its misuse and classification as a drug of abuse. Consequently, salvinorin A and Salvia divinorum are now banned in many countries. Several synthetic efforts have been focused on the improvement of physicochemical and biological properties of salvinorin A: from total synthesis to hundreds of analogues. In this Review, we discuss the impact of salvinorin A in chemistry and neuroscience covering the historical relevance, isolation from natural sources, synthetic efforts, and pharmacological and safety profiles. Altogether, the chemistry behind and the taboo that encloses salvinorin A makes it one of the most exquisite naturally occurring drugs.