Black cohosh (Actaea racemosa)

Definition

Black cohosh (Actaea racemosa, synonym: Cimicifuga racemosa) is a medicinal plant originating from eastern North America, which has been used by native American Indians and Europeans for women’s conditions such as chronic ovaritis and amenorrhea1. Most recently, black cohosh has been used as a therapy for menopausal symptoms such as hot flushes. The characteristic chemical constituents of the roots and rhizomes of black cohosh include cycloartenol-type triterpenoids and cimicifugoside, as well as cinnamic acid derivatives2. The commonly used dosage for black cohosh is 40 to 80 mg of dried rhizome (root) daily.

Prevalence of use

Black cohosh was first listed in the U.S. Pharmacopoeia in 1830 under the name “black snakeroot”. 3 It has been widely used for more than 40 years in Europe and was introduced in Germany in the 1940s for the treatment of menopausal discomfort, dysmenorrhoea, and climacteric neurovegetative complaints.

Theory

Systemic breast cancer treatment can cause premature menopause, which results in hot flushes before the physiological menopause. Hot flushes are also the main adverse effect of the common anti-breast cancer treatment tamoxifen. Hormone replacement therapy (HRT) for hot flushes in breast cancer patients may not be appropriate because of evidence of a relationship between long-term use of HRT and increased risk of breast cancer and cardiovascular disease 5, and potential stimulation of cancer growth by HRT 6. There is therefore an increasing interest in finding safe and effective alternatives to HRT for the treatment of menopausal symptoms in breast cancer patients. Herbal preparations such as black cohosh are used as alternatives to HRT in the treatment of hot flushes 7. The mechanism of action was proposed as being mediated by an inhibitory effect on the hypothalamus, or an effect on neurotransmitters 8, or a possible oestrogenic effect from the phyto-oestrogens 9.

Providers

Black cohosh products are commercially available on the market such as Remifemin® (manufactured by Schaper & Brümmer, Salzgitter, Germany) which is an isopropanolic extract of black cohosh standardised to contain 1 mg of triterpenes per 20 mg of extract 10. Another standardised ethanolic extract of black cohosh is BNO 1055 (Menofem®/Klimadynon®), BIONORICA, Neumarkt, Germany) 11.

Legal issues

In most European countries and the US, plant-based preparations including herbal remedies are regulated as dietary supplements. However, the European Directive on traditional herbal medicinal products allows herbal medicines to be registered as drugs if they have been used medicinally for at least 30 years (including at least 15 years within EU countries) 12.

Clinical studies

Three randomised controlled trials in female breast cancer patients were identified for black cohosh 13 14 22; two of these were double-blind and placebo-controlled 13 22. Results showed that black cohosh was not significantly better than placebo in relieving hot flushes. Black cohosh administered to patients receiving tamoxifen appeared better than usual care with tamoxifen alone; these findings are, however, not conclusive.

In the first double-blind, placebo-controlled trial (n=85), both black cohosh and placebo groups reported a decline in the number and intensity of hot flushes 13. However, the differences between groups were not statistically significant. Significant differences in improvement were observed only for sweating. Black cohosh intake did not alter follicle-stimulating hormone (FSH) or luteinizing hormone (LH) levels. The major limitations of this trial include the small sample size, the high dropout rate (18.8%), the short treatment period (two months), and the low dose of black cohosh (40 mg/day).

The second double-blind, randomized, cross-over clinical trial 22 involving 132 patients reported a mean decrease in hot flash score of 20% (comparing the fourth treatment week to the baseline week) compared with a 27% decrease for patients receiving placebo (P=0.53). Mean hot flash frequency was reduced by 17% with black cohosh and 26% on placebo (P =0 .36). Thirty-four percent of patients preferred the black cohosh treatment, 38% preferred the placebo, and 28% did not prefer either treatment.

The third trial specifically examined the effectiveness of black cohosh for the relief of hot flushes in women with a history of breast cancer 14. A 12-month treatment period of black cohosh combined with tamoxifen showed significantly better effects on the number and severity of hot flushes compared to tamoxifen (usual care) alone. Forty-two out of 90 patients (46.7%) in the herbal treatment group were free of hot flushes while no patient was without hot flushes in the tamoxifen group. Severe hot flushes were reported by 22 patients (24%) in the intervention group, and 34 (74%) in the tamoxifen group. However, this randomised trial has methodological weaknesses, such as being open-label, not placebo-controlled and not blinded 14.

Biological mechanism

Black cohosh has been demonstrated to have organ-specific oestrogenic effects and is characterised as selective oestrogen-receptor modulator 1. However, the most recent investigations do not support an oestrogen receptor-mediated mechanism of action for black cohosh 2. The mechanism of action of black cohosh is still not well understood. Studies found that an ethanol extract of black cohosh did not stimulate growth of oestrogen- and progesterone-positive breast cancer cells in vitro 15 16. Administration of black cohosh has not changed serum FSH or LH levels or vaginal cytological findings 13 17 18 19.

Evidence from in vitro, animal and clinical studies suggests that black cohosh is a safe herbal therapy for menopausal women if taken for a limited period 2. Animal studies showed no evidence of oestrogenic effects on oestrogen-sensitive hormone levels, or changes in uterine weight or vaginal cell histology, and therefore, support the safety of use of black cohosh in oestrogen-sensitive cancer patients or in women for whom HRT is contraindicated 10. Clinical trials identified in this review did not report significant adverse effects in women with breast cancer using black cohosh extracts for 2 to 12 months 13 14 22. The minor adverse effects observed in clinical trials include nausea, vomiting, headaches, dizziness, mastalgia, and weight gain 20. No herb and drug interactions have been reported 20. However, black cohosh was found to alter the response to the agents commonly used to treat breast cancer in an experiment report using mouse breast cancer line 21. In this experiment, the black cohosh extracts increased the cytotoxicity of doxorubicin and docetaxel and decreased the cytotoxicity of cisplatin. Pre-existing liver damage is a contraindication.

In response of the "potential association" between black cohosh and hepatotoxicity, one systematic review by Dietary Supplement Information Expert Committee of the US Pharmacopeia's Council of Experts on the hepatotoxicity 23 found all the reports of liver damage were assigned possible causality, and none were probable or certain causality. The clinical pharmacokinetic and animal toxicological information did not reveal unfavourable information about black cohosh. Based on this safety review, the committee determined that black cohosh products should be labelled to include a cautionary statement. This is a change from the Expert Committee's decision of 2002, which required no such statement.

A systematic review 24 retrieved 13 clinical trials involving more than 2800 patients. All trials indicate relative safety: 97% of all the reported adverse effects were minor, and the only severe ones were not deemed to be related causally to black cohosh. Three postmarketing surveillance studies reported adverse effects in 0%, 12% only mild and transient, and 2% of patients, respectively. Four case series and 8 single case reports were identified: in most of them, no causal relationship was detected and only two case reports concluded a “possible” causality between serious safety problem and the black cohosh medication but without providing further details. The review concluded that a large body of preclinical and clinical studies suggests black cohosh to be relatively safe; however, many of these studies were of short duration. Case reports that suggest severe adverse effects demanded further attention.