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The Magic Mint: Salvia divinorum By: Stephanie Halbleib 2 Introduction • Salvia divinorum is a native perennial shrub to Mexico – Hallucinogenic plant – Lamiaceae mint family (sage, basil, etc.) – Mazatec shamans • Most potent naturally occurring hallucinogen • Legal in most states – DEA states Salvia as a drug of concern Background • Salvia was first documented in 1939 • Salvinorin A isolated in 1982 by X-ray crystallography • 1900s the psychoactive mechanism of Salvia was identified 6 17 Salvinorin A • • • • Active constituent C23H28O8 Neoclerodane class of diterpenes Is not an alkaloid • Excreted through trichomes in the leaves, forms a resin on the leaves • Responsible for observed hallucinogen effects • Kappa opioid receptor agonist 17 Other Substituents • Salvinorin B, C, D, E, & F, and divinaturin A, B, & C • Neoclerodane diterpenoid structure – Salvinorin B • Lower concentrations • Metabolite of salvinorin A – Salvinorin C • Weak affinity for kappa opioid receptor • Lacks psychotropic effects – Salvinorin D and G only • Exhibit affinity for kappa opioid receptor • Overall have shown no significant affinity – Means no evidence to contribute psycho activity. • Research focused on mechanism of salvinorin A 17 History and Current Practices • Traditionally – Chewed, or drink juice of crushed leaves – Induce visions in ceremonies • Today – Chewed, smoked, or tinctures – Marijuana substitute – 1.8 million have tried Salvia 16 Opioid Receptor • Opioid system controls pain, reward, and addictive behaviors • Three opioid receptors, mu, delta and kappa • Activated endogenous by peptides (like endorphins), or exogenously by alkaloid opiates (such as morphine) • Signal transduction is theorized as follows: – Activation is coupled to the G protein which increases phosphodiesterase activity – Breaks down cAMP, producing an inhibitory effect in neurons – Also shown to be coupled to nitrogen type calcium ion channels • Exact activation that Salvinorin A is unknown Hallucinogens • Distinct class of compounds categorized by their chemical structure and pharmacological actions • Salvinorin A does not bind at 5HT2A (serotonin) receptor 17 Detection Methods • Drug Urinalysis – Two types of tests • Drug screening and drug testing – Looks for drug metabolites – Marijuana has 31 different metabolites (most common THCA) – Salvia is undetectable Detection Methods Cont. • Extraction – Organic solvents extract salvinorin A and pigments – Activated charcoal, centrifugation, and evaporation reveals purified salvinorin A • Color test – Indicate which type of substance is present (opium, barbiturates, etc.) – Cannabis uses the Duquenois-Levine test • (deep purple) – No current color test for Salvia (high amount, Marquis Color test could detect Salvinorin A – Not 100% accurate 11 Detection Methods Cont. • Thin Layer Chromatography – Confirm unknown substance with known Rf values – Researchers have been able to use this TLC to show salvinorin A, B, C, and D are in the leaves – Pinkish purple spots – Cannabis, or Salvia? 11 Detection Methods Cont. • Gas Chromatography-Mass Spectrometry – GC separates sample into individual compounds – MS analyzes each compound • Ionizing each compound to create fragments, then measured by mass-to-charge ratios – Salvia different organic solvents can be used (methanol and chloroform) – Salvinorin A is not always the only peak 11 Potency and Methods of Use • Amounts needed for hallucinogenic effect vary •Dose of 200-600μ in humans • Smoking – Salvinorin A in leaves – Lighter • Type and temperature – Inhaling smoke fully 17 • Chewing – Salvinorin A in leaves – Contact with the mucous lining – Ingesting the leaves Effects • Impairs coordination, dream-like awareness, body high, etc. – Disappear when metabolized • After effects-mentally refreshed, headaches, nausea, etc. – Disappear completely in about one day • Does not seem to be toxic – Mice vs. humans 17 Role in Treatment • Therapeutic Potential – Shown to pharmacologically active on inflamed gut and other inflamed tissues – Could be useful for: Alzheimer's, depression, schizophrenia, chronic pain, and AIDS/HIV – Baggott’s survey and self-medication studies have showed improved mood and antidepressant effects 17 Role in Treatment Cont. • Drug Addiction – Endogenous kappa opioid agonist is thought to be the body's natural addiction control mechanism – Kappa opioid receptor shown to influence stressinduced relapse drug seeking behavior – Research suggest Salvia may help treat cocaine addiction • Rats had free access to cocaine until addicted • Had choice of salvinorin A and cocaine. • Rats stopped ingesting cocaine and had little signs of withdraw – Morphine • Affects kappa and mu opioid receptors • mu receptors are believed to cause opiate dependence Discussion • Sensitivity to salvinorin A vary – Many factors • Resin amounts • Salvinorin A’s size • Temperature and type of lighter • More research is needed Conclusion • Further research – Could provide insight into therapeutic potential of kappa opioid receptor and Salvia in treatments – On effects of salvinorin A can help to characterize clinical toxicity and substance abuse • Few human documented cases – Salvia escapes traditional medical testing methods of toxicology • Could pose a problem • No human case studies • Many factors could effect potency levels • Could other mint family species contain salvinorin A, and lead to a Pandora's box? QUESTONS 17 References • • • • • • • • • • • • • • • • • Vortherms, T.A.; Roth, B.L. Salvinorin A: From Natural Product to Human Therapeutics. Molecular Interventions 2006, 6, 257-265. 2 Babu, K.M.; McCurdy, R.; Boyer, E.W. Opioid Receptors and Legal High: Salvia divinorum and Kratom. Clinical Toxicology (Phila.) 2008, 46, 146-152. 3 Lee, D.Y.; Yang, L.; Xu, W.; Deng, G.; Guo, L.; Liu-Chen, L.Y. Synthesis and Biological Evaluation of C-2 Halogenated Analogs of Salvinorin A. Bioorganic Medicinal Chemistry Letters 2010, 20, 5749-5752. 4 Prisinzano, T.E. Psychopharmacology of the Hallucinogenic Sage Salvia divinorum. Life Science 2005, 78, 527-531. 5 Capasso, R.; Borrelli, F.; Zjawiony, J.; Kutrzeba, L.; Aviello, G.; Sarnelli, G.; Capasso, F.; Izzo, A.A. The Hallucinogenic Herb Salvia divinorum and its Active Ingredient Salvinorin A Reduce Inflammation-Induced Hypermotility in Mice. Neurogastroenterol Motil. 2008, 20, 142-148. 6 Winter, J.C. Hallucinogens as Discriminative Stimuli in Animals: LSD, Phenethylamines, and Tryptamines. Psychopharmacology(Berl.) 2009, 203, 251-263. 7 Roth, B.L.; Baner, K.; Westkaemper, R.; Siebert, D.; Rice, K.C.; Steinberg, S.; Ernsberger, P.; Rothman, R.B. Salvinorin A: A Potent Naturally Occurring Nonnitrogenous κ Opioid Selective Agonist. Proc Natl Acad Sci (USA) 2002, 99, 11934-11939. 8 Griffin O.H.; Miller B.L.; Khey D.N. Legally high? Legal considerations of Salvia divinorum Journal of Psychoactive Drugs 2008, 40, 183-191. 9 Johnson, M.W.; Maclean, K.A.; Reissig, C.J.; Prisinzano, T.E.; Griffiths, R.R. Human Psychopharmacology and Doseeffects if Salvinorin A, a Kappa Opioid Agonist Hallucinogen Present in the Plant Salvia divinorum. Drug Alcohol Depend November 2010, pp 1-6. 10 Harris, D.C. Quantitative Chemical Analysis, 7th ed.; Freeman: New York, 2007. 11 Jermain, J.D.; Evans, K.E. Analyzing Salvia Divinorum and its Active Ingredient Salvinorin A Utilizing Thin Layer Chromatography and Gas Chromatography/Mass Spectrometry. Journal of Forensic Science 2009, 45, 612-616. 12 Vohta, R.; Seefeld, A.; Cantrell, F.L.; Clark, R.F. Salvia Divinorum: Exposures Reported to a Statewide Poison Control System Over 10 Year. Journal of Emergency Medicine April 2009, pp1-8. 13 Walentiny, D.M.; Vann, R.E.; Warner, J.A.; King, L.S.; Seltzman, H.H.; Navarro, H.A.; Twine, C.E.; Thomas, B.F.; Gilliam, A.F.; Gilmour, B.P.; Carroll, F.I.; Wiley, J. L. Kappa Opioid Mediation of Cannabinoid Effects of the Potent Hallucinogen, Salvinorin A, in rodents. Psychopharmacology (Berl.) 2010, 210, 275-284. 14 Killinger, B.A.; Peet, M.M.; Baker, L.E. Salvinorin A Fails to Substitute for the Discriminative Stimulus Effects of LSD or Ketamine in Sprague-Dawley rats. Pharmacol Biochemistry Behaviors 2010, 96, 260-265. 15 Chavkin, C.; Sud, S.; Jin, W.; Stewart, J.; Zjawiony, J.K.; Siebert, D.J.; Toth, B.A.; Hufeisen, S.J.; Roth, B.L. Salvinorin A, an Active Component in the Hallucinogenic Sage Salvia divinorum is a Highly Efficacious κ-Opioid Receptor Agonist: Structural and Functional Considerations. Journal of Pharmacology and Experimental Therapeutics 2004, 308, 1197-1203. 16 Google images search (accessed April 22, 2011). 17 Wikipedia Salvia and Salvinorin A http://en.wikipedia.org/wiki/Salvinorin_A (accessed April 15, 20011). 1