A failure in logic through the decades regarding kava.
Hello kava lovers, let’s take a stab at something that quite a number of researchers like to cite as “evidence” which attempts to support the thought that even aqueous (traditional prep) kava preparations can be hepatotoxic, or cause liver damage.
Lucky for us it’s a simple, short adverse event report from, you guessed it, 2001. Also, as is tradition, the details leave much to be desired, however we can tease out the likely culprit, and spoiler alert, it’s not kava.
We’ll be focusing specifically on the following adverse event report details:
Humberston, C. L., J. Akhtar, and E. P. Krenzelok. 2003. “Acute Hepatitis Induced by Kava Kava.” Journal of Toxicology. Clinical Toxicology 41 (2): 109–13. https://doi.org/10.1081/clt-120019123.
The text discusses a case where a 14-year-old girl developed acute hepatitis, a severe inflammation of the liver. Despite initial treatments, her condition worsened, leading to liver failure and necessitating a liver transplant. The report emphasizes the potential hepatotoxicity of kava, however it fails the standard tests of logic. They say she was consuming two tablets per day of these, however…Celestial Seasonings NEVER has released any product outside of the teabag format. These “tablets” don’t and never have existed. While egregious, this might actually be one of the least of the problems with this “report”.
The paper concluded that the consumption of between 30mg/day and 100mg/day kava extract from “Celestial Seasonings” Tea bags was the primary factor for the severe necrotic hepatitis in the 14-year-old girl. However, there seems to be an omission in the study regarding the impact of another drug she was being administered, ranitidine. This could indeed provide a significant counter-argument to the original study, based on several points:
- Incomplete Assessment of Variables: A well-constructed medical study will aim to control for as many variables as possible, particularly those that might reasonably be expected to influence the outcome. Ranitidine, known for its hepatic negative effects, was not addressed in the study at all, thus failing to consider an important variable in the patient’s condition. Additionally, the botanical product in question was not a singular kava product, and contained a multitude of other botanical extracts and ingredients. Finally, the study never ascertained whether the patient did indeed have kavalactones in their system.
- Causation vs Correlation: The assumption made in the study is that kava caused hepatotoxicity because the patient was consuming it. However, this could be a correlation, not causation. The simultaneous intake of ranitidine could be the actual cause. The continuation of liver damage even after cessation of kava supports this argument.
- Contrary Evidence: To ascertain causation, being able to repeat the result is an important aspect in scientific studies. As we’ve mentioned numerous times, no other study has shown repeatable hepatotoxic effects in traditional kava consumption. If the hepatotoxicity was truly due to kava, similar effects should be observable in numerous other studies as well.
- Liver Damage Continuation: It’s significant to note that the patient’s liver values didn’t recover after they stopped taking kava, but ranitidine was (alarmingly) continued until the liver transplant. If kava was indeed the cause, some degree of recovery or at least stabilization would be expected after its discontinuation.
Therefore, taking all into account, the study almost certainly has prematurely concluded the role of kava in causing the severe necrotic hepatitis. More comprehensive investigations and repeatable studies should be conducted, considering all the factors, including potential interactions and individual patient characteristics, to reach a more reliable and valid conclusion. In short Humberston et al incorrectly identified kava as the causative agent in this patient’s etiology of hepatic failure.
Now, here comes the real awful part of all of this. There have been ~50 individual studies which cite this report as evidence towards the liver toxic effects of kava even with traditional preparation. In essence, the entire premise of liver toxicity from water extracted products hinges on extraordinarily poorly recorded documents with inappropriately applied logic and just straight up incorrect conclusions. Consequently, subsequent researchers love to cite this as proof-positive of a hepatotoxic effect from kava, and I’m sorry, but this just ain’t it.
The following non-exhaustive list of papers use this erroneous source to assert that traditional kava is hepatotoxic:
Tarbah, Ali Fuad. 2003. “Analytical Studies on the Kavain Metabolism in Human Specimen and Liver Cell Lines.” Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf.
Behl, Mamta, Abraham Nyska, Rajendra S. Chhabra, Gregory S. Travlos, Laurene M. Fomby, Barney R. Sparrow, Milton R. Hejtmancik, and Po C. Chan. 2011. “Liver Toxicity and Carcinogenicity in F344/N Rats and B6C3F1 Mice Exposed to Kava Kava.” Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association 49 (11): 2820–29. https://doi.org/10.1016/j.fct.2011.07.067.
Soares, Rita B., Ricardo Jorge Dinis-Oliveira, and Nuno G. Oliveira. 2022. “An Updated Review on the Psychoactive, Toxic and Anticancer Properties of Kava.” Journal of Clinical Medicine Research 11 (14). https://doi.org/10.3390/jcm11144039.
[Centers for Disease Control and Prevention]. 2002. “Hepatic Toxicity Possibly Associated with Kava-Containing Products — United States, Germany, and Switzerland, 1999–2002.” Morbidity and Mortality Weekly Report. Surveillance Summaries 51 (47): 1065–67. http://www.jstor.org/stable/23312772.
IARC. 2013. “Kava.” In Some Drugs and Herbal Products, 117–40.
Guo, Lei, Quanzhen Li, Qingsu Xia, Stacey Dial, Po-Chuen Chan, and Peter Fu. 2009. “Analysis of Gene Expression Changes of Drug Metabolizing Enzymes in the Livers of F344 Rats Following Oral Treatment with Kava Extract.” Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association 47 (2): 433–42. https://doi.org/10.1016/j.fct.2008.11.037.
Gruenwald, Joerg, Cordula Mueller, and Skrabal Juergen. 2003. “In-Depth Investigation Into EU Member States Market Restrictions On Kava Products.” Centre for the Development of Entreprise.
Fu, Peter P., Qingsu Xia, Lei Guo, Hongtao Yu, and Po-Chuen Chan. 2008. “Toxicity of Kava Kava.” Journal of Environmental Science and Health. Part C, Environmental Carcinogenesis & Ecotoxicology Reviews 26 (1): 89–112. https://doi.org/10.1080/10590500801907407.
Fu, Dong, and Iqbal Ramzan. 2015. “Use of Kava as a Phytotherapeutic Agent and Kava‐Related Hepatotoxicity.” Phytotherapies, 312–29. https://doi.org/10.1002/9781119006039.ch13.
DiSilvestro, Robert A., Wenyi Zhang, and David J. DiSilvestro. 2007. “Kava Feeding in Rats Does Not Cause Liver Injury nor Enhance Galactosamine-Induced Hepatitis.” Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association 45 (7): 1293–1300. https://doi.org/10.1016/j.fct.2007.01.015.
Clouatre, Dallas L. 2004. “Kava Kava: Examining New Reports of Toxicity.” Toxicology Letters 150: 85–96. https://doi.org/10.1016/j.toxlet.2003.07.005.
Clayton, Natasha P., Katsuhiko Yoshizawa, Grace E. Kissling, Leo T. Burka, Po-Chuen Chan, and Abraham Nyska. 2007. “Immunohistochemical Analysis of Expressions of Hepatic Cytochrome P450 in F344 Rats Following Oral Treatment with Kava Extract.” Experimental and Toxicologic Pathology: Official Journal of the Gesellschaft Fur Toxikologische Pathologie 58: 223–36. https://doi.org/10.1016/j.etp.2006.08.002.
Bodkin, Ryan, Sandra Schneider, Donna Rekkerth, Linda Spillane, and Michael Kamali. 2012. “Rhabdomyolysis Associated with Kava Ingestion.” The American Journal of Emergency Medicine 30 (4): 635.e1–3. https://doi.org/10.1016/j.ajem.2011.01.030.
BfArM. 2002. “Kava Removal From The European Market.” http://lrd.spc.int/ahp-publications/doc_download/578-gr-cis-bfarm-kava-removal.
Ballotin, Vinícius Remus, Lucas Goldmann Bigarella, Ajacio Bandeira de Mello Brandão, Raul Angelo Balbinot, Silvana Sartori Balbinot, and Jonathan Soldera. 2021. “Herb-Induced Liver Injury: Systematic Review and Meta-Analysis.” World Journal of Clinical Cases 9 (20): 5490–5513. https://doi.org/10.12998/wjcc.v9.i20.5490.
Amorim, Maria F. D., Margareth F. F. M. Diniz, Maria S. T. Araújo, João C. L. R. Pita, Jadson G. Dantas, Josué A. Ramalho, Aline L. Xavier, Thayse V. Palomaro, and Nelson L. B. Júnior. 2007. “The Controvertible Role of Kava (Piper Methysticum G. Foster) an Anxiolytic Herb, on Toxic Hepatitis.” Revista Brasileira de Farmacognosia: Orgao Oficial Da Sociedade Brasileira de Farmacognosia 17 (3): 448–54. https://doi.org/10.1590/S0102-695X2007000300020.
Teschke, Rolf, Alexander Genthner, and Albrecht Wolff. 2009. “Kava Hepatotoxicity: Comparison of Aqueous, Ethanolic, Acetonic Kava Extracts and Kava-Herbs Mixtures.” Journal of Ethnopharmacology 123 (3): 378–84. https://doi.org/10.1016/j.jep.2009.03.038.
Various. 2012. “Toxicology and Carcinogenesis Studies of Kava Kava Extract (CAS No. 9000-38-8) in F344/N Rats and B6C3F1 Mice (gavage Studies).” National Toxicology Program 571 (1): 1–186. https://ntp.niehs.nih.gov/publications/reports/tr/500s/tr571/index.html.
Shord, Stacy S., Kanan Shah, and Alvina Lukose. 2009. “Drug-Botanical Interactions: A Review of the Laboratory, Animal, and Human Data for 8 Common Botanicals.” Integrative Cancer Therapies 8 (3): 208–27. https://doi.org/10.1177/1534735409340900.
Teschke, Rolf, Alexander Schwarzenboeck, and Ahmet Akinci. 2008. “Kava Hepatotoxicity: A European View.” The New Zealand Medical Journal 121 (1283): 90–98. https://www.ncbi.nlm.nih.gov/pubmed/18841189.
Ulbricht, Catherine, Ethan Basch, Heather Boon, Edzard Ernst, Paul Hammerness, David Sollars, Candy Tsourounis, Jen Woods, and Stephen Bent. 2005. “Safety Review of Kava (Piper Methysticum) by the Natural Standard Research Collaboration.” Expert Opinion on Drug Safety 4 (4): 779–94. https://doi.org/10.1517/14740338.4.4.779.
Ravichandiran, Velayutham, and Patil Vishal Satish. n.d. “A Review on Hepatotoxicity of Phytomedicines.” Impactfactor.org. http://impactfactor.org/PDF/IJPPR/5/IJPPR,Vol5,Issue3,Article10.pdf.
Pantano, Flaminia, Roberta Tittarelli, Giulio Mannocchi, Simona Zaami, Serafino Ricci, Raffaele Giorgetti, Daniela Terranova, Francesco P. Busardò, and Enrico Marinelli. 2016. “Hepatotoxicity Induced by ‘the 3Ks’: Kava, Kratom and Khat.” International Journal of Molecular Sciences 17 (4): 580. https://doi.org/10.3390/ijms17040580.
Lüde, Saskia, Michael Török, Sandy Dieterle, René Jäggi, Karin Berger Büter, and Stephan Krähenbühl. 2008. “Hepatocellular Toxicity of Kava Leaf and Root Extracts.” Phytomedicine: International Journal of Phytotherapy and Phytopharmacology 15 (1-2): 120–31. https://doi.org/10.1016/j.phymed.2007.11.003.
Ranitidine Toxicity Sources:
Black, M., W. E. Scott Jr, and R. Kanter. 1984. “Possible Ranitidine Hepatotoxicity.” Annals of Internal Medicine 101 (2): 208–10. https://doi.org/10.7326/0003-4819-101-2-208.
Deng, Xiaomin, James P. Luyendyk, Patricia E. Ganey, and Robert A. Roth. 2009. “Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models.” Pharmacological Reviews 61 (3): 262–82. https://doi.org/10.1124/pr.109.001727.
Deng, Xiaomin, James P. Luyendyk, Wei Zou, Jingtao Lu, Ernst Malle, Patricia E. Ganey, and Robert A. Roth. 2007. “Neutrophil Interaction with the Hemostatic System Contributes to Liver Injury in Rats Cotreated with Lipopolysaccharide and Ranitidine.” The Journal of Pharmacology and Experimental Therapeutics 322 (2): 852–61. https://doi.org/10.1124/jpet.107.122069.
Fisher, A. A., and D. G. Le Couteur. 2001. “Nephrotoxicity and Hepatotoxicity of Histamine H2 Receptor Antagonists.” Drug Safety: An International Journal of Medical Toxicology and Drug Experience 24 (1): 39–57. https://doi.org/10.2165/00002018-200124010-00004.
Gulati, K., M. R. Reshi, N. Rai, and A. Ray. 2018. “Hepatotoxicity: Its Mechanisms, Experimental Evaluation and Protective Strategies.” Am J Pharmacol. 2018; 1 (1) 1004. https://www.researchgate.net/profile/Mohd-Reshi-2/publication/354461762_Hepatotoxicity_Its_Mechanisms_Experimental_Evaluation_and_Protective_Strategies_OPEN_ACCESS/links/63e5ad15c002331f72689183/Hepatotoxicity-Its-Mechanisms-Experimental-Evaluation-and-Protective-Strategies-OPEN-ACCESS.pdf.
Hemi eda, Faried A., and E. L-Sayed K. Abdei-Hady. n.d. “Biochemical and Histological Studies on H2-Receptor Antagonist Ranitidine-Induced Hepatotoxicity in Rats.” Vol.
Hemieda, Faried A. E., El-Sayed K. Abdel-Hady, and Mostafa A. Abou Elnga. 2005. “Biochemical and Histological Studies on H2-Receptor Antagonist Ranitidine-Induced Hepatotoxicity in Rats.” Indian Journal of Experimental Biology 43 (9): 782–85. https://www.ncbi.nlm.nih.gov/pubmed/16187528.
Kanashima, R., N. Nagasue, and K. Sakato. 1985. “Ranitidine as an Inhibitor of Liver Regeneration.” American Journal of Surgery 149 (2): 223–27. https://doi.org/10.1016/s0002-9610(85)80074-x.
Luyendyk, James P., Jane F. Maddox, Gregory N. Cosma, Patricia E. Ganey, Gary L. Cockerell, and Robert A. Roth. 2003. “Ranitidine Treatment during a Modest Inflammatory Response Precipitates Idiosyncrasy-like Liver Injury in Rats.” The Journal of Pharmacology and Experimental Therapeutics 307 (1): 9–16. https://doi.org/10.1124/jpet.103.054288.
Luyendyk, James P., Jane F. Maddox, Christopher D. Green, Patricia E. Ganey, and Robert A. Roth. 2004. “Role of Hepatic Fibrin in Idiosyncrasy-like Liver Injury from Lipopolysaccharide-Ranitidine Coexposure in Rats.” Hepatology 40 (6): 1342–51. https://doi.org/10.1002/hep.20492.
Tukov, Francis F., James P. Luyendyk, Patricia E. Ganey, and Robert A. Roth. 2007. “The Role of Tumor Necrosis Factor Alpha in Lipopolysaccharide/ranitidine-Induced Inflammatory Liver Injury.” Toxicological Sciences: An Official Journal of the Society of Toxicology 100 (1): 267–80. https://doi.org/10.1093/toxsci/kfm209.
