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.
Graduate School of Life Sciences, Utrecht University
July 2014, Utrecht, The Netherlands
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.
Salvia divinorum is a very interesting plant among almost 1000 species of Salvia in the world. It is a perennial herb of the Labiatae family, endemic to a small region of Oaxaca, Mexico. Salvia divinorum does not produce flowers on a regular seasonal basis (Valdés et al. 1987; Reisfield 1993) and its pollination and sexual reproduction are still mostly unknown, even though it has been suggested that the plant could be ornithophilous (Reisfield 1993). The usual method of propagation is clonal, both naturally and by humans (Reisfield 1993). The name Salvia divinorum means “Salvia of the seers”.
Traditionally, Salvia divinorum has been used by the Mazatecs, an ancient indigenous Mexican group located in northeast Oaxaca (Figure 1) (Valdés et al. 1983). The Mazatecs employ three main psychoactive substances for their spiritual-healing rituals, which are mushrooms (Psylocibe spp.), morning glory seeds (Rivea corymbosa, Ipomoea purpurea) and Salvia divinorum leaves (Valdés et al. 1983). Among the three, Salvia divinorum was reported as the best “teacher” for healing, the most delicate one, and the first to be employed in shamanic training (Valdés et al. 1983).
Figure 1. Mazatec traditional territory (in blue). (Casselman et al. 2014)
Salvia divinorum has several names among the Mazatecs, and many are related to the Virgin Mary. The association with the Virgin Mary is due to Dominicans and Jesuits who converted indigenous people to Catholicism after the Spanish colonization in the 16th century (Mooney 1911). Traditional Mazatecs names are ska Maria or ska Pastora, spanish names are hojas de Maria (“leaves of the Virgin Mary”), hojas de la Pastora (“leaves of the shepherdess”), hojas de Maria Pastora (“leaves of Virgin Mary the shepherdess”), and hierba Maria (“Mary herb”) (Wasson 1962; Valdés et al. 1983). In Christian tradition the Virgin Mary is not a shepherdess, and Wasson suggested that the attribution of the role of shepherdess could be heritage of the pre-Christian figure “dueno de los animales” (“the lord of the animals”), an important figure in the folk tradition of Central American Indians. Wasson also suggested that the pagan name would have been sanctified by the addition of the Virgin’s name (Wasson 1962).
S. divinorum is used by the Mazatecs for curing at least four illnesses. First, diarrhea and other eliminatory dysfunctions are often treated with the plant. Second, S. divinorum is used in small doses against headache and rheumatisms. Third, an infusion of the plant’s juice is given to people who are near death, as palliative care. Fourth, traditionally a semi-magical illness known as the panzón de barrego (panzón=“swollen belly”), caused by a brujo, an evil shaman, can be cured with S. divinorum (Johnson 1939; Valdés et al. 1983; Ott 1996). Other than physical illnesses, Salvia divinorum is traditionally used for divination practices, spiritual rituals, and training of medical practitioners (Johnson 1939; Ott 1996; Valdés et al. 1983). Valdés reported that the plant was used by a curandero (traditional healer) as a divination tool for investigating diseases that the curandero could not recognize: after treatment with the plant, “the sick person begins to describe the type of illness they are suffering from” (Valdés 2001). Traditionally, fresh leaves are chewed or a juice is made by crushing the leaves and adding water. The leaves are always counted in pairs, and while for medical purposes only 4-5 pairs of leaves are used, usually 20-80 pairs of leaves are used for divination practices (Valdés et al. 1983).