To the Editor: We wish to comment on the case report by Lontos and colleagues on the proposed causal relationship between the herb black cohosh (Cimicifuga racemosa) and acute hepatic failure.1 One other case has been reported in Australia,2 and the evidence linking black cohosh to liver toxicity was weak and contested.3

The medication in the case report presented by Lontos and colleagues1 included a herb (ground ivy) containing a known liver toxin (pulegone). Pulegone is considered a strong hepatotoxin and should not be dismissed, even though it was reported that there was less pulegone in ground ivy than in pennyroyal.

The authors do not indicate the daily dose of the pulegone ingested. The Therapeutic Goods Administration (TGA) made only qualitative analyses of three of the five herbs in the mixture. In our opinion the most suspect ingredient was ground ivy, and it was not assayed. The argument that the TGA could not find a standard for pulegone or ground ivy is untenable given the level of expertise and the capacity of the TGA and its laboratories.

Was the supply company asked to provide analytical evidence of the contents of the herbal extracts? Ground ivy is not known to be hepatotoxic, but it is possible that the extract could have contained ground ivy with pennyroyal, which might explain the hepatoxicity of the mixture. Although uncertain without thoroughly investigating all ingredients in the herbal mixture, this alternative is a possibility. Without thorough investigation of herbal preparations, adverse events attributed to certain herbs remain dubious at best.

Black cohosh has a very good safety record. There is a large body of clinical evidence and research which suggests that this herb has no hepatotoxic effects. Indeed, a German manufacturer has sold more than 350 million daily doses of black cohosh preparations worldwide since the pharmacovigilance system was introduced, and no comparable cases have been reported until these two reports in Australia. An Ames test (salmonella microsomal assay) showed no in-vitro evidence of mutagenic potential of an extract of black cohosh,4 and no chemical or organ toxicities were observed in Wistar rats given up to 5000 mg of a Cimicifuga racemosa extract granulate per kilogram body weight for 26 weeks.5

What may also be of concern is that the TGA may not have the full capabilities to test ingredients used in Australian herbal products. That substitution of herbs with potentially toxic herbs may be a common event, and that neither the TGA nor the manufacturers may have the expertise to prevent deleterious contaminants, is of even greater concern.

Comment: Thomsen and colleagues have pointed to what they believe were uncertainties in the case described by Lontos et al, associating the use of a herbal preparation containing black cohosh with acute liver failure.1 They assert that on the basis of these uncertainties, and other evidence, black cohosh was unlikely to have been the cause of the liver failure.

There are indeed uncertainties about the cause of the illness. The first, and quite critical one, is that we cannot be certain that the patient was given the same herbal materials as those supplied to the Therapeutic Goods Administration (TGA) for analysis. The pharmacist who dispensed the herbal formula for the patient provided the TGA with samples for analysis of each of the five individual extracts in the formula. Documentary evidence supporting the correct identity of the five herbs was supplied in the form of certificates of analysis from the manufacturers of the individual herbal extracts. However, it was not possible to ascertain whether the exact batch of the exact formulation taken by the patient was that which was tested by the TGA.

While the title of the article by Lontos et al suggests a “problem” with black cohosh, the body of the article makes clear that the causative agent(s) are unknown,1 which is in agreement with the letter by Thomsen et al.1

Thomsen and colleagues claim that the TGA did not test the ground ivy extract supplied by Lontos et al, and said that this was because the TGA did not have a standard for pulegone or ground ivy. This is not the case, and the letter by Lontos et al1 does not state that either. The reason the TGA did not test initially for pulegone was because it is a minor constituent of the essential oil of ground ivy. We did not expect there to be any significant levels of this compound. In fact, we have subsequently confirmed that pulegone was not detectable (limit of detection 5 ppm) in the sample of ground ivy extract provided by Lontos et al.

Thomsen and colleagues refer to the good safety record of black cohosh in Australia and internationally, and claim there has been only one other case in Australia where black cohosh was linked to liver toxicity. Some caution is needed in drawing broad conclusions about the safety of herbal medicines. Most countries do not have adverse reaction reporting systems which include herbal remedies. In Australia, where we have a well-developed reporting system, there have been several reports of liver problems in patients taking various preparations containing black cohosh. However, causality has not been established beyond doubt in these cases.

The TGA has state-of-the-art testing facilities and a team of internationally recognised scientific staff. The formulation supplied to the patient was extemporaneously dispensed by a pharmacist. Such medicines are not subject to the regulatory controls of the TGA and would not normally be included in the TGA’s testing program. However, the TGA offered to test the herbal formulation supplied by the pharmacist to assist the clinical team. The results of the TGA’s testing confirmed the absence of undeclared pharmaceuticals in the samples of herbal extracts provided.

In view of these uncertainties, it is not possible to conclusively identify the cause of the patient’s liver failure. On the evidence available it cannot be concluded that black cohosh was a cause. It is simply not possible to rule in or rule out black cohosh, or indeed any of the other herbal extracts in the formulation taken by the patient, as a cause. Where practitioners suspect a complementary medicine is involved in an adverse reaction, providing the exact product and batch taken by the patient is essential if laboratory testing is to help in confirming causality.