Herbal hepatotoxicity by kava: Update on pipermethystine, flavokavain B, and mould hepatotoxins as primarily assumed culprits

Herbal hepatotoxicity by the anxiolytic kava (Piper methysticum Forst. f.) emerged unexpectedly and was observed in a few patients worldwide. Liver injury occurred after the use of traditional aqueous kava extracts in the South Pacific region and of acetonic and ethanolic extracts in Western countries in rare cases, suggesting that the solvents used play no major causative role. In this review, we discuss actual pathogenetic issues of kava hepatotoxicity with special focus on developments regarding pipermethystine, flavokavain B, and mould hepatotoxins as possible culprits. There is abundant data of in vitro cytotoxicity including apoptosis by pipermethystine and flavokavain B added to the incubation media, yet evidence is lacking of in vivo hepatotoxicity in experimental animals under conditions similar to human kava use. Furthermore, in commercial Western kava extracts, pipermethystine was not detectable and flavokavain B was present as a natural compound in amounts much too low to cause experimental liver injury. There is concern, however, that due to high temperature and humidity in the South Pacific area, kava raw material might have been contaminated by mould hepatotoxins such as aflatoxins after harvest and during storage. Whether kava hepatotoxicity may be due to aflatoxicosis or other mould hepatotoxins, requires further studies.