Plant Profiler

Salvia divinorum (Salvia divinorum)

Salvia divinorum (Salvia divinorum) Image
Synonyms / Common Names / Related Terms
Diviner's mint, diviner's sage, divinorin A, divinatorin A, divinatorin B, divinatorin C, divinatorin D, divinatorin E, hardwickiic acid, hierba Maria (Spanish), hojas de la pastora (Spanish), hojas de Maria pastora (Spanish), la hembra (Spanish), la Maria (Spanish), Lamiaceae (family), loliolide, magic mint, María pastora, Mexican mint, mint plant, neoclerodane diterpene, neoclerodane diterpenoids, presqualene alcohol, sage of the seers, Sally-D, salvia, salvinicin A, salvinicin B, salvinicin C, salvinicin D, salvinicin E, salvinicin F, salvinorin A, salvinorin G, salvinorinyl-2-heptanoate, SDE, shepherdess's herb, ska Maria pastora (Mazatec), ska pastora (Mazatec), the female, yerba de Maria (Spanish), yerba Maria (Spanish).

Mechanism of Action


  • Constituents: Salvia divinorum has several known constituents, but salvinorin A is typically known as the active component14, and is selective for kappa(1)-opioid receptors1,17. Laboratory study has shown that salvinorin A is found in both Salvia divinorum leaf extracts and the powdered leaves, but not in related species, such as kitchen sage (Salvia officinalis).14 Divinatorins A-C, also present in salvia, have not showed affinity at opioid receptors.18,19 Other constituents include loliolide20, salvinorinyl-2-heptanoate, divinorin A, salvinicins21, divinatorin C-E, salvinorins D-G22, hardwickiic acid, and presqualene alcohol.
  • Mechanism of action: Salvinorin A, a neoclerodane diterpene, is a naturally occurring hallucinogen and has been compared to the synthetic hallucinogen lysergic acid diethylamide in potency. In vitro study showed that the molecular target of salvinorin A was the kappa opioid receptor3, and salvinorin A is the only known non-nitrogenous and specific kappa-opioid agonist2,4,5,6,7,23,9.
  • Endogenous opioids seem to play a critical role in the regulation of mood states. Some researchers believe that because salvinorin A is selective for kappa opioid receptors, it may represent novel psychotherapeutic compounds for diseases manifested by perceptual distortions (e.g., schizophrenia, dementia, and bipolar disorders).8 One case report suggested that salvia may have antidepressant effects.11 Thus, current study often presents data with structural modification of salvinorin A with mu and delta opioid receptor affinity and activity.24 It has been proposed that the methyl ester and furan ring of salvinorin A are required for opioid activity but that the lactone and ketone functionalities are not.25,26,23,27,28,29 Salvinorin A, salvinorinyl-2-propionate, and salvinorinyl-2-heptanoate were found to be either full (salvinorin A) or partial (2-propionate, 2-heptanoate) agonists for inhibition of forskolin-stimulated cAMP production.30 The substituent at the 2-position of salvinorin A was critical for kappa-opioid receptor binding and activation. Salvinorin A has been observed as a full agonist, similar in efficacy to dynorphin A (the naturally occurring peptide ligand for kappa-opioid receptors).
  • Animal study shows that stimulation of brain kappa-opioid receptors using salvinorin A can trigger depressive-like signs in rats31 and raises the possibility that decreases in extracellular concentrations of dopamine within the nucleus accumbens contribute to these effects16.
  • Interestingly, although some aspects of the subjective effects reported from salvia use were similar to high doses of classical psychedelics with serotonin-2A receptor agonist activity, the intense derealization and impairment reported appear to be a characteristic of salvia5. Based on laboratory study, salvinorin A had no actions at the 5-HT(2A) serotonin receptor, the principal molecular target responsible for the actions of classical hallucinogens.8 In mice, however, salvinorin A has shown an inhibitory effect on striatal dopamine levels.15
  • Based on animal study, intracerebroventricular injection over a dose range of 1-30mcg of both salvinorin A and salvinorinyl-2-propionate produced antinociception in wild-type mice but not in a novel strain of kappa-opioid receptor knockout mice.1 Furthermore, salvinorin A produced a dose-dependent antinociception that peaked at 10 minutes post-injection but rapidly returned to baseline.10
  • Based on animal study, standardized salvia lead extract can depress enteric cholinergic transmission, which may be likely through the activation of kappa-opioid receptors, which supports salvia's traditional antidiarrheal use.12


  • Absorption: The diterpene salvinorin A from salvia, in doses of 200-500mcg produces effects which are subjectively identical to those experienced when the whole herb is ingested.13 Salvinorin A is effectively deactivated by the gastrointestinal system, so alternative routes of absorption must be used to maintain its activity. Traditionally the herb is consumed either by chewing the fresh leaves or by drinking the juices of freshly crushed leaves. The effects of the herb when consumed this way depend on absorption of salvinorin A through the oral mucosa before the herb is swallowed. In animal studies, salvinorin A is often administered intravenously. In one study, the effects of salvinorin A started about 5-15 minutes after injection, and dissipated by 120 minutes.3
  • Metabolism: Based on ex vivo study, salvinorin B is the principal metabolite of salvinorin A.32,33
  • Excretion: Based on laboratory study, salvinorin A was detected in urine (2.4 and 10.9ng/mL) and salvia (11.1 and 25.0ng/mL), but not in sweat patches from two consumers that smoked 75mg salvia leaves.34 Based on in vivo study in rhesus monkeys, the elimination t½ salvinorin A was rapid (56.6 ± 24.8 minutes) for all subjects after 0.032mg/kg intravenous bolus.35 Pharmacokinetic differences (distribution t½, elimination t½, and area under the curve) were observed between males and females, suggesting potential sex differences in its pharmacologic effects. Salvinorin B, the presumed major metabolite, was observed to accumulate ex vivo; however, in this study it never reached the limit of detection.
  • Binding affinity: Salvinorin A has been shown to bind with high affinity and selectivity to the kappa-opioid receptor as an agonist.36 Other studies have been conducted that support salvinorin A's strong affinity for the kappa-opioid receptor.


  1. Ansonoff, M. A., Zhang, J., Czyzyk, T., Rothman, R. B., Stewart, J., Xu, H., Zjwiony, J., Siebert, D. J., Yang, F., Roth, B. L., and Pintar, J. E. Antinociceptive and Hypothermic Effects of Salvinorin A Are Abolished in a Novel Strain of {kappa}-Opioid Receptor-1 Knockout Mice. J Pharmacol Exp Ther 2006;318(2):641-648. 16672569
  2. Beguin, C., Richards, M. R., Wang, Y., Chen, Y., Liu-Chen, L. Y., Ma, Z., Lee, D. Y., Carlezon, W. A., Jr., and Cohen, B. M. Synthesis and in vitro pharmacological evaluation of salvinorin A analogues modified at C(2). Bioorg Med Chem Lett 6-2-2005;15(11):2761-2765. 15869877
  3. Butelman, E. R., Harris, T. J., and Kreek, M. J. The plant-derived hallucinogen, salvinorin A, produces kappa-opioid agonist-like discriminative effects in rhesus monkeys. Psychopharmacology (Berl) 2004;172(2):220-224. 14586540
  4. Fantegrossi, W. E., Kugle, K. M., Valdes, L. J., III, Koreeda, M., and Woods, J. H. Kappa-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. 16286814
  5. Gonzalez, D., Riba, J., Bouso, J. C., Gomez-Jarabo, G., and Barbanoj, M. J. Pattern of use and subjective effects of Salvia divinorum among recreational users. Drug Alcohol Depend 5-20-2006,16720081
  6. Kane, B. E., Nieto, M. J., McCurdy, C. R., and Ferguson, D. M. A unique binding epitope for salvinorin A, a non-nitrogenous kappa opioid receptor agonist. FEBS J 2006;273(9):1966-1974. 16640560
  7. Medana, C., Massolino, C., Pazzi, M., and Baiocchi, C. Determination of salvinorins and divinatorins in Salvia divinorum leaves by liquid chromatography/multistage mass spectrometry. Rapid Commun Mass Spectrom 12-6-2005;20(2):131-136. 16331747
  8. Roth, B. L., Baner, K., Westkaemper, R., Siebert, D., Rice, K. C., Steinberg, S., Ernsberger, P., and Rothman, R. B. Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proc Natl Acad Sci USA 9-3-2002;99(18):11934-11939. 12192085
  9. Wang, Y., Tang, K., Inan, S., Siebert, D., Holzgrabe, U., Lee, D. Y., Huang, P., Li, J. G., Cowan, A., and Liu-Chen, L. Y. Comparison of pharmacological activities of three distinct kappa ligands (Salvinorin A, TRK-820 and 3FLB) on kappa opioid receptors in vitro and their antipruritic and antinociceptive activities in vivo. J Pharmacol Exp Ther 2005;312(1):220-230. 15383632
  10. McCurdy, C. R., Sufka, K. J., Smith, G. H., Warnick, J. E., and Nieto, M. J. Antinociceptive profile of salvinorin A, a structurally unique kappa opioid receptor agonist. Pharmacol Biochem Behav 2006;83(1):109-113. 16434091
  11. Hanes, K. R. Antidepressant effects of the herb Salvia divinorum: a case report. J Clin Psychopharmacol 2001;21(6):634-635. 11763023
  12. Capasso, R., Borrelli, F., Capasso, F., Siebert, D. J., Stewart, D. J., Zjawiony, J. K., and Izzo, A. A. 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. 16371085
  13. Siebert, D. J. Salvia divinorum and salvinorin A: new pharmacologic findings. J Ethnopharmacol 1994;43(1):53-56. 7526076
  14. Bertea, C. M., Luciano, P., Bossi, S., Leoni, F., Baiocchi, C., Medana, C., Azzolin, C. M., Temporale, G., Lombardozzi, M. A., and Maffei, M. E. 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. 16426651
  15. Zhang, Y., Butelman, E. R., Schlussman, S. D., Ho, A., and Kreek, M. J. 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. 15682306
  16. Carlezon, W. A., Jr., Beguin, C., Dinieri, J. A., Baumann, M. H., Richards, M. R., Todtenkopf, M. S., Rothman, R. B., Ma, Z., Lee, D. Y., and Cohen, B. M. Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats. J Pharmacol Exp Ther 2006;316(1):440-447. 16223871
  17. Lee, D. Y., Ma, Z., Liu-Chen, L. Y., Wang, Y., Chen, Y., Carlezon, W. A., Jr., and Cohen, B. New neoclerodane diterpenoids isolated from the leaves of Salvia divinorum and their binding affinities for human kappa opioid receptors. Bioorg Med Chem 10-1-2005;13(19):5635-5639. 16084728
  18. Bigham, A. K., Munro, T. A., Rizzacasa, M. A., and Robins-Browne, R. M. Divinatorins A-C, new neoclerodane diterpenoids from the controlled sage Salvia divinorum. J Nat Prod 2003;66(9):1242-1244. 14510607
  19. Munro, T. A., Goetchius, G. W., Roth, B. L., Vortherms, T. A., and Rizzacasa, M. A. Autoxidation of salvinorin A under basic conditions. J Org Chem 11-25-2005;70(24):10057-10061. 16292839
  20. Valdes, L. J., III. Loliolide from Salvia divinorum. J Nat Prod 1986;49(1):171. 3701340
  21. Valdes, L. J., III, Chang, H. M., Visger, D. C., and Koreeda, M. Salvinorin C, a new neoclerodane diterpene from a bioactive fraction of the hallucinogenic Mexican mint Salvia divinorum. Org Lett 11-29-2001;3(24):3935-3937. 11720573
  22. Munro, T. A. and Rizzacasa, M. A. 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. 12762813
  23. Munro, T. A., Rizzacasa, M. A., Roth, B. L., Toth, B. A., and Yan, F. Studies toward the pharmacophore of salvinorin A, a potent kappa opioid receptor agonist. J Med Chem 1-27-2005;48(2):345-348. 15658846
  24. Harding, W. W., Tidgewell, K., Byrd, N., Cobb, H., Dersch, C. M., Butelman, E. R., Rothman, R. B., and Prisinzano, T. E. Neoclerodane diterpenes as a novel scaffold for mu opioid receptor ligands. J Med Chem 7-28-2005;48(15):4765-4771. 16033256
  25. Harding, W. W., Schmidt, M., Tidgewell, K., Kannan, P., Holden, K. G., Gilmour, B., Navarro, H., Rothman, R. B., and Prisinzano, T. E. Synthetic studies of neoclerodane diterpenes from Salvia divinorum: semisynthesis of salvinicins A and B and other chemical transformations of salvinorin A. J Nat Prod 2006;69(1):107-112. 16441078
  26. Lee, D. Y., He, M., Kondaveti, L., Liu-Chen, L. Y., Ma, Z., Wang, Y., Chen, Y., Li, J. G., Beguin, C., Carlezon, W. A., Jr., and Cohen, B. Synthesis and in vitro pharmacological studies of C(4) modified salvinorin A analogues. Bioorg Med Chem Lett 10-1-2005;15(19):4169-4173. 16051487
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  29. Tidgewell, K., Harding, W. W., Lozama, A., Cobb, H., Shah, K., Kannan, P., Dersch, C. M., Parrish, D., Deschamps, J. R., Rothman, R. B., and Prisinzano, T. E. Synthesis of salvinorin A analogues as opioid receptor probes. J Nat Prod 2006;69(6):914-918. 16792410
  30. Chavkin, C., Sud, S., Jin, W., Stewart, J., Zjawiony, J. K., Siebert, D. J., Toth, B. A., Hufeisen, S. J., and Roth, B. L. Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations. J Pharmacol Exp Ther 2004;308(3):1197-1203. 14718611
  31. Beguin, C., Richards, M. R., Li, J. G., Wang, Y., Xu, W., Liu-Chen, L. Y., Carlezon, W. A., Jr., and Cohen, B. M. Synthesis and in vitro evaluation of salvinorin A analogues: Effect of configuration at C(2) and substitution at C(18). Bioorg Med Chem Lett 6-12-2006,16777411
  32. Barnes, S., Prasain, J. K., Wang, C. C., and Moore, D. R. Applications of LC-MS in the study of the uptake, distribution, metabolism and excretion of bioactive polyphenols from dietary supplements. Life Sci 3-27-2006;78(18):2054-2059. 16460766
  33. Schmidt, M. S., Prisinzano, T. E., Tidgewell, K., Harding, W., Butelman, E. R., Kreek, M. J., and Murry, D. J. Determination of Salvinorin A in body fluids by high performance liquid chromatography-atmospheric pressure chemical ionization. J Chromatogr B AnalytTechnol Biomed Life Sci 4-25-2005;818(2):221-225. 15734162
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  35. Schmidt, M. D., Schmidt, M. S., Butelman, E. R., Harding, W. W., Tidgewell, K., Murry, D. J., Kreek, M. J., and Prisinzano, T. E. Pharmacokinetics of the plant-derived kappa-opioid hallucinogen salvinorin A in nonhuman primates. Synapse 12-1-2005;58(3):208-210. 16138318
  36. Stewart, D. J., Fahmy, H., Roth, B. L., Yan, F., and Zjawiony, J. K. Bioisosteric modification of salvinorin A, a potent and selective kappa-opioid receptor agonist. Arzneimittelforschung 2006;56(4):269-275. 16724512

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