Salvia divinorum
Scientific Name(s): Salvia divinorum Epl. & Jativa-M.
Common Name(s): Diviner's sage, Hojas de Maria, Magic mint, Mystic mint, Purple sticky, Sally D, Ska Maria Pastora, yerba de la pastora, Yerba Maria
Medically reviewed by Drugs.com. Last updated on Oct 24, 2023.
Clinical Overview
Use
Salvia divinorum is a hallucinogen and is illegal in some jurisdictions. Check individual state legislation. Clinical studies suggest Salvia divinorum to act via a potentiation of kappa opioid receptor activity.
Dosing
200 to 500 mcg of salvinorin A, or several leaves, smoked or absorbed perorally, is sufficient to cause hallucinations.
Contraindications
S. divinorum should not be used in people with any mental disease.
Pregnancy/Lactation
Use during pregnancy or lactation is not recommended.
Interactions
None well documented.
Adverse Reactions
None systematically reported.
Toxicology
No toxicity was observed in a 2-week study in mice.
Scientific Family
- Lamiaceae (mint)
Source
S. divinorum is a species of sage native to the Sierra Mazateca in Oaxaca, Mexico. It is a perennial herb that grows 1 m in height, with ovate to acuminate leaves 12 to 15 cm long, and flowers with white corollas and purple calyces in a panicle. It has not been found in the wild and is only known from cultivated material in forest ravines in northeastern Oaxaca.Schultes 1973, PLANTS 2017
History
The plant has been used by the Mazatec people, who also employed a number of other psychotropic plants in extensively documented healing and divinatory rituals.Valdés 1983 The leaves of the plant typically were masticated or the expressed juice ingested. Because the plant is illegal in some jurisdictions, individual state statutes should be consulted. It is widely available through Internet sales.Babu 2008, Bücheler 2005, González 2006, Hoover 2008, Lange 2008, Singh 2007 A protein-coupled receptor method has been established for the identification of S. divinorum based on 5S-rRNA-NTS sequence.Bertea 2006
Chemistry
The psychotropic active agent in S. divinorum was identified as the diterpene salvinorin A, also known as divinorin A.Ortega 1982, Valdes 1984 Salvinorin A is the first example of a hallucinogenic agent that is not an alkaloid. Other diterpenes in the neoclerodane series have been isolated from the plant.Bigham 2003, Harding 2005, Kutrzeba 2009, Munro 2003, Shirota 2006, Valdés 2001 The lactone loliolide has also been isolated from S. divinorum.Valdes 1986 Reviews of the chemical constituents have been published. Casselman 2014
A detailed study of the tissue localization of salvinorin A found it in the peltate glandular trichomes of the leaves.Siebert 2004 Biosynthesis of salvinorin A utilizes the deoxyxylulose pathway, rather than the mevalonate pathway.Kutrzeba 2007
A preparative isolation procedure for salvinorin A using centrifugal partition chromatography has been published.Shirota 2007 Numerous reports describe analytical methods for salvinorin A in leaf material using high-performance liquid chromatography, thin-layer chromatography, and mass spectroscopy.Gruber 1999, Jermain 2009, Medana 2006, Tsujikawa 2008, Wolowich 2006 Similarly, methods using gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry have been developed for the determination of salvinorin A in body fluids.McDonough 2008, Pichini 2005, Schmidt 2005 These methods have been used in initial pharmacokinetic studies in ratsTeksin 2009 and rhesus monkeys. Salvinorin A was rapidly eliminated with salvinorin B, the major metabolite.Schmidt 2005 It stimulated p-glycoprotein adenosine triphosphatase activity in cells, suggesting that it may be a substrate for P-glycoprotein, as well as for several cytochrome P450 enzymes.Teksin 2009
Uses and Pharmacology
CNS effects
The discovery of salvinorin A as responsible for the hallucinogenic activity of the leaves sparked interest in its mechanism of action. While lysergic acid diethylamide, mescaline, and psilocybin all act through serotoninergic pathways, salvinorin A acts as a potent agonist at the kappa-opioid receptor(Roth 2002) while having no effect at the mu- and delta-opioid receptors. It was more effective than several other kappa agonists.(Chavkin 2004) Analysis of activity with mutated kappa-receptors identified key binding sites on the receptor.(Yan 2005)
Animal data
Salvinorin A was active in a mouse tail-flick analgesia model, and the effect was blocked by a kappa-opioid antagonist, but not by mu- or delta-antagonists.(John 2006) Similarly, in a kappa-opioid knockout mouse, salvinorin A had no analgesic or hypothermic effects. The kappa-1 receptor subclass was affected in preference to kappa-2.(Ansonoff 2006) Behavioral studies in mice using inverted screen climbing performance also found kappa-agonism involvement.(Fantegrossi 2005)
Salvinorin A produced reduction in striatal dopamine levels in mice, consistent with a kappa-opioid effect, and these reductions were linked to reduced locomotor activity and conditioned place aversion. Effects were blocked by the kappa-antagonist nor-binaltorphimine.(Zhang 2005) In rats, extracellular levels of dopamine were decreased in the nucleus accumbens without affecting serotonin levels. Effects in forced-swimming tests and intracranial self-stimulation were found as well.(Carlezon 2006)
Like another kappa-opioid agonist, salvinorin A potentiated the effect of the dopamine D2/D3 agonist quinpirole in rats in high doses, but had an opposite effect at low doses.(Beerepoot 2008) Rat studies demonstrated an effect on the cannabinoid reward system with salvinorin A, which was blocked by a cannabinoid receptor type 1 antagonist (rimonabant) and a kappa-opioid antagonist.(Braida 2008)
Salvinorin A modulated the behavioral and molecular effects of cocaine in rats, suggesting that it interfered with dopamine 1 receptor signaling in the striatum.(Chartoff 2008) Other studies found that salvinorin A blocked cocaine-induced drug-seeking in rats, similar to other kappa-agonists.(Morani 2009)
Hallucinogens are extraordinarily difficult to study in animals; however, the measurement of discriminative stimulus effects is capable of sorting drugs into congruent categories. That is, experimental animals are trained to recognize the cues produced by a particular standard drug, and further experiments with other drugs can define the similarity in response to the standard. Thus, in rats, salvinorin A was a sufficient substitute for the kappa-opioid agonist U69593.(Willmore-Fordham 2007) A second group found the same effect in rats with U69593 and U50488.(Baker 2009) In rhesus monkeys, the same substitution was obtained with U69593 and salvinorin A.(Butelman 2004) Biochemical studies by the same group found that salvinorin A and U69593 produced increases in serum prolactin levels, and these effects were blocked by kappa-antagonism. The effect was more robust in females than in males.(Butelman 2007) The reported rapid onset and short duration of action of S. divinorum in humans(Siebert 1994) was paralleled in baboons. Positron emission tomography showed rapid salvinorin A brain uptake and a clearance half-life of 8 minutes. The labeled drug was administered intravenously (IV), and the highest concentrations were found in the cerebellum and visual cortex.(Hooker 2008) Unconditioned responses to IV salvinorin A in rhesus monkeys (facial relaxation, ptosis) were of a similarly rapid onset and short duration.(Butelman 2009) Some of the previously mentioned effects have also been observed in zebrafish.(Braida 2007)
Clinical data
Observational studies of the plant and pure compound have been published(Siebert 1994) while salvinorin A was detected in urine and saliva after plant consumption.(Pichini 2005) Small double-blind, randomized, placebo-controlled trials have been conducted using the Hallucinogen Rating Scale and other similar scales. Marked changes in auditory, visual, and interoceptive sensory input are reported in addition to other effects as could be expected with a mechanism of opioid agonsim by salvinorin A.(Addy 2015, MacLean 2013, Ranganathan 2012)
Other uses
S. divinorum and pure salvinorin A inhibited cholinergic transmission in guinea pig ileum.(Capasso 2006) This may account for traditional use as an antidiarrheal. Several recent reviews have appeared.(Grundmann 2007, Prisinzano 2005, Vortherms 2006)
In mice, salvinorin A inhibited bronchial hyperreactivity comparable to those of non-sensitized controls via significant inhibition of allergen-induced leukotriene and cytokine production as well as inhibition of pulmonary mast cell degranulation.(Rossi 2017)
Dosing
The pure compound salvinorin A is estimated to be psychoactive at doses of 200 to 500 mcg when smoked. Several whole leaves are typically chewed or smoked for a similar effect; however, the leaves must be held in the mouth, because absorption through the oral mucosa is superior to GI absorption.Siebert 1994, Prisinzano 2005, Vortherms 2006
Pregnancy / Lactation
Use in pregnancy and lactation is not recommended.
Interactions
The activation of numerous cytochrome P450 enzymes has been noted in vitro, but not explored, in herb-drug interactions.(Teksin 2009)
Adverse Reactions
A case report was published showing persistent psychosis associated with S. divinorum use.Przekop 2009 A second report found that self-administered S. divinorum was effective in moderate depression.Hanes 2001 Potential for addiction is considered to be muted due to the lack of euphoric effects.Ranganathan 2012
Toxicology
Salvinorin A produced no toxicity in mice in a 2-week, subchronic toxicology study.Mowry 2003 Limited clinical studies suggest a low level of toxicity within certain dosages and a short duration of intoxication effect.Casselman 2014, Dueweke 2015
References
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