Kava

• How It Works

  ava may be effective in reducing anxiety, but liver toxicity is a major concern.

  The active compounds in kava are called kavalactones. In studies in animals and humans, these compounds provide pain relief and act as muscle relaxants and anticonvulsants. Kavalactones might act the same way as the antidepressant drugs, monoamine oxidase inhibitors (MAOIs). Scientists are not sure whether they change the levels of the hormones dopamine and serotonin in the brain.

  Kava is known to cause liver damage.

• Purported Uses
  • To treat anxiety and stress
    Several clinical trials support this use. However, the clear risk of liver damage from kava use outweighs any benefits.
  • To treat insomnia
    No scientific evidence supports this use.
• Patient Warnings
  • Kava may cause liver damage. The British, French, German, and Swiss governments have requested that kava be removed from the market. The Canadian government has warned consumers not to use kava-containing products.
  • Overdose or long-term use can cause low blood platelets and white blood cells, dry flaking skin known as kava dermopathy, respiratory problems, and hearing impairment. Inform your doctor immediately if you have any of these symptoms.
  • Kava may impair your ability to drive or operate heavy machinery.
• Do Not Take If
  • You have liver or kidney problems: Kava may worsen them.
  • You are taking benzodiazepines such as Ativan®, Xanax®, Serax®, Valium®, or Tranxene®: Kava may increase sedation.
  • You drink alcoholic beverages: Kava may increase sedation. Avoid using kava and alcohol at the same time.
  • You are taking barbiturates: In theory, kava may increase sedation and muscle-relaxant effects.
  • You take sedatives: In theory, kava may increase sedation.
  • If you take CYP450 substrate drugs, especially CYP1A2 or CYP2E1 substrate drugs: Kava may increase both their effects and side effects.
  • You take acetaminophen: Kava increased the liver toxicity caused by acetaminophen in laboratory studies.
• Side Effects
  • Headache
  • Impaired reflexes or judgment
  • Visual disturbances
  • Sedation
  • Restlessness
  • Tremor
  • Hangover effect

  Case reports

  • Liver damage (rare): Immediately inform your doctor if you have yellowish discoloration of the skin, eyes, fingernails or toenails, nausea, or vomiting.
  • Low blood platelets and white blood cells with overdose or long-term use. Can also can cause dry flaking skin, respiratory problems, and hearing impairment. Inform your doctor immediately if you have any of these symptoms.
  • Skin eruptions with itching and burning: A few cases were associated with using kava tea or supplements.
  • Impaired driving behavior and signs of intoxication: Associated with kava use.
• Special Point
  • Although kava may provide short-term relief for anxiety, the risk of liver damage outweighs any benefits.
• Scientific Name

  Piper methysticum

• Clinical Summary

  Derived from the rhizome of the plant, kava is from the Pacific Rim and Hawaiian Islands. It is used as a social beverage in those areas and to relieve anxiety, stress, and insomnia. Kavalactones in kava are thought to be the active constituent that produces skeletal muscle relaxation, non-narcotic anesthesia, and local anesthetic effects.

  Clinical data suggest moderate benefits with kava as short-term use for generalized anxiety disorder ⁽³⁹⁾, and no differences in withdrawal or addiction versus placebo ⁽⁴⁰⁾. Several other studies also support the use of kava for relieving anxiety ^{(1) (25) (26)}. It has further been suggested as an alternative to benzodiazepines, which are used to treat anxiety. However, an internet-based study suggests that kava is not superior to placebo in reducing anxiety ⁽³⁾, and a randomized clinical trial reported similar findings ⁽³⁶⁾.

  Although a systematic review showed that kava does not have negative effects on cognition ⁽³⁷⁾, there have been case reports of impairment consistent with CNS depressant effects, including slow, slurred speech and flaccid muscle tone ⁽⁴⁵⁾. In addition, due to concerns of hepatotoxicity, the Canadian, French, and British governments withdrew availability of kava and kava-containing products ^{(4) (11) (23)}.

  The Food and Drug Administration (FDA) has advised consumers about the potential risks of liver injury associated with kava consumption. However, following a World Health Organization (WHO) recommendation to study aqueous extracts of kava, initial research results support the benefits of kava ^(27) (28). Case analyses of 14 patients with hepatic injury resulting from kava use revealed low-quality products, overdose, prolonged use and co-medication as causative factors ⁽²⁹⁾. Additional studies are needed to confirm these findings.

  Kava consumption has been associated with low cancer incidence ⁽³⁰⁾, but one of its constituents was shown to stimulate growth of melanoma cells ⁽³¹⁾.

• Purported Uses
  • Insomnia
  • Restlessness
  • Stress
• Mechanism of Action

  Kavapyrones are centrally-acting skeletal muscle relaxants, anticonvulsants, and peripherally-acting local anesthetics. There are conflicting data on the effects of kavapyrones on CNS levels of dopamine and serotonin ⁽¹⁴⁾. Possible hepatotoxicity mechanisms are thought to be cytochrome P450 inhibition, reduction in liver glutathione content, or inhibition of cyclooxygenase (COX) activity ^(4) (15).

  In vitro and in vivo studies suggest that kavapyrone- and pipermethystine-containing extracts induce mitochondrial dysfunction, oxidative stress, and apoptosis of Hep2G cells ^(16) (17). The major constituent kavain was found to potentiate GABA_A receptors ⁽³⁸⁾.

  Kava enhances acetaminophen-induced cytotoxicity by increasing glutathione (GSH) depletion, resulting in oxidative stress and mitochondrial dysfunction, ultimately resulting in cell death ⁽³⁵⁾.

• Warnings
  • Kava may cause hepatotoxicity, and elevated gamma-glutamyl transpeptidase (GGT) levels were detected in regular kava drinkers ⁽²⁰⁾.
  • The British, French, and Swiss governments have requested that kava be removed from the market ⁽¹¹⁾.
  • The Canadian government has warned consumers not to use kava-containing products ⁽²¹⁾.
  • Discontinue kava use before surgery as it may interact with anesthetics. Kava may also impair ability to drive or operate heavy machinery ^{(6) (45) (53)}.
• Adverse Reactions
  • Headaches ⁽³⁹⁾; hepatotoxicity ^(4) (23), urticaria ⁽³²⁾, reversible dermopathy ⁽²²⁾.
  • Overdose of kava resulted in altered mental status and ataxia ⁽³³⁾.

  Case reports

  • Sebotropic eruptions: Related either to kava supplements or kava tea ingestion ^(41) (42).
  • Hepatotoxicity: Increased risk with prolonged kava usage or co-medication with other botanicals, supplements, or prescription drugs ⁽⁴³⁾.
  • Hepatotoxicity that led to acute liver failure and liver transplant: In a patient who used kava for almost 2 months without evidence of excess dosage ⁽⁴⁴⁾.
  • Impaired driving behavior and signs of intoxication: In 4 cases of self-reported kava use in Iowa which were confirmed with urinalysis to reveal the presence of kavalactones and lack of other drug presence ⁽⁴⁵⁾.
• Herb-Drug Interactions
  • Benzodiazepines: Kava may enhance sedation when administered concurrently. Kava indirectly increases the affinity of GABA receptor binding sites in vitro ⁽²⁴⁾.
  • Barbiturates: Theoretically, kava may have an additive effect on sedation and muscle-relaxant activity, as this has been demonstrated in animals ⁽⁴⁶⁾.
  • Sedatives: Theoretically, kava may have an additive effect with any centrally-acting medication that can potentially cause sedation ⁽⁵⁾.
  • Acetaminophen: Kava enhances hepatic cell cytotoxicity induced by acetaminophen in vitro ⁽³⁵⁾.
  • P-gp: Although inhibition has been shown in vitro ⁽⁵¹⁾, kava does not appear to modulate P-gp activity In healthy subjects ⁽⁵²⁾.
  • Cytochrome P450 substrates (particularly CYP1A2 or CYP2E1): Several reviews have covered the topic of kava HDIs. Generally, the interaction risk is believed to be low ⁽⁴³⁾, with the greatest caution attributed to taking kava with CYP1A2 or CYP2E1 substrate drugs as it may enhance both therapeutic and adverse effects ⁽⁴⁸⁾. It is also noted that study discrepancies are likely due to variations in formulations or the extraction process ⁽⁴³⁾. Nevertheless, the following have been observed:

  1A1: In animal models at very high doses, kava enhanced hepatic CYP1A1 expression ⁽⁴⁷⁾. However, the researchers point out that some may be more sensitive to induction or ingest more kavalactones than acceptable for daily intakes, and that increased CYP1A1 expression may partly contribute to kava-induced hepatotoxicity.

  1A2: In healthy subjects, data are conflicting on whether kava inhibits CYP 1A2 ^(7) (8). In an animal study, kava extracts induced CYP1A2 ⁽¹⁶⁾.

  2D6: Although a case report suggests 2D6 inhibition ⁽⁹⁾, another study did not find 2D6 inhibition in healthy volunteers ⁽⁴⁹⁾.

  2E1: In healthy subjects, kava inhibits CYP2E1 ⁽⁷⁾. In an animal study, kava extracts induced CYP2E1 ⁽¹⁶⁾.

  3A4: In healthy subjects, kava does not appear to inhibit CYP3A4 activity ^(7) (50).

  2C8, 2C9, 2C19, 4A9, 4A11: In vitro studies suggest kava may inhibit these CYP enzymes ^(34) (51), but clinical relevance is uncertain.

• References

  1. Lehrl S. Clinical efficacy of kava extract WS 1490 in sleep disturbances associated with anxiety disorders. Results of a multicenter, randomized, placebo-controlled, double-blind clinical trial. J Affect Disord. Feb 2004;78(2):101-110.

  2. Pittler MH, Ernst E. Efficacy of kava extract for treating anxiety: systematic review and meta-analysis. J Clin Psychopharmacol. Feb 2000;20(1):84-89.

  3. Jacobs BP, Bent S, Tice JA, Blackwell T, Cummings SR. An internet-based randomized, placebo-controlled trial of kava and valerian for anxiety and insomnia. Medicine (Baltimore). Jul 2005;84(4):197-207.

  4. Clouatre DL.Kava kava: examining new reports of toxicity. Toxicol Lett. Apr 15 2004;150(1):85-96.

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  7. Gurley BJ, Gardner SF, Hubbard MA, et al. In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes. Clin Pharmacol Ther. May 2005;77(5):415-426.

  8. Russmann S, Lauterburg BH, Barguil Y, et al. Traditional aqueous kava extracts inhibit cytochrome P450 1A2 in humans: Protective effect against environmental carcinogens? Clin Pharmacol Ther. May 2005;77(5):453-454.

  9. Russmann S, Lauterburg BH, Helbling A. Kava hepatotoxicity. Ann Intern Med. Jul 3 2001;135(1):68-69.

  10. Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Database Syst Rev. 2003(1):CD003383.

  11. Burros M. EATING WELL; New questions about kava’s safety. The New York Times. January 16, 2002.

  12. Jhoo JW, Ang CY, Heinze TM, et al. Identification of C-glycoside flavonoids as potential mutagenic compounds in kava. J Food Sci. Mar 2007;72(2):C120-125.

  13. Foster S, Tyler VE. Tyler’s Honest Herbal: A Sensible Guide to the Use of Herbs and Related Remedies. New York: Haworth Herbal Press; 1999.

  14. Robbers JE, Speedie MK, Tyler VE. Pharmacognosy and pharmacobiotechnology. Baltimore: Williams & Wilkins; 1996.

  15. Raman P, Dewitt DL, Nair MG. Lipid peroxidation and cyclooxygenase enzyme inhibitory activities of acidic aqueous extracts of some dietary supplements. Phytother Res. Feb 2008;22(2):204-212.

  16. Lim ST, Dragull K, Tang CS, Bittenbender HC, Efird JT, Nerurkar PV. Effects of kava alkaloid, pipermethystine, and kavalactones on oxidative stress and cytochrome P450 in F-344 rats. Toxicol Sci. May 2007;97(1):214-221.

  17. Lude S, Torok M, Dieterle S, Jaggi R, Buter KB, Krahenbuhl S. Hepatocellular toxicity of kava leaf and root extracts. Phytomedicine. Jan 2008;15(1-2):120-131.

  18. Keledjian J, Duffield PH, Jamieson DD, Lidgard RO, Duffield AM. Uptake into mouse brain of four compounds present in the psychoactive beverage kava. J Pharm Sci. Dec 1988;77(12):1003-1006.

  19. Schulz V, Hansel R, Tyler VE. Rational Phytotherapy: A Physician’s Guide to Herbal Medicine. 4th ed. New York: Springer; 2001.

  20. Brown AC, Onopa J, Holck P, et al. Traditional kava beverage consumption and liver function tests in a predominantly Tongan population in Hawaii. Clin Toxicol (Phila). Jun-Aug 2007;45(5):549-556.

  21. Canadian Adverse Reaction Newsletter. http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/carn-bcei_v12n4-eng.php#a3. 2002; (12):4. Accessed February 13, 2013.

  22. Norton SA, Ruze P. Kava dermopathy. J Am Acad Dermatol. Jul 1994;31(1):89-97.

  23. Escher M, Desmeules J, Giostra E, Mentha G. Hepatitis associated with Kava, a herbal remedy for anxiety. BMJ. Jan 20 2001;322(7279):139.

  24. Almeida JC, Grimsley EW. Coma from the health food store: interaction between kava and alprazolam. Ann Intern Med. Dec 1 1996;125(11):940-941.

  25. Ernst E. Herbal remedies for anxiety – a systematic review of controlled clinical trials. Phytomedicine. 2006 Feb;13(3):205-8.

  26. Witte S, Loew D, Gaus W. Meta-analysis of the efficacy of the acetonic kava-kava extract WS1490 in patients with non-psychotic anxiety disorders. Phytother Res. 2005 Mar;19(3):183-8.

  27. Sarris J, Kavanagh DJ, Byrne G, Bone KM, Adams J, Deed G. The Kava Anxiety Depression Spectrum Study (KADSS): a randomized, placebo-controlled crossover trial using an aqueous extract of Piper methysticum. Psychopharmacology (Berl). 2009 Aug;205(3):399-407.

  28. Singh YN, Devkota AK. Aqueous kava extracts do not affect liver function tests in rats. Planta Med. 2003 Jun;69(6):496-9.

  29. Teschke R.Kava hepatotoxicity: pathogenetic aspects and prospective considerations. Liver Int. 2010;30:1270–1279.

  30. Steiner GG. The correlation between cancer incidence and kava consumption. Hawaii Med J. 2000 Nov;59(11):420-2.

  31. Matsuda H, Hirata N, Kawaguchi Y, et al. Melanogenesis stimulation in murine B16 melanoma cells by Kava (Piper methysticum) rhizome extract and kavalactones. Biol Pharm Bull. 2006 Apr;29(4):834-7.

  32. Grace R. Kava-induced urticaria. J Am Acad Dermatol. 2005 Nov;53(5):906.

  33. Perez J, Holmes JF. Altered mental status and ataxia secondary to acute Kava ingestion. J Emerg Med. 2005 Jan;28(1):49-51.

  34. Unger M, Frank A. Simultaneous determination of the inhibitory potency of herbal extracts on the activity of six major cytochrome P450 enzymes using liquid chromatography/mass spectrometry and automated online extraction. Rapid Commun Mass Spectrom. 2004;18(19):2273-81.

  35. Yang X, Salminen WF. Kava extract, an herbal alternative for anxiety relief, potentiates acetaminophen-induced cytotoxicity in rat hepatic cells. Phytomedicine. 2011 May 15;18(7):592-600.

  36. Sarris J, Scholey A, Schweitzer I, et al. The acute effects of kava and oxazepam on anxiety, mood, neurocognition; and genetic correlates: a randomized, placebo-controlled, double-blind study. Psychopharmacol. 2012 May;27(3):262-9.

  37. LaPorte E, Sarris J, Stough C, Scholey A. Neurocognitive effects of kava (Piper methysticum): a systematic review. Hum Psychopharmacol. 2011 Mar;26(2):102-11.

  38. Chua HC, Christensen ET, Hoestgaard-Jensen K, et al. Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABAA Receptors: Functional Characteristics and Molecular Mechanism. PLoS One. 2016;11(6):e0157700.

  39. Sarris J, Stough C, Bousman CA, et al. Kava in the treatment of generalized anxiety disorder: a double-blind, randomized, placebo-controlled study. J Clin Psychopharmacol. Oct 2013;33(5):643-648.

  40. Sarris J, Stough C, Teschke R, et al. Kava for the treatment of generalized anxiety disorder RCT: analysis of adverse reactions, liver function, addiction, and sexual effects. Phytother Res. Nov 2013;27(11):1723-1728.

  41. Huynh JC, Asgari MM, Moore MM. Sebotropic eruption associated with use of oral kava kava supplement. Clin Exp Dermatol. Oct 2014;39(7):816-818.

  42. Brown-Joel ZO, Colleran ES, Stone MS. Inflammatory sebotropic reaction associated with kava kava ingestion. JAAD Case Rep. Jun 2018;4(5):437-439.

  43. Gurley BJ, Fifer EK, Gardner Z. Pharmacokinetic herb-drug interactions (part 2): drug interactions involving popular botanical dietary supplements and their clinical relevance. Planta Med. Sep 2012;78(13):1490-1514.

  44. Becker MW, Lourencone EMS, De Mello AF, et al. Liver transplantation and the use of KAVA: Case report. Phytomedicine. Mar 15 2019;56:21-26.

  45. Berry J, Gilbert A, Grodnitzky J. Cases of Kava Impairment in Iowa Drivers. J Forensic Sci. Jul 15 2019.

  46. Wang CZ, Moss J, Yuan CS. Commonly Used Dietary Supplements on Coagulation Function during Surgery. Medicines (Basel). Sep 2015;2(3):157-185.

  47. Yamazaki Y, Hashida H, Arita A, et al. High dose of commercial products of kava (Piper methysticum) markedly enhanced hepatic cytochrome P450 1A1 mRNA expression with liver enlargement in rats. Food Chem Toxicol. Dec 2008;46(12):3732-3738.

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  49. Gurley BJ, Swain A, Hubbard MA, et al. Clinical assessment of CYP2D6-mediated herb-drug interactions in humans: effects of milk thistle, black cohosh, goldenseal, kava kava, St. John’s wort, and Echinacea. Mol Nutr Food Res. Jul 2008;52(7):755-763.

  50. Gurley BJ, Swain A, Hubbard MA, et al. Supplementation with goldenseal (Hydrastis canadensis), but not kava kava (Piper methysticum), inhibits human CYP3A activity in vivo. Clin Pharmacol Ther. Jan 2008;83(1):61-69.

  51. Meng Q, Liu K. Pharmacokinetic interactions between herbal medicines and prescribed drugs: focus on drug metabolic enzymes and transporters. Curr Drug Metab. 2014;15(8):791-807.

  52. Gurley BJ, Swain A, Barone GW, et al. Effect of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on digoxin pharmacokinetics in humans. Drug Metab Dispos. Feb 2007;35(2):240-245.

  53. Asher GN, Corbett AH, Hawke RL. Common Herbal Dietary Supplement-Drug Interactions. Am Fam Physician. Jul 15 2017;96(2):101-107.