Issuu on Google+

American Herbal Pharmacopoeia

®

and herapeutic Compendium

Blue Cohosh Rhizome and Roots

Caulophyllum thalictroides (L.) Michx. C. giganteum (Farw.) Loconte and W. H. Blackw. Standards of Analysis, Quality Control, and Therapeutics Editors Aviva Romm MD CPM Herbalist Tufts School of Medicine Boston, MA Roy Upton RH DAyu American Herbal Pharmacopoeia® Scotts Valley, CA

Associate Editor Pavel Axentiev MS American Herbal Pharmacopoeia® Scotts Valley, CA

Research Associate Diana Swisher MA American Herbal Pharmacopoeia® Scotts Valley, CA


Authors History Michael Flannery MA MLS The Lloyd Library and Museum Cincinnati, OH Roy Upton RH DAyu American Herbal Pharmacopoeia® Scotts Valley, CA Botanical and Macroscopic Identification Alison Graff PhD American Herbal Pharmacopoeia® Scotts Valley, CA Microscopic Identification Prof Dr Reinhard Länger Institute for Pharmacognosy Center of Pharmacy University of Vienna Vienna, Austria Commercial Sources and Handling Lynette Casper BA Planetary Herbals Scotts Valley, CA Constituents Jeanne Rader PhD Food and Drug Administration College Park, MD Analytical High Performance Thin Layer Chromatography (HPTLC) Judy Nichols CAMAG USA Wilmington, NC Therapeutics, Safety Profile Aviva Romm MD CPM Herbalist Tufts School of Medicine Boston, MA Medical Indications Supported by Traditional Use

ISBN: 1-929425-32-5

Aviva Romm MD CPM Herbalist Tufts School of Medicine Boston, MA Francis Brinker ND Eclectic Institute, Inc Program in Integrative Medicine University of Arizona Tucson, AZ Roy Upton RH DAyu American Herbal Pharmacopoeia® Scotts Valley, CA International Status Josef Brinckmann Traditional Medicinals Sebastopol, CA

Reviewers Bharathi Avula PhD Thad Cochran National Center for Natural Products Research School of Pharmacy University of Mississippi University, MS Wendy Applequist PhD Missouri Botanical Gardens St. Louis, MO Cindy Belew CNM University of California San Francisco San Francisco, CA Mary Bove ND MNIMH Brattleboro Naturopathic Clinic Brattleboro, VT Catherine Downey ND LLC Kilauea, HI Ed Fletcher Strategic Sourcing Banner Elk, NC Markus Ganzerra PhD University of Graz Graz, Austria Arthur Haines MS Delta Institute of Natural History Canton, ME Phylis Light Herbalist Appalachian Center for Health

Studies Arab, AL Ed Smith Herbalist Herb Pharm Williams OR Jillian Stansbury ND Battle Ground Naturopathic Clinic Battle Ground, WA Elan Sudberg Alkemists Laboratories Costa Mesa, CA Dawn Whitten ND Lismore, NSW, Australia David Winston RH (AHG) Herbalist and Alchemist Broadway, NJ

Final Reviewers Teresa DeGolier PhD Department of Biological Sciences Bethel University St. Paul, Minnesota Tieraona Low Dog MD Arizona Center for Integrative Medicine University of Arizona Tucson, AZ Errol Norwitz MD PhD Professor of Obstetrics and Gynecology Yale University, School of Medicine New Haven, CT Tibebe Woldemariam PhD California Northstate College of Pharmacy Rancho Cordova, CA

ISSN: 1538-0297

© 2011 American Herbal Pharmacopoeia®

Medical Disclaimer

Design & Composition

PO Box 66809, Scotts Valley, CA 95067 USA

The information contained in this monograph represents a synthesis of the authoritative scientific and traditional data. All efforts have been made to ensure the accuracy of the information and findings presented. Those seeking to utilize botanicals as part of a health care program should do so under the guidance of a qualified health care professional.

Beau Barnett Santa Cruz, CA

All rights reserved. No part of this monograph may be reproduced, stored in a retrieval system, or transmitted in any form or by any means without written permission of the American Herbal Pharmacopoeia®. Literature retrieval provided by CCS Associates Inc, Mountain View, CA. The American Herbal Pharmacopoeia® is a nonprofit corporation 501(c)(3). To purchase monographs or botanical and chemical reference standards, contact the American Herbal Pharmacopoeia® • PO Box 66809 • Scotts Valley, CA 95067 • USA • (831) 461-6318 or visit the AHP website at www.herbal-ahp.org.

Statement of Nonendorsement Reporting on the use of proprietary products reflects studies conducted with these and is not meant to be a product endorsement.

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

Cover Photograph Blue cohosh. © 2012 Richo Cech Blue cohosh rhizome. © 2012 American Herbal Pharmacopoeia


Nomenclature Botanical Nomenclature Caulophyllum thalictroides (L.) Michx. C. giganteum (Farw.) Loconte and W. H. Blackw. syn. C. thalictroides var. giganteum Farw.

Botanical Family Berberidaceae

Pharmaceutical Nomenclature Rhizoma et Radix Caulophyllii

Pharmacopoieial Definition Blue cohosh rhizome and roots consists of fresh or dried rhizomes and roots of Caulophyllum thalictroides and/or C. giganteum, conforming to the methods of identification provided.

Common Names English: Blue cohosh. French: Cohosh blea. German: Blauer Hahnenfluss. Italian: Caulofillo.

genus Thalictrum as anyone familiar with those plants can attest (Hyam and Pankhurst 1995). Caulophyllum thalictroides is one of several “cohoshes” used medicinally, including the most notably among these, black cohosh. However, these are taxonomically unrelated plants that are not typically confused. Blue cohosh was used by numerous tribes, from the Iroquois in the Northeast to the Ojibwa in Minnesota, and by Cherokee, Fox, Menominee, Mohegan, Omaha, Potawatomi, and Ponca. Medical applications by these tribes included its use as an anticonvulsive, sedative, a gynecological aid, and an antirheumatic (Moerman 1998). First mention of the medical use of blue cohosh in Euro-American literature can be found in Peter Smith’s The Indian Doctor’s Dispensatory (1813) where he recommended it, under the name of “squaw root,” as a purgative, catarrhal, and topical for burns. Further interest in this plant was stimulated by Constantine Rafinesque in his Medical Flora (1828). Rafinesque, a prolific and eccentric writer on natural history, referred to the dark blue, berry-like seeds in recommending the name, by which the plant is most commonly known today – blue cohosh. Citing its traditional uses by Native Americans, Rafinesque referred to the plant as “a powerful emmenagogue” promoting “delivery, menstruation, and dropsical discharges” noting that it “deserves to be better known.” John King (1855), the renowned Eclectic physician and prolific author of numerous textbooks on botanical medi-

History Blue cohosh is an indigenous North American medicinal plant widely used by Native Americans and Eclectic physicians that continues to be utilized by modern midwives and herbal medicine practitioners. It has been known by various common names, including blue ginseng, yellow ginseng, and papoose root, the latter generally considered to be based on its use by Native Americans as an emmenagogue and as an aid in childbirth (Erichsen-Brown 1989). However, in 1905, Dr. Swinburne Clymer claimed that the name papoose root was given to blue cohosh because it was used to treat colic and cramps in Indian children. Cohosh is a term attributed to the Algonquins and presumably means “rough” referring to the texture of the roots (Lloyd and Lloyd 1886-1887). The Latin genus name Caulophyllum comes from the Greek kaulos meaning stem, and phyllon meaning leaf, referring to the fact that the leaves terminate in a manner that appears to be a continuation of the stem (Felter and Lloyd 1909). The first published botanical treatment of blue cohosh was by Gronovius in 1739 who originally placed the plant in the genus Leontice (Felter 1892) after a fanciful resemblance of the leaf of the plant to a lion’s foot. Linnaeus (1753) also included it in Leontice. In 1803, Caulophyllum was made a distinct genus by the famed French botanist and explorer Andre Michaux in his posthumously published Flora Boreali-Americana, based on the differences in morphology of the underground parts and other distinguishing characteristics (Loconte and Blackwell 1985). The specific epithet thalictroides refers to its resemblance to plants in the

Figure 1 Historical illustration of blue cohosh Source: Lloyd and Lloyd (1884-1887). American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

1


Table 1 Historical timeline of the medicinal use of blue cohosh rhizome and root Native American use

Widely used by a number of tribes, mainly as an anticonvulsive, antirheumatic, emmenagogue, gynecological aid, partus preparator, and sedative.

1813

First published report of the medicinal uses of blue cohosh by Peter Smith in his The Indian Doctor’s Dispensatory reporting the use of the herb as a purgative, catarrhal, and a topical application for burns.

1828-1830

Constantine Rafinesque in his Medial Flora cites the traditional uses of blue cohosh by Native Americans referring to it as “a powerful emmenagogue” promoting “delivery, menstruation, and dropsical discharges.”

1855

The noted Eclectic physician Dr. John “Pappy” King extols the virtues of blue cohosh as a “preparatory parturient,” regarding it as a gentler and safer alternative to ergot, the primary pharmaceutical used for labor induction at the time.

1891

Dr. John Dye in his Painless Childbirth wrote that blue cohosh was effective in both preventing premature labor and facilitating labor in post-date pregnancies.

1895

Dr. J.S. Ayers reports on his experience with blue cohosh as among “the most successful remedies” for dysmenorrhea, suppressed menses, uterine cramps, and labor.

1866

Blue cohosh is entered into the appendix of the 12th edition of the United States Dispensatory.

1882-1890

Blue cohosh is included in the 6th and 7th edition of the United States Pharmacopoeia.

1908

The Eclectic physician Finley Ellingwood wrote: “The effect of caulophyllum is to prolong gestation till the fetus is fully developed, labor being a physiological process at full term, and not pathological, therefore less protracted, less painful, and less liable to accidents.”

1908-1980s

Use of blue cohosh wanes with the general fall of botanical medicine in North America.

1978

Jeanine Parvati-Baker, herbalist and midwife, mentions blue cohosh as an emmenagogue and uterine tonic.

1981

Botanists propose Caulophyllum giganteum as a separate species. Caulophyllum giganteum was added to Flora of North America in 1997.

1986

Use of blue cohosh for birthing practices is once again popularized by Susun Weed in her Wise Woman Herbal for the Childbearing Year.

1990s

Blue cohosh is among the most widely used herbal agents for stalled labor and labor augmentation.

1996-1998

Case reports call into question the safety of blue cohosh in pregnancy, due to its use being associated with neonatal cardiotoxicity, neonatal stroke, and maternal toxicity.

1999

Mechanistic research identifies potential embryotoxic and teratogenic compounds in blue cohosh, including anagyrine, baptifoline, and N-methylcytisine.

2000-present

Blue cohosh remains popular as an alternative to conventional birth induction, although its use as a partus preparator falls.

cine, extolled the virtues of blue cohosh as a “preparatory parturient.” In this regard King, along with other Eclectics (e.g., John Uri Lloyd), regarded blue cohosh as a gentler and safer alternative to ergot, the primary drug used for labor induction at the time. According to King, blue cohosh “will frequently be found more desirable than ergot for expediting delivery, in all those cases where the delay is owing to fatigue, debility, or want of uterine energy; the contractions it occasions will nearly resemble the natural ones, instead of the continuous, spasmodic contractions effected by ergot.” According to Felter (1892), the popularity of blue cohosh was attributed to King’s inclusion of the botanical in King’s American Dispensatory in 1852, which subsequently led to its increased use among Eclectics and homeopathic physicians. In his American Eclectic Obstetrics (1855), Professor King described a compounded herbal preparation containing blue cohosh, that he named Parturient Balsam. He noted that it gave tone and activity to the uterus when its functions are “torpid or impaired.” King also reported that 2

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

blue cohosh was beneficial in the treatment of after-pains, for which it was to be combined with the uterine antispasmodic Viburnum opulus (cramp bark). In 1891, Dr. John Dye wrote of blue cohosh in his Painless Childbirth that it was effective in both preventing premature labor and facilitating labor in post-date pregnancies. In a presentation before the Homeopathic Medical Society, Dr. JS Ayers reported on his personal experience with blue cohosh, regarding it as among “the most successful remedies” for dysmenorrhea and used it for suppressed menses, uterine cramps, and for labor (Ayers 1895). Felter and Lloyd in their revision of King’s American Dispensatory called Caulophyllum one of the “oldest indigenous Eclectic remedies,” describing the botanical as an oxytocic used to “relieve false pains and uterine irritability; spasmodic uterine contractions; and for uterine subinvolution” (Felter and Lloyd 1898). In addition to its putative oxytocic and abortifacient actions, blue cohosh was also used to allay threatened miscarriage and premature labor. Ellingwood in 1919 wrote: “The effect of caulophyllum is to prolong gestation till the fetus is fully developed, labor


being a physiological process at full term, and not pathological, therefore less protracted, less painful, and less liable to accidents.” In addition to its use in pregnancy and gynecology, blue cohosh was regarded by Eclectics as a diaphoretic, diuretic, and expectorant (Felter 1892) and was extensively used for arthritis of the small joints (Ellingwood 1900). It took considerable time for blue cohosh to be recognized in the pharmaceutical compendia. The botanical is first mentioned in the appendix to the 12th edition of the United States Dispensatory (USD) (1866). The editors referencing the Eclectic uses, wrote of blue cohosh: “It is deemed especially emmenagogue, and is thought also to promote the contractions of the uterus, for which purpose, we learn, it is much employed by the ‘eclectic’ physicians, who consider it also possessed of diaphoretic and various other remedial properties” (Wood et al. 1866). Caulophyllum thalictroides was included as an official drug in the 6th and 7th revisions of the United States Pharmacopoeia in 1882 and 1890. Despite its removal from the list of approved USP substances after 1890, Eclectic practitioners continued to use it for numerous specific indications into the 20th century (Felter and Lloyd 1909), and it continued to appear in subsequent editions of the USD through 1955 (Osol and Farrar 1955). The use of blue cohosh as an antispasmodic, diaphoretic, emmenagogue, and uterotonic, and for stalled labor and some other indications, has persisted among herbalists and naturopathic physicians during the following decades (Kuts-Cheraux 1953; Mitchell 2003; Parvati-Baker 1978; Weed 1986). For these purposes, blue cohosh root and rhizome was used both singularly and in many of the same combinations as used historically by the Eclectics, primarily in tinctures but also in a powdered form. In recent years, case reports of maternal consumption of blue cohosh during late pregnancy have implicated blue cohosh in profound adverse neonatal outcomes, including myocardial infarction, multisystem organ ischemia, and stroke, casting doubt on the wisdom of its continued use as a partus preparator (Finkel and Zarlengo 2004a; Jones and Lawson 1998). Some midwives have reported discontinuation of the use of blue cohosh due to these concerns, while others continue to recommend blue cohosh during pregnancy for threatened abortion, due either to a disbelief that the threat of adverse effects is real or the belief that induction with blue cohosh is safer than induction via conventional means. While a staple among many modern herbal practitioners, blue cohosh is not included in contemporary pharmacopoeias.

thalictroides var. giganteum Farw., which was elevated to the species level by Loconte and Blackwell (1981), based on the presence of larger flowers, fewer flowers per inflorescence, and generally earlier flowering time resulting in reproductive isolation (Loconte and Blackwell 1985). This treatment was later incorporated into the Flora of North America (Loconte 1997). However, not all botanists have adopted this distinction (e.g., Gleason and Cronquist 1998). Irrespective of the taxonomical standpoint, because C. thalictroides sensu lato had a long history of medicinal use prior to 1981 when the segregation of var. giganteum at the species level was proposed, all North American Caulophyllum spp. should be recognized as having similar medicinal value unless comparative chemical or pharmacological testing proves otherwise. Partial supporting evidence for this approach can be seen in the illustration reproduced on the last page, which was originally published in the period before the differentiation between the species became known and features a plant with morphological characteristics of C. giganteum as an example of medicinally used blue cohosh. Following is a botanical treatment of Caulophyllum thalictroides and a diagnostic description of Caulophyllum giganteum, the two North American species of Caulophyllum, consistent with the modern classification (Gleason and Cronquist 1998; Haines 2003; Loconte 1997; Loconte and Blackwell 1985; Michaux 1803 [original citation]). Caulophyllum thalictroides (L.) Michx. Herbaceous perennial from rhizome. Stem: Erect, 20-90 cm tall. Leaves: One or two, compound, deep green, glaucous, petiole short or absent, the first leaf emerging above stem, second just below the inflorescence; first leaf consisting of 4 (sometimes 3) segments; second leaf consisting of 3 (sometimes 2) segments; leaf blade broadly obovate; leaflets 27+, broadly obovate, 3-8 cm long (sometimes up to 10 cm long), 2-10 cm wide, usually 2-3-lobed, bases rounded to wedge-shaped, often somewhat oblique, apices acute; margins entire to lobed;

Identification Botanical Identification The taxon Caulophyllum thalictroides was created by André Michaux in 1803. In 1918, Farwell, noting phenotypic differences within the species, proposed a new variety C.

Figure 2 Blue cohosh rhizome with roots From: Elliot D (1995). Wild Roots. Used with permission. American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

3


Table 2 Comparative morphology of Caulophyllum thalictroides and C. giganteum (C. thalictroides var. giganteum) C. thalictroides

C. giganteum

Leaves: First leaf (3-)4-ternate, second leaf (2-)3-ternate.

Leaves: First leaf (2-)3-ternate; second leaf (1-)2-ternate.

Inflorescence: with 5-70 flowers, relatively dense.

Inflorescence: with 4-18 flowers, relatively sparse.

Photograph courtesy of Arthur Haines, Delta Institute of Natural History, Canton, ME.

Photograph courtesy of Arthur Haines, Delta Institute of Natural History, Canton, ME.

Flower: Bracteoles 1-3 mm, caducous; sepals yellow, purple (rarely), or green, 3-6 mm long, 2-3 mm wide; petals 1-2.5 mm long; stamen filaments 0.5-1.5 mm; pistil 1-3 mm; style 0.25-1 mm long.

Photograph courtesy of Arthur Haines, Delta Institute of Natural History, Canton, ME.

4

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

Flower: Bracteoles 2-4 mm; sepals purple, red, brown, or yellow (rarely), 6-9 x 1-3 mm; petals 2-3 mm; stamen filaments 1.5-2.5 mm; pistil 3-5 mm; style 1-2 mm.

Photograph courtesy of Amanda Ingram, Wabash College, Crawforsville, IN.


3a.

3b.

3c.

3d.

3e.

3f. American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

5


3g.

3h.

3i.

3j. Figure 3 Botanical characteristics of Caulophyllum thalictroides and C. giganteum 3a. Early habit of C. thalictroides. Note nearly coetaneous flowering. 3b. Early habit of C. giganteum. Note subprecocious flowering. 3c. Caulophyllum thalictroides foliage and flowers. 3d. Close-up of a blue cohosh leaf (C. thalictroides). 3e. Close-up of the inflorescence of C. thalictroides (note the purplish-yellow phenotype). 3f. Typical yellow flowers of C. thalictroides. 3g. Blue cohosh plant with ripe “berries” (C. thalictroides). 3h. Blue cohosh “berries” with autumn foliage (C. thalictroides). 3i. Fresh rhizome of blue cohosh (C. thalictroides). 3j. Distribution of C. thalictroides. 3k. Distribution of C. giganteum. Map color key: green = species present and native in the state; yellow = species present and rare; brown = species not present in the state; crosshatched = questionable presence. Photographs courtesy of: (3a, 3b) Arthur Haines, Delta Institute of Natural History, Canton, ME; (3c) Roy Upton, Soquel, CA; (3d, 3f, 3g, 3i) © 2012 Steven Foster; (3e, 3h) H. Zell. Map images (3j, 3k) from: Kartesz JT and The Biota of North America Program (BONAP) (2011). Used with permission.

3k.

6

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012


venation pinnate to palmate. Inflorescence: Terminal, compound cyme with 5-70 flowers, relatively dense. Flower: Bisexual, radially symmetric; bracteoles 3-4, 1-3 mm, caducous; sepals 6, yellow, green, or tinted with purple, 3-6 mm long, 2-3 mm wide; petals 6, thickened, reduced to small fan-shaped bodies, 1-2.5 mm long; stamens 6; filaments 0.51.5 mm; anthers dehiscing by apical valves; ovary superior; carpel 1-3 mm; style 0.25-1 mm long. Fruit: Two drupelike seeds that burst through the ovary wall and develop exposed on short, stout stalks, dark blue, glaucous, 5-8 mm. Chromosome number: 2n = 16. Flowers in late spring, nearly coetaneously (at the same time with leaf expansion). C. giganteum (Farw.) Loconte and W. H. Blackw. syn. C. thalictroides var. giganteum Farw.: Stem: 20-70 cm. Leaves: First leaf consisting of 3 (sometimes 2) segments; second leaf consisting of 2 (sometimes 1) segments; leaflets 5-10 cm long, 3-8 cm wide; other characters like in C. thalictroides. Inflorescence: Terminal, compound cyme with 4-18 flowers, relatively sparse. Flower: Bracteoles 2-4 mm; sepals purple, red, brown, or yellow (rarely), 6-9 mm long, 1-3 mm wide; petals 2-3 mm long; filaments 1.5-2.5 mm long; pistil 3-5 mm; style 1-2 mm long. Chromosome number: 2n = 16. Flowers in early spring, subprecociously (slightly preceding leaf expansion). Distribution: Mesophytic forests of North America. Calulophyllum thalictroides is found from New Brunswick in the northeast to southern Manitoba and south to Missouri, South Carolina, and Alabama. Caulophyllum giganteum is confined to the northern and eastern portion of the range (Quebec to Michigan, Kentucky, and Tennessee).

Fracture (roots): Short, tough; internally grayish-white, consisting of thick bark and a woody central cord composed of starch-bearing parenchyma and, typically, a 4-rayed xylem. Aroma: Acrid and slightly fragrant when fresh root is bruised; slight to none when the root is dry. Powder: Sternutatory (causes sneezing). Taste: Initially sweetish and somewhat bitter, afterwards acrid and pungent. Fresh root has a slight to intensely acrid after-taste.

Figure 4 Cross section of blue cohosh rhizome E = epidermis; Par = parenchyma; P = phloem in the vascular bundle; MR = medullary rays; X = xylem in the vascular bundle. Source: Sayre (1917).

Macroscopic Identification Freshly harvested material consists of a matted and tangled mass of rhizomes and rootlets. When whole, the horizontal rhizome is 10-15 cm long and 6-10 mm thick, with a few upright branches 5-25 cm long and 4-16 mm thick; the cross-section is yellowish-brown and waxy. When cut, as often occurs in commerce, pieces are typically 1-3 cm long and 0.5-1 cm wide. The dried rhizome is hard, irregular, bent, and knotty, externally grayish-brown to dark reddishbrown, slightly annulate; upper surface with numerous depressed cup-shaped stem scars and often remnants of stem bases. The lower surface and lateral portions have numerous grayish-brown or yellowish-brown to dark brown branching roots bearing rootlets that are numerous, densely matted and tangled together, wiry, tough, fibrous, nearly cylindrical, longitudinally wrinkled, up to 13 cm long and 1-2 mm in diameter. When the surface of the fine roots is broken, a thin wiry inner cord is revealed. Organoleptic Profile Texture: Hard. Fracture (rhizome): Short, fibrous, tough and woody; inner surface light grayish-brown or whitish, with a waxy luster; bark thin, numerous narrow wood (xylem) wedges, sometimes in 2 rings, enclosing a large pith. In branches wedges are shorter, more uniform, and in 1 single narrow circle. American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

7


5a.

5b.

5c.

5d.

5e.

5f.

8

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012


5g.

5h.

5i.

5j. Figure 5 Macroscopic characteristics of blue cohosh rhizome and root 5a. Fresh blue cohosh rhizome with roots. 5b. Close-up of the fresh blue cohosh rhizome with roots. Note the depressed stem scars. 5c. Close-up of the blue cohosh rhizome. Note the annulation below the new growth. 5d. Dry blue cohosh rhizome with roots. 5e. Dry blue cohosh rhizome with some of the roots removed. 5f. Close-up of the blue cohosh rhizome. Note the wiry inner cord where the rootlets are broken (indicated with black arrows). 5g. Transverse section of the blue cohosh rhizome. Note the waxy, yellowish color. 5h. Dry blue cohosh rhizomes with most roots broken off. 5i. Cut and sifted (c/s) blue cohosh rhizome and root. 5j. Powdered blue cohosh rhizome and root. Photographs courtesy of American Herbal Pharmacopoeia®, Scotts Valley, CA.

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

9


Microscopic Identification

with slightly thickened cells; endodermis well defined; xylem consisting of vessels and fibers, with only a few short rays penetrating slightly into the region; vessels up to 40 µm diameter.

Rhizome Transverse section: Cork present; cortex of thin-walled parenchyma with occasional sclereids and pitted fibers; secondary phloem parenchymatous, without distinguishing features; secondary xylem vessels in radial lines, arranged with fibers into nearly rectangular radially elongated groups separated by broad medullary rays; vessels up to 40 µm diameter; central pith of thin-walled parenchyma cells with intercellular spaces.

Longitudinal section: Vessels with bordered pits. Starch is present in both rhizome and roots as primarily compound, ovate, very small granules (up to 10 µm). Powder Fragments of vessels with fibers; thin walled parenchyma with small simple spherical starch granules; cork with brown or yellow cell walls.

Longitudinal section: Vessels with bordered pits.

Note: Powder is best viewed prepared with acidified chloral hydrate in glycerol, at 400X magnification.

Root Transverse section: Epidermis brown; cortex of parenchyma

6b.

6a.

6d.

6e.

Figure 6 Microscopic characteristics of blue cohosh rhizome and root 6a. Rhizome transverse section: cork (ck); cortex (c); secondary phloem (sp); sclereids (scl); sieve cells (svc); vascular cambium (cam); vessels and fibers (v + f) in the secondary xylem (sx); and pith (p). 6b. Root transverse section: epidermis (ep); cortex (c); endodermis (end); phloem (ph); and xylem (xy) (ts). 6c. Fibers in the rhizome cortex (ts). 6d. Sclereid in the rhizome cortex (ls). 10

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

6c.

6f.

6e. Secondary xylem of the rhizome, showing radially aligned vessels embedded in fibers (ts). 6f. Root endodermis, phloem, and xylem with a short ray penetrating the region (ts). 6g. Starch granules. ls = longitudinal section; ts = transverse section. Microscopic drawings courtesy of Reinhard Länger, AGES PharmMed, Vienna, Austria.


6a.

6b.

6c.

6d.

6e.

6f.

Figure 7 Microscopic characteristics of blue cohosh rhizome and root 7a. Rhizome transverse section. 7b. Sclereids in the rhizome cortex (polarized light, compensator first order) (ts). 7c. Sclereid in the rhizome cortex (polarized light, compensator first order) (ls). 7d. Secondary xylem of rhizome (ts). 7e. Bordered pitted vessels and fibers in the secondary xylem of the rhizome (ls). 7f. Root transverse section. 7g. Powder: a. Thin-walled parenchyma with small simple spherical starch granules; b. cork with brown/yellow cell walls.

ls = longitudinal section; ts = transverse section. Microscopic photographs courtesy of Reinhard Länger, AGES PharmMed, Vienna, Austria.

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

11


Commercial Sources and Handling Collection The roots of blue cohosh are best harvested in the fall, after the seed has set and the plant has fixed primary and secondary constituents in preparation for its winter dormancy. Collect older, more mature roots, leaving younger roots for future harvests. Rotating between different locations from year to year is a good harvesting practice (Cech 2002; Harding 1908; Lockard and Swanson 2004; Sievers 1930).

Cultivation Hardy to zones 3 to 8 (-7 ºC to -40 ºC). Prefers rich, moist, neutral to slightly acidic, loamy soil (pH 5-6) under the shade of a mixed hardwood forest. Tolerates claylike or sandy soils, provided there is sufficient organic content and surface mulch to prevent the roots from drying out. Plant is sensitive to excess light, preferring areas with a complete forest canopy; full sun can be deleterious. Occasional mottled light is preferred. Does well on northern facing slopes. Caulophyllum thalictroides can be propagated by seeds or root division. Seeds should be devoid of the blue skins, which inhibit germination, and kept moist until planting. The seeds can be planted as soon as the fruits ripen, around midsummer, but flowering will typically not occur until the 3rd or 4th year. Plants grown from seed will need to be in the ground for a relatively long time (up to 5 years) before the roots can be harvested. Fall division of the rootstocks is another means of propagation, though some sources say that established plants should be left undisturbed (Cech 2002; Foster 1993; MBG 2009).

Handling and Processing After harvesting the roots, shake them to remove excess soil and place them in a sack or a bucket, protected from light. If roots are to be shipped fresh and/or stored prior to drying, they should not be used: the native soil helps to protect the roots from fungal diseases, which can ruin washed roots that are stored too long in a sack or pile. Wash roots just prior to drying or processing with a pressure hose or running water, breaking the root/rhizome mass apart to clean away trapped dirt and repeatedly rinsing until water runs clear. Some of the larger crowns may need to be chopped in order to remove lodged mud or stones. However, keep roots as whole as possible, to prevent excessive oxidation (Cech 2002; Lockard and Swanson 2004).

Drying Roots should be air-dried whole, out of the sun, in a warm, well-ventilated area, turning frequently. If drying outside, protect the roots from morning and evening dew (Lockard and Swanson 2004). A forced-air dehydrator is preferable to regular air-drying. Dry for 1 day at a low temperature (21 ºC) with a high air flow, then increase the temperature to high (43 ºC) and dry the roots until they snap (Cech 2002). 12

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

Storage Roots should be stored protected from air, light, heat, moisture, and insect infestation. For optimal storage, keep the roots in airtight, lightproof containers, such as sacks or drums, in a dark, dry, and cool environment. Under these conditions the dried roots will retain their potency for up to 2 years (Cech 2002).

Adulterants No reports of adulteration in the blue cohosh trade today could be located. Historically, a different spe-

cies, twin leaf (Jeffersonia diphylla), of the same family (Berberidaceae) was reported to wholly or partially adulterate lots of blue cohosh (Lloyd and Lloyd 1886-1887; see Table 3).

Qualitative Differentiation The Eclectics often noted that therapeutic preparations should be prepared from freshly dried root (e.g., Scudder 1870).

8a.

8b. Figure 8 Twinleaf (Jeffersonia diphylla), a historical adulterant of blue cohosh 8a. Twinleaf in natural habitat. 8b. Twinleaf (right) next to blue cohosh (left) growing in a cultivated plot. Photographs courtesy of James Steakley.


Table 3 Morphological differentiation of blue cohosh and twin leaf (Jeffersonia diphylla) roots Blue Cohosh

Twin Leaf

Rhizome prominent, the roots only partly concealing it. ¼-1/3 inch in diameter and 4-6 inches long.

Rhizome obscured, much smaller, almost entirely covered with a mass of roots, approximately ¼ inch in diameter and 1-2 inches long. The clump of roots is more extensive than that surrounding blue cohosh rhizome.

The broken rhizome and root are dull ashy color.

The broken rhizome is distinctly yellow or greenish in color.

The roots are smooth, evenly curved, and have but few branches.

The roots are contorted, especially near the extremity, and give rise to numbers of wiry branches, which, associated with the others, nearly hide the rhizome.

Preparations Blue cohosh is used in single ingredient preparations and in formulas as teas, tablets, capsules, and liquid extracts. See Table 10 for traditionally used formulas.

Caulophyllum found in eastern Asia. It shares some similarities with C. thalictroides in the chemical profile; however, to date, C. robustum is not known to be in trade in North America and, therefore, is not fully addressed in this review.

Fluid Extract (Percolation)

Alkaloids

· Dry blue cohosh root: 16 parts by weight.

The primary alkaloids reported in blue cohosh root are the quinolizidine alkaloids N-methylcytisine (also known as caulophylline), baptifoline, and anagyrine and the aporphinoid isoquinoline alkaloid magnoflorine (Figure 9; Betz et al. 1998; Flom et al. 1967; Kennelly et al. 1999; Power and Salway 1913; Satchithanandam et al. 2008; Woldemariam et al. 1997). Woldemariam et al. (1997) extracted powdered blue cohosh root material in 70% ethanol and quantitatively measured the content of the alkaloids by high performance liquid chromatography (HPLC). Betz et al. (1998) identified the 4 constituents in blue cohosh products by gas chromatography-mass spectrometry (GC/MS) and noted that alkaloid content differed significantly between products. Ganzera et al. (2003) used methanol extraction and HPLC/ MS for isolation and identification of the compounds. Satchithanandam et al. (2008) isolated alkaloid standards for magnoflorine, baptifoline, and N-methylcytisine from powdered roots and rhizomes and used the standards to quantify the compounds in a methanolic extract of blue cohosh roots by HPLC. The identities of the alkaloids and saponins were confirmed by HPLC/MS and nuclear magnetic resonance (NMR) spectrometry. Most recently, Avula et al. (2011) reported on the magnoflorine content in blue cohosh roots and rhizomes and their commercial preparations. A more detailed analysis by Kennelly et al. (1999) using GC/MS resulted in isolation of several minor compounds, including the novel alkaloid thalictroidine, an aporphine

· Extracting solvent: 60% aqueous ethanol (3 parts ethanol, 2 parts water by volume). Moisten the powder with the extracting solvent and pack into the percolation cylinder. Reserve the first 14 parts of the percolate. Continue the percolation until the material is exhausted, evaporate the latter portion, and mix with the reserved 14 parts.

Constituents Blue cohosh chemistry has been studied since the mid-19th century (Mayer 1863). For a brief historical review see Ferguson and Edwards (1954). The primary compounds of interest in blue cohosh are alkaloids and saponins. The alkaloids have demonstrated nicotinic and muscarinic receptor activity, and the saponins have been putatively correlated with the uterine stimulatory activity, corresponding to one of the primary medicinal uses of the root. Additionally, several alkaloids were implicated as potential teratogens when used in the early trimester of pregnancy, while the saponins are allegedly associated with neonatal cardiac toxicity reported with the use of blue cohosh close to giving birth as a partus preparator. Caulophyllum robustum Maxim. is a distinct species of

Figure 9 Major alkaloids occurring in blue cohosh rhizome and root American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

13


Table 4 Content of major alkaloids in blue cohosh roots and rhizomes Alkaloid

Content (mg/g dry weight) 11.00

Magnoflorine

Baptifoline

Woldemariam et al. (1997)

5.04 ± 0.15

Root/rhizome

Ganzera et al. (2003)

8.72 ± 3.2

Roots/rhizomes

Satchithanandam et al. (2008)

3.6

Roots

Avula et al. (2011)*

0.75

Roots

Woldemariam et al. (1997)

0.44 ± 0.12

Root/rhizome

Ganzera et al. (2003)

2.02 ± 1.2

Roots/rhizomes

Satchithanandam et al. (2008)

Roots

Woldemariam et al. (1997)

Root/rhizome

Ganzera et al. (2003)

Roots

Woldemariam et al. (1997)

0.14 ± 0.01

Root/rhizome

Ganzera et al. (2003)

4.58 ± 0.9

Roots/rhizomes

Satchithanandam et al. (2008)

0.47 ± 0.01 0.90

N-methylcytisine

Publication reference

Roots

0.18

Anagyrine

Plant part as reported

* Data from Avula et al. (2011) based on HPLC-UV-ELSD analysis.

Saponins Table 5 Difference in content of the blue cohosh alkaloids in roots and rhizome of the same plant Alkaloid Magnoflorine

Baptifoline

Anagyrine

N-methylcytisine

Content (mg/g dry weight)

Plant part

3.72

Root

7.47

Rhizome

0.95

Root

0.33

Rhizome

1.03

Root

0.28

Rhizome

0.39

Root

0.15

Rhizome

Source: Ganzera et al. (2003).

alkaloid taspine earlier reported in dragon’s blood (Croton spp.), as well as several quinolizidine alkaloids, such as α-isolupanine, 5,6-dehydro-α-isolupanine, lupanine, and sparteine. Magnoflorine was proposed as a putative biosynthetic precursor of taspine. Taspine has been reported as being highly cytotoxic (Pieters et al. 1993). Additional alkaloids identified in blue cohosh rhizome and roots include anagyrine, O-acetylbaptifoline, and lupanine, as well as two novel compounds caulophyllumines A and B (Ali and Khan 2008). Thalictroidine isolated by Kennelly et al. (1999) and caulophyllumines isolated by Ali and Khan (2008) were identified by the respective researchers as piperidyl-acetophenone compounds, a rarely occurring type of compounds in plants. The levels of major alkaloids reported in blue cohosh by the separate research groups are compared in Table 4. 14

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

Saponins constitute the second important group of compounds found in blue cohosh. The two most common aglycones are hederagenin (23-hydroxyolean-12-en-28-oic acid) and caulophyllogenin (16α,23-dihydroxyolean-12-en28-oic acid), although other similar pentacyclic structures have been characterized (e.g., Jhoo et al. 2001; Matsuo et al. 2009). Power and Salway (1913) were the first to report two glycosides in C. thalictroides root, which they named caulosaponin and caulophyllosaponin. Hydrolysis of caulosaponin yielded hederagenin (McShefferty and Stenlake 1956, cited in Betz et al. 1998). Almost half a century later, Jhoo et al. (2001) elucidated the structures of 7 triterpene saponins found in n-butanol fraction of a 95%-ethanolic extract of blue cohosh roots and rhizomes using 1H and 13C NMR (Figure 10). The saponins were identified as leonticin D (earlier isolated from Leontice kiangnanensis), caulosides A, B, C, D, and G (having been isolated from C. robustum), and an echinocystic acid-based saponin previously characterized in Pithecellobium dulce. Ali and Khan (2008) reproduced the isolation of 6 of the same glycosides (except the echinocystic acid-based saponin) and isolated and characterized a new saponin, which they named cauloside H, as well as two more compounds previously described in other species, oleanolic acid-based ciwujianoside A and saponin PE. Matsuo et al. (2009), using blue cohosh material obtained from Ontario, Canada, isolated and characterized 22 triterpene glycosides, including the known caulosides A, B, C, and D, leonticin D, several other compounds previously isolated from other species, and 10 novel compounds. The structures of typical saponins reported in blue cohosh by most researchers, are shown in Figure 10. Quantification of saponins in blue cohosh material from various sources was undertaken by several research groups (Table 6). Ganzera et al. (2003) developed a HPLC


CH2OH

Hederagenin

COOR1

COOR1

OH

RO

RO CH2OH

CH2OH

Caulophyllogenin

Hederagenin

Aglycone

R

R1

Cauloside Aa, b, c, d

Hederagenin

α-L-arabinopyranosyl

H

Cauloside Ba, b, c, d

Caulophyllogenin

α-L-arabinopyranosyl

H

Cauloside Ca, b, c, d

Hederagenin

β-D-glucopyranosyl-(1®2)-α-Larabinopyranosyl

H

COOR1

Cauloside Da, b, c, d

OH

Hederagenin

α-L-arabinopyranosyl

α-L-rhamnopyranosyl-(1®4)-βD-glucopyranosyl-(1®6)-β-Dglucopyranoside

β-D-glucopyranosyl-(1®2)-α-Larabinopyranosyl

α-L-rhamnopyranosyl-(1®4)-βD-glucopyranosyl-(1®6)-β-Dglucopyranoside

RO CH2OH

Cauloside Ga, b, d

Hederagenin

Caulophyllogenin

Cauloside Hb, d

Caulophyllogenin

3-O-β-D-glucopyranosyl-(1®2)-α-Larabinopyranosyl

α-L-rhamnopyranosyl-(1®4)-βD-glucopyranosyl-(1®6)-β-Dglucopyranoside

Leonticin Da, b, c, d

Caulophyllogenin

α-L-arabinopyranosyl

α-L-rhamnopyranosyl-(1®4)-βD-glucopyranosyl-(1®6)-β-Dglucopyranoside

Figure 10 Typical saponins of blue cohosh rhizome and root Reported by aJhoo et al. (2001), bAli and Khan (2008), cMatsuo et al. (2009), dAvula et al. (2011).

Table 6 Content of saponins in blue cohosh roots and rhizomes Compound

Content (mg/g dry weight)*

Cauloside A

0.36 ± 0.03

Avula et al. (2011)

Cauloside B

0.70 ± 0.00

Avula et al. (2011)

Cauloside C

0.62 ± 0.03

Avula et al. (2011)

Cauloside D

Leonticin D

Cauloside G Cauloside H Saponin PE

8.70 ± 2.16 15.80 ± 8.52 4.25 ± 0.64 20.68 ± 6.97 15.02 ± 7.41 2.70 ± 0.57 20.93 ± 6.89 28.66 ± 17.75 5.05 ± 0.78 0.23 ± 0.04 Under the limit of detection

Publication reference

Ganzera et al. (2003) Satchithanandam et al. (2008) Avula et al. (2011) Ganzera et al. (2003) Satchithanandam et al. (2008) Avula et al. (2011) Ganzera et al. (2003) Satchithanandam et al. (2008) Avula et al. (2011) Avula et al. (2011) Avula et al. (2011)

* All values are average of the means of different roots ± standard deviation between the roots. American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

15


method with the utilization of ultraviolet light (UV) (310 nm) and evaporative light scattering detection (ELSD) and used it simultaneously with LC/MS to identify and quantify 3 saponins in blue cohosh roots and rhizomes. The saponins identified by Ganzera et al. (2003) were identical to leonticin D (saponin 5 per the authors), cauloside G (saponin 6), and cauloside D (saponin 7). The same 3 saponins were identified by Satchithanandam et al. (2008) who similarly used a HPLC-UV-ELSD system for the simultaneous determination of alkaloids and saponins in blue cohosh roots and rhizomes. The structures of the saponins were confirmed by HPLC/MS and NMR analyses in both studies. These compounds were then used as standards for quantitation of saponins in dietary supplement samples (Satchithanandam et al. 2008). Lastly, Avula et al. (2011) reported their data on the content of saponins determined by ultra-high performance liquid chromatography (UPLC) with UV and ELSD detection (UPLC-UV-ELSD), HPLC-UV-ELSD, and HPTLC. The rapid chromatographic methods (35 minutes for HPLC-UV-ELSD and 8 minutes for UPLC-UVELSD) allowed the separation of 8 triterpene saponins: caulosides A, B, C, D, G, and H, leonticin D, and saponin PE. Wide variations in the content of alkaloids and saponins in blue cohosh products were noted by most researchers (Avula et al. 2011; Betz et al. 1998; Ganzera et al. 2003). Levels of saponins were highest in supplements containing powdered roots/rhizomes and lowest in liquid preparations (hydroethanolic and glycerine extracts), while the levels of alkaloids did not differ much between the types of products (Tables 13 and 14).

A na ly t i ca l

Pharmacological evidence suggests that the putative oxytocic activity of blue cohosh is due to its content of saponins, and, additionally, magnoflorine (El Tahir 1991, cited in Schiff 1996). While there are studies reporting on these compounds (see Constituents), currently no formally validated methods for quantification of blue cohosh saponins or alkaloids exist. The primary analytical goal is, therefore, to properly identify the botanical, taking note that C. thalictroides and C. giganteum should be considered similarly. Potential areas of interest for future analytical work include validating methods for quantitation of total saponins and/or magnoflorine in blue cohosh and, with regards to potentially toxic compounds, the quantitation of N-methylcytisine and anagyrine.

High Performance Thin Layer Chromatography (HPTLC) This method is based on the method by Avula et al. (2011). The mobile phase used in this method provides a more reproducible separation than the original. Sample preparation Dry roots: Mix 0.5 g of milled raw material in 10 mL of methanol-water (1:1). Sonicate for 10 min. Filter through a 0.45 µm PTFE membrane filter or centrifuge for 5 min at 16

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

5000 rpm. The filtrate or supernatant is used as test solution. Liquid preparations: Dilute 1:1 with methanol. Ethanolwater extracts can also often be applied neat. Standard preparation (optional) a) Botanical reference material. Prepare same as sample. b) Chemical standards. 1.0 mg each of fructose and cauloside C are dissolved in 1 mL of methanol each. Reagent preparation Sulfuric acid reagent: Slowly add 20 mL of concentrated sulfuric acid to 180 mL of ice-cooled methanol. Mix well. Bring to room temperature. Chromatographic conditions Stationary phase: HPTLC plates 10 x 10 cm or 20 x 10 cm silica gel 60 F 254. Mobile phase: Dichloromethane, methanol, water (70:30:4). Sample application Apply 2 mL each of test solution and of the standard solutions as 8 mm bands with a minimum distance of 2 mm between bands. Application position should be 8 mm from the lower edge of the plate. Prior to development, condition the plate for 10 minutes at 33% relative humidity. Development 10 x 10 cm or 20 x 10 cm Twin Trough Chamber lined with filter paper, saturated with 5 or 10 mL of developing solvent in each trough for 20 minutes. Developing distance is 70 mm from lower edge of plate. The plate is then dried for 5 minutes in a stream of cold air. Detection Immerse the plate into sulfuric acid reagent for 1 second (or spray the plate evenly with the reagent), allow to dry briefly in a stream of cold air, and heat at 100 °C for 5 min. Examination is performed in white light and under UV 366 nm. Results Compare to the chromatograms provided.

Limit Tests Foreign Organic Matter: Not more than 2%. Total Ash: Not more than 9%, determined on 1 g of powdered root. Acid-insoluble Ash: Not to exceed 5%. Loss on Drying: Not more than 12%, determined on 2 g of powdered root dried at 100 ˚C for 5 hours.


11a.

11b. Figure 11a HPTLC chromatogram of blue cohosh rhizome and root and blue cohosh-containing products (sulfuric acid reagent, UV 366 nm) Discussion of the chromatogram. The standard fructose (Lanes 1 and 25, Rf = 0.24) shows a light brown fluorescent zone. Cauloside C (Lanes 2 and 25, Rf = 0.59) shows a light tan fluorescent zone. The four tightly grouped bands in the lower RF, and the 5 tightly grouped bands the upper Rf correspond to (in ascending order): cauloside H, cauloside G, magnoflorine, leonticin D, cauloside D, cauloside C, saponin PE, cauloside B, and cauloside A. In the blue cohosh samples, fluorescent zones can be detected matching those of fructose and cauloside C in color and position. In between the application position and the position of fructose, there are a series of fluorescent zones (blue at Rf 0.05, brown at Rf 0.13, green at Rf 0.16, and red-brown at Rf 0.18). In between the position of fructose and that of cauloside C, the blue cohosh samples exhibit another series of fluorescent zones (very faint tan at Rf 0.32, blue at Rf 0.46, and bright green at Rf 0.52). Above the zone due to cauloside C, there are two light tan fluorescent zones at Rf 0.70 and 0.76. Other faint fluorescent zones may be visible. The fingerprints of the liquid extracts are varied. The ethanol-water extract on Lane 19 shows a similar profile to the whole root material (Lanes 3-17). The preparation on Lane 20 is Mother’s Cordial, which contains blue cohosh root; however, a blue cohosh fingerprint is not distinguished. The glycerine extracts (Lanes 21-23) show bands in the upper Rf region, matching the whole root, which can be used for identification purposes. Bands corresponding to those in whole root samples are evident in the combination product (Lane 24), making this a potential identification method of blue cohosh in finished products. Figure 11b HPTLC chromatogram of blue cohosh rhizome and root and blue cohosh-containing products (sulfuric acid reagent, white light) Discussion of the chromatogram The standard fructose (Lanes 1 and 25, Rf = 0.24) shows a tan zone. Cauloside C (Lanes 2 and 25, RF = 0.59) shows a violet zone. In the blue cohosh samples, the zone due to cauloside C as well as a grey-brown zone at the position of fructose can be detected. The four tightly grouped bands in the lower Rf and the 5 tightly grouped bands in the upper Rf correspond to (in ascending order): cauloside H, cauloside G, magnoflorine, leonticin D, cauloside D, cauloside C, saponin PE, cauloside B, and cauloside A. In between the

application position and the position of fructose, there are a series of zones (yellow at Rf 0.05, violet at Rf 0.13, and violet at Rf 0.18). In between the position of fructose and the zone due to cauloside C, the samples of blue cohosh exhibit two other zones (violet at Rf 0.26 and a very faint violet at Rf 0.32). Above the zone due to cauloside C, there are two violet zones at Rf 0.70 and 0.76. Other faint zones may be visible. The fingerprints of the liquid extracts are varied but more consistent in white light, compared to UV 366 nm. The ethanol-water extract on Lane 19 shows a similar profile to that of the whole herb. The preparation on Lane 20 is Mother’s Cordial, which contains blue cohosh root; however, a blue cohosh fingerprint is not distinguished. The glycerine extracts (Lanes 21-23) show bands in the upper Rf region matching the whole root, which can be used for identification purposes. Bands corresponding to those in whole root samples are evident in the combination product (Lane 24), making this a potential identification method of blue cohosh in finished products.

Lane 1: Lane 2: Lane 3: Lane 4: Lane 5: Lane 6: Lane 7: Lane 8: Lane 9: Lane 10: Lane 11: Lane 12: Lane 13: Lane 14: Lane 15: Lane 16: Lane 17: Lane 18: Lane 19: Lane 20: Lane 21: Lane 22: Lane 23: Lane 24: Lane 25:

D-(-)-fructose. Cauloside C. Blue cohosh rhizome. Blue cohosh whole rhizome. Blue cohosh root. Blue cohosh root. Blue cohosh root. Blue cohosh root. Blue cohosh root (cultivated). Blue cohosh root (cut & sifted). Blue cohosh root (cut & sifted, commercial). Blue cohosh rhizome (cut & sifted). Blue cohosh root. Blue cohosh root. Blue cohosh root. Blue cohosh freeze dried rhizome/root. Blue cohosh rhizome. Blue cohosh root extract. Blue cohosh liquid formula. Blue cohosh liquid formula (Mother’s Cordial). Blue cohosh alcohol extract w/ glycerin. Blue cohosh extract with glycerin. Blue cohosh alcohol extract w/ glycerin. Blue cohosh formula tablets. D-(-)-fructose/cauloside C (with increasing Rf).

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

17


Th e r a p e u t i c s Blue cohosh is one of the primary botanicals used by midwives for inducing or augmenting labor. There is a plethora of historical information supporting this use. However, no formal clinical trials or animal studies have been performed regarding the botanical’s efficacy in labor. Studies on some of the isolated constituents of blue cohosh root also found in other botanicals (e.g., magnoflorine) may help to elucidate pharmacology of blue cohosh. The safety of the use of the botanical in pregnancy has been questioned due to a potential for maternal and fetal toxicity, a concern raised by case reports of adverse events and animal studies suggesting a causative link between blue cohosh constituents and some cases of teratogenicity. See Safety Profile for the discussion of the use of blue cohosh in pregnancy, most specifically for labor augmentation or induction, within the context of the conventional methods of labor induction.

Pharmacokinetics No pharmacokinetic studies have been performed with blue cohosh root or its primary constituents. Pharmacokinetics of taspine, a minor compound in blue cohosh with a high potential for toxicity, was studied in rats after oral administration (Li et al. 2005). Maximum concentration (Cmax), time to maximum concentration (Tmax), area under the concentration-time curve (AUC), and rate of elimination/ half-life (T1/2) were evaluated (Table 7). Overall, the results indicated that orally administered taspine is absorbed and eliminated slowly. Intravenously administered taspine was shown to accumulate primarily in the lung, with distribution to the liver, spleen, lungs, kidneys, heart, and brain in mice (Lu et al. 2008). A pharmacokinetic study of sparteine was conducted on subjects in Canada (Vinks et al. 1982). Fifteen men and 33 women were given 55.4 mg freebase equivalent of sparteine sulfate. The subjects fasted overnight and no food was allowed for 2 hours after sparteine administration. Urine was collected at 0-4, 4-8, 8-12, and 12-24 hours for 24 hours and analyzed for the presence of sparteine sulfate and its two metabolites, 2- and 5-dehydrosparteine. Two metabolic phenotypes were identified: extensive metabolizers, who excreted 7.4-23.6% of the alkaloid unchanged, and nonmetabolizers, who excreted 54%-74.2% of the alkaloid. The groups also differed in their urinary excretion rates, with poor metabolizers excreting most of the drug in the first 4 hours. However, numerical data on the pharmacokinetic parameters was not provided in the study. Based on the data from Caucasian and Japanese populations, poor metabolizers occur among humans at the frequency of 2%-10% (Ishizaki et al. 1987).

Pharmacodynamics Very limited data exists on the pharmacodynamics of blue cohosh. Most investigations of the botanical to date have focused on its potential for toxicity when used in pregnancy and labor (see Safety Profile). A seminal study on the effects of blue cohosh glycosidic fraction on the cardiac and smooth 18

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

Table 7 Pharmacokinetics (maximum concentration, Cmax; time to reach maximum concentration, Tmax ; area under the concentration/time curve, AUC; elimination half-life, T1/2) of orally administered taspine in rats

Parameter

Value

Cmax, ng/mL

64.15

Tmax, h

2.84

AUC, ng·mL/h T1/2, h

1214.98 10.96

Source: Li et al. (2005).

musculature in animal models was conducted by Ferguson and Edwards (1954). A series of experiments were conducted by university biology students to determine the effects of blue cohosh on tissue contractility in a variety of tissues (e.g., Berger and DeGolier 2008; Forsgren and DeGolier 2011; Stanley 2007; VenOsden and DeGolier 2009); only one of these was published (Berger and DeGolier 2008). Additional pharmacological data may be extracted from studies on individual constituents of blue cohosh root found in other species.

Cardiovascular Effects Blue cohosh has been associated with cardiotoxic and proarrhythmic activity. A case of cardiotoxicity in a neonate whose mother ingested blue cohosh in late pregnancy has been reported, and fetal tachycardia has been observed by midwives using blue cohosh for labor induction (Romm 2009). See Safety Profile for detailed discussion of the reports. Animal Studies Ferguson and Edwards (1954) perfused turtle and frog hearts with blue cohosh “crystalline glycoside solution” at the doses of 0.3-0.6 mg and 0.05-0.14 mg, respectively, and observed positive inotropic effects with slight bradycardia. Larger doses than these produced cardiac arrhythmias resulting in partial heart block and, eventually, systolic arrest. A series of small doses ultimately culminated in the toxicity similar to that produced by a single large dose, suggesting cumulative effects. Perfusion of rat hearts with 10 mg of the extract per 0.1 cc at 38 °C produced a positive inotropic effect with slight tachycardia and a mean reduction in coronary blood flow of 25.6% ± 1.36 (SEM). The same glycoside was reported to possess vasoconstrictive activity, which could potentially lead to hypertension. Contraction of carotid spiral arteries from cattle and hogs was observed in vitro using 2-10 mg of the crystalline glycoside dissolved in 70 cc of perfusion solution, with contractions proportional to the dose (Ferguson and Edwards 1954). Stanley (2007), a university senior at Bethel University (St. Paul, MN), studied the effects of blue cohosh on heart muscle contractility in frog hearts in situ. Three doses (0.5 mg, 2.0 mg, and 5.0 mg) of a blue cohosh extract were applied to the heart. The 2 lower doses exhibited immedi-


ate bradycardic effects, whereas the high dose initially led to tachycardia followed by bradycardia. In all cases, heart rates returned to within 10% of control heart rate 3 minutes after the application of the extract. All three concentrations suppressed heart rate at the time intervals assessed (80 s, 100 s, and 120 s), but only the 2.0 mg dose was significant (P < 0.05) with an approximate drop in heart rate of 20-25%. These findings were confirmed in similar experiments by other students (DeGolier 2011, personal communication to AHP, unreferenced; Johnson 2009; Widstrom 2009). Further experimentation at the same institution showed this activity to be associated with muscarinic and nicotinic receptor interactions (VenOsdel and DeGolier 2009). Hulst (2009) demonstrated that D-tubocurarine, a known nicotinic receptor antagonist, partially suppressed blue cohoshinduced bradycardia in isolated rat hearts. The alkaloid N-methylcytisine, contained in blue cohosh, is a potent nicotinic acetylcholine receptor agonist, while anagyrine has a moderate affinity to muscarinic acetylcholine receptors (Schmeller et al. 1994; see Table 8). Selected compounds from blue cohosh have been known as antiarrhythmic and antihypertensive agents. Magnoflorine has been shown to decrease arterial blood pressure in rabbits (El Tahir 1991, cited in Schiff 1996). Sparteine, identified relatively recently as a minor compound in blue cohosh (Kennelly et al. 1999), is a known noncompetitive nicotinic receptor antagonist and a class 1a antiarrhythmic agent (Na+ channel blocker). Historically, sparteine was used to arrest cardiac arrhythmias, though its role as a cardiac agent was ultimately supplanted by such medications as quinidine and digoxin. Sparteine was not detected by the majority of researchers analyzing blue cohosh. Therefore sparteine, when it occurs in blue cohosh, is likely to occur only in very small concentrations and may or may not contribute to the activity of blue cohosh.

Effects on Uterine Smooth Muscle Tissue Blue cohosh may be considered an oxytocic agent, providing mechanistic support for the traditional use of this herb. Animal Studies Reports of blue cohosh effects on the smooth muscle tissue of the uterus in the scientific literature date back to nearly 100 years ago. An article in the 1916 issue of the Journal of the American Medical Association (Pilcher et al. 1916) reported on the stimulating effect of a blue cohosh solution (1:2000) on isolated uterine strips from guinea pig. The authors stated, however, that it was not expected that this effect would occur clinically. No effect on the uterus was observed when dogs were administered an extract of blue cohosh (Pilcher and Mauer 1918). Later, Ferguson and Edwards (1954) showed by a series of experiments that a crystalline glycoside isolated from blue cohosh caused increased uterine tone and rate of contraction in rats. While treating rat uterine horns (in early estrus) with 0.25-0.5 mg of the glycoside in 70 cc of bath solution, the authors observed an increase in the degree and rate of contraction. At higher concentration (1 mg/70 cc), there was an immediate increase in tone and rate but a decreased

Table 8 Binding (functional strength, IC50) of selected alkaloids from blue cohosh root and rhizome to nicotinic (nAChR) and muscarinic (mAChR) acetylcholine receptors Compound

nAChR IC50, µM

mAChR IC50, µM

Anagyrine

2096

132

Lupanine

5

114

N-Methylcytisine

0.05

417

Sparteine

331

21

Source: Schmeller et al. (1994).

degree of contraction. The dose of 1 mg/cc effected a contraction lasting approximately 90 minutes. Similar results were obtained with rabbit and guinea pig uteri. Further, when using rat uterine strips in early pregnancy, a dose of 0.5 mg in 70 cc of bath solution produced initial uterine contractility alternating with returns to normalcy, with the cycles continuing for approximately 60 minutes. Following that, a second dose of 0.5 mg/70 cc led to an immediate increase in tone. The degree of contraction was increased in situ with the administration of 5 mg/kg of the isolated glycoside to rat intravenously, with a slightly increased contraction rate (Ferguson and Edwards 1954). Doses of 8-10 mg/kg caused rapid and pronounced increase in tone and contraction rate in situ, with a slight decrease in contraction amplitude. Increased tone persisted for approximately 45 minutes. The same doses (8-10 mg/kg) in vivo caused similar but significantly reduced changed in uterine tone (Ferguson and Edwards 1954). Additional assays performed by these researchers indicated that 1 mg of the glycoside was equivalent in activity to 0.00065 units of pituitrin. The authors noted that the aglycone produced the same uterine action as the unhydrolyzed glycoside. In an attempt to confirm the oxytocic effects of blue cohosh reported by Ferguson and Edwards (1954), Berger and DeGolier (2008) suspended murine uterine horns in a smooth muscle bath and exposed them to an aqueous extract of blue cohosh (doses ranging from 0.037-23.8 mg/20 cc buffer solution). The tissues showed an increase in the strength of contractile force, the frequency of the contraction, and basal tonus. Contractile forces were significantly greater with higher doses (P = 0.0027), and dose-dependency was consistent in all stages of estrus observed. Blocking experiments with D-tubocurarine, a nicotinic receptor antagonist, were inconclusive, as decreases in contractile responses were not statistically different from the observed fatigue following controlled cumulative dosing. This suggests that mechanisms other than those modulated by cholinergic receptors are involved in blue cohosh’s action on isolated uterine smooth muscle tissue. Magnoflorine has demonstrated oxytocic activity (El Tahir 1991, cited in Schiff 1996). Sparteine was once widely used in obstetrics for its oxytocic effects in the treatment of uterine inertia, for induction of labor, and for stopping postpartum hemorrhage. Sparteine increases the intensity, frequency, and duration of uterine contractions American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

19


(Stubblefield et al. 1963). The use of sparteine first fell out of favor because of its unpredictability of action. In 1979 the US Food and Drug Administration (FDA) restricted its use due to unpredictable side effects, including uterine rupture and other obstetric complications. In a small percentage of women sparteine reportedly caused tetanic (hypertonic) uterine contractions and, in some cases, fetal bradycardia (though Gray and Plentl (1958) assert that the drug was safe without adverse maternal or fetal effects when used alone rather than combined with other oxytocic drugs). Smaller doses of sparteine are needed for it to elicit oxytocic effects than those used for the treatment of cardiac arrhythmias (Gray and Plentl 1958). The exact amount of sparteine in blue cohosh has not been reported; in most material sparteine occurs in very low concentrations or is not present. In Vitro Data Among the alkaloids present in blue cohosh, N-methylcytisine has a particularly high binding affinity to nicotinic receptors and low binding affinity for muscarinic acetylcholine receptors, while several other constituents display weak binding affinity for nicotinic receptors and greater binding affinity to muscarinic acetylcholine receptors (Table 8). Stimulation of muscarinic receptors in the uterus of the rat was shown to trigger myometrial contractions and uterine artery vasodilatation (Papka et al. 1999). These receptor interactions may have broader effects in other tissues as well. Adrenergic receptors are another type of receptors that are expressed on uterine smooth muscle tissue (Berry et al. 1992; Williams et al. 1976). Magnoflorine, found in relatively high quantities in blue cohosh root, has been shown to bind to a1A-adrenoreceptors (Wang et al. 2010). Activation of a-adrenergic receptors has been linked to reduced production of uterine prostaglandins (Gonzales et al. 1988).

Effects on Smooth Musculature of Other Organs Animal Studies Intestinal smooth muscle spasmogenicity has been observed in the small intestinal tissue of small animals (rat, mouse, rabbit, and guinea pig) after administration of blue cohosh glycoside (Ferguson and Edwards 1954). Doses of 0.1-1.5 mg/70 cc produced a spasmogenic effect with a decrease in the degree of contraction. In the guinea pig, doses of 1-2 mg/250 cc produced initial stimulation followed by depression and complete abolition of peristalsis. In a more recent experiment (Evelsizer and DeGolier 2010), no relaxing or contractile effects of blue cohosh (10 mg) were seen in isolated rat intestinal tissue administered before or after a positive contractile response from norepinephrine. However, blue cohosh did increase the contractile force from the distal colon in a dose-dependent manner, compared to baseline spontaneous motility values (P < 0.05). The ANOVA tests for dose-dependence were less conclusive as some of the tissue responses yielded large variances. Both sparteine and N-methylcytisine have demonstrated nicotine-like action resulting in increased intestinal motility and potential spasmolytic activity (Ambache 1949). 20

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

Magnoflorine was observed to stimulate the isolated guinea pig ileum (El Tahir 1991, cited in Schiff 1996). In another experiment, the effect of an aqueous extract of blue cohosh on the contractility of isolated stomach tissue (longitudinal orientation) of Sprague Dawley rat was evaluated (Forsgren and DeGolier 2011). Blue cohosh powder was dissolved in water and filtered to obtain an aqueous extract. Organ baths were used to measure the contractility in response to 2.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, and 20.0 mg doses of blue cohosh (n = 8 per dose) and 10-5 M acetylcholine given as the control drug. Blue cohosh induced a very small contractile response in the gastric tissues. The effects from different doses were not significantly different from each other (P = 0.2447). The average contractility increased from 0.427 grams of tension in negative control to 0.650 grams of tension after blue cohosh treatment, compared to 0.816 grams of tension evoked by 10-5 M acetylcholine. An aqueous extract of blue cohosh was also tested on isolated vas deferens tissue of the rat. The tissue samples were removed from male Sprague Dawley rats. The blue cohosh extract was prepared similarly to the study above. Organ baths were used to measure contractility with 10-5 M norepinephrine given as the control drug and 2.5 mg, 5 mg, 10 mg, 20 mg, or 30 mg doses of blue cohosh following as treatment. Blue cohosh induced vas deferens contractility and exhibited a high-low dose dependency between 2.5 mg and 20 and 30 mg doses (P = 0.0426, P = 0.0200, respectively). Contractile responses caused by blue cohosh were significantly smaller than those caused by norepinephrine (approximately 25%). Results from the study suggest that the contractile response evoked by blue cohosh may be due to the interaction of the alkaloid magnoflorine, found in blue cohosh, with a-adrenergic receptors of the vas deferens (Leafbled 2011).

Hormonal Effects Blue cohosh was not found to possess direct estrogen receptor (ER)-binding activity (Hunter et al. 2000). However, Eagon et al. (2001) reported that blue cohosh enhances estradiol binding to ER and increases estradiol-induced transcription activity in estrogen-responsive cells, as well as decreases luteinizing hormone (LH) levels and increases serum ceruloplasm oxidase activity, which are measures of estrogenic activity in the liver. Further details of the study were not available.

Miscellaneous Effects Several compounds found in blue cohosh have been characterized in relation to their physiologic activity and interaction with cellular or nuclear receptors. The alkaloids N-methylcytisine and anagyrine as well as minor compounds lupanine and sparteine have demonstrated varying activity at muscarinic and nicotinic acetylcholine receptors (Green et al. 2010; Schmeller et al. 1994; see Table 8). A detailed characterization of physiological actions of N-methylcytisine (aka caulophylline) was performed by Barlow and McLeod (1969) in a series of experiments (Table 9). Magnoflorine


Table 9 Comparison of physiological effects of N-methylcytisine and nicotine Animal model

Effect

N-methylcytisine effective dose, mg

Nicotine effective dose, mg

Stimulation

0.029

0.002

Block

0.411

0.016

Blood pressure

Rise

0.343

0.049

Tibialis muscle

Block

0.147

0.049

Blood pressure

Rise

0.009

0.008

Diaphragm

Block

629.15

32.446

Contraction

5.720

1.622

Increase

5.658

0.162

Physiological target Superior cervical ganglion

Cat

Rat Guinea pig

Ileum

Rabbit

Respiration

Frog

Rectus

Contracture

5.515

1.622

Chicken

Biventer

Contracture

5.127

0.162

Based on Barlow and McLeod (1969).

has been shown to possess adrenergic receptor activity (Wang et al. 2010). Among the saponins, cauloside D was shown to effect dose-dependent activation of all three different subtypes of peroxisome proliferator-activated receptor (PPAR): PPARa, PPARg, and PPARb/d (Quang et al. 2011). PPARs are nuclear receptor proteins involved in the regulation of transcription of a variety of genes, including those involved in inflammation (Ricote et al. 1998). Caulosides A and C were found to possess antineoplastic activity in vitro (Matsuo et al. 2009).

ing dosing was provided. Besides its use by Native American women during labor and as a partus preparator, Smith also reported that blue cohosh was effective for treating uterine inflammation. Three modern sources on Native American ethnobotany (Erichsen-Brown 1989; Moerman 1998; Vogel 1970) reveal only occasional use of blue cohosh for childbirth preparation. However, there is more frequent mention of its use during labor to promote delivery, possibly in arrested labor (Bergner 2001; Erichsen-Brown 1989; Moerman 1998; Vogel 1970).

Medical Indications Supported by Traditional Use

Gynecologic and Obstetric Use Among Physiomedicalists Cook (1869), one of the primary Physiomedicalist writers of the time, reported on a number of obstetric uses of blue cohosh. He noted that blue cohosh was of “especial service in strengthening and relieving painful functional difficulties of the female generative organs,” used blue cohosh for chronic inflammation of the uterus, considered it one of the best antispasmodics for painful menstruation and nervous restlessness during pregnancy, used it as a partus preparator, and stated that it strengthened the uterus through increased enervation of the pelvic nerves, and in this regard, used it for leucorrhea and “insufficient menstruation” as well as “to give tone and comfort to the uterus.” Cook noted that blue cohosh was among the most valuable of all parturients “when the uterine action is becoming weary.” In such cases, the root was used in the Thomsonian preparation Composition Powder or together with the nervine lady’s slipper (Cypripedium spp.) and a small amount of cayenne pepper (Capsicum spp.) or bayberry (Myrica cerifera) bark. Other supporting botanicals used by Cook included spikenard (Aralia spp.), partridge berry (Mitchella repens), uva ursi (Arctostaphylos uva-ursi), lily of the valley (Convallaria majalis), and tulip tree (Liriodendron spp.). Cook also countered the notion that blue cohosh was a “stimulating emmenagogue of harmful proclivities”—which is a view that persists currently—specifically noting that blue cohosh never has an effect of over stimulating excessive uterine

Traditionally, the reputation of blue cohosh root is greatest as an herbal medicine for gynecologic and obstetric concerns. It was also, though less commonly, used for its antispasmodic, diaphoretic, diuretic, anti-rheumatic, nervine, and expectorant effects (Ellingwood 1919; Felter 1922; Felter and Lloyd 1898). As such, it was used in the treatment of rheumatism, sore throat, cough associated with pertussis, and obscurely for complaints such as hiccough, epilepsy, hysteria, colic, and dropsy (Felter and Lloyd 1898). Most of the traditional indications, however, have focused on the female reproductive system. Gynecologic and Obstetric Use Gynecologic and Obstetric Use Among Native Americans The Menominee, Meskwaki, and Potawatomi made a decoction of blue cohosh root to remedy profuse menstruation. The Cherokee and Potawatomi used the plant as an aid for childbirth. The Cherokee relieved “uterine inflammation” with the root, while the Ojibwa used it for dysmenorrhea (Moerman 1998). The only specific information given regarding Native American use in birthing was offered by the “Indian Doctor” Peter Smith who claimed that blue cohosh was used for 2-3 weeks prior to delivery as well as during labor (Smith 1813). No information regard-

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

21


action. Interestingly, Cook (1869) considered blue cohosh inappropriate when there was vaginal dryness, a rigid os, or a sensitive uterus and also considered dried forms of these preparations to be ineffectual as antispasmodics. Cook most often utilized an infusion of the botanicals, i.e., ½ ounce (approximately 14 g) of blue cohosh root to a pint (473 mL) of boiling water, steeped for ½ hour in a covered vessel. For parturition and dysmenorrhea, Cook recommended a dose of 1 ounce (28 g) of this preparation every 30 or 60 minutes. Additionally, Cook made a compound infusion by combining ½ ounce each of blue cohosh and lady’s slipper (Cypripedium spp.) with 1 dram (3.5 g) beth root (Trillium spp.) and 1 scruple (1.2 g) of bayberry (Myrica cerifera), boiling it in 20 ounces (approximately 600 mL) of water, and allowing it to infuse for 30 minutes. This formula was considered an “efficient parturient, sustaining but never overdoing uterine action, quieting the nervous system, maintaining a steady outward circulation, and anticipating hemorrhage and after pains.” One fluid ounce (approximately 30 mL) of the infusion was given every half hour, especially in the latter stage of labor. Both preparations could also be used in tincture form, prepared by macerating 2 ounces (57 g) of milled herb per pint (473 mL) of alcohol for 12 days, at doses of 1-2 fluid drachms (3.7-7.4 mL) three times daily. Another Physiomedicalist, Clymer (1905), repeated many of the same uses described by Cook and noted that it was mostly used as an infusion and only rarely in powdered form. Clymer similarly considered blue cohosh one of the best antispasmodics for uterine cramps, for which it was sometimes combined with wild yam (Dioscorea villosa), black cohosh (Actaea racemosa), cramp bark (Viburnum opulus), or other botanicals. It was believed to strengthen the female reproductive organs and was one of the most valuable oxytocics to assist in prolonged childbirths. In this case it would be administered with a small amount of cayenne (Capsicum annuum) or bayberry (Myrica cerifera) when there was considerable uterine atony. Blue cohosh was also used by Clymer to impart tone to the uterus in cases of oligomenorrhea, treat leucorrhea, and, like Cook, he recommended its use prior to parturition to tone the uterus. Gynecologic and Obstetric Use Among the Eclectics Tincture of fresh blue cohosh root was considered unsurpassed by the Eclectics as a botanical extract for treating amenorrhea and dysmenorrhea, particularly in cases caused by uterine congestion (Adolphus 1897). Symptoms that pointed to the Eclectic preparation Specific Caulophyllum as an indicated remedy were uterine pain with weight and fullness of the pelvis and abdomen and pain in the legs. It was used in cases of uterine displacement, including anteversion, retroversion, and prolapse, as well as subinvolution (Bloyer 1897). At menopause, fresh root tincture was used to mitigate common symptoms, especially restlessness with burning heat of the extremities (Adolphus 1897; Baker 1910). Blue cohosh was given to control uterine hemorrhage. In postpartum hemorrhage ten drops of the tincture given every half hour would “cause firm contractions and arrest 22

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

the flooding” (Jones 1908). Blue cohosh tincture, together with goldenseal (Hydrastis canadensis) root, was given for excessive menstruation (Adolphus 1897). Blue Cohosh Extract Uses Associated With Childbirth In the 19th century ergot was the primary pharmaceutical used for labor induction. The earliest mention of its oxytocic effects was done by Lonicer in his Kräuterbuch (1565) (Lloyd 1921), and it was subsequently used for this purpose by physicians and midwives (van Dongen and de Groot 1995). Ergot caused tetanic, uncontrollable contractions, so was not an ideal substance for safely initiating labor. The Eclectic physicians regarded blue cohosh as a gentler and safer alternative to ergot (Lloyd and Lloyd 1886-1887). It was typically administered for 2-3 weeks or more prior to labor (Osol and Farrar 1947). The writings of the leading Eclectics, including John King and John Milton Scudder, reported on the use of blue cohosh as a partus preparator, for facilitating normal contractions during the birthing process, and for allaying after-pains. For these uses, blue cohosh was considered one of the most valuable remedies. The action of blue cohosh was thought to be due to its ability to tone and facilitate the normal contractility of the uterus. The Lloyds specifically reported on its use during labor when “from fatigue, debility, or impaired uterine nervous energy, the contractions become feeble, inefficient, or very severe and of a spasmodic character, or have entirely ceased.” In this regard, the administration of Caulophyllum in decoction, or in powder, was considered preferable to ergot, as the contractions stimulated by blue cohosh were regarded as less violent and spasmodic than those of ergot and more nearly resembling natural contractions. Blue cohosh was also considered superior to most other agents for treating severe after-pains, given in doses of 2-4 grains (130-260 mg), administered, as necessary, every 1, 2, or 3 hours (Lloyd and Lloyd 1886-1887). In his text American Eclectic Obstetrics (1855), John King recommended a formula Parturient Balsam (Table 10) for giving tone and activity to the uterus when its functions are “torpid or impaired.” A related blue cohosh-containing formula, one more famous and currently still available for gynecologic complaints and as a partus preparator, is Syrupus Mitchellae Compositus (Compound Syrup of Partridgeberry (Mitchella repens)) or, more popularly, Mother’s Cordial. It was prepared similarly to Parturient Balsam. For after-pains, King combined blue cohosh with the uterine antispasmodic cramp bark (Viburnum opulus) (King 1855). Scudder (1870) explained that the action of blue cohosh was to “relieve false pains,” to “effect coordination of the muscular contractions,” and “to increase the power of contractions.” He further noted, “the first and second [actions] are the most marked, yet the third is quite certain.” Of the use of blue cohosh as a partus preparator, Scudder (1898) noted: “We have used it often, and known of its frequently being used by others, for a few weeks prior to confinement, as a preparatory measure to the important changes which take place at that time, with greatest apparent advantage. In many instances, when the females had


Table 10 Popular traditional formulae with blue cohosh

Parturient Balsam Ingredient

Amount

Blue cohosh root

4 oz.

Spikenard (Aralia racemosa) root

4 oz.

Black cohosh (Actaea racemosa syn. Cimicifuga racemosa) root

2 oz.

Partridge berry (Mitchella repens) herb

2 oz.

Queen-of-the-meadow (Eupatorium purpureum) root

2 oz.

Lady’s slipper (Cypripedium pubescens) root

1 oz.

Comfrey (Symphytum officinale) root

1 oz.

Instructions Grind and mix the herbs; macerate in 76% alcohol for 2 days; percolate in hot water until a half-pint of tincture is obtained; set aside. Continue percolation until the solution is almost tasteless, preserving a portion of the final percolate. Boil down the weaker infusion until the two volumes together make 3 pints and mix the 2 solutions. Add 4 pounds of sugar and boil down to ½ gallon syrup. Add the initial halfpint of tincture. If desired, flavor with wintergreen (Gaultheria spp.), sassafras (Sassafras albidum).or other aromatic compound (King 1855).

Mother’s Cordial Ingredient

Amount

Dry partridge berry (Mitchella repens)

8 parts

Blue cohosh root

4 parts

False unicorn (Chamaelirium luteum) root

4 parts

Cramp bark (Viburnum opulus)

4 parts

been invariably the subjects of tedious and difficult labors, by the use of the Leontice for two or three weeks before confinement, all that anticipated difficulty vanished, the labors were rapid and easy, and the recovery speedy when compared with previous confinements. ... We have known many highly intelligent ladies, who after having come to use it once, could not be prevailed to dispense with its use in subsequent pregnancies.” The use of Caulophyllum for facilitating an efficient labor was echoed by a Dr. Locke, who was cited as an authority on drug action and stated: “The drug is used as a parturient and emmenagogue increasing the strength of uterine action. As an antispasmodic in atonic and irritable conditions of the nervous system, it acts nicely. In cramps of the uterus, spasms at the menstrual period, leucorrhea and amenorrhea, it proves an excellent medicine. This drug is a good anti-abortive. It prevents premature labor by giving strength and tone to the uterus. After abortion it relieves the general irritability of the system and prevents hemorrhage. It relieves after pains in hysterical women. For this purpose, give five drops of Specific Medicine Caulophyllum in hot water, every half hour.” (Stephens 1930). When given in small doses as an infusion, some Eclectic physicians believed blue cohosh was of value late in pregnancy to help prepare the uterus to make labor shorter and easier (Scudder 1867). Dr. Edward Case later reported excellent results in preventing prolonged first stage of labor when used beginning about 6 weeks prior to the expected due date. He believed this also shortened the second stage by making the contractions more efficient. Its intelligent

Instructions Follow the instructions for Parturient Balsam above.

use was believed to render the use of forceps unnecessary in many cases (Case 1919). From his experience with deliveries Dr. John Scudder appraised C. thalictroides as an effective parturifacient, stimulating labor by coordinating the muscular contractions and increasing their power. For this he employed the infusion, the fluidextract (1:1), or the tincture (Scudder 1870). King’s American Dispensatory by Felter and Lloyd (1898) describes blue cohosh as an oxytocic, and recommends it to “relieve false pains and uterine irritability; spasmodic uterine contractions; and for uterine subinvolution.” However, only the latter two indications are suggestive of oxytocic activity; the former would be indicative of uterine antispasmodic activity. Ellingwood (1919) deviates from the typical description of the uses of blue cohosh by suggesting its use much earlier in pregnancy both for relieving symptoms that occur in the third trimester (symptoms not specified) and for preventing premature labor, a clinical effect that would seem to be contradictory to its more common use as an oxytocic agent. Ellingwood purports that “[t]he effect of caulophyllum is to prolong gestation until the fetus is fully developed, labor being a physiological process at full term, and not pathological, therefore less protracted, less painful, and less liable to accidents.” By the end of the 19th century, Eclectic authors considered blue cohosh one of the best uterine stimulants for before, during, and after labor and birth. The consensus was that the strengthened contractions mimicked normal uterine contractions with proper intervals and did not American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

23


exceed appropriate intensity or duration. Blue cohosh root alcohol extracts were effective in those cases where the labor was prolonged by weakness or fatigue. It did not produce violent, constant tonic contractions like ergot (Adolphus 1897; Bloyer 1897; Jones 1908; Scudder 1870). A specific manifestation in non-progressing labors that responded well to blue cohosh was the rigid os, for which 10 drops of the tincture were given every half hour (Jones 1908). However, in contrast to the prevailing opinion of the Eclectics, the Physiomedicalist Cook (1869) sites rigid os as a contraindication to blue cohosh use. Numerous other authors of the time reported on the use of alcohol extracts of blue cohosh in relieving cases of afterpains following delivery (Adolphus 1897; Bloyer 1897; Jones 1908; Niederkorn and Versailles 1910). Applications by Naturopathic Physicians The 1953 Naturae Medicina and Naturopathic Dispensatory of Kuts-Cheraux described blue cohosh rhizome and rootlets as antispasmodic, diaphoretic, emmenagogue, and uterotonic. The infusion was to be made by adding 1 ounce (28 g) of the root to a pint of boiling water; 1/2 ounce (15 mL) of this was given every 3 hours. The dose of the tincture was 0.33 to 1 mL, while the fluidextract dose was 0.5 mL. These preparations were used in the treatment of amenorrhea and dysmenorrhea and to facilitate placental expulsion and prevent uterine subinvolution for which they were used in the postpartum. Blue cohosh was considered beneficial in endometritis and ovarian neuralgia, and with black cohosh, was used to treat menopausal pains and pelvic discomfort accompanied by pain radiating down the legs, assuming the absence of serious pelvic pathology (Kuts-Cheraux 1953). John Bastyr reportedly used blue cohosh tincture extensively in his personal practice to strengthen deficient contractions in labor (1-10 drops of tincture, 2-3 times during labor) (Mitchell 2003). Contrary to the contraindication of Cook (1869), Dr. Bastyr used blue cohosh to relax a rigid uterine os. Bill Mitchell (2003) noted that blue cohosh reduced prolonged lochia following delivery, while its emmenagogue and uterine tonic effects are used to treat dysmenorrhea, menorrhagia, and chronic uterine disorders. Uterine prolapse due to tissue laxity is purported to be improved with blue cohosh use. Blue cohosh is also part of the naturopathic treatment for breast tenderness and abdominal bloating due to water retention. Naturopaths prescribe both the tincture and the tea. Use by Contemporary Midwives and Herbalists In 1931, the British herbalist Maude Grieve noted the use of blue cohosh root for dropsy, epilepsy, hysteria, rheumatism, and uterine inflammation, especially chronic cases. She recommended the decoction or infusion to be prepared with 1 ounce (28 g) of root to 1 pint (473 mL) of boiling water, macerated for 1/2 hour, and given at 2-4 fluid ounces (59118 mL) 3-4 times daily. The tincture was to be prepared by adding 3 ounces (85 g) of finely powdered root to a pint (473 mL) of alcohol, soaking it for two weeks, shaking, and filtering. The recommended tincture doses were ½-2 fluid drachms (1.85-7.4 mL), while the fluidextract (1:1) was to 24

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

be given in 10-30 drop doses, and Caulophyllum (sic) at 2-4 grains (130-324 mg). In instances of labor prolonged by debility, fatigue, or want of uterine energy, these were reported to expedite delivery. The midwife-herbalist Jeannine Parvati-Baker (1978) can be credited with reviving the use of blue cohosh as an emmenagogue and uterine tonic. In the early 1980s, there was resurgence in the use of blue cohosh as a partus preparator and for labor induction and augmentation, mostly by those desiring homebirths and returning to the use of natural medicines more generally. Wise Woman Herbal for the Childbearing Year (1986) by Susun Weed and smaller self-published books and manuals by herbalists and midwives provided instruction on the use of blue cohosh as an emmenagogue, an abortifacient, and for labor induction and augmentation. In her book Weed (1986) wrote that blue cohosh “is a reliable remedy when labor needs promoting,” that it “does not stimulate the uterus into irregular contractions or cause any tightness or clamping down of the cervix,” noting further that “if fetal heart-tones are monitored, there may be a noticeable elevation as the blue cohosh starts to work.” Beginning in the 1990s, surveys of midwives indicated that blue cohosh is the most commonly used botanical for inducing and augmenting labor (Allaire et al. 2000; McFarlin et al. 1999; Romm 2009). In addition to directentry midwives, many certified nurse midwives (CNMs) practicing in hospitals and birthing centers also began to rely on blue cohosh as an alternative to conventional methods of labor stimulation and augmentation such as pitocin and prostaglandin products (Allaire et al. 2000; McFarlin et al. 1999). In one study, 64% of midwives reported using blue cohosh to facilitate childbirth (McFarlin et al. 1999). The practice of labor induction with blue cohosh is also a popular choice of pregnant self-prescribers seeking natural alternatives to conventional labor induction. In addition to its use for labor induction, blue cohosh is popularly taken daily during the last 3-6 weeks of pregnancy as a partus preparator in the belief that it can facilitate labor, prevent post-term pregnancy, shorten labor duration, reduce labor pain, and prevent complications such as “failure to progress” and postpartum hemorrhage. Some traditional midwives (e.g., Belew 1999; Romm 2003, 2009) have acknowledged that use of blue cohosh in pregnancy has been associated with adverse fetal outcomes and that it should be avoided in late pregnancy. Blue cohosh should only be used when necessary for labor induction in limited dose and duration, with extreme caution, and only under the supervision of qualified childbirth professional. Worthy of discussion is that use of blue cohosh, or any other botanical agent, for labor induction may be considerably increased, perhaps more greatly so than in historical times, due to the relatively high desire for induction by conventional practitioners for litigious rather than medical reasons. Women who choose home birth are less likely to request or consider induction as a ready option, whereas those receiving conventional obstetric care who are postterm (> 42 weeks) are more likely to be counseled to have


an elective induction. This increases the use of induction agents overall (Caughey et al. 2009; Selo-Ojeme et al. 2010) and potentially results in increased use of natural induction agents, such as blue cohosh, in a manner that is not consistent with traditional use. Use of herbal induction agents in a manner that is more consistent with modern vs. traditional midwifery practice has the potential to increase the exposure of the fetus to the herb’s constituents to a degree greater than that when used traditionally. This may influence both the efficacy and safety of blue cohosh. Changes in health status of women historically and today (physically active versus not) and use of higher acute doses of blue cohosh monopreparations, in contrast to the relatively small doses of combination products used historically, may contribute to a side effect profile that was not evident or reported historically. In addition to its use in pregnancy, contemporary herbal literature often recommends blue cohosh as a uterine tonic and for general gynecologic complaints including amennorhea, dysmenorrhea, menorrhagia, uterine fibroids, dysfunctional uterine bleeding, chronic pelvic pain (Gladstar 1993; Hoffmann 1996; McQuade Crawford 1997; Romm 2003, 2009). As such it is generally combined with a variety of other herbs also used specifically for gynecologic problems. Non-Obstetric, Non-Gynecological Uses In addition to its obstetric uses, blue cohosh was used for various purposes by different Native American tribes. Unfortunately, most reports of its use lack specificity. The Cherokee purportedly gave the roots for “fits and hysterics,” colic, nervousness, and applied it locally for toothache. Both the Iroquois in the north and the Cherokee in the south used the root or its decoction internally for rheumatism, while the Iroquois also used the infusion as a foot and leg bath. The Iroquois, Ponca, and Omaha considered the root decoction highly effective for all types of fever. The Meskwaki and Mohegan decocted the root for a urinary remedy. The Ojibwa used a compound decoction for stomach cramps and indigestion, an infusion of the scraped root for biliousness and for bleeding from the lungs. They also used a decoction of the root for lung troubles. The Ojibwa and Iroquois both used root infusions or decoctions as an emetic (Moerman 1998). The Physiomedicalist Cook (1869) primarily relied on blue cohosh as a general antispasmodic describing it as one of the choicest nervines and antispasmodics, having moderately diffusive and equally stimulating and relaxing effects on the nervous system. For this purpose, blue cohosh and its preparations were used to relieve nervous feebleness with irritability, intestinal cramping, muscle spasms, hysteria, painful menstruation, and colic, among other uses in which antispasmodics would be indicated. With other botanicals (not specified), blue cohosh was used for puerperal convulsions, epilepsy, and chorea, used in neuralgic forms of rheumatism. In the same way that blue cohosh was considered to enervate pelvic nerves to tone the uterus, the botanical was also used as a diuretic, in chronic prostate problems and for weak kidneys. Externally, Cook combined blue cohosh with goldenseal (Hydrastis canadensis) and bayberry bark as a

wash for aphthous ulcers and with wild cherry bark (Prunus spp.) and white pond lily (Nymphea lutea) for sores (Cook 1869). Cook (1869) also reported on a colleague, Dr. E.H. Lowe (Sandwich, IL), who used blue cohosh combined with other diaphoretic relaxants (unspecified) for asthma. Among the Eclectic physicians, non-gynecologic uses included treatment of pulmonary conditions in which there was shortness of breath, as in asthma and bronchial congestion, for which blue cohosh tincture was thought to have a calming and soothing influence (Baker 1910; Bloyer 1897). Ellingwood additionally reported on its use for bronchitis, “pneumonitis,” and whooping cough (Ellingwood 1900). King used a decoction of blue cohosh alone and with goldenseal (Hydrastis canadensis) as a local application for “aphthae and other affections of the mouth” (Lloyd and Lloyd 1886-1887). The alcohol extract was considered an excellent remedy in restlessness and insomnia, especially in nervous women (Baker 1910). For the treatment of chronic rheumatism it was considered more effective than black cohosh (Actaea racemosa), the latter being preferred for the acute form (Scudder 1870). For fevers in children, small doses (unspecified amounts) of tincture were given frequently. The Eclectic physicians employed hydroethanolic extracts of blue cohosh for what would now be called irritable or nervous bladder (Adolphus 1897; Baker 1910; Bloyer 1897). When pelvic congestion was associated with this condition, as well as pain in the rectum or back pain, blue cohosh tincture was considered reliable for relieving the discomfort (Adolphus 1897). Tincture was given in small, frequent doses (Baker 1910). Official and Non-official Compendia Blue cohosh was not recognized in the “regular” medical literature until its appearance in the appendix of the 12th edition of the United States Dispensatory in 1866, in which the editors referred to the experience of the Eclectics in its use as an emmenagogue and for promoting uterine contractions (Wood et al. 1866). Blue cohosh was introduced into the United States Pharmacopoeia in the 6th edition of 1882 and retained in the next edition in 1890, after which it was dropped. Only the whole root was official, not any of its extracts (Felter and Lloyd 1898; Lloyd and Lloyd 1886-1887). An alcoholic (60%) extract of blue cohosh was entered into the first edition of the National Formulary (NF) in 1888 and remained through the 7th edition in 1942. The crude root remained in the NF until the 8th edition in 1946 and was dropped. The average dose for the dried root given in the NF was 0.5 gram, while the fluidextract was given in doses of 0.5 mL (National Formulary 1946). In addition to use of blue cohosh by the Eclectics, numerous dispensatories, pharmacognosy texts, and materia medicas cited the use of blue cohosh as an emmenagogic or oxytocic drug (e.g., Culbreth 1917; Youngken 1930). By the early-mid 20th century, quinine and eventually pituitary extract became the primary medications for labor induction (Benrubi 2000). With the increasing safety and controllability of the latter substances, the switch in the place of delivery from predominantly home to primarily hospital, and with the era of the “botanical physicians” drawing American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

25


to a close, the use of blue cohosh as a common parturient and labor stimulant also dwindled (O’Dowd 2001). Blue cohosh is included in the British Herbal Pharmacopoeia (BHP 1983) as a spasmolytic and emmenagogue. Traditional Preparations Used The Physiomedicalists primarily used blue cohosh root as an infusion and occasionally, in powdered form as a remedy for intestinal cramps, often in combination with other botanicals such as wild yam (Dioscorea spp.) or ginger (Zingiber officinale). It was also used for specific indications in standard formulae, such as Parturient Balsam. Blue cohosh root infusion was made with ½-1 ounce (14-28 g) of cut or powdered root per pint of boiled water, steeped in a covered vessel for 30 minutes. A fluid ounce (30 mL) was given every 30-60 minutes for dysmenorrhea or during childbirth. Otherwise, 1 ounce (30 mL) was given every 2-3 hours, preferably in hot water. Both Physiomedicalists and the Thomsonians recommended the use of the infusion for rheumatism and other chronic conditions taken at 1-2 ounces (30-59 mL) every 4-6 hours (Clymer 1905; Cook 1869). Physiomedicalists also used a tincture prepared by macerating the crushed root in dilute alcohol at a concentration of 2 ounces (57 g) per pint (473 mL) of extract solvent (1:8) for 12 days before filtering. The dose of this preparation given by Cook (1869) was 1-2 teaspoons (4-8 mL) 3 times daily. Dr. Clymer recommended only 5-10 drops (1/3-2/3 mL) per dose of tincture. Blue cohosh was also combined with black cohosh for menstrual cramps (Clymer 1905). Blue cohosh became quite popular with the Eclectics after its endorsement by John King in his Eclectic Dispensatory in 1852. Mother’s Cordial (see Table 10) was described by John King as a uterine tonic and antispasmodic, which he used in all cases “where the functions of the reproductive organs are deranged, as in amenorrhoea, dysmenorrhoea, menorrhagia, leucorrhoea, and to overcome the tendency to habitual abortion.” It was reported as being used more extensively than all other blue cohosh preparations (Lloyd and Lloyd 1886-1887). Dr. John Scudder (1870) employed a tincture of the recently dried root made with eight ounces (227 g) of the root in one pint (473 mL) of 76 proof (38%) alcohol. The Lloyd Brothers Pharmacists preparation Specific Caulophyllum made from the rhizome and roots with 78% alcohol was recommended for use in doses up to 2/3 mL.

Conclusion Traditionally, the primary use of blue cohosh has been in gynecology and obstetrics. In this regard, from a review of the preponderance of medical data, medical practitioners, whether Native American, allopathic, homeopathic, Eclectic, or Physiomedicalist, considered it both a uterine antispasmodic and oxytocic. Many medical practitioners from the late 1800s-early 1900s considered it one of the most reliable agents for inducing normal contractions during labor, as well as using it for preventing premature labor and miscarriage. Different writers had nuanced understandings of the botanical’s effects that differed somewhat, but it was universally relied upon in the birthing process. 26

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

The preponderance of the non-gynecological uses centered around the putative effects of blue cohosh as an antispasmodic, again being widely used by Native Americans and Western medical practitioners for emotional stress, spasmodic pains, colic, muscle spasms, seizures, respiratory constriction, and numerous other indications that could benefit from an antispasmodic effect (e.g., hemoptysis, urinary difficulties). There are no clinical studies of blue cohosh. While this botanical is widely used in gynecological formulas, there is no clinical data and sparse preclinical work supporting its traditional use by Native Americans, early American settlers, the Eclectics and other botanical medicine practitioners of the 1800s, as well as modern midwives and herbalists. Several animal studies demonstrated the ability of blue cohosh to increase uterine tone, providing some mechanistic support for its traditional uses as an antispasmodic and oxytocic. Much of the pharmacological work in animal models is very weak, dated, and based on animal models some of which may have little relevance to oral ingestion of the material in humans (e.g., in situ cardiovascular effects in frogs). In vitro work suggests that compounds in blue cohosh (e.g., N-methylcytisine, anagyrine, magnoflorine) bind with nicotinic and muscarinic acetylcholine receptors and adrenergic receptors. These interactions may correlate with the tissue contraction putatively associated with uterine toning as well as spasmolytic activity, both of which are actions traditionally attributed to blue cohosh. Since concern regarding the potential of blue cohosh for fetal toxicity was raised, its use by midwives has dramatically declined. However, blue cohosh remains one of the most frequently used alternatives to conventional methods of induction, partially based on the choice of the expectant mother or the health practitioner. In most cases, blue cohosh is used by women choosing birthing options that are not offered by most hospitals. These can include home or birth center births, employment of doulas or midwives who may have a predilection to natural methods of induction, or integrative medical practitioners and obstetricians seeking alternatives to conventional induction. In many cases, blue cohosh is specifically used to help avoid the need for conventional induction. Between 1990 and 2006, medical labor induction rates more than doubled from 9.5% to 22.5% of births (Martin et al. 2010). Elective inductions account for a significant proportion of the overall increase in inductions (Tillet 2007). However, there is insufficient data to support the safety or benefit for either mother or neonate of this practice (Moore and Rayburn 2006). Thus, there remains considerable controversy over the risks associated with gestation beyond the 40th week, which is further complicated by the imprecise estimations made by using the last menstrual period or an ultrasound performed after the first trimester as indicators of gestational age. Moreover, elective inductions are associated with increased rates of cesarean section and iatrogenic prematurity, each of which is associated with a host of further risks, complications, and costs to the individual and society, including life-long disability and early death for the neonate (Moore and Rayburn 2006). Midwives


are often more comfortable with expectant management of post-term pregnancy, while many obstetricians recommend elective induction beginning at 40 weeks gestation. On the other hand, women seeking to avoid induction may be more likely to use blue cohosh as a partus preparator. A comprehensive review of the literature establishes a compelling argument for the mechanistic plausibility of blue cohosh being a causal agent in the limited number of adverse events, and the adverse effects observed by midwives (see Safety Profile). However, these cannot be separated from the contextual use of blue cohosh in postdates pregnancies or poor fetal resuscitation efforts where similar adverse events may be observed. While it is impossible, based on the available evidence, to firmly establish causality between the herb and the limited number of case reports of adverse events in pregnancy, the use of blue cohosh in labor should be limited to experts in obstetric care, with close monitoring of fetal heart tones, and only when medically indicated. The use of blue cohosh in early pregnancy is clearly contraindicated due to the significant potential for toxicity to the embryo. Its use as a partus preparator is unadvisable due to the lack of necessity for such use compared to potential for harm.

Actions Antispasmodic, emmenagogue, oxytocic, parturient, uterotonic.

Indications Based on extensive historical and modern traditional use and preliminary pharmacologic data, blue cohosh may be useful in the treatment of amenorrhea, dysmenorrhea, menorrhagia, pelvic congestion syndrome, uterine fibroids, and for facilitating labor.

Substantiated Structure-Function Statements Traditionally used to maintain healthy uterine function and tonicity.

Dosages There is some variation in the doses recommended historically; however, the dose variation is not great. Generally, small frequent doses of the herb (500 mg of powder or 0.5 mL of a 1:5 tincture) were recommended regardless of the form of preparation, and it was often given in combination with other botanicals (e.g., Mitchella repens). Contemporary dosage ranges and frequency of administration recommended in the herbal literature are also within a limited range, however, they are much more variable in the midwifery literature and word-of-mouth use where the doses also tend to be higher and given more frequently for labor induction and augmentation (see Table 11). Both the higher doses and the use of blue cohosh singularly, widely applied today, may be worthy of reconsideration given recent reports of its potential for cardiotoxicity. The historical use of lower doses and the use of blue cohosh combined with other botanicals greatly reduce exposure of the fetus to the putatively toxic compounds in blue cohosh. American Herbal PharmacopoeiaÂŽ â&#x20AC;˘ Blue Cohosh Rhizome and Roots â&#x20AC;˘ 2012

27


Table 11 Blue cohosh dosages

Crude Powder

Tea/ Infusion/ Decoction

Eclectic

Crude powder was used only prepared as an infusion or decoction

National Formulary (1946)

0.5 g

US Dispensatory (Osol and Farrar 1947)

0.5 to 1 g

Contemporary herbal (Mills 2005)

0.9-3 g/day

Eclectic

Decoction or infusion (1 oz/1 pint of water), 2-4 fl oz. every 3-4 hours

National Formulary (1946)/ US Dispensatory (Osol and Farrar 1947)

Decoction (30 g/1 pint of water) in doses of 1-2 oz (Stille et al. 1896)

Contemporary herbal use (Barnes et al. 2007)

0.3-1.0 g as a decoction 3 times/day

Contemporary midwifery use (Romm 2009)

Highly variable, ranging from 15 drops several times daily to numerous droppers daily

Contemporary herbal use (Romm 2009)

Approximately 1-3 500-mg capsules daily

Contemporary midwifery use (Romm 2009)

1-2 capsules (mg/capsule not specified; 450-500 mg is a typical fill of 00 caps), 1-2 times/day

Eclectic

10-30 drops 3-4 times/day

Contemporary herbal use (Barnes et al. 2007)

0.5-1 mL (1:1 in 70% EtOH) 3 times/day

Contemporary midwifery use (Romm 2009)

For labor induction, either 5 drops every hour or 10 drops every 2 hours, to be taken in hot water (McFarlin et al. 1999). Other midwives alternate its use with black cohosh at varying doses, with or without other agents such as castor oil (Downey 2010, personal communication to AHP, unreferenced).

Eclectic (Lloyd and Lloyd 1886-1887)

5-15 drops

National Formulary (1906)

0.5 mL/day fluid extract (1:1)

Eclectic (Lloyd and Lloyd 1886-1887)

1-4 fluid ounces, 3 times/day

Capsules

Tincture

Fluid Extract

Mother’s Cordial

28

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012


Safety Profile Side Effects and Serious Adverse Events Based on traditional use, widespread consumer use, and a comprehensive review of the literature, blue cohosh appears to be generally safe when used at recommended doses and frequency for common gynecologic complaints and other general uses. Side effects and serious adverse events with blue cohosh have been described when used in pregnancy as an abortifacient, as a partus preparator, and for labor induction (see Pregnancy) (Finkel and Zarlengo 2004a; Gunn and Wright 1996; McFarlin et al. 1999; Rao et al. 1998; Rao and Hoffman 2002; Romm 2009). These will be described below. Moreover, the use of blue cohosh for inductions must be critically compared to the need for and risks of conventional means of inductions, many of which may not be medically justified (NPSG 2011), as well as outcomes associated with conventional methods. Reports of Adverse Effects in Pregnancy Anecdotal evidence derived from traditional information and surveys of midwives (Allaire et al. 2000; Bayles 2007; Gibson et al. 2001; McFarlin et al. 1999; Romm 2009) suggests that maternal ingestion of blue cohosh during late pregnancy and labor is a common practice and has been associated with fetal tachycardia during labor (Weed 1986), an increased presence of meconium in the amniotic fluid, and an increased need for neonatal resuscitation at birth. It is difficult to determine whether these effects are secondary to blue cohosh use or are related to the reasons for blue cohosh use, for example, post-dates pregnancy induction or protracted labor, requiring augmentation. Three case reports (Finkel and Zarlengo 2004a; Gunn and Wright 1996; Jones and Lawson 1998) have appeared in the literature suggesting severe adverse neonatal outcomes associated with maternal ingestion of blue cohosh as a partus preparator or as an induction agent, including focal motor seizure, myocardial infarction (MI), ischemic stroke, multi-organ hypoxic injury, permanent central nervous system damage, and profound congestive heart failure (CHF). There is also a single case report of acute nicotinic toxicity in a non-smoking pregnant woman in her first trimester who ingested large quantities of blue cohosh to induce abortion (Rao et al. 1998; Rao and Hoffman 2002; see Overdose). As is most often the case, case reports lack the detailed information needed to make a definitive determination regarding causality. Of significance in assessing reports for botanical preparations, appropriate characterization of the product in question is required. Additionally, a single rat study of a homeopathic Caulophyllum preparation (0.3 mL of 200X and 10,000X dilutions; otherwise unspecified) states that the lower potency of the preparations (200X) “interrupted implantation by dissolving the endometrium at the site of implantation,” while the higher potency dilution led to an increased litter size versus controls (8 vs. 5). This study is of poor methodological quality and does not appear to add any information of relevance to the blue cohosh literature (Chandrasekhar

and Vishwanath 1974). Considering that 200X and 10,000X dilutions will have little to no material traces of the botanical in the preparation, any association with chemical constituents of blue cohosh seems unlikely. Case Reports: Adverse Pregnancy Outcomes With Blue Cohosh Use Gunn and Wright (1996): Blue cohosh, in combination with black cohosh, was administered by a midwife to a woman at 41.6 weeks gestation in an attempted labor induction, which resulted in the delivery of a 3840 g female with Apgar scores of 1, 4, and 5 at 1, 5, and 10 minutes, respectively. Two midwives provided resuscitation and cardiac compressions when the infant was unable to breathe spontaneously after birth at home. Cardiopulmonary resuscitation persisted for 30 minutes, after which the baby gasped and was transferred to the hospital where mechanical ventilation was required. The infant was observed to have seizures and presented with acute tubular necrosis. Computerized tomography (CT) revealed basal ganglia and parasagittal hypoxic injury. At three months, the infant had lower limb spasticity and required nasogastric tube feeding. The authors purported that the hypoxic-ischemic damage was secondary to myocardial toxicity possibly related to blue cohosh ingestion, though they do also question whether inadequate resuscitation was a possible factor. Case discussion: In this case report, no information was provided on the prenatal history, maternal health status, presence of adequate prenatal care, the course of the labor, or fetal monitoring during labor. The baby was born without spontaneous respirations, and resuscitation, which was attempted at home, was excessively prolonged prior to hospital transfer and led to an inappropriate delay in initiating mechanical ventilation. Post-term pregnancy, lengthy attempted resuscitation, and resultant profound neonatal hypoxia are highly plausible explanations for the poor neonatal status and given these significant confounding variables, it is impossible to establish a causal relationship between blue cohosh and the events in this case. It is also important to note that pregnancy persisting past 41 weeks gestation is associated with poorer neonatal outcomes (Bruckner et al. 2008). Jones and Lawson (1998): A 3660 g, 41-week gestational age male was born to a 36-year-old mother of three children after a 1-hour precipitous spontaneous vaginal delivery. She began taking 3 blue cohosh capsules (approximately 500540 mg per capsule) 3 times daily 3 weeks prior to her due date, during which time she noted increased uterine activity and decreased fetal movement. Her medical history was significant only for well-controlled hypothyroidism. Slightly meconium-stained amniotic fluid was noted with spontaneous rupture of membranes 15 minutes prior to delivery. Apgar scores were 6 and 9 at 1 and 5 minutes. By 20 minutes after delivery the infant had developed respiratory distress, acidosis, ischemic hepatitis, and shock and required intubation with mechanical ventilatory support and transport to the neonatal intensive care unit. Chest radiograph revealed cardiomegaly and pulmonary edema; ECG demonstrated American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

29


Table 12 Case reports of adverse effects of blue cohosh

†

WHO Causality Category†

Reference(s)

Case Parameters

Intervention

Adverse Effects

Finkel and Zarlengo (2004a)

Female born by c-section at ~40 weeks gestation after failed attempted vaginal delivery to a healthy 24-year-old G2P0

Tea; dose and duration unspecified

Focal motor seizures of the infant’s right arm at 26 hours after birth; a CT obtained at two days of age showed evolving infarct in a left MCA distribution.

Possible

Initially attributed to blue cohosh thought to either be contaminated with or metabolized to benzoylecgonine; this compound is not a metabolite of blue cohosh nor found in blue cohosh products, and the result was most likely due to a cross-reactivity in immunoassays performed compounded by a misreading of the GC-MS confirmation (Finkel and Zarlengo 2004b).

Gunn and Wright (1996)

Planned homebirth at 41 weeks 6 days gestation following a midwife attempted induction

Unspecified; mixture of blue and black cohosh

Absent spontaneous respirations at birth; multi-organ hypoxic injury; permanent central nervous system damage

Possible

Hypoxia due to postterm pregnancy and/or lengthy resuscitation are confounding factors.

Jones and Lawson (1998)

A 41-wk GA male infant (3.66 kg) delivered in hospital by a 36-year-old G4P3 with well-controlled hypothyroidism

3 tablets blue cohosh (amount in tablet unspecified; usually approximately 450-540 mg per capsule), for 3 weeks prior to due date as a partus preparator

Acute MI, profound CHF, and shock after a precipitous labor with spontaneous delivery; poor peripheral pulses, MR, gallop rhythm, hepatomegaly, deep q-waves on ECG, extensive regional wall motion abnormalities on echocardiogram

Possible

The mother reportedly took 3 times the dose recommended by the midwife; all other causes of MI and CHF were excluded and the authors asserted a likely causal relationship.

Rao et al. (1998); Rao and Hoffmann (2002)

Abortion attempt: 21 year old female at 5-6 weeks gestation

Blue cohosh tincture: 10-20 unspecified doses/ day for 4 days; Slippery elm tea: 15 cups/day for 4 days; Slippery elm and parsley vaginal douches.

Abdominal pain, bilious vomiting, tachycardia, hypertension, diaphoresis, abdominal fasciculations, mild low pelvic cramping.

Possible

Causality was not definitively established but is highly plausible. This must be considered as an overdose, not a typical side effect of blue cohosh.

WHO (2004).

30

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

Discussion


evidence of an acute anterolateral myocardial infarction. A moderate-size persistent ductus arteriosus (PDA) with bidirectional shunt flow and significant pulmonary hypertension were found. Coronary artery origins were found to be entirely normal, and no congenital cardiac anomaly or signs of infection that could explain the infant’s condition were identified. High-frequency ventilation and high-dose vasopressor support were required for 72 hours, after which the infant’s condition gradually stabilized and improved. Extubated on day 21, the infant continued to receive cardiovascular support with oral digoxin, diuretics, and captopril, and the patient was discharged after 31 days. At age 2 the boy continued to require digoxin therapy for persistent cardiomegaly and mildly reduced left ventricular function. The authors concluded, “the clinical picture of cardiogenic shock caused by myocardial ischemia is well explained by the known pharmacologic properties of blue cohosh. Other causes ... were systematically excluded…. The circumstantial evidence relating the cardiac injury seen in our patient to maternal ingestion of blue cohosh is very compelling.” Case discussion: Although causality cannot be definitively established, the case report of Jones and Lawson (1998) demonstrates the most plausible association between maternal blue cohosh ingestion and a neonatal ischemic event of the three published case reports. It is comprehensive, allowing other causes to generally be excluded, and though the blue cohosh product was neither analyzed nor authenticated, dose, duration of use, and form are provided. While the quantity of blue cohosh in the product was not reported, capsules typically contain approximately 450 mg, and the crude rhizomes typically found in powders, capsules, and tablets contain higher concentrations of saponins than the tinctures typically used by midwives (see Tables 13 and 14). Thus this dosage form may have yielded higher concentrations of the putative bioactive compounds of blue cohosh than that typically consumed in a tincture. Additionally, according to the report, the dose consumed was three times higher than what was recommended on the product label. Contradicting the assumptions about the role of blue cohosh in causality is the possibility that the decreased fetal movement observed by the mother signaled an obstetric complication, such as placental insufficiency, that may have led to the eventual outcome. As noted, fetal complications also begin to increase after 41 weeks gestation, independent of blue cohosh use. The cardiomegaly may have been due either to blue cohosh, placental insufficiency, or a combination of the two. Finkel and Zarlengo (2004a): A female infant weighing 3860 g was born at just over 40 weeks of gestation age to a healthy 24-year-old, gravida 2, para 0. The obstetrician had advised the woman to drink a tea made from blue cohosh (product, dose, and reason unspecified). A cesarean section was performed after a failed attempt at vaginal delivery, with no labor details provided. Focal motor seizures of the infant’s right arm began at 26 hours after birth and were controlled with phenobarbital and phenytoin. A computer tomography (CT) scan obtained at 2 days of age showed an evolving infarct in the distribution of the left middle cerebral

artery (MCA). Thrombophilia studies to assess an innate tendency for excessive blood clotting were either negative or normal, and the family history was negative for embolic or thrombotic disease. Urine and meconium were positive for the cocaine metabolite benzoylecgonine on screening by immunoassay, and both results were confirmed by gas chromatography-mass spectrometry (GC/MS). Testing of the contents of the mother’s bottle of blue cohosh and the contents of a sealed bottle of a different preparation of the botanical gave the same results. The authors initially concluded that either benzoylecgonine is a metabolite of both cocaine and blue cohosh, or that the blue cohosh was contaminated with cocaine, only later to retract this statement (see case discussion below). Case discussion: A definitive determination regarding causality cannot be made. Letters to the editor of the New England Journal of Medicine (Chan and Nelson 2004; Potterton 2004) noted that benzoylecgonine is not found in blue cohosh and is not a metabolite of any of the compounds of blue cohosh. Finkel and Zarlengo’s (2004b) response to the letters stated that the initial finding of benzoylecognine may have been an error and postulated that if this was the case, it may have been the result of the cross reaction of a substance in the blue cohosh with an insufficiently specific immunoassay, followed by incorrect interpretation of the GC/MS data, or both. The apparent finding of benzoylecgonine in urine and meconium originally suggested maternal exposure to cocaine or benzoylecgonine, but since the same result was found in case-associated and non-case associated blue cohosh, the cross-reactivity hypothesis seems more likely, While this does not completely rule out cocaine or benzoylecgonine as a contributing or causative factor in the event experienced, it does complicate the assignment of causality to blue cohosh. Safety of Blue Cohosh in the Context of Conventional Birthing Practices Numerous surveys have demonstrated that blue cohosh is widely used by midwives practicing in home, hospital, and birthing center settings (Allaire et al. 2000; Bayles 2007; Gibson et al. 2001; McFarlin et al. 1999; Romm 2009), with as many as 19.5% of CNMs in one survey (Allaire et al. 2000) reporting its use for this purpose. Labor induction for post-term pregnancy is one of the most frequently cited reasons for blue cohosh use. Common reasons for labor induction by midwives are premature rupture of membranes (PROM), post-term pregnancy, and obstetrician or patient pressure to induce labor (Romm 2009). Additional reasons for physician recommended inductions include hypertension and preeclampsia. Blue cohosh is believed by many midwives and mothers to be an effective, safe, and gentle alternative to conventional labor induction practices, such as artificial rupture of membranes (AROM), misoprostol, or pitocin, all of which carry their own risks. AROM may lead to umbilical cord prolapse, umbilical cord compression with fetal heart rate decelerations, and uterine and/or neonatal infection. Oxytocin and misoprostol may cause painful labor requiring anesthesia; tachysystole, which commonly leads to decelerations in the fetal heart rate; uterine rupture (if American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

31


misoprostol is administered in the presence of a uterine scar, i.e. from a previous cesarean) (ACOG 2009), or culminate in cesarean section should pharmaceutical induction fail (Ehrenthal et al. 2010). Blue cohosh is inexpensive and accessible, can be administered at home or in a birthing center, and many women choose to try something “natural” before undergoing conventional induction (Jurgens 2003; McFarlin et al. 1999; Romm 2009; Westfall and Benoit 2004). Commercially available blue cohosh preparations can vary widely in their constituent profiles (see Tables 13-15), making it difficult to estimate exposure to potentially toxic compounds to a mother and fetus. With the preceding case reports and the toxicological plausibility of late-term blue cohosh ingestion being a contributor to the adverse events reported, questions regarding the safety of blue cohosh use in late pregnancy and labor remain. However, the indications that often lead to the use of blue cohosh, for example, post-date pregnancies and prolonged or dysfunctional labor, are themselves independently associated with a number of the adverse effects associated with blue cohosh. These include presence of meconium in the amniotic fluid at birth, fetal distress, and increased need for neonatal resuscitation. Thus it is impossible to know if the relationship between purported adverse effects and blue cohosh use is causal or coincidental. While the case reports are alarming, and the mechanistic plausibility compelling, it is extremely difficult to determine causality from the case reports, with the exception of the attempted abortion. However, even in this case, extremely high doses of blue cohosh were used in conjunction with slippery elm and parsley vaginal douches (Rao et al. 1998; Rao and Hoffman 2002), vaginal mechanical insertions themselves being a known cause of uterine contractions (Winer 2011). Moreover, there are numerous risks associated with obstetric methods of artificial labor induction. Undoubtedly, there will always be women who, either at home or in birthing centers, will opt for what they consider to be a more natural, minimally invasive birthing experience, compared to what is offered in most hospitals. One of the primary issues at this time is that there are no clinical trials that can validate the effectiveness of blue cohosh for labor induction, nor are there any dose-ranging studies, which can truly serve to guide the clinician. Without modern evidence of efficacy or modern evidence of safety, it is highly unlikely that comparative trials with conventional labor induction agents will be undertaken. It should also be noted that while there are definite risks associated with conventional labor induction agents, they are well known and understood primarily because they have undergone randomized controlled trials establishing their effectiveness and risks, so that a meaningful risk/benefit assessment may be made.

Contraindications Due to its potential for emmenagogue activity, reports of adverse neonatal effects, potential toxicity of the constituents (anagyrine, N-methylcytisine, and the saponins), teratogenicity of N-methylcytisine in rodents in vitro (rat embryo culture [REC]), and in vitro embryotoxicity of taspine, 32

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

the use of blue cohosh in pregnancy should be restricted to labor induction in limited dose and duration, with caution, and only under the supervision of qualified childbirth professionals. Blue cohosh should not be used as a partus preparator. Use of this botanical as an abortifacient is not recommended; the high doses required can be toxic to the woman and teratogenic to the fetus. While there are no data on the transport of blue cohosh constituents in mother’s milk, caution dictates that blue cohosh not be used during lactation.

Interactions No case reports or clinical trials of herb-drug or herbsupplement interactions were identified. Madgula et al. (2009) demonstrated in vitro inhibition of the cytochrome P450 (CYP450) enzymes CYP1A2, CYP2C19, CYP3A4, and CYP2D6 by the alkaloids caulophyllumine B, O-acetlybaptifolin, anagyrine, lupanine, and N-methylcytisine and the saponins cauloside C and D. Dietary supplements containing blue cohosh or its constituents should be taken with care in combination with medications whose metabolism is mediated by these enzymes. However, in vitro evidence of hepatic enzyme inhibition often does not equate with clinically relevant alterations in drug metabolism. Moreover, ethanol extracts, the most common preparations used in herbal practice, did not show a strong CYP modulation effect when compared to the isolated alkaloids (Madgula et al. 2009). Due to in vitro effects which suggest that blue cohosh can increase estrogen receptor sensitivity (Eagon et al. 2010; see Hormonal Effects), the botanical may potentially interact with estrogen-based therapies. According to the American Herbal Products Association revised Botanical Safety Handbook (Gardner et al. 2012), blue cohosh was given a Herb-Drug Interaction Rating of A: “Herbs that can be safely consumed with any prescription or non-prescription drugs or other supplements. No case reports of suspected interactions with probability of causality; no significant interactions in clinical trials.”

Pregnancy Due to its action as an oxytocic agent and its potential for teratogenicity and adverse neonatal effects (e.g., cardiac toxicity of the glycosides), blue cohosh should not be used during pregnancy other than during labor or to induce labor and only under the supervision of qualified maternity health care providers. Historically, blue cohosh, sometimes alone and more often in combination, was used to prepare the uterus for labor, to facilitate childbirth, and as an agent to augment labor in cases of dystocia or stalled labor (Jones 1908; King 1855; Lloyd and Lloyd 1886-1887; Scudder 1870). However, three modern case reports of severe neonatal adverse outcomes associated with maternal ingestion of blue cohosh in late pregnancy (Finkel and Zarlengo 2004a; Gunn and Wright 1996; Jones and Lawson 1998), as well as traditional information (Weed 1986), surveys of midwives experienced with blue cohosh use (Romm 2009), and the


putative toxicity of blue cohosh constituents (e.g., anagyrine, N-methylcytisine, the saponins) raise significant concerns regarding its safety.

Mutagenicity Mutagenicity has not been reported with blue cohosh ingestion in animals or humans.

Teratogenicity and Embryotoxicity While there is variation in teratogen susceptibility among species and genotypes, precautions against blue cohosh use during the first trimester of human pregnancy appear to be universally accepted based on known teratogenicity and embryotoxicity of some blue cohosh compounds (e.g., anagyrine, taspine, N-methylcytisine) in animals (Keeler 1984; Kennelly et al. 1999). The teratogenicity of anagyrine, one of the quinolizidine alkaloids in blue cohosh, is well established in certain ruminants, in which it has led to “crooked-calf disease” as a result of pregnant cattle grazing on anagyrine-containing lupines. The mechanism is thought to involve stimulation followed by desensitization of fetal skeletal-muscle type nicotinic acetylcholine receptors (nAChR) (Green et al. 2010). The disease is known to appear only when ingestion occurs in a very narrow window of early gestation, and is not reproducible in sheep or hamsters. In addition, the quantity consumed by a grazing animal (Keeler 1984) is substantially greater than that consumed by humans when using blue cohosh in recommended doses. Nevertheless, Green et al. (2010), using cultured human cells expressing fetal muscle-type nAChR, showed that anagyrine is able to elicit depolarization of cellular membranes at the concentrations of 18.1-19.1 µM. Thus, the embryotoxicity of anagyrine-containing botanicals, such as blue cohosh, in humans remains plausible. N-Methylcytisine, which binds to nicotinic acetylcholine receptors in a manner similar to nicotine (IC50 = 0.05 µM; also see Table 9), has demonstrated teratogenicity in REC, inducing major malformations, such as open anterior neural tube defects, poor or absent eye development, and twisted tail (Kennelly et al. 1999). These effects occurred at medium concentrations (20 µg/mL) and did not inhibit overall growth and development. In addition to teratogenicity, at higher levels (250 µg/mL) there was retardation of growth and morphogenesis. The analytical data suggests that blue cohosh may contain 0.14-4.58 mg/g of N-methylcytisine (Table 4). At the upper recommended dose of 3 g, blue cohosh could yield up to 16.44 mg of N-methylcytisine. Taspine, an alkaloid that occurs in trace amounts in blue cohosh (0.00013% w/w; Kennelly et al. 1999), has been widely investigated as a potential anti-cancer agent, because of its cytotoxicity (Lu et al. 2008) and inhibitory effects on angiogenesis (e.g., Zhang et al. 2008). The compound showed significant embryotoxicity but no teratogenicity in REC. Taspine was lethal at 5 µg/mL and cytotoxicity was observed even at low concentrations of 0.5 µg/mL (Irikura and Kennelly 1999; Kennelly et al. 1999). The concentration expected from the higher end dose of blue cohosh (3 g) could potentially yield approximately 0.4 µg of taspine. The

typical doses used by contemporary midwives and in traditional preparations suggest that exposure would be negligible (see Medical Indications Suggested by Traditional Use). Magnoflorine, an alkaloid with the highest content in blue cohosh and a putative biosynthetic precursor to taspine, was not active in the REC (Satchithanandam et al. 2008). Another investigation into the teratogenic potential of blue cohosh was conducted using a Japanese fish model (medaka; Oryzias latipes). A methanolic extract exhibited in vitro teratogenicity in developing embryos resulting in craniofacial and cardiovasculature abnormalities. These effects were mediated by the Gata2-End1 signaling pathway (Wu et al. 2010). The relevance to humans, if any, is unknown.

Lactation Data on the safety of blue cohosh to infants of lactating mothers ingesting blue cohosh products are lacking. Anagyrine has been implicated in teratogenicity in ruminants (e.g., Keeler 1983). There is a single case report associating severe human congenital “crooked” skeletal malformations in an infant as well as in a litter of puppies and goat kids with maternal ingestion of anagyrine from lupines (Keeler 1984). In these cases, milk from a family goat, which had been foraging on lupine, had been consumed. It has been proposed that this effect requires metabolism by rumen microflora. However, Green et al. (2010) found that anagyrine is able to elicit a response in human cells expressing fetal muscle-type receptors. Blue cohosh samples have been found to contain anagyrine contents in similar quantities to the lupines ingested in the case of the goat milk toxicity. Based on the available information blue cohosh should not be used during lactation.

Carcinogenicity No data on the effect of the root are available. Several constituents (magnoflorine, caulosides A and C) have demonstrated antineoplastic activity in vitro.

Influence on Driving No data are available. Based upon contemporary use by modern practitioners, no effects on driving are to be expected.

Precautions Excessive doses of this herb should be avoided. See Contraindications.

Overdose A 21-year-old non-smoking woman at 5-6 weeks gestation by dates who had taken 10-20 doses (unspecified amount) of blue cohosh tincture daily for 4 days in an abortion attempt presented to the emergency department complaining of two days of abdominal pain and bilious vomiting. On examination she was hypertensive to 149/62, tachycardic to 148 beats/minute, diaphoretic, weak, and had anterior abdominal wall fasciculations. Her gynecologic exam showed a non-tender uterus without cervical dilatation. Ketones were American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

33


Table 13 Content of alkaloids in blue cohosh products Compound

Content*

Publication reference

Powders and capsules, mg/g 8.72 Magnoflorine

Anagyrine

Ganzera et al. 2003

5.8 ± 1.6

Satchithanandam et al. 2008

11.4 ± 1.0

Avula et al. 2011

0.34 ± 0.07

Betz et al. 1998

1.26 1.25 ± 0.49

Baptifoline

0.89 1.9 ± 0.7 0.76 ± 0.13

N-methylcytisine

0.37 3.4 ± 0.8

Ganzera et al. 2003 Betz et al. 1998 Ganzera et al. 2003 Satchithanandam et al. 2008 Betz et al. 1998 Ganzera et al. 2003 Satchithanandam et al. 2008

Liquid products, mg/mL 54.94 Magnoflorine

Anagyrine

1.8 ± 1.0

Ganzera et al. 2003 Satchithanandam et al. 2008

2.08 ± 1.52

Avula et al. 2011

0.017 ± 0.016

Betz et al. 1998

4.05 0.075 ± 0.070

Baptifoline

2.67 1.1 ± 0.8 0.048 ± 0.040

N-methylcytisine

0.26 1.4 ± 0.6

Ganzera et al. 2003 Betz et al. 1998 Ganzera et al. 2003 Satchithanandam et al. 2008 Betz et al. 1998 Ganzera et al. 2003 Satchithanandam et al. 2008

* Values are average of the means of different products ± standard deviation between the products, except for Ganzera et al. (2003) where one product was characterized in each category.

found in urinalysis, and blood laboratory evaluation was normal with a serum quantitative b-hCG of 53,484 IU/L. She was diagnosed with acute nicotinic poisoning, treated with IV rehydration, and her gastrointestinal complaints resolved, with the patient reporting only persistent mild low pelvic cramping. Voluntary termination was planned as an outpatient procedure, and the patient was discharged 24 hours after hospital presentation. It is believed that her nicotinic toxicity symptoms were a result of the nicotine-like activities of N-methylcytisine in blue cohosh (Rao et al. 1998; Rao and Hoffmann 2002). The exhibited symptoms neatly corroborate with nicotinic toxicity that may be secondary to excessive ingestion of N-methylcytisine contained in the botanical. The closest estimate of blue cohosh consumed in this subject is 10-20 doses (typically 1 mL doses), equivalent up to 28 mg of the alkaloid, based on the available data on the concentrations found in products (Table 13). 34

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

Treatment of Overdose Treatment of nicotinic toxicity, which was reported in one case of excessive blue cohosh ingestion, depends on the amount of the toxic substance (in this case, N-methylcytisine) ingested and the severity of symptoms. Hospitalization may be required, as untreated severe nicotinic toxicity can lead to convulsions and death. Treatment ranges from IV hydration to more aggressive medical treatment. Unless there are complications, long-term effects from nicotinic toxicity are rare. In the case involving blue cohosh, IV fluids were the only necessary treatment and the patient was hospitalized overnight only for observation (Rao et al. 1998; Rao and Hoffman 2002).

Toxicity The alkaloids N-methylcytisine, anagyrine, and taspine, among others contained in blue cohosh have been implicated as teratogens in higher animals (Kennelly et al. 1999).


Table 14 Content of saponins in blue cohosh products Compound

Content*

Publication reference

Powders and capsules, mg/g Cauloside A

3.3 ± 0.5

Avula et al. 2011

Cauloside B

4.9 ± 0.3

Avula et al. 2011

Cauloside C

4.06 ± 0.83

Avula et al. 2011

15.64 Cauloside D

Ganzera et al. 2003

12.6 ± 1.0

Satchithanandam et al. 2008

47.19 ± 9.34

Avula et al. 2011

32.32 Cauloside G Cauloside H

Ganzera et al. 2003

20.5 ± 4.9

Satchithanandam et al. 2008

43.3 ± 1.5

Avula et al. 2011

1.86 ± 0.31

Avula et al. 2011

32.71 Leonticin D

Ganzera et al. 2003

11.5 ± 1.2

Satchithanandam et al. 2008

26.0 ± 5.7

Avula et al. 2011

Liquid products, mg/mL Cauloside A

0.99 ± 0.68

Avula et al. 2011

Cauloside B

1.76 ± 0.91

Avula et al. 2011

Cauloside C

1.03 ± 0.57

Avula et al. 2011

0.31 Cauloside D

2.9 ± 2.8 10.82 ± 9.00 1.33

Cauloside G Cauloside H

6.1 ± 5.5

Satchithanandam et al. 2008 Avula et al. 2011 Ganzera et al. 2003 Satchithanandam et al. 2008

11.88 ± 8.38

Avula et al. 2011

0.66 ± 0.39

Avula et al. 2011

1.62 Leonticin D

Ganzera et al. 2003

3.2 ± 2.9 6.35 ± 4.95

Ganzera et al. 2003 Satchithanandam et al. 2008 Avula et al. 2011

* Values are average of the means of different products ± standard deviation between the products, except for Ganzera et al. (2003) where one product was characterized in each category.

Ingestion of blue cohosh has been associated with tachycardia, tachypnea, diaphoresis, hypotension and hypertension, muscle weakness, hyperglycemia, fasciculations, increased small intestine motility, abdominal pain, pelvic cramping, and vomiting (Rao et al. 1998; Rao and Hoffman 2002). These symptoms are consistent with nicotinic poisoning and are likely caused by N-methylcytisine in blue cohosh, which binds to nicotinic receptors more weakly than nicotine, but with significant affinity (Barlow and McLeod 1969; Rao et al. 1998; Rao and Hoffman 2002; Schmeller et al. 1994; also see Table 8). The highest content of N-methylcytisine reported in tinctures, which is

the kind of preparation used by the subject in this report, is 1.6 mg/mL (Satchithanandam et al. 2008). The LD50 of N-methylcytisine in mice was determined as 21 mg/kg by i.v. administration, 51 mg/kg by i.p. administration, and >2500 mg/kg when administered orally (Barlow and McLeod 1969), suggesting that traditionally used blue cohosh preparations present a very low risk of exposure. A crystalline glycoside isolated from blue cohosh was implicated in cardiotoxicity, based on the observation of reduction in coronary blood flow in rat hearts perfused with 10 µg/0.1 cc of the glycoside solution (Ferguson and Edwards 1954). The LD50 of the glycoside, administered i.v., American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

35


in mice was 12 mg/kg, while in rats it was 20 mg/kg, with observed increase in activity, ataxia, and clonic seizures and death ascribed to asphyxia (Ferguson and Edwards 1954). Wide variations in the content of alkaloids and saponins in blue cohosh products were noted by most researchers (Avula et al. 2011; Betz et al. 1998; Ganzera et al. 2003). The levels of alkaloids varied similarly in both types of products, with the exception of one liquid product with an unusually high content of magnoflorine, reported by Ganzera et al. (2003) (Table 13). The levels of saponins were typically highest in supplements containing powdered roots/rhizomes and lowest in liquid preparations (hydroethanolic and glycerine extracts) (Table 14); however, based on the estimations of maximum daily intakes using the recommended doses provided on the product labels, some tinctures may yield high amounts of saponins (Table 15). This is likely due to the inherent variation in the constituent profile in the botanical raw material (see Tables 4 and 6).

Classification of the American Herbal Products Association Safety Rating: Class 2b (Not for use during pregnancy except under the supervision of a qualified healthcare practitioner). Interaction Rating: Class A (Herbs for which no clinically relevant interactions are expected. Notice as “abortifacient,” though the literature and opinion of experts are not consistent on this) (Gardner et al. 2012).

Conclusion The use of blue cohosh outside of pregnancy for common gynecologic complaints does not appear to be associated with significant adverse events or toxicity when the botanical is used in recommended doses. Historically, blue cohosh was considered safe to use as a partus preparator and for labor augmentation. However, contemporary survey data of anecdotal reports by midwives, the case reports presented, and a demonstrated toxicological plausibility between blue cohosh constituents and the adverse events reported suggest that the use of blue cohosh both as a partus preparator and for labor induction must be reconsidered. Reports from midwives implicate an increased incidence of fetal tachycardia, increased meconium, and increased need for neonatal resuscitation when the botanical is used as a partus preparator or for labor induction or augmentation (McFarlin et al. 1999; Romm 2009). A case report by Jones and Lawson (1998) supports a plausible causal relationship between maternal ingestion of blue cohosh as a partus preparator and neonatal cardiogenic shock, while another case report of high dose first trimester ingestion by a healthy, non-smoking young woman attempting to induce an abortion resulted in symptoms of nicotinic toxicity that may putatively be correlated with the blue cohosh alkaloid N-methylcytisine, which binds to nicotinic receptors (Rao et al. 1998; Rao and Hoffman 2002). Of the four published case reports associated with blue cohosh adverse events, a plausible relationship between blue cohosh ingestion and the adverse effects can only be established for two. Compared with the frequent use of 36

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

blue cohosh by midwives and pregnant women, this does not appear to represent a high frequency of severe adverse events. Despite the lack of a significant number of reports of adverse events, the pharmacologic actions of the alkaloid and saponin components in blue cohosh are consistent with mechanisms for reported adverse events. Conversely, the indications that often lead to the use of blue cohosh to induce or augment labor, for example, post-date pregnancy and prolonged or dysfunctional labor, are themselves independently associated with a number of the reported adverse effects including presence of meconium in the amniotic fluid, fetal tachycardia, need for neonatal resuscitation, and increased neonatal morbidity (Mayo Clinic 2011). Similarly, there are numerous risks (e.g., prematurity, tachysystole, fetal heart rate decelerations, and increased rates of cesarean, which are associated with increased maternal morbidity and mortality) associated with conventional methods of labor induction (e.g., misoprostol, pitocin). Thus, a risk/ benefit analysis comparing the use of blue cohosh and conventional methods for induction may shed light on which interventions are the safest. However, without first having studies demonstrating efficacy of blue cohosh for labor induction, such comparative studies are highly improbable. In the case of the attempted abortion, the woman took an unspecified dose; however, it is known that this dose was taken at a frequency approximately 6.5 times higher than recommended and must be considered as an overdose rather than an inherent toxicity of the botanical itself. The potential teratogenic, embryotoxic, and cardioactive effects of blue cohosh represent potential for harm, thus this botanical should never be used during the first trimester of pregnancy. There are ample data to question whether blue cohosh can be used safely in pregnancy at all. However, given the known risks associated with conventional labor induction and the necessity that these be performed in medical settings, it is likely that a number of midwives and pregnant women will choose to continue to use blue cohosh for labor induction and augmentation (Bruckner et al. 2008; Jurgens 2003; McFarlin et al. 1999; Romm 2010; Westfall et al. 2004). Until further research is done, it is recommended that the practice of using blue cohosh as a partus preparator be abandoned. If the botanical is to be used for labor induction or augmentation, it should be used only at the recommended dosage, under the supervision of a qualified maternity health professional, with proper fetal and neonatal monitoring, and using preparations with the lowest level of potentially harmful constituents. Based on available data, tinctures (hydroethanolic extracts) appear to have the lowest concentration of potentially cardiotoxic glycosides. More precise characterization of preparations to establish optimally safe dosage ranges for blue cohosh and a formal study to establish the effectiveness of blue cohosh for labor induction are needed. If it is found effective and dose ranging is established, then a comparison of blue cohosh and conventional obstetric methods of labor induction and augmentation would be appropriate to determine. Additionally, the traditional literature suggests that blue cohosh was seldom used singularly, but was primarily used in combina-


Table 15 Estimated maximum daily intakes (mg) of alkaloids and saponins from blue cohosh products, based on information provided on the product labels Product type Capsules Liquid extracts

Reported as range.

Alkaloids, mg

Saponins, mg

15.6-47.8a

76.5-190.3a

Satchithanandam et al. (2008)

­—

115.6-161.84

Avula et al. (2011)

0.9-17.3

a

Publication reference

9.1-79.1

Satchithanandam et al. (2008)

5.97-302.4

Avula et al. (2011)

a

a

tions (e.g., Mother’s Cordial), thus further limiting exposure to the putatively toxic blue cohosh constituents. If blue cohosh is to be popularly used, greater adherence to the use of such combinations and greater availability of commercial products containing them may be more prudent than use of blue cohosh alone and predominant availability of singleingredient products.

International Status Australia Caulophyllum thalictroides is a substance that may be used as an active ingredient in ‘Listed’ medicines in the Australian Register of Therapeutic Goods (ARTG) for supply in Australia (TGA 2007). Quality: For active ingredients of listed medicines, the quality standards of the British Pharmacopoeia (BP) are the minimum standard that must be applied in its entirety (TGA 2006). Canada Caulophyllum thalictroides rhizome is regulated as an active ingredient of Natural Health Products (NHPs) requiring pre-marketing authorization and issuance of a product license for over-the-counter (OTC) human use. Blue cohosh appears on the list of herbs unacceptable as nonmedicinal use products (HC 1995). Quality: The finished product must comply with the minimum specifications outlined in the current NHPD Compendium of Monographs (NHPD 2007a). As an FYI, I was under the understanding from researchers in Canada that AHP was also accepted by NHP. Indications: Product-specific depending on evidence submitted with product license application. For example, a tincture (1:3) for oral use: (1) traditionally used for the relief of painful menstruation; (2) traditionally used for bronchitis (NHPD 2007b).

United Kingdom Blue cohosh is a General Sale List (GSL) medicine appearing on List B; substances which are present in authorized medicines for general sale (MHRA 2009). Traditional Herbal Medicinal Products (THMPs) containing blue cohosh as an active ingredient require pre-marketing authorization and registration through the Medicines and Healthcare products Regulatory Agency (MHRA). Indications: Product-specific depending on evidence submitted in traditional herbal registration application. No known registered products. United States Blue cohosh preparations can be labeled and marketed as dietary supplement products (USC 1994), requiring FDA notification and substantiation to support structure/ function claim statements. FDA, however, considers blue cohosh to be a dietary supplement of safety concern (FDA 2009). Quality: No blue cohosh monographs are published in the Food Chemicals Codex (FCC) or United States Pharmacopeia - National Formulary (USP-NF). Indications: FDA has received 30-day notification letters for various blue cohosh-containing dietary supplement products. For example, a fluidextract (1:2): (1) supports female reproductive system; (2) encourages healthy menstrual cycling (FDA 2001a); a tincture (1:4): balances uterine function (FDA 2001b); a capsule with 450 mg powdered root: female glandular system support (FDA 2002).

European Union Currently there is no Caulophyllum thalictroides preparation approved for use in the European Community. Regulated as an active ingredient of Traditional Herbal Medicinal Products (THMPs) requiring pre-marketing authorization and product registration (EPCEU 2004). Quality: Herbal medicinal products must be composed of pharmacopoeial quality active ingredients. Indications: Product-specific depending on the evidence submitted by the applicant in its traditional herbal registration application. American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

37


References Blue cohosh Final Bibliography 4/25/2012 [ACOG] American College of Obstetricians and Gynecologists. 2009. Induction of labor. Washington (DC): American College of Obstetricians and Gynecologists. 12 p. Adolphus J. 1897. Restudy the materia medica. Eclec Med J 57:264-5. Ali Z, Khan IA. 2008. Alkaloids and saponins from blue cohosh. Phytochemistry 69:1037-42. Allaire AD, Moos MK, Wells SR. 2000. Complementary and alternative medicine in pregnancy: A survey of North Carolina certified nursemidwives. Obstet Gynecol 95:19-23. Ambache N. 1949. The nicotinic action of substances supposed to be purely smooth-muscle stimulating (B) effect of BaC12 and pilocarpine on the superior cervical ganglion. J Physiol 110:164-72. Avula B, Wang YH, Rumalla CS, Ali Z, Smillie TJ, Khan IA. 2011. Analytical methods for determination of magnoflorine and saponins from roots of Caulophyllum thalictroides (L.) Michx. using UPLC, HPLC, and HPTLC. Pharm Biomed Anal 56:895903. Ayers JS. 1895. Caulophyllum thalictroides. Eclec Med J 4:87-9. Baker VA. 1910. Caulophyllum thalictroides. Eclec Med J 70:117-9. Barlow RB, McLeod LJ. 1969. Some studies on cytisine and its methylated derivatives. Br J Pharm 35:161-74. Bayles BP. 2007. Herbal and other complementary medicine use by Texas midwives. J Midwifery Wom Health 52:473-8. Belew C. 1999. Herbs and the childbearing woman: Guidelines for midwives. J Nurse-Midwifery 44:231-52. Benrubi GI. 2000. Labor 38

induction: historical perspectives. Clin Obstet Gynecol 43:429-32. Berger J, DeGolier T. 2008. Pharmacological effects of the aqueous extract of Caulophyllum thalictroides (blue cohosh) on isolated Mus musculus uteri. Bios 79:103114. Bergner P. 2001. Caulophyllum: Cardiotoxic effects of blue cohosh on a fetus. Med Herbal 12:12-14. Berry JL, Small RC, Hughes SJ, Smith RD, Miller AJ, Hollingsworth M, Edwards G, Weston AH. 1992. Inhibition by adrenergic neurone blocking agents of the relaxation induced by BRL 38227 in vascular, intestinal and uterine smooth muscle. Br J Pharmacol 107:288-95. Betz JM, Andrzejewski D, Troy A, Casey RE, Obermeyer WR, Page SW, Woldemariam TZ. 1998. Gas chromatographic determination of toxic quinolizidine alkaloids in blue cohosh Caulophyllum thalictroides (L.) Michx. Phytochem Anal 9:232-6. [BHP] British Herbal Pharmacopoeia. 1983. British Herbal Pharmacopoeia. 3rd ed. Bournemouth (UK): British Herbal Medicine Assoc. 255 p. Bloyer WE. 1897. Caulophyllum. Eclec Med J 57:628-30. Bruckner TA, Cheng YW, Caughey AB. 2008. Increased neonatal mortality among normal-weight births beyond 41 weeks of gestation in California. Am J Obstet Gyn 421:e1-e7. Case E. 1919. Blue cohosh. Ellingwood’s Therapeutist 13:322-3. Caughey AB, Sundaram V, Kaimal AJ, Cheng YW, Gienger A, Little SE, Lee JF, Wong L, Shaffer BL, Tran SH et al. 2009. Maternal and neonatal outcomes of elective induction of labor. [Internet]. Rockville (MD): Agency Healthcare Research

Quality (US). Report nr: 09E005. Available from: http:// www.ncbi.nlm.nih.gov/books/ NBK38683/?report=printable. Access date: [2012/4/25]. 5 p. Cech R. 2002. Growing at-risk medicinal herbs. Williams (OR): Horizon Herbs. 314 p. Chan GM, Nelson LS. 2004. Correspondence: More on blue cohosh and perinatal stroke. N Engl J Med 351:223941. Chandrasekhar K, Vishwanath CR. 1974. Studies on the effect of Caulophyllum on implantation in rats. J Rep Fertil 38:245-6. Clymer RS. 1905. Nature’s healing agents. 5th ed. Quakertown (PA): Philosophical Pub. 230 p. Reprint edition 1973. Cook WMH. 1869. The physio-medical dispensatory: A treatise on therapeutics, materia medica, and pharmacy, in accordance with the principles of physiological medication. Portland (OR): Eclectic Medical. 832 p. Reprint edition 1985. Culbreth DMR. 1917. A manual of materia medica and pharmacology. 6th ed. Philadelphia: Lea & Febiger. 1001 p. Dye JH. 1891. Painless childbirth or healthy mothers and healthy children: a book for all women. Baltimore: Frank Thomas. 451 p. Eagon PK, Hunter DS, Elm MS, Tress NB, Eagon CL. 2001. Medicinal botanicals: Modulation of estrogen action. Proceedings of the American Association for Cancer Research Annual Meeting 42:270. Ehrenthal DB, Jiang X, Strobino DM. 2010. Labor induction and the risk of a cesarean delivery among nulliparous women at term. Obstet Gyn 116:35-42. El Tahir KEH. 1991. Pharmacological actions of magnoflorine and aristolochic acid-1 isolated from the seeds

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

of Aristolochia bracteata. Int J Pharmaceut 29:101-10. Ellingwood F. 1900. A systematic treatise on materia medica and therapeutics. Chicago: Chicago Medical. 706 p. Ellingwood F. 1919. American materia medica, therapeutics and pharmacognosy. 11th ed. Evanston (IL): Ellingwood’s Therapeutist. 564 p. [EPCEU] European Parliament and the Council of the European Union. 2004. Directive 2004/24/EC of the European Parliament and of the Council of 31 March 2004 amending, as regards traditional herbal medicinal products, Directive 2001/83/ EC on the Community code relating to medicinal products for human use. Off J Euro Union 30:L 136/85-90. Erichsen-Brown C. 1989. Medicinal and other uses of North American plants. New York: Dover. 512 p. Evelsizer A, DeGolier T. 2010. The contractile effects of Caulophyllum thalictroides (blue cohosh) on Rattus norvegicus aortic and intestinal smooth muscle in vitro. J Minn Acad Sci 73:8. [FDA] Food and Drug Administration. 2001a Jan 31. MediHerb Pty Ltd. 30-day FDA Notification Letter: Blue Cohosh 1:2 [Internet]. Access date: [2012/4/13]. Available from: http://www.fda.gov/ ohrms/dockets/dailys/01/ May01/050901/let6893.pdf. [FDA] Food and Drug Administration. 2001b Jan 10. Herbalist & Alchemist 30-day FDA Notification Letter: Blue Cohosh Extract [Internet]. Access date: [2012/4/13]. Available from: http://www.fda. gov/ohrms/dockets/dailys/01/ Jul01/071301/let7766.pdf [FDA] Food and Drug Administration. 2002 Mar 27. Nature’s Sunshine 30-day FDA Notification Letter: Blue Cohosh. [Internet]. Access date: [2012/4/13]. Available from: http://www.fda.gov/


ohrms/dockets/dailys/03/ Apr03/042403/97s-0162let9868-vol75.pdf. [FDA] Food and Drug Administration. 2009. Foods Report. [Internet]. Access date: [2012/4/13]. Available from: http://www.fda.gov/ downloads/AboutFDA/ ReportsManualsForms/ Reports/BudgetReports/2 009FDABudgetSummary/ ucm116140.pdf Felter HW. 1892. Caulophyllum thalictroides. Med Gleaner 3:439-44. Felter HW. 1922. The eclectic materia medica, pharmacology and therapeutics. Volume 1. Portland (OR): Eclec Med. 743 p. Reprint edition 1985. Felter HW, Lloyd JU. 1898. King’s American dispensatory. Volume 1-2. 18th ed. Portland (OR): Eclec Med. 2172 p. Reprint edition 1983. Felter HW, Lloyd JU. 1909. King’s American Dispensatory. Volume 1-2. 19th ed. Cincinnati: Ohio Valley. 2172 p. Ferguson HC, Edwards LD. 1954. A pharmacological study of a crystalline glycoside of Caulophyllum thatlictroides. J Amer Pharm Assoc 43:16-21. Finkel RS, Zarlengo KM. 2004a. Correspondence: Blue cohosh and perinatal stroke. N Engl J Med 351:302-3. Finkel RS, Zarlengo KM. 2004b. Correspondence: More on blue cohosh and perinatal stroke N Engl J Med 351:223941. Flom MS, Doskotch RW, Beal JL. 1967. Isolation and characterization of alkaloids from Caulophyllum thalictroides. J Pharmaceut Sci 56:1515-7. Forsgren A, DeGolier T. 2011. The contractile effects of blue cohosh (Caulophyllum thalictroides) extract on the stomach tissues of rats (Rattus norvegicus) [BS Thesis]. St Paul (MN): Bethel Univ: Available from: Bethel University. Foster S. 1993. Herbal renaissance. Layton (UT): Gibbs-Smith Books. 234 p.

Ganzera M, Dharmaratne HRW, Nanayakkara NPD, Khan IA. 2003. Determination of saponins and alkaloids in Caulophyllum thalictroides (blue cohosh) by high-performance liquid chromatography and evaporative light scattering detection. Phytochem Anal 14:1-7. Gardner Z, et al. 2012. Botanical safety handbook [Forthcoming]. Boca Raton: CRC. Gibson P, Powrie R, Star J. 2001. Herbal and alternative medicine use during pregnancy: A cross-sectional survey. Obstet Gyn 97 Suppl 4:44-5. Gladstar R. 1993. Herbal healing for women: Simple home remedies for women of all ages. New York: Fireside. 303 p. Gleason HA, Cronquist A. 1998. A manual of vascular plants of northeastern United States and adjacent Canada. 2nd ed. New York: NY Botanical Gardens. 910 p. Gonzalez ET, Gimeno MAF, Gimeno AL. 1988. A novel anti-lipolytic action of norepinephrine in uteri isolated from spayed rats appears subserved by the activation of α1 adrenoreceptors diminishing the generation and release of lipolytic prostaglandins. Prostaglan Leuk Essen Fatty Acids 34:101-8. Gray MJ, Plentl A. 1958. Sparteine: A review of its uses in obstetrics. Obstet Gyn 11:204-13. Green BT, Lee ST, Panter KE, Welch KD, Cook D, Pfister JA, Kem WR. 2010. Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptors. Neurotoxicol Teratol 32:383-90. Grieve M. 1931. A modern herbal. 3rd ed. London: Tiger Books Int. 912 p. Reprint edition 1994. Gunn T, Wright IMR. 1996. The use of black and blue cohosh in labour. New Zealand Med J 109:410-1.

Haines A. 2003. Identification of Caulophyllum giganteum. Bot Notes 9:3-5. Harding AR. 1908. Ginseng and other medicinal plants. Columbus (OH): AR Harding. 317 p. [HC] Health Canada. 1995. Bureau of Nonprescription Drugs: Medicinal herbs in traditional herbal medicines: Appendix I: Herbs that are restricted or not accepted as medicinals in THMs. [Internet]. Ottawa (Canada): Minister National Health Welfare. Access date: [2012/4/13]. Available from: http://www.hc-sc.gc.ca/ dhp-mps/alt_formats/hpfbdgpsa/pdf/prodpharma/ herbnonmed_pol-eng.pdf. 25 p. Hoffmann D. 1996. The complete illustrated holistic herbal. Boston (MA): Element Books. 256 p. Hulst J. 2009. D-Tubocurarine partially suppressed the bradycardia response to blue cohosh, Caulophyllum thalictroides, in isolated rat hearts [BS thesis]. St Paul (MN): Bethel Univ. Available from: Bethel University. Hunter DS, Hodges LC, Eagon PK, Vonier PM, Fuchs-Young R, Bergerson JS, Walker CL. 2000. Influence of exogenous estrogen receptor ligands on uterine leiomyoma: evidence from an in vitro/in vivo animal model for uterine fibroids. Environ Health Perspec 108:829-834. Hyam R, Pankhurst R. 1995. Plants and their names: a concise dictionary. Edinburgh: Oxford Univ Pr. 558 p. Irikura B, Kennelly E. 1999. Blue cohosh: A word of caution. Altern Ther Womens Health 1:813. Ishizaki T, Eichelbaum M, Horai Y, Hashimoto K, Chiba K, Dengler HJ. 1987. Evidence for polymorphic oxidation of sparteine in Japanese subjects. Br J Clin Pharmacol 23:482-5. Jhoo JW, Sang S, He K, Cheng XF, Zhu NQ, Stark RE, Zheng QY, Rosen RT, Ho CT. 2001. Characterization of the

triterpene saponins of the roots and rhizomes of blue cohosh (Caulophyllum thalictroides). J Agric Food Chem 49:5969-74. Johnson C. 2009. A comparison of Rubus idaeus, Cimicifuga racemosa, Caulophyllum thalictroides, and Mitchella repens on frog heart rate in situ. [BS thesis]. St Paul (MN): Bethel Univ. Available from: Bethel University. Jones EG. 1908. The true action of Caulophyllum (blue cohosh). Eclec Med J 68:369. Jones TK, Lawson BM. 1998. Profound neonatal congestive heart failure caused by maternal consumption of blue cohosh herbal medication. J Pediat 132:550-3. Jurgens TM. 2003. Potential toxicities of herbal therapies in the developing fetus. Birth Defects Res B Dev Reprod Toxicol 68:496-8. Keeler RF. 1983. Plant metabolites that are teratogenic in offspring and toxic in the dam. Toxicon 1 (Supp 3):221-5. Keeler RF. 1984. Teratogens in plants. J Anim Sci 58:1029. Kennelly EJ, Flynn TJ, EP. M, Roach JA, McCloud TG, Danfor DE, Betz JM. 1999. Detecting potential teratogenic alkaloids from blue cohosh rhizomes using an in vitro rat embryo culture. J Nat Prod 62:1385-9. King J. 1855. American eclectic obstetrics. Cincinnati: Moore Wilstach Keys. 741 p. King J, Newton RS. 1852. The eclectic dispensatory of the United States. Cincinnati: HW Derby. 708 p. Kuts-Cheraux AW. 1953. Naturae medicina and naturopathic dispensatory. Chattanooga (TN): Am Naturopathic Physicians Surg Assoc. 323 p. Reprint edition 1999. Leafbled P. 2011. The effect of the aqueous extract of Caulophyllum thalictroides (blue cohosh) on isolated vas deferens contractility in Rattus norvegicus. [BS Thesis]. St. Paul (MN): Bethel Univ. Available from: Bethel

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

39


University. Li YP, Qiang K, He LC. 2005. Pharmacokinetics of taspine in rats by RP-HPLC. Chin J Pharm Anal 12:2. Linnaeus C. 1753. Species plantarum. Volume 1-2. London: Ray Society. 1959 p. Lloyd JU. 1921. Origin and history of all the pharmacopoeia vegetable drugs, chemicals, and preparations. Cincinnati: Caxton. 449 p. Lloyd JU, Lloyd CG. 188687. Drugs and medicines of North America. Volume 2. Cincinnati: JU Lloyd & CG Lloyd. 162 p. Lockard A, Swanson AQ. 2004. A digger’s guide to medicinal plants. 2 ed. Eolia (MO): American Botanicals. 95 p. Loconte H. 1997. Caulophyllum. In: Flora of North America Editorial Committee, eds. Flora of North America North of Mexico. Volume 3. New York: Oxford University Pr. 274-5 p. Loconte H, Blackwell WH. 1985. Intrageneric taxonomy of Caulophyllum (Berberidaceae). Rhodora 87:463-9. Loconte H, Blackwell WH. 1981. A new species of blue cohosh (Caulophyllum, Berberidaceae) in eastern North America. Phytologia 49:483. Lu W, He C, Zeng XM. 2008. HPLC method for the pharmacokinetics and tissue distribution of taspine solution and taspine liposome after intravenous administrations to mice. J Pharmaceut Biomed Anal 46:170-6. Madgula VL, Ali Z, Smillie T, Khan IA, Walker LA, Khan SI. 2009. Alkaloids and saponins as cytochrome P450 inhibitors from blue cohosh (Caulophyllum thalictroides) in an in vitro assay. Planta Med 75:329-32. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Mathews TJ, Kirmeyer S, Osterman MJK. 2010. Births: Final data for 2007. NVSR 58:1-86. Matsuo Y, Watanabe K, Mimaki Y. 2009. Triterpene glycosides from the underground parts of 40

Caulophyllum thalictroides. J Nat Prod 72:1155-60. Mayer FF. 1863. Note on the proximate principles of some Berberidaceae and Ranunculaceae. Am J Pharm 35:97-100. Mayo Clinic. 2011. Labor induction. [Internet]. Access date: [2010/4/25]. Available from: http://www.mayoclinic. com/health/labor-induction/ MY00642/DSECTION=risks. [MBG] Missouri Botanical Garden. 2009. Caulophyllum thalictroides. [Internet]. Access date: [2012/4/25]. Available from: http://www.mobot.org/ gardeninghelp/plantfinder/ Plant.asp?code=J700. McFarlin BL, Gibson MH, O’Rear J, Harman P. 1999. A national survey of herbal preparation use by nursemidwives for labor stimulation: Review of the literature and recommendations for practice. J Nurse Midwifery 44:205-16. McQuade Crawford A. 1997. Herbal remedies for women. Roseville (CA): Three Rivers. 304 p. McShefferty J, Stenlake JB. 1956. Caulosapogenin and its identity with hederagenin. J Chem Soc 449:2314-6. [MHRA] Medicines and Healthcare products Regulatory Agency. 2009. List B: Consolidated list of substances which are present in authorized medicines for general sale. [Internet]. London (UK): MHRA. Access date: [2012/4/13]. Available from: http://www.mhra.gov.uk/ home/groups/pl-a/documents/ websiteresources/con009485. pdf. 37 p. Michaux A. 1803. Flora BorealiAmericana, Sistens Caracteres Plantarum quas in America septentrionali collegit et detexit. Paris: Apud fratres levrault. 330 p. Mitchell WA Jr. 2003. Plant medicine in practice: Using the teachings of John Bastyr. St. Louis: Churchill Livingstone. 458 p. Moerman DE. 1998. Native American ethnobotany. Portland (OR): Timber. 927 p.

Moore LE, Rayburn WF. 2006. Elective induction of labor. Clin Obstet Gyn 49:698-704. [NF] The National Formulary. 1946. The National Formulary. 8th ed. Washington (DC): Am Pharm Assoc. 850 p. [NHPD] Natural Health Products Directorate. 2007a. NHPD Compendium of Monographs, Version 2.1. [Internet]. Ottawa (ON): Health Canada Natural Health Products Directorate. Access date: [2012/4/13]. Available from: http://www.hcsc.gc.ca/dhp-mps/alt_formats/ hpfb-dgpsa/pdf/prodnatur/ compendium_mono_v2-1-eng. pdf. 33 p. [NHPD] Natural Health Products Directorate. 2007b. Natural Product Number 80003247. Gaia Garden Herbals Blue Cohosh Tincture. [Internet]. Ottawa (ON): NHPD. Access date: [2012/4/13]. Available from: http://webprod.hc-sc.gc.ca/ lnhpd-bdpsnh/index-eng.jsp. Niederkorn J, Versailles O. 1910. Macrotys and caulophyllin. Eclec Med J 70:63-6. [NPSG] Proposed National Patient Safety Goals. 2011. Minimize the overuse of tests, treatments, and procedures to reduce the risk of patient harm. [Internet]: The Joint Commission. Access date: [2012/4/25]. Available from: ***** O’Dowd M. 2001. The history of medications for women: Materia medica woman. New York: Parthenon Pub Group. 455 p. Osol A, Farrar G. 1955. The dispensatory of the United States of America. 25th ed. Philadelphia: JB Lippincott. 2139 p. Osol A, Farrar GE. 1947. The dispensatory of the United States of America. 24th ed. Philadelphia: JB Lippincott. 1928 p. Papka RE, Traurig HH, Schemann M, Collins J, Copelin T, Wilson K. 1999. Cholinergic neurons of the pelvic autonomic ganglia

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

and uterus of the female rat: distribution of axons and presence of muscarinic receptors. Cell Tissue Red 296:293-305. Parvati-Baker J. 1978. Hygieia: A woman’s herbal. [City unknown]: Parvati-Baker. 249 p. Pieters L, De Bruyne T, Claeys M, Vlietinck A, Calomme M, Vanden Berghe D. 1993. Isolation of a dihydrobenzofuran lignan from South American dragon’s blood. J Nat Prod 56:899-906. Pilcher JD, Delzell WR, Burnam GE. 1916. The action of various “female” remedies on the excised uterus of the guinea-pig. J Am Med Assoc 67:490-2. Pilcher JD, Mauer RT. 1918. The action of “female remedies” on intact uteri of animals. Surgery Gyn Obstet 27:97-9. Potterton D. 2004. More on blue cohosh and perinatal stroke. N Engl J Med 351:2239-41; author reply 2239-41. Power FB, Salway AH. 1913. The constituents of the rhizome and roots of Caulophyllum thalictroides. J Chem Soc 103:191-209. Quang TH, Ngan NTT, Minh CV, Kiem PV, Thao NP, Tai BH, Thao NP, Nhiem NX, Song SB, Kim HP. 2011. Effect of triterpenes and triterpene saponins from the stem bark of Kalopanax pictus on the transactivational activities of three PPAR subtypes. Carb Res 346:2567-75. Rafinesque C. 1828. Medical flora: a manual of the medical botany of the United States of North America. Volume 1. Philadelphia: Atkinson Alexander. 268 p. Rao RB, Hoffman RS. 2002. Nicotinic toxicity from tincture of blue cohosh (Caulophyllum thalictroides) used as an abortifacient. Vet Hum Toxicol 44:221-2. Rao RB, Hoffman RS, Desiderio R, Raysor D, Palmer ME, Hung OL. 1998. Nicotinic toxicity from tincture of blue cohosh (Caulophyllum thalictroides) used as an


abortifacient. J Toxicol Clin Toxicol 36:455. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. 1998. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 391:79-82. Romm A. 2003. The natural pregnancy book. Freedom (CA): Crossing 242 p. Romm A. 2010. Botanical medicine for women’s health. St Louis: Churchill Livingstone. 694 p. Romm AJ. 2009. Blue cohosh: History, science, safety, and midwife prescribing of a potentially fetotoxic herb. [Doctor of Medicine Thesis]. New Haven (CT): Yale University. 99 p. Satchithanandam S, Grundel E, Roach J, White KD, Mazzola E, Ganzera M, Rader JI. 2008. Alkaloids and saponins in dietary supplements of blue cohosh (Caulophyllum thalictroides). J AOAC Int 91:21-32. Schiff PL Jr. 1996. The Thalictrum alkaloids: Chemistry and pharmacology. Volume 2. Tarrytown (NY): Elsevier. 1-236 p. Schmeller T, Sauerwein M, Sporer F, Wink M, Müller WE. 1994. Binding of quinolizidine alkaloids to nicotinic and muscarinic acetylcholine receptors. J Nat Prod 57:1316-9. Scudder JM. 1867. Varieties. Eclec Med J 27:199. Scudder JM. 1870. Specific medications and specific medicines. Eclec Med J 30:10. Scudder JM. 1898. The American eclectic materia medica and therapeutics. 12th ed. Cincinnati: Scudder Brothers. 748 p. Selo-Ojeme D, Rogers C, Mohanty A, Zaidi N, Villar R, Shangaris P. 2010. Is induced labour in the nullipara associated with more maternal and perinatal morbidity? Arch Gyn Obstet 284:337-41. Sievers AF. 1930. The herb hunter’s guide. Washington DC: USDA. Misc. Pub. Nr 77. 87 p. Smith P. 1813. The Indian doctor’s dispensatory: being Father Smith’s advice respecting diseases and their cure. Cincinnati: Browne Looker. 108 p. Stanley B. 2007. Caulophyllum thalictroides induces mild bradycardia on frog hearts

in situ. [BS thesis]. St. Paul (MN): Bethel Univ. Available from: Bethel University. Stephens AF. 1930. Caulophyllum thalictroides. The Gleaner 37:[pages unavailable]. Stubblefield CT, Barloon JH, Keltner RO. 1963. Sparteine sulfate: a clinical evaluation of its use in 100 cases. Obstet and Gyn 22:341-5. [TGA] Therapeutic Goods Administration. 2006. Australian Regulatory Guidelines for OTC Medicines (ARGOM). Part II. Listed Complementary Medicines. [Internet]. Woden (AU): Australian Government Department of Health and Ageing Therapeutic Goods Administration. Access date: [2012/4/25]. Available from: http://www.tga.gov.au/pdf/cm-argcm-p2. pdf. 86 p. [TGA] Therapeutic Goods Administration. 2007. Substances that may be used as active ingredients in ‘Listed’ medicines in Australia. [Internet]. Woden (AU): Australian Government Department of Health and Ageing Therapeutic Goods Administration. Access date: [2012/4/25]. Available from: http://www.tga.gov.au/cm/ listsubs.pdf. 169 p. Tillett J. 2007. Elective induction of labor: Not without risks for mother and infant. JPNN 19:39. [USC] United States Congress. 1994. Public Law 103-417: Dietary Supplement Health and Education Act of 1994. Washington (DC): 103rd Congress US. van Dongen PWJ, de Groot ANJA. 1995. History of ergot alkaloids from ergotism to ergometrine. Eur J Obstet 60:109-16. VenOsdel N, DeGolier T. 2009. Using nicotinic and muscarinic receptor antagonism to investigate the mechanism of bradycardia induced by Caulophyllum thalictroides on Rattus norvegicus hearts in vitro. Minn Acad Sci 72:26-7. Vinks A, Inaba T, Otton SV, Kalow W. 1982. Sparteine metabolism in Canadian Caucasians. Clin Pharmacol Ther 31:23-9. Vogel V. 1970. American Indian medicine. Norman (OK): Univ Oklahoma Pr. 578 p. Wang L, Ren J, Sun M, Wang S. 2010. A combined cell membrane chromatography and online HPLC/MS method for

screening compounds from Radix Caulophylli acting on the human 1A-adrenoreceptor. J Pharm Bio Anal 51:1032-6. Weed S. 1986. Wise woman herbal for the childbearing years. Woodstock (NY): Ash Tree. 196 p. Westfall E, Benoit C. 2004. The rhetoric of ‘‘natural’’ in natural childbirth: childbearing women’s perspectives on prolonged pregnancy and induction of labour. Soc Sci Med 59: 1397-408. Widstrom L. 2009. Chronotropic effects of herbal uterine contractile agents on Rana pipiens heart in situ. [BS thesis]. St. Paul (MN): Bethel Univ. Available from: Bethel University. Williams LT, Mullikin D, Lefkowitz RJ. 1976. Identification of α-adrenergic receptors in uterine smooth muscle membranes by [3H]dihydroergocryptine binding. J Biol Chem 251:6915-23. Winer N. 2011. Different methods for the induction of labour in postterm pregnancy. J Gyn Obstet Biol Reprod 40:796-811. Woldemariam TZ, Betz JM, Houghton PJ. 1997. Analysis of aporphine and quinolizidine alkaloids from Caulophyllum thalictroides by densitometry and HPLC. J Pharmaceut Biomed Anal 15:839-43. Wood G, Bache F, Wood H, Remington JP. 1866. The dispensatory of the United States of America. Philadelphia: JB Lippincott. 1704 p. Wu M, Hu Y, Ali Z, Khan I, Verlangeiri AJ, Dasmahapatra AK. 2010. Teratogenic effects of blue cohosh (Caulophyllum thalictroides) in Japanese medaka (Oryzias latipes) are probably mediated through GATA2/EDN1 signaling pathway. Chem Res Toxicol 23:1405-16. Youngken H. 1930. A textbook of pharmacognosy. Philadelphia: P Blakiston’s Son. 817 p. Zhang Y, He L, Meng L, Luo W, Xu H. 2008. Suppression of tumor-induced angiogenesis by taspine isolated from Radix et Rhizoma Leonticis and its mechanism of action in vitro. Cancer Lett 262:103-13.

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012

41


Blue cohosh. The color and relative size of the flowers indicate C. giganteum, the taxon which did not yet exist at the publication time. Source: Millspaugh, American Medicinal Plants: An Illustrated Guide (1887)

42

American Herbal Pharmacopoeia® • Blue Cohosh Rhizome and Roots • 2012


Ta b l e o f C o n t e n t s Nomenclature

#

Botanical Nomenclature Botanical Family Pharmaceutical Nomenclature Pharmacopoeial Definition Common Names

History

#

Identification

#

Botanical Identification Macroscopic Identification Microscopic Identification

Commercial Sources and Handling

#

Collection Cultivation Handling and Processing Drying Storage Adulterants Preparations

Constituents Analytical

# #

High Performance Thin Layer Chromatography (HPTLC) High Performance Liquid Chromatography (HPLC) Limit Tests

Therapeutics

#

Pharmacokinetics Pharmacodynamics Cardiovascular Effects Effects on Uterine Smooth Muscle Tissue Effects on Smooth Musculature of Other Organs Hormonal Effects Miscellaneous Effects Medical Indications Supported by Traditional or Modern Experience Conclusion Actions Indications Substantiated Structure and Function Statement Dosages

Safety Profile

#

Side Effects and Serious Adverse Events Contraindications Interactions Pregnancy Mutagenicity Teratogenicity and Embryotoxicity Lactation Carcinogenicity Influence on Driving Precautions Overdose Treatment of Overdose Toxicology Classification of the American Herbal Products Association Conclusion

International Status

American Herbal Pharmacopoeia速 PO Box 66809 Scotts Valley, CA 95067 US Tel: 1-831-461-6318 Fax: 1-831-475-6219 Email: ahpadmin@got.net Website: www.herbal-ahp.org

#

ISBN 9

781929

425303

1538

0297


Blue Cohosh