Family

Piperaceae.

Habitat and Cultivation

Piper methysticum is a vegetatively propagated cultivar, and botanical authorities believe it was derived from wild species (e.g., Piper wichmanni C. DC). Historically, kava was widely domesticated throughout the Pacific regions of Polynesia, Micronesia, and Melanesia. Currently, commercial cultivation of the major chemotypic variants occurs principally in Fiji, Vanuatu, and Hawaii.

Parts Used

Rootstock, lateral roots. Notably, the outer root bark/peelings and base stem are not used traditionally, although these have been exported for commercial use.

Common Forms

Fresh or dried peeled rootstock and lateral roots, some lower stem.

• Tincture, Fluid Extract:   Greater than 60% alcohol.

• Standardized Solid Extract:   Often acetone extracted, in tablets or encapsulated powder form, usually standardized to 70% total kavalactones. Because chemotypic variants exist, this form of standardization is not necessarily a reliable guide to consistency.

• Synthetic Kavain:   RacemicD,L-kavain has been incorporated into certain proprietary medications in Germany but is not in common use.

Overview

Medically, kava is currently regarded mainly as a herbal anxiolytic agent. Several positive clinical trials suggest kava root extracts may be a safe and effective alternative to benzodiazepine pharmacotherapy for mild anxiety. Recent systematic reviews, including a Cochrane database review, support the efficacy of kava extracts for anxiety and have emphasized their favorable safety profile. ^1-3The “anxiolytic” indication has overshadowed its wider uses in traditional cultural practice and contemporary herbal medicine. Practitioners of botanical medicine consider the herb useful for urogenital indications, including interstitial and infective cystitis, prostatitis, painful micturition from any cause, nocturnal enuresis, as well as for menopausal symptoms, and value it for its musculorelaxant and sedative effects as much as its anxiolytic indications. ⁴

The German Commission E ⁵ approved the use of kava for anxiety in 1990, listing no known adverse effects, but suggested a limitation to duration of use of 3 months and contraindication in “endogenous depression.” The 2002 World Health Organization (WHO) monograph ⁶ echoes the Commission E. The 2003 therapeutic monograph by the European Scientific Cooperative on Phytotherapy (ESCOP) ⁷ indicates the use of the herb for anxiety, tension, and restlessness, considering it safe when used as a short-term monotherapy, but contraindicating in cases of preexisting liver disease and alcohol abuse. A 2004 comprehensive overview of the literature from ethnology to pharmacology, edited by kava authority Singh, ⁸ updates and complements the classic monograph by Lebot.

Commencing in 1998, isolated case reports of possible kava-related hepatoxicity began to emerge. ^9-15On the basis of 28 case reports, the German Bundesinstitut für Arzneimitttel und Medizinprodukte (BfArM; Federal Institute for Drugs and Medical Devices) withdrew product licenses in 2002 from all kava products. Several other countries, including Canada and France took similar action, in 2002 the British Medicines Control Agency (MCA) announced a complete kava product ban, and in 2003 Swissmedic (formerly the Swiss IKS) followed suit. The U.S. Food and Drug Administration (FDA) issued a public advisory in 2001 about concerns of potential kava hepatoxicity, but kava products remain on sale in the United States at this time. A comprehensive review of the controversy is beyond the scope of this monograph; Schmidt ¹⁶ reviews each BfArM case (continuously updated on the internet), and in Mills and Bone's comprehensive 2005 survey, Schmidt et al. ¹⁷ discuss the 82 cases cited by regulatory authorities, with risk-benefit analysis of kava. The ongoing debate over kava hepatoxicity is discussed later under interactions.

Historical/Ethnomedicine Precedent

Indigenous use of kava, practiced for centuries throughout Polynesia and Micronesia, continues in the South Pacific islands. Kava is consumed regularly, primarily as a diluted fresh (on some islands, dried) root juice extract (succus), both as a relaxing social beverage and as a component of traditional ceremony. Folk healers in these communities use various parts of the plant for treating a wide range of ailments, including urogenital and menstrual problems, headaches, respiratory conditions, sleeping difficulties, and many skin problems. ⁸ Western therapeutic use began at the end of the nineteenth century, although the crude drug was available on both sides of the Atlantic several decades earlier. In 1892, Cerna ¹⁸ described kava's anti-inflammatory and analgesic effects on the male and female urinary tract, also noting its central nervous system (CNS) intoxicant properties. The Eclectics tended to underemphasize the CNS effects but described indications for trigeminal and other neuralgias. ¹⁹

The dual affinities of the herb for the CNS and urogenital tract were retained until the late twentieth century, with Weiss ²⁰ classifying kava both as a tranquilizer and as a treatment for “neurogenic” disorders of the bladder in women and prostatitis in men. The increasing promotion of standardized extracts, especially WS1490 (70% kavalactones; Willmar Schwabe), and the adoption of this extract in clinical studies for anxiety in the 1980s and 1990s coincided with the emergence of the now-dominant psychiatric indications of kava as an anxiolytic and a corresponding deemphasis of its other indications.

Known or Potential Therapeutic Uses

• Internal Use:   Anxiety; benzodiazepine drug withdrawal; headache; insomnia; irritable bladder; menopausal symptoms; nervous and muscular tension; neuralgia; prostatitis; restlessness of nonpsychotic origin; rheumatism; urinary tract inflammation, infection, and pain.

• External Use:   Analgesic for joint pain, mouth sores, wounds, and skin conditions.

Key Constituents

Alpha-pyrones known as kavalactones : total content varies according to cultivar type, growing conditions, age, and part used, from a typical range of 5.5% to 8%, ²¹ up to a recorded maximum of 21%. ²² Approximately 18 kavalactones have been described, of which six are considered important: kawain (kavain), dihydrokawian, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin. Other constituents include the alkaloid pipermethysticine in the leaf and bark, chalcones (flavokavins A-C), and cinammalketone. ²³

Therapeutic Dosing Range

• Dried Plant:   6 to 12 g/day by cold maceration, or decoction.

• Tincture, Fluid Extract:   Based on 1:1, 6 to 12 mL/day.

• Standardized Extract:   Typically 100 mg, 70% kavalactones, three times daily (i.e., 210 mg total kavalactones daily).

Traditional South Sea beverage use dosage of kavalactones is controversial, given use of local chemotypes and varying preparation methods, but has been estimated as high as 2500 mg of lactones in one “session,” or 10 cups at approximately 250 mg of lactones per cup. Most ethnobotanical authorities agree, however, that the traditional dose can be significantly greater than that used in botanical medicine.

Strategic Considerations

Before the recent concerns over the potential hepatoxicity of kava extracts, specific interactions of kava with pharmaceutical drugs had not been identified as a significant problem, and the safety of the herb in the preceding decade was considered excellent. The Commission E had pointed out that pharmacodynamic interactions with psychoactive medications, particularly CNS depressants such as barbiturates and alcohol, were theoretically possible. ⁵ WHO mentioned the alprazolam-kava interaction report (see later) but suggested that it was unconfirmed. ⁶ Systematic experimental or clinical investigations of pharmacodynamic kava-drug interactions are not available. Extrapolations have been made from limited pharmacological data and the few available case reports, indicating potential interactions issues with CNS depressants and other centrally acting agents, such as alcohol, alprazolam, and levodopa. These data are reviewed later.

Practitioners versed in botanical prescribing view the coadministration of synthetic drugs with herbs that have identical indications as unnecessary and undesirable, if not frankly contraindicated. (This is independent of underlying pharmacological mechanism because there is rarely a simple homology between the effects of herbal extracts and pharmaceuticals.) A good example is St. John's wort (SJW; see monograph) and the serotonin reuptake inhibitors (SRIs) for depression, or kava and benzodiazepine anxiolytics. Exception may be made in particular clinical circumstances, such as elective withdrawal from the drug. Anecdotal clinical experience is available for use of SJW in SRI drug withdrawal, and kava can be used to support benzodiazepine withdrawal. ²⁴

Hepatotoxicity Controversy and Kava-Drug Interactions

The status of the case reports gathered by Swissmedic, the German BfArM, British MCA, U.S. FDA, and other national bodies to support claims of kava hepatoxicity have been critically reviewed by several authors. ^16,17,25-28Full case details were not initially released for public or expert review, and it subsequently was found that much of the original data were incomplete or defective. Documents from different regulatory authorities contained duplicate cases, errors, and inconsistencies, and in most cases the information provided was significantly below the minimum standards required for rigorous evaluation of potential causality. The emerging expert consensus is that the case for inherent kava hepatoxicity remains unproven, and by implication, the complete banning kava products was precipitous given the clinical trial–demonstrated efficacy and adverse effects profile of the herb for anxiety and its favorable risk-benefit comparison to benzodiazepines. ^17,28Interestingly, the former German Commission E members, generally known for their cautious perspective, unanimously expressed unease at their government's (BfArM) decision to ban kava. ²⁹ A similar statement was made by the Society for Medicinal Plant Research. ³⁰

Various theories of mechanisms have been proposed to account for the case reports of hepatoxicity, including idiosyncratic drug reactions, immunoallergic responses, pharmacogenetic variation in drug-metabolizing enzymes and metabolic bioactivation to toxic intermediates, glutathione depletion, differences between commercial kava preparations in terms of plant parts used, possible contamination with the alkaloid pipermethysticine present in stem peelings, possible adulteration with known hepatotoxic species such as germander, contamination by extracting solvents such as acetone, consumption of pure synthetic kavain preparations versus natural kavalactone mixtures, excessive total kavalactone dose, and variance in kavalactone composition of products. ^{17,26,28,31-33}The overall incidence of verifiable kava-associated hepatotoxic events, estimated on the basis of 3 years’ usage data to be 0.1 case per million daily doses, is very low and compares favorably with the relative incidence of suspected hepatotoxic reactions for common benzodiazepines (diazepam: 2.12 cases per million doses). ¹⁷ Epidemiologically, this is typical of idiosyncratic hepatotoxic drug responses; the apparently low frequency rate partly results from the multifactorial determinants involved in their causation, with the net probability of a critical adverse event occurrence being the sum of all the discrete probabilities of each determinant factor. ³⁴

Logically, in the context of potential kava-drug interactions, several of the hepatoxicity cases determined by reviewers as being unable to support claims of inherent kava hepatoxicity because of concurrent comedication are de facto cases of potential kava-drug interactions. Unfortunately, the well-described problems of report quality and reliability also confound reanalysis of these cases as interactions data. Nonetheless, the hypothesis that kavalactones might pharmacokinetically increase the plasma concentrations of drugs associated with idiosyncratic or inherent hepatoxicity requires evaluation, because several of the cases involved comedication with such agents. These drugs included fluoxetine, paroxetine, acetylsalicylic acid, thiazide diuretics, oral contraceptives, nonsteroidal anti-inflammatory drugs (NSAIDs) including celecoxib and diclofenac, antidiabetic agents, and benzodiazepines. ¹⁶ Most of these are also known substrates, inducers, or inhibitors of drug-metabolizing enzymes, and most have been associated to varying degrees with hepatic adverse reactions.

As with pharmacodynamic interactions, direct studies on kava-drug pharmacokinetic interactions are not currently available. However, experimental data on the effect of kavalactones on cytochrome P450 (CYP450) mixed oxidases suggest a potential for pharmacokinetic herb-drug interactions.

Effects on Drug Metabolism and Bioavailability

Several in vitro studies have determined that both kava preparations and individual kavalactones can exert inhibitory effects on CYP450 isoforms. ^35-39Zou et al. ^37,38compared activity of both recombinant human CYP450 enzymes and human hepatocytes with standard control compounds and addition of kava. They found that an ethanolic extract of kava containing 28% total kavalactones significantly inhibited (in descending order of effect size) CYP450 2C9, 2C19, 3A4, 2D6, 2E1, and 1E2 at both 100 micromolar (µM) and also at lower concentrations of approximately 10 µM. There was good agreement between the two methods used, and the experiments were repeated with individual kavalactones. Of these, desmethoxyyangonin and methysticin were found to be the most potent inhibitors of 1A2, 2C9, 2C19, 2E1, and 3A4 (median inhibition concentration [IC50] <10 µM). At higher doses the authors also established toxic effects on hepatocyte viability, although the concentrations were 100 µM and therefore 10 to 20 times that likely attainable in vivo. ³⁸

Mathews et al. ³⁵ also used a human hepatocyte test system to analyze the in vitro effects of kava extracts (40% lactones) at 100 µM on human P450 enzyme activity compared with positive control substrates. At these high concentrations they found a significant inhibition of 2C9, 2C19, 3A4, 2D6, and 4A9/11. At lower concentrations of 10 µM, individual lactones were tested; 2C9 was significantly inhibited by desmethoxyyangonin, methysticin, and dihydromethysticin; 2C19 by desmethoxyyangonin; 3A4 by desmethoxyyangonin, methysticin, and dihydromethysticin; and 2D6 by meythysticin.

Unger et al. ³⁶ examined the effect of different fractions of a crude ethyl acetate extract of kava root powder for inhibitory activity using a testosterone hydroxylation system to assay 3A4 activity with kava compared to ketoconazole as a positive control. ³⁶ They found a significant inhibition of 3A4 with different solvents used for the kava extract. Using high-performance liquid chromatography (HPLC) fractionation, they established that kavain, dihydrokavain, methysticin, dihydromethysticin, and dihydroyangonin were the most active lactones. However, IC50values were not recorded.

Cote et al. ³⁹ used a standard fluorescence screening assay method to compare traditional water extracts of kava with various commercial solvent extracts against the activity of 1A2, 2C9, 2C19, and 3A4. Kavalactones were present at highest levels in the acetone extracts, which also had the highest CYP450 inhibitory activity. The authors found that 3A4 and 2C19 were inhibited most actively, with IC50values of approximately 1 µg/mL, or about 1 µM. A poster report of a study in six healthy volunteers tested with a probe cocktail for 1A2, 2D6, 2C19, 2E1, and 3A4 found that traditional aqueous extracts only significantly inhibited 1A2. ⁴⁰

Raucy ⁴¹ used an unrelated approach and screened the mechanisms of 3A4 induction by various drugs and natural compounds by examining 3A4 messenger ribonucleic acid (mRNA) values in human hepatocytes incubated with various inducers. Raucy also used a luciferase assay for pregnane X receptor (PXR) activation after transfecting HepG2 cells with plasmids containing hPXR and distal CYP3A4 promoters to assess the possible involvement of PXR in the enzyme induction mechanisms. She found that only kava (of various natural compounds tested) dramatically affected luciferase values consistent with activation of PXR. ⁴¹ However, the concentrations of the kava extract were 100 µM, and lower values were not tested.

Gurley et al. ⁴² performed an in vivo human study with 12 healthy volunteers to investigate the effects of 28 days’ administration of several herbal extracts on probe drug cocktail administered before and after supplementation, designed to test the effects of the herb on single-point CYP450 kinetics. ⁴² In contrast to the in vitro studies, they found no measurable effects with kava on 3A4, 1A2, or 2D6, but pronounced inhibitory effects on 2E1. No elevations of serum hepatic transaminases were noted during the study. 2E1 shares with 1A1 and 1A2 the role of metabolizing aliphatic and aromatic hydrocarbons, but in particular, 2E1 is known to generate carcinogenic intermediates from simple organic compounds (e.g., nitrosamines in cigarette smoke).

Mathews et al. ³⁵ also found evidence for an unidentified metabolic intermediate when methysticin and dihydromethysticin were incubated with human liver microsomes. ³⁵ Zou et al. ⁴³ found the first metabolic intermediate to be identified, dubbed 6-PHO (or 6-phenyl-3-hexen-2-one), demonstrating the reactivity of 6-PHO with reduced glutathione in vitro and also establishing its presence in human urine as a mercapturic (i.e., sulfhydryl) conjugate. The authors speculated that theoretically a nucleophilic compound could conjugate with such metabolic intermediates to form complexes that induce immune-mediated hepatotoxic reactions or direct hepatotoxicity through deoxyribonucleic acid (DNA) alkylation. Tarbah et al. ⁴⁴ examined the metabolism ofD,L-kavain (the synthetic racemate) after oral doses in humans and found that hydroxylation (probably by CYP2D6) was the initial metabolic transformation step, and that sulfated and glucuronated conjugates were found in serum and urine. Full details of the metabolic degradation of the kavalactones remain to be elucidated.

Russmann et al. ⁴⁵ reported an interesting analysis on six healthy subjects who were chronic kava consumers. The subjects gave up kava (traditional aqueous extract) for 30 days, undergoing metabolic phenotyping for CYP450 using five probe substrates at days 1 and 31. Kava abstinence led to a “deinhibition” of CYP1A2, suggesting that the extract normally inhibits this enzyme. The authors suggest this may explain the observed inverse association between kava consumption and cancer through prevention of environmental carcinogen activation. ⁴⁶ However, kava was recently shown to have nuclear factor kappa B (NF-κB) inhibitory properties, and hypothetically this may also confer cancer prevention benefits on the regular traditional kava consumer. ⁴⁷

Collectively, the currently available data on kavalactone effects on CYP450 suggest possibly significant inhibitory effects in vivo. This implies the possibility of pharmacokinetic interactions between kava and drug substrates of CYP450. ⁴⁸ Estimates from existing pharmacokinetic data suggest that the in vitro inhibitory effects at 10-µM concentrations are commensurate with in vivo concentrations after typical kava administration of oral doses at 200 to 250 mg kavalactones. ⁴⁹ Whether biphasic effects are caused by PXR-mediated induction of 3A4 subsequent to mechanism based inhibition effects is not known, but is a possibility. This would be parallel to the effects of SJW extracts, which initially inhibit then induce 3A4 via PXR-mediated transcription (see St. John's Wort monograph). Since CYP450 2C9, 2C19, 2D6, and 2E1 are inhibited by kavalactones and are also subject to common polymorphisms, a level of pharmacogenetic variability in response to kavalactones is supported by the data. A deficiency in 2D6 was identified in one case of hepatotoxicity associated with kava and alcohol use. ⁹ Interestingly, the 2D6 polymorphisms that are prevalent at about ten per cent in Caucasians are absent from Polynesian populations. ⁵⁰

Formation of potentially reactive intermediates from kavalactones during metabolism under certain circumstances cannot be excluded, although currently the potential reactivity or toxicity is not known. Systematic studies of the effects of kava consumption on plasma levels of various medications are urgently needed to clarify all the in vivo implications of the in vitro data. At present, compelling reasons would be required to coadminister kava extracts with narrow-therapeutic-range drugs that are substrates of CYP450 3A4, 2C9, 2C19, 2D6, and 2E1, particularly in polypharmaceutical combination with other drugs that are noted substrates, inhibitors, or inducers of the same enzymes. (Note that the benzodiazepines are primarily metabolized by 3A4 and 2C19 and the halogenated anesthetics by 2E1.) If such coadministration is required, pharmacokinetic interaction management precautions should be taken, such as plasma drug monitoring with clinical correlation, especially during the periods of addition or withdrawal of any of the agents to a regimen. Ideally, phenotyping of “poor metabolizers” should also be conducted.

The potential for additive pharmacodynamic effects with CNS-active drugs, as well as the possibility of pharmacokinetic interactions mediated by CYP450 modulation and the small but finite risks of idiosyncratic hepatotoxicity, all suggest that adoption of comprehensive history taking, identification of proper clinical indications, monopharmacy prescription, and vigilant monitoring for hepatic signs and symptoms are prudent and appropriate with kava use.

• 1.Pittler MH, Ernst E. Efficacy of kava extract for treating anxiety: systematic review and meta-analysis. J Clin Psychopharmacol 2000;20:84-89.View Abstract
• 2.Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Database Syst Rev 2003:CD003383.View Abstract
• 3.Ernst E. Herbal remedies for anxiety: a systematic review of controlled clinical trials. Phytomedicine 2006;13:205-208.View Abstract
• 4.BHMA. Piper methysticum. British Herbal Pharmacopoeia. Bournemouth, UK: British Herbal Medicine Association; 1983:215.
• 5.Kava kava. In: Blumenthal M, Busse W, Goldberg A, et al, eds. The Complete German Commission E Monographs. Austin, Texas: American Botanical Council: Integrative Medicine Communications; 1998:156-157.
• 6.WHO. Rhizoma Piperis Methystici. WHO Monographs on Selected Medicinal Plants. 2 vol. Geneva: World Health Organization; 2002:231-245.
• 7.ESCOP. Piperis Methystici Rhizoma. ESCOP Monographs: the Scientific Foundation for Herbal Medicinal Products. 2nd ed. Exeter, UK: European Scientific Cooperative on Phytotherapy and Thieme; 2003:365-382.
• 8.Singh Y. Kava from Ethnology to Pharmacology. Boca Raton, Fla: CRC Press; 2004.
• 9.Russmann S, Lauterburg BH, Helbling A. Kava hepatotoxicity. Ann Intern Med 2001;135:68-69.View Abstract
• 10.Campo JV, McNabb J, Perel JM et al. Kava-induced fulminant hepatic failure. J Am Acad Child Adolesc Psychiatry 2002;41:631-632.View Abstract
• 11.McGhee H. From the Centers for Disease Control and Prevention. Hepatic toxicity possibly associated with kava-containing products—United States, Germany, and Switzerland, 1999-2002. JAMA 2003;289:36-37.
• 12.Gow PJ, Connelly NJ, Hill RL et al. Fatal fulminant hepatic failure induced by a natural therapy containing kava. Med J Aust 2003;178:442-443.View Abstract
• 13.Brauer RB, Stangl M, Stewart JR et al. Acute liver failure after administration of herbal tranquilizer kava-kava (Piper methysticum). J Clin Psychiatry 2003;64:216-218.View Abstract
• 14.Stickel F, Baumuller H-M, Seitz K et al. Hepatitis induced by kava (Piper methysticum rhizoma). J Hepatol 2003;39:62-67.View Abstract
• 15.Strahl S, Ehret V, Dahm HH, Maier KP. [Necrotizing hepatitis after taking herbal remedies]. Dtsch Med Wochenschr 1998;123:1410-1414.View Abstract
• 16.Schmidt M. Is kava really hepatotoxic? Accessed February 2005 vol; 2003:http://www.uni-muenster.de/Chemie.pb/Kava/kavaframe.html.
• 17.Schmidt M, Morgan M, Bone K et al. Kava: a risk-benefit assessment. In: Mills S, Bone K, eds. The Essential Guide to Herbal Safety. St Louis: Churchill Livingstone; 2005:155-201.
• 18.Cerna D. The Pharmacology of the Newer Materia Medica. Detroit: George Davis; 1892.
• 19.Ellingwood F, Lloyd J. The American Materia Medica: Therapeutics and Pharmacognosy. Eclectic Medical Publications, Portland, Ore; 1983 ed. Cincinnati; 1919.
• 20.Weiss R. Herbal Medicine. Meuss A, Translator. 6th ed. Beaconsfield, UK: Beaconsfield Publishers Ltd; 1988.
• 21.Hänsel R. Characterization and physiological activity of some kava constituents. Pac Sci 1968;22:293-313.
• 22.Lebot V, Johnston E, Zheng Q et al. Morphological, phytochemical and genetic variation in Hawaiian cultivars of ’awa (Piper methysticum, Piperaceae). Econ Bot 1999;53:407-418.
• 23.Cheng D, Lidgard RO, Duffield PH et al. Identification by methane chemical ionization gas chromatography/mass spectrometry of the products obtained by steam distillation and aqueous acid extraction of commercial Piper methysticum. Biomed Environ Mass Spectrom 1988;17:371-376.
• 24.Rasmussen P. Phytotherapy for the treatment of drug withdrawal. Eur J Herbal Med 1997;3:11-22.
• 25.Waller D. Report on kava and liver damage. American Herbal Products Association; Silver Spring, Md. University of Illinois at Chicago, Department of Pharmaceutics and Pharmacodynamics; 2002.
• 26.Anke J, Ramzan I. Kava hepatotoxicity: are we any closer to the truth? Planta Med 2004;70:193-196.
• 27.Singh N, Singh S, Singh Y. Kava: clinical studies and therapeutic implications. In: Singh Y, ed. Kava from Ethnology to Pharmacology. Boca Raton, Fla: CRC Press; 2004:140-164.
• 28.Clouatre DL. Kava kava: examining new reports of toxicity. Toxicol Lett 2004;150:85-96.View Abstract
• 29.Kava Kava: Declaration of the German Commission E [in German]. Z Phytotherapie 2002;4:158.
• 30.Bauer R, Kopp B, Nahrstedt A. Relevant hepatoxoic effects of kava still need to be proven. Planta Med 2003;69:971-972.
• 31.Dragull K, Yoshida WY, Tang C-S. Piperidine alkaloids from Piper methysticum. Phytochemistry 2003;63:193-198.View Abstract
• 32.Whitton PA, Lau A, Salisbury A et al. Kava lactones and the kava-kava controversy. Phytochemistry 2003;64:673-679.View Abstract
• 33.Schmidt M. Are kavalactones the hepatotoxic principle of kava extracts? The pitfalls of the glutathione theory. J Altern Complement Med 2003;9:183-187; author reply 187-188.View Abstract
• 34.Li AP. A review of the common properties of drugs with idiosyncratic hepatotoxicity and the “multiple determinant hypothesis” for the manifestation of idiosyncratic drug toxicity. Chem Biol Interact 2002;142:7-23.View Abstract
• 35.Mathews JM, Etheridge AS, Black SR. Inhibition of human cytochrome P450 activities by kava extract and kavalactones. Drug Metab Dispos 2002;30:1153-1157.View Abstract
• 36.Unger M, Holzgrabe U, Jacobsen W et al. Inhibition of cytochrome P450 3A4 by extracts and kavalactones of Piper methysticum (kava-kava). Planta Med 2002;68:1055-1058.View Abstract
• 37.Zou L, Henderson GL, Harkey MR et al. Effects of kava (kava-kava, ’awa, yaqona, Piper methysticum) on c-DNA-expressed cytochrome P450 enzymes and human cryopreserved hepatocytes. Phytomedicine 2004;11:285-294.View Abstract
• 38.Zou L, Harkey MR, Henderson GL. Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity. Life Sci 2002;71:1579-1589.View Abstract
• 39.Cote CS, Kor C, Cohen J, Auclair K. Composition and biological activity of traditional and commercial kava extracts. Biochem Biophys Res Commun 2004;322:147-152.View Abstract
• 40.Russmann S, Barguil Y, Wenk M et al. Traditional aqueous kava extracts inhibit CYP4501A2 in humans. Clin Pharmacol Ther 2004;75:P83.
• 41.Raucy JL. Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Drug Metab Dispos 2003;31:533-539.View Abstract
• 42.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 2005;77:415-426.View Abstract
• 43.Zou L, Harkey MR, Henderson GL. Synthesis, in vitro reactivity, and identification of 6-phenyl-3-hexen-2-one in human urine after kava-kava (Piper methysticum) ingestion. Planta Med 2005;71:142-146.View Abstract
• 44.Tarbah F, Mahler H, Kardel B et al. Kinetics of kavain and its metabolites after oral application. J Chromatogr B Analyt Technol Biomed Life Sci 2003;789:115-130.View Abstract
• 45.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 2005;77:453-454.
• 46.Steiner GG. The correlation between cancer incidence and kava consumption. Hawaii Med J 2000;59:420-422.
• 47.Folmer F, Blasius R, Morceau F et al. Inhibition of TNFα-induced activation of nuclear factor κB by kava (Piper methysticum) derivatives. Biochem Pharmacol 2006;71:1206-1218.
• 48.Singh YN. Potential for interaction of kava and St. John’s wort with drugs. J Ethnopharmacol 2005;100:108-113.View Abstract
• 49.Anke J, Ramzan I. Pharmacokinetic and pharmacodynamic drug interactions with kava (Piper methysticum Forst. f.). J Ethnopharmacol 2004;93:153-160.View Abstract
• 50.Wanwimolruk S, Bhawan S, Coville PF, Chalcroft SC. Genetic polymorphism of debrisoquine (CYP2D6) and proguanil (CYP2C19) in South Pacific Polynesian populations. Eur J Clin Pharmacol 1998;54:431-435.
• 51.Klohs MW, Keller F, Williams RE et al. A chemical and pharmacological investigation of Piper methysticum Forst. J Med Pharm Chem 1959;1:95-103.View Abstract
• 52.Meyer HJ. [Pharmacology of the active principles of kavaroot (Piper methysticum Forst.)]. Arch Int Pharmacodyn Ther 1962;138:505-536.View Abstract
• 53.Herberg K. Safety-related performance after intake of kava-extract, bromazepam, and their combination. Z Allgemeinmed 1996;72:973-977.
• 54.Jamieson DD, Duffield PH. The antinociceptive actions of kava components in mice. Clin Exp Pharmacol Physiol 1990;17:495-507.View Abstract
• 55.Davies LP, Drew CA, Duffield P et al. Kava pyrones and resin: studies on GABAA, GABAB and benzodiazepine binding sites in rodent brain. Pharmacol Toxicol 1992;71:120-126.View Abstract
• 56.Jussofie A, Schmiz A, Hiemke C. Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain. Psychopharmacology (Berl) 1994;116:469-474.View Abstract
• 57.Holm E, Staedt U, Heep J et al. [The action profile of d,l-kavain: cerebral sites and sleep-wakefulness-rhythm in animals]. Arzneimittelforschung 1991;41:673-683.View Abstract
• 58.Singh Y. Pharmacology and toxicology of kava and kavalactones. In: Singh Y, ed. Kava from Ethnology to Pharmacology. Boca Raton, Fla: CRC Press; 2004:104-139.
• 59.Noyes R Jr, DuPont RL Jr, Pecknold JC et al. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. II. Patient acceptance, side effects, and safety. Arch Gen Psychiatry 1988;45:423-428.View Abstract
• 60.Almeida JC, Grimsley EW. Coma from the health food store: interaction between kava and alprazolam. Ann Intern Med 1996;125:940-941.
• 61.Fugh-Berman A, Ernst E. Herb-drug interactions: review and assessment of report reliability. Br J Clin Pharmacol 2001;52:587-595.View Abstract
• 62.Capasso A, Sorrentino L. Pharmacological studies on the sedative and hypnotic effect of kava kava and Passiflora extracts combination. Phytomedicine 2005;12:39-45.View Abstract
• 63.Baum SS, Hill R, Rommelspacher H. Effect of kava extract and individual kavapyrones on neurotransmitter levels in the nucleus accumbens of rats. Prog Neuropsychopharmacol Biol Psychiatry 1998;22:1105-1120.View Abstract
• 64.Noldner M, Chatterjee SS. Inhibition of haloperidol-induced catalepsy in rats by root extracts from Piper methysticum F. Phytomedicine 1999;6:285-286.View Abstract
• 65.Schelosky L, Raffauf C, Jendroska K, Poewe W. Kava and dopamine antagonism. J Neurol Neurosurg Psychiatry 1995;58:639-640.View Abstract
• 66.Meseguer E, Taboada R, Sanchez V et al. Life-threatening parkinsonism induced by kava-kava. Mov Disord 2002;17:195-196.View Abstract
• 67.Pepping J. Kava: Piper methysticum. Am J Health Syst Pharm 1999;56:957-958, 960.View Abstract
• 68.Jamieson DD, Duffield PH. Positive interaction of ethanol and kava resin in mice. Clin Exp Pharmacol Physiol 1990;17:509-514.View Abstract
• 69.Herberg KW. [Effect of Kava-Special Extract WS 1490 combined with ethyl alcohol on safety-relevant performance parameters]. Blutalkohol 1993;30:96-105.View Abstract
• 70.Foo H, Lemon J. Acute effects of kava, alone or in combination with alcohol on subjective measures of impairment and intoxication and on cognitive performance. Drug Alcohol Rev 1997;16:147-155.View Abstract
• 71.Anke J, Fu S, Ramzan I. Kavalactones fail to inhibit alcohol dehydrogenase in vitro. Phytomedicine 2006;13:192-195.View Abstract
• 72.Mathews JD, Riley MD, Fejo L et al. Effects of the heavy usage of kava on physical health: summary of a pilot survey in an aboriginal community. Med J Aust 1988;148:548-555.View Abstract
• 73.Kretzschmar R, Meyer HJ, Teschendorf HJ. Strychnine antagonistic potency of pyrone compounds of the kavaroot (Piper methysticum Forst.). Experientia 1970;26:283-284.View Abstract
• 74.Kretzschmar R, Meyer HJ. [Comparative studies on the anticonvulsant activity of the pyrone compounds of Piper methysticum Forst]. Arch Int Pharmacodyn Ther 1969;177:261-267.View Abstract
• 75.Jamieson DD, Duffield PH, Cheng D, Duffield AM. 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.View Abstract
• 76.Frey R. [Demonstration of the central effects of d,l-kawain with EEG brain mapping]. Fortschr Med 1991;109:505-508.View Abstract
• 77.Spinella M. Herbal medicines and epilepsy: the potential for benefit and adverse effects. Epilepsy Behav 2001;2:524-532.View Abstract
• 78.Donadio V, Bonsi P, Zele I et al. Myoglobinuria after ingestion of extracts of guarana, Ginkgo biloba and kava. Neurol Sci 2000;21:124.View Abstract
• 79.Uebelhack R, Franke L, Schewe HJ. Inhibition of platelet MAO-B by kava pyrone-enriched extract from Piper methysticum Forster (kava-kava). Pharmacopsychiatry 1998;31:187-192.View Abstract
• 80.Navarro JF, Gallego E, Aviles J. Recurrent severe acute hepatitis and omeprazole. Ann Intern Med 1997;127:1135-1136.View Abstract
• 81.Koury SI, Stone CK, La Charite DD. Omeprazole and the development of acute hepatitis. Eur J Emerg Med 1998;5:467-469.View Abstract
• 82.Romero-Gomez M, Otero MA, Suarez-Garcia E et al. Acute hepatitis related to omeprazole. Am J Gastroenterol 1999;94:1119-1120.View Abstract
• 83.Christe C, Stoller R, Vogt N. Omeprazole-induced hepatotoxicity? A case report. Pharmacoepidemiol Drug Saf 1998;7 Suppl 1:S41-44.View Abstract
• 84.Gleitz J, Beile A, Wilkens P et al. Antithrombotic action of the kava pyrone (+)-kavain prepared from Piper methysticum on human platelets. Planta Med 1997;63:27-30.View Abstract
• 85.Mills S, Bone K. The Essential Guide to Herbal Safety. St Louis: Churchill Livingstone; 2005.