German Kava Ban Lifted by Court – Court Ruling Details

 

Kava (Piper methysticum)

Kava (Piper methysticum)

Excerpts taken from the article: German Kava Ban Lifted by Court: The Alleged Hepatotoxicity of Kava (Piper methysticum) as a Case of Ill-Defined Herbal Drug Identity, Lacking Quality Control, and Misguided Regulatory Politics

Until the year 2002, extracts of the rhizome and roots of the Melanesian plant kava [Piper methys- ticum G. Forst. (Piperaceae)] were marketed in Germany and other countries in the form of me- dicinal products licensed for the treatment of situational anxiety. After receiving a series of case reports concerning alleged liver toxicity, the German regulatory authority BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte; Federal Institute for Drugs and Medical Devices) decided in the summer of 2002 to cancel all drug registrations for all medicinal products containing kava by a simple administration decision, with the exception of homeopathic dilutions of 4D (1 : 10 000) or higher. Formally, the benefit-risk ratio was declared negative. Other regulators outside Germany soon followed this decision. 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].

– A ban that has been contested because of the poor evidence of risks related to kava. Only recently, two German administrative courts decided that the decision of the regulatory authority to ban kava as a measure to ensure consumer safety was inappropriate and even associated with an increased risk due to the higher risk inherent to the therapeutic alternatives. This ruling can be considered as final for at least the German market, as no further appeal has been pursued by the regulatory authorities. However, in order to prevent further misunderstandings, especially in other markets, the current situation calls for a comprehensive presentation of the cardinal facts and misconceptions concerning kava and related drug quality issues.

Possible Theories Concerning the Perceived Liver Damage
The analysis of the case reports by Teschke had revealed only very few case reports with a relatively high probability of having been caused by kava, among them one report with a proven allergic reaction to the product [29], and thus a type of reaction which must be assessed apart from the issue of typically dose-de- pendent toxic reactions. Although the number of cases seems in- significant when compared with the known exposure data (450 million daily doses in ten years according to IMS data), the ob- served cases still demand a pharmacological explanation. Thus, over the past twelve years, several theories have been published, which, all in all, can be summed up in five major lines of thought:

” The “human genetic variability theory”: According to this school of thought, kava preparations are completely harmless to the general population. However, there is a small subgroup of the European Caucasian population lacking the metabolizing liver enzyme cytochrome P450 subtype 2D6 (CYP 2D6), as ob- served in one case report [30]. This mutation might lead to an unusual metabolic pattern in these patients, resulting in the transformation of the normally harmless constituents of kava into toxic metabolites in the liver. This theory suffers from the fact that this would be a typical dose-dependent toxicity. With approximately 7–9% of Caucasians being CYP 2D6-deficient, a much higher number of case reports would be expected not only in Germany, but in all Caucasian populations. This was quite obviously not the case; the observations were almost exclusively restricted to Germany and Switzerland, with the latter country using kava products of German origin.

The “metabolic toxification theory” assumes a toxification of kava constituents through the formation of electrophilic qui- noid metabolites, as demonstrated in vitro in hepatic microsomes [31, 32]. Whereas both hypotheses could provide an ex- planation for liver toxicity in the presence of other drugs (inter- actions at the metabolic level), this type of reaction would, according to the authors, only occur with elevated exposures to kavalactones. With traditional kava drinking in the South Pacific, the kavalactone exposure by far exceeds the exposure with the German kava extract products. The maximum daily dose of German medicinal kava products was 120 mg kavalactones, whereas a single coconut shell of kava would provide > 210 mg [33], calculated with a method for which the results would have to be multiplied by 1.7 to be comparable to the lev- el of modern HPLC methods [34]. Accordingly, Olsen et al. (2011) admit that “there remains no undisputable reason for the increased prevalence of kava-induced hepatotoxicity in Western countries” [32], the fact notwithstanding that such an increased prevalence has not been demonstrated.
The “organic solvent theory”: In traditional kava use of the Pacific Islands, kava is always extracted with water. In contrast, the German medicinal products contained kava extracts pre- pared with ethanol-water mixtures, and one product contained an acetone extract. Organic solvents are used to achieve a better extractability of the kavalactones as the major active constituent fraction of kava rhizomes and roots. The “organic solvent theory” holds that kava may contain non-water-soluble hepatotoxic compounds that are not contained in the traditional aqueous extract, but enriched in the European preparations. This difference might explain why the traditional aqueous kava preparations are considered a safer option than the European organic extracts [35]. However, one must bear in mind that ethanol extracts of kava roots and rhizomes have been in use in Germany for more than 100 years, and were al- ready mentioned for the first time by Lewin in 1886 [36], with no reports on relevant safety issues until the year 1999, when the first case reports of liver toxicity were published in Switzerland with a German-produced product. A recent focus of the debate is flavokavin B, which has been shown to be liver toxic in mice in relatively high doses [37], although others could not confirm this finding [38]. The organic solvent hypothesis has been largely ignored [26,27], but there may still be a relationship between the phytochemical composition of kava preparations and the quality of the herbal material.
The “wrong plant part theory” assumes that European extract manufacturers used wrong plant parts such as leaves or stems. These plant parts may contain the alkaloid pipermethystine with liver-toxic properties [39,40]. However, an analysis of the European kava extracts clearly showed the absence of pi- permethysticine in the German kava extract preparations [41]. The hypothesis of using inappropriate plant parts and/or inappropriate protection against secondary contamination by mould toxins can still not be fully excluded, as it partly mirrors the current trading habits [42–45].
The “adulteration theory”: Again, one should not ignore that kava rhizome and root extracts prepared with ethanol/water mixtures have a history of safe use in Germany dating back to at least 1886. Prior to the mid-1990 s, there was not a single re- port of liver toxicity from anywhere in the world. The question imposes itself: Might there have been a change of kava raw ma- terial quality with a potential impact on kava safety – a change, which might be considered an adulteration? There is increasing evidence that this was, in fact, the case [43, 44, 46]. The “adulteration theory” combines aspects from the aforemen- tioned hypotheses, especially the “wrong plant part theory”. It also requires an additional introduction into the ethnobotani- cal background of kava.
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