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Salvia divinorum

Scientific Name(s): Salvia divinorum Epl. & Jativa-M. Family: Lamiaceae (mints)

Common Name(s): Ska Maria Pastora , hojas de Maria , yerba Maria , magic mint , Sally D , diviner's sage , mystic mint , purple sticky

Uses

Salvia divinorum is a hallucinogen and is illegal in some jurisdictions. Check individual state legislation.

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.

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. 1

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. 2 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. 3 , 4 , 5 , 6 , 7 , 8 A protein-coupled receptor method has been established for the identification of S. divinorum based on 5S-rRNA-NTS sequence. 9

Chemistry

The psychotropic active agent in S. divinorum was identified as the diterpene salvinorin A, also known as divinorin A. 10 , 11 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. 12 , 13 , 14 , 15 , 16 , 17 The lactone loliolide has also been isolated from S. divinorum . 18

A detailed study of the tissue localization of salvinorin A found it in the peltate glandular trichomes of the leaves. 19 Biosynthesis of salvinorin A utilizes the deoxyxylulose pathway, rather than the mevalonate pathway. 20

A preparative isolation procedure for salvinorin A using centrifugal partition chromatography has been published. 21 Numerous reports describe analytical methods for salvinorin A in leaf material using high-performance liquid chromatography, thin-layer chromatography, and mass spectroscopy. 22 , 23 , 24 , 25 , 26 Similarly, methods using gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry have been developed for the determination of salvinorin A in body fluids. 27 , 28 , 29 These methods have been used in initial pharmacokinetic studies in rats 30 and rhesus monkeys. Salvinorin A was rapidly eliminated with salvinorin B, the major metabolite. 31 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. 30

Uses and Pharmacology

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, 32 while having no effect at the mu- and delta-opioid receptors. It was more effective than several other kappa agonists. 33 Analysis of activity with mutated kappa-receptors identified key binding sites on the receptor. 34

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. 35 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. 36 Behavioral studies in mice using inverted screen climbing performance also found kappa-agonism involvement. 37

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. 38 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. 39

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. 40 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. 41

Salvinorin A modulated the behavioral and molecular effects of cocaine in rats, suggesting that it interfered with dopamine 1 receptor signaling in the striatum. 42 Other studies found that salvinorin A blocked cocaine-induced drug-seeking in rats, similar to other kappa-agonists. 43

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. 44 A second group found the same effect in rats with U69593 and U50488. 45 In rhesus monkeys, the same substitution was obtained with U69593 and salvinorin A. 46 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. 47 The reported rapid onset and short duration of action of S. divinorum in humans 48 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. 49 Unconditioned responses to IV salvinorin A in rhesus monkeys (facial relaxation, ptosis) were of a similarly rapid onset and short duration. 50 Some of the previously mentioned effects have also been observed in zebrafish. 51

Clinical data

No systematic human clinical studies of salvinorin A or S. divinorum have been reported in the literature to date. Observational studies of the plant and pure compound have been published, 48 while salvinorin A was detected in urine and saliva after plant consumption. 28

Other uses

S. divinorum and pure salvinorin A inhibited cholinergic transmission in guinea pig ileum. 52 This may account for traditional use as an antidiarrheal. Several recent reviews have appeared. 53 , 54 , 55

Dosage

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. 48 , 54 , 55

Pregnancy/Lactation

Use in pregnancy and lactation is not recommended.

Interactions

The activation of numerous cytochrome P450 enzymes has been noted, but not explored, in herb-drug interactions. 30

Adverse Reactions

A case report was published showing persistent psychosis associated with S. divinorum use. 56 A second report found that self-administered S. divinorum was effective in moderate depression. 57

Toxicology

Salvinorin A produced no toxicity in mice in a 2-week, subchronic toxicology study. 58

Bibliography

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23. Jermain JD, Evans HK. Analyzing Salvia divinorum and its active ingredient salvinorin A utilizing thin layer chromatography and gas chromatography/mass spectrometry. J Forensic Sci . 2009;54(3):612-616.
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25. Tsujikawa K, Kuwayama K, Miyaguchi H, et al. Determination of salvinorin A and salvinorin B in Salvia divinorum -related products circulated in Japan. Forensic Sci Int . 2008;180(2-3):105-109.
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28. Pichini S, Abanades S, Farré M, et al. Quantification of the plant-derived hallucinogen salvinorin A in conventional and non-conventional biological fluids by gas chromatography/mass spectrometry after Salvia divinorum smoking. Rapid Commun Mass Spectrom . 2005;19(12):1649-1656.
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41. Braida D, Limonta V, Capurro V, et al. Involvement of κ-opioid and endocannabinoid system on salvinorin A-induced reward. Biol Psychiatry . 2008;63(3):286-292.
42. Chartoff EH, Potter D, Damez-Werno D, Cohen BM, Carlezon WA Jr. Exposure to the selective κ-opioid receptor agonist salvinorin A modulates the behavioral and molecular effects of cocaine in rats. Neuropsychopharmacology . 2008;33(11):2676-2687.
43. Morani AS, Kivell B, Prisinzano TE, Schenk S. Effect of kappa-opioid receptor agonists U69593, U50488H, spiradoline and salvinorin A on cocaine-induced drug-seeking in rats. Pharmacol Biochem Behav . 2009;94(2):244-249.
44. Willmore-Fordham CB, Krall DM, McCurdy CR, Kinder DH. The hallucinogen derived from Salvia divinorum , salvinorin A, has κ-opioid agonist discriminative stimulus effects in rats. Neuropharmacology . 2007;53(4):481-486.
45. Baker LE, Panos JJ, Killinger BA, et al. Comparison of the discriminative stimulus effects of salvinorin A and its derivatives to U69,593 and U50,488 in rats. Psychopharmacology (Berl) . 2009;203(2):203-211.
46. Butelman ER, Harris TJ, Kreek MJ. The plant-derived hallucinogen, salvinorin A, produces κ-opioid agonist-like discriminative effects in rhesus monkeys. Psychopharmacology (Berl) . 2004;172(2):220-224.
47. Butelman ER, Mandau M, Tidgewell K, Prisinzano TE, Yuferov V, Kreek MJ. Effects of salvinorin A, a κ-opioid hallucinogen, on a neuroendocrine biomarker assay in nonhuman primates with high κ-receptor homology to humans. J Pharmacol Exp Ther . 2007;320(1):300-306.
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49. Hooker JM, Xu Y, Schiffer W, Shea C, Carter P, Fowler JS. Pharmacokinetics of the potent hallucinogen, salvinorin A in primates parallels the rapid onset and short duration of effects in humans. Neuroimage . 2008;41(3):1044-1050.
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51. Braida D, Limonta V, Pegorini S, et al. Hallucinatory and rewarding effect of salvinorin A in zebrafish: κ-opioid and CB1-cannabinoid receptor involvement. Psychopharmacology (Berl) . 2007;190(4):441-448.
52. Capasso R, Borrelli F, Capasso F, et al. The hallucinogenic herb Salvia divinorum and its active ingredient salvinorin A inhibit enteric cholinergic transmission in the guinea-pig ileum. Neurogastroenterol Motil . 2006;18(1):69-75.
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