Kava and kava derived products are generally considered as very safe. In 2002, the German health authorities banned kava extract containing products based on the suspicion of a potential liver toxicity, as derived from adverse event reports. From the case reports and the sales figures of kava extracts, an incidence rate of one potential case in 60 to 125 million patients was deducted. Clinical, pre-clinical and toxicological studies have so far failed to show toxicity for kava preparations and their constituents.
The potential toxicity of a three month respectively six month oral application of 7.3 versus 73 mg/kg body weight of ethanolic full kava extract was tested in rats. The animals were examined for changes in body weight, hematological and liver parameters, and macroscopical and microscopical histological changes in the major organs. No signs of toxicity could be found. These results are in accordance with the medical experience for the use of kava preparations and the long tradition of kava drinking in the South Pacific island states. Specifically, the results do not back the suspicion of potential liver toxicity.
Download Chronic Toxicity of Kava Extract in the Rat, Poster presentation
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Kava (Piper methysticum) and kavalactones were recently suspected to be the cause of drug induced hepatitis. Our in vitro screening was aimed on the detection of cytotoxic effects of differently produced kava extracts and isolated kavalactones
in liver cells. Methods: Kava root powder, an ethanolic full extract, an acetonic special extract and the six major kavalactones (kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin and desmethoxyyangonin) were tested in primary cultured rat hepatocytes and human HepG2 cells using cytotoxicity assays including the MTT test.
Results: The tested kava extracts were essentially non-toxic in the relevant dosage range. Kavalactones showed a differential behaviour with concentration-dependent toxicity only detectable in primary cultured rat hepatocytes, but not in human HepG2 cells (EC50 >200 µg/ml). In rat hepatocytes, only kavain and methysticin (EC50 45 respectively 63 µg/ml) displayed noteworthy effects.
Conclusions: In this in vitro model, neither the tested kava extracts nor the individual kavalactones displayed relevant liver cell toxicity. The results argue against the suspicion of potentially severe hepatotoxicity of kava products.
Download Poster: 53rd Annual Congress of the Society for Medicinal Plant Research, Florence (Italy), August 21-25, 2005
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Preparations from kava (Piper methysticum) have been banned based on the suspicion of adverse liver effects. To date, no convincing proof has been given to substantiate the danger of a relevant toxicity.
We systematically tested kava extracts prepared with acetone or ethanol from two different cultivars, both used for kava extract production: Ava Laau from Samoa, a “noble kava”, and Palisi from Vanuatu, a “Tudei kava” (“two-day” lasting effect). We also tested the influence of aerial parts (stem peelings) on toxicity.
Methods: Extracts were prepared and characterized by the working group of Prof. Nahrstedt at the University of Münster (Germany). Kava plant material was obtained from cultivations. Extracts were tested in HepG2 and Hep3B liver cells, using the MTT test, the Rezasurin blue assay, quantification of LDH leakage and measurements of intracellular ATP and GSH contents.
Results
Only gradual differences in cytotoxicity were found. The sequence of toxicity for ethanolic extracts was roots (noble) < peelings (noble) ≤ roots (Tudei) < peelings (Tudei). In the case of extracts prepared with acetone the toxicity of the Tudei-material was partly reversed: peelings (Tudei) < roots (Tudei). In no case were the EC50 values in a relevant dosage range (1250 to >5000 µg/ml for roots, 800 to >5000 µg/ml for peelings in the MTT test and rezasurin blue assay, with the highest toxicity found with Tudei peelings in the rezasurin blue test in Hep 3B cells).
Conclusions
No hint on relevant liver cell toxicity was found in this battery of in vitro models.
Download: Poster: Comparison of in vitro-cytotoxicity of kava as a function of cultivar, plant part and extraction. 54rd Annual Congress of the Society for Medicinal Plant Research, Helsinki (Finland), August 28 - September 2, 2006
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Publications
U. Mittmann, M. Schmidt, J. Vrastyakova: Akut-anxiolytische Wirksamkeit von Kava-Spissum-Spezialextrakt und Benzodiazepinen als Prämedikation bei chirurgischen Eingriffen – Ergebnisse einer randomisierten, referenzkontrollierten Studie. J. Pharm. Ther. 9(4), 99-108 (2000).
M. Schmidt, A. Nahrstedt: Ist Kava lebertoxisch? Dtsch. Apoth. Ztg. 142(9): 1006-1011 (2001).
M. Schmidt: Lebernebenwirkungen durch Kavaextrakt? Eine Analyse der vom BfArM gelisteten hepatotoxischen Reaktionen. J. orthomol. Med. 9(4): 379-391 (2001).
M. Schmidt, A. Nahrstedt, N.P. Lüpke: Piper methysticum (Kava) in der Diskussion: Betrachtungen zu Qualität, Wirksamkeit und Unbedenklichkeit. Wiener Med. Wschr. 152(15/16): 382-388 (2002).
M. Schmidt, A. Nahrstedt: Aus für pflanzliche Arzneimittel? Das Bundesinstitut für Arzneimittel und Medizinprodukte verwendet fragwürdige Maßnahmen zur Marktbereinigung. Gesellschaftspolitische Kommentare 43(2): 33-35 (2002).
M. Schmidt: Der Fall Kava: Ein Etappensieg im Feldzug gegen die Phytotherapie. Gesellschaftspolitische Kommentare 43(9): 40-44 (2002) und J. orthomol. Med. 11(1): 53-64 (2003).
M. Schmidt: Are kavalactones the hepatotoxic principle of kava extracts? The pitfalls of the glutathione theory. J. Alt. Compl. Med. 9(2): 183-188 (2003).
M. Schmidt: Das Kava-Vertriebsverbot – Eine Maßnahme zur Verbesserung des Verbraucherschutzes? Drogenreport 16(30): 40-43 (2003).
M. Schmidt, M. Morgan, K. None, J. McMillan: Kava: A Risk-Benefit Assessment. In: S. Mills and K. Bone (Hrsg.): The Essential Guide to Herbal Safety. Elsevier Churchill Livingstone: St. Louis (Missouri, USA): 155-221 (2006).
L. Sorrentino, A. Capasso, M. Schmidt: Safety of ethanolic kava extract: Results of a study of chronic toxicity in rats. Phytomedicine 13: 542-549 (2006).
M. Schmidt: Quality criteria for kava. HerbalGram 73: 44-49 (2007).
M. Lechtenberg, B. Quandt, M, Schmidt, A. Nahrstedt: Is the alkaloid pipermethystine connected with the claimed liver toxicity of kava products? Pharmazie 63(1): 71-74 (2008).
Poster
G. Betti, M. Schmidt: A quality management program for Piper methysticum Forst. f. Annual Meeting of the Society for Medicinal Plant Research, Erlangen (Germany), 3. September 2001.
M. Lechtenberg, B. Quandt, M. Schmidt, A. Nahrstedt: Is the Kava alkaloid pipermethystine connected with liver toxicity of kava products? 54th International Meeting of the Society for Medicinal Plant Research, Helsinki (Finland), 29. August – 2. September 2006.
Oral presentations
M. Schmidt: A quality management program for Piper methysticum Forst. F. Jahrestagung der Gesellschaft für Arzneipflanzenforschung, Erlangen (Germany), 3. September 2001.
M. Schmidt: Das Kava-Vertriebsverbot – eine Maßnahme zur Verbesserung des Verbraucherschutzes? 5. Jahrestagung der Gesellschaft für Arzneipflanzenanbau (Artemisia e.V.), Artern/Thüringen (Germany), 28. September 2002.
M. Schmidt: Safety issues in drug registration: Alleged kava hepatotoxicity and risk-benefit evaluation based on international adverse effect reports. European-Pacific Kava Stakeholder Meeting, Brussels (Belgium), 26. August 2003.
M. Schmidt: Herbal medicine in Europe: Risks overestimated, benefits underestimated. Medicine in the 21st Century: Tri-Conference and Bioforum, Shanghai (China), 25.-27. July 2004.
M. Schmidt: Pharmacovigilance: Recent developments for Kava and St. John’s wort. Figon Dutch Medicine Days, Lunteren (The Netherlands), 7. Oktober 2004.
M. Schmidt: The Kava case reports reinterpreted: Critical review of toxicology and pharmacovigilance. International Kava Congress, Suva (Fiji), 1. December 2004.
M. Schmidt: Quality criteria for kava. International Kava Congress, Suva (Fiji), 2. December 2004.
M. Schmidt: Kava (Piper methysticum) und Johanniskraut (Hypericum perforatum): Aktuelles zur Tragödie um zwei bewährte Arzneipflanzen. Symposium of EIGL e.V., Munich (Germany), 16. December 2004.
M. Schmidt: Kava for the treatment of anxiety. The Pro-position. ACCP congress, Orlando (USA), 25. April 2009.