Interaction Of Kava With Drugs

Kava is a herbal sedative with purported calming effect. Kava is prepared from a South Pacific plant (Piper mesthysticum). There are 72 different kava plants, which differ in appearance as well as in their chemical composition. Kava drink is prepared by mixing fresh or dried root with cold water or coconut milk. Kava is available from a variety of manufacturers. The neurological effects of kava are attributed to a group of substituted dihydropyrones called kava lactones.

Heavy consumption of kava has been associated with increased concentrations of 7-glutamyltransferase suggesting potential hepatotoxicity. Escher et al. described a case in which severe hepatitis was associated with kava use. A 50-year-old man took three to four kava capsules daily for 2 months (maximum recommended dose three capsules). Liver function tests showed 60-fold to 70-fold increases in AST and ALT. Tests for viral hepatitis were all negative as were tests for cytomegalovirus and HIV. The patient eventually received a liver transplant (85). Humberston et al. (86) also reported a case of acute hepatitis induced by kava-kava. Other cases of hepatotoxicity due to the use of kava have been documented (87). In January 2003, kava extracts were banned in the entire European Union, Canada and also in the United States (the FDA strongly cautioned against using kava). There are at least 11 cases of serious hepatic failure and four deaths directly linked to kava extract consumption, and there are also 23 reports indirectly linking kava with hepatotoxicity (88).

Recently, it has been demonstrated that several kava lactones are potent inhibitor of several enzymes of cytochrome P 450 system (CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4 and CYP4A9/11). Therefore, there is a potential of drug interaction with kava-kava especially for drugs metabolized by cytochrome P 450 system, but actual systemic studies with human subjects to demonstrate such drug interactions are very limited (89). A recent study involving six healthy human volunteers who consumed traditional aqueous extract of kava indicated that caffeine metabolic ratio increased twofold from 0.3 with consumption of kava to 0.6 at 30 days after the subjects stopped using kava. The later value corresponds to metabolic ratios in healthy subjects. The authors concluded that kava drinking inhibits CYP1A2 (90).

Kava has known sedative effect and it is speculated that kava may interact with central nervous system depressants such as benzodiazepines, alcohol and barbiturates. There is a case report describing interaction of kava with alprazolam. A 54-year-old patient taking alprazolam, cimetidine and terazosin started self-medication with kava for 3 days and was hospitalized. The authors suggested that both kavaloactones and alprazolam have additive effect because both act on the same GABA receptors. Moreover, kavalactones are potent inhibitor of CYP3A4 which metabolizes alprazolam (91). Although in mouse model, kava was shown to have additive effect on alcohol, a clinical study using human subjects indicated that kava did not alter safety-related performance in volunteers taking alcohol (92). Another recent study indicates that kava is unable to inhibit alcohol dehydrogenase activity in vitro (93).

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