A Re-evaluation of Kava

Kava (Piper methysticum), a herbal anxiolytic drug was banned in the UK and other countries. About 70 case reports had suggested hepatotoxicity. This article summarizes the research since the ban. Several theories have emerged to explain possible mechanisms of toxicity. Yet uncertainty as to whether or not kava is hepatotoxic prevails. Some experts therefore believe that the prohibition was not justi? ed. The evidence, however, continues to implicate kava, and the ban was recently upheld by the UK licensing authority.

In 2003, the UK government prohibited the sale of kava (Piper methysticum), a popular and effective herbal anxiolytic [1], marketed in Britain as unlicensed herbal products or food supplements. One year earlier, the German authorities had issued a similar prohibition [2]. The reason was an unacceptable risk of hepatotoxicity. The herbal sector, by and large, felt that a ban was an unnecessary and disproportionate over-reaction. The aim of this article is to summarize the new evidence.

About 100 cases of liver damage have now been associated with the intake of kava worldwide. This ? gure is comparable with those which in the past have led to the ban of mainstream drugs. Some experts, however, argue that causality between the adverse effect and use of kava has not been established with suf? cient certainty. In several cases, liver damage could have been due to other drugs or alcohol taken concomitantly. In other instances, excessive doses of kava had been used. Only in 14 cases was causality deemed to be ‘probable’.

An incidence rate of one potential case of liver damage in 60–125 million kava doses was estimated on the basis of the number of reported cases and the sales ? gures of kava in Germany [2, 3].

Two drug monitoring studies, including a total of 7078 patients taking 120–150 mg kava extract per day, had not found a single case of kava© 2007 The Author Journal compilation © 2007 Blackwell Publishing Ltd induced hepatotoxicity [4]. This seems to imply that the incidence of kava-induced hepatotoxicity is less than 1 per 2500 patients; arguably this could still be a relatively high ? gure. Other data suggest that kava does lead to an increase in liver enzymes [5, 6]. Moreover, none of the drug monitoring studies speci? cally evaluated signs or symptoms of hepatotoxicty, nor were they of long duration.

The above-incidence estimate is less than reliable: neither the true number of cases, nor the total number of patients exposed, nor the cumulative duration of exposure are known with certainty. Kava has been used for centuries in the South Paci? c. Its main active principle seems to be a family of compounds called kavalactones. The Paci? c Islanders used water extracts of kava, apparently without adverse effects [7]. Recent in vitro and animal studies have con? rmed that water fractions of kava are less cytotoxic than organic solvent fractions [8, 9].

Modern commercial products rely on alcohol or acetone extraction, a process which may extract toxic compounds (e. g. alkaloids) from the plant. Some experts therefore believe that the extraction method is the key for understanding the liver damage observed with modern kava preparations [10]. The above-mentioned surveys [5, 6], however, seem to contradict this theory but imply that liver function is impaired even if kava is consumed as an aqueous extract. Another theory holds that suboptimal raw material has contributed to the problem. At the height of the ‘kava boom’ prices were high and kava was in short supply.

Thus kava cultivars (over 80 different cultivars exist) and parts (e. g. peelings of the stump instead of the rhizome), were used. This can yield potentially toxic raw material [11]. It is therefore conceivable that suboptimal raw material contains toxic ingredients which are absent in Br J Clin Pharmacol 64:4 415–417 415 E. Ernst optimal material. Kava preparations based on toxic raw material or unsafe extraction methods should, of course, be prohibited. Therefore these potential explanations of the observed toxicity could be seen as arguments in favour rather than against a ban.

The mechanism of kava hepatotoxicity (if any) is still not well understood [12]. An immunologically mediated idiosyncratic reaction appears to be the most likely explanation, particularly at high doses [13, 14]. Comedication with St John’s Wort (Hypericum perforatum) extracts may potentiate the hepatotoxicity of kava [14]. The constituents of kava, ? avokavin B and pipermethystine, have been shown to be cytotoxic in vitro [8], but other studies seem to show an absence of toxicity in therapeutic doses or even a hepatoprotective effect [15].

A recent overview of toxicological tests in animals implied that kavalactones and kava extracts have a low level of toxicity [9]. Kava has the potential for causing drug interactions through inhibition of the cytochrome P450 enzymes [16–19]. Such interactions could either generate toxic metabolites or increase the toxicity of concomitantly administered drugs. Cytochrome P2D6 de? ciency was postulated to be a risk factor for kava hepatotoxity [20] but CYP2D6 de? ciency cannot account for liver damage in patients not taking drugs metabolized by this route.

No clinically signi? cant interactions with kava have been con? rmed in vivo. In any case, interactions would not account for those case reports where hepatotoxicity occurred without concomitant medications. A crucial point of the ban in Germany where kava was fully licensed was that the anxiolytic ef? cacy of kava was deemed to be uncertain. An updated Cochrane review includes 11 placebo-controlled randomized trials with a total of 645 patients suffering for anxiety [1].

The pooled data of six studies using the Hamilton Anxiety Scale as a common outcome measure yielded a weighted mean difference of 5. 0 (95% con? dence interval 1. 1, 8. 8, P = 0. 01) favouring kava over placebo. Similarly positive conclusions were reached by other investigators [21].

The anxiolytic effects of kava seem to be as powerful as those of conventional anxiolytics [22–24]. Other randomized controlled trials suggest that kava reduces anxiety in perimenopausal women [25], facilitates cognitive function and increases positive affectivity [26] and improves sleep quality [27]. Most of these trials did not monitor liver function; those that did, noted elevations of liver enzymes which, however, were usually not considered to be clinically relevant by the investigators.

The ban on kava in the UK and other countries (e. g. Austria, Germany, France) caused an estimated damage 416 64:4 Br J Clin Pharmacol of US$1. 2 billion to the industry [15]. Some experts now believe that, all things considered, the ban is no longer justi? ed [15]. But expert opinion is, of course, notoriously unreliable. The UK National Association of Health Stores, together with the actress Jenny Seagrove, challenged the ban in the UK High Court, but the claimants lost the case and a subsequent appeal [12].

The Expert Working Group of the UK Medicines and Healthcare Products Regulatory Agency recently concluded that the prohibition order on kava remains justi? ed and proportional [12]. In conclusion, emotional views about the safety of kava (or any other therapy) tend to distract from the facts. The evidence may be complex and uncertainty does prevail but, on the basis of existing evidence, hepatotoxicity cannot presently be ruled out. A number of theories have emerged which may deserve further investigation.

These theories, however, do not throw the hepatotoxic potential of kava into serious doubt. The onus is now on the kava industry to generate data which are compelling. Source of funding; None. References 1 Pittler MH, Ernst E. Kava extract for treating anxiety. The Cochrane Databse of Systematic Reviews 2003; Issue 1, Article no.

CD003383. 2 Schmidt M, Nahrstedt A, Lupke NP. Piper methysticum (Kava) in der Diskussion: Betrachtungen zu Qualitat, Wirksamkeit und Unbedenklichkeit. Wien Med Wochenschr 2002; 152: 382–8. 3 Teschke R, Gaus W, Loew D. Kava extracts: safety and risks including rare hepatotoxicity. Phytomed 2003; 10: 440–6. 4 Stevinson C, Huntley A, Ernst E. A systematic review of the safety of kava extract in the treatment of anxiety. Drug Saf 2002; 25: 251–61. 5 Clough AR, Baillie RS, Currie B. Liver function test abnormalities in users of aqueous kava extracts. J Toxicol 2003, 821–9. 6 Clough AR, Jacups SP, Wang Z.

Health experts of kava use in an eastern Arnhem Land community. Int Med J 2003, 336–40. 7 Singh YN, Devk kota AK. A study on the potential hepatotoxic effects of aqueous kava extracts in rats. International Kava Conference 2004, 30 November–2 December 2004, Suva, Fiji. 8 Jhoo J-W, Freeman JP, Heinze TM, Moody JD, Schnackenberg LK, Beger RD, Dragull K, Tang CS, Ang CYW. In vitro cytoxocity of nonpolar constituents from different parts of kava plant (Piper methysticum). J Agric Food Chem 2006; 54: 3157–62. 9 Sorrentino L, Capasso A, Schmidt M. Safety of ethanolic kava extract: results of a study of chronic toxicity in rats.

Phytomedicine 2006; 13: 542–9. Commentary 10 Whitton PA, Lau A, Salisbury A, Whitehouse J, Evans CS. Kava lactones and the kava-kava controversy. Phytochemistry 2003; 64: 673–9. 11 Schmidt M. The kava liver case reports reinterpreted: a critical review of toxicology and pharmacovigilance. International Kava Conference 2004, 30 November–2 December 2004, Suva, Fiji. 12 MHRA. Report of the Committee on Safety of Medicines Expert Working Group on the safety of Kava. In: http://www. mhra. gov. uk (printed 04/09/2006). 13 Schulze J, Raasch W, Siegers C-P. Toxicity of kava pyrones, drug safety and precautions – a case study.

Phytomed 2003; 10: 68–73. 14 Musch E, Chrissafidou A, Malek M. Acute hepatitis due to kava-kava and St John’s Wort: and immuno-medicated mechanism? Dtsch Med Wochenschr 2006; 131: 1214–7. 15 Gruenwald J. Welcome back Kava? Nutraceuticals World 2006; April 26–7. 16 Mathews JM, Etheridge AS, Black SR. Inhibition of human cytochrome P450 activities by kava extract and kavalactones. Drug Metab Dispos 2002; 30: 1153–7. 17 Singh YN. Potential for interaction of kava and St John’s wort with drugs. J Ethnopharmacol 2006; 100: 108–13. 18 Ma Y, Sachdeva K, Liu J, Lang D, Khan IA, Chichester CO, Yan B.

Desmethoxyyangonin and dihydromethysicin are two major pharmacological kavalaactones with marked activity on the induction of CYP3A23. Drug Metab Dispos 2004; 32: 1317–24. 19 Anke. J, Ramzan I. Pharmacokinetic and pharmacodynamic drug interactions with Kava (Piper methysticum Forst. f. ). J Ethnopharmacol 2004; 93: 153–60. 20 Russmann S, Helbling A. Kava hepatotoxicity. Ann Intern Med 2001; 135: 68–9. 21 Cairney S, Maruff P, Clough AR. The neuro behavioural effects of kava. Aust NZ J Psychiat 2002; 36: 657–62. 22 Lindenberg D, Pitule-Schodel H. D,L-Kavain im Vergleich zu Oxazepam bei Angstzustanden. Fortschr Med 1990; 108:

49–50. 23 Woelk H, Kapoula O, Lehrl S, Schroter K, Weinholz P. Behandlung von Angst-Patienten. Z Allgemeinmed 1993; 69: 271–7. 24 Boerner RJ, Sommer H, Berger W, Kuhn U, Schmidt U, Mannel M. Kava-Kava extract LI 150 is as effective as opipramol and buspirone in generalised anxiety disorder – an 8-week randomized, double-blind, multi-centre clinical trial in 129 out-patients. Phytomed 2003; 10: 38–49. 25 Cagnacci A, Arangino S, Renzi A, Zanni AL, Malmusi S, Volpe A. Kava-Kava administration reduces anxiety in perimenopausal women. Maturitas 2003; 44: 103–9.

26 Thompson R, Ruch W, Hasenohrl RU. Enhanced cognitive performance and cheerful mood by standardized extracts of Piper methysticum (kava-kava). Hum Psychopharmacol 2004; 19: 243–50. 27 Emser W, Bartylla K. Verbesserung der Schlafqualitat. Zur Wirkung von Kava-Extrakt WS 1490 auf das Schlafmuster bei Gesunden. TW Neurol Psychiatr 1991; 5: 636–42.

Received 7 November 2006 Accepted 7 December 2006 Published OnlineEarly 6 June 2007 Correspondence Professor E. Ernst, Peninsula Medical School, Universities of Exeter & Plymouth, 25 Victoria Park Road, Exeter EX2 4NT, UK. Tel: + 44 (0)13 9242 4989; Fax: + 44 (0)13 9242 7562; E-mail: Edzard. [email protected] ac. uk Br J Clin Pharmacol 64:4 417.

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