Revisiting an incorrect, yet highly referenced article.

Hello, kava lovers! Today, we will examine a web document published by Dr. Robert Ashley, MD, from UCLA Health. In this document, Dr. Ashley seeks to caution readers about the risks of kava, particularly in relation to liver damage. Interestingly, this is the same article to which Joe Rogan referred during one of his podcasts to provide a summary of kava. As a result, many viewers rushed to visit this website. However, the information presented in this article is inaccurate at best.

Article: Ashley, Robert D. 2018. “Ask the Doctors - What Are the Risks and Benefits of Kava?” UCLA Health. https://www.uclahealth.org/news/ask-the-doctors-what-are-the-risks-and-benefits-of-kava

First, let us address a significant issue with this "opinion piece." When authors make statements without providing sources, it becomes difficult, if not impossible, to verify the accuracy of their claims. This is true even if the author is a doctor or expert. Without knowing where to find the information, we cannot fact-check it ourselves. Therefore, if you come across information about kava without a clear indication of its source, it is best to view it as an opinion rather than a fact. Remember, anyone can make claims, but without evidence, it is challenging to trust what they say. Always remain vigilant and ask for sources when someone presents information without proper references. In this particular case, the commentator failed to cite any sources to support their opinions, yet many have accepted them as facts. Let us now examine the errors in the author’s writing and reasoning.

Issue #1: In paragraph 2, the author states “inhibit the enzyme monoamine oxidase, and reduce the uptake of the neurotransmitters noradrenaline and dopamine.” This is mostly correct; however, there is one portion that is not. There is no current research which would suggest a reduced reuptake in dopamine. Currently, only two authors attempt to make this assumption (Aughton 2020 & Teschke et al. 2011); however, when one dives further into these two research documents, one would find that neither contains the correct citations to assert this effect. Teschke cites 3 papers (Dehnam et al. 2002, Schmidt et al. 2005, Teschke 2010); however, none of these deal with dopamine, and are all related to norepinephrine. Aughton cites one paper to assert this (Showman et al. 2015); however, this study never addresses dopamine in kava, only regarding St John’s Wort. To summarize, there is no research suggesting that kavalactones inhibit the reuptake of dopamine. 

Issue #2: In paragraph 3, the author speaks about a 2003 study (Pittler & Ernst 2003) that used doses of 60–280 mg, which the author erroneously claims were “significantly higher than what the Pacific Islanders traditionally used”. This is patently false. Personal communications with Dr. Lebot showed kavalactones of approximately 300 mg in one shell of the prepared kava. It was even observed that during long talanoa sessions in Fiji, imbibers consumed more than 8,000 mg of kavalactones in an evening (Aporosa et al. 2020).

Issue #3: Also in paragraph 3, we see the author claim that in these studies “No liver toxicity was reported, but no liver tests were performed”. Here we have great evidence that the author himself conducted minimal research, or possibly none. In this review, a minimum of three studies were identified that focused on liver health and assessed transaminase indicators such as ALT, AST, GGT, or ALP. The inclusion of these studies and their relevance can be verified by referring to the Pittler et al. 2003 document, in which they are explicitly referenced. Hence, the author’s assertion that "no liver tests were performed" is inaccurate, highlighting once again that the author failed to consult their own sources for accurate information.

Issue #4: Here we bump into the adverse event reports that every supplement blog writer loves to focus on. The author here states “More than 100 cases of liver toxicity related to the use of kava have been identified”, and for some strange reason mentions the UK. This in itself is incorrect. In the UK, three cases were reported from 1998 to 2003. However, the World Health Organization chose not to assign a "causality" category to these cases because of the subjective nature of the assessment criteria. The decision to ban kava sales in the United Kingdom was driven by fear rather than concrete evidence, as none of the cases were definitively proven to be caused by kava (House of Commons 2003). The claim of "more than 100 cases'' is misleading, as most these cases were unrelated to kava. In reality, there were only 83 cases. Some reports lacked credibility, including one in which a patient speculated about kava after seeing an internet news report. The patient’s curiosity was the sole basis for this "adverse report". It is strongly recommended to review the Schmidt et al. 2005 paper (Schmidt et al 2005), which provides an overview of all the reports and highlights the astonishing lack of basic patient information gathered by these clinicians.

Issue #5:Concerning glutathione depletion in paragraph #4, the concept of Michael additions impacting kavalactones within the digestive tract would not solely apply to alcoholic tinctures or ritualistic kava beverages. As noted earlier, the volume of kava traditionally consumed in the South Pacific vastly overshadows what is in medical extracts. It is rather improbable that the kavalactones consumed in large amounts during traditional kava ceremonies would undergo substantial changes through digestive Michael additions. 

Given that kavalactones are absorbed in their unaltered state and undeniably contribute to the pharmacological impacts of both ceremonial kava beverages and pharmaceutical standardized extracts, it is crucial to closely examine the implications of potential Michael additions of glutathione to kavalactones. This prevents hasty assumptions.

Numerous factors make this theory less applicable to kavalactones. A crucial factor is that the structure of kavalactones, due to "Steric hindrance", impedes such a reaction, as their reactive sites are not easily accessible. In summary, it is highly doubtful that this was the toxicity source observed during 1998-2003.

It is important to remember that kava and its extraction products are readily available today, and we did not observe this reaction. Furthermore, the theoretical toxicity of kavalactones due to glutathione depletion is not confined to the liver. Clearly, this hypothesis does not offer a satisfactory explanation.

Issue #6: With respect to CYP inhibition, as mentioned in paragraph 4, this issue has generated a significant amount of controversy. However, this can largely be attributed to misconceptions surrounding inhibitory CYP studies conducted in a laboratory setting. The majority of these studies demonstrating this inhibition are in vitro, performed either on animals or through cellular toxicity tests (imagine cells in Petri dishes). Only two studies have been conducted observing human pharmacokinetics in connection with CYP inhibition using several probe drugs or substrates.

A probe substrate is a drug or compound metabolized by a specific enzyme. By investigating how another drug or compound influences the probe substrate’s metabolism, researchers can predict whether that drug or compound inhibits (reduces) or induces (accelerates) the enzyme’s activity. Both Gurly et al. (2005) and Russman et al. (2005) revealed slight inhibition at CYP1A2 and CYP2E1 sites, with more pronounced effects on CYP1A2.

It is important to remember that compared with the inhibitory characteristics of several commonly used psychiatric drugs, these inhibitory effects are extremely minor. Thus, the statement "It also inhibits enzymes involved in the metabolism of many drugs" is misleading. CYP1A2 participates in the metabolism of approximately 9% of clinically used drugs, and CYP2E1 is involved in less than 1% of drugs used clinically. While cells in a Petri dish should beware, for humans, this isn't something we must be overly concerned about.

Issue #7: The author makes a widely inaccurate statement in paragraph #5 while speaking about liver enzymes in Hawaiian kava drinkers. The author obtained this information from Brown et al. (2007). The provided information appears to have some inaccuracies. First, the participant count was 62, not 31, consisting of an equal split between men and women. The author appears to have misunderstood the source they were referencing. Second, the two referenced indicators essentially boil down to one: GGT, a detail that you would understand if you had perused the source thoroughly. This is not a sign of liver damage (Aragon et al. 2010, Carey 2000, Francher et al. 2017, Oh et al. 2017). Differences in typical measurement values, such as ALT/AST, were not statistically significant among these 62 individuals. The study did uncover a strong significant association for elevated GGT in daily kava consumers, but found no meaningful association for ALT, AST, or ALP. None of the cohorts from the study exhibited any visible clinical liver disease. To be clear, an elevated GGT level does not equate to hepatocellular damage.

In conclusion, it is clear that Dr. Ashley’s document on the potential risks of kava, especially regarding liver damage, contains several inaccuracies and misinterpretations. Despite these issues, this document was referenced by Joe Rogan in his podcast and led to widespread misconceptions about kava among his audience.

We identified seven significant problems in the document, each of which highlights the author’s lack of diligence in researching the sources they quoted. This document contains unsourced opinions, incorrect interpretations about the interaction between kavalactones and dopamine, misrepresentations of traditional kava dosage among Pacific Islanders, and an uninformed view of research methodology concerning liver health studies. It also includes a misleading presentation of adverse event reports related to kava consumption, an overly simplified explanation of glutathione depletion and CYP inhibition, and significant inaccuracies in the depiction of a study on Hawaiian kava drinkers.

The document overlooks the complexity of the subjects discussed and instead presents a narrow and often inaccurate perspective. This critique serves as a reminder for us all to approach such information with a healthy degree of skepticism, especially when the sources are not adequately cited or interpreted. As lovers of kava, we need to be well-informed and critical of the information we consume to accurately understand and share the benefits and potential risks associated with our beloved beverage.

Bula/Malok!

Aragon, George, and Zobair M. Younossi. 2010. “When and How to Evaluate Mildly Elevated Liver Enzymes in Apparently Healthy Patients.” Cleveland Clinic Journal of Medicine 77 (3): 195–204. https://doi.org/10.3949/ccjm.77a.09064.

Aughton, Harvey. 2020. “Kava and Balance: The Effects of Traditionally Influenced Kava Consumption on Human Physiology.” The University of Waikato. https://researchcommons.waikato.ac.nz/handle/10289/14110.

Aporosa, Apo S., Martin Atkins, and Richard Brunton. 2020. “Kava Drinking in Traditional Settings: Towards Understanding Effects on Cognitive Function.” Human Psychopharmacology 35 (2): e2725. https://doi.org/10.1002/hup.2725.

Brown, Amy C., Janet Onopa, Peter Holck, Pakieli Kaufusi, Derek Kabasawa, Winston J. Craig, Klaus Dragull, Arieh M. Levine, and Jonathan D. Baker. 2007. “Traditional Kava Beverage Consumption and Liver Function Tests in a Predominantly Tongan Population in Hawaii.” Clinical Toxicology 45 (5): 549–56. https://doi.org/10.1080/15563650701365875.

Carey, D. William. 2000. “How Should a Patient with an Isolated GGT Elevation Be Evaluated?” Cleveland Clinic Journal of Medicine 67 (5): 315–16. https://www.ccjm.org/content/ccjom/67/5/315.full.pdf.

Denham, Alison, Michael Mc INTYRE, M. B. Ac. C., and Julie Whitehouse. 2002. “Kava— the Unfolding Story: Report on a Work-in-Progress.” Journal of Alternative and Complementary Medicine 8 (3): 237–63. https://doi.org/10.1089/10755530260127943.

Fancher, Tonya, Amit Kamboj, and John Onate. 2017. “Interpreting Liver Function Tests.” Current Psychiatry 6 (5): 61–68.

Teschke, Rolf, Samuel X. Qiu, and Vincent Lebot. 2011. “Herbal Hepatotoxicity by Kava: Update on Pipermethystine, Flavokavain B, and Mould Hepatotoxins as Primarily Assumed Culprits.” Digestive and Liver Disease: Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 43 (9): 676–81. https://doi.org/10.1016/j.dld.2011.01.018.

Gurley, Bill J., Stephanie F. Gardner, Martha A. Hubbard, D. Keith Williams, W. Brooks Gentry, Ikhlas A. Khan, and Amit Shah. 2005. “In Vivo Effects of Goldenseal, Kava Kava, Black Cohosh, and Valerian on Human Cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 Phenotypes.” Clinical Pharmacology and Therapeutics 77 (5): 415–26. https://doi.org/10.1016/j.clpt.2005.01.009.

House of Commons, and Westminster. 2003. “Kava-Kava in Food (England) Regulations 2002 and Medicines for Human Use (Kava-Kava) Prohibition Order 2002.” The Stationery Office Ltd. January 30, 2003. https://publications.parliament.uk/pa/cm200203/cmstand/deleg5/st030130/30130s01.htm.

Oh, Robert C., Thomas R. Hustead, Syed M. Ali, and Matthew W. Pantsari. 2017. “Mildly Elevated Liver Transaminase Levels: Causes and Evaluation.” American Family Physician 96 (11): 709–15. https://www.ncbi.nlm.nih.gov/pubmed/29431403.

Pittler, M. H., and E. Ernst. 2003. “Kava Extract versus Placebo for Treating Anxiety.” Cochrane Database of Systematic Reviews, no. 1. https://doi.org/10.1002/14651858.CD003383.

Russmann, Stefan, Bernhard H. Lauterburg, Yann Barguil, Erwan Choblet, Pierre Cabalion, Katharina Rentsch, and Markus Wenk. 2005. “Traditional Aqueous Kava Extracts Inhibit Cytochrome P450 1A2 in Humans: Protective Effect against Environmental Carcinogens?” Clinical Pharmacology and Therapeutics. https://doi.org/10.1016/j.clpt.2005.01.021.

Schmidt, M., M. Bone Morgan, and J. McMillan. 2005. “Kava: A Risk-Benefit Assessment.” In The Essential Guide to Herbal Safety, edited by M. Mills and K. Bone, 155–221. Elsevier Churchill Livingstone. https://docdro.id/vAzAHq7

Showman, Angelique F., Jonathan D. Baker, Christina Linares, Chrystie K. Naeole, Robert Borris, Edward Johnston, Jerry Konanui, and Helen Turner. 2015. “Contemporary Pacific and Western Perspectives on `awa (Piper Methysticum) Toxicology.” Fitoterapia 100 (January): 56–67. https://doi.org/10.1016/j.fitote.2014.11.012.

Teschke, Rolf. 2010. “Kava Hepatotoxicity: Pathogenetic Aspects and Prospective Considerations.” Liver International: Official Journal of the International Association for the Study of the Liver 30 (9): 1270–79. https://doi.org/10.1111/j.1478-3231.2010.02308.x.