In February 2006 the Australian Therapeutic Goods Administration (TGA) issued a policy for a new label warning to be required for all herbal products containing black cohosh (Actaea racemosa L. Ranunculaceae, syn. Cimicifuga racemosa).1 TGA cited at least 47 adverse event reports (AERs) of hepatotoxicity collected worldwide that have been allegedly associated with black cohosh-containing products. Even though some of these products have contained multiple herbs, some observers have classed them as black cohosh-related AERs.
Australia has had a rather tightly regulated market for herbs and other "therapeutic goods" since the passage of the Therapeutic Goods Act of 1990. Of the 47 cases reported worldwide of alleged hepatotoxicity associated with black cohosh-containing preparations, a number of them have been reported in Australian medical journals.2,3 Thus, it is understandable that the TGA has taken an interest and reviewed this issue. Based on its own criteria and processes, TGA decided to issue this warning. In Australia, 4 patients were reportedly hospitalized, including 2 patients who required liver transplants.
"The TGA acknowledged that "Although some reports are confounded by multiple ingredients, by more than one medication or by other medical conditions, there is sufficient evidence of a causal association between black cohosh and serious hepatitis."1 The TGA hastened to add a note about the relative safety of black cohosh: "Éconsidering the widespread use of black cohosh, the incidence of liver reaction appears to be very low." The TGA policy requires the following label statement on black cohosh products:
"Warning: Black cohosh may harm the liver in some individuals. Use under the supervision of a healthcare professional."1
The new policy goes into effect immediately and will apply to all new products with a 12 month phase-in period for existing products.
It is not clear what criteria or process was employed in the TGAÕs safety evaluation process; the publication of the warning did not link to any other documents related to this process. A TGA official involved with this new policy responded to several e-mails sent by this writer requesting clarification on these points, writing that TGA would provide more data on the criteria and process at a future date. [D. Briggs e-mail to M. Blumenthal, March 6, 2006.] However, despite several additional requests, ABC has not received any further communications from TGA.
The first Australian case reports that implicated black cohosh with hepatotoxicity were described in an Australian medical journal.2 The first and more serious case concerned a woman who was reportedly using an undefined black cohosh monopreparation alone for one week to treat menopausal symptoms. She presented with jaundice and subsequently underwent a liver transplant. No specific data is included in the report, e.g., the brand name of the putatively offending product or a botanical or chemical analysis. The authors of the report acknowledge that there were no previous reports of hepatotoxicity associated with black cohosh.
The second case concerned a 43-year-old woman who had taken a preparation containing black cohosh with several other herbs for an undefined period of time.2 The formula reportedly contained the following herbs: skullcap (Scutellaria lateriflora L., Lamiaceae), valerian (Valeriana officinalis L., Valerianaceae), black cohosh, passion flower (Passiflora spp., Passifloraceae), dong quai (Angelica sinensis [Oliv.] Diels, Apiaceae), hops (Humulus lupulus L., Cannabaceae), oats (Avena sativa L., Poaceae), and chasteberry (Vitex agnus-castus L., Verbenaceae).
The reported presence of skullcap has raised some questions among botanically-savvy experts. In some formulations, skullcap has been substituted with the herb germander (Teucrium chamaedrys L., Lamiaceae), a plant that has been previously reported as hepatotoxic3 and has been known as an adulterant for skullcap, at least in the herb trade in the United States during the 1980s.
Whether or not germander substitution has occurred in Australian herbal products is not clear, although an Australian regulatory expert contacted for this article expressed doubts that this is likely since there have been quality control measures instituted throughout the Australian herb industry since the passage of the Therapeutic Goods Act in 1990. Specifically, the germander issue had been raised in the Australian herb industry prior to these case reports, and as a result many suppliers were surveyed by TGA on this issue. By 2002, many of the manufacturers were sensitive to the need to ensure the correct identity of skullcap to preclude the possibility of the adulterant germanderÕs presence. Australia has mandatory adverse event reporting requirements for Listed (e.g., herbs) and Registered (pharmaceutical) medicines. Thus, TGA regulators might take the view that adverse event exposure data from other countries may be weakened by the lack of systematic adverse event reporting systems in those countries.
With regard to the second case report2 discussed above (and others), it appears that no efforts were made to verify the botanical identity of the herbal materials in the formulation. Further, the case report provided no information regarding the plant parts used in this preparationÑa problem that is all too commonly associated with many case reports alleging toxicity associated with the ingestion of botanical preparations. Nor did it provide information regarding the characteristics of the herbal preparation, e.g., the solvent, concentration, manufacturing process, or chemical analysis of the product taken.
Another Australian case of alleged black cohosh-associated liver toxicity involved a 52-year-old woman who was using a multi-ingredient herbal preparation,4 but due to the presence of numerous other botanical ingredients in the preparation, a direct causal association of any of the black cohosh or any of the other individual ingredients cannot be definitively determined. According to this report, "The preparation was made and provided by a pharmacist. The preparation was supplied in a 200 mL bottle and contained a mixture of the fluid extracts of Nepeta hederacea (ground ivy) 80 mL [EditorÕs Note: This is quoted directly from the publication in the Medical Journal of Australia; the preferred binomial for ground ivy probably should be Glechoma hederacea.], Hydrastis canadensis (golden seal) 20 mL, Ginkgo biloba (ginkgo) 40 mL, Avena sativa (oats seed) 40 mL and Cimicifuga racemosa (black cohosh) 20 mL. According to the information supplied by the pharmacist, one gram of herb was contained in each 1 mL of extract, with the exception of golden seal, for which 0.5 g of herb was contained in each milliliter."4
NIH Acknowledges Safety of Black Cohosh
In an American case based on a 57-year-old woman who had been taking numerous prescription medications for 2 years, the black cohosh was presumably a monopreparation taken for about 3 weeks. The patient was not certain about the contents or the brand, as the package had already been discarded.5 The dosage used was not reported. The publication of this case prompted the Center for Science in the Public Interest, a Washington DC-based consumer advocacy organization, to write to the Food and Drug Administration suggesting label warnings, an FDA letter to physicians, and a consumer advisory.6
In response to these concerns, the National Institutes of Health (NIH) held a one-day "Workshop on the Safety of Black Cohosh in Clinical Studies" in November 2004.7 The conclusions were that there was no competent evidence to support concerns about safety with respect to use of black cohosh in breast cancer patients. (To the contrary, there was testimony given regarding clinical trials on such patients using black cohosh in which there were negative findings; CSPI had been concerned about an incomplete study on transgenic mice that had developed lung tumors, but the histology of the tumors has not been conducted to determine if they were malignant and the study has never been published in a peer-reviewed journal.)
Similarly, based on history of use, animal toxicology, and pharmacovigilance data from Europe and elsewhere (51 case reports from various international adverse event reporting databases were acknowledged), the consensus of the experts assembled at the NIH conference concluded that there is inadequate evidence that black cohosh preparations are causally associated with hepatotoxicity. However, NIH concluded that liver enzyme levels will be monitored in all women currently enrolled in NIH-funded trials on black cohosh, as a precautionary measure.
The NIH workshop report states the following:
Ultimately, the workshop participants concluded that a balanced approach be taken with respect to this issue. On the one hand, millions of people have taken black cohosh with very few adverse events reported. On the other hand, those cases of hepatotoxicity associated with products that are known to contain black cohosh and believed to be free from other substances of known toxicity raise concern. Thus, the workshop recommended that appropriate safety parameters should be used in clinical studies of black cohosh. Such measures would include monitoring liver function throughout the study period, specifically looking at alkaline phosphatase (AP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin. And depending on what is being studied, investigators should consider screening potential subjects for liver function to exclude individuals with pre-existing liver problems. At this time, there is no known mechanism with biological plausibility that explains any hepatotoxic activity of black cohosh.7
In June 2005 Schaper & BrŸmmer, the manufacturers of Remifemin¨, the worldÕs most clinically-researched and top-selling black cohosh preparation, introduced into the US market new packaging with the following warning, even though none of the cases of hepatotoxicity reported to date have been associated with this product:
"Consult your healthcare practitioner prior to use if you have a history of liver disease or are taking prescription drugs."8
Consistent with the conclusions of the NIH conference, the various pharmacognosy, pharmacology, toxicology, and medical experts consulted by the American Botanical Council to date do not believe that there are adequate scientific or medical data to support a direct causal connection between black cohosh preparations and cases of hepatotoxicity. So far as ABC has been able to determine, a liver-related warning for black cohosh products is not required in any country other than Australia.
1. Therapeutic Goods Administration. Black cohosh (Cimicifuga racemosa"). New labeling and consumer information for medicines containing Black cohosh (Cimicifuga racemosa"). February 9, 2006. Available at http://www.tga.gov.au/cm/blkcohosh.htm. Accessed February 10, 2006.
2. Whiting PW, Clouston A, Kerlin P. Black cohosh and other herbal remedies associated with acute hepatitis. Med J Austr. 2002;177:432—435.
3. Kouzi SA, McMurtry RJ, Nelson SD. Hepatotoxicity of germander (Teucrium chamaedrys L.) and one of its constituent neoclerodane diterpenes teucrin A in the mouse. Chem Res Toxicol. (United States), November-December 1994;7(6):850-856.
4. Lontos S, Jones RM, Angus PW, Gow PJ. Acute live failure associated with the use of herbal preparations containing black cohosh. Med J Aust. 2003;179:390-391.
5. Cohen SM, O'Connor AM, Hart J, Merel NH, Te HS. Autoimmune hepatitis associated with the use of black cohosh: A case study. Menopause (September-October 2004);11(5):575-577.
6. Cohen B, Schardt D. Letter from Center for Science in the Public Interest to Mark B. McClellan, FDA Commissioner, March 4, 2004.
7. Workshop on the Safety of Black Cohosh in Clinical Studies. National Center for Complementary and Alternative Medicine and Office of Dietary Supplements, National Institutes of Health. November 22, 2004. Available at http://nccam.nih.gov/news/pastmeetings/blackcohosh_mtngsumm.pdf.
8. Remifemin® package text.