Kava and the liver: what the hepatotoxicity debate actually turns on

Kava (Piper methysticum) has one of the better-supported anxiolytic records of any botanical, and a hepatotoxicity signal that got it banned in several countries in the early 2000s. Both things are true, and the reconciliation is in the preparation. What the actives are Kavalactones: kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, desmethoxyyangonin. As a group they positively modulate GABA-A (not at the benzodiazepine site), act on sodium/calcium channels, and inhibit MAO-B. The liver question - Traditional preparation is a WATER extraction of the PEELED root. The hepatotoxicity cases clustered around acetonic/ethanolic commercial extracts and, importantly, material that included aerial parts and root bark. - Aerial parts and root bark carry pipermethystine and flavokavain B, both hepatotoxic in vitro (label that clearly: in vitro, cell-line data, not a human dose-response). Their inclusion in some commercial products is a leading hypothesis for the cases. - Kavalactones inhibit several CYPs in vitro, including CYP2E1 and CYP3A4, and interindividual CYP2D6 deficiency has been proposed as a susceptibility factor. The CYP inhibition also means kava can slow the clearance of co-ingested drugs. The harm-reduction consequence The genuinely risky move is stacking a deliberate CYP inhibitor (for "potentiation") onto kava: you slow the clearance of the very compounds loading the liver, and you add alcohol at your peril (alcohol + kava is a documented bad combination). Full mechanism, the noble/tudei cultivar question and the potentiation thesis: https://wiki.soapbox.community/wiki/Kava and https://wiki.soapbox.community/wiki/Kava_Potentiation Sources: NIH LiverTox monograph on Kava; Teschke R et al. on preparation and hepatotoxicity; WHO assessment (2007).