Black Cohosh

Scientific Name(s): Actaea racemosa L., syn. Cimicifuga racemosa (L.) Nutt. Family: Ranunculaceae.

Common Name(s): Baneberry , black cohosh , black snakeroot , bugbane , cimicifuga , rattleroot , rattleweed , rattletop , traubensilberberze , squawroot , wanzenkraut 1 , 2

Uses

Black cohosh has been used to help manage some symptoms of menopause and as an alternative to hormone replacement therapy (HRT). It may be useful for treatment of hypercholesteremia or peripheral arterial disease. Clinical studies do not support these uses.

Dosing

On the basis of clinical studies, the currently recommended daily dose of black cohosh is a 40% to 60% ethanol or isopropanol extract of 40 to 80 mg herbal drug that is standardized to contain 1 mg of triterpene 27-deoxyactein per 20 mg tablet. Counsel patients that therapeutic effects generally begin after 2 weeks, with maximum effects usually observed within 8 weeks.

Contraindications

Patients with aspirin sensitivity because it contains salicylates.

Pregnancy/Lactation

Black cohosh is contraindicated in pregnancy and may cause premature birth in large doses. Avoid black cohosh during lactation.

Interactions

None well documented.

Adverse Reactions

There is a low incidence of adverse reactions.

Toxicology

Overdose of black cohosh may cause nausea, vomiting, dizziness, nervous system and visual disturbances, reduced pulse rate, and increased perspiration. Case reports primarily document hepatic toxicity; however, cardiovascular and circulatory disorders and 1 case of convulsions have been documented.

Botany

The older name Cimicifuga racemosa L. (Nutt.) has been replaced by the synonym Actaea racemosa L., although both names are commonly used. Black cohosh grows in open woods at the edges of dense forests from Ontario, Canada to Tennessee and west to Missouri in the United States. This perennial grows to 2.5 m and is topped by a long plume of white flowers that bloom from June to September. Its leaflets are shaped irregularly with toothed edges. The word “black” refers to the dark color of the rhizome. The name “cohosh” comes from an Algonquian word meaning “rough,” referring to the surface of the rhizome. 3 The related species Cimicifuga foetida is used in traditional Chinese medicine, while Cimicifuga dahurica (Turcz.) Maximowicz and Cimicifuga heracleifolia Komarov are used in Japan. Polymerase chain reaction protocols have been developed for distinguishing and authenticating the species. 4 , 5

History

American Indians used black cohosh for the treatment of general malaise, kidney ailments, malaria, rheumatism, sore throat, and gynecological disorders (eg, ease of labor, menstrual cramps). North American colonists used the herb for treating amenorrhea, bronchitis, chorea, dropsy, fever, hysteria, itch, lumbago, nervous disorders, snakebite, yellow fever, and uterine disorders. In traditional Chinese medicine, the herb was valued for its anti-inflammatory, analgesic, and antipyretic properties. The plant has been used in Europe since the 17th century to treat joint pain, neuralgia, and pain in pregnancy and labor. Literature reports also document the use of black cohosh for treating influenza, smallpox, acute rheumatism, headache, cough, chorea, and other nervous system disorders. 6 , 7 , 8 It was an important herb in the Eclectic medical movement in the United States in the 19th century, under the name “macrotys.” 9 The old-time remedy Lydia Pinkham's Vegetable Compound (early 1900s) contained many natural ingredients, including black cohosh. 10 The roots and rhizomes are used medicinally. A tea from the root has been recommended for sore throat. The Latin name cimicifuga means “bug repellent,” and the plant has been used for this purpose. A variety of cimicifuga preparations are available commercially. However, Remifemin , the brand name of a standardized extract of the plant, has been widely studied and used in Germany for menopausal management since the mid-1950s. 6 , 11

Chemistry

German reports from the late 1960s discuss the contents of black cohosh. 12 , 13 , 14 The key medicinal components include triterpene glycosides, phenolic acids, flavonoids, volatile oils, and tannins. High-performance liquid chromatography revealed the presence of caffeic acid, ferulic acid, isoferulic acid, cimicifugoside H-1, cimiracemoside A, cimicifugoside H-2, ( 26R )-actein, 26-deoxycimicifugoside, ( 26S )-actein, 23-epi-26-deoxyactein, 23-OAc-shengmanol-3- O -beta-D-xyloside, 26-deoxyactein, 25-OAc-cimigenol-3- O -beta-L-arabinoside, 25-OAc-cimigenol-3- O -beta-D-xyloside, cimigenol-3- O -beta-L-arabinoside, and cimigenol-3- O -beta-D-xyloside. 15 Four phenylpropanoid esters, cimiracemates A-D (14), have been identified. 16 , 17 Black cohosh contains N-methylcytisine, as well as guanidine alkaloids 18 and N-methyl-serotonin. 19 The terpenoid mixture consists of actein, 12-acetylactein, and cimigoside. Other constituents found in the plant include acetic, butyric, formic, oleic, palmitic, and salicylic acids; racemosin; formononetin (an isoflavone); phytosterols; acteina (resinous mixture); and volatile oil. 20 An amorphous resinous substance called cimicifugin (macrotin) accounts for approximately 15% to 20% of the root. Cimigoside (cimifugoside) and 27-deoxyacteine also have been isolated. The triterpene glycoside, 27-deoxyacteine, is used to standardize Remifemin . 21 , 22

An efficient countercurrent chromatography isolation method for black cohosh saponins has been developed. 23 Quantitative chromatographic methods for determining triterpenes and formononetin in black cohosh rhizomes have been published. 24 , 25 Stability of polyphenols and saponins in plant material has been evaluated, 26 and their content in an 85-year-old herbarium specimen has been determined. 27 The pharmacokinetics of 23-epi-26-deoxyactein have been investigated in women administered black cohosh extract, with a measured half-life of approximately 2 hours. 28

Uses and Pharmacology

Black cohosh has been used to control symptoms of menopause as an alternative to conventional HRT therapy. The plant seems to have no stimulatory effect on estrogen-dependent cancers and may even exhibit inhibitory effects against the disease. Black cohosh may also be useful in other areas, such as treatment for HIV, hypercholesteremia, and peripheral arterial disease.

Menopause
In vitro studies

The isoflavone formononetin binds to estrogen receptor preparations; however, it does not reduce serum levels of luteinizing hormone (LH) in ovariectomized rats. 29 N-methyl-serotonin was isolated from black cohosh and shown to bind to 5-HT 7 receptors and induce cyclic adenosine monophosphate (AMP). 30

Animal data

The purported estrogenic effects of the plant could not be reproduced in extensive tests in mice. In 1 study, there was no evidence of a direct or indirect influence on gonadal function. However, other studies indicate that methanol extracts of C. racemosa contain substances that bind to estrogen receptors. 31 Intraperitoneal injection of the extract in ovariectomized rats caused a selective reduction in LH level with almost no effect on follicle-stimulating hormone (FSH) or prolactin levels. 32 One report found no signs of uterine growth or vaginal cornification in ovariectomized rats given black cohosh extract. 33 In a more recent study, standardized cimicifuga extract increased staining of estrogen receptors in the endometrium of ovariectomized rats while lowering Ki67 protein levels. The increase in estrogen receptors due to cimicifuga was less than that produced by estradiol, while estradiol increased Ki67 staining and cimicifuga lowered it. 34 Gene expression of estrogen-receptor alpha was unchanged, while estrogen-receptor beta expression was increased in the uterus of rats treated with cimicifuga. 35 A model of hot flushes in ovariectomized rats that measured peripheral temperatures responded to both estrogens and cimicifuga extract. 8 This suggests that conventional estrogenic action is unlikely to be the explanation for the plant's beneficial effects on menopausal discomfort.

Clinical data

In women treated for 8 weeks with the commercial product Remifemin and LH, but not FSH, levels were reduced. Remifemin is used for the management of menopausal hot flashes, with analysis identifying at least 3 fractions that contribute synergistically to the suppression of LH and bind to estrogen receptors. These data suggest that black cohosh has a measurable effect on certain reproductive hormones. The product may offer an alternative to conventional HRT. In patient populations with a history of estrogen-dependent cancers, Remifemin shows no stimulatory effects on established breast tumor cell lines dependent on estrogen's presence (although it possesses some estrogenic activity). Instead, inhibitory actions were seen. In addition, the product exerts no effect on the endometrium, so it is not necessary to oppose therapy with progesterone as with conventional HRT. The plant extract's action proves to be more like estriol than estradiol, which is associated with a higher risk of breast, ovarian, and endometrial cancers. Estriol exerts its effects mainly on the vaginal lining rather than on the uterine lining, as estradiol does. 36 Black cohosh was no more effective than placebo in reducing the intensity and number of menopausal hot flashes among breast cancer patients in a randomized, double-blind, placebo-controlled study. Of the 85 patients in the study, 42 were assigned to the treatment phase and 43 to placebo. Fifty-nine patients were using tamoxifen and 26 were not. Inclusion criteria included patients reporting menopausal symptoms, such as daily hot flashes, and completion of primary cancer therapy at least 2 months prior to entering the study. Exclusion criteria included using HRT for hot flashes, pregnancy, recurrent or metastatic breast cancer, or history of a major psychiatric illness. Patients were counseled to take 1 tablet by mouth twice daily with meals for 60 days. Before starting any study medication, each patient was asked to record the number of hot flashes, including their intensity. They were asked to do the same on days 27 to 30 and days 57 to 60 of the study. The average reported number of hot flashes declined for both groups; the overall decline from baseline to study completion was approximately 27%. The differences between treatment groups were not significant ( P = 0.86 via analysis of covariance adjusting for baseline number and for tamoxifen use; P = 0.44 via stratified Wilcoxon test in difference from baseline to completion). Other menopausal symptoms were analyzed between the groups in a global rating of health and well-being on a 0 to 100 scale. These symptoms included headaches, poor sleep, heart palpitations, depression, irritability or nervousness, and excessive sweating. Overall, the global rating did not change significantly during the 2-month study. 37 A clinical and endocrinologic study has been performed in 60 patients younger than 40 years of age who had hysterectomies. Four randomized treatment groups included estriol, conjugated estrogens, estrogen-gestagen sequential therapy, or black cohosh extract. Results showed no differences among groups in success of therapy. 38

A standardized preparation BNO 1055 ( Klimadynon/Menofem , 40 mg/day) was compared with conjugated estrogens (0.6 mg/day) in a double-blind, placebo-controlled study and found a reduction in menopausal symptoms as well as the estrogen levels; however, because each arm of the study was small (n = 20 to 22), the difference from placebo did not reach statistical significance. 39 Another study found that black cohosh had an effect on menopausal symptoms only in a subgroup of women with severe symptoms (Kupperman index more than 20). 40

A 12-week, randomized, placebo-controlled, double-blind study in the Netherlands found no effect on menopausal symptoms for a black cohosh and soy isoflavone combination. 41 A larger 5-arm study found no effect on menopausal vasomotor symptoms at 3, 6, and 12 months of treatment with black cohosh alone (160 mg daily) and in combination. 42 A crossover study of 20 mg black cohosh twice a day found no effect compared with placebo. 43 A fixed combination of black cohosh and St. John's wort studied in women with menopausal complaints with a pronounced psychological component, on the other hand, found a highly significant reduction in symptom scores. 44

The Herbal Alternatives for Menopause Study, in addition to examining primary end points, such as hot flash frequency, 42 also studied vaginal cytology, dryness, menstrual cyclicity, and hormone profiles of the subjects; however, no effects were noted on vaginal epithelium, endometrium, or levels of reproductive hormones. 45 A mechanistic study examined LH pulsatility and found a role for central opioid receptors in the actions of black cohosh. Naloxone treatment increased the frequency between LH pulses, especially at night. 46 A study in Spain of overweight postmenopausal women given black cohosh evaluated quality of life measures, finding that menopause and health and psychic domains of the inventory were improved for the black cohosh group. 47 In a 12-month study from the United States, black cohosh failed to reduce vasomotor symptoms as effectively as placebo and did not improve other measures. 48

Several systematic meta-analyses 49 , 50 , 51 have concluded that evidence is very weak for black cohosh effectiveness in ameliorating vasomotor symptoms in menopause. More recent trials have been conducted with standardized preparations and have been powered to detect important effects. These results concluded that black cohosh cannot be recommended for menopausal complaints.

Studied related uses include improvement of in vitro fertilization rates 52 and osteoporosis. 53 The latter use is supported by in vitro studies on osteoblasts 54 , 55 and in ovariectomized rats, where fracture healing was accelerated, albeit by less than those rats treated with estrogens. 56

Miscellaneous

Extracts of black cohosh inhibit the growth of prostate cancer cell lines 57 and breast cancer cell lines. 58 Constituent actein has been shown to have a hypotensive effect in rabbits and cats and to cause peripheral vasodilation in dogs. 59 It has been identified as having anti-HIV activity, 60 antimicrobial activity, 61 in vivo hypocholesterolemic activity, and therapeutic action in peripheral arterial disease by causing peripheral vasodilation and increasing blood flow. 20 In ovariectomized rats, black cohosh led to reduced weight gain and improved blood lipid profiles. 62 Phenolic compounds from black cohosh have been identified with anti-inflammatory properties. 63 , 64 , 65

Dosage

On the basis of clinical studies, to manage symptoms of menopause, the current recommended dose of black cohosh is a 40% to 60% ethanol or isopropanol extract in a daily dose of 40 to 80 mg standardized to contain 1 mg of the triterpene 27-deoxyactein per 20 mg tablet. Therapeutic effects generally begin after 2 weeks, with maximum effects usually within 8 weeks. 6 , 7

Pregnancy/Lactation

Black cohosh should be used with caution in pregnancy. 66 Large doses may cause premature birth. 3 , 20

Interactions

Black cohosh may potentiate the effects of antihypertensive medications in rabbits, but not in dogs or humans. 7 Black cohosh constituents inhibit 4 cytochrome P450 enzymes, 67 which may cause herb-drug interactions.

Adverse Reactions

In a review article on the safety of the herb, uncontrolled reports, postmarketing surveillance, and human clinical trials of more than 2,800 patients demonstrate a low incidence of adverse reactions. 6

Toxicology

Overdose of black cohosh may cause nausea, vomiting, dizziness, nervous system and visual disturbances, reduced pulse rate, and increased perspiration. The constituent actein does not possess toxicity in animal studies. 20 , 22 The current major concern is hepatotoxicity. Numerous case reports of liver damage have been published 68 , 69 , 70 , 71 , 72 , 73 ; however, prospective clinical studies of liver function in women taking black cohosh have failed to find negative effects on liver function. 74 Studies in rats have also failed to detect liver damage. 75 Critical analyses have generally failed to support a direct negative effect of black cohosh on the liver, 76 , 77 , 78 , 79 although a US Pharmacopeia panel recommended a cautionary label statement. 80 It has been suggested that the cases of hepatotoxicity may be due to black cohosh constituent-drug interactions. 67 In addition to hepatotoxicity, cardiovascular and circulatory disorders and 1 case of convulsions have been documented. 22 A case report describes a 45-year-old woman who experienced seizures possibly related to consumption of an herbal preparation containing black cohosh. 81 Another case study associated black cohosh use with coagulation activation and fluid retention. 82 A study in a mouse model of breast cancer found no effect of black cohosh on incidence or onset of cancer, but it did find an increase in frequency of lung metastases in the same mice. 83

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