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Kava (Piper methysticum)


Piper methysticum
Synonyms / Common Names / Related Terms
(+) -dihydrokawain-5-ol, 11-methoxy-5, 5-hydroxydihydrokawain, 6-dihydroyangonin, antares, ava, ava pepper, ava pepper shrub, ava root, awa, bornyl cinnamate, cavain, Fijian kava, flavokavines A and B, gea, gi, grog, intoxicating long pepper, intoxicating pepper, kao, kava kava extract LI 140, kava kava rhizome, kava root, kavain, kavakava, kavalactones, kavapiper, kavapyrones, kavarod, kavasporal forte, kave-kave, kawa, kawa kawa, kawa pepper, Kawa Pfeffer, kew, LI150, long pepper, Macropiper latifolium, malohu, maluk, maori kava, meruk, milik, olanzapine, pepe kava, Piper methysticum, piperis methystici rhizoma, pipermethystine, Rauschpfeffer, rhizoma piperis methystici, Rhizome Di Kava-Kava sakaua, risperidone, sakau, tonga, WS 1490, wurzelstock, yagona, yangona, yaqona, yongona.



Mechanism of Action

Pharmacology:

  • Constituents: Kava contains pyrones, lactones (methysticin, dihydromethysticin (DMH), yangonin, dihydrokawain (DHK), kawain), flavonoids, and alkaloids.17,17,18,,20,21,22,23 Kavain is considered one of the principle biologically active components of kava.
  • Anti-inflammatory effects: Folmer et al. suggested that kavain and flavokavains A and B may play a role in reducing inflammation by regulating inhibition of nuclear factor kappaB (NF-kappaB) and inhibiting the degradation of other pathways.2
  • Anxiolytic properties: Kava extract produced statistically significant dose-dependent anxiolytic-like behavioral changes in both assays of anxiolysis in mice.14 Kava extracts produce significant murine anxiolytic-like behavioral changes and sedation that are not mediated through the benzodiazepine binding site on the GABA(A) receptor complex.14 The results of one animal study involving chicks suggest that dihydrokavain may be necessary and sufficient in mediating the anxiolytic properties of kava extract.24 Kava may selectively act on limbic structures, promoting anxiolysis without sedation.10 (+/-)-Kavain, one of the main active components of kava, may effectively modulate excitatory signals in the hippocampus of guinea pigs.25
  • CYP450 effects: Kava is known to have P450 1A2 inhibiting activity.26 Kava extracts have also induced CYP3A4 and activated human pregnane X receptor (PXR).27 Ma et al. proposed that the induction of CYP3A23 by dihydromethysticin and desmethoxyyangonin involves transcription activation, probably through a PXR-independent or PXR-involved indirect mechanism.
  • Hepatic effects: Potential mechanisms underlying the hepatotoxicity of kava have been related to intracellular glutathione depletion and/or quinone formation.5 Whitton et al. found that aqueous extracts contain glutathione, which has the potential to react with the kava lactones to provide protection against hepatotoxicity, especially when detoxification pathways are saturated.6 Based on a case report, the simultaneous intake of St. John's wort may potentiate the toxicity of kavapyrones. However, Musch et al. have also noted that an immune-mediated mechanism for hepatotoxicty in this case induced by kava, cannot be completely ruled out.8 Furthermore, an unpublished analysis of the in vitro, in vivo, and clinical data shows that kava and its kava lactones are not predictable hepatotoxins.28 Recent studies in rats found that the aqueous extract of kava does not affect liver function tests.29 It is conceivable that different methods of preparation (alcohol, water, or acetonic extraction) yield different kava alkaloids.9 Chronic consumption of traditionally prepared kava beverages by regular kava beverage consumers was associated with an elevation of GGT in 65% of the kava drinkers versus 26% in the controls (p=0.005).7 ALP was elevated in 23% of kava drinkers versus 3% in the controls (p=0.053).
  • Neurologic effects: Kava extract has exhibited neuroprotective activity, which was probably mediated by its constituents methysticin and dihydromethysticin.4 Pyrones have been noted for their anticonvulsive, spasmolytic, and anti-mycotic effects, as well as synergistic hypnotic (barbiturate), analgesic, and local anesthetic effects.30,31,32,33,34,35,36,37 Pyrones exhibit neuroprotective4 and "recovery-supporting" effects on neurological deficits after cerebral infarction in animals.38 These effects have been attributed to calcium channel agonism39,40, sodium channel blocking41,1,42, inhibition of monoamine oxidase16, and inhibition of noradrenaline uptake43. In rats, kava does not appear to interact with benzodiazepine/GABA receptors.44 ,45 Kava seems to facilitate GABA transmission K.11,46 Neuro-physiologic studies with EEG have demonstrated similar activity of kava to GABA agonists.46,11 Interactions with glutamate47, dopamine3, noradrenaline43, serotonin3,39 ,40, and their respective receptors may mediate the anxiolytic effect of kava. Neither high single doses nor chronic administration of kavain, from the lipophilic fraction of kava, alters dopaminergic or serotonergic tissue levels in rats.48 Therefore, dopaminergic or serotonergic effects may reside in the water-soluble fraction of kava.49,50
  • Oncologic effects: Kava's analgesic effect is not antagonized by naloxone13,51, suggesting a mechanism unrelated to opiate receptors. In an animal model, tolerance and dependence formation have not been demonstrated52. Melanogenesis stimulation activity of aqueous ethanolic extracts obtained from several different parts of five Piper species, namely Piper longum, P. kadsura, P. methysticum, P. betle, and P. cubeba, were examined by using cultured murine B16 melanoma cells.53 Among them, the extract of P. methysticum rhizome showed potent stimulatory effect on melanogenesis as did P. nigrum leaf extract. Activity-guided fractionation of kava extract led to the isolation of two active kavalactones, yangonin and 7,8-epoxyyangonin, along with three inactive kavalactones, 5,6-dehydrokawain, (+)-kawain and (+)-methysticin, and a glucosylsterol, daucosterin. 7,8-Epoxyyangonin showed a significant stimulatory effect on melanogenesis in B16 melanoma cells. Yangonin exhibited a weak melanogenesis stimulation activity.

Pharmacodynamics/Kinetics:

  • A psychophysiologic study of kavain (Klinge Pharma, Munich, Germany) found pharmacodynamic peaks at 1-2 hours and eight hours, suggesting active metabolites. Peak levels occurred at 1.8 hours, with an elimination half-life of approximately nine hours and a distribution half-life of 50 minutes.12
  • Absorption: Absorption of kava root extracts may be faster than absorption of isolated lactones.
  • Metabolism: In a study of the metabolism of several kava lactones in male rats, it was observed that about one-half of the 400mg/kg dose of dihydrokavain administered was found in the urine in 48 hours.54 About two-thirds of this was hydroxylated metabolites. The remaining one-third consisted of metabolites formed by the catabolism of the kava lactone and also included hippuric acid. The metabolites of the other kava lactones have also been characterized by analyzing the urine samples from rats.
  • Excretion: Metabolites and unchanged lactones of kava are excreted in human urine and feces.55
  • Kava, and other herbs that have the potential to modulate the activity of drug-metabolizing enzymes (e.g., garlic, ginkgo, echinacea, and stjohnswort, may participate in pharmacokinetic interactions with anticancer drugs.15
  • Bioavailability: In vitro, kavalactones are potentially bioavailable because they all readily crossed the Caco-2 monolayers with apparent permeabilities increasing from 42 x 10(-6) cm/s and most exhibiting more than 70% crossing within 90min.56 Matthias et al. found that the differences in their bioavailability were not all related to kavalactone structural differences, however, because it appears co-extracted compounds may also affect the bioavailability.

References
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  2. Folmer, F., Blasius, R., Morceau, F., Tabudravu, J., Dicato, M., Jaspars, M., and Diederich, M. Inhibition of TNFalpha-induced activation of nuclear factor kappaB by kava (Piper methysticum) derivatives. Biochem Pharmacol 4-14-2006;71(8):1206-1218. 16464438
  3. Baum, S. S., Hill, R., and Rommelspacher, H. Effect of kava extract and individual kavapyrones on neurotransmitter levels in the nucleus accumbens of rats. Prog Neuropsychopharmacol Biol Psychiatry 1998;22(7):1105-1120. 9829291
  4. Backhauss, C. and Krieglstein, J. Extract of kava (Piper methysticum) and its methysticin constituents protect brain tissue against ischemic damage in rodents. European Journal of Pharmacology 5-14-1992;215(2-3):265-269. 1396990
  5. Zhou, S. F., Xue, C. C., Yu, X. Q., and Wang, G. Metabolic activation of herbal and dietary constituents and its clinical and toxicological implications: an update. Curr Drug Metab 2007;8(6):526-553. 17691916
  6. Whitton, P. A., Lau, A., Salisbury, A., Whitehouse, J., and Evans, C. S. Kava lactones and the kava-kava controversy. Phytochemistry 2003;64(3):673-679. 13679089
  7. Brown, A. C., Onopa, J., Holck, P., Kaufusi, P., Kabasawa, D., Craig, W. J., Dragull, K., Levine, A. M., and Baker, J. D. Traditional kava beverage consumption and liver function tests in a predominantly Tongan population in Hawaii. Clin Toxicol (Phila) 2007;45(5):549-556. 17503265
  8. Musch, E., Chrissafidou, A., and Malek, M. [Acute hepatitis due to kava-kava and St John's Wort: an immune-mediated mechanism?]. Dtsch Med Wochenschr  5-26-2006;131(21):1214-1217. 16721710
  9. Currie, B. J. and Clough, A. R. Kava hepatotoxicity with Western herbal products: does it occur with traditional kava use? Med J Aust  5-5-2003;178(9):421-422. 12720503
  10. Holm, E., Staedt, U., Heep, J., Kortsik, C., Behne, F., Kaske, A., and Mennicke, I. [The action profile of D,L-kavain. Cerebral sites and sleep-wakefulness- rhythm in animals]. Arzneimittelforschung  1991;41(7):673-683. 1772452
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  12. Saletu B, Grünberger J, Linzmayer L, and et al. EEG-brain mapping, psychometric and psychophysiological studies on central effects of kavain-a kava plant derivative. Hum Psychopharm 1989;4:169-190.
  13. Jamieson, D. D., Duffield, P. H., Cheng, D., and Duffield, A. M. Comparison of the central nervous system activity of the aqueous and lipid extract of kava (Piper methysticum). Arch Int Pharmacodyn Ther  1989;301:66-80. 2624517
  14. Garrett, K. M., Basmadjian, G., Khan, I. A., Schaneberg, B. T., and Seale, T. W. Extracts of kava (Piper methysticum) induce acute anxiolytic-like behavioral changes in mice. Psychopharmacology (Berl) 2003;170(1):33-41. 12845414
  15. Sparreboom, A., Cox, M. C., Acharya, M. R., and Figg, W. D. Herbal remedies in the United States: potential adverse interactions with anticancer agents. J Clin Oncol 6-15-2004;22(12):2489-2503. 15197212
  16. Uebelhack, R., Franke, L., and Schewe, H. J. Inhibition of platelet MAO-B by kava pyrone-enriched extract from Piper methysticum Forster (kava-kava). Pharmacopsychiatry 1998;31(5):187-192. 9832350
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  18. Duffield AM and Lidgard RO. Analysis of kava resin by gas chromatography and electron impact and methane negative ion chemical ionization mass spectrometry. New trace constituents of kava resin. Biomed Environ Mass Spectr 1986;13:621-626.
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  22. Smith RM, Thakrar H, Arowolo A, and et al. High-performance liquid chromatography of kava lactones from Piper methysticum. J Chromatography 1984;283:303-308.
  23. Young RL, Hylin JW, Plucknett DL, Kawano Y, and Nakayama RT. Analysis for kawa pyrones in extracts of piper methysticum. Phytochemistry 1966;5:795-798.
  24. Feltenstein, M. W., Lambdin, L. C., Ganzera, M., Ranjith, H., Dharmaratne, W., Nanayakkara, N. P., Khan, I. A., and Sufka, K. J. Anxiolytic properties of Piper methysticum extract samples and fractions in the chick social-separation-stress procedure. Phytother Res 2003;17(3):210-216. View 12672148
  25. Langosch, J. M., Normann, C., Schirrmacher, K., Berger, M., and Walden, J. The influence of (+/-)-kavain on population spikes and long-term potentiation in guinea pig hippocampal slices. Comp Biochem Physiol A Mol Integr Physiol 1998;120(3):545-549. 9787833
  26. Jeurissen, S. M., Claassen, F. W., Havlik, J., Bouwmans, E. E., Cnubben, N. H., Sudholter, E. J., Rietjens, I. M., and van Beek, T. A. Development of an on-line high performance liquid chromatography detection system for human cytochrome P450 1A2 inhibitors in extracts of natural products. J Chromatogr A 2-2-2007;1141(1):81-89. 17184784
  27. Ma, Y., Sachdeva, K., Liu, J., Ford, M., Yang, D., Khan, I. A., Chichester, C. O., and Yan, B. Desmethoxyyangonin and dihydromethysticin are two major pharmacological kavalactones with marked activity on the induction of CYP3A23. Drug Metab Dispos 2004;32(11):1317-1324.
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  30. Brüggemann F and Meyer HJ. Die analgetische wirkung der Kawa-inhaltsstoffe dihydrokawain und dihydromethysticin. Arzneimittelforschung  1963;13:407-409.
  31. Hänsel R. Characterization and physiological activity of some Kawa constituents. Pacific Science 1968;22:293-313.
  32. Kretzschmar, R. and Meyer, H. J. [Comparative studies on the anticonvulsant activity of the pyrone compounds of Piper methysticum Forst]. Arch Int Pharmacodyn Ther 1969;177(2):261-277. 5807167
  33. Kretzschmar, R., Meyer, H. J., and Teschendorf, H. J. Strychnine antagonistic potency of pyrone compounds of the kavaroot (Piper methysticum Forst.). Experientia 3-15-1970;26(3):283-284. 5417498
  34. Kretzschmar R, Teschendorf HJ, Ladous A, and et al. On the sedative action of the kava rhizome (piper methyst.). Acta Pharmacol Toxicol 1971;29(4):26.
  35. Meyer, H. J. [Spasmolytic effect of dihydromethysticin, a constituent of Piper methysticum Forst]. Arch Int Pharmacodyn Ther  1965;154(2):449-467. 5891279
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  39. Walden, J., von Wegerer, J., Winter, U., Berger, M., and Grunze, H. Effects of kawain and dihydromethysticin on field potential changes in the hippocampus. Prog Neuropsychopharmacol Biol Psychiatry 1997;21(4):697-706. 9194150
  40. Walden J, von Wegerer J, Winter U, and et al. Actions of kavain and dihydromethysticin on ipsapirone-induced field potential changes in the hippocampus. Human Psychopharm 1997;12:265-270.
  41. Gleitz J, Gottner N, Ameri A, and et al. Kavain inhibits non-stereospecifically veratridine-activated Na+channels. Planta Med 1996;62:580-581.
  42. Magura, E. I., Kopanitsa, M. V., Gleitz, J., Peters, T., and Krishtal, O. A. Kava extract ingredients, (+)-methysticin and (+/-)-kavain inhibit voltage-operated Na(+)-channels in rat CA1 hippocampal neurons. Neuroscience 1997;81(2):345-351. 9300426
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  47. Gleitz, J., Beile, A., and Peters, T. (+/-)-kavain inhibits the veratridine- and KCl-induced increase in intracellular Ca2+ and glutamate-release of rat cerebrocortical synaptosomes. Neuropharmacology 1996;35(2):179-186. 8734487
  48. Boonen, G., Ferger, B., Kuschinsky, K., and Haberlein, H. In vivo effects of the kavapyrones (+)-dihydromethysticin and (+/-)- kavain on dopamine, 3,4-dihydroxyphenylacetic acid, serotonin and 5- hydroxyindoleacetic acid levels in striatal and cortical brain regions. Planta Med 1998;64(6):507-510. 9741294
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  53. Matsuda, H., Hirata, N., Kawaguchi, Y., Naruto, S., Takata, T., Oyama, M., Iinuma, M., and Kubo, M. Melanogenesis stimulation in murine B16 melanoma cells by Kava (Piper methysticum) rhizome extract and kavalactones. Biol Pharm Bull  2006;29(4):834-837. 16595931
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