| Kava-Kava
This herb may effectively treat anxiety disorders, but concomitant use with prescription medicines must be monitored. |
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| Piper methysticum, a large shrub indigenous to the Polynesian area of Oceania, belongs to the black pepper family, Piperaceae, and is commonly known as kava. Over 20 varieties of the kava plant have been recognized. They are perennial shrubs, 1.5 to 3 meters tall, with pale yellow-green, heart-shaped leaves and very short axillary spikes of flowers. Kava carries the folk name “intoxicating pepper” because the root of the plant, when chewed and mixed with saliva, gives a hot, intoxicating juice. It was first described as such by botanist Georg Forster during the voyages of explorer Captain James Cook.
The traditional Hawaiian physician, or Kahuna la’au lapa’au, prescribes many plant products, including kava.1 Common uses include treatments for asthma, rheumatism, gonorrhea, inflammations of the urinary tract and as a sedative. Kava has also long been used in ceremonial rites in Hawaii and Polynesia. In magical ceremonies, kava root is infused and the resulting tea drunk to offer protection against evil and to invite good luck. After being infused and left to steep overnight, the tea is drunk to enhance psychic powers and to induce visions.2 In many areas of the Pacific, kava ceremonies are still important cultural events. In addition, kava has come into popularity within social circles, where it is used in much the same way as cocktails are used in Western society. Like alcohol, kava has been used for social relaxation and euphoric intoxication.3 Today many of the traditional uses of kava, as with many other herbs, are being validated scientifically. Kava contains a number of pharmacologically active constituents that have CNS effects (primarily anxiolytic and sedative activity). With moderate usage, kava has a low adverse effect profile, which helps explain its recent increased popularity in the United States. Chemical Composition and Pharmacological Action Several aromatically substituted delta-lactons (also called alpha-pyrones) characteristic of the kava plant have been isolated from the root-stock of Piper methysticum. Their anticonvulsive, analgesic, sedative and central muscle-relaxing actions (including antagonism to the lethal effect of strychnine) have been confirmed by several laboratories.4-6 Extracts of kava root include various concentrations of such alpha-pyrones as yangonin, desmethoxyyangonin methysticin, kawain and 5,6-dihydro-alpha-pyrones—dihydromethysticin and dihydrokawain—as major constituents. For these pyrones a number of additional pharmacological effects have been described, including potentiation of barbiturates and local anesthetic and antiarrhythmic properties.7 The original assumption that kava-pyrones would activate opioid or dopamine receptors has been excluded. In vitro studies indicate that kawain acts to inhibit voltage-gated (a channel that opens or closes depending on the voltage across the membrane) Ca2+ and Na+ channels.8,9 The sedative effect of kava-pyrones might be mediated by binding to the GABA-A receptor, as suggested by Jussofie and colleagues.10 A recent paper by Gleiz and coworkers further expands the list of pharmacological actions of kava-pyrones: inhibitory actions on cyclooxygenase (COX) activity, causing antithrombotic action.11 Clinical Studies Animal Studies: An in vitro study of kava-pyrones on guinea pig hippocampal slices showed an analgesic effect. Researchers measured potential changes on voltage-gated calcium channels and found that kawain and dihydromethysticin reduced the field potential in a concentration-dependent manner (in the range of 5–40 umol/L).12 Methysticin’s effect was also tested on different in vitro seizure models using rat brain slices. Seizure-like events induced by elevated K+ or low Ca2+ and Mg2+ were reversibly blocked in a concentration range of 10–100 uM. These findings suggest that kava-pyrones could block different forms of epileptic activity.13 Kava extracts and constituents were also tested on focal cerebral ischemia induced in rats and mice. The effects were compared to a typical anticonvulsant, memantine. Kava extracts (150 mg/kg) methysticin and dihydromethysticin (10 and 30 mg/kg), administered at least 30 minutes before ischemia, significantly reduced the infarct area and volume (p < 0.05) in both mouse and rat brains.14 Human Clinical Studies: A recent study involved WS 1490, a special standardized kava extract (70% kava-pyrone), in a 25-week, randomized, multicenter, placebo-controlled, double-blind trial in 101 outpatients with anxiety disorders.15 Inclusion criteria utilized DSM-III-R definitions of anxiety of nonpsychotic origin: agoraphobia, specific phobia, generalized anxiety disorder, and adjustment disorder with anxiety. In the main outcome criterion (the Hamilton Anxiety Scale [HAMA]), WS 1490 showed significant superiority over placebo after 8 weeks of use (p < 0.02). A baseline HAMA was established for each patient and repeated every 4 weeks. Patients were then rated as “very much improved,” “much improved,” “slightly improved,” “no change” or “slightly worse.” After 12 weeks of treatment, the psychopathological states of 69.2% of WS 1490-treated patients were rated as “very much improved” or “much improved,” compared to 37.2% who improved in the placebo group (p = 0.001). In the WS 1490 group, 75.5% of patients showed at least “much improvement,” versus 51.2% in the placebo group (p = 0.015) after 24 weeks of use. This trial demonstrated that short- as well as long-term efficacy of WS 1490 was superior to that of placebo. In addition, the kava compound was well tolerated. Though comparative trials are warranted, this study supports consideration of kava as a treatment alternative to tricyclic antidepressants and benzodiazepines in anxiety disorders. Patients should not use kava without first obtaining medical advice, and doses should not exceed 300 mg/day. Adverse Effects and Allergic Reactions Among heavy users of kava (300 g/week or more), poor health, a puffy face, and a typical scaly rash is more likely to be observed than among lighter users.16 Several clinical parameters of the blood, such as albumin, plasma protein, bilirubin and urea, have been found to be lower than normal in heavy users. In the case of extreme use (well over 300 g/week, but exact level of consumption is unknown), gamma-glutamyl transferase was increased, and 20% of patients were underweight. (The underweight may be associated with poor diet.) Heavy use of kava also resulted in an increase in red blood cell volume and elevated total and HDL (high-density lipoprotein) cholesterol levels.16 Low consumption of kava beverage can result in pupil dilation.17 In one clinical trial using WS 1490, the occurrence of adverse effects was rare. Only two reports (stomach upset in both cases) were rated as “possibly related.”15 The most commonly reported adverse effect of kava usage is kava dermopathy—a yellow, scaly, leprosy-like eruption of the skin and inflammation of the eyes. The pathogenesis of kava dermopathy is unknown, but the condition occurs only with heavy usage (chronic, high doses), as evidenced by observations in the Tongan islands.17 Kava dermopathy rapidly reverses with cessation of consumption. One in vitro study with kawain showed a dose-dependent suppression of platelet aggregation, which may be due to COX-inhibition, although the clinical significance of this finding remains to be determined.11 These collective data would indicate that kava, when used appropriately, is relatively well-tolerated.
Interactions Based on kava’s pharmacology and possible effects on liver function (when used in extreme doses), pharmacists may want to recommend that patients avoid concomitant use with alcohol. In one case, a 54-year old male who was taking kava and a benzodiazepine experienced lethargy and disorientation, possibly due to an interaction between the two agents.18 Until the clinical significance of kava’s antithrombotic action is determined, the use of the preparation with anticoagulant medications should be cautioned. Kava-pyrones found in many extracts of kava are inactivated by heat; therefore, preparations should utilize cold to tepid water. Conclusion Animal studies of kava-pyrones show tranquilizing, anxiety-reducing and muscle-relaxing effects. Many of these studies suggest that the action of kava-pyrones overlaps with that of benzodiazepines, which may be explained by an interaction with GABA-A receptors. The German clinical study15 on patients with anxiety disorders showed benefit of kava treatment with no obvious side effects. However, when kava beverage is used excessively for ritual or other social reasons, detrimental health effects are observed. Therefore, caution should be exercised when using kava preparations. Because there is limited clinical information available regarding kava, careful consideration and follow-up are vital when the preparation is administered. The concomitant use of kava with prescription medications should be closely monitored. |
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References 1. Hope BE, Massey DG, Fournier-Massey G. Hawaiian materia medica for asthma. Hawaiian Med J. 1993;52(6):160-6. 2. Cunningham S. Cunningham’s encyclopedia of magical herbs. 1st ed. St. Paul: Llewellyn; 1992. 3. Singh YN. Kava: an overview. J Ethnopharm. 1992:37:13-45. 4. Meyer HJ, Krettzschmar R. Kava-pyrone-eine neuartige substanzgruppe zentralermuskelrelaxiantien vom vom typ des mephenesins. Klin Wschr. 1966;44:902-903. 5. Keledijan J, Duffield PH, et al. Uptake into mouse brain of four compounds present in psychoactive beverage kava. J Pharm Sci. 1988;77:1003-1006. 6. Gleitz J, Beile A, Peters T. (+/–) Kavain inhibits veratridine-activated voltage-dependent Na+-channels in synaptosomes prepared from rat cerebral cortex. Neuropharmacology. 1995;1133-1138. 7. Meyer HJ. Pharmacology of kava. In: Efron DH, Holmstedt B and Kline NS (Eds.) Etnopharmacologic Search for Psychoactive Drugs. Raven Press; New York, pp 133-140. 8. Gleitz J, Friese J, et al. Anticonvulsive action of (+/–)-kavain estimated from its properties on stimulated synaptosomes and Na+ channel receptor sites. Eur J Pharmacol. 1996;315:89-97. 9. Langosh JM, Normann C, et al. The influence of (+/–) kavain on population spikes and long-term potentiation in guinea pig hippocampal slices. Comp. Biochem Physiol A Mol Integr Physiol 1998;120(3):545-549. 10. Jussofie A, Schmiz A, et al. Kava-pyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain. Psychopharmacology. 1994;116:469-474. 11. Gleitz J, Beile A, Wilkens P, et al. Antithrombotic action of kava pyrone (+)-kavain prepared from Piper methysticum on human platelets. Planta Medica. 1997;63:27-30. 12. Walden J, Wegere J, et al. Effects of kawain and dihydromethysticin on field potential changes in the hippocampus. Prog Neuro-Psychopharmacol & Bio Psychiat. 1997;21:697-706. 13. Schmitz D, Zhang CL, et al. Effects of methysticin on three different models of seizure-like events studied in rat hippocampal and entorhinal cortex slices. Naunyn-Schmiederberg’s Arch Pharmacol. 1995;351:348-355. 14. Backhauss C, Krieglstein J. Extract of kava (Piper methysticum) and its methisticin constituents protect brain tissue against ischemic damage in rodents. Eur J Pharmacol. 1992;215:265-269. 15. Voltz HP, Kieser M. Kava-kava extract WS 1490 versus placebo in anxiety disorders—a randomized placebo-controlled 25-week outpatient trial. Pharmacopsychia. 1997;30:1-5. 16. Mathews JD, Riley MD, 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):548-55. 17. Norton SA, Ruze P. Kava dermopathy. J American Academy Dermatology. 1994;31(1):89-97. 18. Almeida JC, Grimsley EW. Coma from the health food store: interaction between kava and alprazolam. Ann Intern Med. 1996;125(11):940-1. |
