(c) 2023, Eric Yarnell, ND, RH(AHG)
This information is intended for health-care providers and not patients or lay people. This information does not substitute for or overrule decisions made by individual health-care providers giving individualized recommendations to specific patients, but rather is about general issues.
Summary
- Piper methysticum (kava) root is not inherently hepatotoxic.
- Idiosyncratic hepatotoxicity to kava occurs, but it is extremely rare (and not more common than seen with other herbs).
- Only the root of kava should be used, not stem (it is not clear if stem products were ever available or used, but some speculate this may have been a temporary problem with some European products).
- Many drugs are substantially more hepatotoxic than kava, yet are not or were not banned (while kava was in many places, for a while; almost all such bans have been lifted as of 2023 due to lack of any reasonable basis for banning it).
- Kava remains an effective and safe option for most patients with difficulties sleeping, anxiety, phobias, pelvic pain, and other problems.
- There is no evidence that kava is more hazardous in people with pre-existing liver disease of any kind or taking potentially hepatotoxic drugs, though out of an abundance of caution, other herbs with similar actions are often recommended for use instead until and unless more research becomes available.
The Hepatotoxicity Scare
Up to the year 2002, the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), or Federal Institute for Pharmaceuticals and Medicinal Products (somewhat the analog of the FDA in Germany, but dealing with drugs and natural products not food) received 31 reports of hepatotoxicity associated with kava products. BfArM made an administrative decision to revoke all the licenses it had issued allowing sales of kava-containing products. Several other European countries as well as Canada, New Zealand, Australia (partially), Malaysia, Singapore, and Japan then followed suit. This was particularly absurd as many of these countries, including France, had no reports of any problems in their own countries despite widespread use of kava products. The United States never banned kava. In 2014, a German court German court ruled the ban was illegal; this was confirmed by an appeals court in 2015 and all kava products were legalized again in that country after this ruling (Kuchta, et al. 2015).
The Germany court's judgements hit on several key points about this whole ridiculous affair, and why they ruled the ban had been illegal (Kuchta, et al. 2015):
The Germany court's judgements hit on several key points about this whole ridiculous affair, and why they ruled the ban had been illegal (Kuchta, et al. 2015):
- The cases of hepatotoxicity were artificially inflated by double counting several cases.
- Many of the purported cases of kava toxicity were better explained by toxicity from other pharmaceuticals or alcohol.
- Case reports are not sufficient for proof of a causal connection between kava and hepatotoxicity. Under German law, evidence considered for a ban must involve actual proof of a causal relationship.
- The ad hoc process of assessing risk was so shoddy, it was highly likely if different investigators had applied them, different conclusions would have been reach. Using a scientific assessment process, only three of the reported hepatotoxicity cases could reasonably be tied to kava.
- This meant that there was less than 1 case of kava-associated hepatotoxicity per million users, making it so rare, there was no way a ban could be justified on safety grounds.
- Risks of drugs that are potential alternatives to kava are more dangerous, and under German law, it was not lawful to remove the safer choice (and risk assessments must take into account comparisons to related treatments).
- A case that kava was banned due to lack of efficacy was actually due to a change in the needed criteria set by BfArM. The Court ruled that such changes cannot be used to retroactively cancel previously approved licenses.
"...from the cases where a causal relationship seemed probable, an incidence rate of less than 0.02 cases per one million daily doses is calculated, corresponding to less than one case in 50 million days of application [for kava]. This incidence calculation is far below the liver risk for diazepam with one case in 472,000 days of application.” —Schmidt 2003
The lasting effects of this ill-conceived and illegal ban by BfArM are substantial. Pacific Island countries that produce kava lost billions of dollars in sales over the span of the ban. Additionally, kava now seems to be forever tainted with the false idea that it is hepatotoxic. Patients regularly ask me and other health care providers if it is safe, or, after I prescribe it, look it up on the web and become concerned, some so much so that they send me angry messages wondering how I could give them something so dangerous or why didn't I warn them. This leads to many people having no chance to experience the potential benefits of kava based on a fear that is based on nothing. This is a good (bad?) example of the toxic effects of regulatory overreach against herbal products.
While I could not find specific data on how many people suffered severe liver injury (sufficient to require hospitalization or liver transplant) or died from liver disease induced by drugs in Germany in the same time span covered by the handful of cases reported about kava up to 2002, it was clearly far, far higher than any potential issues with kava (even if all the reported cases had been due to kava, which we now know almost none of them likely were). A study of deliberate suicide attempts and successes using acetaminophen (paracetamol) to induce liver failure in Germany from 1995 to 2002 found this was a large and worsening problem (Von Mach, et al. 2003). A report published in 2002, based mostly on data from the UK, found that there were ~500 deaths per year due to acetaminophen-related hepatotoxicity from 1993 to 1997 (Sheen, et al. 2002). While this might have been different in Germany, it is still very likely there were quite a few deaths due to this hepatotoxic drug, yet it was not banned. Double standard, anyone?
The Hunt for Hepatotoxocity
Another unfortunate outcome of this false story of kava being hepatotoxic is a waste of resources searching for explanations for a problem that doesn't exist, or trying to further anti-kava hysteria. Here some of these pointless exercises will be reviewed, but instead they seem to further confirm that kava is not hepatotoxic.
An isolated pyridone alkaloid known as pipermethystine from kava was damaging to hepatocytes in vitro in one assay, while kavalactones were not (Nerurkar, et al. 2004). However, in an assay of many products on the German market, as well as extracts made by hand from kava root and stem, none of this alkaloid could be detected (Lechtenberg, et al. 2008). Only kava leaf extracts were found to contain a tiny amount of this alkaloid, ~0.2%. So some posit that perhaps some extracts containing kava leaf extracts may been in circulation and caused problems, but this doesn't square with the near total absence of any human cases of liver problems clearly attributed to kava, nor the fact that currently no such products could be detected. This is a highly unlikely explanation for the non-problem of kava hepatotoxicity.
An isolated pyridone alkaloid known as pipermethystine from kava was damaging to hepatocytes in vitro in one assay, while kavalactones were not (Nerurkar, et al. 2004). However, in an assay of many products on the German market, as well as extracts made by hand from kava root and stem, none of this alkaloid could be detected (Lechtenberg, et al. 2008). Only kava leaf extracts were found to contain a tiny amount of this alkaloid, ~0.2%. So some posit that perhaps some extracts containing kava leaf extracts may been in circulation and caused problems, but this doesn't square with the near total absence of any human cases of liver problems clearly attributed to kava, nor the fact that currently no such products could be detected. This is a highly unlikely explanation for the non-problem of kava hepatotoxicity.
References
Coulter D, Tamayo C, Sotheeswaran S, Ulbricht C (2007) Assessment of the risk of hepatotoxicity with kava products (World Health Organization).
Kuchta K, Schmidt M, Nahrstedt A (2015) "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" Planta Med 81(18):1647–53.
Lechtenberg M, Quandt B, Schmidt M, Nahrstedt A (2008) “Is the alkaloid pipermethystine connected with the claimed liver toxicity of kava products?” Pharmazie 63(1):71-4.
Nerurkar PV, Dragull K, Tang CS (2004) “In vitro toxicity of kava alkaloid, pipermethysticine, in HepG2 cells as compared to kavalactones” Toxicol Sci 79:106-11.
Schmidt M (2003) "Is kava really hepatotoxic? An analysis of the known data on adverse effects of kava preparations on the liver" Institute of Pharmaceutical Biology and Phytochemistry. [accessed 1 March 2005]
Sheen CL, Dillon JF, Bateman DN, et al. (2002) "Paracetamol toxicity: epidemiology, prevention and costs to the health-care system" QJM 95(9):609–19.
Teschke R (2010) "Kava hepatotoxicity. A clinical review" Ann Hepatol 9(3):251–65.
Von Mach MA, Lauterbach M, Kaes J, et al. (2003) "Deliberate self-poisoning with paracetamol (acetaminophen): An analysis from 1995 to 2002" Dtsch Med Wochenschr 128(1–2):15–9 [in German].
Kuchta K, Schmidt M, Nahrstedt A (2015) "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" Planta Med 81(18):1647–53.
Lechtenberg M, Quandt B, Schmidt M, Nahrstedt A (2008) “Is the alkaloid pipermethystine connected with the claimed liver toxicity of kava products?” Pharmazie 63(1):71-4.
Nerurkar PV, Dragull K, Tang CS (2004) “In vitro toxicity of kava alkaloid, pipermethysticine, in HepG2 cells as compared to kavalactones” Toxicol Sci 79:106-11.
Schmidt M (2003) "Is kava really hepatotoxic? An analysis of the known data on adverse effects of kava preparations on the liver" Institute of Pharmaceutical Biology and Phytochemistry. [accessed 1 March 2005]
Sheen CL, Dillon JF, Bateman DN, et al. (2002) "Paracetamol toxicity: epidemiology, prevention and costs to the health-care system" QJM 95(9):609–19.
Teschke R (2010) "Kava hepatotoxicity. A clinical review" Ann Hepatol 9(3):251–65.
Von Mach MA, Lauterbach M, Kaes J, et al. (2003) "Deliberate self-poisoning with paracetamol (acetaminophen): An analysis from 1995 to 2002" Dtsch Med Wochenschr 128(1–2):15–9 [in German].