Relevant Hepatotoxic Effects of Kava Still Need to be Proven

On June 14, 2002 the German Federal Institute of Drugs and Medical Devices (BfArM) made the decision to withdraw all drug registrations for all products containing kava. The consequences of this ban were felt worldwide and led to an economic disaster in many South Pacific states. Within Europe, the kava ban deprived physicians of an effective and comparatively safe medication, creating a ”therapeutic gap nobody wished for” [1].

The decision to ban kava was rigorously debated in Europe, as many experts questioned the causality of the case reports of liver toxicity. In most cases, retrospective analysis casts considerable doubt on the official causality assessment. Relevant reviews and papers were published prior to and after the kava ban [2], [3], [4], [5], [6], [7], [8], [9], [10], [11].

According to the results of the most recent analysis, kava can potentially cause liver toxicity. However, the incidence of such effects appears to be extremely low: less than one case in one million monthly doses [9]. If indeed hepatotoxic effects of kava exist, they might be related to a rare immunological reaction to a kava metabolite in a small subgroup of the European Caucasian population lacking the metabolizing liver enzyme cytochrome CYP 2D6 [9]. This theory still needs further confirmation, as the discussion of hepatotoxicity is mainly based on only four more or less adequately documented case reports of liver reactions possibly caused by kava. In two of the patients a lack of cytochrome CYP 2D6 was found. Compared to the millions of kava doses ingested within Europe, the number of only two confirmed allergic reactions in patients with an unusual metabolic pattern does not allow the deduction of a general threat to the patients’ health.

The kava ban was not only based on the possibility of severe adverse effects but at the same time on the supposed lack of appropriate clinical studies by most recent standards demonstrating efficacy. Note that the focus is on ”most recent standards”, which generally puts phytotherapy at a disadvantage in comparison to chemically defined drugs. For herbal drugs there is mostly a long-dating experience concerning efficacy as well as tolerability. The studies performed with kava within the last decades cannot, of course, be compliant to the most recent GCP standards, as these were defined much later. In contrast, new chemical entities may have proofs of efficacy according to the latest standards. However, a chemically defined drug with a recent, GCP-compliant proof of efficacy is not necessarily safe, as rare adverse reactions are only detected after administration to a large number of patients.

Kava was thus not only officially judged as potentially dangerous but, in addition, its efficacy was denied. The combination of both factors clearly shifted the risk-benefit evaluation towards the negative side. The Society for Medicinal Plant Research neither accepts the official conclusions drawn from the presentation of fragmentary safety data, nor a negative benefit-risk-ratio of kava on the grounds of missing proofs of efficacy. Scientists who are members of the Society for Medicinal Plant Research created a large part of the published pharmacological and clinical knowledge on kava. Like the members of the Commission E, who published a complaint about the way their expertise was bypassed in the decision-making process, the Society for Medicinal Plant Research would have been happy to be involved in the discussion of kava (adverse) effects.

The Society for Medicinal Plant Research feels that the rationale for the kava ban does not sufficiently take into account the huge body of positive evidence of efficacy and tolerability of kava. A recent meta-analysis on ”Kava extract for treating anxiety” [4] came to the conclusion that, compared with placebo, kava extract appears to be an effective symptomatic treatment option for anxiety; the data available from the reviewed studies suggest that kava is relatively safe for short-term treatment (1 to 24 weeks). Instead, the ban focuses entirely on a small number of case reports, and completely ignores all clinical, pharmacological, toxicological and ethno-pharmacological evidence. The Society for Medicinal Plant Research feels that the public verdict on kava without a rational analysis of the backgrounds of the case reports is indicative of the unequal treatment of herbal medicines and chemically defined drugs when it comes to benefit-risk assessments. Kava is only one rather tragic example of this development within the EU. Positive proofs of efficacy were neglected, whereas the possibility of adverse effects seemed to be blown up and to outweigh all advantages, even though the therapeutic alternatives are in no way safer than kava.

The European scientific community is following with keen interest the struggle for kava in the South Pacific states and Australia. The ideas recently discussed, e. g., the influence of glutathione contents in traditional kava drinks [6], [12], or the potential pipermethysticine content in aerial parts of some kava cultivars surely merit a closer look and an international scientific collaboration. One should, however, always keep in mind that the drug safety protocol implemented by the German health authorities is hotly debated, as a relevant liver toxic potential of kava was never scientifically proven! The case reports discussed for kava are mostly inhomogeneous, and in most cases alternative causes could be identified [3], [7], [9]. A recently published paper on the influence on liver function in rats by aqueous kava extracts showed no incidence for toxicity [13].

Thus, before the question is addressed whether the European registered pharmaceutical extracts are really differing from the traditional kava drinks in the South Pacific, and what potential adulterant might have caused the toxicity, one should first agree that there really is a relevant toxicity. The available details do not allow one to draw this conclusion. The German health authorities clearly should present the additional data they claim to possess in order to allow the question to be addressed scientifically.

Prof. Dr. Rudolf Bauer, President of the Society for Medicinal Plant Research
Prof. Dr. Brigitte Kopp, Vice President of the Society for Medicinal Plant Research
Prof. Dr. Adolf Nahrstedt, Editor of Planta Medica

References

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