2007 Kava Kava Report links 7 deaths and 14 liver transplants to the use of Kava.
The World Health Organization report confirms that Kava acetonic and ethanolic extracts can be toxic to the liver and dangerous. These dangerous extracts are used in most capsules sold in health food stores. The traditional kava preparation which has been prepared for centuries in water, apparently does not have the same risk of liver injury as the health food supplement products.
In 2004 the International Kava Conference was held in Suva, Fiji to discuss new scientific data on the safety and efficacy of kava in view of the bans and restrictions on kava and its derivatives in key export markets. (Fiji, Vanuatu, Samoa and Tonga are the world’s largest exporters of kava.) As a result, IKEC (International Kava Executive Council) implemented several key scientific resolutions, including a request to the World Health Organization (WHO) to work on kava safety evaluations as soon as possible. Specifically, IKEC asked the WHO to collect detailed information from all available sources about kava-related adverse events and the product specifications of the implicated kava. Further, IKEC asked the WHO to review all available information regarding kava safety and toxicity.
In December 2005, the WHO appointed a committee consisting of Dr. David Coulter of New Zealand, Dr. Carmen Tamayo of Canada, Professor Subramaniam Sotheeswaran, a Fijian USP organic chemist, and co-opted member, Catherine Ulbricht, PharmD, Senior Attending Pharmacist, Massachusetts General Hospital. The WHO published the committee’s report – Assessment of the Risk of Hepatotoxicity with Kava Products – in May 2007.
The 91-page report contains:
- Description of kava
- Review of literature
- Analysis of 93 case reports
- Regulatory issues
- Conclusions and recommendations
Description of Kava
Kava is a perennial shrub native to some South Pacific islands. “Some experts consider kava to be a medicinal plant with a very favourable risk profile and to have at the same time, excellent efficacy in the treatment of anxiety and as a muscle relaxant, mood enhancer and sedative.” Kava has been cultivated for centuries traditionally prepared as microsuspensions in water and teas made from powdered kava root. The pharmacologically active components are a group of kava lactones. Other types of preparation include organic (acetonic and ethanolic) extracts and synthetic.
Products prepared from the organic extracts of kava have been those principally used in Europe and North America in pill or capsule form. After almost ten years of widespread use of kava extracts in Europe, warnings about the plant’s safety were issued in 1998 in response to several cases of hepatotoxicity including liver failure and death. In Switzerland, 25% of reports of liver dysfunction included fulminant liver failure requiring liver transplantation. As a result, several European countries banned kava products in 2002, followed by some Asian nations.
By late 2001 and 2002 the US FDA began documenting cases of hepatotoxicity possibly induced by kava preparations. Through the Freedom of Information Act, Saunders & Walker recently received from CFSAN (Center for Food Safety and Applied Nutrition), the US FDA branch overseeing food and dietary supplements, a database report containing 84 adverse events associated with Kava from early 2002 through June 2007. Nevertheless, kava is still available for use in the United States as a dietary supplement for anxiety.
Interestingly, experimental studies and clinical trials suggest that water-based extracts are not toxic. However, there is an apparent cause and effect relationship between the ingestion of acetonic and ethanolic kava extracts and liver toxicity, but the exact mechanism is unknown and the responsible chemical components have not been identified. Scientists believe that the specific cultivar of Piper methysticum and the plant part are factors. An idiosyncratic immune-mediated process and a metabolic abnormality with CYP 2C6 enzyme deficiency have been suggested. It is also possible that chemicals other than kava lactones, such as alkaloids not present in synthetic products or not bioavailable in water extracts, may be responsible for hepatotoxicity from the organic extracts.
Review of Case Reports
Of the 93 case reports that were identified, seven patients died and 14 patients had liver transplants. Eight cases were determined to have a close association between the use of kava and liver dysfunction because the patients recovered on withdrawal of kava and no other plausible cause for the liver problems would be identified. Fifty-three cases were classified as having a possible relationship, but they could not be fully assessed due to insufficient data or other potential causes of liver damage. Five cases had a positive rechallenge, meaning the patient improved on withdrawal of kava, but worsened with reintroduction. Most of the other case reports could not be evaluated due to lack of information.
The committee concluded that there is “significant concern” for a cause and effect relationship between kava products and hepatotoxity, especially for organic extracts. Other risk factors appear to include heavy alcohol intake, pre-existing liver disease, genetic polymorphisms of cytochrome P450 enzymes, excessive dosage, and co-medication with other potentially hepatotoxic drugs and potentially interacting drugs.
The Committee admits that clinical trials of kava have not revealed any hepatotoxicity, yet cautions that “clinical trials usually involve insufficient numbers of patients and do not continue for a sufficient length of time to reliably detect rare reactions. In addition, they are generally designed to assess efficacy and while they collect safety information, the methodology is not primarily aimed at detecting potential toxic effects . . . The absence of reports of hepatotoxicity in clinical trials does not mean that these reactions do not occur.”
- Kava lactones in any type of kava preparation may rarely cause liver problems due to interactions with drugs, excessive alcohol intake, metabolic or immune mediated idiosyncrasy, excessive dosage, or pre-existing liver disease.
- Kava products made from acetonic and ethanoloic extracts cause liver problems on rare occasions, seemingly from non-kava lactone constituents.
The Committee made the following recommendations:
- Studies on all kava products, and further research, especially to identify and gain information about the toxicology of the non-kava lactone constituents.
- A pharmacopoeial standard for kava products should be created referencing standards of quality, plant parts, dosage, and methods of preparation.
- All kava products should be prepared as drugs available only by prescription “in order to better monitor their use and apply necessary controls.”
- “Only the root or rhizome of Piper methysticum G Forst should be used for preparation of medicinal kava. No other species and no aerial parts should be used.”
- Products should be developed from water-based suspensions of kava and synthetic products should be available. Ethanolic and acetonic extracts should be avoided. Kava should not be used in patients with liver disease, with a history of liver disease, or in patients with excessive alcohol intake.