ABC, Herb Experts, and NIH Workshop Find No Direct Causal Relationship between Popular Menopause Remedy and Rare Reports of Liver Problems

Two European health agencies have published warnings for possible liver toxicity for black cohosh products. The United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) announced on July 18, 2006, that warnings will be required on labels of all black cohosh (Actaea racemosa L., Ranunculaceae; syn: Cimicifuga racemosa [L.] Nutt.) products, due to concerns about a suspected association between black cohosh and risk of liver disorders.¹ MHRA, the UK government agency responsible for ensuring the safety of medicines and medical devices, based its decision on the conclusions of the Commission on Human Medicines and the Herbal Medicines Advisory Committee, both of which claimed to have reviewed all available data on the subject and found what they have determined to be a possible association between black cohosh and increased risk of liver disorders. However, at this time there is no scientific evidence in the published pharmacological and toxicological literature supporting this alleged connection with hepatotoxicity. In fact, various black cohosh preparations have shown high levels of safety in numerous clinical trials and widespread, long-term use.

The European Medicines Agency (EMEA) released a press statement on July 18, 2006, urging patients to stop taking black cohosh if they develop signs suggestive of liver injury (i.e., tiredness, loss of appetite, yellowing of the skin and eyes, or severe upper stomach pain with nausea and vomiting or dark urine) and advising healthcare professionals to ask patients about their use of black cohosh products.² The EMEA’s Committee on Herbal Medicinal Products (HMPC) evaluated 42 case reports of hepatotoxicity. Although the vast majority of cases were found to be insufficiently documented or otherwise inappropriate for an analysis, the HMPC ultimately concluded that there is a potential connection between herbal medicinal products containing black cohosh root and hepatotoxicity.² The EMEA policy guidance is to be enforced on a country-by-country basis.

Philip Routledge, chair of the UK Herbal Medicines Advisory Committee, was quoted in a press release from the UK MHRA as saying that, “After reviewing all available data, the Herbal Medicines Advisory Committee has come to the conclusion that black cohosh may be associated with liver disorders. This is rare, but can be serious.”¹

Kent Woods, MHRA’s chief executive, was quoted in the same press release, saying, “In the light of this advice, the MHRA is working with the herbal sector to ensure that labels of black cohosh products carry updated safety warnings. The labels will point out the possible symptoms so that appropriate action can be taken without delay.”¹

The proposed wording for UK products is reported as follows: “Warning: In rare cases, black cohosh may cause liver problems. Consult your doctor if you already have liver disease or become unwell whilst using this product.”³

In August, Health Canada issued a public warning on the potential association of black cohosh and liver toxicity but did not go so far as to propose a warning for product labels.⁴ (See sidebar)

The German government is reportedly conducting an extensive review of black cohosh safety, particularly with respect to the liver-related adverse event reports (Mahady G., personal communication, Sept., 25, 2006).

To date, there is no published scientific evidence supporting the suggestion that black cohosh may have an adverse effect on liver function. While the available adverse event reporting data indicate a possible association between black cohosh and liver disorders in a relatively few rare cases, regulators, clinicians and scientists generally agree that well documented clinical and scientific data are lacking to prove a causal relationship. Black cohosh has had a strong history of safe use by millions of women in Europe, the United States, and in other regions, and many controlled clinical trials support the safety and efficacy of black cohosh preparations in treating menopausal symptoms.

Professor Norman R. Farnsworth, PhD, research professor of pharmacognosy and director of the Program for Collaborative Research in the Pharmaceutical Sciences at the University of Illinois at Chicago (UIC), is currently conducting clinical research on a black cohosh extract under a long-term grant from the National Institutes of Health (NIH) National Center for Complementary and Alternative Medicine (NCCAM). He and his colleagues have conducted a virtually exhaustive review of the pharmacological, toxicological, and clinical literature on black cohosh. “In our black cohosh clinical trials that we have been conducting, in which we have been monitoring liver enzymes in all women enrolled, we have observed no increases in enzyme levels over the one-year trial period,” said Dr. Farnsworth (personal communication, July 20, 2006). Dr. Farnsworth, an internationally recognized herb expert, does not believe that there is adequate scientific or clinical data available upon which to make regulatory policy on black cohosh. (Dr. Farnsworth is a founding member of ABC’s Board of Trustees.)

Professor Edzard Ernst, MD, director of complementary medicine at the Peninsula Medical School, Universities of Exeter & Plymouth in the UK, and an internationally recognized authority on the medical literature of herbs and phytomedicines, stated that only 4 of the case studies reviewed by the MHRA are adequately documented to the extent that any meaningful inferences can be drawn from them. “I understand that regulators have to err on the safe side, but I wonder whether this is not some overreaction as black cohosh has been used for a long time,” said Ernst.³ Supporting the same position taken by Dr. Farnsworth, Dr. Ernst said he was not aware of any scientific or clinical research demonstrating a hepatic mechanism of action for black cohosh (E. Ernst, personal communication, July 20, 2006).

Australia became the first country to require a warning on labels of black cohosh products earlier this year. An article in HerbalGram 71 described the Australian Therapeutic Goods Administration’s (TGA) decision to provide warnings on black cohosh products, which was based on TGA’s concerns about the potential association with liver problems.⁵ 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.”⁶ In establishing this policy, TGA acknowledged that some reports of adverse events have been confounded by multiple ingredients, more than one medication, or by other medical conditions, and that the incidence of liver reaction appears to be very low considering the widespread use of black cohosh. (A TGA official initially agreed to provide an explanation of the criteria and process used in TGA’s decision-making, but has not responded to repeated requests from ABC for such clarification.)

The Swedish government has reportedly been recommending a liver warning on product inserts in black cohosh products for several years; however, according to a spokesperson, regulators do not plan to require a warning on the outside of such black cohosh packages.³

The US NIH held a 1-day Workshop on the Safety of Black Cohosh in Clinical Studies in November 2004.⁷ 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, the workshop participants concluded that liver enzyme levels should be monitored in all women enrolled in NIH-funded trials on black cohosh, as a precautionary measure (as is being done by Professor Farnsworth’s group at UIC).

In June of 2005, Schaper & Brummer, the German manufacturer of Remifemin, the world’s most clinically researched and top-selling black cohosh preparation, introduced into the United States market new packaging with the following warning: “Consult your healthcare practitioner prior to use if you have a history of liver disease or are taking prescription drugs.”⁵

Numerous published, controlled clinical trials support the use of several leading black cohosh preparations for reducing symptoms associated with menopause. Black cohosh has become one of the most popular herbal dietary supplements in the United States, ranked eighth of all single-herb supplements sold in mainstream retail outlets in 2005, according to data from Information Resources in Chicago as reported in HerbalGram 71.⁸

References

1. MHRA action on safety concerns over black cohosh and liver injury [press release]. London: Medicines and Healthcare products Regulatory Agency; July 18, 2006. Available at: http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&useSecondary=true&ssDocName=CON2024116&ssTargetNodeId=389. Accessed July 18, 2006.

2. EMEA public statement on herbal medicinal products containing Cimicifugae racemosae rhizome (black cohosh, root) serious hepatic reactions [press release]. London: European Medicines Agency, July 18, 2006. Available at: http://www.emea.eu.int/pdfs/human/hmpc/26925906en.pdf. Accessed July 19, 2006.

3. Halliday J. Black cohosh liver warnings sweep through Europe. NutraIngredients.com July 19, 2006. Available at: http://www.nutraingredients.com/news/ng.asp?n=69240-mhra-emea-black-cohosh-liver-damage. Accessed July 19, 2006.

4. Health Canada is advising consumers about a possible link between black cohosh and liver damage [advisory]. Ottawa: Health Canada; August 18, 2006. Available at: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2006/2006_72_e.html. Accessed September 6, 2006.

5. Blumenthal M. Australian TGA publishes liver warning policy for black cohosh. HerbalGram. 2006; No. 71:60-61.

6. 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.

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. Blumenthal M, Ferrier GKL, Cavaliere C. Total sales of herbal supplements in the United States show steady growth. HerbalGram. 2006;No. 71:64-66.