Ahp-Blue - Cohosh Textbook of Botanical Macros

Blue Cohosh Root and
Rhizome
Caulophyllum thalictroides (L.) Michx.
C. giganteum (Farw.) Loconte & W. H. Blackw.
American Herbal Pharmacopoeia
and herapeutic Compendium
Editors
Aviva Romm MD CPM Herbalist
Tufts School of Medicine
Boston, MA
Roy Upton RH DAyu
Scotts Valley, CA
Associate Editor
Pavel Axentiev MS
Scotts Valley, CA
Research Associate
Diana Swisher MA
Scotts Valley, CA
Sraxoaios oi Axai\sis, Quaiir\ Coxrioi, axo
Tuiiaiiurics
American Herbal Pharmacopoeia Blue Cohosh Root and Rhizome 2012
2012 American Herbal Pharmacopoeia
PO Box 66809, Scotts Valley, CA 95067 USA
All rights reserved. No part of this monograph may be
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Pharmacopoeia PO Box 66809 Scotts Valley, CA
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at www.herbal-ahp.org.
Medical Disclaimer
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 seek-
ing to utilize botanicals as part of a health care program
should do so under the guidance of a qualified health
care professional.
Statement of Nonendorsement
Reporting on the use of proprietary products reflects stud-
ies conducted with these and is not meant to be a product
endorsement.
Design & Composition
Beau Barnett
Santa Cruz, CA
Cover Photograph
Blue cohosh. 2012 Richo Cech
Blue cohosh root and rhizome.
2012 American Herbal
Pharmacopoeia
ISBN: 1-929425-32-5 ISSN: 1538-0297
Authors
History
Michael Flannery MA MLS
The Lloyd Library and Museum
Cincinnati, OH
Roy Upton RH DAyu
Scotts Valley, CA
Botanical and Macroscopic
Identification
Alison Graff PhD
Scotts Valley, CA
Microscopic Identification
Prof Dr Reinhard Lnger
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
US Food and Drug Administration
College Park, MD
Analytical
High Performance Thin Layer
Chromatography (HPTLC)
Judy Nichols
CAMAG USA
Wilmington, NC
Therapeutics, Safety Profile
Boston, MA
Medical Indications Supported by
Traditional Use
Boston, MA
Francis Brinker ND
Eclectic Institute, Inc.
Program in Integrative Medicine
University of Arizona
Tucson, AZ
Roy Upton RH DAyu
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, Inc.
Banner Elk, NC
Markus Ganzera PhD
University of Innsbruck
Innsbruck, Austria
Arthur Haines MS
Delta Institute of Natural History
Canton, ME
Phylis Light Herbalist
Appalachian Center for Natural
Health
Arab, AL
Ed Smith Herbalist
Herb Pharm, LLC
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, Inc.
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
American Herbal Pharmacopoeia Blue Cohosh Root and Rhizome 2012 1
Design & Composition
Beau Barnett
Santa Cruz, CA
Cover Photograph
Blue cohosh. 2012 Richo Cech
Blue cohosh root and rhizome.
2012 American Herbal
Pharmacopoeia
No me n c l a t u r e
Botanical Nomenclature
Caulophyllum thalictroides (L.) Michx.
C. giganteum (Farw.) Loconte & W. H. Blackw. syn. C.
thalictroides var. giganteum Farw.
Botanical Family
Berberidaceae
Pharmaceutical Nomenclature
Radix et Rhizoma Caulophyllii
Pharmacopoieial Definition
Blue cohosh consists of fresh or dried roots and rhizomes of
Caulophyllum thalictroides and/or C. giganteum, conform-
ing to the methods of identification provided.
Common Names
English: Blue cohosh.
French: Cohosh blea.
German: Blauer Hahnenfluss.
Italian: Caulofillo.
Hi s t o r y
Blue cohosh is an indigenous North American medicinal
plant, widely used by Native Americans and Eclectic phy-
sicians, 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 is generally considered
to be based on its use by Native Americans as an emmena-
gogue 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 resem-
blance of the leaf of the plant to a lions foot. Linnaeus
(1753) also included it in Leontice. In 1803, Caulophyllum
was made a distinct genus by the famed French botanist and
explorer Andr Michaux in his posthumously published
Flora Boreali-Americana, based on the differences in mor-
phology of the underground parts and other distinguishing
characteristics (Loconte and Blackwell 1985). The specific
epithet thalictroides refers to its resemblance to plants in the
genus Thalictrum, as anyone familiar with those plants can
attest (Hyam and Pankhurst 1995).
Blue cohosh is one of several cohoshes used medici-
nally, including, 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).
The first mention of the medical use of blue cohosh
in Euro-American literature can be found in Peter Smiths
The Indian Doctors Dispensatory (1813) where he recom-
mended 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 com-
monly known today blue cohosh. Citing its traditional
uses by Native Americans, Rafinesque referred to the plant
as a powerful emmenagogue, promoting delivery, men-
struation, 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-
cine, extolled the virtues of blue cohosh as a preparatory
Figure 1 Historical illustration of blue cohosh
Source: Lloyd and Lloyd (1884-1887).
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 expedit-
ing 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 Kings inclusion of the botanical in Kings
American Dispensatory in 1852, which subsequently led to
its increased use among Eclectics and homeopathic physi-
cians.
In his American Eclectic Obstetrics (1855), Professor
King described a compounded herbal preparation, contain-
ing 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
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-dates pregnancies. In a presentation before the
Homeopathic Medical Society, Dr. J.S. 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 (1898) in their revision
of Kings American Dispensatory called blue cohosh 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. 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 physi-
ological process at full term, and not pathological, therefore
Table 1 Historical timeline of the medicinal use of blue cohosh
Native American use Blue cohosh is widely used by a number of tribes, mainly as an anticonvulsive, antirheumatic, emmenagogue,
gynecological aid, partus preparator, and a sedative.
1813 First report of the medicinal uses of blue cohosh in The Indian Doctors Dispensatory by Peter Smith is published,
reporting the use of the herb as a purgative, catarrhal, and a topical application for burns.
1828-1830 Constantine Ranesque 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.
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 editions of the United States Pharmacopoeia.
1891 Dr John Dye in his Painless Childbirth writes 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 one of the most successful remedies for
dysmenorrhea, suppressed menses, uterine cramps, and labor.
1908 The Eclectic physician Finley Ellingwood writes: 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, reintroduces blue cohosh as an emmenagogue and uterine tonic.
1981-1997 Botanists propose Caulophyllum giganteum as a separate species; it appears in Volume 3 of the 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 it being associated with neonatal
cardiotoxicity, neonatal stroke, and maternal toxicity.
1999 Mechanistic research identies potential embryotoxic and teratogenic compounds in blue cohosh, including
anagyrine and baptifoline.
2000-present Blue cohosh remains popular as an alternative to conventional birth induction, although its use as a partus
preparator falls due to safety concerns.
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 recog-
nized in the pharmaceutical compendia. The botanical is
first mentioned in the appendix to the 12
th
edition of the
United States Dispensatory (USD) (Wood et al. 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.
Caulophyllum thalictroides was included as an offi-
cial drug in the 6
th
and 7
th
revisions of the United States
Pharmacopoeia in 1882 and 1890. Despite its removal from
the list of USP substances after 1890, Eclectic practitioners
continued to use it for numerous specific indications into
the 20
th
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, diapho-
retic, emmenagogue, and uterotonic, as well as for stalled
labor and some other indications, 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 was used both
singularly and in many of the same combinations as used
historically by the Eclectics, primarily in tinctures, but also
in 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 discon-
tinuation of the use of blue cohosh due to these concerns,
while others have continued 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 was also included in the
British Herbal Pharmacopoeia (BHP 1983) as a spasmolytic
and emmenagogue, but is not in any other contemporary
pharmacopoeias.
I d e n t i f i ca t i o n
Botanical Identification
The taxon Caulophyllum thalictroides was created by Andr
Michaux in 1803. In 1918, Farwell, noting phenotypic dif-
ferences within the species (e.g., presence of larger flowers
and fewer flowers per inflorescence), proposed a new variety
C. thalictroides var. giganteum Farw., which was elevated to
the species level by Loconte and Blackwell (1981), based on
the 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 distinc-
tion. Irrespective of the taxonomical standpoint, because C.
thalictroides in the broad sense

had a long history of medici-
nal use prior to 1981, when the segregation of var. gigan-
teum at the species level was proposed, all North American
Caulophyllum spp. should be recognized as having similar
medicinal value, unless comparative chemical or pharma-
cological testing proves otherwise. Supporting historical
evidence for this approach can be seen in the illustration
of Millspaugh (1887), which was originally published long
before the differentiation of the two Caulophyllum species
(p. 42). The plant shown has morphological characteristics
of C. giganteum.
Following is a diagnostic description of C. thalictroides
and C. giganteum, the two North American species of
Caulophyllum, consistent with the modern classification
(Gleason and Cronquist 1991; Haines 2003; Loconte 1997;
Loconte and Blackwell 1985; Michaux 1803).
Caulophyllum thalictroides (L.) Michx. Herbaceous peren-
nial from rhizome. Stem: Erect, 20-90 cm. 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 typically consisting
Figure 2 Blue cohosh root and rhizome
Source: Elliot (1995). Permission for use granted by Doug Elliot.
3a. 3b.
3c. 3d.
3e. 3f.
Figure 3 Botanical characteristics of Caulophyllum thalictroides
and C. giganteum
3a. Caulophyllum thalictroides foliage and flowers.
3b. Close-up of a blue cohosh leaf (C. thalictroides).
3c. Close-up of the inflorescence of the purple-tinted C.
thalictroides phenotype.
3d. Typical yellow flowers of C. thalictroides.
3e. Blue cohosh with ripe berries (C. thalictroides).
3f. Blue cohosh berries amidst autumn foliage (C.
thalictroides).
3g. Freshly dug blue cohosh rhizome (C. thalictroides).
3h. Distribution of C. thalictroides.
3i. 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; cross-
hatched = questionable presence.
Photographs courtesy of: (3a) Roy Upton, Soquel, CA; (3b, 3d, 3e, 3g) 2012
Steven Foster; (3c, 3f) H. Zell. Map images (3h, 3i) from: Kartesz JT and The
Biota of North America Program (BONAP) (2011). Used with permission.
3g. 3h.
3i.
4a. 4b. 4c.
4d. 4e. 4f.
Figure 4 Comparative morphology of C. thalictroides and C.
giganteum
4a. Early habit of C. thalictroides. Note nearly coetaneous
flowering.
4b. Inflorescence branch of C. thalictroides.
4c. Flower of C. thalictroides.
4d. Early habit of C. giganteum. Note subprecocious flowering.
4e. Inflorescence of C. giganteum.
4f. Flower of C. giganteum.
Photographs courtesy of: (4a-e) Arthur Haines, Delta Institute of Natural
History, Canton, ME; (4f) Amanda Ingram, Wabash College, Crawforsville,
IN.
of 4 (seldom 3) primary segments; second leaf usually
of 3 (seldom 2) primary segments; leaf blade broadly
obovate; leaflets 27+, broadly obovate, 3-8 cm (seldom
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; 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
0.5-1.5 mm; anthers dehiscing by apical valves; ovary
superior; carpel 1-3 mm; style 0.25-1 mm long. Fruit:
Two drupe-like 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 about the
same time with leaf expansion).
C. giganteum (Farw.) Loconte & W. H. Blackw. syn.
C. thalictroides var. giganteum Farw.: Stem: 20-70 cm.
Leaves: First leaf consisting of 3 (seldom 2) primary
segments; second leaf typically of 2 (seldom 1) primary
segments; leaflets 5-10 cm long, 3-8 cm wide; other char-
acters like in C. thalictroides. Inflorescence: Terminal,
compound cyme with 4-18 flowers, relatively sparse.
Flower: Bracteoles 2-4 mm; sepals purple, red, brown,
or, seldom, yellow, 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 por-
tion of the range (Quebec to Michigan, Kentucky, and
Tennessee).
Macroscopic Identification
Freshly harvested material consists of a matted and tangled
mass of rhizomes and roots. 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 whole rhizome is hard, irregu-
lar, bent, and knotty, externally grayish-brown to dark red-
dish-brown, 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- or yellowish-brown to dark brown branching roots
bearing rootlets, which 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 roots is broken, a thin
wiry inner cord is revealed.
Figure 5 Cross section of blue cohosh rhizome
E = epidermis; MR = medullary rays; P = phloem in the vascular bundle; Par
= parenchyma; X = xylem in the vascular bundle.
Source: Sayre (1917).
E
X MR
P
Par
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, some-
times in 2 rings, enclosing a large pith. In branches, wedges
are shorter, more uniform, and in 1 single narrow circle.
Fracture (roots): Short, tough; internally grayish-white,
consisting of thick bark and a woody central cord composed
of starch-bearing parenchyma and, typically, 4-rayed xylem.
Aroma: Acrid and slightly fragrant when fresh root is
bruised; slight to none when the root is dry.
Taste: Initially sweetish and somewhat bitter, afterwards
acrid and pungent. Fresh root has a slight to intensely acrid
aftertaste.
Powder: Light brown to grayish-brown; sternutatory (causes
sneezing).
MR
6a. 6b.
6c. 6d.
6e. 6f.
6g. 6h.
6i. 6j.
Figure 6 Macroscopic characteristics of blue cohosh root and
rhizome
6a. Fresh blue cohosh root and rhizome.
6b. Close-up of the fresh blue cohosh root and rhizome. Note the
depressed stem scars.
6c. Close-up of the fresh blue cohosh rhizome. Note the
annulation below the new growth.
6d. Dry blue cohosh root and rhizome.
6e. Dry blue cohosh rhizome with some of the roots removed.
6f. Close-up of the roots. Note the wiry inner cord where the
roots are broken (indicated with black arrows).
6g. Transverse section of the blue cohosh rhizome. Note the
waxy, yellowish color.
6h. Dry blue cohosh rhizomes with most roots broken off.
6i. Cut and sifted (c/s) blue cohosh root and rhizome.
6j. Powdered blue cohosh root and rhizome.
Photographs courtesy of American Herbal Pharmacopoeia
, Scotts Valley,
CA.
Rhizome
Transverse section: Cork present; cortex of thin-walled paren-
chyma 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 m diameter; cen-
tral pith of thin-walled parenchyma cells with intercellular
spaces.
Longitudinal section: Vessels with bordered pits.
Root
Transverse section: Epidermis brown; cortex of parenchyma
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 m
diameter.
Longitudinal section: Vessels with bordered pits.
Starch is present in both rhizome and the rootlets as primar-
ily compound, ovate, very small (up to 10 m) granules.
Powder
Fragments of vessels with fibers; thin-walled parenchyma
with small, simple, spherical starch granules; cork with
brown or yellow cell walls.
Note: Powder is best viewed prepared with acidified chloral hydrate in glyc-
erol, at 400x magnification.
7b.
7e.
7a.
7f.
7c.
7d.
Figure 7 Microscopic characteristics of blue cohosh root and
rhizome
7a. 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).
7b. Root transverse section: epidermis (ep); cortex (c);
endodermis (end); phloem (ph); and xylem (xy) (ts).
7c. Fibers in the rhizome cortex (ts).
7d. Sclereid in the rhizome cortex (ls).
7e. Secondary xylem of the rhizome, showing radially aligned
vessels embedded in fibers (ts).
7f. Root endodermis, phloem, and xylem with a short ray
penetrating the region (ts).
7g. Starch granules.
ls = longitudinal section; ts = transverse section.
Microscopic drawings courtesy of Reinhard Lnger, AGES PharmMed,
Vienna, Austria.
8a. 8b.
8c. 8d.
8e. 8f.
Figure 8 Microscopic characteristics of blue cohosh root and
rhizome
8a. Rhizome transverse section.
8b. Sclereids in the rhizome cortex (polarized light, compensator
first order) (ts).
8c. Sclereid in the rhizome cortex (polarized light, compensator
first order) (ls).
8d. Secondary xylem of rhizome (ts).
8e. Bordered pitted vessels and fibers in the secondary xylem of
the rhizome (ls).
8f. Root transverse section.
ls = longitudinal section; ts = transverse section.
Microscopic photographs courtesy of Reinhard Lnger, AGES PharmMed,
Vienna, Austria.
Co mme r c i a l S o u r c e s
a n d Ha n d l i n g
Collection
Blue cohosh roots and rhizomes 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 dor-
mancy. Collect older, more mature rhizomes, leaving the
younger ones 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 C to -40 C; 19 F to -40 F).
Prefers rich, moist, neutral to slightly acidic, loamy soil (pH
5-6) under the shade of a mixed hardwood forest. Tolerates
clay-like or sandy soils, provided there is sufficient organic
content and surface mulch to prevent the roots from dry-
ing 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.
Blue cohosh can be propagated by seeds or rootstock
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 they ripen, around midsum-
mer, but flowering will typically not occur until the 3
rd
or 4
th

year. Plants grown from seed will need to be in the ground
for a relatively long time (up to 5 years) before the rhizomes
can be harvested. Fall division of the rootstocks (rhizomes) 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 and rhizomes, shake them to
remove excess soil and place them in a sack or a bucket,
protected from light. If the roots and rhizomes are to be
shipped fresh and/or stored prior to drying, they should
not be washed: The native soil helps to protect the roots
and rhizomes from fungal diseases, which can ruin washed
roots and rhizomes that are stored too long in a sack or pile.
Wash roots and rhizomes just prior to drying or processing,
with a pressure hose or running water, breaking the 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 rhizomes as whole as possible, to prevent excessive oxi-
dation (Cech 2002; Lockard and Swanson 2004).
Drying
Blue cohosh roots and rhizomes should be air-dried whole,
out of the sun, in a warm, well-ventilated area, turning fre-
quently. If drying outside, protect the roots and rhizomes
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 C; 67 F),
with a high air flow, then increase the temperature to high
(43 C; 109 F) and dry until the rhizomes snap (Cech
2002).
Storage
Dry blue cohosh roots and rhizomes should be stored pro-
tected from air, light, heat, moisture, and insect infestation.
For optimal storage, keep the roots and rhizomes in airtight,
lightproof containers, such as sacks or drums, in a dark, dry,
and cool environment. Under these conditions, blue cohosh
will retain its 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 species, twin leaf
(Jeffersonia diphylla), of the same family (Berberidaceae) was
reported to wholly or partially adulterate blue cohosh lots
(Lloyd and Lloyd 1886-1887; see Table 2).
9b.
9a.
Figure 9 Twinleaf (Jeffersonia diphylla), a historical adulterant of
blue cohosh
9a. Twinleaf. Note the characteristic leaves with 2 large segments.
9b. Twinleaf (right) next to blue cohosh (left) growing in a
cultivated plot.
Photographs courtesy of James Steakley.
when used in the early trimester of pregnancy, while the
saponins are allegedly associated with neonatal cardiac toxic-
ity reported with the use of blue cohosh close to giving birth,
as a partus preparator.
Caulophyllum robustum Maxim. is a distinct species of
Caulophyllum found in eastern Asia. It shares some similari-
ties 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.
Alkaloids
The primary alkaloids reported in blue cohosh root and
rhizome are the quinolizidine alkaloids N-methylcytisine
(also known as caulophylline), baptifoline, and anagyrine
and the aporphinoid isoquinoline alkaloid magnoflorine
(Figure 10; 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 material in 70% ethanol and quantitatively mea-
sured the content of the alkaloids by high performance
liquid chromatography (HPLC). Betz et al. (1998) identified
the alkaloids in blue cohosh products by gas chromatogra-
phy-mass spectrometry (GC/MS) and noted that alkaloid
content differed significantly between products. Ganzera et
al. (2003) used methanol extraction and HPLC/MS for isola-
tion 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) spec-
trometry. Most recently, Avula et al. (2011) reported on the
Table 2 Morphological differentiation of dry underground parts of blue cohosh and twin leaf (Jeffersonia diphylla)
Blue cohosh Twin leaf
Rhizome prominent, the roots only partly concealing it, 1/41/3 inch
(0.60.8 cm) in diameter and 46 inches (1015 cm) long, grayish- to
dark reddish-brown externally.
Rhizome obscured, almost entirely covered with a mass of roots,
approximately 1/4 inch (0.6 cm) in diameter and 12 inches (2.55 cm)
long, yellowish-brown externally, with a resinous bark.
The broken rhizome and roots 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.
Qualitative Differentiation
The Eclectics often noted that therapeutic preparations
should be prepared from freshly dried blue cohosh (e.g.,
Scudder 1870).
Preparations
Blue cohosh is used in single ingredient preparations and
in combination with other botanicals, as teas, tablets, cap-
sules, and liquid extracts. See Table 10 for traditionally used
formulae.
Fluid Extract (Percolation)
Dry blue cohosh root and rhizome: 16 parts by weight.
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.
Co n s t i t u e n t s
Blue cohosh chemistry has been studied since the mid-19
th

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 alka-
loids 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 blue cohosh. Additionally,
several alkaloids were implicated as potential teratogens
Figure 10 Major alkaloids occurring in blue cohosh
Magnoflorine N-Methylcytisine Anagyrine Baptifoline
Table 3 Content of major alkaloids in blue cohosh root and rhizome
Alkaloid Content (mg/g dry weight) Plant part as reported Publication reference
Magnoorine
11.00 Roots 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)
Baptifoline
Anagyrine
N-methylcytisine
Table 4 Difference in content of alkaloids between roots and
rhizome of the same blue cohosh plant
Alkaloid
Content (mg/g dry
weight)
Plant part
Magnoflorine
3.72 Root
7.47 Rhizome
Baptifoline
0.95 Root
0.33 Rhizome
Anagyrine
1.03 Root
0.28 Rhizome
N-methylcytisine
0.39 Root
0.15 Rhizome
Source: Ganzera et al. (2003).
magnoflorine content in blue cohosh and its 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
alkaloid taspine, earlier reported in dragons blood (Croton
spp.), as well as several quinolizidine alkaloids, such as
-isolupanine, 5,6-dehydro--isolupanine, lupanine, and
sparteine. Magnoflorine was proposed as a putative bio-
synthetic precursor of taspine. Taspine has been reported
as being highly cytotoxic (Pieters et al. 1993). The follow-
ing alkaloids were identified in blue cohosh by Ali and
Khan (2008): anagyrine, O-acetylbaptifoline, lupanine, as
well as two novel compounds caulophyllumines A and B.
Thalictroidine, isolated by Kennelly et al. (1999), and cau-
lophyllumines, isolated by Ali and Khan (2008), were identi-
fied 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 3.
Saponins
Saponins (glycosides) constitute the second important group
of compounds found in blue cohosh. The two most com-
mon aglycones are hederagenin and caulophyllogenin
(Table 5), 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 blue cohosh, which they named caulosaponin
and caulophyllosaponin. Hydrolysis of caulosaponin yielded
hederagenin (McShefferty and Stenlake 1956, cited in Betz
et al. 1998). Another 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
1
H and
13
C NMR. 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 sapo-
nin) 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, iso-
lated 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
Table 5.
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
method with the utilization of ultraviolet light (UV) (310
Table 6 Content of saponins in blue cohosh root and rhizome
Compound Content (mg/g dry weight)* Publication reference
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
8.70 2.16 Ganzera et al. (2003)
15.80 8.52 Satchithanandam et al. (2008)
4.25 0.64 Avula et al. (2011)
Leonticin D
20.68 6.97 Ganzera et al. (2003)
2.70 0.57 Avula et al. (2011)
Cauloside G
20.93 6.89 Ganzera et al. (2003)
5.05 0.78 Avula et al. (2011)
Cauloside H 0.23 0.04 Avula et al. (2011)
Saponin PE Under the limit of detection Avula et al. (2011)
* All values are average of the means of different roots standard deviation between the roots.
Table 5 Typical saponins of blue cohosh root and rhizome
Compound Aglycone R R
1
Cauloside A
a, b, c, d
Hederagenin
-L-arabinopyranosyl H
Cauloside C
a, b, c, d
-D-glucopyranosyl-(12)--
L-arabinopyranosyl
H
Cauloside D
a, b, c, d
-L-arabinopyranosyl
-L-rhamnopyranosyl-(14)--
D-glucopyranosyl-(16)--D-
glucopyranosyl
Cauloside G
a, b, d
-D-glucopyranosyl-(12)--
L-arabinopyranosyl
glucopyranosyl
Cauloside B
a, b, c, d
Caulophyllogenin
-L-arabinopyranosyl H
Cauloside H
b, d
3-O--D-glucopyranosyl-
(12)--L-arabinopyranosyl
glucopyranosyl
Leonticin D
a, b, c, d
-L-arabinopyranosyl
glucopyranosyl
Reported by
a
Jhoo et al. (2001),
b
Ali and Khan (2008),
c
Matsuo et al. (2009),
d
Avula et al. (2011).
RO
COOR
1
OH
H
H
H
HOH
2
C
CH
2
OH
RO
COOR
1
H
H
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 leon-
ticin 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 deter-
mination 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 per-
formance 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-UV-
ELSD) allowed the separation of 8 triterpene saponins: cau-
losides 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 and rhizomes and lowest in liquid prepara-
tions (hydroethanolic and glycerine extracts), while the
levels of alkaloids did not differ much between the types
of products (see Tables 13 and 14 in the end of the Safety
Profile).
A n a ly t i ca l
Pharmacological evidence suggests that the putative oxyto-
cic activity of blue cohosh is due to its content of saponins
and magnoflorine. While there are studies reporting on the
levels of these compounds (see Constituents), currently no
fully validated methods for quantification of blue cohosh
saponins or alkaloids exist. The primary analytical goal is,
therefore, to properly identify the botanical material, taking
note that C. thalictroides and C. giganteum are considered
similar in their medicinal profiles. Potential areas of interest
for future analytical work on blue cohosh include validat-
ing methods for quantitation of total saponins and magno-
florine and, with regard to potentially toxic compounds,
N-methylcytisine and anagyrine.
High Performance Thin Layer
Chromatography (HPTLC)
This method is based on the method by Avula et al. (2011)
with a modified mobile phase. The mobile phase used in
this method provides a more reproducible separation than
that in the original.
Sample preparation
Dry root and rhizomes: 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 m PTFE membrane filter or centrifuge for
5 min at 5000 rpm. The filtrate or supernatant is used as test
solution.
Liquid preparations: Dilute 1:1 with methanol.
Hydroethanolic extracts can often be applied neat.
Standard preparation
a) Botanical reference material
Prepare same as sample.
b) Chemical standards
1.0 mg 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 F254.
Mobile phase:
Dichloromethane/methanol/water (70:30:4).
Sample application
Apply 2 mL each of test solution and of the standard solu-
tions, as 8 mm bands, with a minimum distance of 2 mm
between the 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 5-10 mL of developing solvent in
each trough for 20 minutes. Developing distance is 70 mm
from the lower edge of the 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,
alternatively, spray the plate evenly with the reagent. Allow
to dry briefly in a stream of cold air. Heat at 100 C for 5
min. Examination is performed under white light and UV
366 nm.
Results
Compare to the chromatograms provided (see Figure 11).
Figure 11a HPTLC chromatogram of blue cohosh and blue cohosh-
containing products (sulfuric acid reagent, UV 366 nm)
Discussion of the chromatogram
The fructose standard (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 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 the blue cohosh samples, fluorescent zones can
be detected matching those of fructose and cauloside C in color
and position. 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). 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 Rf = 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 Mothers 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.

11a.
Lane 1: D-(-)-fructose.
Lane 2: Cauloside C.
Lane 3: Blue cohosh rhizome.
Lane 4: Blue cohosh whole rhizome.
Lane 5: Blue cohosh root.
Lane 9: Blue cohosh root (cultivated).
Lane 10: Blue cohosh root (cut & sifted).
Lane 11: Blue cohosh root (cut & sifted, commercial).
Lane 12: Blue cohosh rhizome (cut & sifted).
Lane 16: Blue cohosh freeze dried rhizome/root.
Lane 18: Blue cohosh root extract.
Lane 19: Blue cohosh liquid formula.
Lane 20: Blue cohosh liquid formula (Mothers Cordial).
Lane 21: Blue cohosh alcohol extract with glycerin.
Lane 22: Blue cohosh extract with glycerin.
Lane 24: Blue cohosh formula tablets.
Lane 25: D-(-)-fructose/cauloside C (with increasing Rf).
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Rf Rf
Figure 11b HPTLC chromatogram of blue cohosh and blue cohosh-
containing products (sulfuric acid reagent, white light)
Discussion of the chromatogram
The fructose standard (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. 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).
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 Rf = 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 root. The preparation on Lane 20 is Mothers
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: D-(-)-fructose.
Lane 2: Cauloside C.
Lane 4: Blue cohosh whole rhizome.
Lane 9: Blue cohosh root (cultivated).
Lane 10: Blue cohosh root (cut & sifted).
Lane 11: Blue cohosh root (cut & sifted, commercial).
Lane 12: Blue cohosh rhizome (cut & sifted).
Lane 16: Blue cohosh freeze dried rhizome/root.
Lane 18: Blue cohosh root extract.
Lane 19: Blue cohosh liquid formula.
Lane 20: Blue cohosh liquid formula (Mothers Cordial).
Lane 22: Blue cohosh extract with glycerin.
Lane 24: Blue cohosh formula tablets.
Lane 25: D-(-)-fructose/cauloside C (with increasing Rf).
11b.
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.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Rf Rf
Th e r a p e u t i c s
Blue cohosh is one of the primary botanicals used by mid-
wives 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 botanicals efficacy in labor. Studies on some
of the constituents of blue cohosh that are also found in
other botanicals (e.g., magnoflorine) may help to elucidate
the 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 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 administra-
tion (Li et al. 2005; 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). Taspine concentrations in blue cohosh appear to
be insignificant, as it has not been detected by the majority
of researchers.
A pharmacokinetic study of sparteine was conducted
on 15 men and 33 women (Vinks et al. 1982). The subjects
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 and analyzed for the pres-
ence of sparteine sulfate and two of its metabolites, 2- and
5-dehydrosparteine. Two metabolic phenotypes were identi-
fied: extensive metabolizers, who excreted 7.4-23.6% of the
alkaloid unchanged, and non-metabolizers, 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. According to the data from Caucasian and
Japanese populations, poor metabolizers occur among
humans at the frequency of 2%-10% (Ishizaki et al. 1987).
Clinical Efficacy and 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
musculature in animal models was conducted by Ferguson
and Edwards (1954). A series of experiments were conduct-
ed 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; Evelsizer and DeGolier
2010; Forsgren and DeGolier 2011; Hulst 2009; Stanley
2007; VenOsden and DeGolier 2009). Additional pharma-
cological data may be extracted from studies on individual
constituents of blue cohosh rhizome found in other species.
Cardiovascular Effects
Blue cohosh has been associated with cardiotoxic and pro-
arrhythmic 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) observed positive inotropic
effects with slight bradycardia in turtle and frog hearts
perfused with blue cohosh crystalline glycoside solution
at the doses of 0.3-0.6 mg and 0.05-0.14 mg, respectively.
Larger doses than these produced cardiac arrhythmias result-
ing 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 coro-
nary blood flow of 25.6% 1.36 (SEM).
The same glycoside was reported to possess vasoconstric-
tive 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 immediate
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 three minutes
after the application of the extract. All three concentrations
Table 7 Pharmacokinetics (maximum concentration, Cmax;
time to reach maximum concentration, Tmax ; area under the
concentration/time curve, AUC; elimination half-life, T
1/2) of orally
administered taspine in rats
Parameter Value
Cmax, ng/mL 64.15
Tmax, h 2.84
AUC, ngmL/h 1214.98
T
1/2, h 10.96
Source: Li et al. (2005).
Table 8 Functional binding strength (IC50) of selected alkaloids
in blue cohosh to nicotinic (nAChR) and muscarinic (mAChR)
acetylcholine receptors
Compound nAChR IC50, M mAChR IC50, M
Anagyrine 2096 132
Lupanine 5 114
N-Methylcytisine 0.05 417
Sparteine 331 21
Source: Schmeller et al. (1994).
suppressed heart rate at the time intervals assessed (80 s, 100
s, and 120 s), but only the 2.0 mg dose effect 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 nico-
tinic receptor antagonist, partially suppressed blue cohosh-
induced bradycardia in isolated rat hearts. The alkaloid
N-methylcytisine, contained in blue cohosh, is a potent
nicotinic acetylcholine receptor agonist, while anagyrine
and lupanine have a moderate affinity to muscarinic acetyl-
choline 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 com-
pound 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 significantly contribute to the activity of blue
cohosh.
Effects on Uterine Smooth Muscle Tissue
Based on the available evidence, blue cohosh may be con-
sidered an oxytocic agent, providing mechanistic support for
its traditional use.
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 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 con-
traction. At higher concentration (1 mg/70 cc), there was an
immediate increase in tone and rate but a decreased degree
of contraction. The dose of 1 mg/cc effected a contraction
that lasted 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 contrac-
tility 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 change in uterine tone (Ferguson
and Edwards 1954). Additional assays performed by these
researchers indicated that 1 mg of the glycoside was equiva-
lent 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 0.037-23.8 mg/20 cc
buffer solution). The tissues showed an increase in strength
of the contractile force, 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 experi-
ments 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 cohoshs action on uterine
smooth muscle tissue.
Magnoflorine has demonstrated oxytocic activity (El
Tahir 1991, cited in Schiff 1996). Sparteine has been known
to increase the intensity, frequency, and duration of uter-
ine contractions (Stubblefield et al. 1963). 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. 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; however, 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 arrhyth-
mias (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 to muscarinic acetylcholine recep-
tors, while several other constituents display weak binding
affinity to 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 vasodila-
tation (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 relative-
ly high quantities in blue cohosh rhizome, has been shown
to bind to a
1A
-adrenoreceptors (Wang et al. 2010). Activation
of a-adrenergic receptors has been linked to reduced pro-
duction 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 depres-
sion and complete abolition of peristalsis. In a more recent
experiment (Evelsizer and DeGolier 2010), no relaxing
or contractile effects of blue cohosh (10 mg) administered
before or after a positive contractile response from norepi-
nephrine were seen in isolated rat intestinal tissue. 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.
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 evalu-
ated (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 ace-
tylcholine 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 with 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 in the same manner as in the
study above. Organ baths were used to measure contractil-
ity with 10
-5
M norepinephrine, given as the control drug,
followed by 2.5 mg, 5 mg, 10 mg, 20 mg, or 30 mg doses of
blue cohosh. 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, respec-
tively). Contractile responses caused by blue cohosh were
significantly smaller (approximately by 25%) than those
caused by norepinephrine. 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-binding activity (Hunter et al. 2000). However,
Eagon et al. (2001) reported that blue cohosh enhances
estradiol binding to estrogen receptors and increases estradi-
ol-induced transcription activity in estrogen-responsive cells,
as well as decreases luteinizing hormone 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 com-
pounds lupanine and sparteine have demonstrated varying
activity at muscarinic and nicotinic acetylcholine recep-
tors (Green et al. 2010; Schmeller et al. 1994; see Table
8). A detailed characterization of physiological actions of
caulophylline (N-methylcytisine) was performed by Barlow
and McLeod (1969) in a series of experiments (Table 9).
Magnoflorine 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 inflamma-
tion (Ricote et al. 1998). Caulosides A and C were found to
possess antineoplastic activity in vitro (Matsuo et al. 2009).
Medical Indications Supported by
Traditional Use
Traditionally, the reputation of blue cohosh rhizome is
greatest as an herbal agent for gynecologic and obstetric
concerns. It was also, though less commonly, used for its
antispasmodic, diaphoretic, diuretic, anti-rheumatic, nerv-
ine, 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 conditions 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 rhizome to remedy profuse men-
struation. The Cherokee and Potawatomi used the plant
as an aid for childbirth. The Cherokee relieved uterine
inflammation with blue cohosh, while the Ojibwa used it
for dysmenorrhea (Moerman 1998). The only specific infor-
mation 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-
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 ethno-
botany (Erichsen-Brown 1989; Moerman 1998; Vogel 1970)
reveal only occasional use of blue cohosh among the tribes
for childbirth preparation. However, there is more frequent
mention of its use during labor to promote delivery, possi-
bly in arrested labor (Bergner 2001; Erichsen-Brown 1989;
Moerman 1998; Vogel 1970).
Gynecologic and Obstetric Use Among Physiomedicalists
Cook (1869), one of the primary Physiomedicalist authors,
reported on a number of obstetric uses of blue cohosh.
Noting that blue cohosh was of especial service in strength-
ening and relieving painful functional difficulties of the
female generative organs, he used blue cohosh for chronic
inflammation of the uterus, considered it one of the best
antispasmodics for painful menstruation and nervous rest-
lessness during pregnancy, used it as a partus preparator,
stated that it strengthened the uterus through increased
enervation of the pelvic nerves, and used it for leucorrhea
and insufficient menstruation as well as to give tone
and comfort to the uterus. In Cooks view, blue cohosh
was among the most valuable of all parturients when the
uterine action is becoming weary, for which cases the root
was used in the Thomsonian preparation Composition
Powder, or in combination with the nervine ladys 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 a view similar
to the one that persists currently specifically noting that
blue cohosh never has an effect of overstimulating excessive
uterine action. Interestingly, Cook considered blue cohosh
inappropriate when there was vaginal dryness, a rigid os,
or a sensitive uterus and also considered dried forms of the
preparations to be ineffectual as antispasmodics. His pre-
ferred form of administration was infusions, e.g., ounce
(approximately 14 g) of blue cohosh rhizome to a pint (473
mL) of boiling water, steeped for hour in a covered ves-
sel. For parturition and dysmenorrhea, Cook recommended
a dose of 1 ounce (approximately 30 mL) of this preparation
Table 9 Comparison of physiological effects of N-methylcytisine and nicotine
Animal model Physiological target Effect
N-methylcytisine effective
dose, mg
Nicotine effective
dose, mg
Cat
Superior cervical ganglion
Stimulation 0.029 0.002
Block 0.411 0.016
Blood pressure Rise 0.343 0.049
Tibialis muscle Block 0.147 0.049
Rat
Blood pressure Rise 0.009 0.008
Diaphragm Block 629.15 32.446
Guinea pig Ileum Contraction 5.720 1.622
Rabbit Respiration Increase 5.658 0.162
Frog Rectus Contracture 5.515 1.622
Chicken Biventer Contracture 5.127 0.162
Based on Barlow and McLeod (1969).
every 30 or 60 minutes. Additionally, Cook made a com-
pound infusion by combining ounce each of blue cohosh
and ladys 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
(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
blue cohosh 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 villo-
sa), black cohosh (Actaea racemosa), cramp bark (Viburnum
opulus), or other botanicals. He believed it to strengthen the
female reproductive organs and to be one of the most valu-
able oxytocics to assist in prolonged childbirths. 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 oligomenor-
rhea, 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 rhizome was considered
unsurpassed by 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 subinvolu-
tion (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
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 19
th
century ergot was the primary pharmaceuti-
cal used for labor induction. The earliest mention of
ergots oxytocic effects appears to be in 1565 by Lonicer
in his Kruterbuch, and it was subsequently used for this
purpose by physicians and midwives (van Dongen and de
Groot 1995). Ergot caused tetanic, uncontrollable contrac-
tions, 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).
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, tincture, or in powder, was considered prefer-
able to ergot, as the contractions stimulated by blue cohosh
were regarded as less violent and spasmodic than those of
ergot. The consensus was that the strengthened contractions
mimicked normal uterine contractions with proper inter-
vals and did not exceed appropriate intensity or duration
(Adolphus 1897; Bloyer 1897; Jones 1908; Scudder 1870).
According to Jones (1908), 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. However, in contrast to this opinion,
Cook (1869) cited rigid os as a contraindication to blue
cohosh use.
Blue cohosh was also considered superior to most other
agents for treating severe after-pains following delivery, given
in doses of 24 grains (130260 mg), administered, as nec-
essary, every 1, 2, or 3 hours (Lloyd and Lloyd 1886-1887).
Numerous other authors of the time reported on the use
of alcohol extracts of blue cohosh in relieving after-pains
(Adolphus 1897; Bloyer 1897; Jones 1908; Niederkorn and
Versailles 1910).
The use of blue cohosh for facilitating an efficient labor
was echoed by a Dr. Locke, cited as an authority on drug
action, who 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 amenor-
rhea, 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).
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 contrac-
tions during the birthing process and for allaying after-pains.
It was typically administered for 23 weeks or more prior
to labor. 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. In his text American
Eclectic Obstetrics (1855), John King recommended a
compound 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 that is more famous and still available for gynecologic
complaints and as a partus preparator, is Syrupus Mitchellae
Compositus (Compound Syrup of Partridgeberry (Mitchella
repens)) or, more popularly, Mothers Cordial. It was pre-
pared similarly to Parturient Balsam. For after-pains, King
combined blue cohosh with the uterine antispasmodic
cramp bark (Viburnum opulus) (King 1855).
Dr. John Scudder believed blue cohosh, when given
in small doses as an infusion, to be of value late in preg-
nancy to help prepare the uterus for shorter and easier
labor (Scudder 1867). 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 that the first
and second [actions] are the most marked, yet the third is
quite certain. From his experience with deliveries, Scudder
(1870) appraised blue cohosh as an effective parturifacient,
stimulating labor by coordinating the muscular contractions
and increasing their power. For this he employed the infu-
sion, the fluid extract (1:1), or the tincture.
By the end of the 19
th
century, Eclectic authors con-
sidered blue cohosh one of the best uterine stimulants for
before, during, and after labor and birth. Kings 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 contrac-
tions; and for uterine subinvolution. (However, only the
latter two indications are suggestive of oxytocic activity;
the former would be indicative of uterine antispasmodic
activity.) Of the use of blue cohosh as a partus preparator,
Scudder (1898) wrote:
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 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 subse-
quent pregnancies.
Dr. Edward Case later reported excellent results in pre-
venting prolonged first stage of labor with blue cohosh use
beginning about 6 weeks prior to the expected due date. He
asserted that this also shortened the second stage by mak-
ing the contractions more efficient, and believed that the
intelligent use of blue cohosh rendered the use of forceps
unnecessary in many cases (Case 1919).
Ellingwood (1919) deviates from the typical description
of the uses of blue cohosh by suggesting its use much earlier
in pregnancy both for relieving unspecified symptoms that
occur in the third trimester 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 ges-
tation until the fetus is fully developed, labor being a physi-
ological process at full term, and not pathological, therefore
less protracted, less painful, and less liable to accidents.
Table 10 Popular traditional formulae with blue cohosh
Ingredient Amount Instructions
Parturient Balsam
Blue cohosh, rhizome and root 4 oz.
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 nal 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 gallon syrup. Add the initial half-
pint of tincture. If desired, avor with wintergreen
(Gaultheria spp.), sassafras (Sassafras albidum).or
other aromatic compound (King 1855).
Spikenard (Aralia racemosa), root 4 oz.
Black cohosh (Actaea racemosa syn. Cimicifuga
racemosa), root
2 oz.
Partridgeberry (Mitchella repens), herb 2 oz.
Queen-of-the-meadow (Eupatorium purpureum), root 2 oz.
Ladys slipper (Cypripedium pubescens), root 1 oz.
Mothers Cordial
Partridgeberry (Mitchella repens), herb 8 oz. Follow the instructions for Parturient Balsam above.
Blue cohosh, rhizome and root 4 oz.
False unicorn (Chamaelirium luteum), root 4 oz.
Cramp bark (Viburnum opulus), bark 4 oz.
Applications by Naturopathic Physicians
The Naturae Medicina and Naturopathic Dispensatory of
Kuts-Cheraux (1953) described blue cohosh rhizome as
antispasmodic, diaphoretic, emmenagogue, and uterotonic.
The infusion was to be made by adding 1 ounce (28 g) of
the root to a pint (473 mL) of boiling water; 1/2 ounce (15
mL) of this was given every 3 hours. The dose of the tincture
was 0.331 mL, while that of the fluid extract was 0.5 mL.
These preparations were used in the treatment of amenor-
rhea and dysmenorrhea and to facilitate placental expulsion
and prevent uterine subinvolution in the postpartum period.
Blue cohosh was considered beneficial in endometritis and
ovarian neuralgia and was used with black cohosh to treat
menopausal pains and pelvic discomfort accompanied by
pain radiating down the legs, assuming the absence of seri-
ous 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 contrain-
dication of Cook (1869), Dr. Bastyr used blue cohosh to
relax a rigid uterine os. Bill Mitchell (2003) noted that
blue cohosh reduces prolonged lochia following delivery,
while its emmenagogue and uterotonic 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 rhizome for dropsy, epilepsy, hysteria, rheu-
matism, 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 hour, and given at 24 fluid ounces
(59-118 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 2 fluid
drachms (1.857.4 mL), while the fluid extract (1:1) was to
be given in 1030 drop doses, and Caulophyllum (sic) at
24 grains (130324 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 pre-
parator 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 mid-
wives 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 contrac-
tions 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 direct-
entry midwives, many certified nurse midwives (CNMs)
practicing in hospitals and birthing centers also began to
rely on blue cohosh as an alternative to conventional meth-
ods 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
(see Safety Profile) and that it should be avoided in late
pregnancy, suggesting that it should only be used when nec-
essary for labor induction in limited dose and duration, with
extreme caution, and only under the supervision of qualified
childbirth professional.
In addition to its use in pregnancy, contemporary
herbal literature often recommends blue cohosh as a uter-
ine tonic and for general gynecologic complaints, including
amennorhea, dysmenorrhea, menorrhagia, uterine fibroids,
dysfunctional uterine bleeding, and 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 other 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 stom-
ach 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 these actions, blue cohosh
and its preparations were used to relieve nervous feeble-
ness 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 rhizome was used
for puerperal convulsions, epilepsy, chorea, and in neuralgic
forms of rheumatism. In the same way that blue cohosh was
considered to innervate 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 (Myrica cerifera) bark as a wash for aphthous ulcers
and with wild cherry (Prunus spp.) bark 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 conges-
tion, 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).
Decoctions of blue cohosh alone and with goldenseal
wereused as local applications for aphthae and other affec-
tions of the mouth (Lloyd and Lloyd 1886-1887). Alcohol
extract was considered an excellent remedy in restlessness
and insomnia, especially in nervous women (Baker 1910).
For the treatment of chronic rheumatism, blue cohosh was
considered more effective than black cohosh (Actaea race-
mosa), the latter being preferred for the acute form (Scudder
1870). For fevers in children, small doses (exact amounts
unspecified) of tincture were given frequently.
The Eclectic physicians employed hydroethanolic
extracts of blue cohosh for what would now be called irrita-
ble or nervous bladder (Adolphus 1897; Baker 1910; Bloyer
1897). When pelvic congestion, as well as pain in the rec-
tum or back pain, were associated with this condition, 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 12
th

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 con-
tractions (Wood et al. 1866). Blue cohosh was introduced
into the United States Pharmacopoeia in the 6
th
edition, in
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 7
th
edition in 1942.
The crude root remained in the NF until the 8
th
edition in
1946 and was dropped. The average dose for the dried root
given in the NF was 0.5 g, while the fluid extract was given
in doses of 0.5 mL (NF 1946). In addition to use of blue
cohosh by the Eclectics, numerous dispensatories, phar-
macognosy texts, and materia medica 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 of the
place of delivery from predominantly home to primarily hos-
pital, and with the era of the botanical physicians drawing
to a close, the use of blue cohosh as a common parturient
and labor stimulant also dwindled (ODowd 2001). Among
the contemporary pharmacopoeias, blue cohosh was includ-
ed only in the British Herbal Pharmacopoeia (BHP 1983) as
a spasmolytic and emmenagogue.
Traditional Preparations Used
The Physiomedicalists primarily used blue cohosh rhizome
as an infusion and occasionally, in powdered form as a rem-
edy for intestinal cramps, often in combination with other
botanicals such as wild yam (Dioscorea villosa) or ginger
(Zingiber officinale). It was also used for specific indications
in standard formulae, such as Parturient Balsam (Table 10).
Blue cohosh infusion was made with 1 ounce (1428 g) of
cut or powdered rhizome 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 23
hours, preferably in hot water. Both Physiomedicalists and
the Thomsonians recommended the use of the infusion
for rheumatism and other chronic conditions taken at 12
ounces (30-59 mL) every 46 hours (Clymer 1905; Cook
1869). Physiomedicalists also used a tincture prepared by
macerating the crushed root in dilute alcohol at a concentra-
tion of 2 ounces (57 g) per pint (473 mL) of extract solvent
(1:8) for 12 days before filtering. The dosage of this prepara-
tion given by Cook (1869) was 12 teaspoons (48 mL) 3
times daily. Clymer (1905) recommended only 5-10 drops
(1/32/3 mL) per dose of tincture. Blue cohosh was also
combined with black cohosh for menstrual cramps.
Blue cohosh became quite popular with the Eclectics
after its endorsement by John King in his Eclectic
Dispensatory in 1852. Mothers Cordial (see Table 10) was
described as a uterine tonic and antispasmodic by John
King, who used this preparation 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). 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 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, medical practitio-
ners whether Native American, allopathic, homeopathic,
Eclectic, or Physiomedicalist considered it both a uterine
antispasmodic and oxytocic. Many medical practitioners
from the late 1800searly 1900s viewed blue cohosh as one
of the most reliable agents for inducing normal contractions
during labor, as well as used it for preventing premature
labor and miscarriage. Different writers had nuanced under-
standings of the botanicals effects that differed somewhat,
but it was universally relied upon in the birthing process.
Non-gynecological uses of blue cohosh centered
around its putative antispasmodic effects, and it was widely
employed in this aspect by Native Americans and Western
medical practitioners for a variety of indications like emo-
tional stress, muscle spasms, colic, seizures, respiratory
constriction, as well as other indications that could benefit
from antispasmodic activity, such as hemoptysis and urinary
difficulties.
While this botanical has been widely used in herbal
gynecological formulae historically as well as by modern
midwives and herbalists, there is no clinical data and
sparse preclinical work to support this traditional use.
Several animal studies demonstrated the ability of blue
cohosh to increase uterine tone, providing some mecha-
nistic support for its traditional uses as an antispasmodic
and oxytocic. Much of the pharmacological work is very
preliminary, based on animal models which may have little
relevance to oral ingestion of preparations from the botani-
cal in humans (e.g., cardiovascular effects in frogs in situ).
In vitro work suggests that compounds in blue cohosh (e.g.,
N-methylcytisine, anagyrine, magnoflorine) bind with nico-
tinic and muscarinic acetylcholine receptors and adrenergic
receptors. These interactions may correlate with the actions
traditionally attributed to blue cohosh those of causing tis-
sue contractions (putatively associated with uterine toning)
and spasmolysis.
Since concern regarding the potential of blue cohosh
for fetal toxicity was raised (see Safety Profile), 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 birth-
ing 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 meth-
ods of induction, or of integrative medical practitioners and
obstetricians seeking alternatives to conventional methods
of induction. Between 1990 and 2006, medical labor induc-
tion rates more than doubled from 9.5% to 22.5% of births
(Martin et al. 2010). Elective inductions account for a signif-
icant 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.
There remains considerable controversy over the risks asso-
ciated with gestation beyond the 40
th
week (Caughey et al.
2009; Selo-Ojeme et al. 2010), which is further complicated
by imprecise estimations based on 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, both being associated with a host of
risks of further complications, including life-long disability
and early death for the neonate (Moore and Rayburn 2006).
In many cases, blue cohosh is specifically used to help avoid
the need for conventional induction. Women seeking to
avoid induction may be more likely to use blue cohosh as
a partus preparator. Midwives are often more comfortable
with expectant management of post-term pregnancy, while
many obstetricians recommend elective induction begin-
ning at 40 weeks gestation.
The increase in the use of induction agents overall
potentially also results in the increased use of natural induc-
tion agents such as blue cohosh in a manner that is
not consistent with traditional use. Differences in health
status of women historically and today (physically active
vs. sedentary) and use of higher acute doses of blue cohosh
mono-preparations, in contrast to the relatively small doses
of combination products, may contribute to a side effect
profile that was not evident or reported historically. A com-
prehensive review of the literature establishes a compelling
argument for mechanistic plausibility of blue cohosh as a
causal agent in the limited number of serious adverse events
and the adverse effects observed by midwives (see Safety
Profile). However, in the few events reported, the putative
toxicity of the botanical cannot be separated from its contex-
tual use in post-dates pregnancies or from other confound-
ing factors, such as poor fetal resuscitation efforts, in both of
which cases similar adverse events may be observed. While
it is impossible, based on the available data, to firmly estab-
lish causality between the botanical and the adverse events
reported, 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 with the potential for harm.
Actions
Antispasmodic, emmenagogue, oxytocic, parturifacient,
uterotonic.
Indications
Based on extensive historical and modern traditional use
and preliminary pharmacologic data, blue cohosh may be
Table 11 Blue cohosh dosages
Crude Powder
National Formulary (1946) 0.5 g
US Dispensatory (Osol and Farrar 1947) 0.51 g
Contemporary use by herbalists 0.93 g daily (Mills and Bone 2005)
Infusion/ Decoction
Eclectic use
Decoction or infusion (1 oz./1 pint of water), 2-4 oz.
every 3-4 hours (Lloyd and Lloyd 1886-1887)
National Dispensatory (Still et al. 1896) Decoction (30 g/1 pint of water) in doses of 1-2 oz.
US Dispensatory (Osol and Farrar 1947) Decoction, in doses equivalent to 0.5-1 g of the herb
Contemporary use by herbalists 0.3-1.0 g as a decoction, 3 times daily (Barnes et al. 2007)
Capsules
Contemporary use by herbalists 1-3 capsules (500 mg/capsule) daily (Romm 2009)
Contemporary use by midwives
1-2 capsules (mg/capsule not specied; 450-500 mg is a
typical ll of 00 caps), 1-2 times daily (Romm 2009)
Tincture
Eclectic use 10-30 drops 3-4 times daily (Lloyd and Lloyd 1886-1887)
Contemporary use by midwives
Highly variable: for labor induction, either 5 drops every
hour or 10 drops every 2 hours, to be taken in hot water
(McFarlin et al. 1999); from 15 drops several times
daily to numerous droppers daily (Romm 2009). Some
midwives alternate blue cohosh with black cohosh at
varying doses, with or without other agents, such as
castor oil (Downey 2010, personal communication to AHP,
unreferenced).
Fluid Extract (1:1)
Eclectic use 5-15 drops (60% ethanol) (Lloyd and Lloyd 1886-1887)
National Formulary (1906) 0.5 mL (60% ethanol) daily
Contemporary use by herbalists 0.5-1 mL (70% ethanol) 3 times daily (Barnes et al. 2007)
Mothers Cordial Eclectic use 1-4 oz., 3 times daily (Lloyd and Lloyd 1886-1887)
useful in the treatment of amenorrhea, dysmenorrhea, men-
orrhagia, 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 histori-
cally; however, the 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 dos-
age 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 (Table 11). Both the higher doses and
the use of blue cohosh singularly, widely applied today, may
be worthy of reconsideration given reports of its potential
for cardiotoxicity (see Safety Profile). The historical use of
lower doses and the use of combinations of blue cohosh with
other botanicals greatly reduce exposure of the fetus to the
putatively toxic compounds in the botanical.
Sa f e t y P r o f i l e
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 outside of pregnancy. Side effects and serious
adverse events have been described in connection with the
use of blue cohosh during pregnancy as an abortifacient,
as a partus preparator, and for labor induction. Because of
these, its uses as an abortifacient and partus preparator are
not recommended. However, the use of blue cohosh for the
inductions must be critically compared to the need for and
risks of conventional means of inductions (NPSG 2011),
as well as outcomes associated with conventional methods.
Moreover, the administration of blue cohosh during labor or
to induce labor should be done only under the supervision
of qualified maternity health care providers.
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 sys-
tem 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 the first trimester of
pregnancy 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 deter-
mination regarding causality. Of significance in assessing
reports for botanical preparations, appropriate characteriza-
tion of the product in question is required.
Additionally, a single rat study of a homeopathic
Caulophyllum preparation (0.3 mL at 200 and 10,000
potencies; otherwise unspecified) states that the lower
potency of the preparations (200) interrupted implantation
by dissolving the endometrium at the site of implantation,
while the higher potency (10,000) led to an increased litter
size compared with controls (8 vs. 5) (Chandrasekhar and
Vishwanath 1974). This study is of poor methodological
quality and does not appear to add any information of rel-
evance to the blue cohosh literature. Considering that 200
and 10,000 potencies will have little to no material traces of
the botanical in the preparation, any association with chemi-
cal 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 induc-
tion, which resulted in the delivery of a 3840 g female with
Apgar scores of 1, 4, and 5 at 1, 5, and 10 minutes, respec-
tively. Two midwives provided resuscitation and cardiac
compressions when the infant was unable to breathe sponta-
neously after birth at home. Cardiopulmonary resuscitation
persisted for 30 minutes, after which the baby gasped and
was transferred to the hospital where mechanical ventila-
tion 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 second-
ary 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 a delay in initiating mechanical
ventilation. Post-term pregnancy, lengthy attempted resusci-
tation, and resultant profound neonatal hypoxia are highly
plausible explanations for the poor neonatal status, and,
given these significant confounding variables, it is impos-
sible to definitively 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 1 blue cohosh tablet (otherwise unspecified)
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 deliv-
ery 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 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 infants condition were identified. High-
frequency ventilation and high-dose vasopressor support
were required for 72 hours, after which the infants condi-
tion 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 con-
cluded that the clinical picture of cardiogenic shock caused
by myocardial ischemia is well explained by the known phar-
macologic 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 mater-
nal 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 authenti-
cated, dose, duration of use, and form are provided. While
the quantity of blue cohosh in the product was not reported,
the crude roots and rhizomes typically found in powders,
tablets, and capsules 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 gesta-
tion, independent of blue cohosh use. The cardiomegaly
may have been due either to blue cohosh, placental insuf-
ficiency, 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
infants 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 mothers 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 con-
cluded that either benzoylecgonine is a metabolite of both
cocaine and blue cohosh, or that the blue cohosh was con-
taminated with cocaine, only later to retract this statement
(see case discussion below).
Case discussion: A definitive determination regarding causal-
ity 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 Zarlengos (2004b) response to
the letters stated that the initial finding of benzoylecgonine
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 benzoylecgo-
nine 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. However, this does not completely rule out cocaine
or benzoylecgonine as contributing or causative factors in
the event experienced, thus complicating 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 hyperten-
sion 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
Table 12 Case reports of adverse effects of blue cohosh
Reference(s) Case parameters Intervention Adverse effects
WHO causality
category
*
Discussion
Gunn and Wright
(1996)
Planned homebirth
at 41 weeks 6 days
gestation following
a midwife-attempted
induction
Unspecied;
mixture of blue
cohosh and black
cohosh
Absent spontaneous
respirations at birth;
multi-organ hypoxic
injury; permanent
central nervous system
damage
Possible Hypoxia due to post-
term pregnancy
and/or lengthy
resuscitation are
confounding factors.
Jones and Lawson
(1998)
A 41-wk GA male
infant delivered
in hospital by a
36-year-old G4P3
with well-controlled
hypothyroidism
3 tablets of blue
cohosh (amount in
tablet unspecied)
daily 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
unspecied 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
Probable Causality was
not denitively
established but is
highly plausible.
This event should
be considered as a
result of overdose,
not a typical adverse
reaction to the
botanical.
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
unspecied
Focal motor seizures
of the infants 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 conrmation
(Finkel and Zarlengo
2004b).
*
Defined in WHO (2004). Categories assigned according to scores calculated from the Naranjo Adverse Drug Reaction Probability Scale (Naranjo et al. 1981):
>9=certain or definite; 5-8=probable; 1-4 = possible; 0 = unlikely.
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 of a mother and fetus.
With the preceding case reports and the toxicological
plausibility of late-term blue cohosh ingestion being a con-
tributor to the adverse events reported, questions regarding
the safety of blue cohosh use in late pregnancy and labor
have arisen. However, the indications that often lead to the
use of blue cohosh, for example, post-dates pregnancies
and prolonged or dysfunctional labor, are themselves inde-
pendently 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 impos-
sible to know if the relationship between the adverse events
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 these case reports, with the exception of the attempted
abortion. However, even in the latter case, extremely high
doses of blue cohosh were used, in conjunction with vagi-
nal douches containing slippery elm and parsley (Rao et al.
1998; Rao and Hoffman 2002), vaginal mechanical inser-
tions themselves being a known cause of uterine contrac-
tions (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 birth-
ing centers, will opt for what they consider to be a more nat-
ural, 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 serve to guide the
clinician. It should 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. Without modern evidence of effi-
cacy or modern evidence of safety, it is highly unlikely that
comparative trials of blue cohosh with conventional labor
induction agents will be undertaken.
Contraindications
Due to its potential for emmenagogic activity, reports of
adverse neonatal effects, potential toxicity of the constituents
(anagyrine, N-methylcytisine, and the saponins), teratoge-
nicity of N-methylcytisine in rodents in vitro (rat embryo
culture [REC]), and in vitro embryotoxicity of taspine,
the use of blue cohosh in pregnancy should be restricted
to labor induction in limited dose and duration, with cau-
tion, 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 mothers
milk, caution dictates that blue cohosh not be used during
lactation.
Interactions
No case reports or clinical trials of herb-drug or herb-
supplement interactions were identified. Madgula et
al. (2009) demonstrated in vitro inhibition of the cyto-
chrome P450 (CYP450) enzymes CYP1A2, CYP2C19,
CYP3A4, and CYP2D6 by the alkaloids caulophyl-
lumine B, O-acetlybaptifolin, anagyrine, lupanine, and
N-methylcytisine and the saponins cauloside C and D.
Dietary supplements containing blue cohosh or its constitu-
ents should be taken with care in combination with medi-
cations 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 iso-
lated 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 inter-
act 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 causal-
ity; 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 combinations, 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 inges-
tion 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 anagy-
rine, 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 graz-
ing on anagyrine-containing lupines. The mechanism is
thought to involve stimulation followed by desensitization
of fetal skeletal-muscle type nicotinic acetylcholine recep-
tors (nAChR) (Green et al. 2010). The disease is known to
appear only when ingestion occurs in a very narrow win-
dow 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 con-
sumed by humans when using blue cohosh in recommend-
ed 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 M. Thus,
the embryotoxicity of anagyrine-containing botanicals, such
as blue cohosh, in humans remains plausible.
N-Methylcytisine, which binds to nicotinic acetylcho-
line receptors in a manner similar to nicotine (IC
50 = 0.05
M; Table 8), 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 medi-
um concentrations (20 g/mL) and did not inhibit overall
growth and development. In addition to teratogenicity, at
higher levels (250 g/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 3). 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 g/mL and cytotoxicity was
observed even at low concentrations of 0.5 g/mL (Irikura
and Kennelly 1999; Kennelly et al. 1999). The concentra-
tion expected from the higher end dose of blue cohosh (3
g) could potentially yield approximately 0.4 g of taspine.
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).
Lactation
Data on the safety of blue cohosh to infants of lactat-
ing mothers ingesting blue cohosh products are lacking.
Anagyrine has been implicated in teratogenicity in rumi-
nants (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 the consumption of milk from a family
goat that had been foraging on anagyrine-containing lupines
(Keeler 1984). 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 con-
tents 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 con-
stituents (magnoflorine, caulosides A and C) have demon-
strated antineoplastic activity in vitro.
Influence on Driving
No data are available. Based upon use by contemporary
practitioners, no effects on driving are to be expected.
Precautions
Excessive doses of this herb should be avoided. See
Overdose below.
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 examina-
tion she was hypertensive to 149/62, tachycardic to 148
beats/minute, diaphoretic, weak, and had anterior abdomi-
nal wall fasciculations. Her gynecologic exam showed a
non-tender uterus without cervical dilatation. Ketones were
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 i.v. 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 (Rao et al. 1998; Rao and
Hoffmann 2002).
The exhibited symptoms neatly corroborate with nico-
tinic toxicity that may be secondary to excessive ingestion
of N-methylcytisine contained in the botanical (see Table
8). The closest estimate of blue cohosh consumed in this
subject is 1020 doses, with the typical tincture dose being
1 mL, which is equivalent up to 28 mg of the alkaloid, based
on the available data on the alkaloid concentrations in blue
cohosh products (Table 13).
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 i.v. hydra-
tion to more aggressive medical treatment. Unless there are
complications, long-term effects from nicotinic toxicity are
rare. In the case involving blue cohosh, i.v. 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 impli-
cated as teratogens in higher animals (Kennelly et al. 1999).
Ingestion of blue cohosh has been associated with
tachycardia, tachypnea, diaphoresis, hypotension and hyper-
tension, muscle weakness, hyperglycemia, fasciculations,
increased small-intestinal motility, abdominal pain, pelvic
cramping, and vomiting (Rao et al. 1998; Rao and Hoffman
2002). These symptoms are consistent with nicotinic poison-
ing and are likely caused by N-methylcytisine in blue cohosh,
which binds to nicotinic receptors more weakly than nico-
tine, but with significant affinity (Barlow and McLeod 1969;
Rao et al. 1998; Rao and Hoffman 2002; Schmeller et al.
1994; see Table 8). The highest content of N-methylcytisine
reported in tinctures, which is the preparation used by the
subject in the report, is 1.6 mg/mL (Satchithanandam et
al. 2008). The LD
50
of N-methylcytisine in mice was deter-
mined 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 g/0.1 cc of the glycoside solution (Ferguson and
Edwards 1954). The LD
50
of the glycoside, administered i.v.,
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 (hydroetha-
nolic and glycerine extracts) (Table 14); however, based on
the estimations of maximum daily intakes using the recom-
mended doses provided on the product labels, some tinc-
tures 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 3 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 consis-
tent on this) (Gardner et al. 2012).
Conclusion
The use of blue cohosh outside of pregnancy, in recom-
mended doses, does not appear to be associated with any
adverse events or toxicity. The potential teratogenic, embryo-
toxic, and cardioactive effects of blue cohosh indicate that
the 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.
Historically, the botanical was considered safe to use as
a partus preparator and for labor augmentation. However,
contemporary survey data of anecdotal reports by midwives,
several case reports of serious adverse events, and the dem-
onstrated toxicological plausibility of blue cohosh constitu-
ents being implicated in the adverse events suggest that blue
cohosh should be used cautiously for labor induction and its
use as a partus preparator must be reconsidered.
According to the adverse drug reaction probability scale
adopted by the World Health Organization (e.g., Holloway
and Green 2003), only one of the reported adverse events
could be assigned the Probable level of causality, i.e., it
was unlikely to be due to any concurrent disease or other
drugs or chemicals (Table 12). This event involved high-
dose ingestion of a blue cohosh preparation by a healthy,
non-smoking young woman in the first trimester of preg-
nancy attempting to induce an abortion, which resulted in
symptoms of nicotinic toxicity that may putatively be cor-
related with the blue cohosh alkaloid N-methylcytisine (Rao
et al. 1998; Rao and Hoffman 2002). In this case, the dose
taken by the woman was unspecified; however, it is known
that this dose was taken at a frequency approximately 6.5
times higher than recommended and should be considered
as an overdose rather than toxicity associated with the appro-
priate use of the botanical.
Table 13 Content of alkaloids in blue cohosh products
Compound Content* Publication reference
Powders and capsules, mg/g
Magnoorine
8.72 Ganzera et al. 2003
5.8 1.6 Satchithanandam et al. 2008
11.4 1.0 Avula et al. 2011
Anagyrine
0.34 0.07 Betz et al. 1998
Baptifoline
1.25 0.49 Betz et al. 1998
N-methylcytisine
0.76 0.13 Betz et al. 1998
Liquid products, mg/mL
Magnoorine
2.08 1.52 Avula et al. 2011
Anagyrine
0.017 0.016 Betz et al. 1998
Baptifoline
0.075 0.070 Betz et al. 1998
N-methylcytisine
0.048 0.040 Betz et al. 1998
* 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.
The three other case reports of adverse pregnancy
outcomes, involving blue cohosh use as a partus preparator
or a labor induction agent, are in the Possible causality
category, i.e., blue cohosh use had temporal association with
the event, but the causality was not confirmed by any other
measures, and the association was confounded by other
factors. Of these events, a plausible relationship between
blue cohosh ingestion and the adverse effects can only be
established for one: 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. Of the remaining two
events, one involved prolonged, inadequate resuscitation,
while the other was confounded by the detection of cocaine
metabolite in the urine, meconium, and the blue cohosh
preparation used.
Despite this lack of conclusive reports of adverse events
associated with blue cohosh use for labor induction or as a
partus preparator, the pharmacological actions of the alka-
loid and saponin components in blue cohosh are consistent
with the mechanisms for the events reported. Conversely,
the indications that often lead to the use of blue cohosh to
induce or augment labor, for example, post-dates pregnancy
and prolonged or dysfunctional labor, are themselves inde-
pendently associated with a number of reported adverse
effects, including presence of meconium in the amni-
otic fluid, fetal tachycardia, need for neonatal resuscitation,
and increased neonatal morbidity (Mayo Clinic 2011).
Compared with the frequent use of blue cohosh by mid-
wives and pregnant women, the case reports presented do
not appear to represent a high risk of severe adverse events.
At the same time, there are numerous risks involved in the
use of conventional methods for labor induction (AROM,
misoprostol, pitocin), including prematurity, tachysystole,
fetal heart rate decelerations, and increased rates of cesar-
ean section, which are associated with increased maternal
morbidity and mortality. Given these known risks and the
necessity that conventional inductions be performed in
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
Cauloside D
47.19 9.34 Avula et al. 2011
Cauloside G
43.3 1.5 Avula et al. 2011
Cauloside H 1.86 0.31 Avula et al. 2011
Leonticin D
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
Cauloside D
10.82 9.00 Avula et al. 2011
Cauloside G
11.88 8.38 Avula et al. 2011
Cauloside H 0.66 0.39 Avula et al. 2011
Leonticin D
6.35 4.95 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.
medical settings, it is likely that a number of midwives and
pregnant women will continue to choose 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). A risk/benefit analysis comparing blue cohosh
and conventional methods of induction may shed light
on which interventions are the safest. However, without
first having formal studies demonstrating efficacy of blue
cohosh for labor induction, the comparative trials are highly
improbable.
Until further research is done, it is recommended
that the practice of using blue cohosh as a partus prepara-
tor be abandoned. If the botanical is to be used for labor
induction or augmentation, it should only be done at the
recommended dosages, under the supervision of a quali-
fied maternity health professional, with proper fetal and
neonatal monitoring, and using preparations with the low-
est level of potentially harmful constituents. Based on the
available data, tinctures (hydroethanolic extracts) appear to
have the lowest concentrations of the potentially cardiotoxic
glycosides. Additionally, traditional literature suggests that
blue cohosh was seldom used singularly, but was primarily
used in combinations (see Table 10), thus further limiting
exposure to the putatively toxic blue cohosh constituents.
Greater adherence to the use of such combinations and
their greater commercial availability may be more prudent
than use of blue cohosh alone and the predominant avail-
ability of single-ingredient products. More precise charac-
terization 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.
I n t e r n a t i o n a l S t a t u s
Australia
Blue cohosh is a substance that may be used as an active
ingredient in medicines in the Listed category in the
Australian Register of Therapeutic Goods (ARTG), for sup-
ply 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
Blue cohosh 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 for non-medicinal use (HC
1995). Quality: The finished product must comply with
the minimum specifications outlined in the Compendium
of Monographs by Natural Health Products Directorate
(NHPD 2007a). Indications: Product-specific, depending
on the evidence submitted with the application for product
license.
European Union
Blue cohosh is regulated as an active ingredient of Traditional
Herbal Medicinal Products (THMPs) requiring pre-market-
ing authorization and product registration (EPCEU 2004).
Currently, there are no blue cohosh preparations approved
for use in the European Union. Quality: Herbal medicinal
products must be composed of pharmacopoeial quality
active ingredients. Indications: Product-specific, depend-
ing on the evidence submitted by the applicant for THMP
registration.
United Kingdom
Blue cohosh is a General Sale List (GSL) medicine appear-
ing 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 the evidence submitted with THMP registra-
tion application. No known registered products.
United States
Blue cohosh preparations can be labeled and marketed
in the US as dietary supplement products (USC 1994).
However, FDA, considers blue cohosh to be a dietary sup-
plement of safety concern (FDA 2009). Quality: No blue
cohosh monographs are published in the Food Chemicals
Codex or United States PharmacopeiaNational Formulary.
Indications: Structure/function claims are allowed for
blue cohosh-containing dietary supplement products.
Manufacturers are responsible for ensuring truthfulness and
accuracy of these claims and must notify the FDA of the
text of the claim within 30 days after marketing the product.
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 Alkaloids, mg Saponins, mg Publication reference
Capsules
15.6-47.8 76.5-190.3 Satchithanandam et al. (2008)
115.6-161.84 Avula et al. (2011)
Liquid extracts
0.9-17.3 9.1-79.1 Satchithanandam et al. (2008)
5.97-302.4 Avula et al. (2011)
Re f e r e n c e s
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Note: The color, relative size, and number of flowers are indicative of C. giganteum, the taxon which
was not recognized at the time of publication of the original.
Nomenclature 1
Botanical Nomenclature
Botanical Family
Pharmaceutical Nomenclature
Pharmacopoeial Definition
Common Names
History 1
Identification 3
Botanical Identification
Macroscopic Identification
Commercial Sources and Handling 12
Collection
Cultivation
Handling and Processing
Drying
Storage
Adulterants
Preparations
Constituents 13
Analytical 16
High Performance Thin Layer Chromatography (HPTLC)
Limit Tests
Therapeutics 19
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 29
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 37
References 38
Ta b l e o f Co n t e n t s
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
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