Medically reviewed on May 17, 2018
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
Salvia divinorum is a hallucinogen and is illegal in some jurisdictions. Check individual state legislation.
200 to 500 mcg of salvinorin A, or several leaves, smoked or absorbed perorally, is sufficient to cause hallucinations.
S. divinorum should not be used in people with any mental disease.
Use during pregnancy or lactation is not recommended.
None well documented.
None systematically reported.
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
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
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. 34Animal 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. 51Clinical 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. 28Other 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
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
Use in pregnancy and lactation is not recommended.
The activation of numerous cytochrome P450 enzymes has been noted, but not explored, in herb-drug interactions. 30
Salvinorin A produced no toxicity in mice in a 2-week, subchronic toxicology study. 58
Bibliography1. Schultes RE, Hoffman A. The Botany and Chemistry of Hallucinogens . Springfield, IL: Charles C. Thomas; 1973:159-161.
2. Valdés LJ ΙΙΙ, Díaz JL, Paul AG. Ethnopharmacology of ska Maria Pastora ( Salvia divinorum , Epling and Játiva-M.). J Ethnopharmacol . 1983;7(3):287-312.
3. Babu KM, McCurdy CR, Boyer EW. Opioid receptors and legal highs: Salvia divinorum and Kratom. Clin Toxicol (Phila) . 2008;46(2):146-152.
4. Bücheler R, Gleiter CH, Schwoerer P, Gaertner I. Use of nonprohibited hallucinogenic plants: increasing relevance for public health? A case report and literature review on the consumption of Salvia divinorum (Diviner's Sage). Pharmacopsychiatry . 2005;38(1):1-5.
5. González D, Riba J, Bouso JC, Gómez-Jarabo G, Barbanoj MJ. Pattern of use and subjective effects of Salvia divinorum among recreational users. Drug Alcohol Depend . 2006;85(2):157-162.
6. Hoover V, Marlowe DB, Patapis NS, Festinger DS, Forman RF. Internet access to Salvia divinorum : implications for policy, prevention, and treatment. J Subst Abuse Treat . 2008;35(1):22-27.
7. Lange JE, Reed MB, Croff JM, Clapp JD. College student use of Salvia divinorum . Drug Alcohol Depend . 2008;94(1-3):263-266.
8. Singh S. Adolescent Salvia substance abuse. Addiction . 2007;102(5):823-824.
9. Bertea CM, Luciano P, Bossi S, et al. PCR and PCR-RFLP of the 5S-rRNA-NTS region and salvinorin A analyses for the rapid and unequivocal determination of Salvia divinorum . Phytochemistry . 2006;67(4):371-378.
10. Ortega A, Bount JF, Manchand PS. Salvinorin, a new trans -neoclerodane diterpene from Salvia divinorum (Labiatae). J Chem Soc Perkin Trans 1 . 1982;2505-2508.
11. Valdes LJ, Butler WM, Hatfield GM, Paul AG, Koreeda M. Divinorin A, a psychotropic terpenoid, and divinorin B from the hallucinogenic Mexican mint Salvia divinorum . J Org Chem . 1984;49(24):4716-4720.
12. Bigham AK, Munro TA, Rizzacasa MA, Robins-Browne RM. Divinatorins A-C, new neoclerodane diterpenoids from the controlled sage Salvia divinorum . J Nat Prod . 2003;66(9):1242-1244.
13. Harding WW, Tidgewell K, Schmidt M, et al. Salvinicins A and B, new neoclerodane diterpenes from Salvia divinorum . Org Lett . 2005;7(14):3017-3020.
14. Kutrzeba LM, Ferreira D, Zjawiony JK. Salvinorins J from Salvia divinorum : mutarotation in the neoclerodane system. J Nat Prod . 2009;72(7):1361-1363.
15. Munro TA, Rizzacasa MA. Salvinorins D-F, new neoclerodane diterpenoids from Salvia divinorum , and an improved method for the isolation of salvinorin A. J Nat Prod . 2003;66(5):703-705.
16. Shirota O, Nagamatsu K, Sekita S. Neo-clerodane diterpenes from the hallucinogenic sage Salvia divinorum [published correction appears in J Natr Prod . 2007;70(2):328]. J Nat Prod . 2006;69(12):1782-1786.
17. Valdés LJ ΙΙΙ, Chang HM, Visger DC, Koreeda M. Salvinorin C, a new neoclerodane diterpene from a bioactive fraction of the hallucinogenic Mexican mint Salvia divinorum . Org Lett . 2001;3(24):3935-3937.
18. Valdes LJ ΙΙΙ. Loliolide from Salvia divinorum . J Nat Prod . 1986;49(1):171.
19. Siebert DJ. Localization of salvinorin A and related compounds in glandular trichomes of the psychoactive sage, Salvia divinorum . Ann Bot . 2004;93(6):763-771.
20. Kutrzeba L, Dayan FE, Howell J, Feng J, Giner JL, Zjawiony JK. Biosynthesis of salvinorin A proceeds via the deoxyxylulose phosphate pathway. Phytochemistry . 2007;68(14):1872-1881.
21. Shirota O, Nagamatsu K, Sekita A. Simple preparative isolation of salvinorin A from the hallucinogenic sage, Salvia divinorum , by centrifugal partition chromatography. J Liq Chromatogr Relat Technol . 2007;30(8):1105-1114.
22. Gruber JW, Siebert DJ, Der Marderosian AH, Hock RS. High performance liquid chromatographic quantification of salvinorin A from tissues of Salvia divinorum Epling & Jativa-M. Anal Chem . 1999;10(1):22-25.
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.
24. Medana C, Massolino C, Pazzi M, Baiocchi C. Determination of salvinorins and divinatorins in Salvia divinorum leaves by liquid chromatography/multistage mass spectrometry. Rapid Commun Mass Spectrom . 2006;20(2):131-136.
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.
26. Wolowich WR, Perkins AM, Cienki JJ. Analysis of the psychoactive terpenoid salvinorin A content in five Salvia divinorum herbal products. Pharmacotherapy . 2006;26(9):1268-1272.
27. McDonough PC, Holler JM, Vorce SP, Bosy TZ, Magluilo J Jr, Past MR. The detection and quantitative analysis of the psychoactive component of Salvia divinorum , salvinorin A, in human biological fluids using liquid chromatography-mass spectrometry. J Anal Toxicol . 2008;32(6):417-421.
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.
29. Schmidt MS, Prisinzano TE, Tidgewell K, et al. Determination of salvinorin A in body fluids by high performance liquid chromatography-atmospheric pressure chemical ionization. J Chromatogr B Analyt Technol Biomed Life Sci . 2005;818(2):221-225.
30. Teksin ZS, Lee IJ, Nemieboka NN, et al. Evaluation of the transport, in vitro metabolism and pharmacokinetics of Salvinorin A, a potent hallucinogen. Eur J Pharm Biopharm . 2009;72(2):471-477.
31. Schmidt MD, Schmidt MS, Butelman ER, et al. Pharmacokinetics of the plant-derived κ-opioid hallucinogen salvinorin A in nonhuman primates. Synapse . 2005;58(3):208-210.
32. Roth BL, Baner K, Westkaemper R, et al. Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proc Natl Acad Sci U S A . 2002;99(18):11934-11939.
33. Chavkin C, Sud S, Jin W, et al. Salvinorin A, an active component of the hallucinogenic sage Salvia divinorum is a highly efficacious κ-opioid receptor agonist: structural and functional considerations. J Pharmacol Exp Ther . 2004;308(3):1197-1203.
34. Yan F, Mosier PD, Westkaemper RB, et al. Identification of the molecular mechanisms by which the diterpenoid salvinorin A binds to κ-opioid receptors. Biochemistry . 2005;44(24):8643-8651.
35. John TF, French LG, Erlichman JS. The antinociceptive effect of salvinorin A in mice. Eur J Pharmacol . 2006;545(2-3):129-133.
36. Ansonoff MA, Zhang J, Czyzyk T, et al. Antinociceptive and hypothermic effects of salvinorin A are abolished in a novel strain of κ-opioid receptor-1 knockout mice. J Pharmacol Exp Ther . 2006;318(2):641-648.
37. Fantegrossi WE, Kugle KM, Valdes LJ ΙΙΙ, Koreeda M, Woods JH. κ-opioid receptor-mediated effects of the plant-derived hallucinogen, salvinorin A, on inverted screen performance in the mouse. Behav Pharmacol . 2005;16(8):627-633.
38. Zhang Y, Butelman ER, Schlussman SD, Ho A, Kreek MJ. Effects of the plant-derived hallucinogen salvinorin A on basal dopamine levels in the caudate putamen and in a conditioned place aversion assay in mice: agonist actions at kappa opioid receptors. Psychopharmacology (Berl) . 2005;179(3):551-558.
39. Carlezon WA Jr, Béguin C, DiNieri JA, et al. Depressive-like effects of the κ-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats. J Pharmacol Exp Ther . 2006;316(1):440-447.
40. Beerepoot P, Lam V, Luu A, Tsoi B, Siebert D, Szechtman H. Effects of salvinorin A on locomotor sensitization to D2/D3 dopamine agonist quinpirole. Neurosci Lett . 2008;446(2-3):101-104.
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.
48. Siebert DJ. Salvia divinorum and salvinorin A: new pharmacologic findings. J Ethnopharmacol . 1994;43(1):53-56.
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.
50. Butelman ER, Prisinzano TE, Deng H, Rus S, Kreek MJ. Unconditioned behavioral effects of the powerful κ-opioid hallucinogen salvinorin A in nonhuman primates: fast onset and entry into cerebrospinal fluid. J Pharmacol Exp Ther . 2009;328(2):588-597.
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.
53. Grundmann O, Phipps SM, Zadezensky I, Butterweck V. Salvia divinorum and salvinorin A: an update on pharmacology and analytical methodology. Planta Med . 2007;73(10):1039-1046.
54. Prisinzano TE. Psychopharmacology of the hallucinogenic sage Salvia divinorum . Life Sci . 2005;78(5):527-531.
55. Vortherms TA, Roth BL. Salvinorin A: from natural product to human therapeutics. Mol Interv . 2006;6(5):257-265.
56. Przekop P, Lee T. Persistent psychosis associated with salvia divinorum use. Am J Psychiatry . 2009;166(7):832.
57. Hanes KR. Antidepressant effects of the herb Salvia divinorum : a case report. J Clin Psychopharmacol . 2001;21(6):634-635.
58. Mowry M, Mosher M, Briner W. Acute physiologic and chronic histologic changes in rats and mice exposed to the unique hallucinogen salvinorin A. J Psychoactive Drugs . 2003;35(3):379-382.
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