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Risk of Kava Hepatotoxicity and the FDA Consumer Advisory
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Rolf Teschke, MD Johannes Schulze, MD
JAMA, November 17, 2010—Vol 304, No. 19 (Reprinted)
In early 2002, The US Food And Drug Administration (FDA) began advising consumers of the potential risk of severe liver injury associated with the use of kava-containing dietary supplements.1
Kava (Piper methysticum) is a plant indigenous to the South Pacific Islands, where it is commonly used to prepare a traditional beverage for social and recreational purposes.2,3
Dietary supplements containing the herbal ingredient kava are promoted for relaxation to relieve stress, anxiety, and tension, as well as for sleeplessness and menopausal symptoms. Kava-containing products have been associated with rare liver injuries in Western countries, and the FDA urged consumers and health care professionals to report any case of liver injury that may be related to the use of kava-containing dietary supplements.1
The FDA also announced its intention to further investigate the relationship, if any, between the use of dietary supplements containing kava and liver injury, which included attempting to determine a biological explanation for the relationship and to identify the different sources of kava in the United States and Europe.
Subsequent analyses by the World Health Organization have shown that the use of kava was associated with the development of liver disease in rare cases,3 confirmed by structured, quantitative, and liver-specific causality assessment methods.4
There is now sound evidence that liver injury was caused by both the traditional water-based kava extracts of the South Pacific and the medicinal solvent-based kava extracts of Western countries,3,5
with flavokavain B as one of the possible culprits.3,6
It remained unclear, however, to what extent the use of ethanol or acetone as solvents might have increased the hepatotoxic risks in patients who consumed medicinal kava extracts.
Further assessments of the pathogenetic factors of kava hepatotoxicity revealed the use of inappropriate kava varieties and plant parts.5
Previously, the existence of more than 200 kava varieties, also called cultivars, had not been considered from the aspects of safety concerns and pharmacovigilance issues. Consequently, in Western countries as well as in the South Pacific region, there has been no regulatory definition advising which of the various kava cultivars should preferentially be used for kava beverages, drugs, and dietary supplements. Specific issues also emerged regarding the peeled kava rhizome that should have been used, but evidence suggests also the use of the kava plant’s aerial parts, which may contain the hepatotoxic alkaloid pipermethysticin.5
Considering the poor quality of kava raw material used for this small number of kava products,2-5
liver injury by kava is basically a preventable disease.
Legal steps to improve safety of kava products had already been initiated at about the same time as the FDA consumer advisory was issued. The Vanuatu Kava Act No. 7 of 2002 describes some protection rules of kava for export, which include kava drugs and kava dietary supplements.7
The Vanuatu legislation differentiates 4 groups of kava cultivars with the noble cultivars as the only group with the option for export. The legislation explicitly excludes other groups of kava cultivars, such as medicinal cultivars and 2-day cultivars, which have previously been used for kava drugs. Excluded from export are plant parts such as stumps, shoots, growing buds, and lateral branches. Kava or kava products may only be exported when each of the following is clearly marked: name of the variety, island of origin, distinct organs of the kava, and the words “Original Vanuatu Kava.” Kava quality requirements for export purposes include a minimum maturation time for the kava plant at harvest of 5 years. It appears that legislation-enforced quality standards for kava products are a first step for increasing their safety in human use.
The group of exportable kava varieties consists of 28 noble kava cultivars, but the Vanuatu legislation provides no preference for one single cultivar.7
In Vanuatu, the major kava producer and exporter, the traditional kava beverage is prepared by cold water extraction of its roots.8
Historic use shows that kava is safe under the strict control of the rituals of Pacific cultures. The traditional beverage is consumed on a daily basis without apparent adverse effects, and kava cultivars considered as noble ones have a long tradition of safe use. Based on local expertise in Vanuatu, one of the preferred noble cultivars is Borogu, with its high amounts of the kavalactones kavain and dihydrokavain as major psychoactive constituents, also known for its rapid effects. For quality control, quantitative assessments are essential regarding kavalactones,2,3,8
pipermethystine,3
flavokavain B, and aflatoxins.6
In line with the Vanuatu Kava Act restricting the use to a noble cultivar,7
and according to recommendations outlined in the Kava World Health Organization report on the use of water-based kava extracts,3
a 3-week randomized, placebo- controlled crossover study with aqueous kava extracts derived from roots of noble kava cultivars was performed in Australian patients with general anxiety.9
The patients were treated with 250 mg of kavalactones per day and safety and efficacy were evaluated. Lack of adverse effects including liver injury was described in this trial, showing effective therapy for patients with anxiety after 1 week, as assessed with the Hamilton Anxiety Rating Scale.4
Overall, therefore, compelling evidence suggests short-term safety and efficacy of kava as an anxiolytic herbal drug. However, additional trials are necessary to evaluate long-term effects and the lowest effective daily dose, using water-based extracts derived from the peeled rhizome and roots of a noble kava cultivar such as Borogu.
Kava products have been banned from the markets of some countries including various European ones, but they are still available in the United States, Canada, Australia, New Zealand, and South Pacific Islands.3,9
Moreover, Internet sales of kava products have gained increasing popularity, although these products are illegal in countries with a regulatory ban. Despite the established potency of a few kava products to cause potentially life-threatening liver injury with requirements for a liver transplant,3,5
and in view of the presumed pathogenetic factors,5,6
the security road beginning with the kava farmer and ending with the consumer is incomplete and not straightforward. There is some kava legislation in Vanuatu to regulate the cultivation, sale, and export of kava and kava products, but other kava-exporting countries in the South Pacific Islands lack any kava legislation. In Australia, there is regulatory limitation regarding the maximum of 250 mg of kavalactones per day derived from water-based kava extracts,9,10
with a limit per dosage of 125 mg kavalactones for any individual tablet or capsule. 10
In this context, the limitation of 250 mg of kavalactones per day, issued many years ago by the Australian Therapeutic Goods Administration (TGA)10
is much lower than the amounts reaching 2571 mg of kavalactones daily consumed with traditional aqueous kava beverages.3
At least for the past 5 years, it appears that the TGA has no negative experience in Australia with kava use limited to 250 mg kavalactones per day.
It is obvious that the consumer advisory issued by the FDA in 2002 should receive an update that takes into account all new aspects worth consideration for safe human use.1
In particular, the kava product should be awater-based kava extract derived from peeled rhizomes and roots of a noble cultivar such as Borogu, of at least 5 years of age, and taken with a daily dose not exceeding 250 mg of kavalactones. This proposal is in line with the FDA’s announcement that it will alert consumers, and if warranted, take additional action as more information becomes available.
In essence, since the mechanisms of liver injury caused by the use of kava products have recently been elucidated, additional information should be provided by the FDA Consumer Advisory to improve consumer safety.
Author Affiliations: Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Johann Wolfgang Goethe-University Frankfurt/Main, Hanau, Germany (Dr Teschke); and Office of the Dean, Faculty of Medicine, Johann Wolfgang Goethe-University of Frankfurt/Main, Germany (Dr Schulze). Corresponding Author: Rolf Teschke, MD, Department of Internal Medicine II, Klinikum Hanau, Teaching Hospital of the Johann Wolfgang Goethe-University of Frankfurt/Main, Leimenstrasse 20, D-63450 Hanau, Germany (rolf.teschke @gmx.de).
Financial Disclosures:
Dr Schulze reports working as a paid consultant for Steigerwald, Darmstadt. Dr Teschke also reports receiving an honorarium from Krewel Meuselbach [Eitorf, Germany] for analyzing kava cases. He also served as an unpaid consultant to BfArM, the German regulatory agency.
©2010 American Medical Association.
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