Kava: Piper methysticum

By Roberta Lee, MD, Dr. Lee is Medical Director of the Center for Health and Healing, Director of Continuing Medical Education, and Co-Director of the Fellowship in Integrative Medicine at Beth Israel's Continuum Center for Health and Healing; she reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.

Kava is a member of the pepper family (piperacea) that has been central to Pacific Island cultures as far back as 2,000 years.1 J.G. Forester, a botanist accompanying Captain Cook on his voyages through the Pacific, is credited as being the first scientist to describe kava. After sampling it, he described kava as tasting mildly peppery and thus assigned the kava plant its Latin name Piper methysticum, which is loosely translated to mean intoxicating pepper.

The exact geographic origin of this plant remains unclear and two hypotheses exist: The first suggests that kava is a plant derived from the Southeast Asia and New Guinea area.2 The second hypothesis suggests that Vanuatu1 served as the original central region from which kava spread to the Melanesian and Pacific Island areas. In 1886, Lewin, a German pharmacologist studying psychoactive plants, characterized kava as a hypnotic based on its pharmacologic effects.3

Ethnobotanical and anthropological texts have documented many different and elaborate ceremonies for kava's use among the numerous Pacific Islands where it has been cultivated. Perhaps the most intriguing ethnobotanical facts surrounding its use is the means by which it has been served in the Pacific. Two methods have been described: The first method, which was widely practiced in Tonga and Samoa, is identified as the "Tongan method" and involves young men or women masticating the root before soaking it in water, followed by decanting (gentle pouring without disturbing the sediment) and serving to others—this method is no longer in active use due to public health issues.4 The second method, often referred to as the "Fiji method," involves mechanical pounding and pulverizing of the root with subsequent dilution with water.4 The second method is widely in use on many islands today.

Traditional medical uses for this plant were extensive and included treatment of: inflammation of the urogenital system, gonorrhea, menstrual problems, migraine headaches, chills, vaginal prolapse, rheumatism, dermatological conditions, and nervousness.1 In the last 150 years, numerous scientific publications on the chemical and pharmacologic activity of kava have given us greater clarity and insight into this plant's pharmacologic value.

During the last 20 years kava gained enormous popularity as an herbal treatment for anxiety, nervousness, insomnia, stress, benzodiazepine withdrawal, and menopausal anxiety. In 1998, kava ranked fifth in the North American botanical sales market.5 However, its use and sales rapidly declined beginning in the fall of 2001 after increasing reports of hepatotoxicity surfaced in association with its use. By the end of 2001, public health authorities in Germany initiated a new evaluation of the benefit-risk ratio of kava. This led to a withdrawal of the drug authorization for kava products by the German health authorities. Many other public health authorities in Europe including Switzerland and other countries around the world followed Germany's example.6 Today, strict warnings exist in countries where sales of kava are permitted, dampening the public and professional use of this botanical product.

Description

P. methysticum is a slow-growing perennial. When cultivated, the plant is harvested when it reaches 2-3 years of age or 2-2.5 meters in height. Kava is cultivated for its rootstock or stump. The stump is a thick tuberous and knotty mass with a fringe of lateral roots. Kavalactones, the active constituents that are responsible for the psychoactive characteristics of this plant, are concentrated in the lateral roots. Propagation has occurred primarily by human cultivation.

The roots are dried or freshly pounded to make a ceremonial beverage, or dried and pulverized to make standardized liquid or solid extracts, alcohol-based tinctures, teas, and salves. Preparations vary in kavalactone content depending on the source of kava. There exist 118 cultivar morphotypes (varieties of plants) which are called P. methysticum, and each morphotype has subtle variations in the percentages of kavalactones present in the rootstock.

The method of kavalactone extraction also determines the kavalactone content, as these constituents are known to be lipophilic. In 2001, lesser-quality products were noted to include the use of the stem peelings as well as the rootstock, diluting the concentration of active constituents and possibly contributing unwanted toxic compounds.7 Standardized preparations are generally extracted to not less than 30% kavalactones in powdered dried extracts or not less than 50% kavalactones in semi-solid (paste) extracts.8

Pharmacology

As noted, kava's psychoactive activity is attributed to a group of compounds known as kavalactones (also known as kavapyrones). These compounds consist of 13 carbon atoms, six of which form a benzene ring attached by a double bond to an unsaturated lactone. There are 18 kavalactones identified in the rhizome, but six major kavalactones are credited for the majority of pharmacologic activity: methysticin, dihydromethysticin, kavain, 5,6-dehydrokavain, 5-6,dehydromethysticin, and yangonin. These constituents are highly concentrated in the roots (15%) and decrease to 5% in the basal stems. A small amount of alkaloids were identified in the rootstock in earlier studies but have not been found to be part of the resinous rootstock responsible for kava's psychoactive properties.9

Although kavalactones such as kavain and methysticin can be synthesized, early studies evaluating the psychoactive effects using these singular compounds reveal that they are less effective physiologically than the natural raw extracts. Thus, it seems that the kavalactones as a group have synergistic pharmacologic activity.10 Other constituents identified in the rhizome include chalcones (flavokavains A, B, and C), a phytosterol, amino acids, and minerals including potassium, calcium, magnesium, sodium, aluminum, and iron.8

Kava's reported neuropharmacologic effects include analgesia, anesthesia, sedation, and hyporeflexia.2 In animal trials, kava has shown anticonvulsive, antispasmodic, and central muscular relaxant effects. Antimycotic properties have also been reported.11 Recently, in vitro studies reported antithrombotic and COX-2 inhibitory activity as well.12

The mechanism of action on the central nervous system (CNS) is not entirely clear. Kava acts on several areas in the CNS. Differing results have been reported across in vitro and in vivo studies, and it remains uncertain whether kava binds at GABA receptors.8,13-17 A possible nor-adrenaline uptake effect was also reported for three kavalactones.18 Activation of mesolimbic dopaminergic neurons resulting in relaxation and slight euphoria has also been reported in an animal trial.19 Additional CNS actions have been reported including interaction with glutamate receptors,20 reduction in monoamine receptors and reduced transmitter release.21

In some studies, kava has been shown to relax skeletal muscle through direct action on the muscle fiber without inducing central nervous depression.22 Kavain applied topically or injected subcutaneously was found to induce local anesthesia, but higher doses caused paralysis of the peripheral nerves.23

Kava at therapeutic doses does not appear to have sedative effects, a potential advantage of this botanical alternative. However, no large trials have examined this aspect of kava. Previous trials have been small and criticized for flaws in methodology.24

Pharmacokinetics

After oral administration, intestinal absorption is extremely rapid (10 minutes) for kavain and dihydrokavain.1 In contrast, methysticin and its dihydro-derivatives are more slowly absorbed (45 minutes).25 When 40 mg/kg of dihydrokavain was given orally, half of it was found in the urine within 48 hours in the form of hydroxylated derivatives.26 Quantitative uptake of four kavalactones in mice brains indicate that kavain and dihydrokavain attain maximal brain concentration within five minutes, whereas desmethoxy-yangonin and yangonin entered the brain more slowly.27 It is generally agreed that kavain and dihydrokavain are the two kavalactones that pass the blood-brain barrier most easily. Peak levels occur (for kavain) at 1.8 hours with an elimination half-life of approximately 9 hours and distribution half-life of 50 minutes.28 In test animals, the LD50 (lethal dose required to kill 50% of subjects) of kavalactones is believed to be approximately 300-400 mg/kg.29

Review of the Evidence

Anxiety

Kava has been evaluated in 14 randomized clinical trials for anxiety with the duration of treatment ranging from four to 25 weeks. A meta-analysis of randomized trials initially published in 2000 and updated in the Cochrane Database 200230 and 200331 concluded that kava had moderate efficacy in the treatment of anxiety. In the meta-analysis, although 14 clinical trials were identified, seven trials were excluded due to a variety of factors including duplicate reporting, concurrent benzodiazepine use, or use of an isolated kavalactone. The remaining seven clinical trials were evaluated and three were selected for analysis involving a total of 198 patients. Pooled data from the three studies that used a common outcome measure, the Hamilton Anxiety Rating Scale (HAM-A), found a significant reduction in mean anxiety score in the kava group as compared to placebo, with a mean difference of 9.69 points (95% confidence interval).30 In the 2003 updated meta-analysis, 11 trials representing a total of 645 participants were eligible for inclusion.31 Six studies using the HAM- A rating scale as a common outcome measure showed that kava was effective for the treatment of anxiety and "relatively safe for short term treatment (1-24 weeks)."31

Menopausal/Perimenopausal Anxiety

Three randomized, placebo-controlled clinical trials examined kava for perimenopausal and menopausal anxiety using kava in a dose of 100 mg/d with hormone replacement therapy,32 or kava at 100 mg/d or 200 mg/d and combined with calcium.33,34 All three trials used the HAM-A or State Trait Anxiety Inventory as an outcome instrument to assess anxiety. In each trial, reduction of anxiety was more pronounced in the kava treatment arms than in the placebo arms.

Equivalence Trials

Several clinical trials comparing kava to benzodiazepines have been performed.35-37 In each of the trials no significant difference was found on anxiety measures. However, the trials lacked placebo arms and the sample sizes of the earlier trials were possibly too small to measure equivalence. In the largest randomized, controlled multicenter trial, 129 outpatients were given either 400 mg of LI 150 (kava), 10 mg of buspirone, or 100 mg of opipramol daily for eight weeks. Subjects were evaluated for anxiety (using HAM-A), sleep quality, quality of life, and well-being. Approximately 70% were classified as responders with a reduction of 50% on the HAM-A scale, with 60% achieving full remission.37 The authors deemed kava a well-tolerated treatment that was as effective as the pharmaceutical agents employed.

In a small (n = 40) randomized placebo-controlled trial, patients with anxiety on benzodiazepines were given increasing amounts of kava (WS 1490) up to 300 mg a day as the benzodiazepines were tapered. The dose adjustments were followed by three weeks of monotherapy with kava or placebo. Patients were monitored for benzodiazepine withdrawal, subjective well-being, and anxiety. Results confirmed the anxiolytic efficacy of kava.38

Unresolved Safety Issues

In recommended doses over short periods of time kava has been regarded as safe. However, since 2001, potential hepatotoxicity of kava has become a concern as more than 30 cases of liver damage in association with its use have been reported in Europe. In several cases, liver transplants were required due to the extent of hepatic damage. An independent assessment of the adverse effects in these cases was undertaken by a noted expert in the field of hepatotoxicology, Donald Waller, PhD, from the University of Illinois at Chicago. He concluded that "there are only a few of these cases in which kava might be directly associated with liver damage. Each of the cases appears to have been hypersensitivity or idiosyncratic based responses."39

As of this writing, the FDA has issued a warning to consumers, and a number of countries have removed kava from public access.6 It remains unclear what dose or what duration of use is correlated with hepatic damage. Equally unclear are the mechanisms responsible for the hepatic damage. Potential causes include the method of extraction of kava causing an increased proportion of one or more kavalactone constituents that predispose some individuals to liver damage, or contamination by alkaloids.

One hypothesis involves the presence of pyridine alkaloids in the form of the alkaloid pipermethystine known to be cytotoxic and present in the stem of kava. Dragull et al suggested that stems rather than lateral roots, the usual source of kava, may have been added as a "contaminant" to supplements but unrecognized by dietary supplement companies as such until patients emerged with liver abnormalities.7

Another hypothesis accounting for the presence of kava hepatotoxicity proposes that there is a group of patients with a polymorphism that creates a cytochrome P450 2D6 deficiency that makes them poor metabolizers of kavalactone metabolites.40 In Europe, there exists a 10% prevalence of the cytochrome P450 2D6 deficiency; however, this phenomenon has not been detected in Pacific Islanders who have used kava ceremonially for hundreds of years. Thus, those with this deficiency taking supplements are hypothesized to develop elevated liver enzymes because they are unable to detoxify intermediary metabolites damaging to the liver.12 In the Pacific Islands, kava is served as a water-extracted preparation, whereas extraction associated with kava supplements employs acetone and alcohol as solvents. Experts believe that the use of acetone and alcohol as an extractant may draw out different kava constituents and/or proportions of kavalactones, making those at risk for hepatotoxicity more vulnerable.41,42

It is estimated that approximately 250 million daily doses of ethanolic kava extract have been ingested in the previous decade with only two causal, firmly related cases of hepatotoxicity. These cases used kava at doses far beyond the recommended levels. Based on these two cases, the Adverse Events Reports (AERs) rate was 0.008 AERs for kava in a million daily doses. Benzodiazepines in contrast have a much higher AERs rate per million daily doses: 0.90 AERs for bromazepam, 1.23 for oxazepam, and 2.12 for diazepam. The authors concluded that changing patients from using kava to a benzodiazepine could potentially increase the risk of adverse effects.43

Guidelines for Use44

Kava should be used primarily for anxiety, and may be considered potentially therapeutic for people with sleep disorders related to anxiety. The American Botanical Council suggested in December 2001 that kava not be taken longer than one month without professional supervision.8 Thus, botanical preparation should be avoided in patients with: known liver disease, chronic use of alcohol, Parkinson's disease, or use in patients who are taking benzodiazepines or other sedative medications. Patients who are pregnant or lactating should not be given this botanical product.

Typical daily dosage for adults using a standardized preparation of 30% kavalactones is a dosage equivalent of 60-120 mg of kavalactones or total dose of 70-210 mg of kava. Most controlled clinical trials are based on three 100 mg doses of a dried extract standardized to 70 mg of kavalactones or 210 mg of kavalactones/d. The onset of response appears to be 2-4 weeks, comparable to prescription anxiolytic medications.8

There is great concern regarding hepatotoxicity, as discussed earlier. In contrast to therapeutic use, heavy chronic use of kava has been associated with renal dysfunction, hematologic abnormalities, pulmonary hypertension, dermopathy, and choreathetosis. These conditions have been cited in case reports and the causal relationship with kava is unclear due to multiple confounding variables and/or incomplete reporting.

Side Effects

A dermatological condition known as kava dermopathy, may appear during prolonged and heavy use. This condition is reversible upon discontinuation.45

Several cases of extrapyramidal side effects46 and the exacerbation of Parkinsonian symptoms47 have been reported after use for 1-4 days. Sedation has been reported anecdotally, although small human studies suggest that kava does not cause neurological-psychological impairment. Apathy has been noted with long-term use.8

Pulmonary hypertension was proposed as a mechanism for shortness of breath in one study where heavy Aboriginal users complained of breathing difficulty (69%) vs. non users (25%).8 Antiplatelet activity was reported with kavain, a single kavalactone. Blood dyscrasias have been reported with heavy intake in Aboriginal kava users.48

Hepatotoxicity has been a concern and was discussed earlier. Gastrointestinal upset has been reported as an infrequent adverse effect in some studies.8

Drug Interactions

Animal studies have reported increases in sedative effects. Kava has been shown in case reports to prolong the sedative action of anesthesia. Kava has been found to potentiate some CNS depressants and to antagonize the effect of dopamine and elicit extrapyramidal effects. Constituents of kava have been shown to have weak MAO inhibitory activity in vitro.

Kavain, an isolated kavalactone, has been reported to have antiplatelet activity.

Preliminary studies indicate that kava may inhibit multiple cytochrome P450 substrates (1A2, 2C9, 2C19, 2D6, 3A4).

Conclusion

Until the last decade, kava has been used safely by Pacific Islanders as a ceremonial and social beverage, serving as a plant of great significance both culturally and medicinally. In the West, we have found kava to be a useful alternative in the management of anxiety, insomnia, and muscle tension. Furthermore, it should be acknowledged that detailed analysis of reports of kava use and hepatotoxicity has found the complication to be infrequent despite widespread use either as a dietary supplement or traditionally prepared beverage. Nonetheless, reports of hepatotoxicity involving kava supplements warrant caution in recommending its use.

Recommendation

Those using kava as an alternative treatment for mild anxiety or perimenopause-related anxiety should do so with caution. The dose should be not more than a dose equivalent to 60-120 mg/d of kavalactones. It should not be taken on a daily basis for more than a month without medical advice and monitoring of hepatic function. Patients should be advised of the potential for synergistic sedative activity if combined with agents such as benzodiazepines. Patients should also be warned that use of kava can adversely affect motor coordination when driving or operating heavy machinery.

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