What long-term side effects are associated with kava?

There are clinical reports of herb-induced liver injury with kava use, especially when taken consistently for longer than a month.^[1] Prolonged kava use has been associated with lower body weight and depressed markers of immune function similar to those seen in alcoholics.^[2][3] Reports of multiple adverse events, liver dysfunction (e.g., hepatotoxicity, hepatitis, hepatic failure), and, in some instances, death have also been reported, but the dose and duration of kava aren’t always consistent or clearly stated in these reports.^{[4][5][6][7][8]}

These accounts, however, may be mistaken in the assumption that kava alone is to blame. While some adverse event reports identify the use of individual kavalactones (rather than a whole root extract), other reports note that kava was taken in addition to another substance with the potential for hepatotoxicity.^[4][9][6]

Additionally, no controlled trials using a standardized kava intervention (i.e, 200–300 mg of standardized extracts, taken for less than 2 months) have reported liver toxicity with the use of moderate dosing. However, not all studies measure liver enzymes or function either.^[10][11] Regardless of whether kava alone or in combination with other factors is to blame for adverse events, caution is advised until clearer evidence is established.

Higher doses of kava (greater than 1,000 mg/day of root extract over 4 weeks) are associated with an increased risk of impaired cytochrome P450 (CYP450) function.^[12] Inhibition of CYP450 is possibly due to kava containing methysticin, as demonstrated by in vitro studies.^[13] In vitro studies have also identified that some kavalactones (desmethoxyyangonin, methysticin, and dihydromethysticin) could inhibit liver enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP4A9/11.^[14][15][16] However, the kavalactone kavain is not yet known to inhibit liver enzymes.^[14]