Native to eastern North America, black cohosh (Actaea racemosa) is an erect perennial in the buttercup (Ranunculaceae) family that reaches four to eight feet in height and has long, wand-like white flowers with numerous showy stamens.1 It is found in rich soils on wooded hillsides of deciduous forests, particularly in Appalachia, and occurs in 25 US states and Ontario and Quebec, from Massachusetts and southern Ontario, to Illinois and Missouri, south to Arkansas and central Alabama, through Georgia and South Carolina.2,3 Black cohosh, the article of commerce, is defined in the United States Pharmacopeia (USP) as the dried rhizome and roots of A. racemosa, containing not less than 0.4% of triterpene glycosides.4
Almost all of the commercial supply of black cohosh rhizome comes from wild collection. Based on 14 years of tonnage surveys carried out by the American Herbal Products Association, at least 3,830,117 lbs (dry weight basis) of black cohosh were harvested from 1997 through 2010, of which 72,751 lbs (1.9%) were produced through cultivation and 3,757,366 lbs (98.1%) were wild collected.5,6 There is some commercial wild collection under US Department of Agriculture (USDA) organic certification regulations in Kentucky, North Carolina, and West Virginia, as well as cultivation in Maine, Missouri, New York, Oregon, and Virginia.7
This article concerns black cohosh only and does not refer to the other botanical species traded with the common name “cohosh,” such as blue cohosh (Caulophyllum thalictroides, Berberidaceae), yellow cohosh (A. podocarpa),8 red cohosh (A. rubra), or white cohosh (A. pachypoda).9,10
HISTORY AND CULTURAL SIGNIFICANCE
HerbalGram issue 45 (1999) includes a comprehensive review by Steven Foster that elaborates on the complicated etymology, taxonomy, ethnobotany, and botanical history of black cohosh,1 which will not be repeated in this profile.
The genus name Actaea is derived from the Greek ακτέα, meaning “elder tree,” because Actaea foliage was believed to resemble that of Sambucus nigra (Adoxaceae). The previously used genus name Cimicifuga is derived from the Latin cimex, meaning “bug,” and fuga, meaning “flight,” due to the observation that Cimicifuga species appear to repel bugs,11 which also explains black cohosh’s other common name, bugbane. The term “cohosh” is an indigenous term of uncertain meaning but was used for four different plants: the aforementioned black, blue, red, and white cohoshes.12 Black cohosh is a traditional Native American medicine described and used by eastern North American tribes including the Cherokee, northeastern Algonquian, and Oklahoma Delaware.1 According to Eclectic pharmacist John Uri Lloyd (1849-1936), indigenous applications that were introduced to early American medical practice included an aqueous decoction preparation for “diseases of women, for debility, to promote perspiration, as a gargle for sore throat, and especially for rheumatism.”13
New York colonial politician and natural scientist Cadwallader Colden (1688-1776) used the Latin name Actaea racemis longissimis and common name “black snakeroot” to refer to black cohosh in his 1742 work Plantae Coldenhamiae, which was later used by Swedish botanist Carl Linnaeus (1707-1778) in the 1749 edition of Acta Societatis Regiae Scientiarum Upsaliensis (“Proceedings of the Royal Society of Science at Uppsala”).14 Colden’s monograph described therapeutic applications in the form of a cataplasm (poultice) for tumores scirrhosos (scirrhous tumors) and a tincture of the root for languor, lassitudine spontanea (lack of energy, weakness, spontaneous lassitude). Letters sent by Colden to English botanist Peter Collinson (1694-1768) in 1743, and to German botanist Johannes Fredericus Gronovius (1690-1762) in 1744,15 took aim at what he believed were errors made in Linnaeus’ 1737 work Genera Plantarum concerning characteristics of the genus Actaea.16 Subsequently, the botanical name Actaea racemis longissimis with the pharmacopeial name “Actaea radix” appeared in Linnaeus’ 1749 work Materia Medica, which listed Virginia as the source of the plant and ascribed sudorific (sweat-inducing) action and medical use for treatment of asthenia virginica,17 a “disease formerly much noticed in Virginia.”18 The genus and species Actaea racemosa appeared four years later in Linnaeus’ 1753 Species Plantarum, wherein he wrote that the species’ habitat was Florida, Virginia, and Canada.19
German botanist Frederick Traugott Pursh (1774-1820) later renamed the plant Cimicifuga serpentaria with the common name “black snake-root” in his 1814 Flora Americae Septentrionalis, providing a brief description of its habitat: occurring in shady, stony woods from Canada to Florida.20 Soon after, English botanist Thomas Nuttall (1786-1859) named it Cimicifuga racemosa in his 1818 work The Genera of North American Plants, in which he posed a question, as if he were doubting his own naming convention: “Does this exceptionable plant belong indeed to Cimicifuga?—A North American genus.”21 One hundred and eighty years later, in 1998, C. racemosa was reclassified as Linnaeus’ original name, Actaea racemosa L., based on DNA analysis.22
In 1820, “Cimicifugae Radix” appeared on the secondary list of substances in the first publication of the USP, with Pursh’s botanical name Cimicifuga serpentaria and the common name “black snake root.”23 The USP secondary list was like a pharmacopeial purgatory, providing a temporary place for “medicines little employed or of doubtful value” that could either be elevated to the primary list in the next revision of the pharmacopeia or degraded toward omission. Ten years later, in the first decennial revision (USP 1 1830), two Latin binomials were listed, the first with Linnaeus’ genus (Actaea) misspelled as Actea racemosa followed by Pursh’s C. serpentaria as a synonym. Its properties were listed as “odour unpleasant; taste bitter, nauseous,” and its medical actions as “astringent, diuretic, sudorific, sub-tonic.”24 Cimicifugae Radix was elevated from the secondary list to the primary list in the second decennial revision (USP 2 1840), this time using Nuttall’s botanical name C. racemosa, erroneously attributing the name to American botanists John Torrey (1796-1873) and Asa Gray (1810-1888).25 Cimicifuga remained official up through the 10th decennial revision (USP 10 1920).4
In 1833, a monograph titled “Cimicifuga, U.S. Secondary, Black Snakeroot” was included in the first edition of the Dispensatory of the United States of America (USD 1 1833) with the botanical names C. racemosa and C. serpentaria.26 The USD monograph described its medicinal actions and uses as:
Cimicifuga unites, with a tonic power, the property of stimulating the secretions, particularly those of the skin, kidneys, and pulmonary mucous membrane. It is thought also by some to have a particular affinity for the uterus. Its common name was probably derived from its supposed power of curing the disease arising from the bite of the rattlesnake. It is employed chiefly in domestic practice as a remedy in rheumatism, dropsy, hysteria, and various affections of the lungs, particularly those resembling consumption. The form of decoction is usually preferred. An ounce of the bruised root may be boiled for a short time in a pint of water, and one or two fluidounces given for a dose several times a day.
In 1888, “Fluid Extract of Cimicifuga” was included as a component of an “unofficinal” preparation called Syrupus Actææ Compositus (“Compound Syrup of Actaea, Compound Syrup of Cimicifuga (or Black Cohosh)”), monographed in the first issue of the American Pharmaceutical Association’s National Formulary (NF I).27 Cimicifuga NF remained in the USD until the 25th edition, published in 1955.28 In this edition, the USD appeared to dismiss black cohosh by paraphrasing a 1932 paper published in the Journal of the American Pharmaceutical Association, which had concluded “that there was no pharmacologic evidence of any therapeutic value of cimicifuga.”29 The USD monograph referred to the eighth edition of The National Formulary (NF VIII 1946) wherein Fluidextract of Cimicifuga and Tincture of Cimicifuga had been official preparations.30
In the early 19th century, case reports of successful use of black cohosh to treat chorea (an abnormal involuntary movement disorder) occasionally appeared in the medical literature. Seven case reports from the early 1830s were described in a paper by Dr. Thomas Story Kirkbride (1809-1883) of Philadelphia in The American Journal of the Medical Sciences.31 Two case studies written by Dr. L.T. Wootten of Lunenburg, Virginia, describing successful treatment of chorea with preparations of powdered black cohosh mixed in syrup of molasses and tincture (“1 oz. of cohosh to 1 pint of good rye whiskey”) were published by Dr. T.J. Garden in the Southern Medical and Surgical Journal.32
The longest marketed medicinal product containing black cohosh is “Lydia E. Pinkham’s Vegetable Compound,” which was brought to market in 1875 by Lydia Estes Pinkham (1819-1883), the founder of the Lydia E. Pinkham Medicine Company (Lynn, Massachusetts). A reformulated version of the product is still available today as an herbal dietary supplement (Lydia Pinkham® Herbal Compound) from Numark Laboratories (Edison, New Jersey). In 19th-century United States, when terms like “menstruation,” “uterine inflammation,” and “painful monthly periods” were rarely spoken out loud, these terms were used in the advertising of the product. The original formulation called for 8 oz aletris (Aletris farinosa, Nartheciaceae) root, then referred to as unicorn root, 6 oz life root (Senecio aureus, Asteraceae), 6 oz black cohosh, 6 oz pleurisy (Asclepias tuberosa, Apocynaceae) root, 12 oz fenugreek (Trigonella foenum-graecum, Fabaceae) seed, and enough alcohol (18% alcohol by volume [ABV]) for 100 pints. For 1,000 bottles of compound, 27 gallons of alcohol were used.33
After Pinkham died in 1883 at age 64, her husband, Isaac, and two of their children, Charles and Aroline, continued to run the business. At the time of Lydia’s death, the company had annual sales of about $300,000. By 1925, the Pinkham Medicine Company had about 450 employees with annual sales of about $3.8 million. Lydia’s great grandson Charles “Charlie” Pinkham was treasurer when the Pinkham family sold the company in 1968 for more than $1 million to Cooper Laboratories, Inc. of Connecticut, after which production was moved to Puerto Rico.34 In 1987, Numark Laboratories, the current marketer, acquired a license to market the Lydia Pinkham formulations.35 The Lydia Pinkham House in Lynn was added to the National Park Service’s National Register of Historic Places in 2014.36
In 1982, the US Food and Drug Administration (FDA) considered inclusion of black cohosh as an active ingredient in its proposal to establish a monograph for over-the-counter (OTC) menstrual drug products. The FDA review panel evaluated one existing drug, the aforementioned Lydia E. Pinkham’s Vegetable Compound, although the formula had changed since the 19th century. The FDA-evaluated formulation contained fluidextracts of black cohosh in combination with extracts of Jamaican dogwood (Piscidia erythrina, Fabaceae), pleurisy root, life root, dandelion (Taraxacum officinale, Asteraceae) root, gentian (Gentiana lutea, Gentianaceae) root, and licorice (Glycyrrhiza glabra, Fabaceae) root. While the agency acknowledged the 150-year history of apparently safe use of black cohosh fluidextract, the FDA stated that no human studies were available on its individual effectiveness in the treatment of primary dysmenorrhea, and therefore classified it in category II, meaning not Generally Recognized as Safe and Effective (GRASE) as an active ingredient of OTC menstrual drug products.37 In 1988, in a subsequent “tentative final monograph” for OTC menstrual drug products, black cohosh remained listed in category II.38 Four years later, the FDA proposed that black cohosh should be classified as not GRASE for use as an active ingredient of orally administered menstrual drug products,39 and passed a final ruling to that effect in 1993.40
In 1989, the German Commission E authority published a positive monograph for black cohosh (Cimicifugawurzelstock – “Cimicifugae racemosae rhizoma”), prepared as an extract (at daily dosage corresponding to 40 mg of dried rhizome) for “premenstrual discomfort, dysmenorrhea or climacteric [menopausal] neurovegetative ailments.”41 After a 70-year pause, in 2001, a proposal was made for black cohosh rhizome to reenter the USP along with additional new monographs for the fluidextract and dry extract forms.42 Six years later, the new monographs became official in the second supplement to the 30th revision (USP 30 2007).43 In 2002, a comprehensive monograph (quality and therapeutics) for “Rhizoma Cimicifugae Racemosae” entered volume two of the WHO Monographs on Selected Medicinal Plants.44 In 2010, and in its 2018 update, the European Medicines Agency (EMA) published a labeling standards monograph for black cohosh that superseded the German Commission E monograph.45
CURRENT AUTHORIZED USES IN COSMETICS, FOODS, AND MEDICINES
In the United States, black cohosh may be used as a component of dietary supplement products, which require FDA notification within 30 days of marketing if a structure-function claim is made and product manufacturing that adheres to current Good Manufacturing Practices (cGMPs).46
In Canada, black cohosh is regulated as an active ingredient of licensed natural health products (NHPs), which require pre-marketing authorization from the Natural and Non-prescription Health Products Directorate (NNHPD). Labels of licensed NHPs prepared from USP-quality black cohosh may carry these claim statements: “Used in Herbal Medicine to help relieve muscle and joint pain associated with rheumatic conditions (such as rheumatoid arthritis, osteoarthritis, and/or fibrositis), and of pain associated with neuralgia (such as sciatica)”; “Used in Herbal Medicine to help relieve the pain associated with menstruation”; “Used in Herbal Medicine to help relieve premenstrual symptoms”; and “To help relieve symptoms associated with menopause.” Regarding quality specifications, the NNHPD monograph states: “The medicinal ingredient may comply with the specifications outlined in the Black Cohosh, Black Cohosh Fluidextract, Powdered Black Cohosh, Powdered Black Cohosh Extract, or the Black Cohosh Tablets Monographs published in the US Pharmacopeia.”47
In the European Union, black cohosh dry extract may be used as an active ingredient of licensed well-established use herbal medicinal products (WEU-HMPs) labeled with the therapeutic indication “for the relief of menopausal complaints such as hot flushes and profuse sweating.”45
Triterpene glycosides,48 primarily actein and cimigenol-3-O-xyloside, are considered to be the primary and characteristic constituents of black cohosh rhizome. In addition, 27-deoxyacetylacteol and other aglycones have been detected. Cimigenol-3-O-arabinoside has been proposed as a species-specific marker.49 Another important component class is the cinnamic acid esters, including fukinolic acid and the cimicifugic acids A, B, E, and F. Minor constituents include caffeic acid, ferulic acid, isoferulic acid, salicylic acid, tannins, resins, fatty acids, starch, and sugar.50 The identity of the primary active ingredient(s) is a subject of contention in the literature and of ongoing investigations. The isoflavone formononetin,51 a long-suspected active compound, could not be detected in black cohosh plants, the botanical drugs, or in extracts (isopropanolic/ethanolic aqueous or methanolic) when researchers analyzed specimens from different geographical origins.52 The same is true for kaempferol53 and genistein.54 Furthermore, various triterpene glycosides and their aglycones were tested in binding assays for their affinity to estrogen receptor beta (ER-β), but no notable binding activity was detected.55,56 While phenolic substances (e.g., cinnamic acid esters) were originally characterized in Asian Cimicifuga species, they have meanwhile also been described for C. racemosa.57,58
In early research, a binding capacity of the constituents of a methanolic black cohosh extract to estrogen receptors (ERs) was elucidated.51,59 This, together with the luteinizing hormone (LH)-suppression observed in clinical studies60 and changes in vaginal cytology attributed to administration of black cohosh rhizome extracts,61,62 suggested efficacy due to an estrogen-like mode of action.63,64 The question of possible estrogenic agonist effects is of central importance for product safety. While phytoestrogens in soy (Glycine max, Fabaceae) and red clover (Trifolium pratense, Fabaceae) support stimulation (e.g., of cell proliferation) by activating ERs in the estrogen-free system, black cohosh does not show a corresponding intrinsic effect.65
Various research groups have presented data that do not support estrogenic activity of black cohosh.66-71 The organ specificity of estrogenic or anti-estrogenic activity is now explained by the different, tissue-dependent occurrence of the two ER isoforms (ER-α and ER-β) as well as evidence of additional organ-specific coactivators and repressors.70 The use of phytoestrogens in patients with breast cancer is associated with risks, as isoflavones may develop hormone-like effects (e.g., proliferation at the endometrium and breast tissue of menopausal women). However, in numerous clinical investigations, it was shown that Remifemin® (Schaper & Brümmer; Salzgitter-Ringelheim, Germany; DER 6-11:1, propan-2-ol 40% [V/V]), an isopropanolic extract of black cohosh, did not influence the mean values of LH, follicle stimulating hormone (FSH), prolactin, estradiol, or sex hormone binding globulin (SHBG), nor did vaginal cytology show any indications of systemic estrogen activity. Also, no increase in endometrial thickness was observed, which could be interpreted in terms of a proliferative stimulation of the endometrium.69,72-85 Similar results were obtained with other extracts of black cohosh.86,87
Constituents of black cohosh could have a pharmacological effect in the central nervous system (CNS), mediated via alterations in opioid receptor activity. These areas of the CNS are also responsible for mediating the primary effects of estrogens.88-90 Furthermore, the actions of black cohosh can be explained by the concomitant presence of ER-modulated but tissue-selective mixed agonistic/antagonistic behavior, and by its CNS-active, neutrotransmitter-modulated pathways.67,91 There appears to be CNS activity, which is thought to have favorable therapeutic effects on menopausal symptoms, as well as positive effects on breast cancer cells and the endometrium through selective estrogen receptor modulation (SERM).67,72-73
Recent reviews summarize the existing knowledge and conclude that the exact modes of action of black cohosh remain unknown.92,93 This would partially explain the inconsistent results of numerous preclinical and clinical investigations. On the other hand, the most recent review suggests reliable efficacy and an overall excellent safety profile based on an assessment of 11,073 patients receiving black cohosh products (93% of which were Remifemin) in 28 clinical trials published between 2000 and 2015.94 Table 1 presents a summary of relevant clinical investigations affecting menopausal symptoms.
Adulteration of black cohosh is a serious concern that can have potential impacts on human health and safety as well as on ecosystems. Types of adulteration include unintentional (e.g., wild collection of look-alike species occurring in the same habitat) and intentional (e.g., substitution with Asian species of Actaea, which are considerably lower in cost than genuine black cohosh), the latter being more common. Known economic adulterants include Actaea cimicifuga (syn. Cimicifuga foetida), A. dahurica (syn. C. dahurica), A. heracleifolia (syn. C. heracleifolia), A. simplex (syn. C. simplex), A. brachycarpa (syn. C. brachycarpa), and possibly Serratula chinensis (Asteraceae). North American Actaea species that grow in the same areas as black cohosh, including A. pachypoda, A. rubra, and A. podocarpa, may also adulterate the supply.119 In response, HerbalGram issue 98 (2013) included a comprehensive review by Steven Foster of black cohosh adulteration,120 as the first in a series of black cohosh educational documents of the Botanical Adulterants Prevention Program (BAPP), led by the American Botanical Council (ABC), the American Herbal Pharmacopoeia (AHP), and the National Center for Natural Products Research (NCNPR) at the University of Mississippi. BAPP published a black cohosh laboratory guidance document by Stefan Gafner, PhD, ABC’s chief science officer, in 2015121 and a botanical adulterants prevention bulletin, also by Gafner, in 2016.119
In 2002, a proposal was made by the US Fish and Wildlife Service (USFWS) to consider including black cohosh in Appendix II of the Convention on International Trade in Endangered Species (CITES). Appendix II lists species that are not currently threatened with extinction but that may become so unless trade is closely controlled. According to the USFWS, the primary threats to black cohosh at that time were habitat loss and over-collection due, in part, to increasing domestic and international demand, with much of the harvest exported to Europe and Australia. Most black cohosh is wild-collected in the eastern United States, impacting tens of millions of individual plants per year, and it is cultivated only on a small scale. The USFWS also stated that “unauthorized collection in National Forests is reported to be extensive, and incidents of poaching from National Parks have been documented in recent years.” Nonetheless, the USFWS notified the public in April 2002 that the United States did not intend to seek an Appendix II listing for black cohosh, but went on to state that in order to control illegal trade and generate additional trade data, it intended to review and consider listing US native species of the genus Cimicifuga in CITES Appendix III.122 Appendix III is a list of species included at the request of a Party (member country) that already regulates trade in the species and that needs the cooperation of other countries to prevent unsustainable or illegal exploitation.
The NatureServe global conservation status rank for black cohosh is G4 (Apparently Secure), meaning it is uncommon but not rare with some cause for long-term concern due to declines or other factors. While NatureServe assigns a national conservation status of N4 (Apparently Secure) in the United States, the status for Canada is N2 (Imperiled), meaning it is at high risk of extinction or elimination due to a very restricted range, very few populations, steep declines, or other factors.2 On the state level, other organizations list the species as endangered in Illinois and Massachusetts.8 The nonprofit organization United Plant Savers places black cohosh on its “Species At-Risk” list.123
In their Appalachian plant monograph, Pengelly and Bennett (2012) caution that as clinical studies continue to strengthen the evidence of efficacy and safety for black cohosh, this inevitably puts more pressure on the raw material supply, which is still, for the most part, wild-collected. They conclude that sustainable wild harvesting is possible, but research thus far does not support it. Therefore, it is suggested that research funding should target experimental cultivation trials in both field and wild-simulated settings.8 In the meantime, there is now certified organic black cohosh coming to market that conforms to the USDA organic wild-crop harvesting practice standard as well as some cultivation taking place on certified organic farms.7
—Josef Brinckmann and Thomas Brendler
- Foster S. Black cohosh: a literature review. HerbalGram. 1999;(45):35-50. Available at: http://herbalgram.org/resources/herbalgram/issues/45/table-of-contents/article2659/. Accessed February 17, 2019.
- NatureServe. NatureServe Explorer: An online encyclopedia of life [web application]. Version 7.1. Arlington, VA: NatureServe; 2017.
- Lonner J. Medicinal Plant Fact Sheet: Cimicifuga racemosa / Black Cohosh. A collaboration of the IUCN Medicinal Plant Specialist Group, PCA-Medicinal Plant Working Group, and North American Pollinator Protection Campaign. Arlington, VA: PCA-Medicinal Plant Working Group; 2007.
- United States Pharmacopeial Convention. United States Pharmacopoeia, Fortieth Revision (USP 40). Rockville, MD: United States Pharmacopeial Convention; 2017.
- American Herbal Products Association. Tonnage Survey of Select North American Wild-Harvested Plants, 2004–2005. Silver Spring, MD: American Herbal Products Association; 2007.
- American Herbal Products Association. Tonnage Surveys of Select North American Wild-Harvested Plants, 2006–2010. Silver Spring, MD: American Herbal Products Association; 2012.
- United States Department of Agriculture. Organic INTEGRITY Database. Washington, DC: USDA Agricultural Marketing Service; 2018.
- Pengelly A, Bennett K. Appalachian Plant Monographs. Black cohosh Actaea racemosa L. Frostburg, MD. Available at: www.frostburg.edu/aces/appalachian-plants/; 2012.
- Bergner P. Red, white, black, and blue: Differentiating the cohoshes. Paper presented at: Traditional Roots Herbal Conference 2017; Portland, OR.
- Henkel A. U.S. Department of Agriculture, Bureau of Plant Industry - Bulletin No. 89. Wild Medicinal Plants of the United States. Washington, DC: Government Printing Office; 1906.
- Tully W. Actaea racemosa. Bost Med Surg J. 1833;8:133-144.
- Lloyd JU. Origin and History of all the Pharmacopeial Vegetable Drugs, Chemicals and Preparations with Bibliography. Washington, DC: American Drug Manufacturers’ Association; 1921.
- Lloyd JU. History of the vegetable drugs of the Pharmacopoeia of the United States. Bulletin of the Lloyd Library. 1911;Bulletin No. 18, Pharmacy Series No. 4.
- Colden C. Plantae Coldenghamiae in provincia Noveboracensi Americes sponte crescentes: quas ad methodum Cl. Linnaei sexualem, anno 1742, &c. / observavit & descripsit Conwallader Colden. Acta Societatis Regiae Scientiarum Upsaliensis. 1749;Anno 4 (1749):81-136.
- Colden C. Collections of the New-York Historical Society for the Year : The Letters and Papers of Cadwallader Colden Volume III 1743-1747. New York, NY: Printed for the Society; 1920.
- Linné Cv. Caroli Linnæi ... Genera plantarum eorumque characteres naturales secundum numerum, figuram, situm, & proportionem omnium fructificationis partium. Lugduni Batavorum: apud C. Wishoff; 1737.
- Linné Cv. Materia medica, liber I : De plantis, digestus secundum genera, loca, nomina, qualitates, vires, differentias, durationes, simplicia, modos, usus, synonyma, culturas, præparata, potentias, composita. Amstelædami: Apud J. Wetstenium; 1749.
- Macculloch J. An Essay on the Remittent and Intermittent Diseases : including, generically Marsh Fever and Neuralgia : comprising under the former, various Anomalies, Obscurities, and consequences, and, under a new Systematic View of the Latter, treating of Tic Douloureux, Sciatica, Headach, Ophthalmia, Toothach, Palsy, and many other modes and consequences of this Generic Disease. Vol. I. London, UK: Longman, Rees, Orme, Brown, and Green; 1828.
- Linné Cv, Salvius L. Caroli Linnaei ... Species plantarum :exhibentes plantas rite cognitas, ad genera relatas, cum differentiis specificis, nominibus trivialibus, synonymis selectis, locis natalibus, secundum systema sexuale digestas. Vol. 2 Holmiae :: Impensis Laurentii Salvii; 1753.
- Pursh F. Flora Americae Septentrionalis, or, A systematic arrangement and description of the plants of North America. Vol. II. London, UK: Printed for White, Cochrane, and Co.; 1814.
- Nuttall T. The Genera of North American Plants, and a Catalogue of the Species, to the Year 1817. Vol. II. Philadelphia, PA: Printed for the author by D. Heartt; 1818.
- Compton JA, Culham A, Jury SL. Reclassification of Actaea to include Cimicifuga and Souliea (Ranunculaceae): phylogeny inferred from morphology, nrDNA ITS, and cpDNA trnL-F sequence variation. Taxon. 1998;47(3):593-634.
- United States Pharmacopoeial Convention. The Pharmacopoeia of the United States of America 1820. Boston, MA: Charles Ewer; 1820.
- United States Pharmacopoeial Convention. The Pharmacopoeia of the United States of America 1830. New York, NY: S. Converse; 1830.
- United States Pharmacopoeial Convention. The Pharmacopoeia of the United States of America, Second Decennial Revision. Philadelphia, PA: Grigg & Elliot; 1842.
- Wood GB, Bache F. The Dispensatory of the United States of America. Philadelphia, PA: Grigg & Elliot; 1833.
- Committee on National Formulary. The National Formulary of Unofficinal Preparations. First Issue. Washington, DC: American Pharmaceutical Association; 1888.
- Osol A, Farrar GE, eds. The Dispensatory of the United States of America. 25th ed. Philadelphia, PA: J.B. Lippincott Company; 1955.
- Macht DI, Cook HM. A pharmacological note on Cimicifuga. J Am Pharm Assoc. 1932;21(4):324-330.
- Committee on National Formulary. The National Formulary Eighth Edition (N.F. VIII). Washington, DC: American Pharmaceutical Association; 1946.
- Kirkbride TS. Observations on the employment of Cimicifuga in the treatment of chorea. Am J Med Sci. November 1839;XLIX:288-291.
- Garden TJ. On the use of black cohosh in chorea. South Med Surg J. 1854;10(5):292-294.
- Commins L. Master’s Thesis: A Parade of Grateful Women: The Surprising Success of Lydia E. Pinkham’s Vegetable Compound and the Language of Women’s Health. Waltham, MA: Department of History, Graduate School of Arts and Sciences Brandeis University; 2013.
- Munsey C. Lydia’s medicine 130 years later. Bottles and Extras. 2003;14(4).
- Lewis JJ. Biography of Lydia Pinkham. May 1, 2017. Available at: www.thoughtco.com/lydia-pinkham-biography-3529532. Accessed April 21, 2018.
- US Department of the Interior National Park Service. National Register of Historic Places Program: Weekly List. October 3, 2014. Available at: www.nps.gov/nr/listings/20141003.htm. Accessed April 22, 2018.
- US Food and Drug Administration (FDA). Orally administered menstrual drug products for over-the-counter human use. Establishment of a monograph. Federal Register. 1982;47(235):55076-55101.
- US Food and Drug Administration (FDA). Orally administered menstrual drug products for over-the-counter human use. Tentative final monograph. Federal Register. 1988;53(221):46194-46202.
- US Food and Drug Administration (FDA). Status of certain additional over-the counter drug Category II and III active ingredients. Notice of proposed rulemaking. Federal Register. 1992;57(165):38568-38575.
- US Food and Drug Administration (FDA). Status of certain additional over-the-counter drug Category II and III active ingredients; Final rule. Federal Register. 1993;58(88):27443-27650.
- Blumenthal M, Busse WR, Goldberg A, et al., eds. The Complete German Commission E Monographs Therapeutic Guide to Herbal Medicines. Austin, TX: American Botanical Council; Boston, MA: Integrative Medicine Communications. 1998.
- United States Pharmacopeial Convention. 28(5) In-process revision: black cohosh. Pharmacopeial Forum. 2001;28(5):1455.
- Mahady GB, Low Dog T, Barrett ML, et al. United States Pharmacopeia review of the black cohosh case reports of hepatotoxicity. Menopause. 2008;15(4 Pt 1):628-638.
- World Health Organization. WHO Monographs on Selected Medicinal Plants Volume 2. Geneva, Switzerland: World Health Organization; 2002.
- Committee on Herbal Medicinal Products (HMPC). European Union herbal monograph on Cimicifuga racemosa (L.) Nutt., rhizoma. London, UK: European Medicines Agency; 2018.
- US Food and Drug Administration. 21 CFR Part 111 Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements; Final Rule. Federal Register. 2007;72(121):34752-34958.
- Natural and Non-prescription Health Products Directorate. Monograph: Black Cohosh. Ottawa, Ontario: Health Canada; 2008.
- Harnischfeger G, Stolze H. Bewährte Wirksubstanzen aus Naturstoffen - Traubensilberkerze. Notebene Medici. 1980;10:446-450.
- He K, Pauli GF, Zheng B, et al. Cimicifuga species identification by high performance liquid chromatography–photodiode array/mass spectrometric/evaporative light scattering detection for quality control of black cohosh products. J Chromatogr A. 2006;1112(1):241-254.
- Bedir E, Khan IA. Cimiracemoside A: a new cycloanostanol xyloside from the rhizome of Cimicifuga racemosa. Chem Pharm Bull (Tokyo). 2000;48(3):425-427.
- Jarry H, Gorkow C, Wuttke W. Treatment of Menopausal Symptoms with Extracts of Cimicifuga racemosa: In vivo and in vitro Evidence for Estrogenic Activity. In: Loew D, Rietbrock N, eds. Phytopharmaka in Forschung und klinischer Anwendung. Heidelberg, Germany: Steinkopff; 1995:99-112.
- Kennelly EJ, Baggett S, Nuntanakorn P, et al. Analysis of thirteen populations of black cohosh for formononetin. Phytomedicine. 2002;9(5):461-467.
- Struck D, Tegtmeier M, Harnischfeger G. Flavones in extracts of Cimicifuga racemosa. Planta Med. 1997;63(3):289.
- McCoy J, Kelly W. Survey of Cimicifuga racemosa for phytoestrogenic flavonoids. In: Book of Abstracts, 212th ACS National Meeting. Orlando, FL: American Chemical Society. 1996.
- Onorato J, Henion JD. Evaluation of triterpene glycoside estrogenic activity using LC/MS and immunoaffinity extraction. Anal Chem. 2001;73(19):4704-4710.
- Beck V, Unterrieder E, Krenn L, Kubelka W, Jungbauer A. Comparison of hormonal activity (estrogen, androgen and progestin) of standardized plant extracts for large scale use in hormone replacement therapy. J Steroid Biochem Mol Biol. 2003;84(2):259-268.
- Takahira M, Kusano A, Shibano M, Kusano G, Miyase T. Piscidic acid and fukiic acid esters from Cimicifuga simplex. Part 24 in the series “Constituents of Cimicifuga spp.”, and Part 2 in the series “Phenolics of Cimicifuga spp.” Phytochemistry. 1998;49(7):2115-2119.
- Takahira M, Kusano A, Shibano M, et al. Three new fukiic acid esters, cimicifugic acids A, B and C, from Cimicifuga Simplex WORMSK. Chem Pharm Bull. 1998;46(2):362-365.
- Jarry H, Harnischfeger G, Düker E. Untersuchungen zur endokrinen Wirksamkeit von Inhaltsstoffen aus Cimicifuga racemosa 2. In vitro-Bindung von Inhaltsstoffen an Östrogenrezeptoren. Planta Med. 1985;51(04):316-319.
- Düker E-M, Kopanski L, Jarry H, Wuttke W. Effects of extracts from Cimicifuga racemosa on gonadotropin release in menopausal women and ovariectomized rats. Planta Med. 1991;57(05):420-424.
- Warnecke G. Beeinflussung klimakterischer Beschwerden durch ein Phytotherapeutikum. Med Welt. 1985;36:871-874.
- Stoll W. Phytotherapeutikum beeinflusst atrophisches Vaginalepithel, Doppelblindversuch Cimicifuga vs Ostrogenpraparat. Therapeutikon. 1987;1:23-31.
- Wade C, Kronenberg F, Kelly A, Murphy PA. Hormone-modulating herbs: implications for women’s health. J Am Med Womens Assoc. 1999;54(4):181-183.
- Holt S. Natural approaches to promote sexual function. Part 2: Stimulants and dietary supplements. Altern Complement Ther. 1999;5(5):279-285.
- Bodinet C, Freudenstein J. Influence of marketed herbal menopause preparations on MCF-7 cell proliferation. Menopause. 2004;11(3):281-289.
- Mahady GB. Is black cohosh estrogenic? Nutr Rev. 2003;61(5):183-186.
- Viereck V, Gründker C, Friess SC, et al. Isopropanolic extract of black cohosh stimulates osteoprotegerin production by human osteoblasts. J Bone Miner Res. 2005;20(11):2036-2043.
- Stromeier S, Petereit F, Nahrstedt A. Phenolic esters from the rhizomes of Cimicifuga racemosa do not cause proliferation effects in MCF-7 cells. Planta Med. 2005;71(06):495-500.
- Morris K, Look RM, Hudson V, Toth-Fejel S, Pommier R. The efficacy and safety of black cohosh for managing menopausal symptoms in breast cancer survivors. Breast Cancer Res Treat. 2003;82(Suppl. 1):S159.
- Hostanska K, Nisslein T, Freudenstein J, Reichling J, Saller R. Cimicifuga racemosa extract inhibits proliferation of estrogen receptor-positive and negative human breast carcinoma cell lines by induction of apoptosis. Breast Cancer Res Treat. 2004;84(2):151-160.
- Seidlová-Wuttke D, Wuttke W. Dermal application of a Cimicifuga racemosa (CR)-containing cream has beneficial effects on acne. Eur J Integr Med. 2008;1:40.
- Nesselhut T, Liske E. Pharmacological measures in postmenopausal women with an isopropanolic aqueous extract of Cimicifugae Racemosae Rhizoma: P-8. Menopause. 1999;6(4):331.
- Boblitz N, Liske E, Wüstenberg P. Traubensilberkerze – Wirksamkeit, Wirkung und Sicherheit von Cimicifuga racemosa in der Gynäkologie. Dtsch Apoth Ztg. 2000;140:2833–2838.
- Jacobson JS, Troxel AB, Evans J, et al. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol. 2001;19(10):2739-2745.
- Liske E, Hänggi W, Zepelin H-HH-v, Boblitz N, Wüstenberg P, Rahlfs VW. 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. 2002;11(2):163-174.
- Hernández Muñoz G, Pluchino S. Cimicifuga racemosa for the treatment of hot flushes in women surviving breast cancer. Maturitas. 2003;44(Suppl. 1):S59-S65.
- Pockaj BA, Loprinzi CL, Sloan JA, et al. Pilot evaluation of black cohosh for the treatment of hot flashes in women. Cancer Investig. 2004;22(4):515-521.
- Nappi R, Malavasi B, Brundu B, Facchinetti F. Efficacy of Cimicifuga racemosa on climacteric complaints: A randomized study versus low-dose transdermal estradiol. Gynecol Endocrinol. 2005;20(1):30-35.
- Fischer J. Cimicifuga racemosa Extrakt (Remifemin®) bei Mamma-Ca-Patientinnen mit klimakterischen Beschwerden unter hormontherapeutischer Behandlung mit Tamoxifen - eine Anwendungsbeobachtung. Freiburg i.Br., Albert-Ludwigs-Universität; 2006.
- Pockaj BA, Gallagher JG, Loprinzi CL, et al. Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG Trial N01CC1. J Clin Oncol. 2006;24(18):2836-2841.
- Rauš K, Brucker C, Gorkow C, Wuttke W. First-time proof of endometrial safety of the special black cohosh extract (Actaea or Cimicifuga racemosa extract) CR BNO 1055. Menopause. 2006;13(4):678-691.
- Zepelin H-HH-v, Meden H, Kostev K, Schröder-Bernhardi D, Stammwitz U, Becher H. Isopropanolic black cohosh extract and recurrence-free survival after breast cancer. Int J Clin Pharmacol Ther. 2007;45(3):143-154.
- Hirschberg AL, Edlund M, Svane G, Azavedo E, Skoog L, von Schoultz B. An isopropanolic extract of black cohosh does not increase mammographic breast density or breast cell proliferation in postmenopausal women. Menopause. 2007;14(1):89-96.
- Ruhlen RL, Haubner J, Tracy JK, et al. Black cohosh does not exert an estrogenic effect on the breast. Nutr Cancer. 2007;59(2):269-277.
- Rostock M, Fischer J, Mumm A, Stammwitz U, Saller R, Bartsch HH. Black cohosh (Cimicifuga racemosa) in tamoxifen-treated breast cancer patients with climacteric complaints – a prospective observational study. Gynecol Endocrinol. 2011;27(10):844-848.
- Reed SD, Newton KM, LaCroix AZ, Grothaus LC, Ehrlich K. Night sweats, sleep disturbance, and depression associated with diminished libido in late menopausal transition and early postmenopause: baseline data from the Herbal Alternatives for Menopause Trial (HALT). Am J Obstet Gynecol. 2007;196(6):593.e591-593.e597.
- 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. 2006;13(2):185-196.
- Liske E. Therapeutic efficacy and safety of Cimicifuga racemosa for gynecologic disorders. Adv Ther. 1998;15(1):45-53.
- Reame NE, Lukacs JL, Padmanabhan V, Eyvazzadeh AD, Smith YR, Zubieta J-K. Black cohosh has central opioid activity in postmenopausal women: evidence from naloxone blockade and positron emission tomography neuroimaging. Menopause. 2008;15(5):832-840.
- . Seidlová-Wuttke D, Wuttke W. Selective estrogen receptor modulator activity of Cimicifuga racemosa extract: Clinical data. Phytomedicine. 2000;7(Suppl. II):SL-9a.
- Garcia De Arriba S, Pickartz S, Naser B, Nolte KU. P139: Cimicifuga racemosa for treatment of vasomotor symptoms: update of mode of action. In: Abstracts for 15th World Congress on Menopause. Climacteric. 2016;19(sup1):89.
- Fritz H, Seely D, McGowan J, et al. Black cohosh and breast cancer: a systematic review. Integr Cancer Ther. 2014;13(1):12-29.
- Drewe J, Bucher KA, Zahner C. A systematic review of non-hormonal treatments of vasomotor symptoms in climacteric and cancer patients. SpringerPlus. 2015;4(1):65.
- Zepelin H-HH-v. 60 years of Cimicifuga racemosa medicinal products. Clinical research milestones, current study findings and current development. Wien Med Wochenschr. 2017;167(7):147-159.
- Pethö A. Umstellung einer Hormonbehandlung auf ein pflanzliches Gynäkologikum möglich? Ärztliche Praxis - Zeitung des Arztes in Klinik und Praxis. 1987;47(Sonderdruck XXXIX):1551-1553.
- Lehmann-Willenbrock B, Reidel HH. Klinische und endokrinologische Untersuchungen zur Therapie ovarieller Ausfallserscheinungen nach Hysterektomie unter Belassung der Adnexe. Zentralbl Gynakol. 1988;110(10):611-618.
- Georgiev DB, Iordanova E. Phytoestrogens - The alternative approach. Maturitas. 1996;27(Suppl 1):213 (abstract P309).
- Mielnik J. Extract of Cimicifuga racemosa in the treatment of neurovegetative symptoms in women in the perimenopausal period. Maturitas. 1996;27(Suppl 1):215 (abstract P 318).
- Wuttke W, Seidlová-Wuttke D, Gorkow C. The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: effects on menopause symptoms and bone markers. Maturitas. 2003;44(Supplement):S67-S77.
- Osmers R, Friede M, Liske E, Schnitker J, Freudenstein J, Zepelin HH-H-v. Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms. Obstet Gynecol. 2005;105(5):1074-1083.
- Schmidt M, Käufeler R, Polasek W. Wirksamkeit und Sicherheit von Traubensilberkerze (Cimicifuga racemosa, Cimifemin®) bei Menopausebeschwerden: Therapiebeobachtung unter Praxisbedingungen. J Menopause. 2005;12(1):27-32.
- Vermes G, Bánhidy F, Acs N. The effects of remifemin on subjective symptoms of menopause. Adv Ther. 2005;22(2):148-154.
- Frei-Kleiner S, Schaffner W, Rahlfs VW, Bodmer C, Birkhäuser M. Cimicifuga racemosa dried ethanolic extract in menopausal disorders: a double-blind placebo-controlled clinical trial. Maturitas. 2005;51(4):397-404.
- Brattström A. Dosisabhängige Überlegenheit eines neu entwickelten Cimicifuga Extraktes (Ze 450). Eine doppelblinde, randomisierte und Plazebo kontrollierte klinische Studie bei menopausalen Beschwerden. Kongressband Phytopharmaka Phytotherapie. 2005:6.
- Kaiser WD, Martin R, Schellenberg R, Schrader E, Saller R. Cimicifuga-racemosa-Extrakt ZE 450 bei Wechseljahrsbeschwerden Praxisstudie. Ars Medici. 2008;17:771-774.
- Schellenberg R, Saller R, Hess L, et al. Dose-dependent effects of the Cimicifuga racemosa extract Ze 450 in the treatment of climacteric complaints: a randomized, placebo-controlled study. Evid Based Complement Alternat Med. 2012;2012(Article ID 260301):10 pages.
- Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: A randomized trial. Ann Intern Med. 2006;145(12):869-879.
- Reed SD, Newton KM, LaCroix AZ, Grothaus LC, Grieco VS, Ehrlich K. Vaginal, endometrial, and reproductive hormone findings: randomized, placebo-controlled trial of black cohosh, multibotanical herbs, and dietary soy for vasomotor symptoms: the Herbal Alternatives for Menopause (HALT) Study. Menopause. 2008;15(1):51-58.
- Briese V, Stammwitz U, Friede M, Zepelin H-HH-v. Black cohosh with or without St. John’s wort for symptom-specific climacteric treatment—Results of a large-scale, controlled, observational study. Maturitas. 2007;57(4):405-414.
- Lopatka L, Totzke U, Schmid A, Käufeler R. Die Traubensilberkerze in der Behandlung menopausaler Beschwerden - Ergebnisse einer Therapiebeobachtung mit Cimifemin® uno. J Menopause. 2007;14(2):16-21.
- Bai W, Zepelin H-HH-v, Wang S, et al. Efficacy and tolerability of a medicinal product containing an isopropanolic black cohosh extract in Chinese women with menopausal symptoms: A randomized, double blind, parallel-controlled study versus tibolone. Maturitas. 2007;58(1):31-41.
- Oktem M, Eroglu D, Karahan HB, Taskintuna N, Kuscu E, Zeyneloglu HB. Black cohosh and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized trial. Adv Ther. 2007;24(2):448-461.
- Geller SE, Shulman LP, van Breemen RB, et al. Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trial. Menopause. 2009;16(6):1156-1166.
- Amsterdam JD, Yao Y, Mao JJ, Soeller I, Rockwell K, Shults J. Randomized, double-blind, placebo-controlled trial of Cimicifuga racemosa (black cohosh) in women with anxiety disorder due to menopause. J Clin Psychopharmacol. 2009;29(5):478-483.
- Li Y, Cui M, Gao S. Efficacy of Remifemin for control of climacteric symptoms. (Article in Chinese). Progr Obstet Gynecol. 2011;20:462-465.
- Drewe J, Zimmermann C, Zahner C. The effect of a Cimicifuga racemosa extracts Ze 450 in the treatment of climacteric complaints – an observational study. Phytomed. 2013;20(8):659-666.
- Mohammad-Alizadeh-Charandabi S, Shahnazi M, Nahaee J, Bayatipayan S. Efficacy of black cohosh (Cimicifuga racemosa L.) in treating early symptoms of menopause: a randomized clinical trial. Chin Med. 2013;8(1):20.
- Shahnazi M, Nahaee J, Mohammad-Alizadeh-Charandabi S, Bayatipayan S. Effect of black cohosh (Cimicifuga racemosa) on vasomotor symptoms in postmenopausal women: a randomized clinical trial. J Caring Sci. 2013;2(2):105-113.
- Gafner S. Botanical adulterants bulletin on adulteration of Actaea racemosa. Botanical Adulterants Bulletin. 2016.
- Foster S. Exploring the peripatetic maze of black cohosh adulteration: a review of the nomenclature, distribution, chemistry, market status, analytical methods, and safety. HerbalGram. 2013(98):32-51. Available at: http://herbalgram.org/resources/herbalgram/issues/98/table-of-contents/hg98feat-blackcohosh/. Accessed February 17, 2019.
- Gafner S. Black Cohosh Laboratory Guidance Document. Austin, TX: ABC-AHP-NCNPR Botanical Adulterants Program; 2015.
- US Fish and Wildlife Service. Conference of the Parties to the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES); Twelfth Regular Meeting; proposed resolutions, decisions, and agenda items being considered; taxa being considered for amendments to the CITES Appendices. Federal Register. 2002;67(75):19207-19235.
- United Plant Savers. Species At-Risk. 2018. Available at: www.unitedplantsavers.org/species-at-risk. Accessed April 21, 2018.