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Kava

Botanical Name: Piper methysticum G. Forster.
Pharmacopoeial Name: Piperis methystici rhizoma.
Common Names: Kava, kava-kava, kawa, ’awa.

Summary Table
herb description

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.

herb in clinical practice

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.

interactions review

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. 17,26,28,31-33The 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.

herb-drug interactions
Alprazolam and Related Triazolobenzodiazepines
Dopamine Agonists and/or Antagonists
Ethanol
theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Anticonvulsant Medications
Caffeine
Monoamine Oxidase (MAO-B) Inhibitors

Selegiline (deprenyl, L-deprenil, L-deprenyl; Atapryl, Carbex, Eldepryl, Jumex, Movergan, Selpak); pargyline (Eutonyl), rasagiline (Azilect).

Uebelhack et al. 79 conducted in vitro tests for MAO-B inhibitory activity by kava extracts and kavalactones in a human platelet system, both with intact and homogenized platelets. They found an IC 50 of 24 µM for intact platelets, with substantially lower values for platelet homogenate. 79 MAO inhibitor activity has not been reported for kavalactones in neurotransmitter studies, and the in vivo effects of the herb are not commensurate with selective MAO-B inhibition. Suggestions have been made of theoretical interactions with MAO inhibitors 67 ; these are speculative.

Proton Pump Inhibitors
Warfarin and Related Oral Vitamin K Antagonist Anticoagulants
Citations
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