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Exploring the Peripatetic Maze of Black Cohosh Adulteration: A Review of the Nomenclature, Distribution, Chemistry, Market Status, Analytical Methods, and Safety
ISSUE:
Page:
32-51

Summary

Black cohosh root and rhizome and their preparations (Actaea racemosa, syn. Cimicifuga racemosa; Ranunculaceae) have been of considerable international market, scientific, and consumer interest for more than 60 years, particularly during the last 15 years in the United States. The increased market demand, nomenclatural confusion of related North American and Asian species, along with case reports of liver toxicity associated with products labeled as black cohosh, have led to both suspicion of and actual identification of economic adulteration of black cohosh commercial supplies. From the mid-1950s through the 1990s, a voluminous body of literature on black cohosh was published based on market experience and clinical use of black cohosh in Germany. Since the late-1990s, a significant body of new analytical chemical, pharmacognostic, pharmacological, and clinical scientific literature has been published relative to the identity, pharmacology, toxicology, and clinical applications of black cohosh. In 1999, the Department of Medicinal Chemistry and Pharmacognosy at the College of Pharmacy, University of Illinois - Chicago (UIC), under the direction of the late Norman R. Farnsworth, PhD, received funding from US National Institutes of Health (NIH) to establish the Center for Botanical Dietary Supplements Research. The emphasis of the Center’s research focused on botanical dietary supplements that may improve women’s health, especially in the areas of menopause, premenstrual syndrome and persistent urinary tract infections. Black cohosh became one of the Center’s primary research subjects. That collective research serves as a model for overcoming challenges associated with research on botanicals (as dietary supplements), including acquiring and identifying plant species, isolating and identifying active constituents, elucidating mechanisms of action, and conducting phase I and phase II clinical studies.1 Research interest in black cohosh also was emphasized by many other research groups, such as the group led by Edward J. Kennelly, PhD, at the Department of Biological Sciences, Lehman College and the Graduate Center, City University of New York, and others too numerous to name. In addition, various herb companies, commercial analytical laboratories, trade organizations, non-governmental organizations, and regulatory agencies have focused on contributing to the general knowledge and understanding of all aspects of black cohosh. This article reviews issues associated with the complexities of black cohosh adulteration, including botanical and nomenclatural considerations; trade and economic issues; various identification, analytical, and authentication challenges; alleged liver toxicity linked to adulterated products; and other data on economic adulteration of products labeled as black cohosh.

Introduction

The root and rhizome of black cohosh are sold as whole, semi-whole, chopped, cut and sifted, dry powders, and liquid and dry extracts. They are widely available in dietary supplement and phytomedicinal formulations in the United States, Canada, Europe, Australia, and elsewhere. In modern phytotherapy, black cohosh preparations are used primarily for the treatment of menopausal symptoms, including hot flashes, heart palpitations, nervousness, irritability, sleep disturbances, tinnitus, vertigo, excessive perspiration, and depressive states associated with menopause, as well as for premenstrual discomfort and painful menstruation.2 Historically, the botanical was specifically considered to have an affiliation with the nervous system and uterus, and was used for a host of nervous system disorders and as a uterine tonic and antispasmodic.3

Product forms with the most market experience and evaluation in clinical studies are Remifemin®, an oral formulation, standardized to triterpene glycosides, of an isopropanolic black cohosh extract,4 and Menopret® (Klimadynon®), an ethanolic extract. Remifemin has been manufactured by Schaper & Brümmer GmbH & Co. KG (Salzgitter-Ringelheim, Germany) since 1956. Bionorica (Neumarkt, Germany) produces Menopret (Klimadynon).5*

Black cohosh raw materials and their extracts are widely known in the herb industry to be adulterated with related species of Actaea (syn. Cimicifuga) from China. The American Herbal Products Association (AHPA) provides information and links to analytical tools and methods to help identify adulteration of raw materials and ingredients through its Botanicals Authentication Program6 and its Known Adulterants recommendations incorporated into AHPA’s Guidance Policies.7 According to AHPA, “The economic adulteration of black cohosh root and rhizome with other species is well established.”8

A detailed microscopic identification of A. racemosa as well as closely related species are provided by the American Herbal Pharmacopoeia (AHP) in its recently published Microscopic Characterizations of Botanical Medicines (CRC Press, 2011).3 AHP also published a comprehensive review of quality control and authentication specifications of black cohosh and its adulterants in its Black Cohosh Rhizome monograph (2002), which provides comprehensive guidance on known adulterants that includes the botanical, microscopic, and chemical analyses of black cohosh.9

Botanical, Taxonomic and Nomenclatural Considerations

The genus Actaea includes 28 species from the Northern Hemisphere.10 Compton et al.11-13 analyzed morphological and genetic data and supported the combination of the genus concepts of Actaea, Cimicifuga, and Souliea — essentially reverting to Linnaeus’s 1753 concept of the genus Actaea. Previously, the major morphological basis for separating Cimicifuga from Actaea was fruit type. Actaea has a berry-like fruit and Cimicifuga has a dry follicle.

Black cohosh is an erect, smooth-stemmed perennial that grows from four-to-eight feet (75-250 cm) in height. The large, alternate, triternately compound leaves are borne on short, clasping petioles. The ovate, acute leaflets, two-to-three inches (3-8 cm) in length, are thin, smooth, and two-to-three-lobed with sharply double-serrate margins. The long, wand-like, white inflorescence, about one inch (2.5 cm) in diameter, are borne on a terminal branching spike-like raceme. The main feature of the flowers are the numerous showy stamens, consisting of slender filaments with white anthers. Four or five small, concave, greenish-white sepals are larger than the nearly inconspicuous, stamen-like petals. The solitary white pistil is smooth to somewhat pubescent and sessile (attached at the base without a stalk or petiole). The fruit is a dry, oval-ribbed follicle that splits along a ventricle suture with eight-to-10 triangular brown seeds in two rows. In the southern United States, it begins blooming in mid-to-late June. Toward the northern part of its range, blooming begins as late as early August.14

Voucher Specimens and Identification

Bennett and Balick (2008) emphasize the fact that in the field of medicinal plant research, unless a plant can be unambiguously identified, reproducibility — the fundamental underpinning of science — is uncertain. To aid reproducibility, a preserved herbarium specimen to which the correct scientific name has been applied should be deposited in a properly curated collection. Two common problems, they note, are the frequent misuse of binomials in medicinal plant publications, and the lack of author citations for binomials. In a PubMed search of 100 titles or abstracts on medicinal plants, they found that 20% contained errors in the botanical name, emphasizing that the misspelling of binomials is an inexcusable error.15 For example, a PubMed search for the misspelled “Actea” (rather than the correctly spelled Actaea) retrieves three citations.

A practice in the medicinal plant literature, which is often not followed, is that every study should reference the relevant scientific specimen and indicate where the specimen is curated for reference. The voucher itself is more important than the correct identification, as an erroneous scientific name attributed to a voucher can be corrected or amended at a later date.

In accordance with the International Code of Botanical Nomenclature, there is only one accepted scientific name for a taxon. However, Bennett and Balick use black cohosh as a well-known example to which synonyms are applied. The choice of the scientific name depends on the interpretation of taxonomic data by a given specialist. For example, in the treatment of the Ranunculaceae (buttercup family) in Flora of North America, separation of the genera Actaea and Cimicifuga is maintained.16,17

Similarly, in the 2001 treatment of the Ranunculaceae in Flora of China, Actaea, Cimicifuga, and Souliea18-20 are treated separately with the caveat, “Elsewhere (Compton et al., Taxon 47:593-634. 1998), Cimicifuga has been transferred to Actaea. However, for the present account, as in FRPS [Flora Reipublicae Popularis Sinicae], one of us (Li) prefers to maintain Cimicifuga as distinct.”19

In the case of black cohosh and its relatives, researchers must be cognizant of relevant synonyms in retrieving scientific papers published in the last 15 years.

Plant names associated with black cohosh and its relatives are easily confused in the scientific literature. Some research groups refer to studied species under the taxonomic concept of Cimicifuga, while others embrace the broader generic concept of Actaea as defined by Compton and colleagues in their 1998 reclassification.12 The practical application of the taxonomy is not as easy as simply replacing the genus name “Actaea” for “Cimicifuga” when referring to species under either genus name.

For example, C. Ma et al. (2011) provide methods for authentication and differentiation of Actaea species using high-performance liquid chromatography (HPLC) coupled with electrospray ionization time-of-flight mass spectrometry (HPLC-TOF-ESI-MS). The study states that in addition to A. racemosa, there are eight more North American species of Actaea. However, the authors include both A. podocarpa and “A. americana,” the latter a synonym of no botanical standing for A. podocarpa. Actaea podocarpa formerly was known as Cimicifuga americana, and it appears that in this case the genus name “Actaea” was erroneously substituted for Cimicifuga. Fortunately, the chemical profiles for A. podocarpa and the purported “A. americana” in the study are virtually identical. Therefore, there are only eight North American Actaea species, rather than nine, as suggested by C. Ma et al.21

Furthermore, when exploring the historical record, the reader should be aware of additional nomenclature complexities. The genus name “Macrotrys,” established by C.S. Rafinesque in 1808 as a new designation for Cimicifuga racemosa, was subsequently misspelled “Macrotys” (omitting the second “r”) in several of the eight editions of the popular Manual of Botany by Amos Eaton (1776-1842), published from 1817-1840, and widely used as a standard field reference until the mid-19th century. Black cohosh was adopted as a drug by the Eclectic medical movement in the mid-19th century, and the Eclectics nearly universally referred to the drug under the misspelled genus name “Macrotys,” perpetuating the error of Eaton. The common name black cohosh did not come into widespread use until the late 19th century. Macrotys and black snakeroot were widely used as common names for black cohosh until about 1900.14,22

Comments on Names of Source Plants of Chinese Extracts

Various Chinese species of Actaea are source plants of the traditional Chinese medicine sheng-ma (shengma). Three Actaea/Cimicifuga species are official source plants of sheng-ma: A. heracleifolia (C. heracleifolia, aka da-san-ye sheng-ma), A. dahurica (C. dahurica, C. dahurica var. simplex, aka xin-gan sheng-ma), and A. cimicifuga (C. foetida, aka sheng-ma). Actaea simplex (A. cimicifuga var. simplex, C. simplex, C. foetida var. simplex) is known as ye-sheng-ma.

Actaea simplex is the most commonly cultivated Asian species related to black cohosh in American horticulture and an excellent example of the confused nomenclature of black cohosh relatives in commercial trade, extending beyond sourcing of botanical dietary supplement ingredients. Actaea simplex is known by numerous botanical synonyms, including “Cimicifuga ramosa,” which is not a misspelling of “C. racemosa.” “Cimicifuga ramosa” cultivars are widely available as perennials in American horticulture, particularly selections in the “atropurpurea group” which have purple-to-bronze foliage. Cultivar names are expressed as the scientific name, followed by the cultivar designation enclosed in single quotes. For example, one cultivar is Cimicifuga ramosa ‘James Compton,’ named for botanist and taxonomist James Compton, PhD, recent monographer of the genus Actaea.12 To further confuse matters, many nurseries offer “Actaea ramosa” bronze-foliage cultivars, even though the name “Actaea ramosa” never was published as a scientific name for any plant. Here, the genus name “Actaea” simply has been used to replace the genus name Cimicifuga with no attempt to determine the correct botanical name for the plant at hand. A simple Google search for “Cimicifuga ramosa” will return numerous sites listing bronze-foliaged cultivars of A. simplex as “Cimicifuga racemosa” or “Actaea ramosa.” This example is highly indicative of the confused understanding and application of binomials in the Actaea/Cimicifuga genus nomenclatural complex.

The root of Vernonia aspera (Asteraceae; also known as roughleaf ironweed) is an obscure Chinese folk medicine known as hei-sheng-ma,23 which translates to “black cohosh” (hei=black). It occurs on open grassy slopes in mountains above 3,000 feet in south China (Guizhou, Hainan, and Yunnan provinces), as well as India, Laos, Myanmar, Nepal, Thailand, and Vietnam, and is known by at least 12 botanical synonyms in six genera.24,25 A PubMed search using all 13 names in the botanical literature returned no results on scientific studies published on Vernonia aspera or any of the synonyms. This author located no reference to Vernonia aspera in any of the chemical analytical studies on Actaea/Cimicifuga adulteration. There is a virtual dearth of scientific literature on Vernonia aspera, yet multiple listings as a source plant of “black cohosh extract” on wholesale Chinese websites are common. Is the plant actually used as a base-material for extract, spiked with triterpenes to make it appear to be a black cohosh extract? Or is this simply yet another case of confused nomenclature lost in translation from Chinese to English on Internet sites?

The AHP monograph on black cohosh makes reference to guang-dong sheng-ma as a common substitute for sheng-ma in the Asian market.9 Serratula chinensis (Chinese sawwort root, syn. Rhaponticum chinense, Centaurea missionis; Asteraceae) is found on grassy slopes, thickets, and forest edges in western Anhui, Fujian, southeast Gansu, north and northeast Guangdong, Guizhou, Henan, Hubei, Hunan, Jiangsu, Jiangxi, south Shaanxi, Sichuan, Yunnan, and south Zhejiang provinces in China.26 According to Professor De-An Guo, PhD, director of the Shanghai Center for Traditional Chinese Medicine Modernization, hei sheng-ma also refers to Serratula chinensis, which may be collected by Chinese exporters since it has the same name (in Chinese) as black cohosh. He noted that as far as he can determine, there is no commercial cultivation of A. racemosa in China (personal communication to S. Foster and M. Blumenthal, March 25, 2013). The scientific literature on Serratula chinensis also is exceedingly sparse. A PubMed search retrieved only one citation — a 2007 study in which Ling et al. reported on the isolation and structure of a new cerebroside from the species, the first report of the occurrence of cerebrosides in the genus Serratula.27

The sheer volume of offerings, prices ranges, varied specifications, and differing species listed as “black cohosh extract” from Chinese sources require that the daunted buyer attempting to source black cohosh work closely with a qualified analytical lab to authenticate black cohosh extracts before securing any supply source.

Sampling of Names from Chinese Wholesale “Black Cohosh Extract Sources

According to the nomenclature reference AHPA’s Herbs of Commerce,28 the only acceptable species to which the common name “black cohosh” applies is Actaea racemosa (syn. Cimicifuga racemosa). Herbs of Commerce is formally recognized in Title 21 of the US Code of Federal Regulations (CFR)29 as a primary reference for the appropriate labeling of herbal products in the US, and, therefore, non-compliance with this text — unless otherwise scientifically warranted — is a violation of dietary supplement good manufacturing practices (GMPs), and other regulations pertaining to product labeling. According to the same text, Chinese species of Actaea (syn. Cimicifuga) are required to be identified by the standard common name “Chinese cimicifuga.” This name is subsequently required in finished-product labeling, thus clearly distinguishing between Asian and North American species contained in a product. Any designation of a botanical material or finished product in the United States by the common name of “black cohosh” on product labels (and presumably in the supply chain) is required to be Actaea racemosa and no other species. To apply the name “black cohosh” to any other species violates the CFR and results in adulteration of the finished product offered to consumers.

Much of the material offered from wholesale sources of Chinese origin appear to be offered as “black cohosh” rather than “Chinese cimicifuga,” as listed in Herbs of Commerce. An Internet search conducted on Google with the simple search phrase “Black Cohosh Wholesale China” led to a first hit at alibaba.com, which returned 2,440 black cohosh herbal extracts on 77 pages. Searching the landing page for “black cohosh root extract”30 returned 1,670 herbal extracts listed on 47 pages. Random price ranges for extracts were between $1.00-$300.00/kg, with ranges of availability from various suppliers offered at as little as a few grams per week up to five tons per week. Several plant species under various correct or incorrect spellings of common and or technical names were listed as the source of “black cohosh extract(s).” For example, “ISO9000 & Kosher certificate black cohosh extract,” 2.5% triterpenoides (HPLC) of “Cimicifuga romose (L) Nutt.” was offered by Sanyuan Jinrui Natural Ingredients Co., Ltd. (Xi’an, Shaanxi, China) at $5-60/kg.31 Hunan Naturalin Bio-Resources Co., Ltd. (Changsa, Hunan, China), offered 2.5% triterpene glycosides “black cohosh extracts” from “Cimicifuga foetida L.”32 Xi’an Aladdin Biological Technology Co., Ltd. (Xi’an, Shaanxi, China) offered “Black Cohosh Extract,” citing the Latin name Vernonia aspera (Roxb.) Buch.-Ham.33 This illustrates the myriad offerings encountered in a simple search and represents random samples of 18 different supply source site links out of 38 suppliers listed on just one of 47 pages returned on the alibaba.com website search of “black cohosh root extract.” The names mentioned above — “Cimicifuga romose,” Cimicifuga foetida, and Vernonia aspera — were observed on more than one page in this very limited random sample. A follow-up search for “Cimicifuga romose” (an apparent and often repeated misspelling) returned a list of 387 products from 53 suppliers.34 A search for “Cimicifuga foetida” returned 121 products from 24 suppliers, most of which also called the products offered “black cohosh extract.”35 A follow-up search of “Vernonia aspera extract” returned a list of 17 products from 11 suppliers.36 In all 17 instances, the name “Vernonia aspera extract” was associated with products labeled as “black cohosh extract.” As stated, none of the aforementioned Chinese species are acceptable as “black cohosh” and clearly are represented as adulterated products under Title 21 of the CFR.

The Price of Authentic North American Black Cohosh

Price differences between authenticated North American black cohosh and Chinese species sold labeled as “black cohosh” provide the obvious incentive for economic adulteration. Estimates suggest that between 300,000-380,000 lbs (136,078-172,365 kg) of wild-harvested crude, dried, whole black cohosh root enter the wholesale trade from the US (as of the 2011 season) with prices from supplier/dealer to manufacturers/processors ranging from $4.50-$7.50/lb ($9.92-$16.54/kg). Some cultivated material is sold in small lots, mostly to small manufacturers at about $8.00/lb ($17.80/kg), but is not believed to represent a significant percentage of the wholesale black cohosh supply. (Fletcher E., email to S. Foster and M. Blumenthal, April 2-5, 2013).

Cultivated wholesale black cohosh root for the medicinal herb trade is not economically feasible to produce, at least not at the present time. The time frame for growth from seed to production of roots of large enough size for the medicinal market is estimated at six-to-eight years, which would require at least doubling and perhaps tripling the price compared with wild-harvested material to recoup the investment in time and inputs. At this point, cultivated material — compared with the relative abundance and much lower price of wild-harvested material — provides little incentive to commercial growers except in vertically integrated operations with a desire or need to control supply sources. (Fletcher E., email to S. Foster and M. Blumenthal, April 2-5, 2013).

Chinese sources sell powdered material or extract to the US market, rather than crude raw material. Authenticated black cohosh extract at $50.00/kg can be expected to be three-to-four times the price of Chinese-supplied extract (averaging around $15.00/kg), depending upon quantities. Prices paid for Chinese-supplied black cohosh ranged from $6-$8.50/kg (including shipping) while US-supplied black cohosh ranges from $14.50-$16.50/kg. Obviously, prices vary considerably based on root quality, form (whole, cut, powdered), and quantities purchased, but the overall trend shows an economic adulteration incentive with the price of Chinese material running at about 25-30 percent, or in some cases, much less, of that of authenticated black cohosh in wholesale trade (Fletcher E., email to S. Foster and M. Blumenthal, April 2-5, 2013; Wanzer C., email to M. Blumenthal, April 4 and 5, 2013).

Habitat and Conservation

Black cohosh occurs in moist, mixed deciduous eastern North American forests and forest margins, often in mountainous terrain from Massachusetts south to Georgia, west to northwest and north central Arkansas and the adjacent Ozarks of Missouri, north through the Ohio River Valley to southern Ontario. Although not of significant conservation concern at the national level, at the extremities of the plant’s natural range it may be considered rare at the state level.

Conservation concerns expressed by various groups including the US National Park Service, World Wildlife Fund, United Plant Savers, and others prompted the US Fish and Wildlife Service (USFWS) to request information and recommendations for species to consider for changes to CITES (Convention on International Trade in Endangered Species of Wild Fauna and Flora) in the US Federal Register in June of 2001.37 At the time, USFWS was considering recommending black cohosh for a CITES Appendix II listing, which may have monitored and/or restricted black cohosh in international trade.

AHPA responded to the USFWS request for information with a detailed commentary on the suspected over-harvest of black cohosh root for export.38 Subsequently, USFWS published a notice in the Federal Register in April of 2002 stating that it would not seek an Appendix II listing, but that it intended to review and consider listing US native species of Cimicifuga (Actaea) in Appendix III.39 CITES Appendix III includes species listed by one member country in which assistance in controlling trade is sought from other CITES Parties, in which case trade would be permitted only among CITES Parties if the member country that listed the species issued an appropriate export permit and certificate of origin. However, no action was taken at the CITES Conference of the Parties (COP 12) held in Santiago, Chile, in November of 2002. As of March 2006, active consideration to list black cohosh and its relatives was withdrawn by the USFWS, though the agency has been monitoring and will continue to monitor status.40

The information provided by AHPA in response to the initial request for information and recommendations appears largely responsible for the lack of action taken to list black cohosh to a CITES Appendix. In the past decade, Remifemin-manufacturer Schaper & Brümmer GmbH & Co. KG has established large-scale commercial production of black cohosh in Germany in order to better control and secure its supply source. The company’s production quantity is unknown and not reflected in trade data, though this commercial production may contribute to an overall trend of stabilization in wild-harvested tonnage and decreased conservation concerns from wild harvest.

Ed Fletcher of Strategic Sourcing Inc., an experienced trader and consultant on North American medicinal plants and a supplier of wild-harvested and cultivated black cohosh rhizomes/roots, observes that habitat depletion is the most detrimental factor to current wild populations of black cohosh. He believes that managed stands of wild black cohosh regenerate adequately to be self-sustaining. Population sustainability is achieved in part by high seed production in wild populations and relatively high germination rates, which helps to ensure the ability of populations to recover from harvest impacts (personal communication, September 6, 2011).

Trade Data on Black Cohosh

In a detailed analysis of black cohosh rhizome trade from the US, Brinckmann (2010)41 provided information on production scenarios, conservation status, trade volume, and market prices, along with information on quality expectations and pharmacopeial definitions. One of the problems in monitoring international trade in black cohosh is that the commodity does not have a unique 10-digit tariff code assigned to it under the Harmonized Tariff Schedule of the United States (HTSUS). The only estimates of annual trade volume and percentage of cultivated and wild-harvested black cohosh come from AHPA’s annual tonnage surveys of member companies that are primary raw material producers (direct buyers from point of origin) with data on up to 26 wild-harvested botanical commodities collected from 1997 to 2010 (Table 1).

 

Retail sales ranking of black cohosh products in the food, drug, and mass market channel as well as the health and natural foods channel in the US have remained relatively stable over the past six years, as reflected in trade data summarized in HerbalGram’s annual Herb Market Reports (Tables 2 and 3).

Summary

Black cohosh root and rhizome and their preparations (Actaea racemosa, syn. Cimicifuga racemosa; Ranunculaceae) have been of considerable international market, scientific, and consumer interest for more than 60 years, particularly during the last 15 years in the United States. The increased market demand, nomenclatural confusion of related North American and Asian species, along with case reports of liver toxicity associated with products labeled as black cohosh, have led to both suspicion of and actual identification of economic adulteration of black cohosh commercial supplies. From the mid-1950s through the 1990s, a voluminous body of literature on black cohosh was published based on market experience and clinical use of black cohosh in Germany. Since the late-1990s, a significant body of new analytical chemical, pharmacognostic, pharmacological, and clinical scientific literature has been published relative to the identity, pharmacology, toxicology, and clinical applications of black cohosh. In 1999, the Department of Medicinal Chemistry and Pharmacognosy at the College of Pharmacy, University of Illinois - Chicago (UIC), under the direction of the late Norman R. Farnsworth, PhD, received funding from US National Institutes of Health (NIH) to establish the Center for Botanical Dietary Supplements Research. The emphasis of the Center’s research focused on botanical dietary supplements that may improve women’s health, especially in the areas of menopause, premenstrual syndrome and persistent urinary tract infections. Black cohosh became one of the Center’s primary research subjects. That collective research serves as a model for overcoming challenges associated with research on botanicals (as dietary supplements), including acquiring and identifying plant species, isolating and identifying active constituents, elucidating mechanisms of action, and conducting phase I and phase II clinical studies.1 Research interest in black cohosh also was emphasized by many other research groups, such as the group led by Edward J. Kennelly, PhD, at the Department of Biological Sciences, Lehman College and the Graduate Center, City University of New York, and others too numerous to name. In addition, various herb companies, commercial analytical laboratories, trade organizations, non-governmental organizations, and regulatory agencies have focused on contributing to the general knowledge and understanding of all aspects of black cohosh. This article reviews issues associated with the complexities of black cohosh adulteration, including botanical and nomenclatural considerations; trade and economic issues; various identification, analytical, and authentication challenges; alleged liver toxicity linked to adulterated products; and other data on economic adulteration of products labeled as black cohosh.

Introduction

The root and rhizome of black cohosh are sold as whole, semi-whole, chopped, cut and sifted, dry powders, and liquid and dry extracts. They are widely available in dietary supplement and phytomedicinal formulations in the United States, Canada, Europe, Australia, and elsewhere. In modern phytotherapy, black cohosh preparations are used primarily for the treatment of menopausal symptoms, including hot flashes, heart palpitations, nervousness, irritability, sleep disturbances, tinnitus, vertigo, excessive perspiration, and depressive states associated with menopause, as well as for premenstrual discomfort and painful menstruation.2 Historically, the botanical was specifically considered to have an affiliation with the nervous system and uterus, and was used for a host of nervous system disorders and as a uterine tonic and antispasmodic.3

Product forms with the most market experience and evaluation in clinical studies are Remifemin®, an oral formulation, standardized to triterpene glycosides, of an isopropanolic black cohosh extract,4 and Menopret® (Klimadynon®), an ethanolic extract. Remifemin has been manufactured by Schaper & Brümmer GmbH & Co. KG (Salzgitter-Ringelheim, Germany) since 1956. Bionorica (Neumarkt, Germany) produces Menopret (Klimadynon).5*

Black cohosh raw materials and their extracts are widely known in the herb industry to be adulterated with related species of Actaea (syn. Cimicifuga) from China. The American Herbal Products Association (AHPA) provides information and links to analytical tools and methods to help identify adulteration of raw materials and ingredients through its Botanicals Authentication Program6 and its Known Adulterants recommendations incorporated into AHPA’s Guidance Policies.7 According to AHPA, “The economic adulteration of black cohosh root and rhizome with other species is well established.”8

A detailed microscopic identification of A. racemosa as well as closely related species are provided by the American Herbal Pharmacopoeia (AHP) in its recently published Microscopic Characterizations of Botanical Medicines (CRC Press, 2011).3 AHP also published a comprehensive review of quality control and authentication specifications of black cohosh and its adulterants in its Black Cohosh Rhizome monograph (2002), which provides comprehensive guidance on known adulterants that includes the botanical, microscopic, and chemical analyses of black cohosh.9

Botanical, Taxonomic and Nomenclatural Considerations

The genus Actaea includes 28 species from the Northern Hemisphere.10 Compton et al.11-13 analyzed morphological and genetic data and supported the combination of the genus concepts of Actaea, Cimicifuga, and Souliea — essentially reverting to Linnaeus’s 1753 concept of the genus Actaea. Previously, the major morphological basis for separating Cimicifuga from Actaea was fruit type. Actaea has a berry-like fruit and Cimicifuga has a dry follicle.

Black cohosh is an erect, smooth-stemmed perennial that grows from four-to-eight feet (75-250 cm) in height. The large, alternate, triternately compound leaves are borne on short, clasping petioles. The ovate, acute leaflets, two-to-three inches (3-8 cm) in length, are thin, smooth, and two-to-three-lobed with sharply double-serrate margins. The long, wand-like, white inflorescence, about one inch (2.5 cm) in diameter, are borne on a terminal branching spike-like raceme. The main feature of the flowers are the numerous showy stamens, consisting of slender filaments with white anthers. Four or five small, concave, greenish-white sepals are larger than the nearly inconspicuous, stamen-like petals. The solitary white pistil is smooth to somewhat pubescent and sessile (attached at the base without a stalk or petiole). The fruit is a dry, oval-ribbed follicle that splits along a ventricle suture with eight-to-10 triangular brown seeds in two rows. In the southern United States, it begins blooming in mid-to-late June. Toward the northern part of its range, blooming begins as late as early August.14

Voucher Specimens and Identification

Bennett and Balick (2008) emphasize the fact that in the field of medicinal plant research, unless a plant can be unambiguously identified, reproducibility — the fundamental underpinning of science — is uncertain. To aid reproducibility, a preserved herbarium specimen to which the correct scientific name has been applied should be deposited in a properly curated collection. Two common problems, they note, are the frequent misuse of binomials in medicinal plant publications, and the lack of author citations for binomials. In a PubMed search of 100 titles or abstracts on medicinal plants, they found that 20% contained errors in the botanical name, emphasizing that the misspelling of binomials is an inexcusable error.15 For example, a PubMed search for the misspelled “Actea” (rather than the correctly spelled Actaea) retrieves three citations.

A practice in the medicinal plant literature, which is often not followed, is that every study should reference the relevant scientific specimen and indicate where the specimen is curated for reference. The voucher itself is more important than the correct identification, as an erroneous scientific name attributed to a voucher can be corrected or amended at a later date.

In accordance with the International Code of Botanical Nomenclature, there is only one accepted scientific name for a taxon. However, Bennett and Balick use black cohosh as a well-known example to which synonyms are applied. The choice of the scientific name depends on the interpretation of taxonomic data by a given specialist. For example, in the treatment of the Ranunculaceae (buttercup family) in Flora of North America, separation of the genera Actaea and Cimicifuga is maintained.16,17

Similarly, in the 2001 treatment of the Ranunculaceae in Flora of China, Actaea, Cimicifuga, and Souliea18-20 are treated separately with the caveat, “Elsewhere (Compton et al., Taxon 47:593-634. 1998), Cimicifuga has been transferred to Actaea. However, for the present account, as in FRPS [Flora Reipublicae Popularis Sinicae], one of us (Li) prefers to maintain Cimicifuga as distinct.”19

In the case of black cohosh and its relatives, researchers must be cognizant of relevant synonyms in retrieving scientific papers published in the last 15 years.

Plant names associated with black cohosh and its relatives are easily confused in the scientific literature. Some research groups refer to studied species under the taxonomic concept of Cimicifuga, while others embrace the broader generic concept of Actaea as defined by Compton and colleagues in their 1998 reclassification.12 The practical application of the taxonomy is not as easy as simply replacing the genus name “Actaea” for “Cimicifuga” when referring to species under either genus name.

For example, C. Ma et al. (2011) provide methods for authentication and differentiation of Actaea species using high-performance liquid chromatography (HPLC) coupled with electrospray ionization time-of-flight mass spectrometry (HPLC-TOF-ESI-MS). The study states that in addition to A. racemosa, there are eight more North American species of Actaea. However, the authors include both A. podocarpa and “A. americana,” the latter a synonym of no botanical standing for A. podocarpa. Actaea podocarpa formerly was known as Cimicifuga americana, and it appears that in this case the genus name “Actaea” was erroneously substituted for Cimicifuga. Fortunately, the chemical profiles for A. podocarpa and the purported “A. americana” in the study are virtually identical. Therefore, there are only eight North American Actaea species, rather than nine, as suggested by C. Ma et al.21

Furthermore, when exploring the historical record, the reader should be aware of additional nomenclature complexities. The genus name “Macrotrys,” established by C.S. Rafinesque in 1808 as a new designation for Cimicifuga racemosa, was subsequently misspelled “Macrotys” (omitting the second “r”) in several of the eight editions of the popular Manual of Botany by Amos Eaton (1776-1842), published from 1817-1840, and widely used as a standard field reference until the mid-19th century. Black cohosh was adopted as a drug by the Eclectic medical movement in the mid-19th century, and the Eclectics nearly universally referred to the drug under the misspelled genus name “Macrotys,” perpetuating the error of Eaton. The common name black cohosh did not come into widespread use until the late 19th century. Macrotys and black snakeroot were widely used as common names for black cohosh until about 1900.14,22

Comments on Names of Source Plants of Chinese Extracts

Various Chinese species of Actaea are source plants of the traditional Chinese medicine sheng-ma (shengma). Three Actaea/Cimicifuga species are official source plants of sheng-ma: A. heracleifolia (C. heracleifolia, aka da-san-ye sheng-ma), A. dahurica (C. dahurica, C. dahurica var. simplex, aka xin-gan sheng-ma), and A. cimicifuga (C. foetida, aka sheng-ma). Actaea simplex (A. cimicifuga var. simplex, C. simplex, C. foetida var. simplex) is known as ye-sheng-ma.

Actaea simplex is the most commonly cultivated Asian species related to black cohosh in American horticulture and an excellent example of the confused nomenclature of black cohosh relatives in commercial trade, extending beyond sourcing of botanical dietary supplement ingredients. Actaea simplex is known by numerous botanical synonyms, including “Cimicifuga ramosa,” which is not a misspelling of “C. racemosa.” “Cimicifuga ramosa” cultivars are widely available as perennials in American horticulture, particularly selections in the “atropurpurea group” which have purple-to-bronze foliage. Cultivar names are expressed as the scientific name, followed by the cultivar designation enclosed in single quotes. For example, one cultivar is Cimicifuga ramosa ‘James Compton,’ named for botanist and taxonomist James Compton, PhD, recent monographer of the genus Actaea.12 To further confuse matters, many nurseries offer “Actaea ramosa” bronze-foliage cultivars, even though the name “Actaea ramosa” never was published as a scientific name for any plant. Here, the genus name “Actaea” simply has been used to replace the genus name Cimicifuga with no attempt to determine the correct botanical name for the plant at hand. A simple Google search for “Cimicifuga ramosa” will return numerous sites listing bronze-foliaged cultivars of A. simplex as “Cimicifuga racemosa” or “Actaea ramosa.” This example is highly indicative of the confused understanding and application of binomials in the Actaea/Cimicifuga genus nomenclatural complex.

The root of Vernonia aspera (Asteraceae; also known as roughleaf ironweed) is an obscure Chinese folk medicine known as hei-sheng-ma,23 which translates to “black cohosh” (hei=black). It occurs on open grassy slopes in mountains above 3,000 feet in south China (Guizhou, Hainan, and Yunnan provinces), as well as India, Laos, Myanmar, Nepal, Thailand, and Vietnam, and is known by at least 12 botanical synonyms in six genera.24,25 A PubMed search using all 13 names in the botanical literature returned no results on scientific studies published on Vernonia aspera or any of the synonyms. This author located no reference to Vernonia aspera in any of the chemical analytical studies on Actaea/Cimicifuga adulteration. There is a virtual dearth of scientific literature on Vernonia aspera, yet multiple listings as a source plant of “black cohosh extract” on wholesale Chinese websites are common. Is the plant actually used as a base-material for extract, spiked with triterpenes to make it appear to be a black cohosh extract? Or is this simply yet another case of confused nomenclature lost in translation from Chinese to English on Internet sites?

The AHP monograph on black cohosh makes reference to guang-dong sheng-ma as a common substitute for sheng-ma in the Asian market.9 Serratula chinensis (Chinese sawwort root, syn. Rhaponticum chinense, Centaurea missionis; Asteraceae) is found on grassy slopes, thickets, and forest edges in western Anhui, Fujian, southeast Gansu, north and northeast Guangdong, Guizhou, Henan, Hubei, Hunan, Jiangsu, Jiangxi, south Shaanxi, Sichuan, Yunnan, and south Zhejiang provinces in China.26 According to Professor De-An Guo, PhD, director of the Shanghai Center for Traditional Chinese Medicine Modernization, hei sheng-ma also refers to Serratula chinensis, which may be collected by Chinese exporters since it has the same name (in Chinese) as black cohosh. He noted that as far as he can determine, there is no commercial cultivation of A. racemosa in China (personal communication to S. Foster and M. Blumenthal, March 25, 2013). The scientific literature on Serratula chinensis also is exceedingly sparse. A PubMed search retrieved only one citation — a 2007 study in which Ling et al. reported on the isolation and structure of a new cerebroside from the species, the first report of the occurrence of cerebrosides in the genus Serratula.27

The sheer volume of offerings, prices ranges, varied specifications, and differing species listed as “black cohosh extract” from Chinese sources require that the daunted buyer attempting to source black cohosh work closely with a qualified analytical lab to authenticate black cohosh extracts before securing any supply source.

Sampling of Names from Chinese Wholesale “Black Cohosh Extract Sources”

According to the nomenclature reference AHPA’s Herbs of Commerce,28 the only acceptable species to which the common name “black cohosh” applies is Actaea racemosa (syn. Cimicifuga racemosa). Herbs of Commerce is formally recognized in Title 21 of the US Code of Federal Regulations (CFR)29 as a primary reference for the appropriate labeling of herbal products in the US, and, therefore, non-compliance with this text — unless otherwise scientifically warranted — is a violation of dietary supplement good manufacturing practices (GMPs), and other regulations pertaining to product labeling. According to the same text, Chinese species of Actaea (syn. Cimicifuga) are required to be identified by the standard common name “Chinese cimicifuga.” This name is subsequently required in finished-product labeling, thus clearly distinguishing between Asian and North American species contained in a product. Any designation of a botanical material or finished product in the United States by the common name of “black cohosh” on product labels (and presumably in the supply chain) is required to be Actaea racemosa and no other species. To apply the name “black cohosh” to any other species violates the CFR and results in adulteration of the finished product offered to consumers.

Much of the material offered from wholesale sources of Chinese origin appear to be offered as “black cohosh” rather than “Chinese cimicifuga,” as listed in Herbs of Commerce. An Internet search conducted on Google with the simple search phrase “Black Cohosh Wholesale China” led to a first hit at alibaba.com, which returned 2,440 black cohosh herbal extracts on 77 pages. Searching the landing page for “black cohosh root extract”30 returned 1,670 herbal extracts listed on 47 pages. Random price ranges for extracts were between $1.00-$300.00/kg, with ranges of availability from various suppliers offered at as little as a few grams per week up to five tons per week. Several plant species under various correct or incorrect spellings of common and or technical names were listed as the source of “black cohosh extract(s).” For example, “ISO9000 & Kosher certificate black cohosh extract,” 2.5% triterpenoides (HPLC) of “Cimicifuga romose (L) Nutt.” was offered by Sanyuan Jinrui Natural Ingredients Co., Ltd. (Xi’an, Shaanxi, China) at $5-60/kg.31 Hunan Naturalin Bio-Resources Co., Ltd. (Changsa, Hunan, China), offered 2.5% triterpene glycosides “black cohosh extracts” from “Cimicifuga foetida L.”32 Xi’an Aladdin Biological Technology Co., Ltd. (Xi’an, Shaanxi, China) offered “Black Cohosh Extract,” citing the Latin name Vernonia aspera (Roxb.) Buch.-Ham.33 This illustrates the myriad offerings encountered in a simple search and represents random samples of 18 different supply source site links out of 38 suppliers listed on just one of 47 pages returned on the alibaba.com website search of “black cohosh root extract.” The names mentioned above — “Cimicifuga romose,” Cimicifuga foetida, and Vernonia aspera — were observed on more than one page in this very limited random sample. A follow-up search for “Cimicifuga romose” (an apparent and often repeated misspelling) returned a list of 387 products from 53 suppliers.34 A search for “Cimicifuga foetida” returned 121 products from 24 suppliers, most of which also called the products offered “black cohosh extract.”35 A follow-up search of “Vernonia aspera extract” returned a list of 17 products from 11 suppliers.36 In all 17 instances, the name “Vernonia aspera extract” was associated with products labeled as “black cohosh extract.” As stated, none of the aforementioned Chinese species are acceptable as “black cohosh” and clearly are represented as adulterated products under Title 21 of the CFR.

The Price of Authentic North American Black Cohosh

Price differences between authenticated North American black cohosh and Chinese species sold labeled as “black cohosh” provide the obvious incentive for economic adulteration. Estimates suggest that between 300,000-380,000 lbs (136,078-172,365 kg) of wild-harvested crude, dried, whole black cohosh root enter the wholesale trade from the US (as of the 2011 season) with prices from supplier/dealer to manufacturers/processors ranging from $4.50-$7.50/lb ($9.92-$16.54/kg). Some cultivated material is sold in small lots, mostly to small manufacturers at about $8.00/lb ($17.80/kg), but is not believed to represent a significant percentage of the wholesale black cohosh supply. (Fletcher E., email to S. Foster and M. Blumenthal, April 2-5, 2013).

Cultivated wholesale black cohosh root for the medicinal herb trade is not economically feasible to produce, at least not at the present time. The time frame for growth from seed to production of roots of large enough size for the medicinal market is estimated at six-to-eight years, which would require at least doubling and perhaps tripling the price compared with wild-harvested material to recoup the investment in time and inputs. At this point, cultivated material — compared with the relative abundance and much lower price of wild-harvested material — provides little incentive to commercial growers except in vertically integrated operations with a desire or need to control supply sources. (Fletcher E., email to S. Foster and M. Blumenthal, April 2-5, 2013).

Chinese sources sell powdered material or extract to the US market, rather than crude raw material. Authenticated black cohosh extract at $50.00/kg can be expected to be three-to-four times the price of Chinese-supplied extract (averaging around $15.00/kg), depending upon quantities. Prices paid for Chinese-supplied black cohosh ranged from $6-$8.50/kg (including shipping) while US-supplied black cohosh ranges from $14.50-$16.50/kg. Obviously, prices vary considerably based on root quality, form (whole, cut, powdered), and quantities purchased, but the overall trend shows an economic adulteration incentive with the price of Chinese material running at about 25-30 percent, or in some cases, much less, of that of authenticated black cohosh in wholesale trade (Fletcher E., email to S. Foster and M. Blumenthal, April 2-5, 2013; Wanzer C., email to M. Blumenthal, April 4 and 5, 2013).

Habitat and Conservation

Black cohosh occurs in moist, mixed deciduous eastern North American forests and forest margins, often in mountainous terrain from Massachusetts south to Georgia, west to northwest and north central Arkansas and the adjacent Ozarks of Missouri, north through the Ohio River Valley to southern Ontario. Although not of significant conservation concern at the national level, at the extremities of the plant’s natural range it may be considered rare at the state level.

Conservation concerns expressed by various groups including the US National Park Service, World Wildlife Fund, United Plant Savers, and others prompted the US Fish and Wildlife Service (USFWS) to request information and recommendations for species to consider for changes to CITES (Convention on International Trade in Endangered Species of Wild Fauna and Flora) in the US Federal Register in June of 2001.37 At the time, USFWS was considering recommending black cohosh for a CITES Appendix II listing, which may have monitored and/or restricted black cohosh in international trade.

AHPA responded to the USFWS request for information with a detailed commentary on the suspected over-harvest of black cohosh root for export.38 Subsequently, USFWS published a notice in the Federal Register in April of 2002 stating that it would not seek an Appendix II listing, but that it intended to review and consider listing US native species of Cimicifuga (Actaea) in Appendix III.39 CITES Appendix III includes species listed by one member country in which assistance in controlling trade is sought from other CITES Parties, in which case trade would be permitted only among CITES Parties if the member country that listed the species issued an appropriate export permit and certificate of origin. However, no action was taken at the CITES Conference of the Parties (COP 12) held in Santiago, Chile, in November of 2002. As of March 2006, active consideration to list black cohosh and its relatives was withdrawn by the USFWS, though the agency has been monitoring and will continue to monitor status.40

The information provided by AHPA in response to the initial request for information and recommendations appears largely responsible for the lack of action taken to list black cohosh to a CITES Appendix. In the past decade, Remifemin-manufacturer Schaper & Brümmer GmbH & Co. KG has established large-scale commercial production of black cohosh in Germany in order to better control and secure its supply source. The company’s production quantity is unknown and not reflected in trade data, though this commercial production may contribute to an overall trend of stabilization in wild-harvested tonnage and decreased conservation concerns from wild harvest.

Ed Fletcher of Strategic Sourcing Inc., an experienced trader and consultant on North American medicinal plants and a supplier of wild-harvested and cultivated black cohosh rhizomes/roots, observes that habitat depletion is the most detrimental factor to current wild populations of black cohosh. He believes that managed stands of wild black cohosh regenerate adequately to be self-sustaining. Population sustainability is achieved in part by high seed production in wild populations and relatively high germination rates, which helps to ensure the ability of populations to recover from harvest impacts (personal communication, September 6, 2011).

Trade Data on Black Cohosh

In a detailed analysis of black cohosh rhizome trade from the US, Brinckmann (2010)41 provided information on production scenarios, conservation status, trade volume, and market prices, along with information on quality expectations and pharmacopeial definitions. One of the problems in monitoring international trade in black cohosh is that the commodity does not have a unique 10-digit tariff code assigned to it under the Harmonized Tariff Schedule of the United States (HTSUS). The only estimates of annual trade volume and percentage of cultivated and wild-harvested black cohosh come from AHPA’s annual tonnage surveys of member companies that are primary raw material producers (direct buyers from point of origin) with data on up to 26 wild-harvested botanical commodities collected from 1997 to 2010 (Table 1).

Potential Confusion of North American Actaea/Cimicifuga Species

Accidental A. racemosa adulteration or inadvertent admixture to commercial lots may occur with several North American Actaea species that share the same habitat and whose ranges overlap. Actaea podocarpa (syn. C. americana, A. americana) occurs in a narrow range in the central Appalachian mountains from Pennsylvania south to Georgia. Appalachian bugbane (A. cordifolia, syn. C. cordifolia, C. rubifolia, C. racemosa var. cordifolia, A. rubifolia) has a narrow range limited to a few counties in Pennsylvania, Virginia, Tennessee, Alabama, Kentucky, and southern Illinois and Indiana. Actaea pachypoda and A. rubra also share overlapping ranges with A. racemosa. All five species are known to occur in the same habitat, often in sterile populations, with few distinguishing features if flowers and/or fruits are not available. This could result in unintentional admixture of one or more of the above species in commercial lots of A. racemosa.14

Fletcher noted that, in practical terms in Appalachia, A. podocarpa (yellow cohosh) is the species that most closely resembles black cohosh. Wildcrafters pass over other Actaea species because the roots/rhizomes are smaller, and they know that buyers will not purchase other Actaea species. However, once the roots are dry they become visually more difficult to differentiate (personal communication, September 6, 2011).

In the AHP Black Cohosh Rhizome monograph, Upton et al. (2002) suggest that yellow cohosh (A. podocarpa) is unintentionally but commonly mixed with A. racemosa based on similarities of above-ground morphological features. The AHP monograph provides a table showing unique visual features that provide distinction between A. racemosa and A. podocarpa fruit, seed, pistils, pedicels, bracts, and staminodea. When fresh, black cohosh root is black and yellow cohosh root is yellow, though once dried they are more difficult to differentiate. Also, A. podocarpa blooms about three weeks later than A. racemosa.9

DNA Analysis and Barcoding

Several DNA studies on Actaea have been published distinguishing A. racemosa from other Actaea species, as well as increasing awareness of geographical and chemical diversity in the genus.

In a comprehensive paper explaining DNA barcoding as it relates to accuracy of identification of medicinal plants published in HerbalGram 97, Y.C. Ma et al. of the Canadian Phytopharmaceutical Corporation,48 suggest that DNA barcoding is emerging as a useful methodology in the quality control toolbox to help reduce misidentification and adulteration of medicinal plants. The practical application of DNA barcoding to plant identification is an evolving field, circumscribed by key limiting factors such as standardization minimalism and scalability. In animals, a fragment of a single gene (cytochrome c oxidase 1) is the accepted standard for ease of species differentiation. However, no single region of plant DNA provides universal sequence quality and species discrimination of plants, leading to development of various proposed methods or a combination of methods to correctly identify plants based on their DNA barcodes.

Y.C. Ma et al. explain that a short region of DNA is used to identify species in DNA barcoding. First, a small sample of DNA has to be extracted from the specimens. Second, the selected barcode region undergoes polymerase chain reaction (PCR) amplification. The PCR result is purified and sequenced; then, the DNA sequence is compared to a library/database to identify the species.

Researchers in China at the Institute of Medicinal Plant Development (IMPLAD) in Beijing and the Institute of Chinese Medicine at The Chinese University of Hong Kong have taken the lead internationally in developing DNA barcoding of botanical ingredients including medicinal plants and their adulterants. The Medicinal Materials DNA Barcode Database,49 for example, covers 1,658 plant species. The 2015 Pharmacopoeia of the People’s Republic of China likely may be the first national pharmacopeia to contain detailed DNA protocols for authentication of herbal medicines.

In order to distinguish among sympatric eastern North American species of Actaea, several research groups have effectively applied DNA fingerprinting methods. Xu et al. (2003) found that random amplified polymorphic DNA (RAPD) analyses could distinguish A. racemosa, A. podocarpa, and A. cordifolia when no powdered plant materials were available.50

Zerega et al. (2002) used Amplified Fragment Length Polymorphism (AFLP) DNA fingerprinting to analyze black cohosh in relationship to its relatives with overlapping ranges. The method was applied to commercial black cohosh products, and, in two products, verification of the presence of A. racemosa was confirmed along with the absence of other eastern North American Actaea species. However, use of this method was unable to verify the presence or absence of Actaea species in black cohosh tea bags and coated tablets. Variables such as rhizome temperature drying, storage conditions, processing techniques, age, and storage quality of finished products could have individually or collectively contributed to the degradation of DNA, with loss of AFLP markers, highlighting the limitation of the method.51 The results also supported the uniting of Cimicifuga with Actaea by Compton et al.,12 and suggest that the morphologically dissimilar A. racemosa and A. pachypoda are the most closely related eastern North American Actaea species in terms of genetics.

Pate et al. (2012) applied isolating microsatellite DNA loci to develop molecular markers for A. racemosa from living specimens throughout the plant’s geographical range. The aim of the research was to measure genetic diversity across the species’ range as a tool to examine potential genetic depletion in the southeastern United States, and provide a context for detecting possible genetic variations in triterpene glycoside production. The characteristics of seven microsatellite regions provide a comparative genetic library for use in the future assessment of population structure and genetic relationships, which also could aid in assessing genetic variables for active compound production.52

Baker et al. (2012) applied another method of identifying two matK nucleotides from the DNA sequences (barcodes) of black cohosh that consistently and unambiguously distinguishes black cohosh from all related species. In a sampling of 40 dietary supplement products labeled as “black cohosh” arbitrarily purchased on the Internet and from New York metropolitan-area stores, the researchers found that of 36 samples sequenced, 27 (75%) exactly matched black cohosh. Nine samples (25%) had sequences identical to three Asian Actaea species (A. cimicifuga, A. dahurica, and A. simplex). As noted above, Actaea simplex is widely available in American horticulture, but often mislabeled, adding to potential confusion.

Significantly, none of the samples studied contained any North American Actaea species other than A. racemosa, suggesting that wild collectors, buyers of wild-collected North American material, and their customers’ quality control procedures are achieving success at maintaining correct identity of authentic A. racemosa in North American-sourced black cohosh supplies.

Four dietary supplements could not be identified using the lab’s PCR amplification protocol, presumably because the DNA was degraded, possibly when heat was applied during processing. Nevertheless, the method described in the Baker et al. paper using matK sequence supplemented by nrITS2 can consistently and unambiguously differentiate black cohosh, assuming that the DNA is not degraded.53‡

Chemical Differentiation of Actaea species

Various studies on the chemical constituents of black cohosh reveal that the two principal compound groups in the plant are triterpene glycosides (at least 43 reported to date) and polyphenolic derivatives, which have been the major focus of analysis and characterization of black cohosh products. However, in an effort to conclusively identify standardization methods based on active compounds and biological activity, the late Professor Farnsworth’s research group at UIC reported new potential bioactive compounds from black cohosh. Fabricant et al. (2005), as part of an effort to produce a standardized, definable extract for use in the UIC black cohosh clinical trials, reported on the isolation and characterization of a new cyclic guanidine alkaloid, cimipronidine, the first guanidine isolated from a plant in the Ranunculaceae.54 Gödecke et al. (2009) isolated and characterized three new guanidine alkaloids including cylo-cimipronidine and cimipronidine methyl ester (both congenors of cimipronidine), and a new alkaloid given the trivial name dopargine, a derivative of dopamine. These and other compounds, including 3-hydyroxytyrosol 3-O-glucoside, may contribute significant biological activity in polar fractions of an extract produced for use in clinical trials, and they are being researched further for their serotonin receptor pathways, and possible central nervous system and antioxidant activity.55

With respect to polyphenolic compounds, in 2006, Nuntanakorn et al. reported on the identity of 17 polyphenols including hydroxycinnamic acid derivatives (caffeic acid, ferulic acid, and isoferulic acid); fukiic acid derivatives (fukinolic acid and cimicifugic acids A and B); and piscidic acid ester derivatives (cimicifugic acids E and F). In addition, they reported — for the first time — the presence of six additional phenolic compounds including protocatechuic acid, protocatechualdehyde, p-coumaric acid, 1-isoferuloyl-β-D-glucopyranoside, ferulate-1-methyl ester, and cimicifugic acid D. They also isolated two new compounds, a lignin — actaealactone — and a phenylpropanoid ester derivative — cimicifugic acid G — with structures determined based on nuclear magnetic resonance (NMR) spectrometry analysis.56

In 2007, Nuntanakorn et al. published a method to distinguish among various eastern North American Actaea species based on phenolic component fingerprints. A reversed-phase high-performance liquid chromatography (RP-HPLC) method with diode array detection (DAD) is useful for distinguishing the eastern North American Actaea species A. pachypoda, A. podocarpa, A. racemosa, and A. rubra based on polyphenolic components. Described as a simple, reliable, and convenient method less complex than distinguishing triterpene glycoside fingerprints, the method provides qualitative and quantitative polyphenolic fingerprints to reliably distinguish these four species. The method was validated with respect to sensitivity, linearity, precision, accuracy, and recovery.

The eight polyphenolic compounds detected included caffeic acid, ferulic acid, isoferulic acid, fukinolic acid, and cimicifugic acids A, B, E, and F. Actaea racemosa contains all eight polyphenolic compounds. Actaea rubra has a similar phenolic profile to A. racemosa, but different ratios of polyphenols with higher levels of cimicifugic acids A and B as the predominant polyphenols, while fukinolic acid is the most abundant polyphenol in A. racemosa. Cimicifugic acid F was not found in A. rubra. In A. pachypoda, isoferulic acid and cimicifugic acid A are the only two predominant polyphenols. Actaea podocarpa contains cimicifugic acids A and B as the only two predominant polyphenols. The sympatric eastern North American species A. cordifolia (syn. C. cordifolia, C. racemosa var. cordifolia, C. rubifolia) does not seem to have been tested. An additional eight populations of black cohosh from New York to North Carolina and Tennessee were examined, all of which had similar profiles of polyphenolic constituents. Replication of the method could be applied to more collections of North American Actaea species.57

Further Analytical Tools and Methods for Authentication

The analytical tools and methods to assure that black cohosh (A. racemosa syn. C. racemosa) is properly identified are numerous, precise, and widely known to experts in the herb trade and the natural products research community. A combination of the use of several analytical methods may be necessary for proper authentication of black cohosh and to rule out economic adulteration or inadvertent admixture of related species.

In its black cohosh guidance document, AHPA advocates the relatively inexpensive method of high-performance thin-layer chromatography (HPTLC), citing the methodology of Verbitski et al. (2008)58 for authentication of black cohosh in comparison to other North American species of Actaea/Cimicifuga. The HPTLC methods of Ankli et al. (2008) of CAMAG Laboratories59 in Switzerland are suggested for detecting adulteration of black cohosh from Chinese species of Actaea/Cimicifuga. Members of the HPTLC Association can access further details of these methods through the organization’s website (no open access).60

C. Ma et al. (2011)21 provide further methods for authentication and differentiation of Actaea species, using HPLC coupled with the HPLC-TOF-ESI-MS technique. They identified 15 chemical markers including three marker compounds that were unambiguously identified using authentic standards, and an additional 12 marker compounds tentatively identified by fragmentation patterns when compared with previously reported data.

The analytical methods described in the paper that distinguish 15 marker compounds inform differences among four types of Actaea classified as follows: (1) species other than A. racemosa, (2) Asian species of Actaea, (3) Actaea racemosa, and (4) North American species other than A. racemosa.

Of note, three cimifugin derivatives and a 16,23-diketoshengmanol class triterpene marker were found useful to differentiate species other than A. racemosa. For example, the cimifugin derivative prim-O-cimifugin was present in Asian and North American species except for A. laciniata, A. podocarpa, and A. racemosa; therefore, the presence of that compound in a “black cohosh” product would indicate adulteration.

The alkaloid cimicifugaine (syn. cimicifine A) was found to be unique to Asian species of Actaea (including A. heracleifolia, A. mairei, A. dahurica, and A. yunnanensis). The presence of this alkaloid is useful for identifying the presence of Asian Actaea species, and if found in a product labeled as containing “black cohosh,” would again indicate adulteration.

A single compound, 12 β,21-dihydroxycimigenol-3-O-L-arabinoside, was found in high concentration in A. racemosa, but was absent from all other North American and Asian Actaea species tested; therefore, it is useful in detecting unadulterated A. racemosa product.21

Another compound, cimigenol-3-O-a-L-arabinoside (syn. cimiracemoside C, cimicifugoside M), was reported by He et al. (2000) to be unique to A. racemosa and hence reported to be a useful marker compound for A. racemosa.61 However, Ma et al., using the highly sensitive methods in the time-of-flight mass spectrometry analysis, detected the compound in three additional North American species and one variety of Actaea, as well as three Asian species of Actaea.

In addition, other published analytical methods for unambiguous identification of black cohosh include the HPLC method of Avula et al. (2007).62 Avula et al. (2009) provide a UPLC/UV/ELSD (ultra performance liquid chromatography/ultra-violet/evaporative light scattering detection) method and identification by UPLC-MS (ultra performance liquid chromatography/mass spectrometry).63 The HPLC-photodiode array (PDA)/mass spectrometric (MS/ ELSD) method of He and colleagues (2006) provides more guidance.64 A LC/TIS/MS (liquid chromatography/turbo ion spray/mass spectrometry method) developed by Wang et al. (2006) presents fingerprints of six commercial black cohosh products along with six related Asian species. The method produces LC/MS fingerprints that provide reliable and reproducible methods useful for identification of Actaea/Cimicifuga species and validation of commercial products.65

Gafner et al. (2006) noted that the evaluation of chemical fingerprinting using a combination of techniques is especially useful in the quality control of black cohosh, since the majority of triterpene glycosides of A. racemosa also occur in several other Actaea species. An identification procedure based on a few marker compounds may not be enough to rule out every adulterant. They compared HPLC-UV, HPLC-MS, HPLC-ELSD, and HPTLC fingerprints of five Actaea species (A. racemosa, A. rubra, A. pachypoda, A. podocarpa, and a Chinese Actaea species sold as A. heracleifolia by the supply source). HPTLC gives good separation of phenolics and triterpene glycosides, but A. rubra, A. podocarpa, and A. pachypoda showed very similar fingerprints to A. racemosa, leading the authors to conclude that it was difficult to determine identification of A. racemosa by HPTLC alone. HPLC-UV showed distinct differences between A. racemosa and the Chinese Actaea species, but there was little distinction between A. racemosa and A. podocarpa, plus A. rubra and A. pachypoda exhibited almost exactly the same HPLC-UV trace. However, HPLC-ELSD coupled with HPLC-MS provided unambiguous identification of A. racemosa, according to the authors. None of the techniques were able to unambiguously distinguish between the two closely-related North American species A. rubra and A pachypoda.66

Dr. Kennelly’s research group at Lehman College at the City University of New York, with collaborating researchers at various institutions, has published a series of papers on the identity of black cohosh components and authentication.§ Remarkably, Jiang et al. (2005) found that an 85-year-old black cohosh specimen collected in 1919 by H.H. Rusby had comparable quality and quantities of four triterpene glycosides and six phenolic constituents, compared with modern plant material, confirming the potential stability of those constituents in storage.67 Jiang et al. (2006), analyzed 11 commercial products from the US labeled as black cohosh using HPLC-PDA+LS(SIM) and found that three products contained the marker compound cimifugin (and not cimiracemoside C), indicating they contained Asian Actaea species rather than authentic black cohosh, and one product contained a mixture of black cohosh and an Asian Actaea species.68 A more recent paper (Jiang et al., 2011) from this same group used HPLC/LC-MS analysis to distinguish HPLC fingerprints for both polyphenols and triterpene glycosides from samples of 15 Actaea species including eight North American species and seven Asian species. Of note, cimifugin was detected in all Asian species tested as well as three American species of Actaea, but was absent from A. racemosa, as well as three closely related North American species (A. podocarpa, A. pachypoda, and A. rubra).69

In addition, the United States Pharmacopeial Convention (USP) has published authentication methods for black cohosh.70 Health Canada’s monograph,71 the EC European Medicines Agency monograph,72 and related documents all provide further guidance for quality assessment, authentication, and use guidance for black cohosh products.

Products Labeled “Black Cohosh” and Alleged Liver Toxicity

Since 2002, beginning with several case reports from Australia, presumed herb-induced liver injury has been linked to products labeled as containing black cohosh. Reactive alerts by regulatory bodies, when assessing causality, gave preference to quantity of cases over quality of case data.73 On November 22, 2004, the NIH, NIH National Center for Complementary and Alternative Medicine (NCCAM), and the NIH Office of Dietary Supplements (ODS) convened a workshop on the safety of black cohosh in clinical studies in response to the case reports of hepatotoxicity.

The workshop brought together experts active in multidisciplinary research on black cohosh to gain a better understanding of reported hepatotoxicity in humans and focused on issues relative to NIH-funded studies on black cohosh. The late Professor Farnsworth, citing research from his laboratory at UIC, underscored that there was increasing concern that some of the black cohosh products marketed in the US may not be genuine black cohosh but one (or more) of the Chinese Actaea species instead. Consensus was expressed that, given variables in preparations and possible adulteration and/or contamination, NIH grant recipients should have allowable budget costs for verification of research materials. One of the 40 participants at the workshop, Wolfgang Wuttke, MD, of the University of Göttingen in Germany — and principle investigator on several clinical trials on Klimadynon — expressed that his reviews of the black cohosh clinical literature found few if any effects on the liver, and was surprised at the level of concern about black cohosh-associated hepatotoxicity in the US.74

Australia’s Therapeutic Goods Administration (TGA) was the first regulatory agency to require a warning label for black cohosh products. In 2005, TGA reviewed the safety of black cohosh in relation to possible cases of liver toxicity that at the time included 47 international case reports — nine of which were from Australia. As of February 2006, TGA required black cohosh products to include the following label statement: “Warning: Black cohosh may harm the liver in some individuals. Use under the supervision of a healthcare professional.” Following the initial safety review, TGA convened an expert advisory group that concluded that there appears to be an association with products labeled as “black cohosh” and liver disease, but it was very rare.75 A revised warning stated, “In very rare cases, black cohosh has been associated with liver failure. If you experience yellowing of the skin or eyes, dark urine, nausea, vomiting, unusual tiredness, weakness, stomach or abdominal pain, and/or loss of appetite, stop using this product and see your doctor.”76

In July of 2006, the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) followed with a suggested product-label warning in conjunction with a public statement by the European Agency for the Evaluation of Medicinal Products/Herbal Medicinal Products Committee (EMEA/HMPC) advising patients and healthcare professionals to be aware of the liver toxicity linked to black cohosh-labeled products. Of the 42 poorly documented case reports evaluated in the world literature, a temporal causality association was made in four cases.77 Health Canada issued a brief notice in a July 2005 issue of the Canadian Adverse Reaction Newsletter encouraging healthcare providers, manufacturers, and the public to be aware of international reports of liver toxicity associated with black cohosh.78 A follow-up consumer advisory about a possible link between health products containing the herbal medicine black cohosh and liver damage was issued on August 18, 2006.

Continued media reports and regulatory agency warnings regarding the possible association of black cohosh and hepatotoxicity led to the inevitable — lawsuits. Grant and Beck v. Pharmavite and Nutraceutical Corporation involved a case of a 50-year-old woman who claimed to take 500 mg daily of a black cohosh product before the onset of jaundice, leading to a diagnosis of autoimmune hepatitis. The patient required a liver transplant. The case was reported by Levitsky et al. in a 2005 issue of Digestive Diseases and Sciences.79 An erratum to the paper was published in the same journal in 2008.80 One of the authors, Michael F. Sorrell, MD, a gastroenterologist, was one of the treating physicians of co-plaintiff Susan M. Grant, and was retained as an expert witness. According to court documents, only after Dr. Sorrell was retained as an expert witness did he submit a report on Grant’s case for publication, which allegedly linked her liver disease to black cohosh. The published case report included a statement that the patient “did not drink alcohol or use illicit drugs, and was not taking any medications, including other herbal medications, acetaminophen [and] nonsteroidal anti-inflammatory drugs.”81 However, the plaintiff’s testimony did reveal that she regularly consumed wine, used ibuprofen (an NSAID) on a regular basis, and was prescribed the antiviral drug valacyclovir, all of which may contribute to liver disease. The court granted the defendants a summary judgment resulting in dismissal.81,82

A June 26, 2007 press release from the USP announced that the USP Dietary Supplements Information Expert Committee (DSI-EC) voted to require new labeling suggesting a potential link between black cohosh and liver damage. A proposed Interim Revision Announcement with the cautionary statement for black cohosh was released in Pharmacopeial Forum 33(5), for a 60-day public comment period.83

In a press release dated January 11, 2008, AHPA urged USP to drop label cautions on black cohosh, noting the following: (1) “USP has not considered the full range of products that may contain a variety of different forms of black cohosh or that the proposed caution is actually warranted for all dosages and use patterns,” and (2) “That the need for a cautionary statement was based on an inappropriately narrow review of case reports, which without supportive data are insufficient to justify the proposed cautionary labeling.”84

In 2008, the USP DSI-EC published a thorough review of alleged black cohosh hepatotoxicity case reports, and regulatory actions and reactions. The extensive review of adverse event reports (AERs) by Mahady et al.82 stated that the DSI-EC observed that the link between black cohosh and liver damage reports were weak and of uncertain causality. Weaknesses of reviewed data found incomplete case information and unknown products, potentially confounding variables such as the use of alcohol and other medications, and preexisting liver disease risk factors. Despite these and other limitations on available data, DSI-EC decided to reclassify black cohosh as “Class 2” for the purposes of a USP black cohosh monograph, requiring a label caution stating the following: “Discontinue use and consult a healthcare practitioner if you have a liver disorder or develop symptoms of liver trouble, such as abdominal pain, dark urine, or jaundice.” The label caution applies only to products that are represented as conforming to specifications of an official USP-NF monograph.82,85

Hepatotoxicity of Commercial Products Labeled as Containing “Black Cohosh” Linked to Plant Species Misidentification

Despite numerous cases reports of hepatotoxicity linked to products labeled as containing black cohosh, with at least 82 cases reported worldwide as of early 2010, causality has remained controversial. A report associating hepatotoxicity from commercial products labeled as containing black cohosh linked to plant species misidentification was presented in a poster session by Robin J. Marles, PhD, and colleagues of various branches of Health Canada, on March 23, 2010, at a symposium titled “Developments in Botanical Dietary Supplements Research from 1994 to Today,” organized by the UIC College of Pharmacy, in honor of the late Professor Farnsworth’s 80th birthday.86 By March, 2010, Dr. Marles and colleagues at Health Canada reported that the agency under Canadian regulations had licensed at least 78 natural health products (NHPs) containing black cohosh and that an unknown number of additional unauthorized products on the market had yet to come into compliance with NHP regulations.

Dr. Marles and colleagues obtained the same lots of black cohosh products from retail outlets and from the manufacturer of four products of the same brand of black cohosh-labeled products, including a product labeled as containing only black cohosh, along with three additional combination products produced by the manufacturer. The products had been linked to probable adverse liver reactions. Actein, 23-epi-26-doexyactein, and black cohosh powder reference standards were obtained from USP. Cimiracemoside C and cimifugin were purchased from ChromaDex (Santa Ana, CA). LC-MS (liquid chromatography-mass spectrometry) with a photodiode array detector (PDA) was used to analyze the products. Health Canada’s analysis of three products, and the manufacturer’s analysis of a fourth product, all showed there was no authentic black cohosh in the products when compared with chemical reference standards. The probable adulterant was reported to be A. cimicifuga (C. foetida), but their raw material supplier reportedly believed it to be A. dahurica (C. dahurica) based on adjacent warehouse storage of the two Chinese species. Again, these products were associated with cases of probable adverse liver reactions.

After the testing was completed, Dr. Marles et al. reported that Health Canada contacted all licensees for black cohosh products, of which 52 were found to have used an appropriate authentication method [not characterized in the poster in relation to the licensees’ method(s)], seven licensees requested cancellation of their license, five did not provide enough information to determine compliance, and two did not respond. There were 11 licensees using the same third-party laboratory that was reported to be using an non-validated method returning false positive results.86

Painter et al. (2010) reported on Canadian products linked to six cases of liver toxicity associated with products labeled as black cohosh. The products were analyzed according to methods described by Dr. Marles and colleagues and were found to contain Actaea species other than black cohosh. In two other cases of purported black cohosh liver toxicity connected with products unlicensed by Health Canada, the products connected with the cases were not obtained for chemical analysis. They suggested greater vigilance in reporting liver reactions of products labeled as containing black cohosh.87

In June 2007, the NIH ODS convened a workshop on the current state of knowledge for black cohosh in Gaithersburg, Maryland. A summary of workshop results by Betz et al. (2009) noted that in contrast to adverse event reports, clinical trials and other human studies involving more than 3,000 subjects, there was not a single report of serious liver problems in any of the trials. In two cases, mildly elevated liver enzymes were reported but judged to be clinically insignificant.88

In a detailed, vigorous causality assessment — using a diagnostic algorithm — of the four cases of alleged black cohosh liver toxicity suspected by EMEA/HMPC, Teschke et al. (2009) found no evidence for the causal association between black cohosh and liver injury.89 An analysis and review of the quality and causality of all published case reports plus spontaneous reports of alleged black cohosh toxicity assessed by the scale of the Council for the International Organizations of Sciences (CIOMS) showed lack of causality for black cohosh in all cases. In this review, Teschke and colleagues concluded that true black cohosh may not produce an overt risk of hepatotoxicity, but quality problems in some products may require additional regulatory quality specifications. They wrote that the focus should be on quality specifications to ensure that any problems of impurities, misidentifications, and adulteration of black cohosh products are identified.73,89

A review of adverse events associated with black cohosh products was conducted by Borrelli and Ernst (2008),90 which found that clinical studies suggest black cohosh to be safe; the authors noted that case reports for which causal attribution is problematic require urgent further investigation.

Conclusions

Numerous monographs such as those produced by AHP, USP, Health Canada, and other authoritative official and non-official organizations provide the details necessary for unambiguous authentication of genuine North American black cohosh (Actaea racemosa, syn. Cimicifuga racemosa) using relatively simple organoleptic, macroscopic, and microscopic classical pharmacognosy methods, coupled with relatively inexpensive and widely available chemical analytical methods such as HPTLC. AHPA offers a guidance document on its website with suggestions to industry of reliable, dependable methods with references to readily available literature. In addition, AHPA provides sources for the availability of reference compound standards, as well as member companies that can supply chemical reference standards, botanical voucher specimens, or commercial labs with proven and known expertise to unambiguously authenticate black cohosh raw material and extracts. Depending upon the condition of raw material, DNA authentication methods also are available. In addition, more expensive, sophisticated, and perhaps less widely available chemical analytical methods using the latest technologies delivering unambiguous information, identification, and authentication have been published in the chemical analytical literature in the last 15 years, especially since 2006.

Beginning in 2002, case reports, many of which are inadequately documented, have appeared in the medical literature associating potential hepatotoxicity to products labeled as containing black cohosh. Suspicions arose that those cases may be associated with adulteration (perhaps with Asian species of Actaea/Cimicifuga), but in a vast majority of such reports, the alleged offending product was not retained nor were its contents analyzed by a competent phytochemist. A 2010 report by Dr. Marles and colleagues at Health Canada linked known cases of hepatotoxicity to black cohosh-labeled “natural health products” (as they are termed in Canada) that contained Asian relatives of black cohosh, thereby more closely implicating the Asian adulterant(s) with some of the recent cases of hepatotoxicity associated with products labeled as containing black cohosh.

Commercial Chinese websites offering “black cohosh extract” in tonnage at prices that vary by 300-fold list botanical source species for extract as an Actaea or Cimicifuga species, or sometimes as Vernonia aspera (hei shengma). Another member of the Asteraceae, Serratula chinensis, also may be sourced as hei-shengma (black cohosh), but is usually seen under the Chinese name guang-dong shengma. Analytical methods were not found for distinguishing these species in the supply chain.

To comply with appropriate current Good Manufacturing Practices (cGMPs) as required by law in the United States and many other countries requires only the will to do so and the subsequent access to appropriate quality control resources. Mislabeling or confusion may be due to simple language and translation variations, or, in some cases, the actual intent to sell a lower-cost material that is not an acceptable substitute for authentic North American black cohosh. However, these are possibly moot points as all of the identification and authentication scientific tools necessary to distinguish authentic black cohosh from any other plant materials of any origin are readily available.

Solving the problem of economic adulteration of black cohosh products is within reach. Many in the herb industry are acutely aware of the need for fulfillment of cGMPs as FDA increases cGMP inspections, compliance, and the issuance of warning letters.|| Clearly, the crux of the problem of black cohosh adulteration lies squarely on the doorstep of intentional economic adulteration with less expensive materials from China.

* There are varying levels of evidence from clinical trials that may be used to support many of these health uses; mention of these uses here is merely for the purpose of acknowledging the range of use of black cohosh preparations and is not an endorsement or statement of support by the author or publisher of confirmed efficacy.

Per 21 CFR 101.4(h): “The common or usual name of ingredients of dietary supplements that are botanicals (including fungi and algae) shall be consistent with the names standardized in [the American Herbal Products Association’s] Herbs of Commerce, 1992 edition, which is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51.”

‡Those readers interested in a better understanding of the value and limitations of DNA barcoding are encouraged to visit the Barcode of Life website (www.barcodeoflife.org), which contains both introductory and technical details, along with many additional information resources on species identification via DNA barcoding, with links to the Barcode of Life Database (maintained by the University of Guelph in Ontario). See, for example: Wallace LJ, Boilard SMAL, Eagle SHC, Spall, JL, Shokralla S, Hajibabaei M. DNA barcodes for everyday life: Routine authentication of Natural Products. Food Research International. 2012;49(1):446-452.

§A collaborating botanist who co-authored many papers with Dr. Kennelly’s group, Timothy Motley, PhD, the J. Robert Stiffler Professor of Botany at Old Dominion University, died at age 47 on March 28, 2013. A tribute article is available on page 77.

|| The Director of FDA’s Dietary Supplement Programs within the Center for Food Safety and Applied Nutrition, Daniel S. Fabricant, received his PhD in Pharmacognosy from the University of Illinois at Chicago under the tutelage of major and dissertation advisor the late Norman R. Farnsworth. Dr. Fabricant’s dissertation was “Pharmacognostic Investigation of Black Cohosh (Cimicifuga racemosa (L.) Nutt.)”.91

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