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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/pdqcis/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-pdqcis-lrg.png" alt="Cover of PDQ Cancer Information Summaries" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>PDQ Cancer Information Summaries [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK566616_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK566616_dtls__"><div>Bethesda (MD): <a href="http://www.cancer.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Cancer Institute (US)</a>; 2002-.</div></div><div class="half_rhythm"></div><div class="bk_noprnt"><form method="get" action="/books/n/pdqcis/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK566616_"><span class="title" itemprop="name">Black Cohosh (PDQ®)</span></h1><div class="subtitle whole_rhythm">Health Professional Version</div><p class="contrib-group"><span itemprop="author">PDQ Integrative, Alternative, and Complementary Therapies Editorial Board</span>.</p><p class="small">Published online: October 14, 2021.</p><p class="small">Created: <span itemprop="datePublished">January 8, 2021</span>.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p id="CDR0000803263__1">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of black cohosh in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.</p><p id="CDR0000803263__2">This summary is reviewed regularly and updated as necessary by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p></div><div id="CDR0000803263__3"><h2 id="_CDR0000803263__3_">Overview</h2><p id="CDR0000803263__8">This <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045333/" class="def">cancer</a> information summary provides an overview of the use of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321355/" class="def">black cohosh</a> as a treatment in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000444971/" class="def">breast cancer</a> patients and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000450125/" class="def">survivors</a>, generally for the relief of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045022/" class="def">symptoms</a> or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046580/" class="def">side effects</a>. The summary provides a brief history of black cohosh research, the results of laboratory and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045961/" class="def">clinical trials</a>, and possible side effects of black cohosh use.</p><p id="CDR0000803263__9">This summary contains the following key information:</p><ul id="CDR0000803263__10"><li class="half_rhythm"><div>The roots and rhizomes of black cohosh are used for various medicinal purposes ranging from <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045056/" class="def">gynecologic</a> to other <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407758/" class="def">disorders</a>.</div></li><li class="half_rhythm"><div>Black cohosh was first used by Native Americans; it is now commonly used in Europe.</div></li><li class="half_rhythm"><div>Black cohosh is frequently studied as a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044964/" class="def">complementary therapy</a> for breast cancer patients and survivors to reduce <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000256578/" class="def">vasomotor</a> symptoms associated with treatment-induced <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046296/" class="def">menopause</a>.</div></li><li class="half_rhythm"><div>Purported estrogenic actions of black cohosh are refuted by current, up-to-date laboratory and clinical studies of commercially available hydroalcoholic <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407760/" class="def">extracts</a>; suggestions of serotonergic activity are well supported.</div></li><li class="half_rhythm"><div>Recent findings show that black cohosh contains a large variety of constituents that are chemically related to <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046481/" class="def">central nervous system</a>–active <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045065/" class="def">molecules</a>, which have not been studied in detail yet.</div></li><li class="half_rhythm"><div>Commercially available hydroalcoholic extracts of black cohosh have been well tolerated, with very rare serious <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044922/" class="def">adverse effects</a> reported.</div></li><li class="half_rhythm"><div><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000286105/" class="def">Observational</a> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285990/" class="def">open-label</a> studies indicate benefits of black cohosh on climacteric symptoms in cancer and noncancer populations, though gold-standard clinical investigations fail to confirm this effect.</div></li><li class="half_rhythm"><div>Given both the evidence and variability of previous findings, including the lack of demonstration of a clinical benefit against <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046688/" class="def">placebo</a> and underexplored constituents, further <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044517/" class="def">preclinical</a> and clinical studies of black cohosh are warranted. </div></li></ul></div><div id="CDR0000803263__4"><h2 id="_CDR0000803263__4_">General Information</h2><p id="CDR0000803263__11">Native to eastern and midwestern North America, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321355/" class="def">black cohosh</a> (<i>Actaea racemosa</i>, also known as <i>Cimicifuga racemosa</i>) [<a class="bk_pop" href="#CDR0000803263_rl_4_1">1</a>] is a member of the buttercup family (<i>Ranunculaceae</i>).[<a class="bk_pop" href="#CDR0000803263_rl_4_2">2</a>,<a class="bk_pop" href="#CDR0000803263_rl_4_3">3</a>] Black cohosh has many synonyms, including <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321357/" class="def">black snakeroot</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321360/" class="def">bugbane</a>, rattleroot, squawroot, and macrotrys or macrotys.[<a class="bk_pop" href="#CDR0000803263_rl_4_2">2</a>-<a class="bk_pop" href="#CDR0000803263_rl_4_4">4</a>] The roots and rhizomes of the black cohosh plant are used for medicinal preparations.</p><p id="CDR0000803263__12">Various types of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407760/" class="def">extracts</a> of black cohosh roots and rhizomes have been studied for their <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000643008/" class="def">chemical</a> composition and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044510/" class="def">biological</a> activity. <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373086/" class="def">Lipophilic</a> extracts have predominantly been used in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044512/" class="def">laboratory studies</a> and only infrequently in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045961/" class="def">clinical trials</a>.[<a class="bk_pop" href="#CDR0000803263_rl_4_3">3</a>] The most commonly used clinical preparations of black cohosh (e.g., Remifemin® and BNO 1055) are made from hydrophilic (typically hydroalcoholic) extracts.[<a class="bk_pop" href="#CDR0000803263_rl_4_4">4</a>] Lipophilic extracts have <i><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045733/" class="def">in vitro</a></i> effects on <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046076/" class="def">estrogen</a>-regulated <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045693/" class="def">genes</a>, whereas hydrophilic extracts generally do not.[<a class="bk_pop" href="#CDR0000803263_rl_4_3">3</a>] </p><p id="CDR0000803263__13">Several of the chemical constituents of black cohosh extracts have biological activities that have been demonstrated through <i>in vitro</i> studies and are candidate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045776/" class="def">markers</a> for the observed <i><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046352/" class="def">in vivo</a></i> and clinical effects. Triterpene glycosides have structures similar to <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046601/" class="def">steroids</a>,[<a class="bk_pop" href="#CDR0000803263_rl_4_4">4</a>] but no apparent direct binding to the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046409/" class="def">estrogen receptor</a>.[<a class="bk_pop" href="#CDR0000803263_rl_4_3">3</a>] One of the most abundant of such glycosides, 23-epi-26-deoxyactein, is specific for black cohosh and is the constituent usually chosen for standardization of commercial products.[<a class="bk_pop" href="#CDR0000803263_rl_4_2">2</a>,<a class="bk_pop" href="#CDR0000803263_rl_4_3">3</a>] At least 40 different triterpene glycoside analogues have been identified in black cohosh (<i>A. racemosa</i>), including actein and cimicifugoside congeners.[<a class="bk_pop" href="#CDR0000803263_rl_4_2">2</a>,<a class="bk_pop" href="#CDR0000803263_rl_4_3">3</a>]</p><p id="CDR0000803263__14">Other chemical constituents of black cohosh extracts include <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000462664/" class="def">aromatic</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000642987/" class="def">acid</a> phenolpropanoids related to caffeic and ferulic acid, along with the black cohosh-specific fukinolic acid.[<a class="bk_pop" href="#CDR0000803263_rl_4_5">5</a>] The plant also contains a large variety of guanidine <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000043994/" class="def">alkaloids</a>, which have been explored chemically but not studied biologically.</p><p id="CDR0000803263__15">Various plants that resemble black cohosh have been mistakenly or intentionally included in some commercial black cohosh products or plants. Such <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000686042/" class="def">adulteration</a> can be detected by methods such as microscopy, high-performance thin-layer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000655048/" class="def">chromatography</a>, high-performance liquid chromatography ultraviolet, and <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045671/" class="def">DNA</a> barcoding.[<a class="bk_pop" href="#CDR0000803263_rl_4_2">2</a>]</p><p id="CDR0000803263__16">Black cohosh root, rhizome, and associated preparations have gained considerable international market and consumer interest for more than 60 years, particularly gaining U.S. interest within the last 15 years.[<a class="bk_pop" href="#CDR0000803263_rl_4_6">6</a>] A market report released by the American Botanical Council stated that black cohosh extract was among the 15 top-selling <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000463714/" class="def">herbal</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373932/" class="def">dietary supplements</a> by the food, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000348921/" class="def">drug</a>, and mass-market channel in the United States in 2019, with total sales nearing $30 million.[<a class="bk_pop" href="#CDR0000803263_rl_4_7">7</a>] Growth in market demand for black cohosh has led to an increased need for scientific evidence of quality, safety, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000346517/" class="def">efficacy.</a>[<a class="bk_pop" href="#CDR0000803263_rl_4_4">4</a>,<a class="bk_pop" href="#CDR0000803263_rl_4_5">5</a>,<a class="bk_pop" href="#CDR0000803263_rl_4_8">8</a>]</p><p id="CDR0000803263__65">Companies distribute black cohosh as a dietary supplement. In the United States, dietary supplements are regulated as foods, not drugs. Therefore, premarket evaluation and approval of such supplements by the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000454785/" class="def">U.S. Food and Drug Administration</a> (FDA) are not required unless specific disease <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000439419/" class="def">prevention</a> or treatment claims are made. The FDA can remove dietary supplements from the market that are deemed unsafe. Because dietary supplements are not formally reviewed for manufacturing consistency, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of black cohosh as a treatment for <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045333/" class="def">cancer</a> or any other medical <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000651193/" class="def">condition</a>.</p><div id="CDR0000803263_rl_4"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000803263_rl_4_1">European Union Herbal Monograph on Cimicifuga racemosa (L.) Nutt., rhizoma. London, United Kingdom: Committee on Herbal Medicinal Products, 2018. <a href="https://www.ema.europa.eu/en/documents/herbal-monograph/final-european-union-herbal-monograph-cimicifuga-racemosa-l-nutt-rhizome-revision-1_en.pdf" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed June 17, 2021.</div></li><li><div class="bk_ref" id="CDR0000803263_rl_4_2">Predny ML, De Angelis P, Chamberlain JL: Black cohosh (Actaea racemosa): an annotated bibliography. U.S. Department of Agriculture Forest Service, Southern Research Station, 2006. General Technical Report SRS 97.</div></li><li><div class="bk_ref" id="CDR0000803263_rl_4_3">Fabricant DS, Krause EC, Farnsworth NR: Black cohosh. In: Coates PM, Blackman MR, Cragg GM: Encyclopedia of Dietary Supplements. 2<sup>nd</sup> ed. CRC Press, 2015, pp 60-74.</div></li><li><div class="bk_ref" id="CDR0000803263_rl_4_4">Qiu F, McAlpine JB, Krause EC, et al.: Pharmacognosy of black cohosh: the phytochemical and biological profile of a major botanical dietary supplement. Prog Chem Org Nat Prod 99: 1-68, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/25296437" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25296437</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_4_5">Gafner S: Black Cohosh Laboratory Guidance Document. ABC-AHP-NCNPR Botanical Adulterants Program, 2015.</div></li><li><div class="bk_ref" id="CDR0000803263_rl_4_6">Foster S: Exploring the peripatetic maze of black cohosh adulteration: a review of the nomenclature, distribution, chemistry, market status, analytical methods, and safety. HerbalGram (98): 32-51, 2013. <a href="http://cms.herbalgram.org/herbalgram/issue98/hg98feat-blackcohosh.html?ts=1607542950&signature=b2202e7be549be2dd4bb828e9b7430a3" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed December 3, 2020..</div></li><li><div class="bk_ref" id="CDR0000803263_rl_4_7">Smith T, May G, Eckl V, et al.: US sales of herbal supplements increase by 8.6% in 2019. HerbalGram (127): 54-69, 2020. <a href="http://cms.herbalgram.org/herbalgram/issue127/hg127-mktrpt-2019.html" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed December 3, 2020..</div></li><li><div class="bk_ref" id="CDR0000803263_rl_4_8">Gafner S: Botanical adulterants bulletin on adulteration of actaea racemosa. Black Cohosh - Botanical Adulterants Bulletin 1-5, 2016.</div></li></ol></div></div><div id="CDR0000803263__17"><h2 id="_CDR0000803263__17_">History</h2><p id="CDR0000803263__18"><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321355/" class="def">Black cohosh</a> was in use by Native Americans when Europeans arrived in the New World.[<a class="bk_pop" href="#CDR0000803263_rl_17_1">1</a>] Among the reported indications for black cohosh in traditional Native American <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000482419/" class="def">medicine</a> were various female <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000651193/" class="def">conditions</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044086/" class="def">rheumatism</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000450108/" class="def">fever</a> (possibly due to malaria), general malaise, sore <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000439429/" class="def">throat</a>, childbirth, and snakebite.[<a class="bk_pop" href="#CDR0000803263_rl_17_1">1</a>,<a class="bk_pop" href="#CDR0000803263_rl_17_2">2</a>] Early European settlers, and subsequently American eclectic <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390246/" class="def">physicians</a>, assimilated the use of black cohosh and began exporting the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000463714/" class="def">herb</a> to Europe as early as the 18th century.[<a class="bk_pop" href="#CDR0000803263_rl_17_1">1</a>]</p><p id="CDR0000803263__19">Europeans have used black cohosh to treat <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046296/" class="def">menopausal</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045022/" class="def">symptoms</a> for over 50 years. In Germany, the Commission E approved black cohosh as a treatment for dysmenorrhea, menopausal symptoms, heart palpitations, nervousness, irritability, sleep disturbances, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000482287/" class="def">tinnitus</a>, vertigo, perspiration, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000430479/" class="def">depression</a>.[<a class="bk_pop" href="#CDR0000803263_rl_17_1">1</a>]</p><p id="CDR0000803263__20">Various sources suggested that the recommended <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044664/" class="def">dose</a> of crude drug is 40 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044213/" class="def">mg</a> per day.[<a class="bk_pop" href="#CDR0000803263_rl_17_1">1</a>,<a class="bk_pop" href="#CDR0000803263_rl_17_3">3</a>] At least one trial compared two different doses (39 mg and 127.3 mg) [<a class="bk_pop" href="#CDR0000803263_rl_17_4">4</a>] in women with menopausal symptoms and found equivalent beneficial effects at both doses. The lack of long-term safety studies has led some groups to recommend limiting the use of black cohosh to a maximum of 6 months.[<a class="bk_pop" href="#CDR0000803263_rl_17_1">1</a>,<a class="bk_pop" href="#CDR0000803263_rl_17_5">5</a>]</p><div id="CDR0000803263_rl_17"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000803263_rl_17_1">Predny ML, De Angelis P, Chamberlain JL: Black cohosh (Actaea racemosa): an annotated bibliography. U.S. Department of Agriculture Forest Service, Southern Research Station, 2006. General Technical Report SRS 97.</div></li><li><div class="bk_ref" id="CDR0000803263_rl_17_2">Qiu F, McAlpine JB, Krause EC, et al.: Pharmacognosy of black cohosh: the phytochemical and biological profile of a major botanical dietary supplement. Prog Chem Org Nat Prod 99: 1-68, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/25296437" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25296437</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_17_3">Fabricant DS, Krause EC, Farnsworth NR: Black cohosh. In: Coates PM, Blackman MR, Cragg GM: Encyclopedia of Dietary Supplements. 2<sup>nd</sup> ed. CRC Press, 2015, pp 60-74.</div></li><li><div class="bk_ref" id="CDR0000803263_rl_17_4">Liske E, Hänggi W, Henneicke-von Zepelin HH, 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 Womens Health Gend Based Med 11 (2): 163-74, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/11975864" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11975864</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_17_5">Cimicifugae Rhizoma. Amsterdam,
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The Netherlands: European Medicines Agency, 2018. <a href="https://www.ema.europa.eu/en/medicines/herbal/cimicifugae-rhizoma" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed December 2, 2020.</div></li></ol></div></div><div id="CDR0000803263__21"><h2 id="_CDR0000803263__21_">Laboratory/Animal/Preclinical Studies</h2><div id="CDR0000803263__22"><h3>Mechanism of Action</h3><p id="CDR0000803263__23">Given the apparent <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044168/" class="def">clinical</a> effects of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321355/" class="def">black cohosh</a> on <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046296/" class="def">menopausal</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045022/" class="def">symptoms</a>, early preclinical investigations searched for an anticipated estrogenic activity. These <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000651211/" class="def">research studies</a> demonstrated differences between <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373086/" class="def">lipophilic</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407760/" class="def">extracts</a>, which often had evidence of estrogenic activity,[<a class="bk_pop" href="#CDR0000803263_rl_21_1">1</a>] and the hydroalcoholic extracts of the type contained in the most commonly used clinical products, which generally lacked such activity.[<a class="bk_pop" href="#CDR0000803263_rl_21_1">1</a>,<a class="bk_pop" href="#CDR0000803263_rl_21_2">2</a>]</p><p id="CDR0000803263__24">Considering the recent discovery of nitrogenous black cohosh constituents,[<a class="bk_pop" href="#CDR0000803263_rl_21_2">2</a>] subsequent hypotheses for the activity of black cohosh involve potential effects on hypothalamic <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000458085/" class="def">neurotransmitter</a> regulation systems,[<a class="bk_pop" href="#CDR0000803263_rl_21_1">1</a>,<a class="bk_pop" href="#CDR0000803263_rl_21_3">3</a>] such as those involving
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the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044026/" class="def">endogenous</a> central opioid system.[<a class="bk_pop" href="#CDR0000803263_rl_21_4">4</a>] This <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044209/" class="def">hypothesis</a> is supported by the observation that while black cohosh treatment alone has no effect on <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000643019/" class="def">luteinizing hormone</a> (LH) activity, induction of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045228/" class="def">naloxone</a> blockade of µ-opioid <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044958/" class="def">receptors</a> in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045269/" class="def">postmenopausal</a> women treated with Remifemin® leads to the suppression of LH activity.[<a class="bk_pop" href="#CDR0000803263_rl_21_4">4</a>] <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046218/" class="def">Positron emission tomography</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046361/" class="def">imaging</a> in women treated with black cohosh indicated selective µ-opioid receptor availability, with increased availability in regions responsible for emotional and cognitive processing, and pronounced reductions observed in areas associated with the human <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046688/" class="def">placebo</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044085/" class="def">response</a>.[<a class="bk_pop" href="#CDR0000803263_rl_21_4">4</a>] Given such results, and the comparatively high frequency of placebo responsiveness in black cohosh <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045961/" class="def">clinical trials</a>, both pharmacologic and placebo effects simultaneously affecting the endogenous opioid system are suggested. </p></div><div id="CDR0000803263_rl_21"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000803263_rl_21_1">Fabricant DS, Krause EC, Farnsworth NR: Black cohosh. In: Coates PM, Blackman MR, Cragg GM: Encyclopedia of Dietary Supplements. 2<sup>nd</sup> ed. CRC Press, 2015, pp 60-74.</div></li><li><div class="bk_ref" id="CDR0000803263_rl_21_2">Qiu F, McAlpine JB, Krause EC, et al.: Pharmacognosy of black cohosh: the phytochemical and biological profile of a major botanical dietary supplement. Prog Chem Org Nat Prod 99: 1-68, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/25296437" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25296437</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_21_3">Fritz H, Seely D, McGowan J, et al.: Black cohosh and breast cancer: a systematic review. Integr Cancer Ther 13 (1): 12-29, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/23439657" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23439657</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_21_4">Reame NE, Lukacs JL, Padmanabhan V, et al.: Black cohosh has central opioid activity in postmenopausal women: evidence from naloxone blockade and positron emission tomography neuroimaging. Menopause 15 (5): 832-40, 2008 Sep-Oct. [<a href="/pmc/articles/PMC2915573/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2915573</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18521048" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18521048</span></a>]</div></li></ol></div></div><div id="CDR0000803263__25"><h2 id="_CDR0000803263__25_">Human/Clinical Studies</h2><div id="CDR0000803263__26"><h3>Mechanism of Action, Pharmacokinetics, Pharmacodynamics</h3><p id="CDR0000803263__27">Given that the clinically utilized hydrophilic <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407760/" class="def">extracts</a> of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321355/" class="def">black cohosh</a> roots and rhizomes are not estrogenic, alternative mechanisms of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046296/" class="def">menopausal</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045022/" class="def">symptom</a> relief have been proposed, one of which suggests serotonergic activity by triterpenes to minimize episodes of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000256567/" class="def">hot flashes</a> and bone loss.[<a class="bk_pop" href="#CDR0000803263_rl_25_1">1</a>-<a class="bk_pop" href="#CDR0000803263_rl_25_4">4</a>] While this finding warrants further investigation, it is currently common practice to standardize the content of commercially available black cohosh supplements to certain triterpene <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000422394/" class="def">compounds</a> related to actein, such as 23-epi-26-deoxyactein. Likewise, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044324/" class="def">pharmacokinetic</a> (PK) investigations of black cohosh triterpenes are more commonly reported.</p><p id="CDR0000803263__28">The maximum-tolerated <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044664/" class="def">dose</a> and PK of 23-epi-26-deoxyactein, the most abundant triterpene found in the plant,[<a class="bk_pop" href="#CDR0000803263_rl_25_5">5</a>] has been evaluated in a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045830/" class="def">phase I clinical trial</a>. Single doses of an ethanolic black cohosh extract containing 1.4 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044213/" class="def">mg</a>, 2.8 mg, or 5.6 mg of 23-epi-26-deoxyactein (32 mg, 64 mg, or 128 mg of black cohosh, respectively) were administered to 15 healthy menopausal women.[<a class="bk_pop" href="#CDR0000803263_rl_25_1">1</a>] <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390238/" class="def">Analysis</a> of the compound in sera indicates a half-life of about 2 hours for all administered dosages (2.1 ± 0.4, 2.7 ± 0.4, and 3.0 ± 1.0 h, respectively). First-order kinetics is also indicated, with maximum <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000683342/" class="def">concentration</a> and area under the curve increasing proportionately with dosage. It is suggested that 23-epi-26-deoxyactein is excreted intact in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046508/" class="def">bile</a> and degraded in the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046189/" class="def">gastrointestinal tract</a>, as no metabolites of the compound were detected in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046642/" class="def">urine</a> or sera, and only a negligible amount (<0.01%) of the compound was recovered in urine 24 hours after <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044068/" class="def">oral</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000478733/" class="def">administration</a>; specific proof of predominant <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044970/" class="def">biliary</a> secretion is needed.[<a class="bk_pop" href="#CDR0000803263_rl_25_1">1</a>] In the same study, no <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044643/" class="def">alteration</a> in circulating <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045713/" class="def">hormone</a> levels <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000305990/" class="def">(estradiol</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000643012/" class="def">follicle-stimulating hormone</a>, luteinizing hormone) was observed in this population relative to <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000467830/" class="def">baseline</a> (<i>P</i> < .05), changes have not been observed in similar investigations of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045921/" class="def">systemic</a> hormone levels or those monitoring for estrogenic effects on <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000304766/" class="def">breast</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045044/" class="def">endometrial</a>, or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044308/" class="def">vaginal</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046683/" class="def">tissues</a>.[<a class="bk_pop" href="#CDR0000803263_rl_25_2">2</a>]</p><p id="CDR0000803263__29">Although <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044007/" class="def">case reports</a> suggested connections between the use of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373932/" class="def">dietary supplements</a> containing black cohosh and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046312/" class="def">liver</a> damage, no evidence of hepatotoxicity—or any other form of serious toxicity—was found in systematic reviews of results from <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045961/" class="def">clinical trials</a> of a chemically standardized black cohosh preparation; regardless of dosage administered, no liver function <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045776/" class="def">markers</a> were altered.[<a class="bk_pop" href="#CDR0000803263_rl_25_1">1</a>]</p><p id="CDR0000803263__30">Reports of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045709/" class="def">hepatic</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044922/" class="def">adverse effects</a> include one case of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045585/" class="def">acute</a> liver failure, two cases of <i><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046371/" class="def">hepatitis</a></i> (without further description), and two cases indicating mild elevation of liver function markers, though many of these patients were taking multiple <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000367458/" class="def">botanical</a> products simultaneously.[<a class="bk_pop" href="#CDR0000803263_rl_25_6">6</a>] An episode of autoimmune hepatitis is questionably related to the use of black cohosh. Although noteworthy, many of these reports are anecdotal in nature.[<a class="bk_pop" href="#CDR0000803263_rl_25_6">6</a>] Furthermore, a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000691484/" class="def">meta-analysis</a> of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045858/" class="def">randomized</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045673/" class="def">double-blind</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044014/" class="def">controlled clinical trials</a> does not demonstrate evidence of black cohosh causing adverse effects on liver function.[<a class="bk_pop" href="#CDR0000803263_rl_25_7">7</a>] Indications of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445093/" class="def">toxicity</a> are reportedly caused by manufacturer contamination or adulteration with other toxic products,[<a class="bk_pop" href="#CDR0000803263_rl_25_1">1</a>] necessitating mechanisms of botanical authentication and proper methods of manufacturing the product. The not-infrequent adulteration of black cohosh with Asian <i>Actaea</i> species that contain significantly different phytoconstituents is the most plausible cause of the reported potential adverse hepatic effects.[<a class="bk_pop" href="#CDR0000803263_rl_25_8">8</a>,<a class="bk_pop" href="#CDR0000803263_rl_25_9">9</a>]</p><p id="CDR0000803263__31">Acute toxicity of black cohosh is also purported to occur through interactions with pharmaceutical agents.[<a class="bk_pop" href="#CDR0000803263_rl_25_1">1</a>,<a class="bk_pop" href="#CDR0000803263_rl_25_10">10</a>] Though substantial <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000463714/" class="def">herb</a>-<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000348921/" class="def">drug</a> interactions can occur in this manner with certain herbs such as St. John’s wort, <i><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046352/" class="def">in vivo</a></i> analysis of black cohosh <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046173/" class="def">metabolism</a> does not suggest this interaction. Black cohosh <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045916/" class="def">supplementation</a> does not significantly alter the expression or activity of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044056/" class="def">metabolic</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046081/" class="def">enzymes</a> CYP3A4, CYP1A2, or CYP2E1.[<a class="bk_pop" href="#CDR0000803263_rl_25_10">10</a>] While a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044167/" class="def">statistically significant</a> decrease in the CYP2D6 <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460203/" class="def">phenotype</a> (approximately 7%; <i>P</i> = .02) has been observed in a human study, the clinical relevancy of this finding is questionable [<a class="bk_pop" href="#CDR0000803263_rl_25_10">10</a>]—especially since a very high dose was used for this particular investigation (1,090 mg bid). Studies have yet to verify this effect;[<a class="bk_pop" href="#CDR0000803263_rl_25_2">2</a>] however, given that tamoxifen is a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044229/" class="def">selective estrogen receptor modulator</a> and is primarily metabolized by CYP2D6, even mild inhibition of the enzyme by black cohosh may warrant consideration.[<a class="bk_pop" href="#CDR0000803263_rl_25_2">2</a>] </p></div><div id="CDR0000803263__32"><h3>Prevention of Breast Cancer/Recurrence </h3><p id="CDR0000803263__33"><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000286105/" class="def">Observational studies</a> of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045269/" class="def">postmenopausal</a> women without a history of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000444971/" class="def">breast cancer</a> indicated no significant association between the use of black cohosh and development of the disease when compared with nonuse (<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000618612/" class="def">hazard ratio</a> = 1.17; 95% confidence interval [CI], 0.75–1.82; adjusted <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000618610/" class="def">odds ratio</a> [OR], 0.80; 95% CI, 0.63–1.00).[<a class="bk_pop" href="#CDR0000803263_rl_25_2">2</a>]</p><p id="CDR0000803263__34">One study suggested a possible protective effect. This <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000348989/" class="def">case-control trial</a> evaluated whether the use of hormone-related supplements, including black cohosh for the management of menopausal symptoms, was associated with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045333/" class="def">cancer</a> risk or protection.[<a class="bk_pop" href="#CDR0000803263_rl_25_11">11</a>] A 53% decreased risk in the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046145/" class="def">incidence</a> of breast cancer was observed among postmenopausal women taking black cohosh compared with nonusers (adjusted OR, 0.47; 95% CI, 0.27–0.82). In subset analyses, ever-use of tamoxifen or raloxifene prior to cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046450/" class="def">diagnosis</a> (as a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045487/" class="def">chemopreventive</a> agent rather than a treatment for cancer) was not a significant confounder in the protective relationship observed between black cohosh use and breast cancer occurrence.[<a class="bk_pop" href="#CDR0000803263_rl_25_11">11</a>]</p><p id="CDR0000803263__35"><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045861/" class="def">Recurrence</a>-free survival was also evaluated as a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044163/" class="def">primary endpoint</a> measure in a sample of breast cancer patients and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000450125/" class="def">survivors</a> (n = 18,861), 1,102 of whom had received a product containing a black cohosh extract (i.e., Remifemin® or Remifemin® plus; R/R+, a 40% isopropanol black cohosh extract, with or without St. John’s wort extract,[<a class="bk_pop" href="#CDR0000803263_rl_25_12">12</a>] respectively).[<a class="bk_pop" href="#CDR0000803263_rl_25_13">13</a>] This <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000286525/" class="def">retrospective cohort study</a> reported a significantly lower risk of recurrence in R/R+ users compared with nonusers over a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285973/" class="def">mean</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045981/" class="def">observation</a> time of 3.6 years.[<a class="bk_pop" href="#CDR0000803263_rl_25_13">13</a>] This decrease was observed in patients who also received tamoxifen. These results suggest that R/R+ is not likely to promote breast cancer recurrence or inhibit the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000043985/" class="def">therapeutic</a> effect of tamoxifen.[<a class="bk_pop" href="#CDR0000803263_rl_25_13">13</a>] No other studies have reported to further explore a potential beneficial effect of black cohosh extracts on breast cancer recurrence.</p></div><div id="CDR0000803263__36"><h3>Effect on Menopausal Symptoms </h3><p id="CDR0000803263__37">Several studies have investigated black cohosh in treating women suffering from climacteric complaints, including breast cancer patients and survivors.[<a class="bk_pop" href="#CDR0000803263_rl_25_2">2</a>,<a class="bk_pop" href="#CDR0000803263_rl_25_3">3</a>] Analyses of the effect of black cohosh preparations on these symptoms in patients with other cancers have not yet been reported. </p></div><div id="CDR0000803263__38"><h3>Breast Cancer Patients</h3><p id="CDR0000803263__39">Observational and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285990/" class="def">open-label</a> studies have demonstrated reductions in the number and severity of hot flashes among breast cancer patients undergoing adjuvant <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044411/" class="def">endocrine therapy</a> complemented with black cohosh; however, randomized, double-blind, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044840/" class="def">placebo-controlled</a> clinical trials have failed to demonstrate reductions greater than that seen with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046688/" class="def">placebo</a>.[<a class="bk_pop" href="#CDR0000803263_rl_25_2">2</a>]</p><p id="CDR0000803263__40">Significant declines in hot flash frequency and severity and other menopausal symptoms are reported in a review of observational studies of breast cancer patients and survivors taking Remifemin® (20–40 mg/d), with or without tamoxifen or raloxifene.[<a class="bk_pop" href="#CDR0000803263_rl_25_2">2</a>] <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044079/" class="def">Prospective</a> trials indicated reductions as high as 56% (95% CI = 40%–71%) in hot flash scores (daily frequency times average severity).[<a class="bk_pop" href="#CDR0000803263_rl_25_2">2</a>] Self-<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000430407/" class="def">assessment</a> of menopausal symptoms through the Menopausal Rating Scale (MRS II) has also been evaluated among breast cancer patients on Remifemin® (40 mg/d) plus tamoxifen (10–40 mg/d), indicating significant declines in menopausal symptomology (<i>P</i> < .001) from baseline, and after 1, 3, and 6 months of black cohosh treatment.[<a class="bk_pop" href="#CDR0000803263_rl_25_2">2</a>]</p><p id="CDR0000803263__41">Statistically significant reductions in hot flash symptomology have also been observed in open-label administration of another black cohosh product, CR BNO 1055 from Bionorica in Germany (40 mg/d), in breast cancer survivors who received <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045587/" class="def">adjuvant therapy</a> with tamoxifen; however, double-blind studies so far have failed to show this to be a specific effect.[<a class="bk_pop" href="#CDR0000803263_rl_25_2">2</a>]</p><p id="CDR0000803263__42">Thus far, two randomized, placebo-controlled, double-blind clinical trials have assessed the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000346517/" class="def">efficacy</a> of black cohosh use (one trial used black cohosh extract;[<a class="bk_pop" href="#CDR0000803263_rl_25_14">14</a>] the other trial used an uncharacterized black cohosh product [<a class="bk_pop" href="#CDR0000803263_rl_25_15">15</a>]) on hot flashes—or related <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000256578/" class="def">vasomotor</a> symptoms—in breast cancer survivors who received a selective estrogen receptor modulator (SERM). Neither study indicated a significant difference in menopausal symptomology between women taking the supplement (20–40 mg/d), or an identical-appearing placebo, with or without the use of tamoxifen (10–40 mg) or raloxifene (dosage not provided).[<a class="bk_pop" href="#CDR0000803263_rl_25_2">2</a>,<a class="bk_pop" href="#CDR0000803263_rl_25_14">14</a>]</p><p id="CDR0000803263__43">One randomized clinical study specifically evaluated the preventative effect of Remifemin® on symptoms of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046296/" class="def">menopause</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045090/" class="def">syndrome</a> (MPS) in breast cancer patients who received <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044574/" class="def">luteinizing hormone-releasing hormone</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044919/" class="def">analogs</a> (LHRH-a).[<a class="bk_pop" href="#CDR0000803263_rl_25_3">3</a>] Some patients received LHRH-a treatment in addition to an <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044232/" class="def">aromatase inhibitor</a> or SERM, though no significant difference in use was found between the treatment group and the control group.[<a class="bk_pop" href="#CDR0000803263_rl_25_3">3</a>] Evaluation of MPS was assessed using Kupperman Menopausal Index (KMI) scores. Symptomology increased in both groups throughout the course of study; however, KMI scores of patients on LHRH-a treatment (goserelin, n = 32; leuprorelin, n = 10) with Remifemin® (40 mg/d) were significantly lower than those on adjuvant therapy alone (goserelin, n = 28; leuprorelin, n = 15) at each time point in this 12-week clinical trial (<i>P</i> < .01). </p><p id="CDR0000803263__44">Given these conflicting results in observational and randomized clinical trials, a large placebo effect is presumably at play, especially considering the subjective nature of many of the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000346519/" class="def">endpoint</a> measures.[<a class="bk_pop" href="#CDR0000803263_rl_25_2">2</a>] Furthermore, the beneficial effect observed through an open-label study left unconfirmed through double-blind studies further obscured the understanding of the true effect of black cohosh in alleviating climacteric symptoms in this patient population; however, given the unlikely negative impact on breast cancer risk or recurrence,[<a class="bk_pop" href="#CDR0000803263_rl_25_11">11</a>,<a class="bk_pop" href="#CDR0000803263_rl_25_13">13</a>] along with evidence of relative safety, more research is warranted.[<a class="bk_pop" href="#CDR0000803263_rl_25_1">1</a>,<a class="bk_pop" href="#CDR0000803263_rl_25_2">2</a>,<a class="bk_pop" href="#CDR0000803263_rl_25_7">7</a>,<a class="bk_pop" href="#CDR0000803263_rl_25_10">10</a>]</p></div><div id="CDR0000803263__45"><h3>Noncancer Patients</h3><p id="CDR0000803263__46">The efficacy of black cohosh supplementation on vasomotor symptoms has also been evaluated in noncancer populations; however, these findings to date remain inconsistent.</p><p id="CDR0000803263__47">A meta-analysis of 16 randomized controlled trials investigated the efficacy of monopreparations of black cohosh compared with interventions including placebo, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000330178/" class="def">red clover</a>, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045374/" class="def">fluoxetine</a> in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045268/" class="def">premenopausal</a> and postmenopausal women. No significant difference in hot flash frequency or menopausal symptom scores between the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044758/" class="def">experimental</a> group and control group were detected.[<a class="bk_pop" href="#CDR0000803263_rl_25_16">16</a>] While three trials demonstrated a significant reduction in hot flash frequency and menopausal symptom score for hormonal treatment compared with black cohosh, substantial heterogeneity was observed between studies included for review,[<a class="bk_pop" href="#CDR0000803263_rl_25_16">16</a>] thus necessitating further investigation in this area. </p><p id="CDR0000803263__48">Similarly, the Herbal Alternatives for Menopause (HALT) study investigated the effect of black cohosh (CimiPure®, 70% ethanol extract standardized to 2.5% triterpene glycosides, 160 mg/d) and an encapsulated multibotanical-containing black cohosh (ProGyne; black cohosh, 200 mg/d, along with nine other ingredients),[<a class="bk_pop" href="#CDR0000803263_rl_25_17">17</a>] both of which failed to show a benefit greater than that of placebo.[<a class="bk_pop" href="#CDR0000803263_rl_25_18">18</a>]</p><p id="CDR0000803263__49">Randomized controlled investigations of black cohosh used as monopreparations [<a class="bk_pop" href="#CDR0000803263_rl_25_16">16</a>] or within multibotanical preparations [<a class="bk_pop" href="#CDR0000803263_rl_25_18">18</a>] have yet proven effective in reducing climacteric complaints among women without a history of breast cancer.</p></div><div id="CDR0000803263__50"><h3>Management of Other Conditions</h3><div id="CDR0000803263__51"><h4>Bone mineral density</h4><p id="CDR0000803263__52">The therapeutic effects of black cohosh on bone metabolism have also been investigated as a secondary <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000467853/" class="def">outcome</a> measure in a randomized, double-blind clinical trial, comparing results to that of conjugated estrogens (CE) and placebo.[<a class="bk_pop" href="#CDR0000803263_rl_25_19">19</a>] Daily administration of the black cohosh extract containing commercial product CR BNO 1055 (40 mg/d) demonstrated an effect equipotent to that of CE (0.6 mg) after 3 months of treatment. Analyses of bone turnover markers indicated a significant improvement above placebo values on bone metabolism in both the black cohosh and CE groups (<i>P</i> = .0138, both groups).[<a class="bk_pop" href="#CDR0000803263_rl_25_19">19</a>] Unlike other groups, women treated with CR BNO 1055 displayed a significant increase in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044088/" class="def">serum</a> bone-specific alkaline phosphatase levels (<i>P</i> = .0358), indicating increases in bone formation. The effect demonstrated with CE supplementation was comparable, though distinct; compared with placebo, women displayed a significant decrease in bone degradation, as measured by serum levels of the C-terminal breakdown product of bone-specific type-1 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044196/" class="def">collagen</a> (<i>P</i> = .0181). Likewise, while the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000797426/" class="def">mechanism of action</a> may be different than that of CE, black cohosh does appear to have an osteoprotective effect in postmenopausal women.[<a class="bk_pop" href="#CDR0000803263_rl_25_19">19</a>] Potential benefits on bone metabolism are further supported in an uncontrolled trial by increases in osteocalcin levels in women receiving the supplement.[<a class="bk_pop" href="#CDR0000803263_rl_25_20">20</a>]</p><div id="CDR0000803263__62" class="table"><h3><span class="title">Table 1. Clinical Studies of Black Cohosh<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK566616.4/table/CDR0000803263__62/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000803263__62_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;"> Reference</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Trial Design</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;"><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000651193/" class="def">Condition</a> Treated</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">No. of Patients: Enrolled; Treated; Placebo or No Treatment Control<sup>b</sup></th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;">Primary Outcome</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;"><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044011/" class="def">Concurrent Therapy</a> Used</th><th colspan="1" rowspan="1" style="text-align:center;vertical-align:top;"><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000446533/" class="def">Level of Evidence</a> Score<sup>c</sup></th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000803263_rl_25_14">14</a>] </td><td colspan="1" rowspan="1" style="vertical-align:top;">Randomized, double-blind, placebo-controlled, crossover trial</td><td colspan="1" rowspan="1" style="vertical-align:top;">Hot flashes</td><td colspan="1" rowspan="1" style="vertical-align:top;">131; 66; 65 (crossover in treated and placebo groups)</td><td colspan="1" rowspan="1" style="vertical-align:top;">No difference in hot flashes from black cohosh compared with placebo after 8 weeks of treatment (primary outcome)</td><td colspan="1" rowspan="1" style="vertical-align:top;">Various <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046367/" class="def">hormonal therapies</a></td><td colspan="1" rowspan="1" style="vertical-align:top;">1iC</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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[<a class="bk_pop" href="#CDR0000803263_rl_25_15">15</a>]
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">Randomized, double-blind, placebo-controlled trial</td><td colspan="1" rowspan="1" style="vertical-align:top;">Hot flashes</td><td colspan="1" rowspan="1" style="vertical-align:top;">85; 42; 43</td><td colspan="1" rowspan="1" style="vertical-align:top;">No difference in the number of hot flashes from placebo at 57 to 60 days</td><td colspan="1" rowspan="1" style="vertical-align:top;">Tamoxifen</td><td colspan="1" rowspan="1" style="vertical-align:top;">1iC</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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[<a class="bk_pop" href="#CDR0000803263_rl_25_3">3</a>]
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">Randomized controlled trial</td><td colspan="1" rowspan="1" style="vertical-align:top;">Menopausal symptoms</td><td colspan="1" rowspan="1" style="vertical-align:top;">85; 42; 43</td><td colspan="1" rowspan="1" style="vertical-align:top;">Menopausal symptoms (measured by KMI) significantly lower in patients treated with black cohosh</td><td colspan="1" rowspan="1" style="vertical-align:top;">LHRH-a</td><td colspan="1" rowspan="1" style="vertical-align:top;">1iiC</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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[<a class="bk_pop" href="#CDR0000803263_rl_25_4">4</a>]
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">Randomized, double-blind, placebo-controlled trial</td><td colspan="1" rowspan="1" style="vertical-align:top;">Bone metabolism</td><td colspan="1" rowspan="1" style="vertical-align:top;">62; 20 (black cohosh), 22 (conjugated estrogens); 20 (placebo)</td><td colspan="1" rowspan="1" style="vertical-align:top;">Statistically significant increase in bone-specific alkaline phosphatase level</td><td colspan="1" rowspan="1" style="vertical-align:top;">Unknown</td><td colspan="1" rowspan="1" style="vertical-align:top;">1iC</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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[<a class="bk_pop" href="#CDR0000803263_rl_25_11">11</a>]
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">Retrospective case-control</td><td colspan="1" rowspan="1" style="vertical-align:top;">Breast cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000439419/" class="def">prevention</a></td><td colspan="1" rowspan="1" style="vertical-align:top;">101; 25; 76</td><td colspan="1" rowspan="1" style="vertical-align:top;"> Statistically significant OR (0.47) for developing breast cancer in women who took black cohosh supplements</td><td colspan="1" rowspan="1" style="vertical-align:top;">Various therapies</td><td colspan="1" rowspan="1" style="vertical-align:top;">2Di</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">
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[<a class="bk_pop" href="#CDR0000803263_rl_25_13">13</a>]
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">Observational retrospective cohort</td><td colspan="1" rowspan="1" style="vertical-align:top;">Breast cancer recurrence</td><td colspan="1" rowspan="1" style="vertical-align:top;">18,861; 1,102; 17,759</td><td colspan="1" rowspan="1" style="vertical-align:top;">Did not promote breast cancer recurrence or inhibit the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000043985/" class="def">therapeutic</a> effect of tamoxifen</td><td colspan="1" rowspan="1" style="vertical-align:top;">Tamoxifen</td><td colspan="1" rowspan="1" style="vertical-align:top;">2Di</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">KMI = Kupperman Menopausal Index; LHRH-a = luteinizing hormone-releasing hormone analogs; OR = odds ratio.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Refer to text and the <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI Dictionary of Cancer Terms</a> for additional information and definition of terms.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>b</sup>Number of patients treated plus number of patient controls may not equal number of patients enrolled; number of patients enrolled equals number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated equals number of enrolled patients who were given the treatment being studied AND for whom results were reported.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>c</sup>For information about levels of evidence analysis and an explanation of the level of evidence scores, refer to <a href="/books/n/pdqcis/CDR0000256874/">Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies</a>.</p></div></dd></dl></div></div></div></div></div><div id="CDR0000803263_rl_25"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000803263_rl_25_1">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 87 (2): 219-25, 2010. [<a href="/pmc/articles/PMC3635811/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3635811</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20032972" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20032972</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_2">Fritz H, Seely D, McGowan J, et al.: Black cohosh and breast cancer: a systematic review. Integr Cancer Ther 13 (1): 12-29, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/23439657" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23439657</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_3">Wang C, Huang Q, Liang CL, et al.: Effect of cimicifuga racemosa on menopausal syndrome caused by LHRH-a in breast cancer. J Ethnopharmacol 238: 111840, 2019. [<a href="https://pubmed.ncbi.nlm.nih.gov/30935866" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30935866</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_4">Wuttke W, Gorkow C, Seidlová-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 13 (2): 185-96, 2006 Mar-Apr. [<a href="https://pubmed.ncbi.nlm.nih.gov/16645532" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16645532</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_5">Gafner S: Black Cohosh Laboratory Guidance Document. ABC-AHP-NCNPR Botanical Adulterants Program, 2015.</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_6">Cohen SM, O'Connor AM, Hart J, et al.: Autoimmune hepatitis associated with the use of black cohosh: a case study. Menopause 11 (5): 575-7, 2004 Sep-Oct. [<a href="https://pubmed.ncbi.nlm.nih.gov/15356412" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15356412</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_7">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 18 (4): 366-75, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21228727" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21228727</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_8">Foster S: Exploring the peripatetic maze of black cohosh adulteration: a review of the nomenclature, distribution, chemistry, market status, analytical methods, and safety. HerbalGram (98): 32-51, 2013. <a href="http://cms.herbalgram.org/herbalgram/issue98/hg98feat-blackcohosh.html?ts=1607542950&signature=b2202e7be549be2dd4bb828e9b7430a3" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed December 3, 2020..</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_9">Gafner S: Botanical adulterants bulletin on adulteration of actaea racemosa. Black Cohosh - Botanical Adulterants Bulletin 1-5, 2016.</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_10">Gurley B, Hubbard MA, Williams DK, et al.: Assessing the clinical significance of botanical supplementation on human cytochrome P450 3A activity: comparison of a milk thistle and black cohosh product to rifampin and clarithromycin. J Clin Pharmacol 46 (2): 201-13, 2006. [<a href="/pmc/articles/PMC1865122/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1865122</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16432272" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16432272</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_11">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 120 (7): 1523-8, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17205521" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17205521</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_12">Qiu F, McAlpine JB, Krause EC, et al.: Pharmacognosy of black cohosh: the phytochemical and biological profile of a major botanical dietary supplement. Prog Chem Org Nat Prod 99: 1-68, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/25296437" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25296437</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_13">Henneicke-von Zepelin HH, Meden H, Kostev K, et al.: Isopropanolic black cohosh extract and recurrence-free survival after breast cancer. Int J Clin Pharmacol Ther 45 (3): 143-54, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17416109" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17416109</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_14">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 24 (18): 2836-41, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16782922" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16782922</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_15">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 19 (10): 2739-45, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11352967" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11352967</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_16">Leach MJ, Moore V: Black cohosh (Cimicifuga spp.) for menopausal symptoms. Cochrane Database Syst Rev (9): CD007244, 2012. [<a href="/pmc/articles/PMC6599854/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6599854</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22972105" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22972105</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_17">NIH-Funded HALT Study Finds Black Cohosh Ineffective for Treating Menopausal Symptoms. Morrisville, NC: Relias Media, 2007. <a href="https://www.reliasmedia.com/articles/102608-nih-funded-halt-study-finds-black-cohosh-ineffective-for-treating-menopausal-symptoms" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed December 2, 2020.</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_18">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 15 (1): 51-8, 2008 Jan-Feb. [<a href="https://pubmed.ncbi.nlm.nih.gov/18257142" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18257142</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_19">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 44 (Suppl 1): S67-77, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12609561" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12609561</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_25_20">Raus K, Brucker C, Gorkow C, et al.: First-time proof of endometrial safety of the special black cohosh extract (Actaea or Cimicifuga racemosa extract) CR BNO 1055. Menopause 13 (4): 678-91, 2006 Jul-Aug. [<a href="https://pubmed.ncbi.nlm.nih.gov/16837890" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16837890</span></a>]</div></li></ol></div></div><div id="CDR0000803263__53"><h2 id="_CDR0000803263__53_">Adverse Effects</h2><p id="CDR0000803263__54">In general, the hydroalcoholic <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321355/" class="def">black cohosh</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407760/" class="def">extracts</a> that are widely used as components in commercially available products—and those used in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045961/" class="def">clinical trials</a>—have been very well tolerated, producing rare serious <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044922/" class="def">adverse effects</a>, which are likely due to product quality issues (adulteration) rather than black cohosh itself. An overview of the adverse events from a systematic review of the results of several clinical trials, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000689749/" class="def">postmarketing surveillance studies</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044006/" class="def">case series</a>, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044007/" class="def">case reports</a> found only rare serious adverse events that may not have been induced by black cohosh.[<a class="bk_pop" href="#CDR0000803263_rl_53_1">1</a>] The most common minor adverse effects noted in these trials were <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045692/" class="def">gastrointestinal</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045022/" class="def">symptoms</a> (e.g., <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390302/" class="def">nausea</a>) and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044938/" class="def">musculoskeletal</a> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044013/" class="def">connective tissue</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407758/" class="def">disorders</a> (e.g., <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000458080/" class="def">joint</a> pain, rashes).[<a class="bk_pop" href="#CDR0000803263_rl_53_1">1</a>]</p><div id="CDR0000803263__55"><h3>Herb-Drug Interactions</h3><p id="CDR0000803263__56">A small number of studies have explored the potential for black cohosh extracts to interfere with the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046173/" class="def">metabolism</a> or activity of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000348921/" class="def">drugs</a>. One group studied the <i><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046352/" class="def">in vivo</a></i> effect of black cohosh extracts on cytochrome P450 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046081/" class="def">enzymes</a> at <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044664/" class="def">doses</a> up to 1,090 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044213/" class="def">mg</a> bid (0.2% triterpene glycosides) and found only weak inhibition of CYP2D6 [<a class="bk_pop" href="#CDR0000803263_rl_53_2">2</a>] and no effect on CYP3A4.[<a class="bk_pop" href="#CDR0000803263_rl_53_3">3</a>] A single case report suggested a possible effect of a black cohosh extract on reducing the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407756/" class="def">cholesterol</a>-lowering effects of statins.[<a class="bk_pop" href="#CDR0000803263_rl_53_4">4</a>]</p></div><div id="CDR0000803263_rl_53"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000803263_rl_53_1">Borrelli F, Ernst E: Black cohosh (Cimicifuga racemosa): a systematic review of adverse events. Am J Obstet Gynecol 199 (5): 455-66, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18984078" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18984078</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_53_2">Gurley BJ, Gardner SF, Hubbard MA, et al.: In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes. Clin Pharmacol Ther 77 (5): 415-26, 2005. [<a href="/pmc/articles/PMC1894911/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1894911</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15900287" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15900287</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_53_3">Gurley BJ, Swain A, Hubbard MA, et al.: Clinical assessment of CYP2D6-mediated herb-drug interactions in humans: effects of milk thistle, black cohosh, goldenseal, kava kava, St. John's wort, and Echinacea. Mol Nutr Food Res 52 (7): 755-63, 2008. [<a href="/pmc/articles/PMC2562884/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2562884</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18214849" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18214849</span></a>]</div></li><li><div class="bk_ref" id="CDR0000803263_rl_53_4">Asher GN, Corbett AH, Hawke RL: Common Herbal Dietary Supplement-Drug Interactions. Am Fam Physician 96 (2): 101-107, 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/28762712" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28762712</span></a>]</div></li></ol></div></div><div id="CDR0000803263__57"><h2 id="_CDR0000803263__57_">Summary of the Evidence for Black Cohosh </h2><p id="CDR0000803263__58">To assist readers in evaluating the results of human studies of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044964/" class="def">integrative, alternative, and complementary therapies</a> for <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045333/" class="def">cancer</a>, the strength of the evidence (i.e., the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000446533/" class="def">levels of evidence</a>) associated with each type of treatment is provided whenever possible. To qualify for a level of evidence <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390238/" class="def">analysis</a>, a study must:</p><ul id="CDR0000803263__59"><li class="half_rhythm"><div>Be published in a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000537399/" class="def">peer-reviewed scientific journal</a> and include sufficient parameters about the quality and reproducibility of the investigated material derived from <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321355/" class="def">black cohosh</a>.</div></li><li class="half_rhythm"><div>Report on <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000043985/" class="def">therapeutic</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000467853/" class="def">outcome</a> or outcomes, such as <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046634/" class="def">tumor</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044085/" class="def">response</a>, improvement in survival, or measured improvement in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045417/" class="def">quality of life</a>.</div></li><li class="half_rhythm"><div>Describe <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044168/" class="def">clinical</a> findings in sufficient detail for a meaningful evaluation to be made.</div></li></ul><p id="CDR0000803263__60">Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000346519/" class="def">endpoints</a>) measured. The resulting two scores are then combined to produce an overall score. A level of evidence score cannot be assigned to black cohosh because there has been insufficient <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000774488/" class="def">clinical research</a> done. For an explanation of the scores and additional information about levels of evidence analysis of CAM treatments for cancer, refer to <a href="/books/n/pdqcis/CDR0000256874/">Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies</a></p><p id="CDR0000803263__61">The Committee on Herbal Medicinal Products of the European Medicines Agency describes black cohosh products as a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000482419/" class="def">medicine</a> that may be used for the treatment of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046296/" class="def">menopausal</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045022/" class="def">symptoms</a>, based on their <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000430407/" class="def">assessment</a> of the results of around 20 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045961/" class="def">clinical trials</a> involving over 6,000 patients who received black cohosh.[<a class="bk_pop" href="#CDR0000803263_rl_57_1">1</a>] However, the lack of demonstration of a clinical benefit significantly greater than that of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046688/" class="def">placebo</a> and the fact that much less research has been performed with cancer patients should lead to extra caution when its use in such patients is being considered .</p><div id="CDR0000803263_rl_57"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000803263_rl_57_1">Cimicifugae Rhizoma. Amsterdam,
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The Netherlands: European Medicines Agency, 2018. <a href="https://www.ema.europa.eu/en/medicines/herbal/cimicifugae-rhizoma" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed December 2, 2020.</div></li></ol></div></div><div id="CDR0000803263__5"><h2 id="_CDR0000803263__5_">Changes to This Summary (10/14/2021)</h2><p id="CDR0000803263__6">The PDQ cancer information summaries are reviewed regularly and updated as
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new information becomes available. This section describes the latest
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changes made to this summary as of the date above.</p><p id="CDR0000803263__66">
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<b>
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<a href="#CDR0000803263__4">General Information</a>
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</b>
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</p><p id="CDR0000803263__68">Added <a href="#CDR0000803263__13">text</a> to state that at least 40 different triterpene glycoside analogues have been identified in black cohosh, including actein and cimicifugoside congeners.</p><p id="CDR0000803263__69">
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<b>
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<a href="#CDR0000803263__25">Human/Clinical Studies</a>
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</b>
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</p><p id="CDR0000803263__70">Added <a href="#CDR0000803263__43">text</a> to state that some patients received luteinizing hormone-releasing hormone analogs treatment in addition to an aromatase inhibitor or selective estrogen receptor modulator, though no significant difference in use was found between the treatment group and control group.</p><p id="CDR0000803263__71">Added Wuttke et al. as <a href="#CDR0000803263__52">reference 19</a>.</p><p id="CDR0000803263__disclaimerHP_3">This summary is written and maintained by the <a href="https://www.cancer.gov/publications/pdq/editorial-boards/cam" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Integrative, Alternative, and Complementary Therapies Editorial Board</a>, which is
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editorially independent of NCI. The summary reflects an independent review of
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the literature and does not represent a policy statement of NCI or NIH. More
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information about summary policies and the role of the PDQ Editorial Boards in
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maintaining the PDQ summaries can be found on the <a href="#CDR0000803263__AboutThis_1">About This PDQ Summary</a> and <a href="https://www.cancer.gov/publications/pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ® - NCI's Comprehensive Cancer Database</a> pages.
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</p></div><div id="CDR0000803263__AboutThis_1"><h2 id="_CDR0000803263__AboutThis_1_">About This PDQ Summary</h2><div id="CDR0000803263__AboutThis_2"><h3>Purpose of This Summary</h3><p id="CDR0000803263__AboutThis_3">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of black cohosh in people with cancer.. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.</p></div><div id="CDR0000803263__AboutThis_4"><h3>Reviewers and Updates</h3><p id="CDR0000803263__AboutThis_5">This summary is reviewed regularly and updated as necessary by the <a href="https://www.cancer.gov/publications/pdq/editorial-boards/cam" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Integrative, Alternative, and Complementary Therapies Editorial Board</a>, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p><p id="CDR0000803263__AboutThis_22"> Board members review recently published articles each month to determine whether an article should:</p><ul id="CDR0000803263__AboutThis_6"><li class="half_rhythm"><div>be discussed at a meeting,</div></li><li class="half_rhythm"><div>be cited with text, or</div></li><li class="half_rhythm"><div>replace or update an existing article that is already cited.</div></li></ul><p id="CDR0000803263__AboutThis_7">Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.</p><p id="CDR0000803263__AboutThis_9">Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's <a href="https://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.</p></div><div id="CDR0000803263__AboutThis_10"><h3>Levels of Evidence</h3><p id="CDR0000803263__AboutThis_11">Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Integrative, Alternative, and Complementary Therapies Editorial Board uses a <a href="/books/n/pdqcis/CDR0000256874/">formal evidence ranking system</a> in developing its level-of-evidence designations.</p></div><div id="CDR0000803263__AboutThis_12"><h3>Permission to Use This Summary</h3><p id="CDR0000803263__AboutThis_13">PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”</p><p id="CDR0000803263__AboutThis_14">The preferred citation for this PDQ summary is:</p><p id="CDR0000803263__AboutThis_15">PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Black Cohosh. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: <a href="https://www.cancer.gov/about-cancer/treatment/cam/hp/black-cohosh-pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.cancer.gov/about-cancer/treatment/cam/hp/black-cohosh-pdq</a>. Accessed <MM/DD/YYYY>. </p><p id="CDR0000803263__AboutThis_16">Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in <a href="https://visualsonline.cancer.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Visuals Online</a>, a collection of over 2,000 scientific images.
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</p></div><div id="CDR0000803263__AboutThis_17"><h3>Disclaimer</h3><p id="CDR0000803263__AboutThis_19">The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the <a href="https://www.cancer.gov/about-cancer/managing-care" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Managing Cancer Care</a> page.</p></div><div id="CDR0000803263__AboutThis_20"><h3>Contact Us</h3><p id="CDR0000803263__AboutThis_21">More information about contacting us or receiving help with the Cancer.gov website can be found on our <a href="https://www.cancer.gov/contact" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Contact Us for Help</a> page. Questions can also be submitted to Cancer.gov through the website’s <a href="https://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>.</p></div></div></div></div>
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Black Cohosh (PDQ®): Health Professional Version. 2021 Oct 14. In: PDQ Cancer Information Summaries [Internet]. 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