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ABC, Herb Experts, and NIH Workshop Find No Direct Causal Relationship between Popular Menopause Remedy and “Rare” Reports of Liver Problems
(Austin, TX, July 20, 2006). The United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) announced on July 18 that warnings will be required on labels of all black cohosh (Actaea racemosa; syn: Cimicifuga racemosa) 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, the nonprofit American Botanical Council (ABC), in association with several leading internationally-recognized herbal experts, emphasized that there is no scientific evidence to support the alleged connection and that black cohosh preparations have shown high levels of safety in numerous clinical trials and widespread, long-term use.
The European Medicines Agency (EMEA) also released a press statement on July 18, 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 it “considered that there is a potential connection between herbal medicinal products containing [black cohosh, root] and hepatotoxicity.”2 The EMEA’s policy is considered guidance 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 having said, “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 Chief Executive, was quoted in the same press release as 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 According to an article in NutraIngredients (www.nutraingredients.com), the proposed wording to appear on UK product packaging is: “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
The American Botanical Council (ABC), an independent, nonprofit research and education organization, has reviewed much of the published literature on black cohosh. “To date, there is no credible scientific evidence supporting the notion that black cohosh has an adverse influence on liver function,” said Mark Blumenthal, ABC Founder and Executive Director. “While the available adverse event reporting data indicate a possible association between black cohosh and liver disorders in a relatively few ‘rare’ cases,” he noted, “well documented clinical and scientific data are lacking to prove a causal relationship. Black cohosh has 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,” he added.
Professor Norman R. Farnsworth, 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’s (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,” Prof. Farnsworth told ABC (Farnsworth NR, personal communication with M Blumenthal, July 20, 2006). He added, “The notion that regulators in any country believe that black cohosh may be hepatotoxic based on the scant information currently available is ludicrous. To make public policy on such poor data is not rational.” (Prof. Farnsworth is a world-renowned expert on medicinal plant research and also a founding member of ABC’s Board of Trustees.)
Professor Edzard Ernst, Director of Complementary Medicine at the Peninsula Medical School, Universities of Exeter & Plymouth in the UK, and internationally recognized authority on the medical literature of herbs and phytomedicines, was quoted as saying 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.”3 “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,” he was quoted as saying. 3 Supporting the same position taken by ABC and Prof. Farnsworth, Professor Ernst said he was not aware of any scientific or clinical research demonstrating a hepatic mechanism of action for black cohosh. (Professor Ernst confirmed accuracy of content in email to ABC, July 20, 2006).
Australia became the first country to require a warning on labels of black cohosh products earlier this year. A story in the March issue of HerbalEGram (revised and being published in HerbalGram 71 in August) described the Australian Therapeutic Goods Administration’s (TGA) decision to provide warnings on black cohosh products, based on TGA’s concerns about the potential association with liver problems.4,5 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 the 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 U.S. NIH held a one-day “Workshop on the Safety of Black Cohosh in Clinical Studies” in November of 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 Prof. Farnsworth’s group at UIC).
In 2003 the National Center for Natural Products Research (NCNPR) sponsored a conference on herbal preparations and ways to assess for their potential hepatotoxic effects, under a cooperative agreement with the Center for Food Safety and Applied Nutrition (CFSAN) and the Food and Drug Administration (FDA).8 (A report on this conference and the issues discussed are available on the ABC website in the HerbalGram database.)
In June of 2005, Schaper & Brümmer, 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, even though none of the cases of hepatotoxicy reported to date had 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.”4,5
The American Botanical Council will continue to follow this story and publish an article regarding the MHRA and EMEA’s actions regarding black cohosh in its August issue of HerbalEGram, a special monthly e-newsletter for ABC members and stakeholders.
About Black Cohosh
Black cohosh, also known by either its scientific names (Actaea racemosa and Cimicifuga racemosa) is a member of the buttercup family (Ranunculaceae) native to the Eastern United States. The roots and rhizomes (lateral roots) of the herb have a long history of use by native American tribes to deal with genitourinary complaints in women. An isopropanolic extract of black cohosh (Remifemin®) has been used in German clinical practice since the mid-1950s with safe and effective results, and black cohosh preparations have been approved by the German government as safe and effective nonprescription medications for treatment of menopausal symptoms.
In the past few years black cohosh has become increasingly popular as the most widely-used natural alternative to hormone replacement therapy (HRT). The herb’s popularity with middle-aged women and gynecologists grew significantly after the summer of 2003 when a large-scale government-sponsored clinical trial on HRT was halted prematurely after evidence that HRT was responsible for an increase in cancer and cardiovascular disease in menopausal women.
Black cohosh preparations 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 the new issue of HerbalGram (#71), ABC’s quarterly journal.9
About the American Botanical Council
Established in 1988, the American Botanical Council (ABC) is the leading nonprofit, member-based international organization working to educate consumers, healthcare professionals, researchers, educators, industry, and the media on the safe and effective use of herbs and medicinal plant products. Located on a 2.5 acre site in Austin, Texas, ABC is the publisher of HerbalGram, a peer-reviewed quarterly journal; HerbalEGram, a monthly electronic newsletter; and HerbClip, a bimonthly review service of recent scientific and clinical publications. The ABC Clinical Guide to Herbs, a continuing education and reference book, contains extensive monographs on the safety and efficacy of 29 popular herbs, including black cohosh. More information is available at http://www.herbalgram.org/.
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. Blumenthal M. Australian TGA publishes liver warning policy for black cohosh. HerbalEGram, March 2006;3(3). http://www.herbalgram.org/default.asp?c=australianlabelwarning; July 19, 2006.
5. Blumenthal M. Australian TGA publishes liver warning policy for black cohosh. HerbalGram. 2006; No. 71:60-61 [in press].
6. Therapeutic Goods Administration. Black cohosh (Cimicifuga racemosa). New labeling and consumer information for medicines containing Black cohosh (Cimicifuga racemosa). Feb. 9, 2006. Available at: http://www.tga.gov.au/cm/blkcohosh.htm. Accessed Feb. 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. Nov. 22, 2004. Available at: http://nccam.nih.gov/news/pastmeetings/blackcohosh_mtngsumm.pdf.
8. Walker L. Hepatotoxicity assessment for botanical dietary supplements. HerbalGram. 2005;65:64-66.
9. Blumenthal M, Ferrier GKL, Cavaliere C. Total sales of herbal supplements in the United States show steady growth. HerbalGram. 2006;71:64-66.
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