Natural Standard Monograph (www.naturalstandard.com) Copyright © 2004. Synonyms/Common Names/Related Substances: Actaea macrotys, Actaea racemosa L., actee a grappes, Amerikanisches wanzenkraut, baneberry, black snakeroot, botrophis serpentaria, bugwort, cohosh bugbane, Cimicifuga, Cimicifugae racemosae rhizoma, cimicifugawurzelstock, herbe au punaise, macrotys, Macrotys actaeoides, rich weed, rattle root, rattle snakeroot, rattle top, rattle weed, richweed, schwarze schlangenwurzel, solvlys, squaw root, Thalictrodes racemosa, Traubensilberkerze, Wanzwnkraut. Note: Do not confuse black cohosh with blue cohosh (Caulophyllum thalictroides), which contains potentially cardiotoxic/vasoconstrictive chemicals. Do not confuse black cohosh (Cimicifuga racemosa) with cimicifuga foetida, bugbane, fairy candles, or sheng ma; these are species from the same family (Ranunculaceae) with different therapeutic effects.

Black cohosh is popular as an alternative to hormonal therapy in the treatment of menopausal (climacteric) symptoms such as hot flashes, mood disturbances, diaphoresis, palpitations, and vaginal dryness. Several controlled trials and case series have reported black cohosh to improve menopausal symptoms for up to six months. Although these initial studies are suggestive, they have been few in number and have universally suffered from methodological weaknesses.

The mechanism of action of black cohosh remains unclear, and the effects on estrogen receptors or hormonal levels (if any) have not been fully elucidated. Recent publications suggest that there may be no direct effects on estrogen receptors, although this is an area of active controversy (1;2;3;4;5;6;7;8). Safety and efficacy data beyond six months are not available, although recent reports suggest safety of short-term use, including in women experiencing menopausal symptoms for whom estrogen replacement therapy is contraindicated (9;10). Nonetheless, due to a lack of long-term follow-up, caution is advisable until better-quality safety data are available. Use of black cohosh in high-risk populations (such as in women with a history of breast cancer) should be under the supervision of a licensed healthcare professional.

Indication Evidence Grade Menopausal symptoms B Arthritis pain (rheumatoid arthritis, osteoarthritis) C

Amenorrhea, antitussive, anxiety, aphrodisiac, appetite stimulant, asthma, astringent, back pain, bronchitis, cardiac diseases, cervical dysplasia, chorea, depression, diarrhea, diaphoretic, dysmenorrhea, edema, endocarditis, endometriosis, fever, fibrocystic disease, gall bladder disorders, headache, hypertension (11), infertility, inflammation, insect repellent, labor induction, leukorrhea, liver disease, malaise, malaria, mastitis, miscarriage, myalgia, nephritis, neurovegetative complaints, osteoporosis, palpitations, pancreatitis, parturition, pertussis (whooping cough), polycystic breast disease, polycystic ovarian syndrome, polymenorrhea, premenstrual syndrome (PMS), pruritis, sleep disorders, snakebites, sore throat, tinnitus, thromobocytopenia, uterine bleeding, uterine fibroids, uterine prolapse (12), vertigo, yellow fever (13).

	Black Cohosh has been approved by the German expert panel, the Commission E, for premenstrual discomfort (weight gain, swelling, mood fluctuations, breast tenderness), dysmenorrhea, and peri-menopausal symptoms, and is a popular therapy in Europe for these uses.
	Native North Americans used the roots of black cohosh primarily for gynecologic conditions, joint pains, and labor pain relief. Other members of the genus Cimicifuga have been used within traditional Asian healing models as anti-inflammatory and analgesic agents. Black cohosh has been studied primarily in Germany over the past 40 years, with a standardized extract (Remifemin®) available since the 1950s.
	In a survey of 500 nurse-midwives in the United States, out of 172 respondents, 33% indicated that they use black cohosh to stimulate labor (14).
	Members of the genus Cimicifuga, notably C. dahurica (Turcz. Ex Fish. & C.A. Mey.) and C. japonica (Thunb.) Spreng, are frequently used within many traditional Asian healing models.

	Likely Safe: When used for up to six months in otherwise healthy, non-pregnant, non-lactating individuals. Long-term safety data are not available.
	Possibly Safe: When taken by individuals with a history of hormone-sensitive conditions, such as breast cancer, uterine cancer, or endometriosis due to possible estrogenic effects and unknown risks (15;16), although there is recent evidence that estrogenic properties may not be clinically relevant (1;2;3;4;5;6;7;8). Black cohosh has been found to inhibit the growth of breast cancer cells in vitro (17;18), and has been well tolerated in breast cancer patients for six weeks taken concomitantly with tamoxifen (19) and in breast cancer survivors with hot flashes (10).
	Possibly Unsafe: When taken as a labor-inducing agent concomitantly with blue cohosh (Caulophyllum thalictroides). There is a report of severe multi-organ hypoxic injury in a child delivered naturally (at-home) with the aid of blue and black cohosh, who was not breathing at the time of birth (20;21;14).
	Likely Unsafe: When taken during pregnancy due to possible emmenagogic (menstrual flow stimulating) effects (particularly during the first two trimesters).

Recommended doses are based on those most commonly used in available trials, or on historical practice. However, with natural products it is often not clear what the optimal doses are to balance efficacy and safety. Preparation of products may vary from manufacturer to manufacturer, and from batch to batch within one manufacturer. Because it is often not clear what are the active components of a product, standardization may not be possible, and the clinical effects of different brands may not be comparable.

The dosage of black cohosh is often based on its content of triterpines, calculated as 27-deoxyactein. The German product Remifemin®, used in the majority of clinical studies, contains an alcoholic extract of black cohosh rhizoma standardized to contain 1mg of 27-deoxyactein per 20mg tablet (22). The manufacturing process and dosing recommendations for Remifemin® have changed over the past 20 years, and doses used in different studies may not be comparable. A standardized liquid formulation of Remifemin® was used in some studies.

	Tablets: For peri-menopausal symptoms, studies have used 20-40mg Remifemin® tablets (corresponding to 1-2mg 27-deoxyactein) twice daily or 40 drops of a liquid ethanolic extract. The manufacturing process and dosing recommendations for Remifemin® have changed over the past 20 years, and doses used in different studies may not be comparable. The dosing regimen currently recommended is 20mg twice daily. A study of 40mg/day vs. 127mg/day of an isopropanolic extract of black cohosh for six months reported similar effects on menopausal symptoms (23)
	Dried rhizome (root): The British Herbal Compendium has recommended 40-200mg dried rhizome daily in divided doses, although traditional doses have been as high as 1 gram three times daily.
	Tincture/Liquid: The British Herbal Compendium has recommended 0.4-2mL of a (1:10) 60% ethanol tincture daily.
	Other: Powdered root or tea 1-2g three times daily has been used.

Insufficient evidence to recommend.

Anecdotally, overdose of black cohosh may cause headache, nausea, vomiting, dizziness, bradycardia, visual disturbances, and perspiration. A review of the literature reveals no reports of toxicity in humans (24). In animals, administration of high doses of black cohosh for up to six months did not result in toxicity (25), and no specific organ toxicity was seen in rats fed high doses (up to 5g extract/kg) for 26 weeks (26). In an in vitro study, no evidence of mutagenicity from an isopropanolic extract of black cohosh was noted (27).

	Avoid if allergic to black cohosh or other members of the Ranunculaceae (buttercup or crowfoot) family.
	Native black cohosh contains small amounts of salicylic acid, but it is not clear how much (if any) is present in commercially available or standardized extracts. Caution is warranted in patients allergic to aspirin or other salicylates.

	General: Reviews of the literature have reported black cohosh to be generally well tolerated in recommended doses for up to six months (12;28;23;29;9;7). The potential effects of black cohosh on estrogen-sensitive conditions such as breast cancer, uterine cancer, or endometriosis are not known.
	Neurologic/CNS: Tonic-clonic seizures were reported in a 45-year old woman who had been taking black cohosh, chaste tree berries/seeds (Vitex agnus-castus), and evening primrose oil (Oenothera biennis) for four months, who also consumed alcohol (30). The relative contribution of each agent is not clear. Anecdotally, high doses of black cohosh may cause frontal headaches, dizziness, diaphoresis, and visual disturbances.
	Cardiovascular: Arrhythmia of unspecified type was reported in one patient in a 2-month placebo controlled trial of black cohosh (n= 85) (19). Anecdotally, high doses of black cohosh may cause bradycardia. In a 1962 study, acteina, a constituent of black cohosh, was found to cause peripheral vasodilation in humans, and was noted to elicit hypotension in animals (31). Additional supporting data in humans is lacking.
	Gastrointestinal (hepatitis): There are three reported cases in Australia of hepatitis in patients taking herbal combinations containing black cohosh, including two cases of fulminant hepatic failure requiring transplantation (32;33). The specific role of black cohosh in these cases is not clear. In 2003, a case report was published of acute liver failure in a 52-year-old woman using an herbal combination for three months (for tinnitus) including black cohosh and several other herbs (200mL bottle containing fluid extracts of black cohosh 20mL, Nepeta hederacea [ground ivy] 80mL, Hydrastis canadensis [goldenseal] 20mL, Ginkgo biloba 40mL, Avena sativa [oat seed] 40mL; concentration: 1 gram of each herb per 1mL of extract, except golden seal [0.5 grams per 1mL]; patient ingested 7.5mL twice daily as needed, with an estimated 600mL total taken over 3 months). Liver transplant was required. Laboratory analysis revealed no undeclared drugs in the preparation (which had been prepared by the patient's pharmacist). Notably, ground ivy contains very low concentrations of pulegone, a known hepatotoxin. Some authors feel that these cases have not been adequately substantiated, and given the widespread use of black cohosh and paucity of other such reports, merit further investigation (34).
	Gastrointestinal (gastrointestinal symptoms): Mild gastrointestinal discomfort was found in 7% of a clinical sample of 629 women taking black cohosh (35). Constipation was noted in one subject, and indigestion in another subject taking both black cohosh and tamoxifen in a placebo controlled trial (19). Anecdotally, high doses of black cohosh may cause nausea and vomiting.
	Endocrine (estrogenic effects): The estrogenic activity of black cohosh remains debated, and specific estrogenic constituents have not been identified. It is not clear if black cohosh is safe in individuals with hormone-sensitive conditions such as breast cancer, uterine cancer, or endometriosis. Recent publications suggest that there may be no direct effects on estrogen receptors, although this is an area of active controversy (1;2;3;4;5;6;7;8). Safety and efficacy data beyond six months are not available, although recent reports suggest safety of short-term use, including in women experiencing menopausal symptoms for whom estrogen replacement therapy is contraindicated (9;10). In a two month trial in breast cancer survivors, endometrial hyperplasia was noted in one patient taking both black cohosh and tamoxifen (out of 42 subjects receiving black cohosh), and one instance each was noted of vaginal bleeding, weight gain, dilation and curettage, hysterectomy and breast cancer recurrence (19). The influence of black cohosh alone or in combination with tamoxifen is not clear in these cases, although these complications were not reported among 43 non-black cohosh subjects. Black cohosh was administered for 12 months in combination with tamoxifen to 136 breast-cancer survivors for the prevention of hot flashes, and was well-tolerated, although long-term safety data are not available (10). In animals and in vitro, initial reports of estrogen receptor binding activity (36) stand in contrast with more recent data suggesting no significant estrogen receptor binding activity or estrogenic activities (37;38;39;16). One in vitro study found no effects of black cohosh alone on estrogen receptors, but reported that black cohosh antagonized proliferative effects on cells induced by estradiol (40). Several studies have aimed to assess estrogenic activity by measuring luteinizing hormone (LH), follicle stimulating hormone (FSH), or prolactin levels (41;42). One study reported lower FSH levels (but not LH) in patients treated with black cohosh vs. placebo (n=110), although the results are not clear due to lack of known baseline hormone levels in either group (41). Results from other trials have found no effects on these hormone levels after up to six months of black cohosh therapy (43;29;19). Administered to female infantile mice, premature onset of estrus could not be precipitated by black cohosh (44). Estrogenic effects on vaginal epithelium were noted in one 3-month trial of black cohosh (45), while a more recent 6-month trial reported no effects on vaginal cytology (23). Nonetheless, due to a lack of long-term follow-up safety data, caution is advisable until better-quality safety data are available. Use of black cohosh in high-risk populations (such as in women with a history of breast cancer) should be under the supervision of a licensed healthcare professional.
	Oncologic: It remains unclear if black cohosh possesses estrogenic activity that may affect hormone-sensitive cancers, such as some types of breast or uterine cancer. Initial in vitro studies have reported black cohosh to possess inhibitory effects on estrogen responsive cancer cell lines/breast cancer cells (46;17;18). In a two month trial in breast cancer survivors, endometrial hyperplasia was noted in one patient taking both black cohosh and tamoxifen (out of 42 subjects receiving black cohosh), and one instance each was noted of vaginal bleeding, weight gain, dilation and curettage, hysterectomy and breast cancer recurrence (19). The influence of black cohosh alone or in combination with tamoxifen is not clear in these cases, although these complications were not reported among 43 non-black cohosh subjects. Black cohosh was administered for 12 months in combination with tamoxifen to 136 breast-cancer survivors for the prevention of hot flashes, and was well-tolerated, although long-term safety data are not available (10).
	Hematologic: It is not clear if black cohosh increases the risk of blood clots or stroke, and there have been no reports of these complications from the small number of existing case studies and trials. It is not clear if black cohosh possesses a similar mechanism of action as estrogen and raloxifene, which have been associated with these complications.
	Musculoskeletal: It has been hypothesized that black cohosh may exert negative effects on bone resorption, or that black cohosh, as potential substitute for estrogen therapy, may not possess the beneficial effects that estrogen may have on bone mass. However, there are no supporting human data in this area.

	Use cautiously in patients with known allergy to aspirin, other salicylates, or members of the Ranunculaceae (buttercup or crowfoot) family.
	Use cautiously in patients with known estrogen sensitive conditions, such as breast cancer, uterine cancer, or endometriosis. Effects are not known.
	Use cautiously in patients on hormone replacement therapy, including tamoxifen or raloxifene. Effects of black cohosh are not known.
	Use cautiously in patients with known seizure disorder based on one case report.
	Use cautiously in patients on antihypertensive medications, due to a theoretical risk of hypotension.
	Use cautiously in patients with history of thromboembolic disease or stroke. Although there are no reports of these complications in the available literature, there may be a theoretical risk.
	Use cautiously in patients with liver disease, due to three case reports of liver damage.
	If black cohosh is used as an alternative to prescription hormone replacement therapy, follow bone mass and be aware that beneficial effects on bone mass may not occur.

	Safety during pregnancy has not been established, and may be inadvisable due to purported effects on the uterus ("uterotonic" effects), and possible estrogenic properties.
	In a survey of 500 nurse-midwives in the United States, out of 172 respondents, 33% indicated that they use black cohosh to stimulate labor (14). There is one report of severe multi-organ hypoxic injury in a child delivered "naturally" with the aid of both blue and black cohosh (Caulophyllum thalictroides) who was not breathing at the time of birth (21). The child survived with permanent central nervous system damage. Notably, blue cohosh possesses a vasoconstrictive glycoside which may have been responsible for the adverse effects.
	There is insufficient evidence regarding use of black cohosh during lactation, and it is therefore not recommended.
	Tinctures may be ill-advised during pregnancy due to high alcohol content, although the absolute quantity of alcohol ingested from tinctures at recommended doses is likely to be relatively small.

	Hormone Replacement Therapy (HRT), Oral Contraceptives (OCPs): The estrogenic activity of black cohosh remains debated. Specific estrogenic constituents have not been identified, and it is not clear how (or if) black cohosh interacts with estrogens/estrogen receptors and/or progestins. Recent publications suggest that there may be no direct effects on estrogen receptors, although this is an area of active controversy (1;2;3;4;5;6;7;8). Therefore, caution is warranted in individuals taking both black cohosh and estrogens due to unknown effects, and interactions data in this area are lacking. In animals and in vitro, initial reports of estrogen receptor binding activity (36) stand in contrast with more recent data suggesting no significant estrogen receptor binding activity or estrogenic activities (37;38;39;16). One in vitro study found no effects of black cohosh alone on estrogen receptors, but reported that black cohosh antagonized proliferative effects on cells induced by estradiol (40). Several studies have aimed to assess estrogenic activity by measuring luteinizing hormone (LH), follicle stimulating hormone (FSH), or prolactin levels (41;42). One study reported lower FSH levels (but not LH) in patients treated with black cohosh vs. placebo (n=110), although baseline hormone levels were not known in either group (41). Results from other trials have found no effects on these hormone levels after up to six months of black cohosh therapy (43;29;19). Administered to female infantile mice, premature onset of estrus could not be precipitated by black cohosh (44). Estrogenic effects on vaginal epithelium were noted in one 3-month trial of black cohosh (45), while a more recent 6-month trial reported no effects on vaginal cytology (23).
	Tamoxifen, Raloxifene: Controversy surrounds the use of black cohosh in combination with tamoxifen. In a 2003 randomized, open-label controlled trial of black cohosh for the prevention of hot flashes in women survivors of breast cancer taking tamoxifen, 136 women, ages 36-52, received either black cohosh (CR BNO 1055, Menofem/Klimadynon, 20mg daily) with their tamoxifen, or tamoxifen alone (10). After 12 months, 24.4% of black cohosh subjects experienced hot flashes, compared to 73.9% in the tamoxifen-only group (p<0.01). These results are promising, although the introduction of bias due to the open-label design is possible. Long-term follow-up of disease-free interval was not conducted, and therefore the safety of black cohosh in breast cancer patients was not established. In a 2001 trial of 85 breast cancer survivors, endometrial hyperplasia was noted in one patient taking both black cohosh and tamoxifen (out of 42 subjects receiving black cohosh), and one instance each was noted of vaginal bleeding, weight gain, dilation and curettage, hysterectomy and breast cancer recurrence (19). The influence of black cohosh alone or in combination with tamoxifen are not clear in these cases, although these complications were not reported among 43 non-black cohosh subjects. In this study, no improvements in hot flashes, other menopausal symptoms, or overall well-being were noted over a two month period (in contrast to other preliminary research suggesting efficacy of black cohosh for menopausal symptoms). It is not clear if tamoxifen antagonized the effects of black cohosh, or if hot flashes induced by tamoxifen are refractory to black cohosh therapy. Although this trial suggests black cohosh may not be useful in the short-term treatment of tamoxifen-related hot flashes, due to methodological weaknesses, further study is warranted. Also in this trial, constipation was noted in one subject, and indigestion in one subject (19). Recent in vitro study suggests possible additive anti-proliferative effects of black cohosh and tamoxifen (47).
	Hypotensive Drugs: Due to theoretical hypotensive effects, black cohosh should be used cautiously with other hypotensive agents (31;11). There have been reports of hypotension in animals, although human data are limited in this area; increased peripheral blood flow was associated with black cohosh administration in a 1962 study (31).
	Anti-platelet Drugs, Anticoagulants: Native black cohosh contains small amounts of salicylic acid, and may potentiate the anti-platelet effects of other agents. This is a theoretical concern, as it is not clear if therapeutic amounts of salicylates are present in commercial or processed black cohosh products.
	Disulfiram (Antabuse®): Tinctures may contain high alcohol content, and theoretically may elicit a disulfiram reaction.
	Metronidazole (Flagyl®): A disulfiram reaction can occur when metronidazole and alcohol are used concomitantly. Due to the high alcohol content in some tinctures, this combination theoretically may cause such a reaction.

	Anti-platelet/Anticoagulant Herbs and Supplements: Native black cohosh contains small amounts of salicylic acid, and may potentiate the anti-platelet effects of other agents. This is a theoretical concern, as it is not clear if therapeutic amounts of salicylates are present in commercial or processed black cohosh products.
	Herbs and Supplements Containing Phytoestrogens: The estrogenic activity of black cohosh remains debated. Specific estrogenic constituents have not been identified, and it is not clear if black cohosh interacts with other estrogenic compounds. Recent publications suggest that there may be no direct effects on estrogen receptors, although this is an area of active controversy (1;2;3;4;5;6;7;8). Therefore, caution is warranted in subjects taking both black cohosh and herbs containing phytoestrogens due to unknown effects, and interactions data in this area are lacking. In animals and in vitro, initial reports of estrogen receptor binding activity (36) stand in contrast to more recent data suggesting no significant estrogen receptor binding activity or estrogenic activities (37;38;39;16). Several studies have aimed to assess estrogenic activity by measuring luteinizing hormone (LH), follicle stimulating hormone (FSH), or prolactin levels (41;42). One study reported lower FSH levels (but not LH) in patients treated with black cohosh vs. placebo (n=110), although baseline hormone levels were not known in either group (41). Results from other trials have found no effects on these hormone levels after up to six months of black cohosh therapy (43;29;19). Administered to female infantile mice, premature onset of estrus could not be precipitated by black cohosh (44). Estrogenic effects on vaginal epithelium were noted in one 3-month trial of black cohosh (45), while a more recent 6-month trial reported no effects on vaginal cytology (23).
	Evening Primrose Oil, Chasteberry: Tonic-clonic seizures have been reported in a 45-year old woman who had been taking black cohosh, chaste tree (berries and seeds), and primrose oil for four months, who also consumed alcohol (30). The relative contribution of each agent or risk of combination is not clear.
	Blue cohosh (Caulophyllum thalictroides): Both black cohosh and blue cohosh (Caulophyllum thalictroides) are commonly used by nurse-midwives in the United States to assist birth (14). There is a report of severe multi-organ hypoxic injury in a child delivered "naturally" with the aid of both blue and black cohosh, who was not breathing at the time of birth (20;21;14). The child survived with permanent central nervous system damage. Notably, blue cohosh possesses a vasoconstrictive glycoside which may have been responsible for the adverse effects.
	American pennyroyal: Pennyroyal (Hedeoma pulegioides L.) and black cohosh are sometimes taken together to induce abortion, although the use of these herbs together cannot be recommended due to the possibility of increased toxicity and death. There is a case report of a 24-year-old woman who took 48-56% of pennyroyal herb in an alcohol base and an unknown amount of black cohosh root for 2 weeks in an attempt to induce abortion (48). Following a single subsequent dose of this combination, the patient died within 48 hours.

	Constituents: Constituents of black cohosh with proposed or demonstrated pharmacological activity include triterpine glycosides (actein, 27-deoxyactein, cimicifugoside) (17), cyclolanostanol xylosides (49) formononetin, and organic acids (isoferulic, salicylic acid).
	Estrogenic effects: It is not clear what constituent(s) of black cohosh, if any, possesses estrogenic properties. In animals and in vitro, initial reports of estrogen receptor binding activity (36) stand in contrast with more recent data suggesting no significant estrogen receptor binding activity or estrogenic activities (37;1;2;38;39;16). One in vitro study found no effects of black cohosh alone on estrogen receptors, but reported that black cohosh antagonized proliferative effects on cells induced by estradiol (40). Several studies have aimed to assess estrogen activity by measuring luteinizing hormone (LH), follicle stimulating hormone (FSH), or prolactin levels (41;42). One study reported lower FSH levels (but not LH) in patients treated with black cohosh vs. placebo (n=110), although baseline hormone levels were not known in either group (41). Results from other trials have found no effects on these hormone levels after up to six months of black cohosh therapy (43;29;19). Administered to female infantile mice, premature onset of estrus could not be precipitated by black cohosh (44). Estrogenic effects on vaginal epithelium were noted in one 3-month trial of black cohosh (45), while a more recent 6-month trial reported no effects on vaginal cytology (23).
	CNS effects: Recent studies suggest that the mechanism of action of black cohosh may be centrally mediated, with possible action at the level of serotonin or dopamine receptors (8;6).
	Cancer cell lines: In vitro studies have reported black cohosh to possess inhibitory effects on estrogen responsive cancer cell lines/breast cancer cells (46;17;18).
	Vascular effects: In a 1962 study, acteina, a constituent of black cohosh, was found to cause peripheral vasodilation, and has been noted to elicit hypotension in animals (31). Additional supporting data in humans is lacking.
	Other: Cimicifugoside from Cimicifuga simplex has been found to inhibit cellular thymidine-3H uptake, and to act as a selective inhibitor of nucleoside transport into mammalian cells (50;51;13;50).

	Native American and Chinese herbalists have traditionally used black cohosh for a variety of ailments, and as an insect repellent.
	In the 19th century, black cohosh was used by medical practitioners for a variety of rheumatic disorders, dysmenorrhea, and to induce labor. An Eclectic physician of obstetrics and gynecology in the 1800s, John King, was a strong proponent of medicinal use of this herb. A popular product sold in the United States in the late 1800s for menstrual cramps was Lydia E. Pinkham's Vegetable Compound, which contained black cohosh and alcohol.
	Black cohosh has been widely used in Germany since the 1950s, principally for disorders associated with menopause and menstruation.

Condition Study Design Author, Year N Statistically Significant? Quality of Study 0-2=poor 3-4=good 5=excellent Magnitude of Benefit ARR NNT Comments Menopausal symptoms Randomized, double-blind, placebo controlled, equivalence study Stoll, 1987 80 Yes 4 Medium NA NA 8mg Remifemin (black cohosh) vs. conjugated estrogens or placebo for 12 weeks. Black cohosh superior to placebo & equal to estrogens on Kupperman Index, HAM-A, & vaginal epithelial proliferation; hot flashes reduced more than estrogens. Menopausal symptoms (breast cancer survivors) Randomized, double-blind, placebo controlled Jacobson, 2001 85 NA 3 None NA NA No improvement in hot flashes in breast cancer survivors from black cohosh vs. placebo. 69% of subjects taking tamoxifen. 19% dropout. Menopausal symptoms Dosing trial (randomized, double-blind) Liske and Wüstenberg, 1998 152 NA 3 Large NA NA Published conference abstract. 40mg vs. 127mg per day of black cohosh extract for 6 months. No differences found in Kupperman Index, LH, FSH, or vaginal epithelium. No placebo group. Menopausal symptoms Randomized, double-blind, placebo controlled Boblitz, 2000 179 Yes 2 Medium NA NA Published conference abstract. Fixed combination of black cohosh and St. John's wort improved Kupperman Index after 6 weeks. Menopausal symptoms Equivalence trial, randomized, non-blinded, no placebo Lehmann-Willenbrock, 1988 60 NA 1 Medium NA NA Black cohosh vs. 3 hormone replacement therapies for 6 months in hysterectomy patients. Equal improvements in all groups on Kupperman Index. Sample size may have been inadequate. Menopausal symptoms Equivalence trial, non-blinded, no placebo Warnecke, 1985 60 Yes 1 Medium NA NA Black cohosh vs. conjugated estrogens vs. diazepam. Equal improvement on Kupperman Index and HAM-A. Hot flashes in breast cancer survivors using tamoxifen Randomized, controlled, open-label trial Hernandez, 2003 139 Yes 4 Medium 49.5% 2 Tamoxifen plus black cohosh vs. tamoxifen alone reported to reduce hot flash incidence. Open-label design allows for bias.

	Summary: Black cohosh is popular as an alternative to prescription hormonal therapy in the treatment of menopausal (climacteric) symptoms such as hot flashes, mood disturbances, diaphoresis, palpitations, and vaginal dryness. Several controlled trials and case series have reported black cohosh to improve menopausal symptoms for up to six months. Although these initial studies are suggestive, they have been small in number and have universally suffered from methodological weaknesses. Most trials have utilized a standardized measurement scale to assess menopausal symptoms called the Kupperman Index, which does not measure vaginal dryness/atrophy, but does measure paresthesias and vertigo (which are not classically associated with menopause). The mechanism of action of black cohosh remains unclear, and effects on estrogen receptors or hormonal levels have not been demonstrated. Safety and efficacy data beyond six months are not available. Therefore, while the available evidence does suggest possible efficacy of black cohosh for the short-term treatment of menopausal symptoms, this is an area where a well-designed, long-term, three-arm (black cohosh vs. standard therapy vs. placebo) evaluation of efficacy and safety is warranted.
	Randomized controlled trials: In a randomized, double-blind trial, Stoll et al. compared 4mg of black cohosh extract (Remifemin®) taken twice daily vs. 0.625mg conjugated estrogens vs. placebo in 80 women with menopausal symptoms (45). Outcomes measures included the Kupperman Index, anxiety as measured by the Hamilton anxiety scale (HAM-A), and proliferation of vaginal epithelium. After 12 weeks, all measures were significantly improved in the black cohosh group vs. placebo, with reported equivalence to conjugated estrogens. In a separate measure of and frequency of hot flashes, improvement in the black cohosh group was superior to estrogens or placebo, with a mean reduction in the black cohosh group from 4.9 to 0.7 hot flashes per day vs. 5.2 to 3.2 in the estrogen group (which was similar to placebo). Despite methodological weaknesses of this study, including incomplete descriptions of baseline patient characteristics, blinding, or randomization, the three-arm design and use of multiple outcomes measures add strength to the results.
	Jacobson et al. conducted a randomized, double-blind study in 85 breast cancer survivors who had completed their primary breast cancer treatment and were experiencing hot flashes (19). In this group, 69% were taking tamoxifen. Subjects were randomized to receive either an unidentified black cohosh preparation or placebo for two months, after which time both groups were reported to experience significant reductions in hot flashes, with no advantage of black cohosh over placebo in the 81% of subjects that completed the study. No between-group differences were detected on visual analog scales of well-being, global health, or menopausal symptoms (diaphoresis, palpitations, sleep quality, depression, anxiety, headache). The weaknesses of this study include the short duration, which may not be adequate to assess menopausal symptoms, concomitant use of tamoxifen, which induces hot flashes which may require a different treatment approach than menopausal hot flashes, unclear black cohosh product used, and large dropout (19%) without adequate analysis of dropouts. Nonetheless, these negative results warrant further evaluation, particularly in the setting of tamoxifen use, which may be common in women who seek black cohosh as an alternative to estrogen therapy (or in women with breast cancer history or risk).
	In a six-month randomized, non-blinded study, Lehmann-Willenbrock and Riedel randomized 60 women younger than 40-years-old who had undergone hysterectomy (but were left with at least one ovary) to receive either black cohosh (two tablets 20mg Remifemin® twice daily), estriol (1mg daily), conjugated estrogens (1.25mg once daily), or estrogen/progestin combination (one tablet of unclear dosage daily) (29). Notably, these were not cancer patients, and had undergone hysterectomy for non-malignant conditions. Subjects were all experiencing menopausal symptoms prior to the study. Outcomes measures included a modified Kupperman Index (a sum score of menopausal symptoms), as well as serum LH and FSH levels. Assessment at 1, 2, 3, and 6 months found improvements on the Kupperman Index to be comparable in all groups. The Kupperman Index score was noted to decrease in all groups by at least 50% vs. baseline (more in the conjugated estrogen and estrogen-gestagen groups without statistical significance). FSH and LH levels decreased in all hormonal replacement groups, but not in the black cohosh group. These results are compromised by the lack of placebo group, poor description of baseline patient characteristics, and unclear procedures for blinding or randomization. The small sample size despite multiple subgroups, without a power calculation to determine adequate sample size, leave open the possibility that results are due to lack of statistical power, rather than true equivalence of therapies.
	In a non-blinded study of 60 women with menopausal symptoms, Warnecke compared black cohosh (40 drops of daily Remifemin® liquid twice daily, standardized to 27-deoxyactein) vs. 0.625mg of conjugated estrogens daily vs. 2mg of the benzodiazepine diazepam daily (52). Outcomes measures included the Kupperman Index of menopausal symptoms, Hamilton anxiety scale (HAM-A), Clinical Global Impressions (CGI) scale, and a patient self-assessment scale for depression. After 12 weeks, statistically significant improvements were noted in both groups in Kupperman, HAM-A, and self-assessment scores, without differences between groups. Non-significant improvements were noted in CGI scores in both groups. Although suggestive, the lack of placebo group or blinding allows for the influence of bias and confounders. The results may reflect the natural history of menopausal symptoms, rather than the benefits of therapy.
	Hernandez et al. investigated the use of black cohosh for the prevention of hot flashes in women survivors of breast cancer taking tamoxifen (10). In this randomized, open-label controlled trial, 136 women, ages 36-52, received either black cohosh (CR BNO 1055, Menofem/Klimadynon, 20mg daily) with their tamoxifen, or tamoxifen alone. After 12 months, 24.4% of black cohosh subjects experienced hot flashes, compared to 73.9% in the tamoxifen-only group (p<0.01). These results are promising, although the introduction of bias due to the open-label design is possible. Long-term follow-up of disease-free interval was not conducted, and therefore the safety of black cohosh in breast cancer patients was not established.
	Case series: In a case series, 40 drops of daily Remifemin® (standardized to 27-deoxyactein) was administered for 6-8 weeks to 629 women with menopausal symptoms (35). Primary outcome measures included diaphoresis, hot flashes, headache, palpitations, and anxiety. After four weeks, 80% of subjects were reported to have experienced symptomatic relief. Although suggestive, this study is limited by the lack of a control group. The observed improvements may therefore reflect the natural history of menopausal symptoms to wax and wane, or confounding by a "placebo effect" (rather than effects of black cohosh).
	Two poor quality case series with similar designs have been reported from gynecology practices (53;54). In combination, 86 cases were presented of women treated with Remifemin® liquid, 40 drops twice daily for approximately 3 months. Improvements were reported in Kupperman Index scores for menopausal symptoms, and in Clinical Global Impressions (CGI) score. Although suggestive, the short duration and lack of controls weakens these results.
	Dosing study: In a published abstract, Liske and Wüstenberg reported a comparison of two doses of an iso-propanolic extract black cohosh (23). Menopausal women (n=152, ages 43-60 years) were randomized to receive either 40mg or 127mg of black cohosh daily for six months. Improvements on the Kupperman Index were reported after two weeks in both groups. After six months, the groups were found to have similar results on the Kupperman Index (90% of subjects in both groups improving), without changes in either group in levels of LH, FSH, or prolactin, and without changes in vaginal epithelial proliferation. Although this report suggests equal efficacy of the two doses of black cohosh, the lack of placebo arm weakens the results: benefits over time due to the natural history of menopausal symptoms to wax and wane cannot be ruled out as causative. In addition, as a published abstract, descriptions of methodology were limited. Although no power calculation was conducted, the sample size was likely adequate to detect between-group differences.
	Combination product: Boblitz et al. conducted a double-blind, randomized, placebo controlled trial of Remifemin® plus, a fixed combination of St. John's wort (Hypericum perforatum) and black cohosh (55). In this study, 179 patients with complaints associated with menopause were treated with two capsules given together once daily of either Remifemin® plus or placebo. The Kupperman Index of those ingesting Remifemin® decreased from 31.4 to 18.7 compared with a decrease in the placebo group from 30.3 to 22.3 (p<0.001). Psychological parameters were also significantly improved in the Remifemin® plus group. However, it is not possible to separate the possible effects of black cohosh from St. John's wort, which has been found to improve symptoms of mild-to-moderate depression, and may exert influence on Kupperman measures. As a published abstract, this report included only limited descriptions of baseline patient characteristics and methods.

Summary: Literature review reveals no high-quality studies of black cohosh monotherapy for symptoms of rheumatoid arthritis or osteoarthritis. Native black cohosh does contain small amounts of salicylates, although it is not clear if these are present in therapeutic amounts in commercial preparations. One study of a combination product containing black cohosh and several other salicylate-containing herbs for rheumatoid arthritis or osteoarthritis found small improvements in pain scores, but no improvement in joint function or decrease in self-medication with analgesics.

Evidence: A randomized, double-blind, placebo controlled trial administered a fixed combination product (Reumalex®) to 82 male and female patients with rheumatoid arthritis or osteoarthritis (56). Each Reumalex® tablet contains 35mg black cohosh, 100mg white willow bark, 25mg sarsaparilla (4:1), 17mg poplar bark (7:1), and 40mg guaiacum resin. Notably, several constituents contain salicylates, and it has been estimated that each Reumalex® tablet may include up to 10-20mg of salicylates. Two Reumalex® tablets or placebo was administered to subjects over a two-month period. Outcomes measures included scores on the validated Arthritis Impact Measurement Scales Health Status Questionnaire (AIMS-2). Small significant improvements in pain were noted in the Reumalex® group vs. placebo, although there were no other significant differences between groups, including measures of joint function and use of over-the-counter analgesics. These results cannot be extrapolated to any of the constituents alone.

	Remifemin® (originally manufactured by Schaper & Brümmer; now manufactured and distributed by GlaxoSmithKline).
	CR BNO 1055 (Menofem/Klimadynon).
	Other trade names: Biophylin®, Black Cohosh liquid extract (Bio-pro), Black Cohosh Root Powder (Global Botanical), Cimisan®, Femilla N®, Klimadyon®, Ligvites®, Vegetex®.
	Combination products: Black Cohosh CX, Cimicifuga-Amyda-Shell Decoction, Estroven, FC with Dong Quai, GNC Menopause Formula, Natrol, Nature's Herbs, Qingwei san, Remifemin® plus (black cohosh plus St. John's wort), Reumalex® (35mg black cohosh, 100mg white willow bark, 25mg sarsaparilla [4:1], 17mg poplar bark [7:1], and 40mg guaiacum resin).

Remifemin®

Authors/Editors: Victor Mendoza, MD (Washington University Medical Center); Ivo Foppa, MD, ScD (Harvard School of Public Health); Ernie-Paul Barrette, MD, FACP (Case Western Reserve University School of Medicine); Steve Bent, MD (University of California, San Francisco); Michael Smith, M.R.PharmS, ND (Canadian College of Naturopathic Medicine); Paul Hammerness, MD (Harvard Medical School), Catherine Ulbricht, PharmD (Massachusetts General Hospital); Ethan Basch, MD (Natural Standard Research Collaboration).

Blinded Peer Review: Natural Standard Editorial Board.

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