Scientific Name(s): Piper methysticum Forst.f. Family: Piperaceae (black peppers)
Common Name(s): Kava , kawa , kava-kava , awa , yangona , kawain , kavain , ava , kava pepper , intoxicating pepper , kava root , kew , sakau , tonga , wurzelstock , rauschpfeffer
Kava has mild sedative effects and is used for nervous anxiety, stress, and restlessness. However, clinical information lacks consensus, and there are limited comparative studies, depending on the use.
The German Commission E recommends dosages of kavalactones 60 to 120 mg daily for no longer than 3 months without medical evaluation. Clinical studies have reported that dosages of kavalactones 60 to 240 mg/day are effective.
Kava and kava-containing products are not recommended for use in children younger than 12 years of age, or in patients with renal disease, thrombocytopenia, or neutropenia. 1 Additionally, patients with depression, liver disease, and Parkinson disease should avoid using kava.
Documented adverse effects. Avoid use. 2
Kava may increase the CNS adverse reactions of alprazolam. Patients should avoid concomitant use of kava and alprazolam. Worsening of Parkinson symptoms was reported in a patient during coadministration of kava and levodopa.
Heavy kava use can cause visual disturbances and a scaly skin rash.
Rare cases of severe liver toxicity have been reported.
Kava is the dried rhizome and roots of P. methysticum , a large shrub widely cultivated in many Pacific islands, including Hawaii, Tahiti, and New Guinea. The plant can grow as tall as 3 m in height, 3 , 4 has large, heart-shaped leaves, and is propagated exclusively by root cuttings. It is thought to be derived from the wild species Piper wichmannii C. DC. 5 Many cultivars of kava are recognized. The comparative chemistry and ethnopharmacology have been studied in detail, and 121 named cultivars from 51 islands have been grouped into 6 chemotypes. 6 , 7 , 8
The kava beverage is prepared from the roots of the plant, which are chewed or pulverized and then steeped in water. The cloudy mixture is filtered and served at room temperature. Kava has been an important part of Pacific island ceremonial cultures for many centuries, with elaborate rituals attending its consumption. 9 The kava beverage is used to symbolize respect and hospitality to visiting dignitaries. 10 Traces of kava extract on archaeological artifacts from Fiji have been identified by mass spectrometry. 11 Its main use has been to induce a relaxed state in the participants in a kava ceremony by initially causing a numbing and astringent effect in the mouth, followed by anxiolytic and muscle relaxant effects. Eventually, a state of sleep is induced and no hangover effects are experienced. 4 , 12 , 13 The efficacy of kava is not diminished with continued use. 4
An 1886 monograph on kava 14 stimulated research and isolation of the kavalactones (also known as kavapyrones), the primary bioactive constituents of kava root that are poorly water soluble. 15 A total of 18 kavalactones have been isolated in kava root extract. 16 The 6 major kavalactones are kawain, 7,8-dihydrokawain, methysticin, 7,8-dihydromethysticin, yangonin, and demethoxyyangonin, 15 , 16 , 17 which occur in varying proportions in different cultivars. The first 4 kavalactones listed are chiral enantiomers, and the last 2 are achiral enantiomers. 15 On a dry weight basis, the content of kavalactone ranges from 3% to 20%. 15 , 16 The structures of the kavalactones were first elucidated in the 1930s, 18 although many of the pure compounds were first isolated in the 19th century. They were later synthesized in racemic and optically pure forms. 19 , 20 , 21 Full nuclear magnetic resonance assignments have been made for the kavalactones. 22 While the kavalactones are characteristic of P. methysticum , individual kavalactones occur in other plant families (ie, Lauraceae, Gesneriaceae, Zingiberaceae). 23 A process for the commercial production of kava extract has been patented, 24 and the use of supercritical fluid extraction of kavalactones from the root has been demonstrated. 25 Many methods have been developed for the analysis of kavalactones. These include thin layer chromatography, 26 gas chromatography, 27 high-performance liquid chromatography (HPLC), 28 , 29 , 30 gas chromatography-mass spectrometry (GC-MS), 18 , 31 , 32 , 33 chiral HPLC, 34 HPLC-MS, 35 and micellar electrokinetic chromatography. 36 The metabolism of the kavalactones has been studied in humans. 37 The uptake of kavalactones into mouse brain also has been studied. 38 The latter study found elevated brain levels of kawain when the whole resin was administered, compared with kawain alone. This supported the observation that the total kava resin has greater pharmacologic effect than the sum of the individual kavalactones, presumably because of the saturation of common metabolic pathways utilized by these compounds.
Other constituents of kava include 2 chalcones, flavokawains A and B, 39 that were postulated to cause dermopathy in heavy kava users. 40 A patent claims production of an extract with very low chalcone content. 24 Several minor alkaloids also have been isolated from kava roots 41 and leaves. 42
Uses and PharmacologyCNS effects
Chewing kava causes numbness in the mouth because of the local anesthetic action of the kavalactones, which is similar to that produced by cocaine, and lasts longer than benzocaine. 43 In addition, it produces a mild euphoria characterized by feelings of contentment and fluent and lively speech. Sight, smell, and sound are also heightened. 4 Higher doses may lead to muscle weakness, especially in the legs, although some observers relate this to sitting for long periods during the “kava ceremony” rather than to kava itself. Very high doses may induce a deep sleep. CNS effects appear to be mediated by the blockage of voltage-gated sodium and calcium channels ultimately suppressing glutamate release. The kavalactones desmethoxyyangonin and methysticin are believed to block the metabolism of monoamine oxidase-B, producing psychotropic effects. 44 , 45 Sedative and antianxiety properties may result from kava's effects on facilitating gamma-aminobutyric acid (GABA)ergic transmission. 46
The molecular mechanism of action of kavalactones and kava is not entirely clear.Animal data
Kavalactones at concentrations from 0.1 to 100 mcM enhanced the binding of bicuculline to the GABA receptor by only 20% to 30%. 47 Another study found weak displacement of diazepam from rat brain membranes by kavalactones but no effect on binding of GABA or of baclofen. 48 The observation that strychnine-induced convulsions are effectively antagonized by several kavalactones supports a possible effect on the glycine receptor. 49 Kava extract and methysticin also were found to protect rats against ischemic brain damage, although several kavalactones were not active in this model. 50 This protection might operate through antagonism of the excitatory amino acids glutamate and aspartate. Inhibition of uptake of norepinephrine, but not serotonin, by kavalactones at high doses was observed. 48 No effect on dopamine or serotonin levels was found in a chronic experiment with kavalactones in rats. 51
A somewhat more persuasive mechanism involves kavalactone inhibition of various neuronal sodium channels. Patch clamp experiments with voltage-gated sodium channels of rat hippocampal neurons found that kavalactones could rapidly and reversibly lower peak amplitudes of sodium currents. 52 A noncompetitive inhibition of the binding of batrachotoxinin benzoate to voltage-gated sodium channels by kavalactones was demonstrated in saturation-binding experiments. 53 Less potently, kavalactones blocked veratridine-activated sodium channels, but had no effect on glutamate release from brain slices. 54 In rat brain synaptosomes, kavalactones appeared to interact with voltage-dependent sodium and calcium channels. 48 , 51 , 55 High concentrations of synthetic kawain relaxed evoked contractile activity in a guinea pig ileum preparation, showing that smooth muscle also is affected by kavalactones. 56 A fluorescently labeled kawain derivative was studied using fluorescence correlation spectroscopy and bound specifically and saturably to cultivated human cortical neurons. 57
Neurophysiological studies of sleep/wakefulness in cats showed decreased muscle tone and duration of wakefulness, marked changes in electroencephalogram (EEG), and increased sleep with kava. Involvement of the amygdala and other limbic structures of the brain was deduced. 58 These effects were distinct from those of tricyclic antidepressants and benzodiazepines.
The pharmacokinetics of kavalactones have been explained to some extent. In rats, dihydrokawain was completely excreted within 48 hours, primarily through urinary excretion of hydroxylated metabolites. Bile and feces did not appear to be important routes of excretion. However, lactones (eg, kawain) with poorer oral absorption than dihydrokawain were found unchanged in feces. The octanol-water partition coefficient for yangonin is 1,500; thus, these compounds are quite nonpolar and water-insoluble. This accounts in part for their poor oral absorption. 59 Because the metabolites of kavalactones are different in humans than in rats, 37 the pharmacokinetics also may differ. Kavalactones have a half-life of 9 hours and achieve peak plasma levels 1.8 hours after administration. 14 Kinetics of entry of kavalactones into mouse brains after intraperitoneal injection have been studied, and kawain and dihydrokawain were rapidly absorbed and quickly eliminated within several minutes, while yangonin and desmoethoxyyangonin were more slowly incorporated and eliminated. 38Clinical data
Concerns about impaired performance under the influence of kava have motivated several studies in humans. One small study found insignificant decreases in cognitive function when using kava, with only the extent of body sway showing an increase. Subjects' rating of intoxication under kava was low to moderate, while respiration, heart rate, and blood pressure were unaffected. Kava lowered arousal rating without affecting stress rating, although the decrease was not statistically significant. 60 Another small study of 12 patients compared the effects of kava and oxazepam on behavior and event-related potentials in a word recognition task. While oxazepam produced pronounced negative effects on performance, no effects were seen with kava. 61 A study of reaction time by the same authors concluded that kava may increase attention slightly, in contrast to oxazepam, which impaired attention. 62 Kawain in EEG studies showed mild sedation at high doses (600 mg) but not at lower doses (200 mg). 63 Kava had no effect on alertness and long-term memory in a subsequent trial. 64 Minor changes in vision and balance were detected with kava in one subject. 65Anxiety
Clinical studies of kava have produced evidence of substantial efficacy in mild to moderate anxiety.Animal data
Research reveals no animal data regarding the use of kava for anxiety.Clinical data
In Germany, several investigations have reviewed kava in comparison with other CNS-active herbal products. 66 Kawain was compared with oxazepam in a double-blind study of 58 patients and was equally effective and safe. 67 Over 4 weeks, kava extract progressively reduced anxiety compared with placebo in 60 patients with no reported adverse reactions. 68 A longer 25-week, double-blind, placebo-controlled study of 101 patients with anxiety disorders found that Hamilton Anxiety Scale (HAMA) scores decreased faster with kava than with placebo. 69 A similar 4-week study found kava extract effective using both HAMA and Clinical Global Impression Scale scores. 70
The first US study of kava in anxiety was reported at a conference but has not been published. The study found similar therapeutic effects of kava extract under double-blind, placebo-controlled conditions. 71 A combination of kava and hormone replacement therapy for menopause symptoms was undertaken in Italy over a period of 6 months. Kava with hormone therapy accelerated the improvement in anxiety scores over single treatments alone. 72
Positive results in a sleep study involving 12 patients were found with kava extract WS 1490, as measured by EEG, electromyography, and subjective measures. No adverse effects on rapid eye movement sleep were found. 73 A clinical study of kava's ability to moderate cardiac symptoms in generalized anxiety disorder found that it improved baroreflex control (BRC) of heart rate, but not respiratory sinus arrhythmia, and improvement in BRC was associated with overall clinical improvement in kava-treated patients. 74
The effects of kava extract WS 1490 were assessed on sleep disturbances associated with anxiety disorders. After 4 weeks of double-blind treatment, the assessment of quality of sleep and recuperative effect after sleep were statistically significant in comparison with placebo. Thus, a potential role for kava in improving sleep in patients with anxiety was suggested. 75
The transition from benzodiazepines to kava extract WS 1490 in treatment of anxiety was monitored in a 5-week study involving 40 patients. While symptoms of benzodiazepine withdrawal were not controlled by kava, anxiety was reduced and symptoms decreased after kava treatment compared with during benzodiazepine therapy. 76 A meta-analysis of clinical trials of kava extracts in anxiety has been conducted. Seven trials met the acceptance criteria for inclusion and found kava superior to placebo in the treatment of anxiety as noted by a reduction in the total score of the HAMA. 77
A randomized, double-blind, placebo-controlled study was conducted to assess the effects of kava (total kavalactones 100 mg 3 times daily for 4 weeks) on anxiety. When compared with placebo, there were no statistically significant differences (+2.6 [95%, confidence interval (CI) −0.8 to +6.2]) in reductions of anxiety as measured by the State subtest of the State-Trait Anxiety Inventory. Kava also does not appear to improve measures of insomnia. 78
Additionally, data from 3 randomized, double-blind, placebo-controlled trials assessing the efficacy of kava for the treatment of generalized anxiety disorder were analyzed. From these studies, it did not appear that kava was efficacious for the treatment of generalized anxiety disorder. 79Menopausal symptoms
Kavalactones are purportedly used to relieve anxiolytic effects associated with menopause through modulation of GABA-A receptors in nerve endings. 80Animal data
Research reveals no animal data regarding the use of kava for the treatment of menopausal symptoms.Clinical data
Menopause-related anxiety was successfully treated with kava extract in an 8-week study of 40 women, with rapid onset of efficacy. 81 A 12-week study also found improvement in menopausal symptoms; however, poor compliance in the placebo group confounded interpretation. 82 In a randomized, prospective study, 68 perimenopausal women requiring therapy for climacteric symptoms were randomized to receive 3 months of calcium 1 g/day plus either kava 100 mg/day (kavapyrones 55 mg), 200 mg/day (kavapyrones 110 mg), or no other therapies. Perimenopause was defined as amenorrhea for 6 to 24 months in women between 47 and 53 years of age with hot flushes occurring at least 3 times daily for at least 1 week and a follicle-stimulating hormone level of greater than 30 units/L. In the control group, there were no differences with regard to anxiety, depression, or climacteric symptoms after 1 and 3 months. Patients treated with kava 100 mg/day had a significant decline in anxiety after 1 and 3 months of therapy ( P < 0.025). A similar effect was noted in patients treated with kava 200 mg/day for anxiety at 1 and 3 months ( P < 0.0003). Patients treated with both doses of kava experienced improvements in depression after 1 and 3 months of treatment as compared with baseline ( P < 0.002). Climacteric symptoms were also reduced in both kava treatment groups after 1 and 3 months ( P < 0.006). The authors concluded that kava may be an effective short-term alternative for improving mood disturbances and climacteric symptoms in women with perimenopausal symptoms. 83
In another study, the effects of hormone replacement therapy with and without kava were assessed for a total of 6 months in 40 women with menopausal anxiety. Subjects with physiological menopause were randomized to receive 50 mcg/day of estrogen with progestin plus either kava extract 100 mg/day or placebo. Subjects with surgically induced menopause were randomly assigned to receive estrogen 50 mcg/day plus either kava 100 mg/day or placebo. A reduction in anxiety scores as measured by the HAMA was noted after 3 and 6 months of treatment for all 4 treatment groups. However, the groups receiving kava extract had a larger reduction in anxiety scores compared with those who did not. Specifically, after 6 months of therapy, HAMA scores were reduced 55% compared with baseline for the patients with physiologically induced menopause receiving kava and hormone placement therapy ( P < 0.05) and reduced 23% for those receiving only hormone replacement therapy. In the surgically induced menopause group, HAMA scores were reduced 53% for those receiving hormone replacement therapy and kava, compared with baseline, and reduced 26% for those receiving only hormone replacement therapy. 72Other uses
Kavalactones, especially kawain, have modest anticonvulsant activity in electroshock and metrazol models. 84 Kawain showed an antithrombotic effect on platelets, dose-dependently blocking platelet aggregation, adenosine 5′-triphosphate release and synthesis of prostaglandins at high micromolar concentrations. 85 Despite a reputation as an antimicrobial agent in urinary tract infections, kava extracts demonstrated very minimal antifungal and no antimicrobial or antiviral activity. 86
Preliminary data collected from the Pacific Islands suggest that kava consumption is possibly associated with a lower incidence of cancer. 87
The German Commission E recommends dosages of kavalactones 60 to 120 mg daily for no longer than 3 months without medical evaluation. 88 However, clinical studies have reported that dosages of kavalactones 60 to 240 mg/day are effective. 13 Kava does not appear to be addictive at therapeutic dosages. 89 An aqueous extract can be prepared by chopping 30 g of the kava roots and extracting with 300 mL of cold water. The traditional extract was derived from 10 g of powdered crude drug and 100 mL of water to yield a product containing kavapyrones 72.6 mg, representing a daily dose of kavapyrones 210 mg when 300 mL are consumed. 12 A study using a special extract of kava containing 70% kavalactones found a dosage of 150 mg/day to be effective for the treatment of anxiety. 43 When used as a sedative, kavalactones 180 to 210 mg may be given 1 hour before bedtime. 4
Documented adverse effects. Avoid use. 2
In experimental conditions, kava was demonstrated to be an inhibitor of the following CYP-450 isoenzymes: 1A2 (56% inhibition), 2C9 (92%), 2C19 (86%), 2D6 (73%), 3A4 (78%), and 4A9/11 (65%), with no changes in the activity of 2A6, 2C8, or 2E1. 13 , 90 However, in a study of 12 healthy women, kava produced a 40% reduction in 2E1 as measured by phenotypic ratios. 91 Thus, any medications involving metabolism by these isoenzymes could theoretically have increased levels. However, an in vivo study of kava supplementation for 14 days did not reveal any significant changes on the pharmacokinetics parameters of midazolam, a known CYP3A4 substrate. 92 Kava's actions are potentiated by alcohol, benzodiazepines (eg, alprazolam), and barbiturates although this well-known interaction is poorly documented in the clinical toxicology literature. 4 , 43 , 93 , 94 In one study, alcohol combined with kava appeared to worsen sedation, intoxication, and cognitive impairment. 95 Coadministration of levodopa and kava can increase parkinsonian symptoms. 43 Drugs affecting dopamine, such as haloperidol, risperidone, and metoclopramide among others, are associated with increased adverse reactions, especially parkinsonian symptoms, when given concomitantly with kava-containing products. 96 , 97 Digoxin given concomitantly with kava may increase the toxicity of digoxin. 43 However, a study of 20 healthy humans receiving digoxin and kava did not find any significant effects on the pharmacokinetic parameters of digoxin. 98 Given that kava is associated with anticonvulsant effects, it is possible that combining kava with anticonvulsants could result in potentiation of lethargy and cognitive impairment. 95 Additive effects may be noted in patients receiving monoamine oxidase inhibitors and kava-containing products. 97 Kavain has been reported to have antithrombotic action; thus, interactions with antiplatelets or anticoagulants is possible. 97 Patients receiving kava should avoid other herbals and supplements that are hepatotoxic (ie, valerian, androstenedione, chaparral). 4
Acute adverse reactions of kava consumption may include oral anesthetic effects (especially of the tongue), sedation, euphoria, muscle weakness, tremors, blepharospasms, saccadic slowing, saccadic dysmetria, and ataxia. 45 , 99 Heavy consumption of kava has long been known to produce a scaly skin rash on the palms of the hands, soles of the feet, and back known as kava dermopathy and is similar to pellagra; however, supplementation with niacin did not reverse the condition. 43 , 100 Cessation of kava use causes reduction or disappearance of the dermopathy. It was suggested that the flavokawain pigments were responsible for this toxicity 40 ; despite the lack of any scientific proof, these pigments are commonly removed in the production of commercial extracts. 24 Poor nutritional status and other general adverse reactions were seen in an Australian aboriginal community where (nontraditional) kava consumption was very heavy. 101 Urinary retention was reported in a case report involving a 61-year-old Tongan man who had consumed 1 L of kava and who had no history of prostate problems. 102 Visual impairment, including near-point accommodation, enlargement of the pupils, and disturbances in occulomotor equilibrium, also have been described. 16 , 43 , 65 Kava extracts may also exacerbate Parkinson disease in patients with this condition and may interfere with cholesterol metabolism. 16 Other adverse reactions associated with long-term use of kava include hair loss, dizziness, stupor, gastrointestinal discomfort, extrapyramidal effects, partial loss of hearing, hypertension, shortness of breath, loss of appetite, and reductions in body weight. 43 , 103 Kava does not appear to adversely affect cognitive functioning. It does not affect alertness, speed of recalling information, or word recognition tasks. 46
Kava-containing extracts should be avoided in children younger than 12 years of age and in patients with renal disease, thrombocytopenia, and neutropenia. 1 Additionally, patients with depression, liver disease, and Parkinson disease should avoid products containing kava. 43 Patients who frequently consume alcohol or those taking any medication or herbal product with hepatotoxic products should consult a health care provider before using any kava-containing products. Patients who begin receiving kava and notice signs and symptoms of liver disease (ie, abdominal pain, brown urine, fatigue, jaundice, light-colored stools, loss of appetite, nausea, vomiting, weakness) should discontinue use of the product and consult their health care provider. 10
Kava has been implicated in a string of reports of fulminant hepatic failure in Europe and the United States. 45 , 88 , 104 , 105 The Food and Drug Administration (FDA) and Australian and Canadian authorities have issued warnings to consumers and health care providers on the potential for liver damage from kava products. 106 In the United States, 2 cases of liver failure associated with kava have been investigated. In the first case, a 45-year-old woman reported nausea and vomiting within 8 weeks of beginning a twice daily supplement containing kava (30% kavalactones, 75 mg). The patient reported a 4-day use of rabeprazole and drank alcohol only 1 to 2 times a year. Once symptomatic, the patient discontinued treatment with kava and was later hospitalized with jaundice and hepatitis with a liver biopsy that indicated subfulminant hepatic necrosis. She required liver transplantation and resumed normal activities following the procedure. The second case involves a 14-year-old girl who experienced nausea, vomiting, anorexia, and fatigue and had been using 2 kava-containing products over a 4-month period, one for 44 days and one for 7 days. One week later, she was hospitalized with acute hepatitis. The patient required liver transplantation and recovered following the procedure. 107 A definite link has not been determined between kava and the observed severe cases of hepatotoxicity; interactions between kava and prescription or over-the-counter drugs have not been ruled out at this time.
Case reports from Germany indicate that hepatotoxicity has been documented in patients receiving alcoholic and acetone extracts. 108 Concomitant use of alcohol and kava extracts may potentiate the risk for hepatotoxicity. In a cross-sectional study of an Aboriginal population, alkaline phosphatase and gamma glutamyltransferase (GGT) levels were elevated in current kava users compared with recent and nonusers, while there were no differences noted in alanine transaminase levels. 109 Similar findings were noted in a study of the Tongan population in Hawaii. Patients consuming kava were 5 times more likely to have GGT elevations than nondrinkers (95% CI, 1.56 to 18.06). 110 A cross-sectional study found that alkaline phosphatase levels normalized 1 to 2 months after abstinence from kava consumption, and gamma glutamyl transferase levels normalized after 1 year. 111 Caution dictates that patients with any predisposition to liver problems should avoid use of kava. A systematic review of kava safety issues has been published. 112 The incidence of hepatotoxicity is clearly too low to have been detected in previous clinical trials. 113
Several theories have postulated why kava causes hepatotoxicity. One theory is that heavy demand for kava products led to the addition of kava leaves and stems to kava root products, and that the alkaloid pipermethystine found in the leaves and stems, but not in roots, is responsible for liver toxicity. Cytotoxicity of pipermethystine (50 to 100 mcM) to HepG2 cells has been demonstrated in support of this theory. 114 Another theory known as the “glutathione theory” suggests that aqueous extracts used historically in the South Pacific containing glutathione have the potential to react with kavalactones to provide hepatoprotection as opposed to those chemically derived and on the market. Additionally, several studies indicated that kavalactones are inhibitors of isoenzymes of the CYP-450 system increasing the risk for drug-herbal interactions, especially in formulations containing high concentrations of methysticin and dihydromethysticin. Hepatotoxicity may also result with coadministration of alcohol, because kava decreases the conversion of ethanol to acetaldehyde. Alcohol may also reduce the detoxification of kavalactones. Another theory postulated regarding the hepatotoxicity of kava is that the risk for liver damage is increased in patients with CYP2D6 deficiencies, a major pathway for kavalactones. This is a phenomenon seen in approximately 10% of white patients and rarely in Polynesian patients, which may explain a higher incidence of liver toxicity in patients in Europe compared with the Pacific Islands. Lastly, immunological and/or toxicological reactions may be implicated in causing hepatotoxicity from kava. 115 Specifically, kavalactones appear to inhibit cyclooxygenase enzymes COX-1 and COX-2. The mediators derived from the production of COX-2 have been shown to be hepatoprotective, and this inhibition may be contributing to hepatotoxicity noted with kava. 14 However, short-term use of kava (ie, 1 to 24 months) is generally considered to be relatively safe. 116
In a case report of a kava overdose, a 37-year-old man presented to the emergency department with leg weakness, severe vertigo, slurred speech, and the inability to stand on multiple attempts. After 4 hours, his ataxia resolved and his mental status and slurring of speech improved. Thus, overdosage of kava may acutely cause mental status changes and vertigo. 117
Bibliography1. Ernst E. The risk-benefit profile of commonly used herbal therapies: gingko, St. John's wort, ginseng, echinacea, saw palmetto, and kava [published correction appears in Ann Intern Med . 2003;138(1):79]. Ann Intern Med . 2002;136(1):42-53.
2. Ernst E. Herbal medicinal products during pregnancy: are they safe? BJOG . 2002;109(3):227-235.
3. Singh YN. Kava: an overview. J Ethnopharmacol . 1992;37(1):13-45.
4. Freeman LW. Mosby's Complementary & Alternative Medicine: A Research-Based Approach. 3rd ed. St. Louis, MO: Mosby Elsevier; 2009:431-434.
5. Lebot V, Levesque J. Evidence for conspecificity of Piper methysticum forst. f. and Piper wichmannii C. DC. Biochem Syst Ecol . 1996;24(7-8):775-782.
6. Lebot V, Levesque J. Genetic control of kavalactone chemotypes in Piper methysticum cultivars. Phytochem . 1996;43(2):397-403.
7. Lebot V, Johnston E, Zheng QY, McKern D, McKenna DJ. Morphological, phytochemical, and genetic variation in Hawaiian cultivars of 'awa (kava, Piper methysticum , Piperaceae). Econ Bot . 1999;53(4):407-418.
8. Siméoni P, Lebot V. Identification of factors determining kavalactone content and chemotype in kava ( Piper methysticum Forst f.). Biochem Syst Ecol . 2002;30(5):413-424.
9. Holmes LD. The function of kava in modern Samoan culture. In: Efron DH, Holmstedt B, Kline NS, eds. Ethnopharmacologic Search for Psychoactive Drugs . New York, NY: Raven Press; 1979:107.
10. Blumenthal M. The ABC Clinical Guide to Herbs . 1st ed. Austin, TX: American Botanical Council; 2003:262-269.
11. Hocart CH, Fankhauser B, Buckle DW. Chemical archaeology of kava, a potent brew. Rapid Commun Mass Spectrom . 1993;7(3):219-224.
12. Teschke R, Gaus W, Loew D. Kava extracts: safety and risks including rare hepatotoxicity. Phytomedicine . 2003;10(5):440-446.
13. Robbers JE, Tyler VE. Tyler's Herbs of Choice: The Therapeutic Use of Phytomedicinals . New York, NY: Haworth Herbal Press; 1999:157-159.
14. Lewin, L. Über Piper Methysticum (Kawa) . Berlin: A. Hirschwald; 1886.
15. Denham A, McIntyre M, Whitehouse J. Kava—the unfolding story: report on a work-in-progress. J Altern Complement Med . 2002;8(3):237-263.
16. Clouatre DL. Kava kava: examining new reports of toxicity. Toxicol Lett . 2004;150(1):85-96.
17. Smith RM. Kava lactones in Piper methysticum from Fiji. Phytochem . 1983;22(4):1055-1056.
18. Borsche W, Peitzsch W. Constituents of kava root. X. Kawain and dihydrokawain. Chem Ber . 1930;63B:2414-4217.
19. Klohs MW, Keller F, Williams RE. Piper methysticum Forst. II. The synthesis of dl -methysticin and dl -dihydromethysticin. J Org Chem . 1959;24(11):1829-1830.
20. Israili ZH, Smissman EE. Synthesis of kavain, dihydrokavain, and analogues. J Org Chem . 1976;41(26):4070-4074.
21. Spino C, Mayes N, Desfosses H. Enantioselective synthesis of (+)- and (−)-dihydrokawain. Tetrahedron Lett . 1996;37(36):6503-6506.
22. Dharmaratne HR, Nanayakkara NP, Khan IA. Kavalactones from Piper methysticum , and their 13 C NMR spectroscopic analyses. Phytochemistry . 2002;59(4):429-433.
23. Kuster RM, Mpalatinos MA, de Holanda MC, Lima P, Brand ET, Parente JP. GC-MS determination of kava-pyrones in Alpinia zerumbet leaves. J High Resolut Chromatogr . 1999;22(2):129-130.
24. Schwabe KP. Kava-kava extract, process for the production thereof and use thereof. 1994; US Patent 5296224. March 22, 1994.
25. Lopez-Avila V, Benedicto J. Supercritical fluid extraction of kava lactones from Piper methysticum (kava) herb. J High Resolut Chromatogr . 1997;20(10):555-559.
26. Gracza L, Ruff P. Eifache methode zur trennung und quantitativen bestimmung von Kawa-Laktonen durch hochleistungs-flüssigkeits-chromatographie. J Chromatogr A . 1980;193(3):486-490.
27. Duve RN. Gas-liquid chromatographic determination of major constituents of Piper methysticum . Analyst . 1981;106(1259):160-165.
28. Smith RM, Thakrar H, Arowolo TA, Shafi AA. High-performance liquid chromatography of kava lactones from Piper methysticum . J Chromatogr A . 1984;283:303-308.
29. Häberlein H, Boonen G, Beck MA. Piper methysticum : enantiomeric separation of kavapyrones by high performance liquid chromatography. Planta Med . 1997;63(1):63-65.
30. Shao Y, He K, Zheng B, Zheng Q. Reversed-phase high-performance liquid chromatographic method for quantitative analysis of the six major kavalactones in Piper methysticum . J Chromatogr A . 1998;825(1):1-8.
31. Duffield AM, Lidgard RO. Analysis of kava resin by gas chromatography and electron impact and methane negative ion chemical ionization mass spectrometry. Biomed Environ Mass Spectrom . 1986;13:621-626.
32. Cheng D, Lidgard RO, Duffield PH, Duffield AM, Brophy JJ. 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(5):371-376.
33. Duffield AM, Lidgard RO, Low GK. Analysis of the constituents of Piper methysticum by gas chromatography methane chemical ionization mass spectrometry. Biomed Environ Mass Spectrom . 1986;13:305-313.
34. Boonen G, Beck MA, Häberlein H. Contribution to the quantitative and enantioselective determination of kavapyrones by high-performance liquid chromatography on ChiraSpher NT material. J Chromatogr B Biomed Sci Appl . 1997;702(1-2):240-244.
35. He XG, Lin LZ, Lian LZ. Electrospray high performance liquid chromatography-mass spectrometry in phytochemical analysis of kava ( Piper methysticum ) extract. Planta Med . 1997;63(1):70-74.
36. Lechtenberg M, Quandt B, Kohlenberg F-J, Nahrstedt A. Qualitative and quantitative micellar electrokinetic chromatography of kavalactones from dry extracts of Piper methysticum Forst. and commercial drugs. J Chromatogr A . 1999;848(1-2):457-464.
37. Duffield AM, Jamieson DD, Lidgard RO, Duffield PH, Bourne DJ. Identification of some human urinary metabolites of the intoxicating beverage kava. J Chromatogr . 1989;475:273-281.
38. 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 . 1988;77(12):1003-1006.
39. Haensel R, Baehr P, Elich J. Isolation and characterization of 2 as yet unknown dyes of kava rhizomes [in German]. Arch Pharm . 1961;294/66:739-743.
40. Shulgin AT. The narcotic pepper—the chemistry and pharmacology of Piper methysticum and related species. Bull Narc . 1973;25(2):59-74.
41. Smith RM. Pipermethysticine, a novel pyridone alkaloid from Piper methysticum . Tetrahedron . 1979;35(3):437-439.
42. Jaggy H, Achenbach H. Cepharadione A from Piper methysticum . Planta Med . 1992;58(1):111.
43. Fetrow CW, Avila JR. Professional's Handbook of Complementary & Alternative Medicines . 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:472-477.
44. Geier FP, Konstantinowicz T. Kava treatment in patients with anxiety. Phytother Res . 2004;18(4):297-300.
45. Humberston CL, Akhtar J, Krenzelok EP. Acute hepatitis induced by kava kava. J Toxicol Clin Toxicol . 2003;41(2):109-113.
46. Singh YN, Singh NN. Therapeutic potential of kava in the treatment of anxiety disorders. CNS Drugs . 2002;16(11):731-743.
47. Boonen G, Häberlein H. Influence of genuine kavapyrone enantiomers on the GABA-A binding site. Planta Med . 1998;64(6):504-506.
48. Davies L, Drew C, Duffield P, Jamieson D. Effects of kava on benzodiazepine and GABA receptor binding. Eur J Pharmacol . 1990;183(2):558.
49. Kretzschmar R, Meyer HJ, Teschendorf HJ. Strychnine antagonistic potency of pyrone compounds of the kavaroot ( Piper methysticum Forst.). Experientia . 1970;26(3):283-284.
50. Backhauss C, Krieglstein J. Extract of kava ( Piper methysticum ) and its methysticin constituents protect brain tissue against ischemic damage in rodents. Eur J Pharmacol . 1992;215(2-3):265-269.
51. Seitz U, Schüle A, Gleitz J. [3H]-Monoamine uptake inhibition properties of kava pyrones. Planta Med . 1997;63(6):548-549.
52. Magura EI, Kopanitsa MV, Gleitz J, Peters T, Krishtal OA. Kava extract ingredients, (+)-methysticin and (±)-kavain inhibit voltage-operated Na + -channels in rat CA1 hippocampal neurons [published correction appears in Neuroscience . 1998;84(1):323]. Neuroscience . 1997;81(2):345-351.
53. Friese J, Gleitz J. Kavain, dihydrokavain, and dihydromethysticin non-competitively inhibit the specific binding of [3H]-batrachotoxinin-A 20-alpha-benzoate to receptor site 2 of voltage-gated Na + channels. Planta Med . 1998;64(5):458-459.
54. Gleitz J, Gottner N, Ameri A, Peters T. Kavain inhibits non-stereospecifically veratridine-activated Na + channels. Planta Med . 1996;62(6):580-581.
55. Gleitz J, Friese J, Beile A, Ameri A, Peters T. Anticonvulsive action of (±)-kavain estimated from its properties on stimulated synaptosomes and Na + channel receptor sites. Eur J Pharmacol . 1996;315(1):89-97.
56. Seitz U, Ameri A, Pelzer H, Gleitz J, Peters T. Relaxation of evoked contractile activity of isolated guinea-pig ileum by (±)-kavain. Planta Med . 1997;63(4):303-306.
57. Boonen G, Pramanik A, Rigler R, Häberlein H. Evidence for specific interactions between kavain and human cortical neurons monitored by fluorescence correlation spectroscopy. Planta Med . 2000;66(1):7-10.
58. Holm E, Staedt U, Heep J, et al. The action profile of D,L-kavain. Cerebral sites and sleep-wakefulness-rhythm in animals [in German]. Arzneimittelforschung . 1991;41(7):673-683.
59. Rasmussen AK, Scheline RR, Solheim E, Hänsel R. Metabolism of some kava pyrones in the rat. Xenobiotica . 1979;9(1):1-16.
60. Prescott J, Jamieson D, Emdur N, Duffield P. Acute effects of kava on measures of cognitive performance, physiological function and mood. Drug Alcohol Rev . 1993;12(1):49-57.
61. Münte TF, Heinze HJ, Matzke M, Steitz J. Effects of oxazepam and an extract of kava roots ( Piper methysticum ) on event-related potentials in a word recognition task. Neuropsychobiology . 1993;27(1):46-53.
62. Heinze HJ, Munthe TF, Steitz J, Matzke M. Pharmacopsychological effects of oxazepam and kava extract in a visual search paradigm assessed with event-related potentials. Pharmacopsychiatry . 1994;27(6):224-230.
63. Saletu B, Grünberger J, Linzmayer L, Anderer P. EEG-brain mapping, psychometric and psychophysiological studies on central effects of kavain—a kava plant derivative. Human Psychopharmacol . 1989;4(3):169-190.
64. Russell PN, Bakker D, Singh NN. The effects of kava on alerting and speed of access of information from long-term memory. Bull Psychon Soc . 1987;25(4):236-237.
65. Garner LF, Klinger JD. Some visual effects caused by the beverage kava. J Ethnopharmacol . 1985;13(3):307-311.
66. Schulz V, Hübner WD, Ploch M. Clinical trials with phyto-psychopharmacological agents. Phytomedicine . 1997;4(4):379-387.
67. Lindenberg D, Pitule-Schödel H. D,L-kavain in comparison with oxazepam in anxiety disorders, a double-blind study of clinical effectiveness [in German]. Fortschr Med . 1990;108(2):49-50, 53-54.
68. Kinzler E, Krömer J, Lehmann E. Effect of a special kava extract in patients with anxiety-, tension-, and excitation states of non-psychotic genesis. Double blind study with placebos over 4 weeks [in German]. Arzneimittelforschung . 1991;41(6):584-588.
69. Volz HP, Kieser M. Kava-kava extract WS 1490 versus placebo in anxiety disorders—a randomized placebo-controlled 25-week outpatient trial. Pharmacopsychiatry . 1997;30(1):1-5.
70. Lehmann E, Kinzler E, Friedmann J. Efficacy of a special kava extract ( Piper methysticum ) in patients with states of anxiety, tension and excitedness of non-mental origin—a double-blind placebo controlled study of four weeks treatment. Phytomedicine . 1996;3(2):113-119.
71. Singh NN, Ellis CR, Singh YN. A double-blind, placebo controlled study of the effects of kava ( Kavatrol ) on daily stress and anxiety in adults. Altern Ther . 1998;4:97.
72. De Leo V, la Marca A, Morgante G, Lanzetta D, Florio P, Petraglia F. Evaluation of combining kava extract with hormone replacement therapy in the treatment of postmenopausal anxiety. Maturitas . 2001;39(2):185-188.
73. Emser W, Bartylla K. Improvement in quality of sleep: effect of kava extract WS 1490 on the sleep patterns in healthy people. TW Neurol Psychiatr . 1991;5:636-642.
74. Watkins LL, Connor KM, Davidson JR. Effect of kava extract on vagal cardiac control in generalized anxiety disorder: preliminary findings. J Psychopharmacol . 2001;15(4):283-286.
75. 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 [published correction appears in J Affect Disord . 2004;83(2-3):287]. J Affect Disorders . 2004;78(2):101-110.
76. Malsch U, Kieser M. Efficacy of kava-kava in the treatment of non-psychotic anxiety, following pretreatment with benzodiazepines. Psychopharmacology (Berl) . 2001;157(3):277-283.
77. Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Database Syst Rev . 2003;(1):CD003383.
78. 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) . 2005;84(4):197-207.
79. Connor KM, Payne V, Davidson JR. Kava in generalized anxiety disorder: three placebo-controlled trials. Int Clin Psychopharmacol . 2006;21(5):249-253.
80. Huntley AL, Ernst E. A systematic review of herbal medicinal products for the treatment of menopausal symptoms. Menopause . 2003;10(5):465-476.
81. Warnecke G. Psychosomatic dysfunctions in the female climacteric. Clinical effectiveness and tolerance of kava extract WS 1490 [in German]. Fortschr Med . 1991;109(4):119-122.
82. Warnecke G, Pfaender H, Gerster G, Gracza E. Wirksamheit von kawa-kawa-extrakt beim klimakterischen syndrom. Z Phytother . 1990;11:81-86.
83. Cagnacci A, Arangion S, Renzi A, Zanni AL, Malmusi S, Volpe A. Kava-kava administration reduces anxiety in perimenopausal women. Maturitas . 2003;44(2):103-109.
84. Furgiuele AR, Kinnard WJ, Aceto MD, Buckley JP. Central activity of aqueous extracts of Piper methysticum (kava). J Pharm Sci . 1965;54:247-252.
85. Gleitz J, Beile A, Wilkens P, Ameri A, Peters T. Antithrombotic action of the kava pyrone (+)-kavain prepared from Piper methysticum on human platelets. Planta Med . 1997;63(1):27-30.
86. Locher CP, Burch MT, Mower HF, et al. Anti-microbial activity and anti-complement activity of extracts obtained from selected Hawaiian medicinal plants. J Ethnopharmacol . 1995;49(1):23-32.
87. Blumenthal M, Busse WR, Goldber A, et al, eds. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines . Austin, TX: American Botanical Council; Integrative Medicine Communications; 1998:156-157.
88. Steiner GG. The correlation between cancer incidence and kava consumption. Hawaii Med J . 2000;59(11):420-422.
89. Jorm AF, Christensen H, Griffiths KM, Parslow RA, Rodgers B, Blewitt KA. Effectiveness of complementary and self-help treatments for anxiety disorders. Med J Aust . 2004;181(suppl 7):S29-S46.
90. Mathews JM, Etheridge AS, Black SR. Inhibition of human cytochrome P450 activities by kava extract and kavalactones. Drug Metab Dispos . 2002;30(11):1153-1157.
91. 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(5):415-426.
92. 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 . 2008;83(1):61-69.
93. Almeida JC, Grimsley EW. Coma from the health food store: interaction between kava and alprazolam. Ann Intern Med . 1996;125(11):940-941.
94. Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med . 1998;158(20):2200-2211.
95. 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(2):147-155.
96. Bressler G. Herb-drug interactions: interactions between kava and prescription medications. Geriatrics . 2005;60(9):24-25.
97. Anke J, Ramzan I. Pharmacokinetic and pharmacodynamic drug interactions with kava ( Piper methysticum Forst.f.). J Ethnopharmacol . 2004;93(2-3):153-160.
98. 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 . 2007;35(2):240-245.
99. Cairney S, Maruff P, Clough AR, Collie A, Currie J, Currie BJ. Saccade and cognitive impairment associated with kava intoxication. Humn Psychopharmacol . 2003;18(7):525-533.
100. Ruze P. Kava-induced dermopathy: a niacin deficiency? Lancet . 1990;335(8703):1442-1445.
101. 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(11):548-555.
102. Leung N. Acute urinary retention secondary to kava ingestion. Emerg Med Australas . 2004;16(1):94.
103. Ernst E. Safety concerns about kava. Lancet . 2002;359(9320):1865.
104. Campo JV, McNabb J, Perel JM, Mazariegos GV, Hasegawa SL, Reyes J. Kava-induced fulminant hepatic failure. J Am Acad Child Adolesc Psychiatry . 2002;41(6):631-632.
105. Wooltorton E. Herbal kava: reports of liver toxicity. CMAJ . 2002;166(6):777.
106. Consumer advisory: kava-containing dietary supplements may be associated with severe liver injury. U.S. Food and Drug Administration. Center for Food Safety and Applied Nutrition. http://www.cfsan.fda.gov/~dms/addskava.html . Published March 25, 2002. Accessed April 30, 2009.
107. 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(1):36-37.
108. Stickel F, Baumüller HM, Seitz K, et al. Hepatitis induced by kava ( Piper methysticum rhizoma). J Hepatol . 2003;39(1):62-67.
109. Clough AR, Jacups SP, Wang Z, et al. Health effects of kava use in an eastern Arnhem Land Aboriginal community. Intern Med J . 2003;33(8):336-340.
110. 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) . 2007;45(5):549-556.
111. Clough AR, Bailie RS, Currie B. Liver function test abnormalities in users of aqueous kava extracts. J Toxicol Clin Toxicol . 2003;41(6):821-829.
112. Stevinson C, Huntley A, Ernst E. A systematic review of the safety of kava extract in the treatment of anxiety. Drug Saf . 2002;25(4):251-261.
113. Connor KM, Davidson JR, Churchill LE. Adverse-effect profile of kava. CNS Spectr . 2001;6(10):848, 850-853.
114. Nerurkar PV, Dragull K, Tang CS. In vitro toxicity of kava alkaloid, pipermethystine, in HepG2 cells compared to kavalactones. Toxicol Sci . 2004;79(1):106-111.
115. Anke J, Ramzan I. Kava hepatotoxicity: are we any closer to the truth? Planta Med . 2004;70(3):193-196.
116. Society for Medicinal Plant Research. Relevant hepatotoxic effects of kava still need to be proven. A statement of the Society for Medicinal Plant Research. Planta Med . 2003;69(11):971-972.
117. Perez J, Holmes JF. Altered mental status and ataxia secondary to acute kava ingestion. J Emerg Med . 2005;28(1):49-51.
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