Kava update:( recent case reports associate it with liver damage which was severe (hepatic failure) a European perspective June 2006 .....

[Guest guest]

NZMJ Obituaries 1887-June 2006

Copyright

Other journals

Journal of the New Zealand Medical Association, 05-November-2004, Vol 117

No 1205

Kava update: a European perspective

Edzard Ernst

Kava is the beverage prepared from the rhizome of the kava plant (Piper

methysticum Forster), and is traditionally used for recreational or

medicinal purposes by the islanders of the South Pacific. Its active

ingredients are kava pyrones (eg, kavain1), which are thought to mediate

effects on GABAA receptors, particularly in the hippocampus (region of the

brain) and amygdale complex. Numerous clinical trials have shown kava to

be an effective anxiolytic, and a Cochrane Review leaves little doubt

about its efficacy.2

Kava was also deemed to be a safe remedy,3,4 but recent case reports

associate it with liver damage which was severe (hepatic failure) in some

instances.5 Today, about 70 cases of various degrees of liver damage have

been documented worldwide.6 Kava-containing products were therefore

banned, first in Germany and Switzerland and subsequently in several other

countries.6 Australia also currently bans kava supplements while New

Zealand authorities recommend that labels should warn against the

possibility of liver damage and a watching brief should be kept over the

issue.7 This article is an attempt to summarise recent developments on the

safety of kava.

Several experts have implied that the German authorities’ decision to

withdraw kava from the market was politically, not scientifically,

motivated.8 Since Germany has the reputation of having generally sound

expertise on herbal medicine, other national authorities tended to follow

the German example of a ban. There is, however, evidence from Canada that

the ban is less than effective.9 In several countries, the regulatory

authorities are being taken to court by lobbyists who argue that the ban

was not justified. In the United Kingdom (UK), a recent judgement rejected

the challenge to the kava ban by 420 health stores.10

Meanwhile, several in-depth analyses of the known cases of hepatotoxicity

have emerged.11,12 They conclude that about 80% of these patients took

kava overdoses and/or self-medicated kava for longer than 3 months. Most

patients administered comedications with known hepatotoxicity. A typical

Australian case was published recently13 in which a 56-year old woman

developed fatal liver failure after taking a kava preparation for 3

months. The fatality was rated as ‘probably’ caused by kava toxicity, even

though the patient had taken two other herbal remedies associated with

liver damage and the cause of death was progressive blood loss after liver

transplant which is clearly not directly related to kava. Generally

speaking, causality is not well established and kava taken as recommended

may not be as toxic as the regulators seem to believe.

Others have pointed out that liver damage is likely to be the result of

non-traditional ways of production of commercially available kava

supplements. The traditional kava beverage is essentially a water extract.

Australian epidemiological studies suggest that regular users of the

traditional water extract consume quantities equivalent to 10–50 times the

recommended daily dose without signs of liver damage.14 Yet two cases of

hepatitis have been recently associated with ingesting traditional aqueous

kava extracts for 4–5 weeks.15 Commercial kava supplements are produced

through alcohol or acetone extraction. It is conceivable that different

methods yield different kava alkaloids.16,17 UK scientists suggested that

differences between aqueous and acetonic extraction are associated with

differences in toxicity; indeed, only water extraction delivers sufficient

glutathione which seems to be essential for protection against

hepatotoxicity.18

Another possible explanation for liver damage is that suboptimal raw

material was used during the ‘kava boom’ of the late 1990s. For instance,

manufacturers purchased peelings of the kava stump which contain the

hepatotoxic alkaloid pipermethystine not normally contained in good

quality kava supplements.19 A further explanation is the possibility of a

genetic difference between Europeans and Pacific Islanders, which could

protect the latter group from kava-induced liver damage.17 Comparative

toxicity studies are required to improve our understanding of these

issues.

The mechanism of kava hepatotoxicity (if any) is not yet understood.

Direct toxicity is unlikely but an immunologically mediated idiosyncratic

mechanism appears the most likely explanation, particularly at high doses

of kava intake.20 Kava also has the potential for causing drug

interactions through inhibition of P450 enzymes responsible for the

metabolism of numerous pharmaceuticals.21 The importance of this finding

is, however, not clear at present.

Even though few direct comparisons have been published, the efficacy of

kava seems to be similar to that of benzodiazepines.2 Therefore it is

relevant to note that a rough estimation of the incidence of liver damage

yields similar results for kava and benzodiazepines.20 There seems to be

little difference between the reported incidence of kava-induced

hepatotoxicity and that of other psychoactive drugs such as valproic acid,

fluoxetine, paroxetine, sertraline, fluvoxamine, impiramine, and

codeine.22 Of course, the seriousness of the liver damage also needs

consideration, but there are only very few cases of serious hepatoxicity

associated with kava.3–8 The many adverse effects (other than

hepatotoxicity) of psychoactive drugs (eg, sedation, dependence, memory

impairment, accidents) should also be taken into account.23

Meanwhile more positive trial data have emerged, which were not available

when kava was banned in Germany. They showed that kava reduces anxiety in

perimenopausal women24 and is as effective as opipramol or buspirone for

generalised anxiety disorder.25 A further randomised, placebo-controlled

trial demonstrated that kava is more effective than placebo in improving

sleep in patients suffering from sleep disturbances associated with

non-psychotic anxiety disorders.26 In none of these studies was there

evidence of liver toxicity or other adverse events, but clinical studies

are of course too small for detecting rare adverse events.

Vis a vis the totality of this new evidence, German physicians now

recommend kava as an herbal anxiolytic at a dose of 120–210 mg

kavapyrone/day. The length of medication should be limited to 1–2 months,

and liver enzymes should be checked before and during kava medication.27

This recommendation is, of course, more theoretical than practical: in

Germany, kava remains ‘off limits’ and, in other countries, it is marketed

as a food supplement for which such advice is not legally enforceable.

Food Standards Australia and New Zealand (FSANZ) currently propose to

prohibit the use of organic solvents or root peelings of the plant in the

production of kava products.28

Based on the data available to date, my personal impression is that the

traditional water extract seems to have no or only low hepatotoxicity.

Commercial acetone or alcohol extracts are associated with serious liver

damage in extremely rare cases. The risk/benefit balance of such products

may nevertheless turn out to be positive, particularly in comparison to

that of synthetic psychoactive drugs. But, to err on the safe side, I

would recommend caution until our knowledge is more complete.

Author information: Edzard Ernst, Director, Complementary Medicine,

Peninsula Medical School, Universities of Exeter and Plymouth, UK

Correspondence: Professor Edzard Ernst, Complementary Medicine, Peninsula

Medical School, Universities of Exeter and Plymouth, 25 Park

Road, Exeter EX2 4NT, UK. Fax: +44 1392 427562; email:

Edzard.Ernst@...

References:

Ernst E, Pittler MH, Stevinson C, White AR. The desktop guide to

complementary and alternative medicine. Edinburgh: Mosby; 2001.

Pittler MH, Ernst E. Kava extract for treating anxiety. In: The Cochrane

Library, Issue 1. Oxford: 2002.

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.

Bilia AR, Gallori S, Vincieri FF. Kava-kava and anxiety: growing knowledge

about the efficacy and safety. Life Sci. 2002;70:2581–97.

Stickel F, Baumüller H-M, Seitz K, et al. Hepatitis induced by Kava (Piper

methysticum rhizoma). J Hepatol. 2003;39:62–7.

Ernst E. Cave kava. FACT. 2002;7:323-4.

Friends of Freedom Inc. Kava Kava Re: WHO; 2004. Available online. URL:

http://www.taxtyranny.ca/images/HTML/KavaKava/19Kava-Kava.html Accessed

October 2004.

Loew D, Gaus W. Kava-Kava. Tragödie einer Fehlbeurteilung. Zeitschr

Phytother. 2002;23:267–81.

Mills E, Singh R, Ross C, et al. Sale of kava extract in some health food

stores. CMAJ. 2003;169:1158–9.

Rozenberg J. Seagrove fails to lift ban on herbal remedy. London:

The Daily Telegraph; 2004 Dec 8.

Teschke R. Kava, Kava-Pyrone und toxische Leberschäden. Z Gastroenterol

2003;41:395–404.

Teschke R, Gaus W, Loew D. Kava extracts: safety and risks including rare

hepatotoxicity. Phytomed. 2003;10:440–6.

Gow PJ, Connelly NJ, Hill RL, et al. Fatal fulminant hepatic failure

induced by a natural therapy containing kava. Med J Aust. 2003;178:442–3.

Clough A. Epidemiological studies on kava use. Cited without reference by

Whitton et al. 2004 (ref 18).

Russmann S, Barguil Y, Cabalion P, et al. Hepatic injury due to

traditional aqueous extracts of kava root in New Caledonia. Eur J

Gastroenterol Hepatol. 2003;15:1033–6.

Currie BJ, Clough AR. Kava hepatotoxicity with Western herbal products:

does it occur with traditional kava use? Med J Aust. 2003;178:421–2.

Moulds RFW, Malani J. Kava: herbal panacea or liver poison? Med J Aust

2003;178:451–3.

Whitton PA, Lau A, Salisbury A, et al. Kava lactones and the kava-kava

controversy. Phytochemistry. 2003;64:673–9.

Tang CS, Dragull K, Nerurkar P. Fighting to save Hawaii's Kava industry.

CAM Magazine 2003 May:6.

Schulze J, Raasch W, Siegers C-P. Toxicity of kava pyrones, drug safety

and precautions – a case study. Phytomed. 2003;10:68–73.

Mathews JM, Etheridge AS, Black SR. Inhibition of human cytochrome P450

activities by kava extract and kavalactones. Drug Metabol Dispos.

2002;30:1153–7.

Shen WW. The metabolism of psychoactive drugs: a review of enzymatic

biotransformation and inhibition. Biol Psychiatry. 1997;41:814–26.

Gale C, Oakley-Browne M. Anxiety disorder. BMJ. 2000;321:1204–7.

Cagnacci A, Arangino S, Renzi A, et al. Kava-Kava administration reduces

anxiety in perimenopausal women. Maturitas. 2003;44:103–9.

Boerner RJ, Sommer H, Berger W, et al. 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.

Lehrl S. Clinical efficacy of kava extract WS ® 1490 in sleep disturbances

associated with anxiety disorders. Results of a multicenter, randomized,

placebo-controlled, double-blind clinical trial. J Affective Disorders.

2004;78:101–10.

Teschke R. Hepatotoxizität durch Kava-Kava. Deutsches Ärzteblatt

2002;99:A3411–A3418.

Anon. FSANZ sticks to guns on kava. NUTRAIngredients.com. Available

online. URL: http://www.nutraingredients.com/news/news-ng.asp?id=38787

Accessed October 2004.

Current issue | Search journal | Archived issues | Classifieds | Hotline

(free ads)

Subscribe | Contribute | Advertise | Contact Us | Copyright | Other

Journals

" and the beat goes on....... " Sonny Bono " It's not the years in your life that

count. It's the life in your years. " Abraham Lincoln

__________________________________________________