Black Cohosh

• How It Works

  There is some evidence that black cohosh is effective for menopausal symptoms. More research is needed.

  It is not clear if black cohosh is beneficial for menopausal symptoms due to conflicting results from various studies. There is not enough evidence to support its anticancer effects in humans. Patients should use caution because liver toxicity has been reported from use of black cohosh.

• Purported Uses
  • Menopausal symptoms
    A few studies showed that black cohosh may help relieve menopausal symptoms.
  • To ease painful or heavy menstruation
    Clinical trials have not evaluated this use.
  • Premenstrual syndrome (PMS)
    There are no clinical data to support use of black cohosh for PMS.
  • As a sedative
    There are no data to back this claim.
  • Hot flashes
    Clinical trial results are mixed.
• Patient Warnings

  Black cohosh should not be confused with blue cohosh.

• Do Not Take If
  • You are taking Tamoxifen: Black cohosh may interfere with the action of tamoxifen, but clinical relevance is not known.
  • You are taking Chemotherapy drugs: Black cohosh may increase the toxicity of doxorubicin and docetaxel. Clinical signficance has yet to be determined.
  • You are taking drugs that are substrates of Cytochrome P450 3A4: Black cohosh may increase the side effects of these drugs.
  • You are taking Simvastatin: Black cohosh and actein (a compound isolated from black cohosh) have synergistic effects with simvastatin, resulting in increased activity. But there is also potential for increased side effects.
• Side Effects
  • Stomach upset
  • Liver failure
  • Hepatotoxicity (liver toxicity) has been reported following use of black cohosh.
  • Two cases of liver injury resembling autoimmune hepatitis were reported after taking black cohosh. Both patients responded to treatment with corticosteroids.
  • A case of coagulation activation, fluid retention, and transient autoimmune hepatitis has been reported associated with use of black cohosh.
  • Bradycardia (slowing of heart beat) was observed in a woman taking black cohosh.
  • Orobuccolingual dyskinesia (OBLD), involving interference with speech, tongue-biting, and eating difficulties, has been reported in a 46-year-old woman while taking a herbal supplement containing black cohosh and ginseng^.
• Special Point

  Because it is still unclear whether black cohosh has estrogenic effects, women with estrogen receptor-positive (ER+) cancers should avoid this supplement.

• Brand Name

  Remifemin®, Menofem®, Klimadynon®

• Scientific Name

  Cimicifuga racemosa

• Clinical Summary

  Obtained from root of the plant, black cohosh is used as a dietary supplement to relieve symptoms of menopause and dysmenorrhea. It has antiosteoporotic effects ⁽⁸⁾ and enhances bone formation ⁽⁹⁾. Clinical studies indicate that black cohosh by itself, ^{(1) (2) (3)} or in combination with other herbs ⁽⁴⁾, ⁽⁵⁾ is effective in the treatment of menopausal symptoms, but data are conflicting ^{(6) (31) (32) (36) (45)}. Conclusions of a meta analysis indicate insufficient evidence to support use for menopausal symptoms ⁽⁴⁰⁾.

  Investigations of black cohosh for treating hot flashes, due to breast cancer treatment, also yielded mixed results ^{(10) (11) (12)}. In other studies, supplementation did not enhance bone density, improve menopausal symptoms, or the 10-year risk of coronary heart disease in early postmenopausal women ⁽³⁷⁾, but was reported to improve sleep ⁽⁵³⁾. A black cohosh extract demonstrated anti-diabetic potential in a murine model ⁽⁴⁶⁾. Human studies have yet to be conducted.

  Black cohosh has also been evaluated for potential anticancer effects. Preclinical findings indicate that it decreases prostate cancer cell proliferation ⁽¹⁴⁾ and induces an apoptotic response in liver cells ⁽²¹⁾. However, it also increased the incidence of metastatic disease in mice ⁽¹⁶⁾. Whether it has similar effects in breast cancer patients is not clear, although a retrospective observational study of breast cancer patients found that black cohosh enhanced disease-free survival ⁽¹⁵⁾.

  Hepatoxicity has been associated with use of black cohosh ⁽³⁴⁾, but data are conflicting ⁽³⁹⁾.

• Purported Uses
  • Dysmenorrhea
  • Menopausal symptoms
  • Premenstrual syndrome
  • Sedation
• Mechanism of Action

  Black cohosh relieves menopausal symptoms likely by mimicking neurostransmitters: dopaminergic, noradrenergic, serotoninergic and GABAergic effects have been demonstrated ⁽⁴⁹⁾. It was believed to have estrogenic effects due to its ability to relieve menopausal symptoms in women ⁽⁴⁰⁾. However, studies show that it has no effect on the levels of LH, FSH, prolactin, or estradiol ⁽²⁴⁾. A black cohosh extract was shown to have antiproliferative and antiestrogenic effects in ER-negative cells, which suggests that such effects are mediated via an estrogen-independent pathway ⁽²⁵⁾, possibly through HER-2 signaling ⁽²⁶⁾.

  Black cohosh repressed the expression of cyclin D1 and ID3, and inhibited proliferation of HepG2, p53 positive, liver cells ⁽⁴³⁾. In prostate cancer cells, it demonstrated antiproliferative effects, via impaired equilibrative nucleoside transporter (ENT) activity, resulting in hindered nucleoside uptake ⁽⁵⁰⁾. Black cohosh was also reported to induce apoptosis and suppress estradiol-induced cell proliferation in human endometrial adenocarcinoma cells ⁽⁵⁵⁾.

  Hepatotoxicity is a major concern with black cohosh use. Evaluation of liver biopsies from two patients who took black cohosh supplements showed the pattern of pathological injury of liver cells to be identical to toxic necrosis, seen during autoimmune hepatitis ⁽⁵¹⁾.

• Warnings
  • Black cohosh should not be confused with blue cohosh.
  • Whether black cohosh possesses estrogenic activity is still not clear. This product should be used under the supervision of a physician.
  • After reviewing 30 independent cases of reported hepatoxicity associated with black cohosh intake, the United States Pharmacopeia’s Botanical Expert Committee decided that black cohosh products should include a statement of caution concerning their use ⁽²⁸⁾.
  • A recent survey reported poor quality control of several black cohosh products ⁽⁴⁴⁾.
• Adverse Reactions
  • Gastrointestinal upset and rashes are most common followed by dizziness, headaches, nausea, and vomiting when higher than normal doses are taken ⁽²⁷⁾
  • Hepatotoxicity has been reported following use of black cohosh ^{(18) (20) (33) (34) (47)}.
  • Two cases of liver injury resembling autoimmune hepatitis were reported after taking black cohosh. Both patients responded to treatment with corticosteroids ⁽³⁵⁾.
  • A case of coagulation activation, fluid retention, and transient autoimmune hepatitis has been reported associated with use of black cohosh ⁽³⁸⁾.
  • Bradycardia was observed in a woman following use of black cohosh ⁽⁴¹⁾.
  • Orobuccolingual dyskinesia (OBLD), involving interference with speech, tongue-biting, and eating difficulties, has been reported in a 46-year-old woman while taking a herbal supplement containing black cohosh and ginseng ⁽⁴⁸⁾.
• Herb-Drug Interactions

  Tamoxifen: Black cohosh may interfere with the action of tamoxifen  ⁽⁴²⁾. Clinical relevance is not known.
  Chemotherapy drugs: Black cohosh may increase the toxicity of doxorubicin and docetaxel ⁽¹³⁾. Clinical signficance has yet to be determined.
  Cytochrome P450 3A4: Black cohosh may interact with drugs that are metabolized by CYP3A4 enzyme ⁽¹⁷⁾.
  Simvastatin: Black cohosh and actein (a compound isolated from black cohosh) have synergistic effects with simvastatin, resulting in enhanced activity. But there is also potential for increased side effects ⁽⁵⁶⁾.

• References

  1. Anon. Remifemin: A Plant-based Gynecological Agent. Germany: Schaper & Brümmer; 1997.

  2. Liske E, et al. Physiological investigation of a unique extract of black cohosh (Cimicifugae racemosae rhizoma): a 6-month clinical study demonstrates no systemic estrogenic effect. J Women Health Gend Based Med 2002;11:163-74.

  3. Oktem M, Eroglu D, Karahan HB, et al. Black cohosh and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized trial. Adv Ther. Mar-Apr 2007;24(2):448-461.

  4. 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):247-55.

  5. Briese V, Stammwitz U, Friede M, Henneicke-von Zepelin HH. Black cohosh with or without St. John’s wort for symptom-specific climacteric treatment—results of a large-scale, controlled, observational study. Maturitas. Aug 20 2007;57(4):405-414.

  6. Newton KM, Reed SD, LaCroix AZ, et al. Treatment of vasomotor symptoms of menopause with black cohosh, mutibotanicals, soy, hormone therapy, or placebo. Ann Intern Med 2006;145:869-879.

  7. Bai W, Henneicke-von Zepelin HH, Wang S, et al. Efficacy and tolerability of a medicinal product containing an isopropanolic black cohosh extract in Chinese women with menopausal symptoms: a randomized, double blind, parallel-controlled study versus tibolone. Maturitas. Sep 20 2007;58(1):31-41.

  8. Wuttke W, Gorkow C, Seidlova-Wuttke D. Effects of black cohosh (Cimicifuga racemosa) on bone turnover, vaginal mucosa, and various blood parameters in postmenopausal women: a double-blind, placebo-controlled, and conjugated estrogens-controlled study. Menopause 2006; 13(2):185-96.

  9. 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 Sep;43(3):567-73.

  10. Hernandez Munoz G, Pluchino S. Cimicifuga racemosa for the treatment of hot flushes in women surviving breast cancer. Maturitas. 2003 Mar 14;44 Suppl 1:S59-65.

  11. 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;19:2739-45.

  12. 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):2836-41.

  13. Rockwell S, Liu Y, Higgins SA. Alteration of the effects of cancer therapy agents on breast cancer cells by the herbal medicine black cohosh. Breast Cancer Res Treat 2005;90(3):233-9.

  14. Jarry H, Stromeier S, Wuttke W, Nahrstedt A. Petasiphenone, a phenol isolated from Cimicifuga racemosa, in vitro inhibits proliferation of the human prostate cancer cell line LNCaP. Planta Med. Feb 2007;73(2):184-187.

  15. Zepelin HH, Meden H, Kostev K, et al. Isopropanolic black cohosh extract and recurrence-free survival after breast cancer. Int J Clin Pharmacol Ther. Mar 2007;45(3):143-154.

  16. Davis VL, Jayo MJ, Ho A, et al. Black cohosh increases metastatic mammary cancer in transgenic mice expressing c-erbB2. Cancer Res. 2008 Oct 15;68(20):8377-83.

  17. Tsukamoto S, Aburatani M, Ohta T. Isolation of CYP3A4 Inhibitors from the Black Cohosh (Cimicifuga racemosa). Evid Based Complement Alternat Med. Jun 2005;2(2):223-226.

  18. Cohen SM, O’Connor AM, Hart J, et al. Autoimmune hepatitis associated with the use of black cohosh: a case study. Menopause 2004;11(5):575-77.

  19. Levitsky J, Alli TA, Wisecarver J, et al. Fulminant liver failure associated with the use of black cohosh. Dig Dis Sci. Mar 2005;50(3):538-539.

  20. Lontos S, Jones RM, Angus PW, Gow PJ. Acute liver failure associated with the use of herbal preparations containing black cohosh. MJA 2003;179(7): 390-91.

  21. Lude S, Torok M, Dieterle S, et al. Hepatic effects of Cimicifuga racemosa extract in vivo and in vitro. Cell Mol Life Sci. Nov 2007;64(21):2848-2857.

  22. Newall C. Herbal Medicines, A Guide for Health Care Professionals. London: Pharmaceutical Press; 1996.

  23. Zierau O, Bodinet C, Kolba S, et al. Antiestrogenic activities of Cimicifuga racemosa extracts. J Steroid Biochem Mol Biol 2002;80:125-30.

  24. Liske E. Therapeutic efficacy and safety of Cimicifuga racemosa for gynecologic disorders. Adv Ther. Jan-Feb 1998;15(1):45-53.

  25. Garita-Hernandez M, Calzado MA, Caballero FJ, et al. The growth inhibitory activity of the Cimicifuga racemosa extract Ze450 is mediated through estrogen and progesterone receptors-independent pathways. Planta Med 2006:72(4):317-23.

  26. Einbond LS, Wen-Cai Y, He K, et al. Growth inhibitory activity of extracts and compounds from Cimicifuga species on human breast cancer cells. Phytomedicine. Jun 2008;15(6-7):504-511.

  27. Low Dog T, Powell KL, Weisman SM. Critical evaluation of the safety of Cimicifuga racemosa in menopause symptom relief. Menopause. Jul-Aug 2003;10(4):299-313.

  28. Mahady GB, Dog TL, Barrett ML, et al. United States Pharmacopeia review of the black cohosh case reports of hepatotoxicity. Menopause. Mar 12 2008.

  29. Rebbeck TR, Troxel AB, Norman S, et al. A retrospective case-control study of the use of hormone-related supplements and association with breast cancer. Int J Cancer. Apr 1 2007;120(7):1523-1528.

  30. Duker EM, Kopanski L, Jarry H, Wuttke W. Effects of extracts of Cimicifuga racemosa (Remifemin) on gonadotropin release in menopausal women and ovariectomized rats. Planta Med 1991;57:420.

  31. Reed SD, Newton KM, LaCroix AZ, et al. 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 Jan-Feb;15(1):51-8.

  32. 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 Nov-Dec;16(6):1156-66.

  33. 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 Aug;21(8):941-5.

  34. Vannacci A, Lapi F, Gallo E, et al. A case of hepatitis associated with long-term use of Cimicifuga racemosa. Altern Ther Health Med. 2009 May-Jun;15(3):62-3.

  35. 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.

  36. Shams T, Setia MS, Hemmings R, et al. Efficacy of black cohosh-containing preparations on menopausal symptoms: a meta-analysis.  Altern Ther Health Med. 2010 Jan-Feb;16(1):36-44.

  37. 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 Jul;17(4):791-800.

  38. 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 Apr;13(2):187-91.

  39. Naser B, Schnitker J, Minkin MJ, et al. Suspected black cohosh hepatotoxicity: no evidence by meta-analysis of randomized controlled clinical trials for isopropanolic black cohosh extract. Menopause. 2011 Apr;18(4):366-75.

  40. Leach MJ, Moore V. Black cohosh (Cimicifuga spp.) for menopausal symptoms. Cochrane Database Syst Rev. 2012 Sep 12;9:CD007244.

  41. McKenzie SC, Rahman A.  Bradycardia in a patient taking black cohosh. Med J Aust. 2010 Oct 18;193(8):479-81.

  42. Li J, Gödecke T, Chen SN, et al. In vitro metabolic interactions between black cohosh (Cimicifuga racemosa) and tamoxifen via inhibition of cytochromes P450 2D6 and 3A4. Xenobiotica.2011 Aug 9. [Epub ahead of print]

  43. Einbond LS, Soffritti M, Esposti DD, et al. Pharmacological mechanisms of black cohosh in Sprague-Dawley rats. Fitoterapia. 2012 Apr;83(3):461-8.

  44. Teschke R, Schwarzenboeck A, Schmidt-Taenzer W, Wolff A, Hennermann KH. Herb induced liver injury presumably caused by black cohosh: a survey of initially purported cases and herbal quality specifications. Ann Hepatol. 2011 Jul-Sep;10(3):249-59.

  45. Tanmahasamut P, Vichinsartvichai P, Rattanachaiyanont M, Techatraisak K, Dangrat C, Sardod P. Cimicifuga racemosa extract for relieving menopausal symptoms: a randomized controlled trial. Climacteric. 2014 Sep 22:1-7.

  46. Moser C, Vickers SP, Brammer R, Cheetham SC, Drewe J. Antidiabetic effects of the Cimicifuga racemosa extract Ze 450 in vitro and in vivo in ob/ob mice.Phytomedicine. 2014 Sep 25;21(11):1382-9.

  47. Lim TY, Considine A, Quaglia A, Shawcross DL. Subacute liver failure secondary to black cohosh leading to liver transplantation. BMJ Case Rep. 2013 Jul 5;2013.

  48. Sen A.Orobuccolingual dyskinesia after long-term use of black cohosh and ginseng. J Neuropsychiatry Clin Neurosci. 2013 Fall;25(4):E50.

  49. Wuttke W, Jarry H, Haunschild J, Stecher G, Schuh M, Seidlova-Wuttke D.The non-estrogenic alternative for the treatment of climacteric complaints: Black cohosh (Cimicifuga or Actaea racemosa). J Steroid Biochem Mol Biol. 2014 Jan;139:302-10.

  50. Dueregger A, Guggenberger F, Barthelmes J, et al. Attenuation of nucleoside and anti-cancer nucleoside analog drug uptake in prostate cancer cells by Cimicifuga racemosa extract BNO-1055. Phytomedicine. 2013 Nov 15;20(14):1306-14.

  51. Enbom ET, Le MD, Oesterich L, Rutgers J, French SW. Mechanism of hepatotoxicity due to black cohosh (Cimicifuga racemosa): histological, immunohistochemical and electron microscopy analysis of two liver biopsies with clinical correlation. Exp Mol Pathol. 2014 Jun;96(3):279-83.

  52. Cimicifuga racemosa. Altern Med Rev. 2003 May;8(2):186-9.

  53. Jiang K, Jin Y, Huang L, et al. Black cohosh improves objective sleep in postmenopausal women with sleep disturbance. Climacteric. 2015;18(4):559-67.

  54. Da YM, Niu KY, Liu SY, et al. Does Cimicifuga racemosa have the effects like estrogen on the sublingual gland in ovariectomized rats?. 2017 Mar 14;50(1):11.

  55. Dai X, Liu J, Nian Y, Qiu MH, Luo Y, Zhang J. A novel cycloartane triterpenoid from Cimicifuga induces apoptotic and autophagic cell death in human colon cancer HT-29 cells. Oncol Rep. 2017 Apr;37(4):2079-2086.

  56. Einbond LS, Soffritti M, Esposti DD, et al. A transcriptomic analysis of black cohosh: Actein alters cholesterol biosynthesis pathways and synergizes with simvastatin. Food Chem Toxicol. 2018 Oct;120:356-366.