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Planta Med 2015; 81(18): 1647-1653
DOI: 10.1055/s-0035-1558295
Perspectives
Georg Thieme Verlag KG Stuttgart · New York

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

Kenny Kuchta
1   National Institute of Health Sciences, Division of Pharmacognosy, Phytochemistry and Narcotics, Setagaya-ku, Kamiyoga, Tokyo, Japan
,
Mathias Schmidt
2   HerbResearch Germany, Tussenhausen-Mattsies, Germany
,
Adolf Nahrstedt
3   Institut für Pharmazeutische Biologie und Phytochemie, Westf. Wilhelms-Universität, Münster, Germany
› Author Affiliations
Further Information

Publication History

received 08 September 2015
revised 19 October 2015

accepted 23 October 2015

Publication Date:
22 December 2015 (online)

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Abstract

Kava, the rhizome and roots of Piper methysticum, are one of the most important social pillars of Melanesian societies. They have been used for more than 1000 years in social gatherings for the preparation of beverages with relaxing effects. During the colonial period, extract preparations found their way into Western medicinal systems, with experience especially concerning the treatment of situational anxiety dating back more than 100 years. It therefore came as a surprise when the safety of kava was suddenly questioned based on the observation of a series of case reports of liver toxicity in 1999 and 2000. These case reports ultimately led to a ban of kava products in Europe – 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.

Key words

Piper methysticum - Piperaceae - Kava - efficacy - hepatotoxicity - risk-benefit-relation - drug quality
 

  • References

  • 1 Anonymous Kava-Kava: Eine Lücke, die keiner wollte. Interview mit Prof. Volker Faust. Natura Med 2002; 17: 14
    PubMedGoogle Scholar
  • 2 Ernst E. Marktrücknahme des pflanzlichen Anxiolytikums Kava: Nutzen unter-, Risiken überschätzt?. Münchn Med Wschr 2003; 144: 40
    PubMedGoogle Scholar
  • 3 Loew D, Gaus W. Kava-Kava. Tragödie einer Fehlentscheidung. Z Phytother 2002; 23: 267-281
    PubMedGoogle Scholar
  • 4 Loew D. Zum Widerruf von Kava-Extrakten. Politikum oder fachliche Fehlbeurteilung?. Ärzteztsch Naturheilverf 2003; 44: 884-896
    PubMedGoogle Scholar
  • 5 Loew D. Widerruf der Zulassung von Kava-Extrakten. War die Entscheidung des BfArM gerechtfertigt?. Dt Apotheker Ztg 2005; 145: 5362-5364
    PubMedGoogle Scholar
  • 6 Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Database Syst Rev 2003; (1) CD003383
    PubMedGoogle Scholar
  • 7 Schmidt M, Nahrstedt A. Ist Kava lebertoxisch? Eine Analyse der bekannten Daten zum Leberrisiko von Kava-Präparaten. Dtsch Apoth Ztg 2002; 142: 1006-1011
    PubMedGoogle Scholar
  • 8 Schmidt M. Are kavalactones the hepatotoxic principle of kava extracts? The pitfalls of the glutathione theory. J Altern Complement Med 2003; 9: 183-187 author reply 187–188
    CrossrefPubMedGoogle Scholar
  • 9 Stevinson C, Huntley A, Ernst E. A systematic review of the safety of kava extract in the treatment of anxiety. Drug Saf 2002; 25: 251-261
    CrossrefPubMedGoogle Scholar
  • 10 Teschke R, Gaus W, Loew D. Kava extracts: safety and risks including rare hepatotoxicity. Phytomedicine 2003; 10: 440-446
    CrossrefPubMedGoogle Scholar
  • 11 Teschke R. Kava-induzierte Leberschäden – Was ist gesichert?. Dtsch Apoth Ztg 2003; 143: 4011-4021
    PubMedGoogle Scholar
  • 12 Teschke R. Nicht einmal eine Verschreibungspflicht. FAZ 2003; 54: 8
    PubMedGoogle Scholar
  • 13 Singh YN, Devkota AK. Aqueous kava extracts do not affect liver function tests in rats. Planta Med 2003; 69: 496-499
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Bauer R, Kopp B, Nahrstedt A. Relevant hepatotoxic effects of kava still need to be proven. A statement of the Society for Medicinal Plant Research. Planta Med 2003; 69: 971-972
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Schmidt M. German court ruling reverses kava ban; German regulatory authority appeals decision. HerbalGram 2014; 103: 38-43
    PubMedGoogle Scholar
  • 16 Kraft K. Verwaltungsgericht Köln kippt das Kava-Verbot. Z Phytother 2014; 35: 186-189
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Sarris J, Kavanagh DJ, Byrne G, Bone KM, Adams J, Deed G. The Kava Anxiety Depression Spectrum Study (KADSS): a randomized, placebo-controlled crossover trial using an aqueous extract of Piper methysticum . Psychopharmacology (Berl) 2009; 205: 399-407
    CrossrefPubMedGoogle Scholar
  • 18 Sarris J, Kavanagh DJ, Deed G, Bone KM. St. Johnʼs wort and Kava in treating major depressive disorder with comorbid anxiety: a randomised double-blind placebo-controlled pilot trial. Hum Psychopharmacol 2009; 24: 41-48
    CrossrefPubMedGoogle Scholar
  • 19 Sarris J, Stough C, Bousman CA, Wahid ZT, Murray G, Teschke R, Savage KM, Dowell A, Ng C, Schweitzer I. Kava in the treatment of generalized anxiety disorder: a double-blind, randomized, placebo-controlled study. J Clin Psychopharmacol 2013; 33: 643-648
    CrossrefPubMedGoogle Scholar
  • 20 Sarris J, Stough C, Teschke R, Wahid ZT, Bousman CA, Murray G, Savage KM, Mouatt P, Ng C, Schweitzer I. Kava for the treatment of generalized anxiety disorder RCT: analysis of adverse reactions, liver function, addiction, and sexual effects. Phytother Res 2013; 27: 1723-1728
    CrossrefPubMedGoogle Scholar
  • 21 Sarris J, Scholey A, Schweitzer I, Bousman C, Laporte E, Ng C, Murray G, Stough C. The acute effects of kava and oxazepam on anxiety, mood, neurocognition; and genetic correlates: a randomized, placebo-controlled, double-blind study. Hum Psychopharmacol 2012; 27: 262-269
    CrossrefPubMedGoogle Scholar
  • 22 Schmidt M, Nahrstedt A, Lüpke NP. Piper methysticum (Kava) in der Diskussion: Betrachtungen zu Qualität, Wirksamkeit und Unbedenklichkeit. Wien Med Wochenschr 2002; 152: 382-388
    CrossrefPubMedGoogle Scholar
  • 23 Teschke R, Schwarzenboeck A, Hennermann KH. Causality assessment in hepatotoxicity by drugs and dietary supplements. Br J Clin Pharmacol 2008; 66: 758-766
    CrossrefPubMedGoogle Scholar
  • 24 Teschke R, Schwarzenboeck A, Hennermann KH. Kava hepatotoxicity: a clinical survey and critical analysis of 26 suspected cases. Eur J Gastroenterol Hepatol 2008; 20: 1182-1193
    CrossrefPubMedGoogle Scholar
  • 25 Teschke R, Frenzel C, Schulze J, Eickhoff A. Herbal hepatotoxicity: challenges and pitfalls of causality assessment methods. World J Gastroenterol 2013; 19: 2864-2882
    PubMedGoogle Scholar
  • 26 Teschke R, Fuchs J, Bahre R, Genthner A, Wolff A. Kava hepatotoxicity: comparative study of two structured quantitative methods for causality assessment. J Clin Pharm Ther 2010; 35: 545-563
    CrossrefPubMedGoogle Scholar
  • 27 Teschke R, Wolff A. Kava hepatotoxicity: regulatory data selection and causality assessment. Dig Liver Dis 2009; 41: 891-901
    CrossrefPubMedGoogle Scholar
  • 28 Teschke R, Wolff A. Regulatory causality evaluation methods applied in kava hepatotoxicity: are they appropriate?. Regul Toxicol Pharmacol 2011; 59: 1-7
    CrossrefPubMedGoogle Scholar
  • 29 Strahl S, Ehret V, Dahm HH, Maier KP. Nekrotisierende Hepatitis nach Einnahme pflanzlicher Heilmittel. Dtsch Med Wochenschr 1998; 123: 1410-1414
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Russmann S, Lauterburg BH, Helbling A. Kava hepatotoxicity. Ann Intern Med 2001; 135: 68-69
    PubMedGoogle Scholar
  • 31 Johnson BM, Qiu SX, Zhang S, Zhang F, Burdette JE, Yu L, Bolton JL, van Breemen RB. Identification of novel electrophilic metabolites of Piper methysticum Forst (Kava). Chem Res Toxicol 2003; 16: 733-740
    CrossrefPubMedGoogle Scholar
  • 32 Olsen LR, Grillo MP, Skonberg C. Constituents in kava extracts potentially involved in hepatotoxicity: a review. Chem Res Toxicol 2011; 24: 992-1002
    CrossrefPubMedGoogle Scholar
  • 33 Hänsel R, Lazar J. Kawapyrone. Inhaltsstoffe des Rauschpfeffers in pflanzlichen Sedativa. Dtsch Apoth Ztg 1985; 125: 2056-2058
    PubMedGoogle Scholar
  • 34 Gaedcke F. SL-49: Pharmaceutical characterization of Kava-Kava extracts and their formulations. Phytomed 2000; 7 (Suppl. 02) 27
    PubMedGoogle Scholar
  • 35 Anonymous Assessment of the risk of hepatotoxicity with kava products. Geneva: World Health Organization; 2007
    Google Scholar
  • 36 Lewin L. Über Piper methysticum (Kawa-Kawa). Berl Klin Wschr 1886; 1: 7-10
    PubMedGoogle Scholar
  • 37 Zhou P, Gross S, Liu JH, Yu BY, Feng LL, Nolta J, Sharma V, Piwnica-Worms D, Qiu SX. Flavokawain B, the hepatotoxic constituent from kava root, induces GSH-sensitive oxidative stress through modulation of IKK/NF-kappaB and MAPK signaling pathways. FASEB J 2010; 24: 4722-4732
    CrossrefPubMedGoogle Scholar
  • 38 Li X, Liu Z, Xu X, Blair CA, Sun Z, Xie J, Lilly MB, Zi X. Kava components down-regulate expression of ar and ar splice variants and reduce growth in patient-derived prostate cancer xenografts in mice. PLoS One 2012; 7: e31213
    CrossrefPubMedGoogle Scholar
  • 39 Dragull K, Yoshida WY, Tang CS. Piperidine alkaloids from Piper methysticum . Phytochemistry 2003; 63: 193-198
    CrossrefPubMedGoogle Scholar
  • 40 Nerurkar PV, Dragull K, Tang CS. In vitro toxicity of kava alkaloid, pipermethystine, in HepG2 cells compared to kavalactones. Toxicol Sci 2004; 79: 106-111
    CrossrefPubMedGoogle Scholar
  • 41 Lechtenberg M, Quandt B, Schmidt M, Nahrstedt A. Is the alkaloid pipermethystine connected with the claimed liver toxicity of Kava products?. Pharmazie 2008; 63: 71-74
    PubMedGoogle Scholar
  • 42 Teschke R, Qiu SX, Xuan TD, Lebot V. Kava and kava hepatotoxicity: requirements for novel experimental, ethnobotanical and clinical studies based on a review of the evidence. Phytother Res 2011; 25: 1263-1274
    PubMedGoogle Scholar
  • 43 Teschke R, Lebot V. Proposal for a kava quality standardization code. Food Chem Toxicol 2011; 49: 2503-2516
    CrossrefPubMedGoogle Scholar
  • 44 Schmidt M, Carreno I, Vergano P. Technical assistance to the integration to the multilateral trading system and support to the integrated framework. Ref: 9 ACP RPR 140‐039/11: Establishment of health and safety standards for the production and export of kava-based products. Brussels: ACP-EU-TBT; 2012
    Google Scholar
  • 45 Lebot V. The quality of kava consumed in the South Pacific. HerbalGram 2006; 71: 34-37
    PubMedGoogle Scholar
  • 46 Schmidt M. Quality criteria for kava. HerbalGram 2007; 73: 44-49
    PubMedGoogle Scholar
  • 47 Lebot V, Merlin M, Lindstrom L. Kava, the Pacific elixir. New Haven: Yale University Press; 1992
    Google Scholar
  • 48 Siméoni P, Lebot V. Buveurs de kava. Port Vila, Vanuatu: Géo-consulte; 2014
    Google Scholar
  • 49 Lebot V. Kava in the Pacific. High Level Conference on Kava: Port Vila, Vanuatu; 2012
    Google Scholar
  • 50 Kaul PN, Joshi S. Alternative medicine: herbal drugs and their critical appraisal, Part II. Chapter 2: Kava-Kava. In: Jucker E, editor Progress in drug research, Vol. 57. Basel: Springer; 2001: 5-24
    Google Scholar
  • 51 Narayanapillai SC, Leitzman P, OʼSullivan MG, Xing C. Flavokawains A and B in kava, not dihydromethysticin, potentiate acetaminophen-induced hepatotoxicity in C57BL/6 mice. Chem Res Toxicol 2014; 27: 1871-1876
    CrossrefPubMedGoogle Scholar
  • 52 Lebot V, Do TK, Legendre L. Detection of flavokavins (A, B, C) in cultivars of kava (Piper methysticum) using high performance thin layer chromatography (HPTLC). Food Chem 2014; 151: 554-560
    CrossrefPubMedGoogle Scholar
  • 53 Schmidt M. “Noble” vs. “Two-day” Phytochemical quality and analytical specifications. High Level Conference on Kava: Port Vila, Vanuatu; 2012
    Google Scholar
  • 54 Teschke R, Sarris J, Schweitzer I. Kava hepatotoxicity in traditional and modern use: the presumed Pacific kava paradox hypothesis revisited. Br J Clin Pharmacol 2012; 73: 170-174
    CrossrefPubMedGoogle Scholar
  • 55 Kraft M, Spahn TW, Menzel J, Senninger N, Dietl KH, Herbst H, Domschke W, Lerch MM. Fulminant liver failure after administration of the herbal antidepressant kava-kava. Dtsch Med Wochenschr 2001; 126: 970-972
    Article in Thieme ConnectPubMedGoogle Scholar