Black cohosh is a native eastern North American plant that
was used as traditional medicine by Native Americans.
Extracts of the roots and rhizomes were used for analgesic,
sedative, and anti-inflammatory properties.More recently,
root and rhizome black cohosh preparations have had a
rich clinical history, spanning almost 60 years of study.
These studies have primarily focused on relieving climacteric
symptoms associated with menopause as a possible
alternative to classical hormone or estrogen replacement
The common name for black cohosh [Actaea racemosa L.
syn., Cimicifuga racemosa (L.) Nutt. (Ranunculaceae, Buttercup
Family)] originated with North American Indians.
The term cohosh is thought to be an Algonquian
word meaning “rough,” with reference to the texture
of the thick, knotted roots and underground stems (rhizomes).
A New World plant used by Native Americans,
it was most abundant in the Ohio River Valley, but it
could also be found from Maine to Wisconsin, south
along the Allegheny Mountains to Georgia, and west to
Various common names have been used to refer to
black cohosh, including black snakeroot, bugbane, rattleroot,
squawroot, and macrotys. It is a member of the Ranunculaceae
or Buttercup family, which includes other
medicinal plants such as aconite, goldenseal, and pulsatilla.
It has been known by the scientific name C. racemosa
and recently has been assigned to A. racemosa. The
generic name Cimicifuga derives from the Latin cimex
(a kind of bug) and fugare (to put to flight), which is
perhaps indicative of the use of some strongly smelling
close relatives to repel insects. The specific epithet racemosa
refers to the flowering stalk, termed a raceme. The
name rattleroot is indicative of the rattling sound made by
the dry seeds in their pods. This plant prefers the shade
of rich open hardwood forests, but it will tolerate some
Black cohosh has been used clinically for relief of
climacteric symptoms for more than 60 years, and its popularity
in the United States as a botanical dietary supplement
has increased due to the recently recognized potential
risks associated with classical estrogen replacement
therapy or hormone replacement therapy (1,2). The part
of the black cohosh plant used in medicinal preparations
is the root and rhizome. It was officially recognized in the
United States Pharmacopeia (USP) from the first edition in
1820 to 1936 and in the National Formulary from 1936 to
1950. The eclectic physicians used a preparation of black
cohosh called macrotys. It was considered one of the bestknown,
specific medicines for heavy, tensive, and aching
pains as it was noted to have a direct influence on the
female reproductive organs.
While the mechanism of action has not been completely
elucidated, recent literature suggests that alleviation
of climacteric symptoms is mediated through neurotransmitter
regulation and not through classical estrogen
receptor (ER) endocrine pathways (3,4).
More than 60 triterpene glycosides, most with a 9,19
cycloartane skeleton, and unique to Actaea spp., have
been reported from the roots and rhizomes of A. racemosa
(5,6). The compound 23-epi-26-deoxyactein (formerly
27-deoxyactein) is the constituent usually selected for
standardization of commercial products based on its
abundance in the roots and rhizomes (7–12). The pharmacokinetics
of 23-epi-26-deoxyactein in serum and urine has
recently been reported (13). While triterpenes are structurally
similar to steroids and possess a broad range of
biological activity (14–17), no significant ligand binding
affinity was found toward ER- in the evaluation of 23-
epi-26-deoxyactein, cimiracemoside F and cimicifuga,
and their respective aglycones (18). This, coupled with
the lack of demonstrated estrogenic activity in A. racemosa
extracts, has called into question the notion that black cohosh
acts through direct ER binding by the triterpenes, as
has been hypothesized (19–23).
In addition to the triterpene saponins, the roots and
rhizomes of black cohosh also contain a number of aromatic
acids/polyphenols that possess a wide array of biological
activities (5,24–26). Caffeic acid, which is found
widely across all species of flowering plants, has shown
pregnant mare anti gonadotropin activity (27–29), rat uterine
antispasmodic activity (30), and smooth muscle relaxant/
antispasmolytic activity in rats (31) and guinea
pig ileum (32). Ferulic acid, also more or less ubiquitous
among flowering plants, has demonstrated luteinizing
hormone (LH) release inhibition (33), follicle-stimulating
hormone (FSH) release stimulation (33), antiestrogenic activity
(34), prolactin stimulation in cows (35) and inhibition
in rats (33), and uterine relaxant/antispasmolytic
activity in rats (36). Fukinolic acid produced an estrogenic
effect on MCF-7 cells with reference to estradiol
(37). A more recent study refuted this effect and demonstrated
a lack of estrogenic effect for 10 other phenolic
esters, many of which are unique to Actaea spp. (caffeoyl glycolic
acid; 2-caffeoylquinic acid (cimicifuga acid
D); 3,4-dihydroxyphenyl caffeate (petasiphenone); 3,4-
dihydroxyphenyl-2-oxopropyl isoferulic (cimici phenol);
3,4-dihydroxyphenyl isoferulic (cimici phenone); cimicifuga
acids A, B, E, F; and folic acid) from black
Studies on the phenolic acid constituents of black
cohosh have shown antioxidant activity (24,39) that may
correlate with or prove useful in the determination of the
mechanism of action of black cohosh. In addition, a number
of plant sterols and fatty acids, generally regarded as
ubiquitous in the plant kingdom, are contained in the roots
and rhizomes for which the biological activities probably
do not relate to the mechanism of action of black cohosh
(5). In the past 5 years, novel guanidine alkaloids have
been isolated from A. racemosa underground parts (40,41).
New phytochemical methodology called pH zone refinement
gradient centrifugal partitioning chromatography
coupled with a sensitive liquid chromatography–mass
spectral dereplication method led to the identification of
N-(omega)-methylserotonin as a potential active principle
with serotonergic properties (41). Alkaloids have also been
reported from other Actaea spp. roots and rhizomes (42,43).
There has been some debate over the occurrence
of the weakly estrogenic compound formononetin in the
plant (44–49). Although there has been at least one report
of its occurrence in A. racemosa (46), prior studies using
plant material collected from different sites in the Eastern
United States at different times of the year failed to find
formononetin (47,48). More recent studies on both commercial
black cohosh products and wild-crafted material,
incorporating both high-performance liquid chromatography
with mass spectral and photodiode array detection,
confirmed the prior findings of no detectable formononetin
in black cohosh (8,49).
A. racemosa syn. C. racemosa is an erect, smooth-stemmed
perennial 1–2.5 m in height. Large compound leaves are
alternately arranged and triternate on short clasping petioles.
Basal leaf petioles are grooved in young specimens.
This shallow, narrow sulcus in A. racemosa disappears as
the petiole enlarges, whereas it remains present throughout
the life of the two related eastern North American
species, A. cordifolia DC syn. C. rubifolia Kearney and
A. podocarpa DC syn. C. americana Michx (50). Terminal
leaflets of A. racemosa are acute and glabrous with sharp
serrated margins, often trilobate, occasionally bilobed.
Fruits are ovoid follicles occurring sessile on the pedicel.
The flowering portion, the raceme, is a long wandlike
structure with showy white flowers. The flowers possess
numerous characteristic stamen and slender filaments
with distinctive white anthers (51). The roots and rhizomes
are branched and knotted structures with a dark brown
exterior and are internally white and mealy or brown and
waxy. The upper rhizome surface has several buds and numerous
large stem bases terminated frequently by deep,
cup-shaped, radiating scars, each of which show a radiate
structure or less frequently fibrous strands. Lower and lateral
surfaces exhibit numerous root scars and a few short
roots. The fracture is horny, the odor slight, and the taste
bitter and acrid (52).
Black Cohosh EFFECTS ON CLIMACTERIC SYMPTOMS
RELATED TO MENOPAUSE
With a history of clinical study spanning almost 60 years,
mainly in Europe (53), black cohosh is one of the more popular
alternatives to hormone replacement therapy. Most
of the clinical research over this span has been performed
on the product known as Remifemin R , whose formula
has changed over the years. However, a number of other
commercial formulations are also available. In 2007, black
cohosh was the 50th best-selling dietary supplement in
the United States with sales of approximately $52 million
(USD), according to the Nutrition Business Journal (54).
Black cohosh clinical study outcomes have been
evaluated using a variety of tools, including self- or physician
assessments of symptom scores and physiological
parameters. Typical measurements include psychological,
neurovegetative, somatic, and physiological markers of
menopause or relief from the climacteric symptoms of
menopause. As in all clinical trials, study design is vital,
so studies that are adequately powered, incorporate
proper controls, and are designed to address confounders
relevant to climacteric symptoms such as the placebo
effect and botanical product quality should be given
more weight than studies that are not as well designed
Placebo effects in menopausal trials are generally
large (60) and reflect underlying fluctuations of symptoms.
Therefore, any well-designed study must adjust
the appropriate variables (i.e., study duration, number
of subjects (n), and/or dosage) to account for such an effect.
In the evidence-based medicine model, the gold standard
in terms of efficacy involves randomized, controlled
trials (RCTs). Many RCTs on black cohosh exist. When
high-quality studies are combined, more than 3000 subjects
have been randomized, with the more recent studies
adding layers of design sophistication. For example,
double-blind, multicenter, placebo-controlled trials that
provide details regarding clinical material specifications
are becoming more prevalent (55–60).
A recent phase III, double-blind, randomized,
placebo-controlled crossover trial of the effectiveness of
black cohosh for the management of hot flashes was conducted
over two 4-week periods (one capsule, 20 mg bid)
(61). The study used a daily hot flash diary and found
that subjects receiving the black cohosh material reported
a mean 20% decrease in hot flash score (comparing the
fourth treatment week to the baseline week) versus a 27%
decrease for patients on placebo (P = 0.53), mean hot flash
frequency was reduced 17% in the black cohosh group and
26% on placebo (P = 0.36). Thus, the authors concluded
that the study did not provide any evidence that black
cohosh reduced hot flashes more than the placebo. Critics
of the study point to the short duration and low dose as
potential confounders of the results.
The Herbal Alternatives for Menopause trial or
HALT trial compared the efficacy of 160 mg daily black
62 Fabricant et al.
cohosh against several other interventions (200 mg daily
multi botanical with black cohosh and nine other ingredients;
200 mg daily multi botanical plus dietary soy counseling;
0.625 mg daily conjugated equine estrogen with or
without 2.5 mg medroxyprogesterone acetate daily; and
placebo) in 351 menopausal and postmenopausal women
of ages 45–55 years with two or more vasomotor symptoms
per day. Results did not suggest efficacy for any of
the herbal interventions when compared with placebo at
any time point over the 1-year course of the study (62).
The Jacobson study (63), spanning only 60 days of
treatment, suggests that the short study duration may
have limited the findings (60). In addition, all the study
participants had a history of breast cancer. The authors
reported that the median number of hot flashes decreased
27% in both the placebo and black cohosh groups. No significant
differences were observed between groups. Thus,
black cohosh, on the basis of this study, was no more effective
than placebo in the treatment of hot flashes. The
source and formulation of the extract used in this study
was not specified. A more recent open-label study that
treated breast cancer survivors with either Tamoxifen R or
a combination of BNO 1055, a proprietary black cohosh extract,
with Tamoxifen suggested a reduction in the number
and severity of hot flashes in the combination treatment
In another randomized, double-blind, placebo controlled
study that lasted 12 weeks, black cohosh was
compared with standard conjugated estrogen (CE) therapy
(0.625 mg/daily). Patients’ physical and psychological
symptoms were measured every 4 weeks. The end
result of the study was that the patients treated with
black cohosh had significantly lower index scores on
both the Kupperman menopausal (KM) and the Hamilton
menopausal (HAM-A) scales compared with placebo,
indicating a decrease in severity and frequency of hot
flashes. In addition, this study showed an increase in the
number of estrogenized cells in the vaginal epithelium in
the black cohosh treatment arm, which could indicate an
estrogenic action in this tissue (65).
In 2003, a similar study compared effects of two
different preparations of BNO 1055 extract and CE therapy
on climacteric symptoms and serum markers of
bone metabolism (66). The study outcomes were evaluated
using patient self-assessment (diary and menopause
rating scale), CrossLaps (to measure bone resorption),
bone specific alkaline phosphatase (marker of bone formation),
and endometrial thickness (measured by ultrasound).
Both BNO 1055 extracts were equipotent to CE
therapy and significantly greater than placebo at reducing
climacteric complaints. In addition, the study showed
that both BNO 1055 preparations had beneficial effects
on bone metabolism in serum. Specifically, an increase in
bone-specific alkaline phosphatase and no reduction in
bone resorption were noted indicating an increase in bone
turnover formation. No change in endometrial thickness
was observed in either BNO 1055 treatment groups, but it
was significantly increased with CE therapy. An increase
in superficial vaginal cells was observed in the CE and
both BNO 1055 treatment groups. The authors of the study
hypothesized that the activity of both BNO 1055 preparations
was similar to the effects of selective estrogen receptor
modulating (SERM), that is, Raloxifene R therapy on
bone and neurovegetative climacteric symptoms, without
any uterotrophic effects (66).
A recent high-quality, double-blind, randomized
study evaluated the effects of two dosages (low, 39 mg;
high, 127 mg) of a Remifemin extract on menopausal
symptoms. Effectiveness was measured using the KM index,
self-assessment depression scale (SDS), clinical global
impression scale (CGI), serum levels of LH and FSH,
sex hormone–binding globulin, prolactin, 17–estradiol,
and vaginal cytology. Reductions in the KM and SDS indices
were significant. Global efficacy (CGI) was scored
at good to very good in 80% (low dosage) and 90%
(high dosage) of the patients in the treatment groups (67).
No effect on serum hormone levels or vaginal cytology
was shown, prompting the authors of the study to suggest
that black cohosh does not have a direct estrogenic
effect on the serum hormone levels or vaginal epithelium
(68). Two recent open-label studies using unspecified
types of extracts reported reduced KM index scores.
One study reported a significant reduction in 1 month
(69), while the other, which also used the HAM-A scale,
recorded a 90% improvement in climacteric symptoms
in menopausal women after 3 months of black cohosh
Chung and colleagues (71) examined a combination
of black cohosh and St. John’s wort (Gynoplus R ) inamulti center
RCT in 89 peri- or postmenopausal women with
climacteric symptoms. Subjects were treated for 12 weeks
with either the Gynoplus extract or placebo. In addition
to climacteric complaints, investigators also examined effects
on vaginal atrophy, serum hormone levels (FSH, LH),
and lipid profiles [total cholesterol, high-density lipoprotein
(HDL) cholesterol, low-density lipoprotein cholesterol,
and triglyceride]. Significant improvements in climacteric
symptoms and hot flashes, as well as an increase
in HDL, were observed in the Gynoplus group by 4 weeks
and maintained after 12 weeks, but there was no significant
impact on vaginal atrophy.
In a 12-month, randomized, four-arm, double-blind
clinical trial of standardized black cohosh, red clover,
placebo, and 0.625 mg conjugated equine estrogens plus
2.5 mg medroxyprogesterone acetate (conjugated equine
estrogens (CEE) and medroxyprogesterone acetate (MPA);
n = 89), black cohosh did not significantly reduce the
frequency of vasomotor symptoms as compared with
placebo. The primary outcome measures were reduction
in vasomotor symptoms (hot flashes and night sweats) by
black cohosh and red clover compared with placebo; secondary
outcomes included safety evaluation, reduction in
somatic symptoms, relief of sexual dysfunction, and overall
improvement in quality of life. Reductions in number of
vasomotor symptoms after a 12-month intervention were
as follows: black cohosh (34%), red clover (57%), placebo
(63%), and CEE/MPA (94%), with only CEE/MPA differing
significantly from placebo. Secondary measures indicated
that both botanicals were safe as administered. In
general, there were no improvements in other menopausal
A 12-week trial investigating the effects of black cohosh
on menopause-related anxiety disorder found no
statistically significant anxiolytic effect of black cohosh
However, small sample size, choice of
black cohosh preparation, and dosage used may have
Black Cohosh 63
contributed to the negative results according to the study’s
More details of the human studies discussed here,
as well as others, are presented in Table 1.
BIOCHEMISTRY AND FUNCTIONS
Despite the extensive clinical research, the mechanism of
action of black cohosh on menopausal and other symptoms
remains unclear, which is consistent with the varied
results from clinical trials.A Majority of the older literature
suggest a direct estrogenic effect. More recent hypotheses
have proposed an effect on the limbic system (hypothalamus)
or an effect on the neurotransmitters involved in
regulation of this system as being responsible for the activity
of black cohosh. Data fall into the following categories.
Estrogen Receptor Competitive Binding
The first report of ER-binding activity of black cohosh
indicated this as a possible mechanism of action (74).
Additional studies were carried out to substantiate this
purported endocrine activity (75,76). However, a factor
frequently overlooked regarding black cohosh receptor
binding studies is the lipophilic nature of the extracts
tested. Chemically, lipophilic extracts and fractions that
display ER-binding activity are significantly different
from the typical hydroalcoholic extracts used to make
products for human consumption. A lipophilic extract of
the plant showed relatively weak (35 g/mL) ER binding
on rat uteri (75). Another study also confirmed the ERbinding
activity of an unspecified lipophilic subfraction
on ovariectomized (ovx) rat uterine cells, with no binding
activity seen with a hydroalcoholic extract (76).
Recent reports have contradicted the ER-binding
affinity of black cohosh extracts (4,20,22,77,78). A root extract
tested in an in vitro competitive cytosolic ER (from
livers of ovx rat) binding assay with diethylstilbestrol
(50), an inhibitor of estrogen binding, showed a significant
inhibition of estradiol binding in the presence of diethylstilbestrol
(77). However, no binding was demonstrated
for the black cohosh extract. A hydroalcoholic A. racemosa
rhizome extract (50% aqueous ethanol) was assayed for
ER binding in intact human breast cancer cell lines MCF-7
and T-47-D. Again no binding affinity was shown for the
black cohosh extract. However, binding activity was evident
for other hydroalcoholic plant extracts, such as red
clover (78). In another study, a high concentration (200g/
mL) methanol extract of black cohosh displayed no binding
affinity for recombinant diluted ER- and ER- (20).
A study using BNO 1055 showed contrasting results
(79). The extract displayed dose-dependent competition
with radio-labeled estradiol in both a porcine and human
endometrial cytosolic ER ligand-binding assay system.
However, the extract did not displace human recombinant
ER- and ER-. These contradictory findings prompted
the authors to suggest that their product contains estrogenic
compounds that have binding affinity for a putative
ER-. The absence of a direct estrogenic effect was again
confirmed in a human study (21). Postmenopausal Women
took black cohosh extract for 12 weeks followed by a 12-
week washout. Black cohosh demonstrated no effect on
estrogenic markers in serum and no effect on pS2 or cellular
morphology in nipple aspirate fluid (21).
As with the receptor-binding assays, the nature of the extract
or fraction is a decisive factor in the expression of
ERs. A lipophilic and hydrophilic black cohosh extract
was studied for luciferase expression in a MCF-7 – and
-ER expressing subclone (80). The lipophilic extract at
35 g/mL activated transcription of the estrogen regulated
genes, while the hydrophilic extract showed no
activity. A recent study measuring an extract at a low concentration
(4.75 g/L) increased ER levels in human MCF-
7 cells as did estradiol (81). An unspecified black cohosh
extract tested in a transient gene expression assay using
HeLa cells co-transfected with an estrogen-dependent reporter
plasmid in the presence of human ER- or ER-
cDNA failed to show transactivation of the gene (82).
Plasma Hormone Levels
The effect of black cohosh on serum concentrations of FSH
and LH has been studied extensively. Crude alcoholic extracts
suppressed plasma LH with no effect on FSH in
ovx rats (75,77). Further fractionation of the crude extract
resulted in activity of the lipophilic fraction while
the hydrophilic fractions were devoid of this activity (74).
A later study in rats using lipophilic and hydrophilic extracts
at high doses (140 and 216 mg/rat, IP) resulted in
LH suppression with a single injection administration of
the lipophilic but not the hydrophilic extract (75). Another
study reported LH suppression in ovx rats with
an unspecified dose of black cohosh extract (83). A recent
study compared the effect of BNO 1055 with that
of estradiol on LH levels (79). Extract administered subcutaneously
at a dosage of 60 mg/day for 7 days was
reported to reduce LH levels in the treated animals. However,
another study reported no estrogen agonistic effects
on FSH, LH, or prolactin levels in ovx rats using the 7,12-
Dimethylbenz(a)anthracene model following 7 weeks of
daily administration of a 40% isopropanolic extract of the
plant (Remifemin) (84).
The effect of black cohosh on prolactin secretion in pituitary
cell cultures was measured using an unspecified
extract (85). Basal and Thyrotropin-releasing hormone
(TRH)-stimulated prolactin levels were significantly reduced
at doses of 10 and 100 g/mL. This effect was
reversed by the addition of haloperidol (D2-antagonist) to
the cell cultures, suggesting dopaminergic regulation of
hormone secretion by black cohosh.
The black cohosh extract BNO 1055 (60 mg/rat, SC) has
been shown to increase the expression of collagen I and
osteocalcin in rats in a manner similar to that produced
by 8 g of estradiol in ovx rats (79). An additional study
using BNO 1055 demonstrated an osteoprotective effect
as shown by a reduced loss of bone mineral density in
rat tibia after 3 months of administration (81). A study
using an unspecified isopropanol extract of black cohosh
showed reduced urinary markers of bone loss. The authors
64 Fabricant et al.
Table 1 Selected Black Cohosh Clinical Studies
Author (reference no.) Year Extract/formulation/dosage Study length N Outcome measure/result Study design
Kessel Kaul (110) 1957 Remifemin R
60 drops 2 wk 63 Alleviation of climacteric complaints in 95%
Schotten (111) 1958 Remifemin 20 drops 3–4 wk 22 Alleviation of neurovegetative and psychic
complaints associated with menopause and
Foldes (53) 1959 Remifemin, 3 tablets/day Unknown 41 31 patients of the verum group responded
to the treatment with a decrease in
Starfinger (112) 1960 Remifemin, 3–20 drops/day 1 yr 105 Decreased climacteric complaints without
incidence of side effects or resulting in
non physiological bleeding
Brucker (113) 1960 Remifemin, tablets, variable
Variable 87 (517) Alleviation of menopausal complaints Case series
Heizer (114) 1960 Remifemin, tablets 3–6/day 2–18 mo 66 Alleviation of menopausal (neurovegetative
and psychic) complaints in 47% of patients
with intact uteri and 35% with
Gorlich (115) 1962 Remifemin, tablets, variable
Variable 41 (258) Alleviation of climacteric and vascular
symptoms in 85% of patients
Schildge (116) 1964 Remifemin, fluid extract
Variable 135 Euphoric and mild sedative-calming effects
in all pts
Stolze (117) 1982 Remifemin, fluid extract
6–8 wk 629 Alleviation of neurovegetative and
psychological menopausal symptoms in
80% of patients
Daiber (118) 1983 Remifemin, fluid extract
12 wk 36 Alleviation of climacteric complaints (hot
flashes, insomnia, sweating, and
Open, KMI, CGI
Vorberg (119) 1984 Remifemin, fluid extract
12 wk 50 Significant or highly significant alleviation of
menopausal (neurovegetative and psychic)
complaints; study included subjects
contraindicated to hormone therapy
open, KMI, CGI,
Warnecke (120) 1985 Remifemin, fluid extract
12 wk 20 Significant alleviation of symptoms (psychic
and neurovegetative) in the black cohosh,
conjugated estrogen, and diazepam groups.
Vaginal cytology of treatment group was
comparable to estrogenic stimulation
open, KMI, HAM-A,
Stoll (121) 1987 Remifemin, tablets
equivalent to 8 mg
12 wk 26 Significant alleviation of climacteric
symptoms (vaginal atrophy, neurovegetative
and psychic complaints) in comparison with
estrogen and placebo groups
Petho (122) 1987 Remifemin, tablets,
6 mo 50 KMI decreased significantly from 17.6 to
9.2, correlates with a significant reduction
in neurovegetative symptoms. Severity of
subjective self-assessments of subjects
physical and psychological symptoms
Open, KMI, patient
and Riedel (123)
1988 Remifemin, tablets
equivalent to 8 mg
6 mo 15 Significant alleviation of climacteric
symptoms in black cohosh and drug
treatment groups. No significant change in
gonadotropin (FSH, LH) levels
Duker et al. (75) 1991 Remifemin, tablets
equivalent to 40 mg dried
2 mo 110 LH suppression In vitro study using
Black Cohosh 65
Table 1 Selected Black Cohosh Clinical Studies (Continued)
Author (reference no.) Year Extract/formulation/dosage Study length N Outcome measure/result Study design
1995 Cimisan R
4–8 wk 157 89% of patients showed symptom improvement
after 4 wk. At final visit, the efficacy was assessed
as very good, 40%; good, 41%; sufficient, 12%;
Mielnik (69) 1997 Uncharacterized extract,
4 mg daily
6 mo 34 Alleviation of climacteric (neurovegetative)
symptoms in 76% of patients after 1 mo
1997 Uncharacterized extract,
3 mo 50 Alleviation of climacteric symptoms in 90% of
patients. Increase in vaginal cell proliferation
(VMI) in 40% of treated women
Nesselhut and Liske
1999 Remifemin, tablets,
equivalent to 136 mg dried
3 mo 28 Good to very good alleviation of 10 menopausal
symptoms in 80% of study participants
Jacobson, et al. (63) 2001 Remifemin, tablets
equivalent to 40 mg dried
60 days 42a No change in median number or intensity of hot
Liske et al. (67) 2002 Unique Cimicifuga
equivalent to 39 or
6 mo 152 No direct systemic estrogenic effect on serum
levels of FSH, LH, SHBG, prolactin, and 17-
estradiol. No change in vaginal cytology. Higher
dose had a more significant reduction in KM
index after 6 mo. Significant reduction with both
doses in neurovegetative and psychic complaints
trial, KMI, SDS,
Hernandez Munoz and
2003 BNO 1055 12 mo 136 Combination therapy with tamoxifen (20 mg)
reduced severity and incidence of hot flashes
Wuttke et al. (64) 2003 Klimadynon R
/BNO 1055 3 mo 62 Equipotent to 0.6 CE for relief of climacteric
complaints and for bone resorption. No effect on
Verhoeven et al.
2005 125 mg soy extract daily
(providing 50 mg
isoflavones including 24 mg
genistein and 21.5 mg
daidzein), 1500 mg evening
primrose oil extract
(providing 150 mg gamma
linoleic acid), 100 mg
Actaea racemosa L. extract
(providing 8 mg
deoxyacetein), 200 mg
calcium, 1.25 mg vitamin D,
and 10 IU vitamin E,
placebo group received
2000 mg olive oil daily
12 wk 124 Subjects were experiencing at least five
vasomotor symptoms every 24 hr at study entry.
At weeks 6 and 12, all scores in both groups had
improved compared with baseline, though the
overall difference in scores between the groups
was not statistically significant
index and Greene
Nappi et al. (127) 2005 Aqueous isopropanolic
extract 40 mg/day
3 mo 64 Postmenopausal women were recruited. Both CR
and low-dose TTSE2 significantly reduced the
number of hot flushes per day (P < 0.001) and
vasomotor symptoms (P < 0.001), starting at
the first month of treatment. Such a positive
effect was maintained throughout the 3 mo of
observation, without any significant difference
between the two treatments. An identical effect
was evident also for both anxiety (P < 0.001)
and depression (P < 0.001), which were
significantly reduced following 3 mo of both CR
and low-dose TTSE2. Total cholesterol was
unchanged by CR treatment but significantly
(P < 0.033) reduced by 3 mo of low-dose TTSE2.
A slight but significant increase of HDL cholesterol
66 Fabricant et al.
Table 1 Selected Black Cohosh Clinical Studies (Continued)
Author (reference no.) Year Extract/formulation/dosage Study length N Outcome measure/result Study design
(P < 0.04) was found only in women treated with
CR, while LDL-cholesterol levels were significantly
lowered by 3 mo of both CR (P < 0.003) and
low-dose TTSE2 (P < 0.002). Triglyceride levels
were not affected by both treatments nor was liver
function. FSH, LH, and cortisol were not
significantly affected after the 3-mo treatment,
while PRL (P < 0.005) and 17–E2 (P <
0.001) were increased slightly only by low-dose
TTSE2. Endometrial thickness was not affected by
either CR or low-dose TTSE2
Frei-Kleiner et al.
2005 6.5 mg dry rhizome extract;
60% ethanol extraction
solvent. Dose = 1 cap daily
12 wk 122 Menopausal women were recruited. The primary
efficacy analysis showed no superiority of the
tested black cohosh extract compared with
placebo. However, in the subgroup of patients
with a Kupperman index > or = 20 a significant
superiority regarding this index could be
demonstrated (P < 0.018). A decrease of 47%
and 21% was observed in the black cohosh and
placebo group, respectively. The weekly weighted
scores of hot flashes (P < 0.052) and the
Menopause Rating Scale (P < 0.009) showed
similar results. Prevalence and intensity of the
adverse events did not differ in the two treatment
Pockaj et al. (61) 2006 20 mg C. racemosa and
rhizome extract standardized
to contain 1 mg of triterpene
glycosides as calculated by
132 Toxicity was minimal and not different by
treatment group. Patients receiving black cohosh
reported a mean decrease in hot flash score of
20% (comparing the fourth treatment week with
the baseline week) compared with a 27%
decrease for patients on placebo (P = 0.53).
Mean hot flash frequency was reduced 17% on
black cohosh and 26% on placebo (P = 0.36).
Patient treatment preferences were measured
after completion of both treatment periods by
ascertaining which treatment period, if any, the
patient preferred. Thirty-four percent of patients
preferred the black cohosh treatment, 38%
preferred the placebo, and 28% did not prefer
trial. Primary end
point was the
flash score (a
average daily hot
flash severity and
the baseline week
and the last study
week of the first
Newton et al. (HALT)
2006 (i) Black cohosh, 160 mg
daily; (ii) multi botanical with
black cohosh, 200 mg daily,
and 9 other ingredients;
(iii) multi botanical plus
dietary soy counseling;
(iv) conjugated equine
estrogen, 0.625 mg daily,
with or without
acetate, 2.5 mg daily; or
1 yr 351 Women aged 45–55 yr with two or more
vasomotor symptoms per day were recruited.
Vasomotor symptoms per day, symptom intensity,
Wiklund Vasomotor Symptom Subscale score did
not differ between the herbal interventions and
placebo at 3, 6, or 12 mo or for the average over
all the follow-up time points (P > 0.05 for all
comparisons) with 1 exception: At 12 mo,
symptom intensity was significantly worse with
the multi botanical plus soy intervention than with
placebo (P > 0.016). The difference in
vasomotor symptoms per day between placebo
and any of the herbal treatments at any time
point was less than one symptom per day; for the
average over all the follow-up time points, the
difference was less than 0.55 symptom per day.
The difference for hormone therapy versus
placebo was −4.06 vasomotor symptoms per day
for the average over all the follow-up time points
(95% CI, −5.93 to −2.19 symptoms per day;
Black Cohosh 67
Table 1 Selected Black Cohosh Clinical Studies (Continued)
P > 0.001). Differences between treatment
groups smaller than 1.5 vasomotor
symptoms per day cannot be ruled out.
Black cohosh containing therapies had no
demonstrable effects on lipids, glucose,
insulin, or fibrinogen (124)
Raus et al. (129) 2006 Dried aqueous/ethanolic
(58% vol/vol) extract CR
BNO 1055 of the rhizome of
Actaea or CR (black cohosh)
1 yr 400 Postmenopausal women with symptoms
related to estrogen deficiency were
recruited. The lack of endometrial
proliferation and improvement of climacteric
complaints as well as only a few gynecologic
organ-related adverse events are reported
for the first time after a treatment period of
Sammartino et al.
2006 Group A (n = 40) was
treated with 1 tablet/day
per os containing a
combination of isoflavones
[soy germ extracts, Glycine
max, no OGM-SoyLife:
150 mg, titrated in
isoflavones (40%) =
60 mg], lignans [flaxseed
OGM-LinumLife: 100 mg,
titrated in lignans (20%) =
20 mg] and C. racemosa
[50 mg, titrated in
triterpene (2.5%) =
1.25 mg] (Euclim R
Wassermann, Italy); group B
(n = 40) was treated with
of 28 days
80 Healthy postmenopausal women were
recruited. At baseline no significant
difference was detected in KI between
groups A and B; however, after three cycles
of treatment, KI was significantly (P >
0.05) lower in group A compared with
baseline and with group B
Gurley et al. (131) 2006 Milk thistle (300 mg, three
times daily, standardized to
contain 80% silymarin),
black cohosh extract
(20 mg, twice daily,
standardized to 2.5%
rifampin (300 mg, twice
daily), and clarithromycin
(500 mg, twice daily)
14 days 16 Young adults (8 females) (age, mean °æ
SD = 26 °æ 5 yr; weight, 75 °æ 13 kg)
compared with the effects of rifampin and
clarithromycin, the botanical supplements
milk thistle and black cohosh produced no
significant changes in the disposition of
digoxin, a clinically recognized P-gp
substrate with a narrow therapeutic index.
Accordingly, these two supplements appear
to pose no clinically significant risk for
P-gp-mediated herb–drug interactions
Rebbeck et al. (132) 2007 Varied Case-control
HRS varied significantly by race, with African
American women being more likely than
European American women to use any
herbal preparation (19.2% vs. 14.7%, P =
0.003) as well as specific preparations
including black cohosh (5.4% vs. 2.0%,
P > 0.003), ginseng (12.5% vs. 7.9%,
P < 0.001) and red clover (4.7% vs. 0.6%,
P < 0.001). Use of black cohosh had a
significant breast cancer protective effect
(adjusted odds ratio 0.39, 95% CI:
0.22–0.70). This association was similar
among women who reported use of either
black cohosh or Remifemin (a herbal
preparation derived from black cohosh;
adjusted odds ratio 0.47, 95% CI:
68 Fabricant et al.
Table 1 Selected Black Cohosh Clinical Studies (Continued)
Hirschberg et al.
2007 Remifemin (batch no.
229690), one tablet twice
daily. Each tablet contains
0.018–0.026 mL liquid
extract of black cohosh
corresponding to 20 mg
herbal drug [i.e., 2.5 mg dry
extract, extraction agent
isopropanol 40% (vol/vol)],
6 mo 74 None of the women showed any increase
in mammographic breast density.
Furthermore, there was no increase in
breast cell proliferation. The mean change
°æ SD in proportion of Ki-67-positive cells
was 0.5% °æ 2.4% (median, 0.0; 95%
CI=−1.32–0.34) for paired samples.
The mean change in endometrial thickness
°æ SD was 0.0 °æ 0.9 mm (median, 0.0). A
modest number of adverse events were
possibly related to treatment, but none of
these were serious. Laboratory findings
and vital signs were normal
Chung et al. (71) 2007 Gynoplus (264 mg tablet
with 0.0364 mL Cimicifuga
equivalent to 1 mg terpene
glycosides; 84 mg dried
extract, equivalent to 0.25
mg hypericin, with 80%
12 wk 89 Kupperman index (KI) for climacteric
complaints. Vaginal maturation indices,
serum estradiol, FSH, LH, total cholesterol,
HDL-cholesterol, LDL-cholesterol, and
triglyceride levels. Significant
improvements in climacteric symptoms
and hot flashes, as well as an increase in
HDL (from 58.32 °æ 11.64 to 59.74 °æ
10.54) were observed in the Gynoplus
group by 4 wk and maintained after 12 wk,
compared with the placebo group. There
was no significant impact on superficial
Ruhlen et al. (22) 2007 Remifemin R and CimiPure
(2.5% triterpenes; 40 mg
capsule contains 1 mg
61 Subjects experienced relief of menopausal
symptoms, with reversion to baseline after
washout. No effect on serum estrogenic
markers. No effect on pS2 or cell
morphology in nipple aspirate
Gurley et al. (134) 2008 Milk thistle (300 mg, three
times daily, standardized to
contain 80% silymarin),
black cohosh extract
(40 mg, twice daily,
standardized to 2.5%
rifampin (300 mg, twice
daily), and clarithromycin
(500 mg, twice daily)
14 days 19 Young adults [9 women; age (mean °æ SD)
= 28 °æ 6 yr; weight = 76.5 °æ 16.4 kg].
Milk thistle and black cohosh appear to
have no clinically relevant effect on CYP3A
activity in vivo. Neither spontaneous
reports from study participants nor their
responses to questions asked by study
nurses regarding supplement/medication
usage revealed any serious adverse events
Amsterdam et al. (73) 2009 12 wk 28 (15
The primary outcome measure was
changed over time in total HAM-A scores.
Secondary outcomes included a change in
scores on the Beck Anxiety Inventory,
Green Climacteric Scale (GCS), and
Psychological General Well-Being Index
(PGWBI) and the proportion of patients
with a change of 50% or higher in baseline
HAM-A scores. There was neither a
significant group difference in change over
time in total HAM-A scores (P = 0.294)
nor a group difference in the proportion of
subjects with a reduction of 50% or higher
in baseline HAM-A scores at study end
point (P = 0.79). There was a significantly
greater reduction in the total GCS scores
during placebo (vs. black cohosh; P =
0.035) but no group difference in change
over time in the GCS subscale scores or in
the PGWBI (P = 0.140). One subject
(3.6%) taking black cohosh discontinued
treatment because of adverse events
Black Cohosh 69
Table 1 Selected Black Cohosh Clinical Studies (Continued)
Geller et al. (72) 2009 12 mo 89 Primary outcome measures were reduction
in vasomotor symptoms (hot flashes and
night sweats) by black cohosh and red
clover compared with placebo; secondary
outcomes included safety evaluation,
reduction of somatic symptoms, relief of
sexual dysfunction, and overall improvement
in quality of life. Reductions in number of
vasomotor symptoms after a 12-mo
intervention were as follows: black cohosh
(34%), red clover (57%), placebo (63%),
and CEE/MPA (94%), with only CEE/MPA
differing significantly from placebo. Black
cohosh and red clover did not significantly
reduce the frequency of vasomotor
symptoms as compared with placebo.
Secondary measures indicated that both
botanicals were safe as administered. In
general, there were no improvements in
other menopausal symptoms
Studies listed by year of publication.
aAll with breast cancer history.
Abbreviations: CGI, Clinician’s Global Impression scale; HAM-A, Hamilton Anxiety scale; KMI, Kupperman Menopausal Index; MSS, unspecified menopausal index
using the Likert scale; Open, open-labeled; POMS, Profile of Mood States Scale; SDS, Self-Assessment Depression scale; VAS, Visual Analog Scale; VMI, Vaginal
of this study suggested the action was similar to that of the
SERM Raloxifene (86).Afollow-up study using BNO 1055
versus CE therapy showed beneficial effects of the extract
on bone metabolism in humans, specifically an increase in
bone-specific alkaline phosphatase in serum(64). While no
direct correlation between species has been established, it
is of note that studies of Asian Cimicifuga species have
demonstrated similar activity and may be of importance
for further investigation of this biological activity (87,88).
Uterine Weight/Estrous Induction
Uterine and ovarian weight increase, cell cornification,
and an increased duration of estrous are generally considered
evidence of endometrial estrogenic activity. However,
it has recently been proposed that uterine weight
is a poor marker for endometrial effects (89). Three studies
demonstrating that black cohosh extracts increased the
uterine weight of ovx rats have been reported (50,77,90)
with two of the studies using an undescribed root extract
(77,90). One study on immature mice reported similar
findings (50). By contrast, two studies on ovx rats
(79,91), as well as four studies on immature mice, reported
the converse (79,81,83,92). One of these studies
found that although there was no increase in uterine or
ovarian weight, the duration of estrous was significantly
increased by black cohosh (92). A subsequent study by the
authors and collaborators demonstrated no attenuation
in uterine weight at variable doses (4, 40, and 400 mg/
kg/day) of a 40% isopropanol extract in ovx rats (4).
An unspecified black cohosh extract failed to significantly
induce growth of MCF-7 cells when compared with untreated
control cells (81). A study using isopropanolic and
ethanolic extracts also failed to induce growth of MCF-7
CNS Effects and Neurotransmitter Binding
A murine study using an unspecified extract (25–100
mg/kg, orally) measured effects on body temperature and
ketamine-induced sleep time using bromocriptine (D2–
agonist) as a positive control. Pretreatment with sulpiride
(D2 blocker) suggested a receptor-mediated dopaminergic
effect (84). An additional mouse study was carried
out to characterize neurotransmitter levels in the striatum
and hippocampus after pretreatment with the extract
for 21 days (94). Serotonin and dopamine metabolic levels
in the striatum were substantially lower in comparison
with the control group. These studies have led to
the hypothesis that dopaminergic, rather than estrogenic,
activity is responsible for the reported success of black cohosh
in reducing climacteric symptoms (95,96). A study
by the authors and collaborators has pointed to the effects
of black cohosh being mediated by serotonin (5-HT)
receptors (4). Three different extracts (100% methanol,
40% isopropanol, 75% ethanol) were found to bind to the
5-HT7-receptor subtype at IC50 ≤ 3.12 g/mL. The 40%
isopropanol extract inhibited (3H)-lysergic acid diethylamide
binding to the 5-HT7 receptor with greater potency
than (3H)-8-hydroxy-2(di-N-propylamino)tetralin to the
rat 5-HT1A. Analysis of ligand-binding data suggests that
the methanol extract functioned as a mixed competitive
ligand of the 5HT7 receptor. Further testing of the
methanol extract in 293T-5-HT7 transfected HEK cells
raised cAMP levels; these raised levels were reversed in
the presence of the 5-HT antagonist methiothepin, indicating
a receptor-mediated process and possible agonist
activity local to the receptor (4).
70 Fabricant et al.
A black cohosh methanol extract protected S30 breast cancer
cells against menadione-inducedDNAdamage at variable
concentrations and scavenged DPPH free radicals at
a concentration of 99 M (38).
USE IN PREGNANT/LACTATING WOMEN
Despite an absence of mutagenic effects reported to date,
the use of black cohosh during pregnancy is contraindicated
according toWHOsuggestions (97). Data are inconclusive
regarding the effects on lactation.
Recommended doses for black cohosh are as follows:
1. Dried rhizome and root: 1 g up to three times daily.
2. Tincture (1:10): 0.4 mL daily (40–60% alcohol vol/vol).
3. Fluid extract (1:1): 20 drops twice daily (60% ethanol
vol/vol, equivalent to 40 mg dried herb).
4. Tablet equivalence: two tablets a day (equivalent to
40 mg dried extract).
The Commission E monograph also recommends
that usage not be extended for more than 6 months due to
a lack of long-term safety data. Experimental data are not
available to suggest this 6-month limit.
ADVERSE EFFECTS SAFETY
A majority of adverse event reports (AERs) for black
cohosh have been associated with Remifemin products,
probably due to its widespread use. Thus, the AER data
may speak more to the safety of this particular product
rather than black cohosh extracts in general. In clinical
trials, minor cases of nausea, vomiting, dizziness, and
headaches have been reported (61–73). An analysis of the
safety data from published clinical trials, case studies,
postmarketing surveillance studies, spontaneous report
programs, and phase I studies was carried out (99). The
data obtained from more than 20 studies, including more
than 2000 patients, suggest that adverse event occurrence
with black cohosh is rare, and that such events are mild
and reversible, the most common being gastrointestinal
upset and rashes. The same review investigated black cohosh
preparation and AERs and concluded that adverse
events are rare, mild, and reversible (99).
That said, black cohosh has garnered a great deal of
attention with respect to its safety over the past 5 years,
with the emergence of a few case reports citing acute hepatitis,
convulsions, cardiovascular, and circulatory insult
(100–104). It is important to note that in a number of
these reports, no effort was made to positively identify
the botanical associated with the event as black cohosh.
In one case, depositions taken during a legal proceeding
revealed that the lack of alcohol consumption and concomitant
medications reported in a published case report
(101) was inaccurate (105). Underreporting of adverse effects
may also be a common problem with botanical supplement
(100–104). However, these case reports have generated
much interest within the research community, so
much so that two workshops have been convened by the
National Institutes of Health (NIH) on the specific issue
of the safety of black cohosh preparations: one workshop
sponsored by the National Center for Complementary and
Alternative Medicine (NCCAM) and the Office of Dietary
Supplements (ODS) in November 2004 and a more recent
workshop sponsored by the ODS held in June 2007. The
report from the 2004 workshop indicated that there is “no
plausible mechanism of liver toxicity.” The 2007 workshop
offered no conclusions on safety to contradict those
of the 2004 meeting regarding hepatotoxicity of black cohosh
preparations. The 2007 workshop did recommend
that active steps be taken to monitor liver health in human
clinical trials of black cohosh (106).
It is also noteworthy that in the 2004 workshop, it
was agreed that “suspected hepatotoxicity should not be
broadcast when toxicity has not been demonstrated.” Despite
concerns by some scientists, a warning statement on
commercial black cohosh product labels was mandated
in Australia by the Therapeutic Goods Administration
(TGA), and the European Medicines Agency (EMEA) released
a press statement on July 18, 2006, urging patients
to stop taking black cohosh if they develop signs suggestive
of liver injury. It is noteworthy that it is not clear and
has never been fully disclosed as to how these agencies
reached their decision and what the scientific data were
that led to these warning statements.
While the notion of idiosyncratic hepatotoxicity was
raised in the June 2007 workshop by toxicologists from the
Food and Drug Administration (FDA), it was acknowledged
by these toxicologists that without data from a
mandatory adverse event reporting system, no real conclusion
on causality regarding idiosyncratic hepatotoxicity
can be drawn from case reports.
In the September–October 2007 edition of USP’s
Pharmacopeial Forum (100), the USP proposed the addition
of a cautionary statement for USP quality black
cohosh products with regard to liver toxicity. The American
Botanical Council (ABC) responded that given the
long history of safe black cohosh use and the lack of clear
scientific evidence for toxicity, there is not enough information
for such a warning. The ABC noted that of the 42
case reports of toxicity cited by the USP, only 18 met criteria
for assessment based on a standard-rating scale, and
of these, 3 met criteria for “possible” toxicity, and 2 for
“probable” toxicity. Many case reports were also said to
lack adequate documentation regarding the actual identity
of the black cohosh used and possible confounding
COMPENDIAL REGULATORY STATUS
Black cohosh products are regulated and marketed in the
United States as dietary supplements under the provisions
of the Dietary Supplement Health and Education
Act (DSHEA) of 1994 (U.S.C. § 321). Dried black cohosh
fluid extract, powdered black cohosh extract, and black
cohosh tablets now have official standing in dietary supplement
monographs in the United States Pharmacopoeia-–
National Formulary (108). In the European Union nations,
Black Cohosh 71
black cohosh products are approved as nonprescription
phytomedicines when administered orally in compliance
with the German Commission E monographs (109).
With the elevated concern surrounding side effects
related to classical hormone/estrogen therapy for
menopause, modulation of certain climacteric symptoms
of menopause by both dopaminergic and serotonergic
drugs is becoming a more viable and frequent treatment
option. A review of the clinical trials associated with black
cohosh leads to the conclusion that women using hydroalcoholic
extracts of the rhizomes and roots of this plant may
gain relief from climacteric symptoms (i.e., hot flashes)
in comparison with placebo over the short term, whereas
longer studies have not shown the same degree of efficacy.
Further clouding the review of these clinical trials is the
wide variety and different types of extracts administered
in published studies. Early in vitro studies reported that
black cohosh extracts acted on ERs or had a sort direct
effect on ERs. Now it is becoming clear that the beneficial
effect of reducing hot flashes is related, at least in
part, to serotonergic or dopaminergic mechanisms that
regulate hypothalamic control and possibly mediate estrogenic
mechanisms. As mentioned earlier, the controversy
surrounding a purported direct estrogenic mechanism of
action may also be due to variance in the extracts assayed.
Overall, given variation in trial length, extract types, and
other potential confounders, the efficacy of black cohosh
as a treatment for menopausal symptoms is uncertain and
further rigorous trials seem warranted.
1. Ravdin PM, Cronin KA, Howlader N, et al. The decrease in
breast-cancer incidence in 2003 in the United States. N Engl
J Med 2007; 356(16):1670–1674.
2. Nelson HD,Humphrey LL, Nygren P, et al. Postmenopausal
hormone replacement therapy: scientific review. JAMA
3. Rhyu MR, Lu J,Webster DE, et al. Black cohosh (Actaea racemosa,
Cimicifuga racemosa) behaves as a mixed competitive
ligand and partial agonist at the human mu opiate receptor.
J Agric Food Chem 2006; 54(26):9852–9857.
4. Burdette JE, Liu J, Chen SN, et al. Black cohosh acts as a
mixed competitive ligand and partial agonist of the serotonin
receptor. J Agric Food Chem 2003; 51(19):5661–5670.
5. Farnsworth NR. NAPRALERT Database. Chicago, IL: University
of Illinois at Chicago, 2003. http://www.napralert
.org. Accessed May 3, 2010.
6. Chen SN, Lankin DC, Nikolic D, et al. Chlorination diversifies
Cimicifuga racemosa triterpene glycosides. J Nat Prod
7. Qiu SX, Dan C, Ding LS, et al. A triterpene glycoside from
black cohosh that inhibits osteoclastogenesis by modulating
RANKL and TNF-alpha signaling pathways. Chem Biol
8. Jiang B, Kronenberg F, Nuntanakorn P, et al. Evaluation
of the botanical authenticity and phytochemical profile
of black cohosh products by high-performance liquid
chromatography with selected ion monitoring liquid
chromatography-mass spectrometry. J Agric Food Chem
9. He K, Pauli GF, Zheng B, et al. Cimicifuga species identification
by high performance liquid chromatographyphotodiode
array/mass spectrometric/evaporative light
scattering detection for quality control of black cohosh
products. J Chromatogr A 2006; 1112(1–2):241–254.
10. Lai GF,Wang YF, Fan LM, et al. Triterpenoid glycoside from
Cimicifuga racemosa. J Asian Nat Prod Res 2005; 7(5):695–699.
11. Chen SN, LiW, Fabricant DS, et al. Isolation, structure elucidation,
and absolute configuration of 26-deoxyactein from
Cimicifuga racemosa and clarification of nomenclature associated
with 27-deoxyactein. J Nat Prod 2002; 65(4):601–605.
12. Wang HK, Sakurai N, Shih CY, et al. LC/TIS-MS fingerprint
profiling of Cimicifuga species and analysis of 23-epi-26-
deoxyactein in Cimicifuga racemosa commercial products. J
Agric Food Chem 2005; 53(5):1379–1386.
13. van Breemen RB, Liang W, Banuvar S, et al. Pharmacokinetics
of 23-epi-26-deoxyactein in women after oral administration
of a standardized extract of black cohosh. Clin
Pharmacol Ther 2010; 87(2):219–225.
14. Sun LR, Qing C, Zhang YL, et al. Cimicifoetisides A and B,
two cytotoxic cycloartane triterpenoid glycosides from the
rhizomes of Cimicifuga foetida, inhibit proliferation of cancer
cells. Beilstein J Org Chem 2007; 3:3.
15. Li JX, Yu ZY. Cimicifugae rhizoma: from origins, bioactive
constituents to clinical outcomes. Curr Med Chem 2006;
16. Tian Z, Pan RL, Si J, et al. Cytotoxicity of cycloartane triterpenoids
from aerial part of Cimicifuga foetida. Fitoterapia
17. Tsukamoto S, Aburatani M, Ohta T. Isolation of CYP3A4
inhibitors from the black cohosh (Cimicifuga racemosa). Evid
Based Complement Alternat Med 2005; 2(2):223–226.
18. Onorato J, Henion JD. Evaluation of triterpene glycoside
estrogenic activity using LC/MS and immunoaffinity extraction.
Anal Chem 2001; 73(19):4704–4710.
19. Stute P, Nisslein T, G¨ otte M, et al. Effects of black cohosh
on estrogen biosynthesis in normal breast tissue in vitro.
Maturitas 2007; 57(4):382–391.
20. Kretzschmar G, Nisslein T, Zierau O, et al. No estrogen-like
effects of an isopropanolic extract of rhizoma Cimicifugae
racemosae on uterus and vena cava of rats after 17 day treatment.
J Steroid Biochem Mol Biol 2005; 97(3):271–277.
21. Liu J, Burdette JE, Xu H, et al. Evaluation of estrogenic
activity of plant extracts for the potential treatment
of menopausal symptoms. J Agric Food Chem 2001;
22. Ruhlen RL, Haubner J, Tracy JK, et al. Black cohosh does not
exert an estrogenic effect on the breast. Nutr Cancer 2007;
23. Gaube F, Wolfl S, Pusch L, et al. Gene expression profiling
reveals effects of Cimicifuga racemosa (L.) NUTT. (black cohosh)
on the estrogen receptor positive human breast cancer
cell line MCF-7. BMC Pharmacol 2007; 7(1):11.
24. Li W, Sun Y, Liang W, et al. Identification of caffeic acid
derivatives in Actaea racemosa (Cimicifuga racemosa, black cohosh)
by liquid chromatography/tandem mass spectrometry.
Rapid Commun Mass Spectrom 2003; 17(9):978–982.
25. Nuntanakorn P, Jiang B, Einbond LS, et al. Polyphenolic
constituents of Actaea racemosa. J Nat Prod 2006; 69(3):314–
26. Hostanska K, Nisslein T, Freudenstein J, et al. Evaluation
of cell death caused by triterpene glycosides and phenolic
substances from Cimicifuga racemosa extract in human MCF-
7 breast cancer cells. Biol Pharm Bull 2004; 27(12):1970–1975.
27. Gumbinger HG,WinterhoffH, Sourgens H, et al. Formation
of compounds with antigonadotropic activity from inactive
phenolic precursors. Contraception 1981; 23(6):661–666.
28. Winterhoff H, Gumbinger HG, Sourgens H. On the antigonadotropic
activity of Lithospermum and Lycopus species
72 Fabricant et al.
and some of their phenolic constituents. Planta Med 1988;
29. Andary C. Caffeic acid glucoside esters and their pharmacology.
In: Scalbert A, ed. Polyphenolic Phenomena. Paris:
INRA Editions, 1993:237–245.
30. Ortiz de Urbina JJ, Martin ML, Sevilla MA, et al. Antispasmodic
activity on rat smooth muscle of polyphenol compounds
caffeic and protocatechic acids. Phytother Res 1990;
31. Trute A, Gross J, Mutschler E, et al. In vitro antispasmodic
compounds of the dry extract obtained from Hedera helix.
Planta Med 1997; 63(2):125–129.
32. Saturnino PC, Saturnino A, De Martino C, et al. Flavonol
glycosides from Aristeguietia discolor and their inhibitory
activity on electrically-stimulated guinea pig ileum. Int J
Pharmacogn 1997; 35(5):305–312.
33. Okamoto R, Sakamoto S, Noguchi K. Effects of ferulic acid
on FSH, LH and prolactin levels in serum and pituitary tissue
of male rats (author’s transl). Nippon Naibunpi Gakkai
Zasshi 1976; 52(9):953–958.
34. de Man E, Peeke HV. Dietary ferulic acid, biochanin A,
and the inhibition of reproductive behavior in Japanese
quail (Coturnix coturnix). Pharmacol Biochem Behav 1982;
35. Gorewit RC. Pituitary and thyroid hormone responses of
heifers after ferulic acid administration. J Dairy Sci 1983;
36. Ozaki Y, Ma JP. Inhibitory effects of tetramethylpyrazine
and ferulic acid on spontaneous movement of rat uterus in
situ. Chem Pharm Bull (Tokyo) 1990; 38(6):1620–1623.
37. Kruse SO, L¨ohning A, Pauli GF, et al. Fukiic and piscidic
acid esters from the rhizome of Cimicifuga racemosa and the
in vitro estrogenic activity of fukinolic acid. Planta Med
38. Stromeier S, Petereit F, Nahrstedt A. Phenolic esters from
the rhizomes of Cimicifuga racemosa do not cause proliferation
effects in MCF-7 cells. Planta Med 2005; 71(6):495–
39. Burdette JE, Chen SN, Lu ZZ, et al. Black cohosh (Cimicifuga
racemosa L.) protects against menadione-induced DNA
damage through scavenging of reactive oxygen species:
bioassay-directed isolation and characterization of active
principles. J Agric Food Chem 2002; 50(24):7022–7028.
40. Fabricant DS, Nikolic D, Lankin DC, et al. Cimipronidine,
a cyclic guanidine alkaloid from Cimicifuga racemosa. J Nat
Prod 2005; 68(8):1266–1270.
41. G¨odecke T, Lankin DC, Nikolic D, et al. Guanidine alkaloids
and Pictet–Spengler adducts from black cohosh (Cimicifuga
racemosa) (dagger). J Nat Prod 2009; 72(3):433–437.
42. G¨odecke T, Nikolic D, Lankin DC, et al. Phytochemistry
of cimicifugic acids and associated bases in Cimicifuga
racemosa root extracts. Phytochem Anal 2009; 20(2):120–
43. Dan C, Zhou Y, Ye D, et al. Cimicifugadine from Cimicifuga
foetida, a new class of triterpene alkaloids with novel reactivity.
Org Lett 2007; 9(9):1813–1816.
44. Kusano G. Studies on the constituents of Cimicifuga species.
Yakugaku Zasshi 2001; 121(7):497–521.
45. Struck D, Tegtmeier M, Harnischfeger G. Flavones in extracts
of C. racemosa. Planta Med 1997; 63:289.
46. Panossian A, Danielyan A, Mamikonyan G, et al. Methods
of phytochemical standardisation of rhizoma Cimicifugae
racemosae. Phytochem Anal 2004; 15(2):100–108.
47. Kennelly EJ, Baggett S, Nuntanakorn P, et al. Analysis of
thirteen populations of black cohosh for formononetin. Phytomedicine
48. Fabricant D, Li W, Chen SN, et al. Geographical and diurnal
variation of chemical constituents of Cimicifuga racemosa
(L.) Nutt. In: Botanical Dietary Supplements: Natural Products
at a Crossroad. Asilomar, CA: American Society of Pharmacognosy,
49. Jiang B, Kronenberg F, Balick MJ, et al. Analysis of
formononetin from black cohosh (Actaea racemosa). Phytomedicine
50. Ramsey GW. A comparison of vegetative characteristics of
several genera with those of the genus Cimicfuga (Ranunculaceae).
SIDA 1988; 13(1):57–63.
51. Ramsey GW. Morphological considerations in the North
American Cimicifuga (Ranunculaceae). Castanea 1987;
52. Youngken H. A Textbook of Pharmacognosy. 4th ed. Vol.
xiv. Philadelphia, PA: P. Blakiston’s son and Co, 1936:924.
53. Foldes J. The actions of an extract of C. racemosa. Arzneimittelforschung
54. Nutrition Business Journal, Global Supplement&Nutrition
Industry Report 2007, 2008:381. http://nutritionbusiness
supplement nutrition industry report 2007/. Accessed
May 3, 2010.
55. Swanson CA. Suggested guidelines for articles about botanical
dietary supplements. Am J Clin Nutr 2002; 75(1):
56. Gagnier J, Boon H, Rochon P, et al. Improving the quality of
reporting of randomized controlled trials evaluating herbal
interventions: implementing the CONSORT statement (corrected).
Explore (NY) 2006; 2(2):143–149.
57. Gagnier JJ, Boon H, Rochon P, et al. Recommendations for
reporting randomized controlled trials of herbal interventions:
explanation and elaboration. J Clin Epidemiol 2006;
58. Gagnier JJ, Boon H, Rochon P, et al. Reporting randomized,
controlled trials of herbal interventions: an elaborated
CONSORT statement. Ann Intern Med 2006; 144(5):364–
59. Mills EJ, Wu P, Gagnier J, et al. The quality of randomized
trial reporting in leading medical journals since the revised
CONSORT statement. Contemp Clin Trials 2005; 26(4):480–
60. Nelson HD, Haney E, Humphrey L, et al. Management
of Menopause-Related Symptoms, 2005. http://www.ahrq
.gov/clinic/epcsums/menosum.htm. Accessed May 3,
61. Pockaj BA, Gallagher JG, Loprinzi CL, et al. Phase III
double-blind, randomized, placebo-controlled crossover
trial of black cohosh in the management of hot flashes: NCCTG
Trial N01CC1. J Clin Oncol 2006; 24(18):2836–2841.
62. Newton KM, Reed SD, LaCroix AZ, et al. Treatment of vasomotor
symptoms of menopause with black cohosh, multibotanicals,
soy, hormone therapy, or placebo: a randomized
trial. Ann Intern Med. 2006; 145(12):869–879.
63. Jacobson JS, Troxel AB, Evans J, et al. Randomized trial
of black cohosh for the treatment of hot flashes among
women with a history of breast cancer. J Clin Oncol 2001;
64. Wuttke W, Seidlova-Wuttke D, Gorkow C. The Cimicifuga
preparation BNO 1055 vs. conjugated estrogens
in a double-blind placebo-controlled study: effects on
menopause symptoms and bone markers. Maturitas 2003;
65. Stoll W. Phytopharmacon influences atrophic vaginal epithelium:
double-blind study—Cimicifuga vs. estrogenic
substances. Therapeuticum 1987; 1:23–31.
66. HernandezMunozG, Pluchino S. Cimicifuga racemosa for the
treatment of hot flushes in women surviving breast cancer.
Maturitas 2003; 44(suppl 1):S59–S65.
67. Liske E, H¨anggi W, Henneicke-von Zepelin HH, et al.
Physiological investigation of a unique extract of
black cohosh (Cimicifugae racemosae rhizoma): a 6-month
Black Cohosh 73
clinical study demonstrates no systemic estrogenic effect.
J Womens Health Gend Based Med 2002; 11(2):163–
68. Russell L, Hicks GS, Low AK, et al. Phytoestrogens: a viable
option? Am J Med Sci 2002; 324(4):185–188.
69. Mielnik J. Cimicifuga racemosa in the treatment of neuro vegetative
symptoms in women in the perimenopausal period.
Maturitas 1997; 27(suppl):215.
70. Georgiev DB, Iordanova E. Phytoestrogens—the alternative
approach (abstract). Maturitas 1997; 27(suppl):P309.
71. Chung DJ, Kim HY, Park KH, et al. Black cohosh and St.
John’s wort (GYNO-Plus) for climacteric symptoms. Yonsei
Med J 2007; 48(2):289–294.
72. Geller SE, Shulman LP, van Breemen RB, et al. Safety and
efficacy of black cohosh and red clover for the management
of vasomotor symptoms: a randomized controlled
trial. Menopause 2009; 16(6):1156–11566.
73. Amsterdam JD, Yao Y, Mao JJ, et al. Randomized, doubleblind,
placebo-controlled trial of Cimicifuga racemosa (black
cohosh) inwomenwith anxiety disorder due to menopause.
J Clin Psychopharmacol 2009; 29(5):478–483.
74. Jarry H, Harnischfeger G, Duker E. The endocrine effects
of constituents of Cimicifuga racemosa. 2. In vitro binding of
constituents to estrogen receptors. PlantaMed1985; (4):316–
75. D¨ uker EM, Kopanski L, Jarry H, et al. Effects of extracts
from Cimicifuga racemosa on gonadotropin release in
menopausal women and ovariectomized rats. Planta Med
76. Jarry H, Harnischfeger G. Endocrine effects of constituents
of Cimicifuga racemosa. 1. The effect on serum levels of
pituitary hormones in ovariectomized rats. Planta Med
77. Eagon CL, Elm MS, Eagon PK. Estrogenicity of traditional
Chinese andWestern herbal remedies. ProcAmAssoc Cancer
Res 1996; 37:284.
78. Zava DT, Dollbaum CM, Blen M. Estrogen and progestin
bioactivity of foods, herbs, and spices. Proc Soc Exp Biol
Med 1998; 217(3):369–378.
79. Jarry H, Metten M, Spengler B, et al. In vitro effects of
the Cimicifuga racemosa extract BNO 1055. Maturitas 2003;
80. Liu ZP, Yu B, Huo JS, et al. Estrogenic effects of Cimicifuga
racemosa (black cohosh) in mice and on estrogen receptors
in MCF-7 cells. J Med Food 2001; 4(3):171–178.
81. Jarry H, Leonhardt S, Duls C, et al. Organ specific effects
of C. racemosa in brain and uterus. In: 23rd International
LOF-Symposium on Phyto-Oestrogens. Belgium, 1999.
82. Amato P, Christophe S, Mellon PL. Estrogenic activity of
herbs commonly used as remedies for menopausal symptoms.
Menopause 2002; 9(2):145–150.
83. Eagon PK, Tress NB, Ayer HA, et al. Medicinal botanicals
with hormonal activity. Proc Am Assoc Cancer Res 1999;
84. Freudenstein J, Dasenbrock C, Nisslein T. Lack of promotion
of estrogen-dependent mammary gland tumors in vivo
by an isopropanolic Cimicifuga racemosa extract. Cancer Res
85. Lohning A, Verspohl E, Winterhoff H. Pharmacological
studies on the dopaminergic activity of C. racemosa.
In: 23rd International LOF-Symposium on “Phyto-
Oestrogens”. Belgium, 1999.
86. Seidlov´a-Wuttke D, Jarry H, Becker T, et al. Pharmacology
of Cimicifuga racemosa extract BNO 1055 in rats: bone, fat
and uterus. Maturitas 2003; 44(suppl 1):S39–S50.
87. Nisslein T, Freudenstein J. Effects of black cohosh on urinary
bone markers and femoral density in an ovx-rat model.
In:World Congress on Osteoporosis. Chicago, IL, 2000. Abstract
88. Li JX, Kadota S, Li HY, et al. Effects of Cimicifugae rhizoma
rats and bone mineral density in ovariectomized rats.
Phytomedicine 1997; 3(4):379–385.
89. Li JX, Kadota S, Li HY, et al. The effect of traditional
medicines on bone resorption induced by parathyroid hormone
(PTH) in tissue culture: a detailed study on cimicifuga
rhizome. J Trad Med 1996; 13:50–58.
90. Johnson EB, Muto MG, Yanushpolsky EH, et al. Phytoestrogen
supplementation and endometrial cancer. Obstet
Gynecol 2001; 98(5, pt 2):947–950.
91. Eagon CL, Elm MS, Teepe AG, et al. Medicinal botanicals:
estrogenicity in rat uterus and liver. Proc Am Assoc Cancer
Res 1997; 38:293.
92. Einer-Jensen N, Zhao J, Andersen KP, et al. Cimicifuga and
Melbrosia lack oestrogenic effects in mice and rats. Maturitas
93. Liu Z, Yang Z, Zhu M, et al. Estrogenicity of black cohosh
(Cimicifuga racemosa) and its effect on estrogen receptor level
in human breast cancer MCF-7 cells.Wei ShengYan Jiu 2001;
94. Zierau O, Bodinet C, Kolba S, et al. Antiestrogenic activities
of Cimicifuga racemosa extracts. J Steroid Biochem Mol Biol
95. Lohning A,WinterhoffH. Neurotransmitter concentrations
after three weeks treatment with Cimicifuga racemosa (abstract).
Phytomedicine 2000; 7(suppl 2):13.
96. Borrelli F, Izzo AA, Ernst E. Pharmacological effects of Cimicifuga
racemosa. Life Sci 2003; 73(10):1215–1229.
97. Mahady GB, Fong HHS, Farnsworth NR. Botanical Dietary
Supplements: Quality, Safety and Efficacy. Lisse, The
Netherlands: Swets & Zeitlinger, 2001:350.
98. Black Cohosh. Standards of analysis, quality control and
therapeutics. In: Upton R, ed. American Herbal Pharmacopoeia
and Therapeutic Compendium. Santa Cruz: AHP,
99. Huntley A, Ernst E. A systematic review of the safety of
black cohosh. Menopause 2003; 10(1):58–64.
100. Cohen SM, O’Connor AM, Hart J, et al. Autoimmune hepatitis
associated with the use of black cohosh: a case study.
Menopause 2004; 11(5):575–577.
101. Levitsky J, Alli TA, Wisecarver J, et al. Fulminant liver failure
associated with the use of black cohosh. Dig Dis Sci
102. Lontos S, Jones RM, Angus PW, et al. Acute liver failure
associated with the use of herbal preparations containing
black cohosh. Med J Aust 2003; 179(7):390–391.
103. Lynch CR, Folkers ME, Hutson WR. Fulminant hepatic failure
associated with the use of black cohosh: a case report.
Liver Transpl 2006; 12(6):989–992.
104. Whiting PW, Clouston A, Kerlin P. Black cohosh and other
herbal remedies associated with acute hepatitis. Med J Aust
105. U.S. Nebraska District Court case number 8:05-cv-00066;
Document # 90–97 and 90–98.
106. Betz JM, Anderson L,Avigan MI, et al. Black cohosh: considerations
of safety and benefit. Nutr Today 2009; 44(4):155–
107. USP. Interim Revision Announcement. USP Pharmacopeial
Forum 33(5) (September–October), 2007:954–962.
108. http://abc.herbalgram.org/site/PageServer?pagename =
PR 103107. Accessed February 6, 2010.
109. USP 31—NF 26, 2008:908–912.
110. Kesselkaul O. Treatment of climacteric disorders with
Remifemin. Med Monatsschr. 1957; 11(2):87–88.
111. Schotten EW. Erfahrungen mit dem Cimicifuga-Praparat
Remifemin. Landarzt 1958; 34(11):353–354.
112. StarfingerW. Therapie mit ostrogen wirksamen Pflanzenextrakten.
Medizin Heute 1960; 9(4):173–174.
74 Fabricant et al.
113. Brucker A. Essay on the phytotherapy of hormonal disorders
in women. MedWelt 1960; 44:2331–2333.
114. Heizer H. Criticism on Cimicifuga therapy in hormonal
disorders in women. Med Klin 1960; 55:232–233.
115. Gorlich N. Treatment of ovarian disorders in general practice.
Arztl Prax 1962; 14:1742–1743.
116. Schildge E. Essay on the treatment of premenstrual and
menopausal mood swings and depressive states. Ringelh
Biol Umsch 1964; 19(2):18–22.
117. Stolze H. Der andere weg, Klimacterische Beschwerden zu
behandlen. Gyne 1982; 3:14–16.
118. Daiber W. Klimakterische Beschwerden: ohne Hormone
zum Erfolg. Arzt Prax 1983; 35:1946–1947.
119. VorbergG. Therapy of climacteric complaints. Z Allgemeinmed
120. Warnecke G. Influence of a phytopharmaceutical on climacteric
complaints. MeizinischeWelt 1985; 36:871–874.
121. StollW. Phytotherapeutikum beeinflusst atrophischesVaginalepithel.
Doppelblindversuch cimicifuga vs ostrogenpraparat.
Therapeutikon 1987; 1:23–31.
122. Petho A. Klimakterische beschwerden. Umsteelung einer
Hormonbehandlung auf ein pflanzliches Gynakologikum
moglich? Arzt Prax 1987; 38:1551–1553.
123. Lehmann-Willenbrock E, Riedel H-H. Clinical and endocrinological
studies on the therapy of ovarian defunctionalization
symptoms after hysterectomy sparing the adnexa
(in German). Zentralbl Gynakol 110: 611–618 1988.
124. Baier-Jagodinski G. Praxisstudie mit Cimisan bei klimakterischen
Beschwerden, Pramenstruallen syndrom und Dysmenorrhoe.
Natur Heilpraxis Naturmedizin 1995; 48:1284–
125. Nesselhut T, Liske E. Pharmacological measures in postmenopausal
women with an isopropanolic aqueous extract
of Comicifugae racemosae rhizoma. Menopause 1999; 6(4):331.
126. Verhoeven MO, van der Mooren MJ, van de Weijer
PH, et al; CuraTrial Research Group. Effect of a combination
of isoflavones and Actaea racemosa Linnaeus
on climacteric symptoms in healthy symptomatic perimenopausal
women: a 12-week randomized, placebocontrolled,
double-blind study. Menopause 2005; 12(4):412–
127. Nappi RE, Malavasi B, Brundu B, et al. Efficacy of Cimicifuga
racemosa on climacteric complaints: a randomized study
versus low-dose transdermal estradiol. Gynecol Endocrinol
128. Frei-Kleiner S, Schaffner W, Rahlfs VW, et al. Cimicifuga
racemosa dried ethanolic extract in menopausal disorders:
a double-blind placebo-controlled clinical trial. Maturitas
129. Raus K, Brucker C, Gorkow C, et al. First-time proof of endometrial
safety of the special black cohosh extract (Actaea
or Cimicifuga racemosa extract) CR BNO 1055. Menopause
130. Sammartino A, Tommaselli GA, GarganoV, et al. Short-term
effects of a combination of isoflavones, lignans and Cimicifuga
racemosa on climacteric-related symptoms in postmenopausal
women: a double-blind, randomized, placebocontrolled
trial. Gynecol Endocrinol 2006; 22(11):646–
131. Gurley BJ, Barone GW, Williams DK, et al. Effect of milk
thistle (Silybum marianum) and black cohosh (Cimicifuga
racemosa) supplementation on digoxin pharmacokinetics in
humans. Drug Metab Dispos 2006; 34(1):69–74.
132. Rebbeck TR, Troxel AB, Norman S, et al. A retrospective
case-control study of the use of hormone-related supplements
and association with breast cancer. Int J Cancer 2007;
133. Hirschberg AL, Edlund M, Svane G, et al. An isopropanolic
extract of black cohosh does not increase mammographic
breast density or breast cell proliferation in postmenopausal
women. Menopause 2007; 14(1):89–96.
134. Gurley BJ, Swain A, Hubbard MA, et al. Clinical assessment
of CYP2D6-mediated herb-drug interactions in humans: effects
of milk thistle, black cohosh, goldenseal, kava kava,
St. John’s wort, and Echinacea. Mol Nutr Food Res. 2008;