(2004; 358 pages)
Rhizoma Cimicifugae Racemosae
Rhizoma Cimicifugae Racemosae consists of the dried rhizomes and roots of Cimicifuga racemosa (L.) Nutt. (Ranunculaceae) (1)1.
1 Rhizomes and roots of Cimicifuga heracleifolia Kom., C. dahurica (Turcz.) Maxim. or C. foetida L. are referred to as Rhizoma Cimicifugae in the Pharmacopoeia of the People’s Republic of China (2). Rhizomes and roots of C. simplex Warm. and related species are referred to under the same name in The Japanese pharmacopoeia (3).
Actaea gyrostachya Wender, A. orthostachya Wender, A. monogyna Walt., A. Racemosa L., Bortrophis actaeoides Raf., B. serpentaria Raf., Christophoriana canadensis racemosa Gouan, Cimicifuga racemosa (Torr) Bart., C. serpentaria Pursh, Macrotis racemosa Sweet, M. serpentaria Raf., Macrotrys actaeiodes Raf. (4-6).
Selected vernacular names
Actée à grappes, black cohosh, black root, black snakeroot, bugbane, bugwort, bugwort rattleroot, cimicifuga, cohosh bugbane, Frauen Wurzel, herbe aux punaises, macrotnys, macrotys, macroty’s, natsushirogiku, Qatil el baq, racine d’actée à grappes, rattle root, rattle snake root, rattle top, rattleweed, rich weed, schwarze Schlangenwurzel, squaw root, squawroot, Traubensilberkerze, Wanzenkraut, zilberkaars (7-9).
Indigenous to eastern North America (9).
A perennial herb, up to 1-2.5 m high; subterranean part consists of a thick, knotted rhizome system. Leaves compound, pinnate, up to 7cm long; leaflets serrate along the margin, subcordate to subcuneate at the base. Inflorescence a long, wand-like raceme of white flowers with numerous stamens (9, 10).
Plant material of interest: dried rhizomes and roots
Mixture of entire and broken dried rhizomes and roots. Rhizome dark-brown, hard, sub-cylindrical and somewhat knotted; 1-2.5 cm in diameter and 2-15 cm long, with numerous, closely-arranged, upright or curved branches, each terminating in the remains of a bud or a circular, cup-shaped scar; branches about 1 cm in diameter and up to 3 cm long, marked with distinct, encircling leaf scars; fracture horny; transverse surface showing a thin outer bark surrounding a ring of numerous pale, narrow wedges of vascular tissue alternating with dark medullary rays; a large central pith.
Roots attached to under surface of the rhizome or, more usually, broken off leaving circular scars. Roots dark brown, 1-3 mm in diameter, brittle, nearly cylindrical or obtusely quadrangular, longitudinally wrinkled; fracture short; transverse surface showing a distinct cambium line separating the wide outer bark from the central region composed of 3-6 wedges of lignified xylem tissue united at their apices and separated by broad, non-lignified medullary rays (1, 9).
Odour: slight; taste: slightly bitter (1, 9).
Rhizome: yellowish-brown, suberized epidermis, several layers of starch- and resin-containing cortical parenchyma, 2 circles of open, collateral, fibrovascular bundles, the outer bundles being smaller than the inner; medullary rays separate the bundles and contain starch grains, spherical or polygonal, simple or 2-3 or even up to 6 compound; individual grains 3-15 µm in diameter with central slit-shaped hilum. Xylem contains tracheae with bordered pits and numerous strongly lignified wood fibres; and a central pith with cells resembling those of the cortex.
Root: thin epidermis, a cortex, separated into 2 zones by a distinct endodermis, and 4-6, occasionally 3, open, collateral fibrovascular bundles separated by broad, wedge-shaped medullary rays (1, 9).
Powdered plant material
Light brown, odourless with a bitter taste; abundant starch grains, often occurring in masses in numerous fragments of thin-walled parenchyma; groups of small, lignified vessels with closely arranged bordered pits or, less frequently, with reticulate thickening; lignified thin-walled fibres and xylem parenchyma; fragments of brown suberized cells with thickened walls (1).
General identity tests
Macroscopic and microscopic and microchemical examinations (1, 9), and thinlayer chromatography for the presence of characteristic flavonoids and phenolic acids (1, 11).
Tests for specific microorganisms and microbial contamination limits are as described in the WHO guidelines on quality control methods for medicinal plants (12).
Foreign organic matter
Not more than 5% stem bases and not more than 2% other foreign matter (1).
Not more than 10% (1).
Not more than 4% (1).
Not less than 10% (1).
Loss on drying
Not more than 12% (5).
The recommended maximum limit of aldrin and dieldrin is not more than 0.05 mg/kg (13). For other pesticides, see the European pharmacopoeia (13), and the WHO guidelines on quality control methods for medicinal plants (12) and pesticide residues (14).
For maximum limits and analysis of heavy metals, consult the WHO guidelines on quality control methods for medicinal plants (12).
Where applicable, consult the WHO guidelines on quality control methods for medicinal plants (12) for the analysis of radioactive isotopes.
Other purity tests
Chemical, sulfated ash and alcohol-soluble extractive tests to be established in accordance with national requirements.
Qualitative assessments may be based on the triterpene and isoflavonoid content. Concentration ranges and quantitative methods need to be established. A high-performance liquid chromatography method is available for the quantitative analysis of flavones (15).
Major chemical constituents
The major and characteristic constituents include the cycloartanol-based triterpenes acteol, acetylacteol, 26-deoxyacteol, cimigenol, actein, 26-deoxyactein and cimicifugoside. (E)-Isoferulic acid and the isoflavone formononetin are also found (4, 15-17). However, the latter compound could not be detected in alcohol extracts of the root (15). The structures of the representative constituents are presented below.
Uses supported by clinical data
Treatment of climacteric symptoms such as hot flushes, profuse sweating, sleeping disorders and nervous irritability (18-26).
Uses described in pharmacopoeias and in traditional systems of medicine
Treatment of premenstrual syndrome and dysmenorrhoea (27, 28).
Uses described in folk medicine, not supported by experimental or clinical data
Treatment of coughs, dyspepsia, epilepsy, intercostal myalgia, rheumatoid arthritis, sciatica, snake bites, tinnitus and whooping cough (1, 8, 9, 28, 29).
The estrogenic effects of Rhizoma Cimicifugae Racemosae are controversial, and have been assessed both in vitro and in vivo. The in vitro proliferation of human mammary carcinoma cells (cell line 435) was measured after treatment with an isopropyl alcohol extract of the rhizome. Treatment using concentrations below 2.5µg/ml did not enhance growth of the cells. However, concentrations of 2.5µg/ml and above significantly inhibited cell proliferation (30). Similar results were obtained using the estrogen receptor-positive human mammary carcinoma cell line MCF-7. When these cells were treated with a 40% isopropyl alcohol extract of the rhizome at concentrations ranging from 1ng/ml to 100µg/ml, the extract induced a dose-dependent inhibition of cell proliferation and also augmented the antiproliferative effects of tamoxifen (31). An extract of the rhizome (extract not specified) was tested in vivo for possible estrogenic effects in female rats. The extract was added to a standard liquid diet and fed to ovariectomized rats daily for 3 weeks. An increase in uterine weight was observed, along with an increase in serum ceruloplasmin levels, suggesting estrogenic activity of the extract (32). However, in a short-term study, intragastric or subcutaneous administration of a 50% ethanol extract of the rhizome (30, 300 or 3000 mg/kg body weight) to immature mice daily for 3 days did not have any estrogenic effects, as assessed by changes in uterine weight and vaginal cytology (33). Constituents of a chloroform fraction, isolated from a methanol extract of the rhizome, bound to the estrogen receptors of isolated rat uteri in vitro. Formononetin, a minor constituent of the extract, showed a low binding affinity to the estrogen receptor (11.5µmol/l) (34). The effects of formononetin and a dichloromethane extract of the rhizome on luteinizing hormone secretion were tested in vivo (35). Ovariectomized rats received nine intraperitoneal injections over 5 days (equivalent to a total dose of 10mg formononetin or 108mg extract). The extract, but not formononetin, reduced the serum concentration of luteinizing hormone (34, 35). Intraperitoneal (but not intragastric) administration of a chloroform (140 mg), 60% ethanol (0.3 ml) or dichloromethane (27 mg) extract of the rhizome reduced the serum concentration of luteinizing hormone in ovariectomized rats after 3-3.5 days of treatment (34, 36, 37). Serum folliclestimulating hormone and prolactin levels, however, were not affected (34). Intragastric administration of a 95% ethanol extract of the rhizome (0.05 ml/animal daily) had no effect on genital functions in female mice (38).
The effects of estradiol on estrogen-dependent brain and uterine functions were compared with those of a dichloromethane fraction of a hydroalcoholic rhizome extract. Daily injection of the extract (60 mg/rat) or estradiol for 3 weeks reduced serum luteinizing hormone levels, but only estradiol increased uterine weight. Up-regulation of estrogen receptor-α gene expression was observed in MCF-7 mammary carcinoma cells treated with either the extract (35µg/ml) or estradiol. The results suggest that the dichloromethane fraction of the extract may act as a selective modulator of the estrogen receptor (39).
Subcutaneous injection of an ethanol extract of the crude drug (100mg/kg body weight) reduced carrageenan-induced footpad oedema in rats by 32% (40).
The following studies were all performed using oral administration of either a 40% isopropyl alcohol or 60% ethanol extract of Rhizoma Cimicifugae Racemosae.
In a placebo-controlled clinical trial, 110 women with climacteric symptoms were treated with the ethanol extract (8 mg daily) for 2 months. Although a significant reduction in serum luteinizing hormone levels was observed in the treated group (P < 0.01), there was no effect on follicle-stimulating hormone levels (37).
A 12-week double-blind, placebo-controlled study of 80 women (aged 45-58 years) compared the efficacy of the rhizome extract (8mg daily) with either conjugated estrogens (0.625 mg daily) or placebo for the treatment of climacteric symptoms and vaginal atrophy. The group treated with the extract showed a greater reduction in climacteric symptoms than groups treated with either conjugated estrogens or placebo, as demonstrated by a significant reduction in both the Kupperman Index and Hamilton Rating Scale for Anxiety (Hamilton Anxiety Rating Scale), and by the proliferative status of the vaginal epithelium (P < 0.001) (23).
The efficacy of the isopropyl alcohol extract for the treatment of climacteric symptoms induced by hysterectomy was assessed in a randomized comparison trial without controls. Sixty women under the age of 40, who had undergone a hysterectomy, but retained one ovary, were treated daily with either the extract (8 mg), estriol (1 mg), conjugated estrogens (1.25 mg) or an estrogen-progesterone combination. After 4, 8, 12 and 24 weeks of treatment, a significant decrease in climacteric symptoms was reported by the patients in all treatment groups (P < 0.01). This was verified by a reduction in a modified Kupperman index. Conjugated estrogens or the estrogen-progesterone combination appeared to be slightly more effective than the extract; however, no significant difference between the three treatments was observed. Serum levels of luteinizing hormone and follicle-stimulating hormone did not change significantly in any of the groups (P > 0.05) (20).
In a study without controls of 50 women with climacteric complaints, after administration of the ethanol extract (40 drops twice daily for 12 weeks), patients with moderate symptoms required no further treatment (25).
A randomized controlled trial involving 60 women aged 45-60 years compared the efficacy of the ethanol extract with hormone replacement therapy (0.6 mg conjugated estrogens) or 2 mg diazepam for the treatment of climacteric symptoms. Clinical assessment of the patients was based on three indicators: the menopause index (for hot flushes, nocturnal sweating, nervousness, headache and palpitations), and the Hamilton Anxiety Rating Scale and selfassessment depression scale (for psychological symptoms). Patients were treated with either the extract (40 drops twice daily), conjugated estrogens (0.625 mg daily) or diazepam (2 mg daily) for 12 weeks. All three forms of therapy reduced all three indicators. The extract and conjugated estrogens also reduced atrophic changes in the vaginal mucosa (26).
In a study without controls, 36 women with climacteric symptoms were treated with the ethanol extract (40 drops) twice daily for 12 weeks. A significant decrease in the average values of the Kupperman index was reported (P < 0.001), and an increase in the values of the Clinical Global Impression scale was observed (18).
A placebo-controlled clinical trial assessed the efficacy of a rhizome extract for the treatment of 82 women with climacteric symptoms. In the group treated with the extract, 31 women reported a considerable decrease in symptoms, while 10 women with severe climacteric symptoms did not show improvement. In the placebo group, a reduction of symptoms was seen in four women; symptoms were unchanged in 37 women (19).
In a study without controls, 50 women with climacteric symptoms, who had received at least one or two intramuscular injections of estradiol valerate (4mg) and prasterone enantate (200 mg) during 1-2 months prior to the trial, were treated with the isopropyl alcohol extract (2 tablets twice daily) for 6 months. The therapeutic results were rated as good to very good in 41 of the patients: during the treatment period 28 required no further injections, 21 patients required one injection and one patient required two injections. The Kupperman index decreased significantly (P < 0.001), indicating successful treatment of symptoms (22).
A multicentre, drug-monitoring study without controls of 629 women with climacteric symptoms assessed the efficacy of the ethanol extract (40 drops twice daily) for 8 weeks. Symptoms improved in over 80% of all patients after 6-8 weeks of treatment (24).
A 6-month randomized, double-blind clinical trial compared two different doses of the isopropyl alcohol extract (40 and 127 mg daily) in 152 women with climacteric symptoms. A decrease in the Kupperman index was observed after 2 weeks in both treatment groups. Both dosages showed similar levels of efficacy and safety. After 6 months, approximately 90% of patients had responded to the treatment. No effects on vaginal cytology or the levels of luteinizing hormone, follicle-stimulating hormone, sex hormone binding-globulin, prolactin and estradiol were observed (21, 41, 42).
A review of eight clinical trials assessed the efficacy of extracts of the crude drug for the alleviation of climacteric symptoms in women. It concluded that preparations of the rhizome may be a safe and effective alternative to estrogen replacement therapy for patients for whom the replacement therapy is contraindicated or refused (43).
General gynaecological disorders
Five case studies have described the successful use of a 40% isopropyl alcohol or 60% ethanol extract of the rhizome in the treatment of a total of 833 women with gynaecological disorders (e.g. climacteric symptoms) and menstrual disorders (e.g. primary or secondary amenorrhoea, and premenstrual disorders) (44-48).
Owing to its potential estrogenic effects (39) and the lack of data on its safety, Rhizoma Cimicifugae Racemosae should not be used during pregnancy or lactation, or in children under the age of 12 years.
No information available.
Carcinogenesis, mutagenesis, impairment of fertility
A 40% isopropyl alcohol extract of the crude drug was not mutagenic in the Salmonella/microsome assay using S. typhimurium strains TA98 or TA100 (16).
Pregnancy: teratogenic effects
Intragastric administration of up to 2 g/kg body weight of the crude drug, as a component of two traditional Chinese medicines, to pregnant rats daily on days 7-17 of gestation was not teratogenic (49, 50). (See also Contraindications.)
Pregnancy: non-teratogenic effects
No information available on general precautions or precautions concerning drug interactions or drug and laboratory test interactions.
Minor gastrointestinal upset and headache (19, 23-25).
Crude drug, and isopropyl alcohol or ethanol extracts (16). Store in a wellclosed container, protected from light and moisture.
(Unless otherwise indicated)
Daily dosage: 40-60% isopropyl alcohol or ethanol extracts of the crude drug (18-20, 22-26, 37, 42), corresponding to 40 mg drug (27).
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