SAFETY ISSUES AFFECTING HERBS:
THE CASE OF KAVA
Kava (Piper methysticum) has recently joined the ranks of herbs that have been suspected of causing liver inflammation in some users. These relatively rare but serious reactions have been attributed to the Western herbs comfrey, germander, and chaparral, and to the Chinese herbs ho-shou-wu, Jin Bu Huan (a patent medicine containing an herbal active ingredient, tetrahydropalmatine), and an herb formula used in England for treatment of eczema. Further, other Western herbs, less commonly used, have been said to cause such reactions, and a letter to the editor of the Journal of the American Medical Association from a German clinic suggested that 1% of users of Chinese herbs experienced such reactions.
In many of the cases of hepatic reaction, questions have been raised about the purported connection to the herb use. Some of the people with inflamed livers had been taking drugs that could have caused the reactions; some consumed alcohol in large quantities; some may have had hepatic viruses that were responsible. Also, there were some cases where unusually large amounts of the herbs were consumed, suggesting that the liver inflammation might not have occurred within the normal dosage range. In a few cases, the reported adverse reactions to the herbs were simply mistaken reports: the item consumed did not actually include the herb.
Despite all the questions raised about the adverse reactions to herbs, some of the cases cannot be readily explained as anything but a rare reaction, at least with all information currently available. There is no doubt that some herbs contain substances that can adversely affect the liver, such as the herbs that have high levels of toxic pyrrolizidine alkaloids (see: Safety issues affecting herbs: pyrrolizidine alkaloids). But, even without ingesting any toxins, there are some people who experience unexpected reactions to herbs or drugs, referred to as idiosyncratic reactions. These responses, which could include hepatic inflammation, are possibly due to predisposing genetic factors or even immunological factors, resulting in a reaction to a substance that is not toxic for most people.
With the uncertainties about causation and extent of the problem, it is difficult for government agencies, health authorities, and product manufacturers to ignore any group of reported adverse reactions even when the cases are poorly reported or have confounding features. In this instance, the widely used anti-anxiety herb kava was reported as a possible causative agent in at least 28 cases of liver reactions in Germany and Switzerland (1). This is a small number out of the hundreds of thousands of users of kava in those countries: it has been estimated that 250 million doses of kava were consumed in Europe during the past decade. According to Mark Blumenthal of the American Botanical Council: "There have been at least 13 clinical studies conducted on 619 participants demonstrating kava's positive effects for anxiety, mental function, reaction time, sleep quality, and peri-menopausal symptoms, with two published meta-analyses of three of the trials that met the highest criteria for evaluation, that kava was safe and more effective than placebo in treating symptoms of anxiety.
Initially, based on four early case reports, a specific widely used kava preparation was banned in Switzerland. This product, which had a very high concentration of the main active components, called kavalactones (70%), was made by acetone-based extraction. While some herbalists immediately jumped at the opportunity to blame the use of acetone (which itself is a liver toxin and might extract ingredients different than those obtained by more traditional methods) as a probable cause rather than the herb (2), this connection soon fell apart. The fact is that there is no acetone left after manufacture and most of the other cases of liver reaction to kava reported later were not associated with an acetone extraction method. For example, alcohol extracts were found to be involved as well (alcohol is used to prepare tinctures that many herbalists prefer and recommend to children and others). Alcohol extracts of kava were consumed in 5 of the 6 cases of most serious liver problems that were said to be associated with use of the kava extracts.
Being quick to blame this particular extract is problematic for several reasons. First, it gives credence to the claim that the herb material was responsible for the liver reaction even though the records might have been incomplete. After further investigations, all but one or two of the reported cases of kava-induced liver toxicity have been shown to have little or no support for a causative connection. Second, it displays an unfortunate tendency for herb proponents to proclaim the benefits of non-traditional herb preparations when favorable clinical studies are reported, but save their objections to these same non-traditional preparations until a problem has already been discovered. For example, the acetone extracts had been the subject of 7 widely reported controlled clinical trials that indicated both efficacy and safety. Third, it reveals an unwillingness to investigate first and draw conclusions later. As Mark Blumenthal points out: "It should come as no surprise that the initial reports in Switzerland pertain to the acetone extract, since it dominates the market there with an approximately 80%-85% share....Interestingly, the decision by the Swiss authorities [to ban the sale of this product] was made despite the fact that in three cases other potentially hepatotoxic drugs (e.g. diclofenac) had been taken and concurrent viral infections and alcohol use or abuse could not be ruled out."
The government and industrial authorities in Germany investigated the reported cases and found that "in most of the reported cases, the causality between kava intake and liver reactions is not clear because further medication was used which might have caused liver toxicity. Furthermore, in many cases, detailed information on the patients' history, co-medication, consumption of alcohol, and further particulars are missing, thus not permitting sound evaluation of these cases." An investigation by Donald Waller (Professor of Pharmacology and Toxicology) was undertaken for the American Herb Products Association (AHPA). In a letter to the president of that trade group (3), Dr. Waller described his examination of adverse event reports received posted by the U.S. FDA. As an example of his findings, one of the reports involved a woman who was hospitalized for congestive heart failure and renal failure (disorders not blamed on kava ingestion). According to the report, the woman was taking no less than 20 different supplement products, containing at least 60 different ingredients, plus several over the counter medications. The patient reported using kava "occasionally." The patient also reported daily alcohol use with binge drinking on weekends. A biopsy revealed that the patient had liver cirrhosis. Attributing this liver disorder to kava, especially with the limited information available, would appear to be an unjustifiable stretch.
Dr. Waller concludes his report:
…kava when taken in appropriate doses for reasonable periods of time has no scientifically established potential for causing liver damage. However as with any pharmacologically active agent, there is always the possibility of drug interactions, preexisting disease conditions and idiosyncratic or hypersensitivity reactions, which can exacerbate the toxicity of such an agent. Increased surveillance or reports of adverse effects and judicious use of kava-derived products under the conditions recommended by the natural products industry would be a most prudent approach to confirm its safety and minimize any risk of liver damage. The medical community and the general public should be made aware that concomitant intake of prescription drugs associated with liver damage, excessive alcohol consumption and preexisting liver disease or hepatitis with compromised liver function are conditions which may preclude any kava consumption.
Unfortunately, however, at least one case reported in Europe seemed to have a clear link to kava ingestion, according to the reports issued thus far. The investigations are ongoing. In the meantime, some countries have banned the sale of kava products (e.g., France), or recommended voluntary withdrawal of consumer products until more information is gathered (e.g., England), while others are working out possible restrictions on sale of kava products, such as limiting it to prescription only (e.g., Germany).
ITM has provided two formulas with kava in its White Tiger line. Melakava has been available since 1995 and contains in each tablet 500 mg of powdered kava root, with about 3% kava lactones, providing 15-30 mg of kava lactones per recommended dose (1-2 tablets before bed). There have been no complaints associated with use of unprocessed kava root. Nardova has been available since 1999 and contains in each tablet 250 mg of kava extract, 12:1, with 30% kava lactones. This provides about 75 mg of kava lactones per tablet, which is recommended to be used 1 tablet each time, 1-2 times daily (or 1-2 tablets before bed); the German Commission E has conservatively indicated that the proper range of dosage for kava extracts is 60-120 mg kavalactones per day, which is very close to the 75-150 mg obtained with this product. Many of the adverse reaction reports appear to be associated with the higher dosage products and higher concentration extracts, with people consuming up to 4 times the recommended dosage (e.g., about 500 mg of kavalactones per day). Therefore, at this time, there is no evidence that either of these formulas would be harmful-on the basis of their content of kava powder or dried extracts-when used normally (as per label instructions). ITM recommends that practitioners ask their patients to stick to the label instructions. Patients who need to use the herbs for prolonged periods (e.g., more than 6 months) should check their liver functions to assure no problems with use of the herbs or other things they may be taking. Practitioners should inform their patients that there have been rare reports of adverse liver reactions to use of some kava preparations. After further investigations of the case reports and decisions by the health authorities in the countries involved, ITM may opt to remove kava from one or both products. Currently these formulas are prescribed by health professionals and meet the standards being considered in most countries.
The following reference materials were used by ITM to provide this early notification. These items may not be available for general viewing until a later time. This article will be updated accordingly. The best information on this subject can be obtained by visiting the American Botanical Council website www.herbalgram.org.