What Are the Safety Concerns Surrounding the Use of Black Cohosh?

Q&A 364.4

What are the safety concerns surrounding the use of black cohosh?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals

Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp

Date prepared: 21st October 2014

Background

The extensive media interest surrounding the safety of hormone replacement therapy (HRT) has meant that many women are considering other options for control of menopausal symptoms. Many herbal medicines and dietary supplements have been actively marketed as remedies for menopausal symptoms[1],[2].

Black cohosh (Cimicifuga racemosa L. Nutt) is a coarse perennial woodland herb native to North America, where it has been traditionally used by native American Indians for the treatment of various ailments, including menstrual and menopausal problems1,[3].

The mechanism of action of black cohosh is not well understood. It appears to exert an oestrogenic effect, although studies have shown that it does not act directly on oestrogen receptors 3.

There have been several concerns raised about the safety of black cohosh, in particular hepatotoxicity.

This Medicines Q&A assesses and summarises the available evidence regarding safety concerns of black cohosh.

Answer

Herbal medicines which are unlicensed or that are not regulated under the MHRA’s Traditional Herbal Registration scheme are not subject to specific standards of safety or quality. The amount of active constituents in herbal products is subject to variation depending on factors such as parts of the plant used, growing and harvesting conditions, and methods of extraction [4],[5]. Long term safety of black cohosh is unknown; some studies have evaluated use of the herb for up to a year, but most research is limited to 6 months treatments 3.

Interactions

Interaction / Severity / Onset / Likelihood / Management / Substantiation / Notes
Hepatotoxic drugs and herbal medicines / High / Unknown / Possible / Avoid combinations / Theoretical / May be increased risk of liver failure and hepatitis in combination with other hepatotoxic drugs and herbal medicines
Tamoxifen / High / Unknown / Unknown / Avoid / Poor- in vitro research / An enhanced effect of tamoxifen may occur.
Atorvastatin / High / Delayed / Possible / Avoid concomitant use / Poor-One case report / Elevated LFTs with the combination, which resolved on dechallenge. This may be due to inhibition of CYP3A4 enzymes
Cisplatin / High / Unknown / Possible / Avoid / Animal research / Black cohosh may decrease effectiveness of cisplatin
Immunosuppressants / High / Unknown / Possible / Avoid / Poor- One case report with confounders / See details below
CYP2D6 substrates / Moderate / Unknown / Possible / Avoid / Conflicting / Black cohosh may inhibit CYP2D6 enzymes, although evidence is conflicting.

Because of the lack of information available about herbal medicines, lack of a documented interaction does not necessarily mean none exists; it may just mean that the possibility of an interaction has not yet been studied 2. A summary of possible interactions with black cohosh may be found in table 1.

Table 1. Interactions of black cohosh 3,4

Cancer

Conflicting evidence surrounds whether or not black cohosh has oestrogenic activity. If it does act on oestrogen receptors, there is a risk that it may negatively affect hormone sensitive cancers. In vitro animal studies suggest that black cohosh may increase the risk of metastasis in women with pre-existing breast cancer 3,[6].

A systematic review, including both interventional and observational data, concluded that current evidence does not support an association between black cohosh and increased risk of breast cancer, but that further research in the area is warranted.[7] Due to the lack of clear safety data, women with a history of breast or other hormone sensitive cancers should avoid use of black cohosh 3.

Transplantation

One case report describes an acute kidney transplant rejection in a patient who was taking black cohosh and alfafa supplements. Alfafa supplements may have immunostimulating effects, so may be more likely to have induced the rejection than black cohosh. Although causality of the transplant rejection has not been established, it would be prudent for patients who have undergone transplantation, or who are taking immunosuppressant medications, to avoid black cohosh until further information is known about its use in this patient group 3,4,[8].

Liver disease

Several case reports describe hepatotoxicity, many of which required liver transplantation. Due to the potentially serious nature of this adverse reaction, the use of black cohosh should be discouraged, especially since liver failure can develop suddenly. Patients who still decide to take black cohosh should have regular liver function tests 3.

One case report describes a 54 year old woman who presented with acute severe hepatic failure after 8 months of taking a black cohosh supplement. She required a liver transplant and died whilst undergoing the operation due to uncontrollable haemorrhage [9]. In other cases, jaundice and deranged LFTs have developed following use of black cohosh for menopausal symptoms, requiring transplantation [10].

Reports of hepatotoxicity have also been received through national pharmacovigilance schemes worldwide, including the MHRA’s Yellow Card Scheme 9,[11]. Although causality has not been established through these case reports, and many have methodological limitations, these reports have prompted the MHRA to recommend that warnings regarding the possibility of hepatotoxicity should be added to products containing black cohosh[12]. Use of black cohosh is contra-indicated in patients with pre-existing liver disease 3,9. Teschke et al has recently assessed the likelihood of causality based on published case reports and spontaneous reports by applying the liver-specific CIOMS (Council for the International Organisation of Sciences) assessment scale. In each study they found a lack of causality in all cases and inadequate reporting of confounding factors [13],[14],[15].

Firenzuoli et al conducted a survey of 107 patients who had undergone 12 months continual treatment with black cohosh. The study found no signs of hepatotoxicity or hepatic disease in any of the participants [16].

A meta-analysis of randomised, double blind controlled trials found no clinically significant effects on liver enzymes in five trials with a total of 1,117 women who had been treated with isopropanolic black cohosh extract [17]. The trials included in the meta analysis were of 3 months or 6 months duration.

In October 2012, the MHRA released a statement reminding the healthcare professionals and the public of the risk of liver failure with black cohosh remedies. This was in response to a serious case of liver failure resulting in a liver transplant. The MHRA reiterated the importance of selecting a registered product and ensuring that patients read the information leaflets and consult a qualified healthcare professional prior to taking a black cohosh product[18].

Case reports describing liver failure probably caused by black cohosh continue to emerge in the medical literature.[19],[20]

Protein S deficiency

There is a theoretical risk that black cohosh may increase risk of thrombosis in patients with protein S deficiency 3. This is dependent on black cohosh having oestrogenic effects. One case report describes a patient suffering retinal vein thrombosis following use of a product containing black cohosh, although causality was not established due to the presence of other herbal extracts in the product[21].

Pregnancy and Lactation

Traditionally, black cohosh has been used to induce labour. There is, however, insufficient available data to justify its use in this manner 10,[22].

One case report describes the use of a mixture of blue and black cohosh for induction of labour in a previously uneventful pregnancy. The child was born with low apgar scores and no spontaneous breathing which resulted in hypoxia, acute necrosis and seizures. The quality of the report was limited by lack of detail regarding the product used and a reliance on animal studies to suggest the clinical activity of the herbs 4,10.

Theoretically, the possibility of oestrogenic effects may result in an increased risk of miscarriage. There is, however, insufficient data to suggest this may be the case 4. This lack of data on the use of black cohosh during pregnancy means that its use should be avoided during pregnancy 10.

There is no data available about levels of black cohosh in breast milk, or any reports of paediatric concerns caused by breast feeding, although there is a theoretical risk that its oestrogenic activity may reduce lactation. Because of this lack of safety data, Black cohosh preparations should not be recommended in lactating women 4,[23].

For more information on the use of herbal medicines in breast-feeding women, see Medicines Q&A 93 Is it safe for breast feeding women to take herbal medicines?

Adverse effects

Side effects reported on use of black cohosh include GI upset, cramping, rash, headache, dizziness, weight gain, and peripheral and facial oedema, which appear to occur rarely, (less than 1 in 1000, but more than 1 in 10,000 patients) 4,[24].

Very rarely, breast tenderness, and vaginal spotting may occur.

Liver disorders and deranged LFTs are reported as a rare side effect (see above) 4,20.

Other reports of adverse reactions include: seizures, asthenia and muscle damage, cutaneous pseudolymphoma, cutaneous vasculitis and endometrial hyperplasia 4,9. Bradycardia, coagulation activation, and fluid retention have also been linked with black cohosh use in the literature[25],[26].

Summary

Black cohosh is a herbal product commonly used for relief of menopausal symptoms. There are a number of safety concerns surrounding use of black cohosh, but because of limited and poor quality data, many concerns remain theoretical. In addition to this, as herbal products are subject to variations in quality, safety and efficacy, their use should not be recommended routinely.

CKS guidelines state that the use of complementary medicines for control of menopausal symptoms is not recommended, and if these products are being used, the following advice should be given:

¨  The efficacy of these products has not yet been established.

¨  There is very little control over the quality of the products available, which may vary considerably.

¨  Some of these treatments (ginseng, black cohosh, and red clover) have oestrogenic properties and should not be used in women with contraindications to oestrogen (e.g. breast cancer)

¨  Long-term safety (e.g. effects on the breast and endometrium) has not been assessed.

¨  Some treatments may have serious adverse effects (e.g. liver toxicity has been reported with black cohosh and kava)[27]

Limitations
This Q&A considers only the safety concerns of black cohosh. It does not take into account in detail the efficacy data, which would need to be considered when treatment decisions are being undertaken. The amount of good quality information available about herbal medicines is often limited due to the lack of regulation of these products. Many of the safety concerns are theoretical or are based on case reports only.

Quality Assurance

Prepared by

Hayley Johnson, Regional Drug & Therapeutics Centre

Date Prepared

21st October 2014

Checked by
Nancy Kane, Regional Drug & Therapeutics Centre

Date of check

21st October 2014

Search strategy

Embase (incorporating Medline, Via NHS Evidence

: Cimicifuga Racemosa /ae
/ct

/it

ALTMEDEX
MHRA
Natural Medicines Database
CKS Guidelines

References

1

Available through NICE Evidence Search at www.evidence.nhs.uk

[1] Mahady GB, Fabricant D, Chadwick LR et al. Black Cohosh: An Alternative Therapy for Menopause?. Nutr Clin Care 2002; 5(6): 283-289

[2] NHS Knowledge Service. Behind the Headlines: Dangers of herbal cures. NHS Choices 2009 accessed via http://www.nhs.uk/news/2009/01January/Pages/Menopauseherbalremedies.aspx on 21/10/2014

[3] Natural Medicines Comprehensive Database: Black cohosh. 3120 West March Lane, PO Box 8190, Stockton, California. Accessed via http://naturaldatabase.therapeuticresearch.com/home.aspx?cs= on 21/10/2014.

[4] ALTMEDEX ® system: Hammerly M, Koffler K, Marray M et al: Black Cohosh. In: Klasco RK (Ed): ALTMEDEX system (electronic version). Truven Health Analytics Greenwood Village, Colorado USA. Available at: http://www.micromedexsolutions.com/home/dispatch. Cited 21/10/2014

[5] Herbal Medicines Regulation and Safety. The Medicines and Healthcare Products Regulatory Authority. Accessed via http://www.mhra.gov.uk/Howweregulate/Medicines/Herbalmedicines/index.htm on 21/10/14.

[6] Davis VL, Jayo MJ, Ho, A et al. Black Cohosh increases metastatic mammary cancer in transgenic mice expressing c-erbB2. Cancer Res 2008: 68(20): 8377-8383

[7] Fritz H, Seely D, McGowan J et al. Black cohosh and breast cancer: a systematic review. Integrative Cancer Therapies; 2014: 13(1): 12-29

[8] Light TD and Light JA. Acute Renal Transplant Rejection Possibly Related to Herbal Medications. Am J Transplant 2003: 3(12): 1608-1609.

[9] Lynch CR, Folkers ME, and Hutson WR. Fulminant Hepatic Failure Associated with the Use of Black Cohosh: A Case Report. Liver Transplantation 2006; 12: 989-992.

[10] Cohosh, Black In: Herbal Medicines. [online] London: Pharmaceutical Press. Accessed via http://www.medicinescomplete.com/ on 21/10/14.

[11] MHRA: Cimicifuga: Drug Analysis Print. Accessed via http://www.mhra.gov.uk/Onlineservices/Medicines/Druganalysisprints/index.htm on 21/10/14.

[12] Press Release: MHRA action on safety concerns over black cohosh and liver injury. MHRA 2006.

[13] Teschke R, Schwarzenboeck A, Schmidt-Taenzer et al. Herb-induced liver injury presumable caused by black cohosh: A survey of initially of purported cases and herbal quality specifications. Annals of Hepatology 2011; 11(3): 249-259

[14] Tescke R, Schmidt-Taenzer W, Wolff A. Spontaneous reports of assumed herbal hepatotoxicity by black cohosh: is the liver unspecific Naranjo scale precise enough to ascertain causality? Pharmacoepidemiology & Drug Safety. 2011; 20(6): 567-582

[15] Teschke R. Black Cohosh and suspected hepatotoxicity: inconsitencies, confounding variables, and prospective use of a diagnostic causality algorithm. A critical review. Menopause 2010; 17(2): 426-440

[16] Firenzuoli F, Gori L, and di Sarsina P. Black Cohosh Hepatic Safety: Follow-up of 107 Patients Consuming a Special cimicifuga racemosa rhizome Herbal Extract and Review of Literature. Evidence Based Complementary and Alternative Medicine 2008; doi: 10.1093/ecam/nen009.

[17] Naser B, Schnitker J and Minkin M et al. Suspected black cohosh hepatotoxicity: no evidence by meta-analyisis of rendomised controlled clinical trials for isopropanolic black cohosh extract. Menopause 2011; 18(4): 366-375

[18] Liver Failure case highlights need to use black cohosh remedies carefully. Medicines and Healthcare Products Regulatory Agency Press Release 29/10/2012 Accessed via http://www.mhra.gov.uk/NewsCentre/Pressreleases/CON199545 on 21/10/2014