Health Care Professional Information

Scientific Name
Piper methysticum
Common Name

Kava-kava, kawa, kavain, rauschpfeffer, intoxicating long pepper, tonga, yagona, yaqona

Brand Name

Latain®

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.
The kavalactones, thought responsible for kava's activity, produce skeletal muscle relaxation, non-narcotic anesthesia, and local anesthetic effects.
An Internet-based study showed that kava is not superior to placebo in reducing anxiety (3) ; a randomized clinical trial reported similar findings (36). However, data from several studies support use of kava for relieving anxiety (1) (25) (26). It has also been suggested as an alternative to benzodiazepines, used to treat anxiety. A systematic review showed that kava does not have negative effects on cognition (37).
Although available data suggest kava's benefits for anxiety, the Canadian, French, and British governments withdrew kava and kava-containing products due to concerns of hepatotoxicity (4) (11) (23).
The Food and Drug Administration (FDA) advises consumers about the potential risks of liver injury associated with consumption of kava. 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 the 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
Constituents
  • Kavapyrones
  • Kavalactones
  • C-glycoside flavonoids
  • Piprmethystine
    (12) (16)
Mechanism of Action

Kavapyrones are centrally-acting skeletal muscle relaxants, anticonvulsants, and peripherally-acting local anesthetics. There are conflicting data on teh effects of kavapyrones on CNS levels of dopamine and serotonin (14). Possible mechanisms for kava's hepatotoxicity are thought to be by inhibition of cytochrome P450, 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).
Kava also enhances acetaminophen-induced cytotoxicity by increasing glutathione (GSH) depletion, resulting in oxidative stress and mitochondrial dysfunction, ultimately resulting in cell death (35).

Pharmacokinetics

Absorption:
The kavapyrones, kawain and dihydrokawain, were well absorbed following oral administration in mice. Plasma levels of 2 micrograms/ml were detected 30 minutes after initial oral dose of 100 mg/kg kava extract (standardized to 70% kavapyrones). It should be noted that extraction and preparation of dosage form could affect bioavailability.
Distribution:
Dihydrokawain, kawain, desmethoxyyangonin, and yangonin have been shown to cross the blood-brain barrier in mice. (18)
Elimination: Plasma half-life of kavapyrones range from 90 minutes to several hours. (19)

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).
Adverse Reactions
  • Hepatotoxicity (4) (23), Urticaria (32), and reversible dermopathy (22) have been reported following use of kava.
  • Overdose of kava resulted in altered mental status and ataxia (33).
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; however, this has only been demonstrated in animals.
Sedatives: Theoretically, kava may have an additive effect with any centrally-acting medication that can potentially cause sedation.
(5)
Cytochrome P450 substrates: Kava inhibits CYP2E1 (7), CYP1A2/2C8/2C9/2C19/2D6, 3A4 (8) (9) (34), and can affect the intracellular concentration of drugs metabolized by these enzymes.
Acetaminophen: Kava enhances the hepatic cell-cytotoxicity induced by acetaminophen in vitro (35).

Literature Summary and Critique

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. 2004 Feb;78(2):101-10.
A multicenter, randomized, double-blind clinical study of Kava special extract WS 1490 and its use in sleep disturbances associated with anxiety. 61 patients participated in the trial. Patients were given either 200 mg WS 1490 kava extract or placebo daily over a period of four weeks. Patients were scored on the Hamilton Anxiety Rating Scale (HAMA). Improvement in scores for 'quality of sleep' and 'recuperative effect after sleep' for patients after completing treatment with kava was statistically significant compared with those receiving placebo. No drug-related adverse effects were noted. A full quarter of patients did not comply with study protocol.

Jacobs B, et al. An Internet-Based Randomized, Placebo-Controlled Trial of Kava and Valerian for Anxiety and Insomnia. Medicine 2005 Jul;84(4):197-207.
An Internet-based double-blind study found that kava is no more effective than an placebo for anxiety. 391 patients were recruited through e-mail or advertisements on web sites. The participants were randomly assigned to 1 of 3 treatment groups that were given capsules containing either kava, valerian, or a placebo for 4 weeks. At the end of the study, patients who received kava or valerian had similar improvements in anxiety symptoms and in sleep as compared to the placebo group. Kava group and the placebo group reported similar adverse events with no report on hepatotoxicity.

Brown AC, 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.
To determine if chronic kava beverage consumption may result in hepatotoxicity, liver functional analysis was carried out in 31 healthy, adult kava drinkers and 31 healthy, adult non-kava drinkers. Liver enzymes including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGT) as well as total bilirubin, direct bilirubin, indirect bilirubin, and albumin were determined. Individuals regularly consuming kava beverage were more likely to have elevated GGT levels. Further studies are required to determine if GGT levels can be reduced upon abstaining from kava drinking. In addition, determining whether elevated GGT levels mediate kava-induced hepatotoxicity is necessary.

Dosage (Inside MSKCC Only)
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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.
  5. Brinker F. Herb Contraindications and Drug Interactions. 3rd ed. Sandy (OR): Eclectic Medical Publishers; 2001.
  6. Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. JAMA. Jul 11 2001;286(2):208-216.
  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, 2002;F.
  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.

Consumer Information

How It Works

Bottom Line: Kava 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.
Research Evidence

Anxiety:
A meta-analysis, which is a complete search of all articles that have been published on a topic, was performed for trials that used kava to treat anxiety. Out of seven trials, all found that kava works better than placebo in reducing anxiety, but five reported adverse effects to kava.

An Internet-based study with 391 participants found that kava is no more effective than a placebo for anxiety. Patients were recruited through e-mail or advertisements on web sites and assigned by chance to receive either kava, valerian, or a placebo for 4 weeks. At the end of the study, patients who received kava or valerian had similar improvements in anxiety symptoms as compared to the patients who received an inactive placebo. No severe adverse events were reported.

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 effect).
  • You take sedatives (In theory, kava may increase sedation).
  • If you are taking drugs that are substrates of Cytochrome P4502E1, CYP1A2/2C8/2C9/2C19/2D6 and 3A4 (kava may increase the risk of side effects of these drugs).
  • You take Acetaminophen (kava increased the cytotoxicity induced by acetaminophen in in rat liver cells).
Side Effects
  • Headache
  • Impaired reflexes or judgment
  • Visual disturbances
  • Sedation
  • Restlessness
  • Tremor
  • Hangover effect
  • Liver damage (rare): Immediately inform your doctor if you have yellowish discoloration of the skin, eyes, fingernails or toenails, nausea, or vomiting.
  • 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.
Special Point
  • Although kava may provide short-term relief for anxiety, the risk of liver damage outweighs any benefits.
E-mail your questions and comments to aboutherbs@mskcc.org.