Risk of kava hepatotoxicity and the FDA consumer advisory.

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. 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. 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. 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, confirmed by structured, quantitative, and liver-specific causality assessment methods. 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, with flavokavain B as one of the possible culprits. 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. 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. Considering the poor quality of kava raw material used for this small number of kava products, 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. 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. In Vanuatu, the major kava producer and exporter, the traditional kava beverage is prepared by cold water extraction of its roots. 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.