Scientific Name(s): Actaea racemosa L., syn. Cimicifuga racemosa (L.) Nutt. Family: Ranunculaceae.
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.
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.
Patients with aspirin sensitivity because it contains salicylates.
Black cohosh is contraindicated in pregnancy and may cause premature birth in large doses. Avoid black cohosh during lactation.
None well documented.
There is a low incidence of adverse reactions.
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.
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 has been replaced by the synonym Actaea racemosa L., although both names are commonly used.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
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
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). 30Animal 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. 56Miscellaneous
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
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
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.
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
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
Bibliography1. Borrelli F, Izzo AA, Ernst E. Pharmacological effects of Cimicifuga racemosa . Life Sci . 2003:73(10):1215-1229.
2. Meyer JE. The Herbalist . Chicago, IL: Rand McNally; 1960.
3. Dobelis IN, ed. Magic and Medicine of Plants . Pleasantville, NY: Reader's Digest Association; 1986.
4. Xue CY, Li DZ, Wang QZ. Application of LightCycler polymerase chain reaction and melting curve analysis to the authentication of the traditional Chinese medicinal plant Cimicifuga foetida . Planta Med . 2009;75(8):873-875.
5. Zerega NJ, Mori S, Lindquist C, Zheng Q, Motley TJ. Using amplified fragment length polymorphisms (AFLP) to identify black cohosh ( Actaea racemosa ). Econ Bot . 2002;56(2):154-164.
6. Low Dog T, Powell KL, Weisman SM. Critical evaluation of the safety of Cimicifuga racemosa in menopause symptom relief. Menopause . 2003;10(4):299-313.
7. Pepping J. Black cohosh: Cimicifuga racemosa . Am J Health Syst Pharm . 1999;56(14):1400-1402.
8. Winterhoff H, Spengler B, Christoffel V, Butterweck V, Löhning A. Cimicifuga extract BNO 1055: reduction of hot flushes and hints on antidepressant activity. Maturitas . 2003;44(suppl 1):S51-S58.
9. Felter HW, ed. American Medicinal Plants. Eclectic Medical Journal Publications . Sandy, OR: Eclectic Medical; 1900.
10. Tyler VE. Was Lydia E. Pinkham's Vegetable Compound an effective remedy? Pharm Hist . 1995;37(1):24-28.
11. Murray M. Remifenin: answers to common questions. Am J Nat Med . 1997;4:3-5.
12. Linde H. Contents of Cimicifuga racemosa . 2. On the structure of actein [in German]. Arch Pharm Ber Dtsch Pharm Ges . 1967;300(10):885-892.
13. Linde H. Contents of Cimicifuga racemosa . 3. On the constitution of the rings A, B and C of actein [in German]. Arch Pharm Ber Dtsch Pharm Ges . 1967;300(12):982-992.
14. Linde H. Contents of Cimicifuga racemosa . 5. 27-desoxyacetylacteol [in German]. Arch Pharm Ber Dtsch Pharm Ges . 1968;301(5):335-341.
15. Chen SN, Fabricant DS, Lu ZZ, Fong HH, Farnsworth NR. Cimiracemosides I-P, new 9,19-cyclolanostane triterpene glycosides from Cimicifuga racemosa . J Nat Prod . 2002;65(10):1391-1397.
16. Chen SN, Fabricant DS, Lu ZZ, Zhang H, Fong HH, Farnsworth NR. Cimiracemates A-D, phenylpropanoid esters from the rhizomes of Cimicifuga racemosa . Phytochemistry . 2002;61(4):409-413.
17. Li W, Sun Y, Liang W, Fitzloff JF, van Breemen RB. Identification of caffeic acid derivatives in Actea racemosa ( Cimicifuga racemosa , black cohosh) by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom . 2003:17(9):978-982.
18. Gödecke T, Lankin DC, Nikolic D, et al. Guanidine alkaloids and Pictet-Spengler adducts from black cohosh ( Cimicifuga racemosa ). J Nat Prod . 2009;72(3):433-437.
19. Gödecke T, Nikolic D, Lankin DC, et al. Phytochemistry of cimicifugic acids and associated bases in Cimicifuga racemosa root extracts. Phytochem Anal . 2009;20(2):120-133.
20. Newall CA, Anderson LA, Phillipson JD. Black Cohosh. In: Newall CA, Anderson LA, Phillipson JD. Herbal Medicines: A Guide for Health-Care Professionals . London, England: Pharmaceutical Press; 1996:80-81.
21. Berger S, Junior P, Kopanski L. 27-deoxyactein: a new polycyclic triterpenoid glycoside from Actaea racemosa . Planta Med . 1988;54(6):579-580.
22. Huntley A, Ernst E. A systematic review of the safety of black cohosh. Menopause . 2003;10(1):58-64.
23. Cicek SS, Schwaiger S, Ellmerer EP, Stuppner H. Development of a fast and convenient method for the isolation of triterpene saponins from Actaea racemosa by high-speed countercurrent chromatography coupled with evaporative light scattering detection. Planta Med . 2010;76(5):467-473.
24. Kennelly EJ, Baggett S, Nuntanakorn P, et al. Analysis of thirteen populations of black cohosh for formononetin. Phytomedicine . 2002;9(5):461-467.
25. Avula B, Wang YH, Smillie TJ, Khan IA. Quantitative determination of triterpenoids and formononetin in rhizomes of black cohosh ( Actaea racemosa ) and dietary supplements by using UPLC-UV/ELS detection and identification by UPLC-MS. Planta Med . 2009;75(4):381-386.
26. Jiang B, Lyles JT, Reynertson KA, Kronenberg F, Kennelly EJ. Stability evaluation of selected polyphenols and triterpene glycosides in black cohosh. J Agric Food Chem . 2008;56(20):9510-9519.
27. Jiang B, Yang H, Nuntanakorn P, Balick MJ, Kronenberg F, Kennelly EJ. The value of plant collections in ethnopharmacology: a case study of an 85-year-old black cohosh ( Actaea racemosa L.) sample. J Ethnopharmacol . 2005;96(3):521-528.
28. van Breemen RB, Liang W, Banuvar S, et al. Pharmacokinetics of 23-epi-26-deoxyactein in women after oral administration of a standardized extract of black cohosh. Clin Pharmacol Ther . 2010;87(2):219-225.
29. Jarry H, Harnischfeger G, Düker E. The endocrine effects of constituents of Cimicifuga racemosa . 2. In vitro binding of constituents to estrogen receptors [in German]. Planta Med . 1985;51(4):316-319.
30. Powell SL, Gödecke T, Nikolic D, et al. In vitro serotonergic activity of black cohosh and identification of N(omega)-methylserotonin as a potential active constituent. J Agric Food Chem . 2008;56(24):11718-11726.
31. Jarry H, Metten M, Spengler B, Christoffel V, Wuttke W. In vitro effects of the Cimicifuga racemosa extract BNO 1055. Maturitas . 2003;44(suppl 1):S31-S38.
32. Jarry H, Harnischfeger G. Endocrine effects of constituents of Cimicifuga racemosa . 1. The effect on serum levels of pituitary hormones in ovariectomized rats [in German]. Planta Med . 1985;51(1):46-49.
33. Einer-Jensen N, Zhao J, Andersen KP, Kristoffersen K. Cimicifuga and Melbrosia lack oestrogenic effects in mice and rats [in German]. Maturitas . 1996;25(2):149-153.
34. Alves DL, Lima SM, da Silva CR, et al. Effects of Trifolium pratense and Cimicifuga racemosa on the endometrium of Wistar rats. Maturitas . 2008;61(4):364-370.
35. Seidlova-Wuttke D, Jarry H, Wuttke W. Effects of estradiol benzoate, raloxifen and an ethanolic extract of Cimicifuga racemosa in nonclassical estrogen regulated organs of ovariectomized rats. Planta Med . 2009;75(12):1279-1285.
36. Düker EM, Kopanski L, Jarry H, Wuttke W. Effects of extracts from Cimicifuga racemosa on gonadotropin release in menopausal women and ovariectomized rats. Planta Med . 1991;57(5):420-424.
37. Jacobson JS, Troxel AB, Evans J, et al. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol . 2001;19(10):2739-2745.
38. Lehmann-Willenbrock E, Riedel HH. Clinical and endocrinologic studies of the treatment of ovarian insufficiency manifestations following hysterectomy with intact adnexa [in German]. Zentralbl Gynakol . 1988;110(10):611-618.
39. Wuttke W, Seidlová-Wuttke D, Gorkow C. The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: effects on menopause symptoms and bone markers. Maturitas . 2003;44(suppl 1):S67-S77.
40. Frei-Kleiner S, Schaffner W, Rahlfs VW, Bodmer Ch, Birkhäuser M. Cimicifuga racemosa dried ethanolic extract in menopausal disorders: a double-blind placebo-controlled clinical trial. Maturitas . 2005;51(4):397-404.
41. Verhoeven MO, van der Mooren MJ, van de Weijer PH, Verdegem PJ, van der Burgt LM, Kenemans P; CuraTrial Research Group. Effect of a combination of isoflavones and Actaea racemosa Linnaeus on climacteric symptoms in healthy symptomatic perimenopausal women: a 12-week randomized, placebo-controlled, double-blind study. Menopause . 2005;12(4):412-420.
42. Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med . 2006;145(12):869-879.
43. Pockaj BA, Gallagher JG, Loprinzi CL, et al. Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG Trial N01CC1. J Clin Oncol . 2006;24(18):2836-2841.
44. Uebelhack R, Blohmer JU, Graubaum HJ, Busch R, Gruenwald J, Wernecke KD. Black cohosh and St. John's wort for climacteric complaints: a randomized trial. Obstet Gynecol . 2006;107(2, pt 1):247-255.
45. Reed SD, Newton KM, LaCroix AZ, Grothaus LC, Grieco VS, Ehrlich K. Vaginal, endometrial, and reproductive hormone findings: randomized, placebo-controlled trial of black cohosh, multibotanical herbs, and dietary soy for vasomotor symptoms: the Herbal Alternatives for Menopause (HALT) Study. Menopause . 2008;15(1):51-58.
46. Reame NE, Lukacs JL, Padmanabhan V, Eyvazzadeh AD, Smith YR, Zubieta JK. Black cohosh has central opioid activity in postmenopausal women: evidence from naloxone blockade and positron emission tomography neuroimaging. Menopause . 2008;15(5):832-840.
47. Juliá Mollá MD, García-Sánchez Y, Romen Sarri A, Pérez-López FR. Cimicifuga racemosa treatment and health related quality of life in post-menopausal Spanish women. Gynecol Endocrinol . 2009;25(1):21-26.
48. Geller SE, Shulman LP, van Breemen RB, et al. Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trial. Menopause . 2009;16(6):1156-1166.
49. Borrelli F, Ernst E. Black cohosh ( Cimicifuga racemosa ) for menopausal symptoms: a systematic review of its efficacy. Pharmacol Res . 2008;58(1):8-14.
50. Palacio C, Masri G, Mooradian AD. Black cohosh for the management of menopausal symptoms: a systematic review of clinical trials. Drugs Aging . 2009;26(1):23-36.
51. Shams T, Setia MS, Hemmings R, McCusker J, Sewitch M, Ciampi A. Efficacy of black cohosh-containing preparations on menopausal symptoms: a meta-analysis. Altern Ther Health Med . 2010;16(1):36-44.
52. Shahin AY, Ismail AM, Shaaban OM. Supplementation of clomiphene citrate cycles with Cimicifuga racemosa or ethinyl oestradiol—a randomized trial. Reprod Biomed Online . 2009;19(4):501-507.
53. Bebenek M, Kemmler W, von Stengel S, Engelke K, Kalender WA. Effect of exercise and Cimicifuga racemosa (CR BNO 1055) on bone mineral density, 10-year coronary heart disease risk, and menopausal complaints: the randomized controlled Training and Cimicifuga racemosa Erlangen (TRACE) study. Menopause . 2010;17(4):791-800.
54. Garcia-Pérez MA, Pineda B, Hermenegildo C, Tarín JJ, Cano A. Isopropanolic Cimicifuga racemosa is favorable on bone markers but neutral on an osteoblastic cell line. Fertil Steril . 2009;91(4)(suppl):1347-1350.
55. Chan BY, Lau KS, Jiang B, Kennelly EJ, Kronenberg F, Kung AW. Ethanolic extract of Actaea racemosa (black cohosh) potentiates bone nodule formation in MC3T3-E1 preosteoblast cells. Bone . 2008;43(3):567-573.
56. Kolios L, Schumann J, Sehmisch S, et al. Effects of black cohosh ( Cimicifuga racemosa ) and estrogen on metaphyseal fracture healing in the early stage of osteoporosis in ovariectomized rats. Planta Med . 2010;76(9):850-857.
57. Jarry H, Thelen P, Christoffel V, Spengler B, Wuttke W. Cimicifuga racemosa extract BNO 1055 inhibits proliferation of the human prostate cancer cell line LNCaP. Phytomedicine . 2005;12(3):178-182.
58. Einbond LS, Shimizu M, Xiao D, et al. Growth inhibitory activity of extracts and purified components of black cohosh on human breast cancer cells. Breast Cancer Res Treat . 2004;83(3):221-231.
59. Genazzani E, Sorrentino L. Vascular action of acteina: active constituent of Actaea racemosa L. Nature . 1962;194:544-545.
60. Sakurai N, Wu JH, Sashida Y, et al. Anti-AIDS Agents. Part 57: Actein, an anti-HIV principle from the rhizome of Cimicifuga racemosa (black cohosh), and the anti-HIV activity of related saponins. Bioorg Med Chem Lett . 2004;14(5):1329-1332.
61. Bukowiecki H, Michalska Z. Anatomical studies of the vegetable organs of Actaea L. genus. Acta Pol Pharm . 1972;29(4):432-438.
62. Rachoń D, Vortherms T, Seidlová-Wuttke D, Wuttke W. Effects of black cohosh extract on body weight gain, intra-abdominal fat accumulation, plasma lipids and glucose tolerance in ovariectomized Sprague-Dawley rats. Maturitas . 2008;60(3-4):209-215.
63. Schmid D, Gruber M, Woehs F, et al. Inhibition of inducible nitric oxide synthesis by Cimicifuga racemosa ( Actaea racemosa , black cohosh) extracts in LPS-stimulated RAW 264.7 macrophages. J Pharm Pharmacol . 2009;61(8):1089-1096.
64. Schmid D, Woehs F, Svoboda M, Thalhammer T, Chiba P, Moeslinger T. Aqueous extracts of Cimicifuga racemosa and phenolcarboxylic constituents inhibit production of proinflammatory cytokines in LPS-stimulated human whole blood. Can J Physiol Pharmacol . 2009;87(11):963-972.
65. Yang CL, Chik SC, Li JC, Cheung BK, Lau AS. Identification of the bioactive constituent and its mechanisms of action in mediating the anti-inflammatory effects of black cohosh and related Cimicifuga species on human primary blood macrophages. J Med Chem . 2009;52(21):6707-6715.
66. Dugoua JJ, Seely D, Perri D, Koren G, Mills E. Safety and efficacy of black cohosh ( Cimicifuga racemosa ) during pregnancy and lactation. Can J Clin Pharmacol . 2006;13(3):e257-e261.
67. Huang Y, Jiang B, Nuntanakorn P, et al. Fukinolic acid derivatives and triterpene glycosides from black cohosh inhibit CYP isozymes, but are not cytotoxic to Hep-G2 cells in vitro. Curr Drug Saf . 2010;5(2):118-124.
68. Whiting PW, Clouston A, Kerlin P. Black cohosh and other herbal remedies associated with acute hepatitis. Med J Aust . 2002;177(8):440-443.
69. Guzman G, Kallwitz ER, Wojewoda C, et al. Liver injury with features mimicking autoimmune hepatitis following the use of black cohosh. Case Report Med . 2009;2009:918156.
70. Naser B, Liske E. Liver failure associated with the use of black cohosh for menopausal symptoms. Med J Aust . 2009;190(2):99.
71. Pierard S, Coche JC, Lanthier P, et al. Severe hepatitis associated with the use of black cohosh: a report of two cases and an advice for caution. Eur J Gastroenterol Hepatol . 2009;21(8):941-945.
72. Joy D, Joy J, Duane P. Black cohosh: a cause of abnormal postmenopausal liver function tests. Climacteric . 2008;11(1):84-88.
73. Lontos S, Jones RM, Angus PW, Gow PJ. Acute liver failure associated with the use of herbal preparations containing black cohosh. Med J Aust . 2003;179(7):390-391.
74. Nasr A, Nafeh H. Influence of black cohosh ( Cimicifuga racemosa ) use by postmenopausal women on total hepatic perfusion and liver functions. Fertil Steril . 2009;92(5):1780-1782.
75. Mazzanti G, Di Sotto A, Franchitto A, et al. Effects of Cimicifuga racemosa extract on liver morphology and hepatic function indices. Phytomedicine . 2008;15(11):1021-1024.
76. Borrelli F, Ernst E. Black cohosh ( Cimicifuga racemosa ): a systematic review of adverse events. Am J Obstet Gynecol . 2008;199(5):455-466.
77. Teschke R, Schwarzenboeck A. Suspected hepatotoxicity by Cimicifugae racemosae rhizoma (black cohosh, root): critical analysis and structured causality assessment. Phytomedicine . 2009;16(1):72-84.
78. Teschke R, Bahre R, Fuchs J, Wolff A. Black cohosh hepatotoxicity: quantitative causality evaluation in nine suspected cases. Menopause . 2009;16(5):956-965.
79. Teschke R. Black cohosh and suspected hepatotoxicity: inconsistencies, confounding variables, and prospective use of a diagnostic causality algorithm. A critical review. Menopause . 2010;17(2):426-440.
80. Mahady GB, Low Dog T, Barrett ML, et al. United States Pharmacopeia review of the black cohosh case reports of hepatotoxicity. Menopause . 2008;15(4, pt 1):628-638.
81. Shuster J. Black cohosh root? Chasteberry tree? Seizures! Hosp Pharm . 1996;31:1553-1554.
82. Zimmermann R, Witte A, Voll RE, Strobel J, Frieser M. Coagulation activation and fluid retention associated with the use of black cohosh: A case study. Climacteric . 2010;13(2):187-191.
83. 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.
Copyright © 2009 Wolters Kluwer Health