Black Cohosh Presentation Created by: Shannon Liu, Anthony Der

Black Cohosh: About the Plant Cimicifuga racemosa Roots and rhizomes are the basis for the extraction (not the flowers) ◦ Can be extracted using alcohols Extracts contain 26-deoxyactein ◦ Member of the triterpene glycosides ◦ In most extractions, approximately 1 mg of triperpene per 20 mg dose of extract Generally grown in temperate to cold weather in damp, fertile soil (forests). [12]

Traditional Uses Most common treatments using black cohosh: hormonal imbalances ◦ Primarily menopause and breast cancer  Effectiveness has been tested in controlled studies  Popular in Germany for climacteric symptoms (time before menopause)  One of the very first trials testing the effectiveness of black cohosh was run in 1989 by the German Commission E ◦ Traditional uses dating back to Native Americans for other remedies for:  Sore throat  inducing lactation  Diuretics  Fever  Gynecological disorders  “Conditions that affected women’s reproductive organs” [13], [14]

Marketed Uses and Disclaimers Some books/sites recommend growing and extracting your own black cohosh roots by collecting black cohosh, drying the roots, and then creating tinctures out of them Possible side effects ◦ Nausea ◦ Vomiting ◦ upset stomach ◦ A few reports of liver disease Overdose of black cohosh ◦ Dizziness ◦ Slowed heart rate ◦ Tremors ◦ Light-headedness No long term data (more than 6 months) ◦ Therefore generally not recommended to take for more than 6 months Shown to have possible interactions with hormonal replacement drugs [15]

Female Reproductive System Key concepts ◦ Anatomy – ovary, endometrium ◦ Ovariectomy ◦ Estrogen and estrogen receptors (ER) Menopause ◦ Lowered hormone levels [10]

Pharmacodynamics Mechanism of action: unknown, but possible estrogenic effect ◦ 4 studies indicate some estrogenic effect ◦ 3 studies indicate no relationship [1] – [9]

Pharmacodynamics Evidence for Estrogen Receptor (ER) mechanism Kruse et al: Fukinloic acid caused increased proliferation of an estrogen dependent MCF-7 cell system  Fukinolic acid has estrogenic activity Düker et al: Remifemin suppresses LH levels, due to at least 3 synergistically acting compounds Dixon: consumption of phytoestrogen-rich foods causes inhibition of MCF-7 and T-47 breast cancer cell growth Liu, Yang et al: increasing dosage of black cohosh allowed for uterine weight increase, prolonged estrus  Black cohosh has a stimulating effect on estrogen receptors. [1], [2], [4], [5]

Pharmacodynamics Refuting evidence for Estrogen Receptor mechanism Liu, Burdette et al: No indication of estrogenic activity in estrogen receptors of endometrial cells Einer et al: no relationship between black cohosh and uterine weight Freudenstein et al: administered black cohosh or estrogen after inducing tumors and performing ovariectomy in rats; no significant difference in cancer growth or estrogen sensitive organs [3], [6], [7]

Pharmacokinetics Minimal research on pharmacokinetics of black cohosh ◦ Some evidence that it weakly inhibits CYP2D6 (Gurley et al) Clinical study underway: Pharmacokinetics of Black Cohosh ◦ Duke University Medical Center, NCCAM ◦ Investigation of levels of components of black cohosh obtained in the blood of healthy women taking Remifemin. [8]

Black Cohosh and Breast Cancer (First Study) Approximately 2/3 of breast cancer survivors undergo hot flashes ◦ A double blind study was done to see if black cohosh would minimize the hot flashes received by the women ◦ Women were selected based off of a demographic survey and also had other criteria met (completed primary therapy at least two months before trial) ◦ Instructed to take tablets twice daily with meals for 60 days.  The women were supposed to count the number of hot flashes for a three day period before the trial as well as severity (on a 1-3 scale, of mild, moderate, or severe)  At the day mark and the day mark the women went through the same process [15]

Black Cohosh and Breast Cancer (First Study) Total of 85 study participants ◦ Both the placebo and no placebo group reported lowered number of hot flashes  Although 59 of the patients were using tamoxifen, this had no foreseeable effect on the study  However, the overall difference between the placebo group and the group taking the black cohosh extract pill was not significant  (P =.86 via analysis of covariance adjusting for baseline number and for tamoxifen use) ◦ Limitation of the study  Trial period was only for 2 months, due to concern of patients dropping out of the study due to lack of benefits  16 people out of the 85 dropped out of the study [15]

Black Cohosh and Breast Cancer (Second Study) Another, similar study was done also involving 132 women with breast cancer and hot flashes ◦ A double blind study, with the trial being 2 4-weeks long ◦ In this study, a daily hot flash record was kept instead of three specific dates ◦ Once again, the amount of hot flashes experienced by women decreased in both the placebo groups and the Black Cohosh group, yet the difference between the two was not significant enough to show that Black Cohosh was the cause of the decrease. ◦ Placebo effect [16], [17]

Black Cohosh and Menopause A study of 351 women peri or postmenopausal women between the ages of 45 and 55, were randomly assigned a 150 or 200 mg of a Black cohosh, a dietary supplement, a hormonal therapy pill, or a placebo ◦ The black cohosh was provided by Pure World Inc. ◦ This study lasted for a year ◦ Once again, the study indicated that the black cohosh groups had no significant difference with the women that were in the placebo group  Any decreases in hot flashes were mostly contributed to either the placebo effect, or that hot flashes naturally decline over time [18]

Black Cohosh: It Works? One study claimed that black cohosh was effective in treating climacteric symptoms in women. ◦ Double blind study, with 304 women for twelve weeks 2.5 mg isopropanolic extract of Cimicifuga Racemosa in the black cohosh pill. ◦ Results showed a significant change of the patients using the black cohosh pill So What Went Wrong? ◦ The data reporting is skewed, the scale used in the data does not accurately measure the amount of hot flashes per day, but actually measures the relationship between ability to sleep and type of pill taken without taking into account the number of hot flashes each women had. [19]

Contraindictions Until the relationship between black cohosh and hormones has been better established, women should avoid taking black cohosh… ◦ During pregnancy ◦ For the treatment of breast cancer ◦ In combination with other hormonal treatments Herb-drug interactions of black cohosh have not yet been sufficiently studied [11]

Black Cohosh in summary… Alternative medicine sometimes used to alleviate menopausal symptoms, some evidence of anti- cancer Few studies supporting effectiveness of black cohosh for the above but also many refuting the effectiveness ◦ Most studies have their own limitations, which hinder the effectiveness of the study  Number of people in the study  Duration of study  Limited info on extraction and dosage Further research can be done to solidify existing evidence

References 1. Kruse SO, Lohning A, Pauli GF, Winterhoff H, Nahrstedt A: Fukiic and piscidic acid esters from the rhizome of Cimicifuga racemosa and the in vitro estrogenic activity of fukinolic acid. Planta Medica 65: , Düker EM, Kopanski L, Jarry H, Wuttke W: Effects of extracts from Cimicifuga racemosa on gonadotropin release in menopausal women and ovariectomized rats. Planta Medica 57: , Liu J, Burdette JE, Xu H, et al.: Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms. Journal of Agricultural and Food Chemistry. 49: , Dixon-Shanies D, Shaikh N: Growth inhibition of human breast cancer cells by herbs and phytoestrogens. Oncology Reports 6: , Liu Z, Yang Z, Zhu M, Huo J: Estrogenicity of black cohosh (Cimicifuga racemosa) and its effect on estrogen receptor level in human breast cancer MCF-7 cells (in Chinese). Wei Sheng Yan Jiu 30: 77-80, Einer-Jensen N, Zhao J, Anderson KP, Kristoffersen K: Cimicifuga and Melbrosia lack oestrogenic effects in mice and rats. Maturitas 25: , Freudenstein J, Dasenbrock C, Nisslein T: Lack of promotion of estrogen-dependent mammary gland tumors in vivo by an isopropanolic Cimicifuga racemosa extract. Cancer Research 62: , Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry DB, Khan IA, Shah A. In Vivo Effects of Goldenseal, Kava Kava, Black Cohosh, and Valerian on Human Cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 Phenotypes. Clinical Pharmacology & Therapeutics 77: , National Center for Complementary and Alternative Medicine, NIH Office of Dietary Supplements. Workshop on the Safety of Black Cohosh in Clinical Studies. November 22, Silverthorn, D (2007). Human Physiology. San Francisco, CA: Pearson.

References 11. Office of Dietary Supplements and National Center for Complementary and Alternative Medicine. Questions and Answers About Black Cohosh and the Symptoms of Menopause 12. Duke JA: Handbook of Medicinal Herbs. Boca Raton, FL: CRC Press, 2001: Foster S: Black cohosh: Cimicifuga racemosa: a literature review. HerbalGram 45: 35-49, Upton, R, ed. Black Cohosh Rhizome Actaea racemosa L. syn. Cimicifuga racemosa (L.) Nutt. Standards of analysis, quality control, and therapeutics. American Herbal Pharmacopoeia and Therapeutic Compendium. Santa Cruz, CA. American Herbal Pharmacopoeia, 2002: Judith S. Jacobson, Andrea B. Troxel, Joel Evans, Lorissa Klaus, Linda Vahdat, David Kinne, K. M. Steve Lo, Anne Moore, Pamela J. Rosenman, Elizabeth L. Kaufman, Alfred I. Neugut, and Victor R. Grann Randomized Trial of Black Cohosh for the Treatment of Hot Flashes Among Women With a History of Breast Cancer J Clin Oncol May 15;19(10): Sloan JA, Loprinzi CL, Novotny PJ, et al: Methodologic lessons learned from hot flash studies. J Clin Oncol 19: , Pockaj BA, Gallagher JG, Loprinzi CL, Stella PJ, Barton DL, Sloan JA, Lavasseur BI, Rao RM, Fitch TR, Rowland KM, Novotny PJ, Flynn PJ, Richelson E, Fauq AH Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG Trial N01CC1. J Clin Oncol Jun 20;24(18): 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 Dec 19;145(12): Osmers R, Friede M, Liske E, Schnitker J, Freudenstein J, Henneicke-von Zepelin HH. Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms. Obstet Gynecol Sep;106(3):644