Black Cohosh
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Actaea racemosa L. (syn. Cimicifuga racemosa [L.] Nutt.)
[Fam. Ranunculaceae]
Overview
Black cohosh is indigenous to the
Eastern United States and Canada, and has a long and widely recognized
medicinal tradition (Blumenthal et al.,
2000; Liske, 1998). Native Americans and early colonists used black cohosh root
to treat conditions including general malaise, malaria, rheumatism,
abnormalities in kidney function, sore throat, menstrual irregularities, and
childbirth (Blumenthal et al., 2000;
Boon and Smith, 1999; Liske, 1998). In Chinese medicine, rhizomes of many
different species of Actaea have been traditionally used to
treat inflammation, fever, headache, pain, sore throat, and chills (Foster,
1999; Liske, 1998). Black cohosh has been used in Europe for more than 40 years
to treat symptoms associated with menopause (Foster, 1999). In 1996, nearly 10
million retail units of a standardized ethanolic and isopropanolic extract were
sold monthly in Germany, Australia, and the U.S. (Blumenthal et al., 2000; Pizzorno and Murray,
1999). The herb has become increasingly popular as a dietary supplement in the
U.S., with retail sales in mainstream markets in 2000 ranking 14th of all
herbals (Blumenthal, 2001). Currently, black cohosh root is approved as a
nonprescription drug to treat premenstrual discomfort, dysmennorhea, and
neurovegetative complaints associated with menopause by the German Commission E
(Blumenthal et al 1998; Liske, 1998).
Description
Crude preparations of black cohosh
consist of the dried rhizome and roots of Actaea
racemosa L. (syn. Cimicifuga racemosa
[L.]) (Foster, 1999; McGuffin et al.,
2000) [Fam. Ranunculaceae], harvested
in the fall (Blumenthal et al., 2000;
Bradley, 1992). Some commercial extracts have been standardized based upon
triterpene glycoside content (Liske, 1998; McKenna, 1998). Remifemin®,
a German standardized oral formulation used in all of the black cohosh clinical
studies published through 2000, contains 20 mg of black cohosh extract
standardized to 1 mg triterpene glycosides (calculated as 27-deoxyactein) per
tablet or twenty drops (Blumenthal et al.,
2000; Liske, 1998; McKenna, 1998).
Primary Uses
Gynecology
Menopause: Neurovegetative complaints
associated with menopause, including hot flashes, heart palpitations, nervousness,
irritability, sleep disturbances, tinnitus, vertigo, perspiration, and
depression (Liske et al., 2002; Düker
et al., 1991; Lehmann-Willenbrock and Riedel, 1988;
Blumenthal et al., 1998; Bratman and
Kroll, 1999; Pethö, 1987; Stoll, 1987; Warnecke, 1985; Vorberg, 1984; Daiber
1983; Stolze 1982)
Premenstrual discomfort (Blumenthal et al., 1998; Bratman and Kroll, 1999)
Dysmenorrhea (Blumenthal et al., 1998; Bratman and Kroll, 1999)
Other Potential Uses
Treatment of surgical ovarian deficiencies
(Lehmann-Willenbrock and Riedel, 1988; Liske, 1998)
Dosage
In clinical studies before 1996, the
dose was 2x2 tablets/day, or 2x40 drops/day, which is equivalent to 48–140 mg
of black cohosh extract per day (Foster, 1999; Liske, 1998). A recent clinical
trial comparing two different dosages of Remifemin® (40 mg vs. 127
mg daily), for six months, in 116 women with menopausal complaints, found
similar safety and efficacy profiles for both doses (Liske et al., 2002). Based upon the results of this trial, a recommended
dose equivalent to 40 mg of black cohosh (dried root) daily is currently
recommended (Liske, 1998). Nevertheless, the dosage in most of the clinical
trials shown in the table below is 80 mg daily of the extract (the doses in the
studies using liquid preparation form at 40 drops twice daily are equivalent to
80 mg daily).
Internal
Crude Preparations
Dried
rhizome and root: 40–200 mg daily (Bradley, 1992).
Decoction: Daily
dose 240 ml boiling water poured onto 40–200
mg black cohosh (cut, dried root) and simmered for 10–15 minutes (Bradley,
1992).
Fluid
extract: 1:1 (g/ml) 90% alcohol, 0.3–1.0 ml (Karnick, 1994); 0.3–2.0 ml (Newall et al., 1996).
Tincture:
1:10 (g/ml) 40–60% alcohol, 0.4–2.0
ml (Bradley, 1992); 2–4 ml (Newall et al.,
1996; Wren, 1988), 40 drops are taken twice daily (Hunter, 1999; Warnecke,
1985).
Standardized Preparations
Extract: 40%–60% ethanolic
or isopropyl alcohol extracts of the rhizome with monitoring of active
compounds (triterpene glycosides) (Liske, 1998; Liske et al., 2002), corresponding to 40 mg of black cohosh daily
(Blumenthal et al., 1998).
Duration of Administration
The German Commission E monograph
recommends a maximum treatment duration of six months (Blumenthal et al., 1998). Some authors have suggested
that this is due to a lack of clinical trials longer than six months published
at the time the monograph was compiled (Bratman and Kroll, 1999; McKenna,
1998). According to Professor H. Schilcher, vice-president of the Commission E,
the reason for this limitation is predicated on the Commission’s desire to
ensure that women return to their healthcare provider for periodic examinations
at six-month intervals. The limitation is not based on any concerns about the
long-term safety of black cohosh. Based on a long history (33 years) of black
cohosh use in Germany at the time the monograph was written in 1989, and on the
herb’s general safety in long-term use (including data from clinical
experience, post-marketing studies, and market data on daily doses prescribed,
adverse events reports, etc.), the Commission E considered allowing unlimited
duration of use of black cohosh without concern for safety. However, in
Germany, prescriptions for hormone replacement therapy (HRT) are limited to a
six-month duration in order to ensure that women return to their healthcare
provider for general checkups; in the case of black cohosh, the Commission E
treated it with the same limitations as HRT (Schilcher, 2001). The relative
safety of black cohosh in long-term use is also supported by pharmacological
and clinical research. In a six-month chronic toxicity study, followed by an
eight-week recovery period, up to 1,800 mg/kg body weight, or roughly 90 times
the therapeutic dose, of black cohosh granulate
was administered to rats, and no detectable anomalies or toxic effects were
observed (Korn, 1991). Although this study may support long-term use of black
cohosh (Pizzorno and Murray, 1999), studies of carcinogens in rats must
typically be two years long to equate to long-term use in humans (Cott, 2000).
Ames tests (in vitro Salmonella microsomal assays) performed
on isopropanolic extracts showed no evidence of mutagenicity (Bratman and
Kroll, 1999; Liske, 1998). Although long-term studies may be warranted to
satisfy current standards in toxicology, these findings suggest that black
cohosh may be considered relatively safe for long-term therapy (Liske, 1998;
Pizzorno and Murray, 1999).
Chemistry
Constituents of black cohosh root and
rhizome include triterpene glycosides: actein, cimicifugoside, cimigoside,
27-deoxyactein, deoxyacetylacteol, and racemoside (Bradley, 1992; Bratman and
Kroll, 1999; McKenna, 1998; Newall et al.,
1996). Eight new triterpene glycosides named cimiracemosides A-H have been
identified (Shao et al., 2000). Some
references state that it also contains isoflavones including formononetin
(Bradley, 1992; Jarry et al., 1985;
Pizzorno and Murray, 1999). Note:
Although Jarry and coworkers reported the isolation of formononetin from a
methanolic extract in 1985, more recent studies of Remifemin® (an
isopropyl/ethanolic extract) along with five other commercial preparations
failed to identify appreciable levels of the flavonoids (Liske, 1998; Foster,
1999; Stuck et al., 1997). An
analysis of wild black cohosh from 13 different locations and two leading
commercial extracts resulted in no detectable levels of formononetin (Kennelly
et al., 2002). A recent review suggests black cohosh does not contain isoflavones (Hagels et al., 2000). Constituents of black cohosh root and rhizomes also
include the aromatic acids, isoferulic acid and salicylic acid (Bradley, 1992;
Newall et al., 1996; Pizzorno and
Murray, 1999) and other constituents including tannins, resin, phytosterols,
fatty acids, starch, and sugars (Bradley, 1992; Foster, 1999; Newall et al., 1996).
Pharmacological Actions
Studies refuting the estrogenic activity of black cohosh:
Human
A good-clinical-practices-compliance
study (40 mg vs. 127 mg daily) in postmenopausal women yielded no estrogen-like
lutenizing hormone (LH) or follicle-stimulating hormone (FSH) suppression. In
addition, endogenous estradiol, sex hormone-binding globulin (SHBG), and
prolactin levels remain unaffected (Liske et
al., 1998; Liske et al., 2002).
Estrogenic changes in vaginal cytological parameters (e.g., degree of vaginal
proliferation) were not observed (Liske et
al., 1998; Liske et al., 2002).
No increase in thickness of the endometrium, no changes in vaginal cell status,
and no changes in the hormone values of LH, FSH, prolactin, estradiol were
observed before and after a black cohosh treatment (Nesselhut and Liske, 1999).
Animal
No estrogen-like uterine effects or
changes in vaginal cytology were detected in animal experiments using an
ethanolic extract (Einer-Jensen et al.,
1996). In rats with artificially (DMBA) induced breast tumors, it was
demonstrated that different doses of an isopropanolic black cohosh extract (1x,
10x, 100x human therapeutic dose) did not cause stimulation of mammary tumors
compared to the placebo group. Estrogen substitution with mestranol resulted in
a progression of the tumors. No estrogenic-agonistic effects on prolactin, LH,
FSH, or on the uterine tissue were seen (Freudenstein et al., 2000). Pyridinoline and deoxypyridinoline as markers of
bone metabolism in rats declined significantly under black cohosh
administration (isopropanolic extract) compared to the control, suggesting
potential benefits in retarding bone loss (Nisslein and Freudenstein, 2000).
In vitro
Formononetin, the isoflavone thought to
be an active estrogenic component of black cohosh in earlier studies (Jarry et al., 1985; Jarry and Harnischfeger,
1985), is not detected in the commercially available isopropanolic and
ethanolic extract (Struck et al.,
1997) and is not a constituent of the dried root (Hagels et al., 2000). An isopropanolic/alcoholic extract inhibits the
proliferation of estrogen-receptor positive (ER+) human breast cancer cell
lines (MDA MB 435S) (Nesselhut et al.,
1993). Investigations show that an isopropanolic-aqueous extract does not
stimulate the proliferation of ER+ human breast cancer cell lines (MCF-7), but
the extract does produce a dose-dependent inhibition of DNA synthesis, an
antagonization of estradiol activity, and a synergistic increase in the
anti-proliferative effect of tamoxifen (Freudenstein and Bodinet, 1999). An
ethanolic black cohosh extract inhibited growth of T-47D human breast cancer
cells (Dixon-Shanies and Shaikh, 1999).
Studies supporting the estrogenic activity of black cohosh:
Human
Earlier research
showed that black cohosh improves neurovegetative symptoms (hot flashes,
increased perspiration, headache, vertigo, heart palpitations, tinnitus) and
psychological complaints (nervousness, irritability, sleep disturbances,
depressive mood) associated with menopause or hormonal deficiencies experienced
by hysterectomized/ovariectomized patients (Stolze, 1982; Daiber, 1983;
Vorberg, 1984; Warnecke, 1985; Stoll, 1987; Pethö, 1987; Lehmann-Willenbrock
and Reidel, 1988; Lieberman, 1998; Liske, 1998); proliferation of vaginal
epithelium (Stoll, 1987). Three alcoholic fractions produced endocrine effects
that inhibit LH secretion, but not FSH secretion, in menopausal women. The
authors hypothesize that this is an estrogen-like effect (Düker et al., 1991).
In vitro
A methanolic extract demonstrated
endocrine activity in an in vitro
estrogen-receptor assay. The three fractions identified were believed to
compete with estradiol for binding sites on estrogen receptors (Jarry et al., 1985).
Mechanism of Action
Although estrogen-like effects, such as LH suppression, have
been proposed as the primary mechanism of action in alleviating the symptoms of
menopause, results of recent animal investigations and clinical studies
indicate that the mode of action is not identical with estrogen. On the
contrary, estrogen-agonistic and estrogen-antagonistic effects on different
target organs indicate a tissue selectivity for black cohosh ingredients
(Boblitz et al., 2000). Although some
studies suggest black cohosh has an estrogen-like effect based on its observed
LH-suppressive activity, a definite mechanism of action has not been
established (Düker et al., 1991). A
recent animal study failed to detect estrogen-like uterine effects or changes
in vaginal cytology with black cohosh administration. Thus, the authors
concluded that LH suppression was associated with neurotransmitter interference
instead of estrogenic activity (Einer-Jensen et al., 1996). Similarly, another study comparing two different
dosages of Remifemin® (40 mg vs. 127 mg daily) showed no effect on
hormonal levels of LH, FSH, SHBG, prolactin, or estradiol, or on vaginal
cytological parameters; however, menopausal symptoms were clearly alleviated
(Liske et al., 2002, 1998). Although
the authors cannot definitively explain the mechanism responsible for the
efficacy of black cohosh in the treatment of menopausal complaints, they agree
that Remifemin® does not exert a hormonal (estrogenic) effect (Liske
et al., 2002, 1998).
Contraindications
None known (Blumenthal et
al., 1998; Pizzorno and Murray, 1999).
Note:
Despite earlier concerns about the possible estrogenicity of black cohosh, and
thus a possible contraindication for women with estrogen-positive breast
cancer, as explained in the Pharmacology and Mechanism of Action sections above
and in the discussion below, it is clearly established that black cohosh is not
estrogenic. Thus, no such contraindication is warranted.
According to an in
vitro study, the use of an isopropanolic aqueous extract of black cohosh
reportedly inhibited the proliferation of estrogen-receptor positive (ER+)
human breast cancer cells and, although still debated, the present data
indicate that black cohosh does not increase the risk of developing breast
cancer (Nesselhut et al., 1993).
Another in vitro study reported that
Remifemin® extract did not stimulate the proliferation of ER+ human
breast cancer cells (Freudenstein and Bodinet, 1999). In addition, the extract
inhibited DNA synthesis in a dose-dependent manner, antagonized the estrogenic
activity of estradiol, and enhanced the anti-proliferative effect of tamoxifen
(Freudenstein and Bodinet, 1999). In rats with artificially (DMBA) induced
breast tumors, it could be demonstrated that different doses of an
isopropanolic black cohosh extract (1x, 10x, 100x human therapeutic dose) did
not cause any stimulation of mammary tumors compared to the placebo group.
Estrogen substitution with mestranol resulted in a progression of the tumors.
No estrogenic-agonistic effects on prolactin, LH, or FSH, or on uterine tissue
were seen (Freudenstein et al.,
2000).
Pregnancy and Lactation: Not
recommended during pregnancy due to its emmenagogue and uterine-stimulant
effect (based on empirical observations) (Brinker, 2001; McGuffin et al., 1997). Not recommended during
lactation (based on empirical observations) (Brinker, 2001; McGuffin et al., 1997).
Adverse Effects
Occasional gastrointestinal discomfort has been reported
(Blumenthal et al., 1998; Foster,
1999; McGuffin et al., 1997).
Vertigo, headache, nausea, vomiting, impaired vision, and impaired circulation
have been reported with overdose (Foster, 1999; McGuffin et al., 1997).
Drug Interactions
None known (Blumenthal et
al., 1998; Brinker, 2001), including in cases of simultaneous
administration of standardized black cohosh extracts and estrogen-replacement
therapy (McKenna, 1998; Pethö, 1987; Warnecke, 1985).
American Herbal Products Association (AHPA) Safety Rating
Class 2b: Not
to be used during pregnancy.
Class 2c: Not
to be used while nursing (McGuffin et al.,
1997).
Regulatory Status
Canada: Regulated
as a drug if single dose is sufficiently high or as a potential “New Drug” for
specific nontraditional use claims (HPB, 1993). Included in the Drugs Directorate “List of Herbs Unacceptable as
Non-medicinal Ingredients in Oral Use Products” (Health Canada 1995a). When
identified as a Traditional Herbal Medicine (THM) or as a homeopathic drug,
black cohosh is regulated as a nonprescription over-the-counter (OTC) drug
requiring premarket authorization and assignment of a drug identification
number (DIN) (Health Canada, 1995b; Health Canada, 2001; WHO, 1998).
France:
Traditional medicine.
Germany:
Fresh or dried rhizome with attached roots is an approved nonprescription drug
for oral use in the German Commission E Monographs (Blumenthal et al., 1998). The fresh rhizome and
roots for preparation of hydro-alcoholic mother tincture and liquid dilutions
are an official drug of the German
Homeopathic Pharmacopoeia (GHP, 1993). No monograph in the German Pharmacopoeia (DAB).
Sweden: Classified
as a natural remedy; intended for self-medication; require advance application
for marketing authorization. A monograph for the product Remifemin®
is published in the Medical Products Agency (MPA) “Authorised Natural Remedies”
(MPA, 1999, 2001; WHO, 1998).
Switzerland: Approved
as single-ingredient Herbal Medicine and as a component of multiple-ingredient
Homeopathic Medicines, both classified by the Interkantonale Kontrollstelle für Heilmittel (IKS) as List D
medicinal products with sales limited to pharmacies and drugstores, without
prescription (Morant and Ruppanner, 2001; WHO, 1998).
U.K.: OTC
herbal medicine specified in the General
Sale List, Schedule 1 (medicinal products requiring a full product
license), Table A (for internal or external use); 200 mg maximum single dose
and maximum daily dose (GSL, 1990).
U.S.:
Dietary
supplement (USC, 1994). The homeopathic mother tincture 1:10 (w/v), 55% (v/v), of fresh or dried black cohosh root, is a Class C OTC drug of
the Homeopathic Pharmacopoeia of the
United States (HPUS, 1990).
Clinical Review
Ten clinical studies are outlined in the following table,
“Clinical Studies on Black Cohosh,” including a total of 1,371 participants.
Nine of these studies demonstrated positive effects for menopausal symptoms.
Numerous clinical trials with varied methods and designs have been conducted on
the standardized isopropanolic/ethanolic extract of black cohosh root,
Remifemin®, from 1981 to the present. Five of the studies were
open-label, and evaluated the effectiveness of the extract as a monotherapy for
the treatment of menopausal complaints (Pethö, 1987; Warnecke, 1985; Vorberg,
1984; Daiber, 1983; Stolze, 1982). Two studies, a randomized, double-blind (R,
DB) study (Liske et al., 1998), and a
randomized study (Lehmann-Willenbrock and Reidel, 1988) compared black cohosh
extract to conventional hormonal therapy in the treatment of complaints
associated with menopause or hormonal deficiencies in
ovariectomized/hysterectomized patients. One open-label, randomized, controlled
study compared the efficacy of three different black cohosh therapies to
conjugated estrogens and diazepam for menopausal problems (Warnecke, 1985). One
R, DB study compared two dosages of Remifemin® for the treatment of
menopausal symptoms (Liske et al.,
1998). A decrease in the Kupperman-Menopause Index (KPI) was reported in five
clinical studies on black cohosh extract (Liske et al., 1998; Lehmann-Willenbrock and Reidel, 1988; Stoll, 1987;
Vorberg, 1984; Daiber, 1983).
Branded Products
Remifemin®: GlaxoSmithKline / One Franklin Plaza
/ Philadelphia, PA 19102 / U.S.A. / Tel: (800) 366-8900. One tablet contains
black cohosh extract corresponding to 20 mg of crude drug standardized to 1%
27-deoxyacteine.
Remifemin® drops: Schaper & Brümmer GmbH
& Co. KG. / Bahnhofstrasse 35 / 38259 Salzgitter / Ringelheim / Germany /
Tel: +49-5341-30-70 / Fax: +49-5341-30-71-24 / Email: info@schaperbruemmer.de /
www.schaper-bruemmer.com/. Twenty drops correspond to 20 mg of crude drug. This product is no longer available.
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