Potential Toxicity of Kava Extracts in Western Populations

An age-old traditional drink prepared from kava roots extracted in water used to be consumed during ceremonies in the South Pacific regions. Later, this drink came to be adopted in Western countries, because of its soothing effect. However, several cases of liver toxicity were reported upon its consumption. The toxicity was limited to those who belonged to Western countries. The reasons behind this exclusive toxicity of kava to the western population have remained unidentified. The present review investigated factors responsible for the toxicity of kava, based on the results obtained from other studies.

Kava extract was a regularly used social drink in the South Pacific regions. Consumption after export to markets in Europe, U.S. and Canada was followed by reports of liver toxicity, leading to a ban on the product. Investigations have not yet been successful in ascertaining the reason behind this toxicity. Several tests have shown that there is an increase in liver enzymes, as a delayed response to ingestion of kava extracts. Although reports from the World Health Organization (WHO) did not zero in on the exact mechanism of the toxicity, they identified several risk factors, such as the solvent used for extraction (water or organic), concomitant alcohol intake, intake of other drugs, existing liver malfunctions, excess kava consumption, genetic variation and liver enzymes involved in the metabolism of kava. The composition of kava and the lactones present in it have been thoroughly analyzed in several studies. Observations on the side effects in traditional kava consumers showed minor symptoms like gastric disturbances, anxiety, drowsiness, tremor, headache, exhaustion and skin rashes, but none was related to liver toxicity. Therefore, this study was undertaken to identify the reasons for liver toxicity in consumers of the drink from Western countries.

A literature review was done to examine possible factors that may be responsible for liver toxicity of kava extracts. These included composition and concentration of individual lactones present in the extracts, extract preparation methods, in vivo hepatotoxicity and cytotoxicity tests on rats. Inhibition of cytochrome P450 metabolic enzymes and transporters, effect on drug metabolism and removal, genetic variation leading to altered structure of P450 were also considered as causative factors. Inclusion of aerial parts of kava in extract preparation, estimation of minor constituents, role of glutathione (GSH) conjugation in detoxification, and the formation of chemically active intermediates and metabolites were included as possible factors.

Data/Results/Key findings
* Commercial preparations use aerial parts of the kava plant, which have higher lactone concentrations.
* Hepatotoxicity was noted in rats at an oral kava dose of ~0.5 to 1 g lactones/kg/day for nearly one to three months.
* Consumption of large quantities of aqueous kava extract could inhibit P450 enzymes, leading to impaired drug metabolism.
* The intestinal concentration of kava is sufficient to inhibit transporters like P-glycoprotein (Pgp).
* Caucasians, being generally constitutionally poor metabolizers, are genetically predisposed to accumulation of toxic levels of alkaloids.
* A minor ingredient, Flavokavain B, is the most cytotoxic element in kava root.
* Addition of GSH showed potential detoxification effect by reducing cell death.
* Certain reactive chemical metabolites were found in kava extracts.

Next steps/Shortcomings
Animal toxicity tests have failed to give reproducible results, as the mechanism of liver toxicity is very different in humans. Future work is warranted to study the role of P450 enzymes, introduction of safe variants of kava, genetic analysis of persons who have suffered from hepatotoxicity, and the minor constituents of kava extracts.

Kava drink has been consumed for several centuries in the South Pacific and no fatal side effects have been observed until date. However, cases of liver toxicity were reported from the West.  The present study clearly shows that it is not the kava itself but several variables during processing that result in liver problems. These range from plant species used to other co-drugs consumed along with kava extracts. In spite of an in-depth analysis, the authors of this review state, “To date, there remains no indisputable reason for the increased prevalence of kava-induced hepatotoxicity in Western countries.” The mechanism of toxicity is still not clear and future studies on constituents of kava, such as ?avokavains, are recommended.

For More Information:
Constituents in Kava Extracts Potentially Involved in Hepatotoxicity: A Review

Publication Journal: Chemical Research in Toxicology, 2011
By Line R. Olsen; Mark P. Grillo; University of Copenhagen, Denmark and Amgen Inc., South San Francisco, California

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