The United Kingdom’s Committee on Safety of Medicines (CSM) Expert Working Group (EWG) on the Safety of Kava released an extensive report in July 2006 reviewing all available data on kava safety and concluded that the UK’s ban on kava products, effective since 2003, should remain unchanged.¹ According to a press release on the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) website, “The EWG, the CSM, and the Medicines Commission determined that kava was associated with an unacceptable risk of idiosyncratic hepatotoxicity which could not be minimized or prevented by any regulatory measures other than the removal of kava products from the market.”²

In the UK, licensed products containing kava (Piper methysticum Forst, Piperaceae) as active ingredients were voluntarily withdrawn from sale by manufacturers in 2001, following concerns raised within several countries of a suspected association between kava use and liver hepatotoxicity.¹ According to a UK source, these licenses related to old kava products; no company had licensed kava for reduction of anxiety or stress, the primary use for kava as a phytomedicine as formerly licensed in several EU countries. Because most kava products sold in the UK were unlicensed and sold as foods, safety is a priority and the presence of potentially serious adverse effects is not tolerated; the labeling of these products is not based on an analysis of risk versus benefit, as is done with licensed medicines. Following a review of evidence by the CSM and EWG, the UK government decided to ban all kava products effective January of 2003.³ The government mandated that evidence regarding kava safety would be reviewed 2 years after this prohibition.¹ The MHRA carried out a public consultation and reviewed available literature regarding kava safety between January and April of 2005. The EWG then met again to consider available data in October of 2005.

At the time of the UK’s ban on kava, 68 case reports had been collected from various regulating agencies as evidence of a suspected association between kava use and liver hepatotoxicity. By the time of the EWG’s review, this number had risen to 110 case reports. The majority of the evidence consists of spontaneous case reports, which the EWG acknowledges “are anecdotal records and have many limitations.” For example, the particular products that were used were not always specified. Unfortunately, the other types of clinical data were not helpful in revealing adverse reactions, and although there has been some evidence of efficacy in clinical trials, these trials have not been helpful in attempts to assess the issue of potential hepatotoxicity. The EWG report concludes that the sum of available evidence strongly suggests a link between kava and hepatotoxicity although no direct causality has been scientifically established. According to the report, “It is the degree of severity associated with some of the case reports that is of greatest concern. Although many patients experienced only mild changes in liver function or jaundice, some patients experienced more serious hepatitis or liver failure that, on 11 occasions, required liver transplants.”¹ According to the report, hepatotoxicity directly or indirectly resulted in the deaths of 9 individuals, including 2 of the patients who received liver transplants.

The EWG considered ways of reducing risk to consumers, but it was not possible to identify at-risk patients and, as unlicensed products, label warnings would have been voluntary, or extracts that would be marketed as medicines would have to be shown to be beneficial in a risk-benefit analysis from a review of both clinical trials and the case reports.

The EWG considered a number of theories regarding the proposed mechanism of hepatotoxicity for kava, but it concluded that all theories lacked direct evidence and require further research. The EWG further argued that, although some studies have attempted to determine a mechanism of hepatotoxicty of kava, such studies have not been conducted in a systematic way and have raised more questions than they have answered. As it is generally well known that there are no recognized animal models for the identification of idiosyncratic hepatotoxicity, the EWG suggested that it might be worth confirming the cytotoxic effects of kava in vivo. The EWG also recommended that future research on the topic “focus on more modern methods which combine metabolic, toxicological, and functional end-points, with particular focus being placed on the chemical moieties responsible for the liver damage, the mechanism by which they cause the damage, and what factors contribute to individual susceptibility.”¹

The MHRA will review any new evidence submitted regarding suspected associations between kava use and liver hepatotoxicity and will reevaluate the kava ban if significant new data are received. The MHRA will also seek expert advice from the recently established Herbal Medicines Advisory Committee (HMAC) as needed. The EWG’s 87-page report can be accessed online via the MHRA press release at http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&useSecondary=true&ssDocName=CON2024228&ssTargetNodeId=663.

References

1. Report of the CSM’s expert working group on the safety of kava [report]. London: Committee on Safety of Medicines Expert Working Group on the safety of Kava; July 2006.

2. Report of the committee on safety of medicines expert working group on the safety of kava [press release]. London: Medicines and Healthcare products Regulating Agency; July 2006.

3. The Medicines for Human Use (Kava-kava) (Prohibition) Order 2002. Statutory Instrument 2002 No. 3170. Available at: http://www.opsi.gov.uk/si/si2002/20023170.htm. Accessed August 1, 2006.