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Black Cohosh

Botanical Name: Cimicifuga racemosa (L.) Nutt.
Pharmacopoeial Name: Rhizoma cimicifugae racemosae.
Synonym: Actea racemosa L.
Common Names: Black cohosh, black snakeroot, macrotys (historical).

Summary Table
Drug/Class Interaction TypeMechanism and SignificanceManagement
Androgen blockade
LHRH antagonists
Black cohosh reduces drug-induced vasomotor adverse effects.
Established effect in women, but only anecdotal support for the interaction in men.
Coadminister with professional management and monitoring.
Hormone replacement therapy (HRT)
Black cohosh supports reduced HRT doses, or tapered withdrawal by reducing symptoms associated with climacteric.Consider adoption, especially for HRT withdrawal.
Tamoxifen, Raloxifene
Black cohosh reduces drug-induced climacteric symptoms, may synergize with SERM antitumor effects in estrogen receptor–positive cancer.Consider coadministering with professional management.
LHRH , Luteinizing hormone–releasing hormone; SERMs , selective estrogen response modulators.
herb description



Related Species

None; blue cohosh ( Caulophyllum thalactroides L.) is a different species botanically and medicinally. Asian varieties sold as sheng ma may be derived from Actea foetida or Actea dahrica and are not interchangeable.

Habitat and Cultivation

Native to eastern North America; 95% of black cohosh is wild-crafted, and the impact of annual harvests of 600,000 to 700,000 pounds (1998) on the viability of wild populations is a cause for concern.

Parts Used

Rhizome and roots.

Common Forms

  • Dried:   Powdered rhizome and root.

  • Tincture:   1:3 to 1:10 60% alcohol-dried.

Fluid Extract: 1:1 60% to 90% alcohol-dried.

  • Standardized Extracts:   Commercial extracts standardized to 2.5% triterpene glycosides are available. Clinical trials have largely been based on Remifemin, a proprietary isopropanolic formulation available as liquid and tablet form equivalent to a 1:1 g/mL fluid extract, or BNO 1055, an ethanolic extract sold as Klimadynon/Menafem. (See constituents discussed later for labeling of 27-deoxyactein marker compound.)

Note: Herbal practitioners may use fresh herb material, but this is not common in commerce.

herb in clinical practice


Modern use of black cohosh is dominated by its perception as a remedy for various symptoms associated with menopause. In 1989 the German Commission E approved its use for dysmenorrhea, premenstrual discomfort, and neurovegetative ailments associated with menopause. Increasing concern about the adverse effects of conventional hormone replacement therapy (HRT), coupled with clinical trial support for menopausal applications and promotion of standardized European isopropanolic preparations of black cohosh, has led to a narrowing of focus on the herb as a gynecological remedy, especially for menopausal issues. Therapeutic monographs of the herb include those by the British Herbal Medical Association (BHMA), 1 German Commission E, 2 and more recently by the World Health Organization (WHO), 3 American Herbal Pharmacopoeia , 4 and European Scientific Cooperative on Phytotherapy (ESCOP). 5

Contrary to initial research assumptions of its “estrogenic” properties, recent studies on black cohosh suggest that it is in fact antiestrogenic. Lacking any phytoestrogenic isoflavone constituents, newer data have demonstrated dopaminergic and serotonergic receptor binding. Ongoing developments in estrogen receptor molecular biology continue to add to the complex emerging picture. The traditionally known affinities of black cohosh for the nervous and musculoskeletal systems, its cardiovascular effects, and the broad scope of its gynecological indications (which extend far beyond the specific issue of climacteric symptoms) increasingly appear to have an underlying basis in the neuroendocrine pharmacology of the herb, although this awaits full elucidation.

Historical/Ethnomedicine Precedent

Black cohosh was used by Native Americans for general malaise, various gynecological conditions, kidney ailments, malaria, rheumatism, sore throat, and snakebite. 6 The early colonists also used the herb, reputedly for menorrhea, uterine disorders, nervous disorders, lumbago, snakebite, and various infectious conditions, including malaria. 7 Cimicifuga was a primary remedy for the Eclectic physicians, who termed it “macrotys.” The Eclectics used different forms of the herb, including fresh and dried extracts and a “resinoid” concentrate. This was employed for a wide range of neuromuscular, gynecological, and obstetrical conditions, including neuralgia, headache, rheumatism, false labor, labor, postpartum pain, “partus preparator” (to encourage natural contractions during labor), mastitis, atony of the uterus, and amenorrhea, as well as for a variety of nervous system disorders, including chorea, convulsions, delirium tremens, nervous excitability, spasmodic cough, and pertussis. Interestingly, Eclectic use included male urogenital conditions such as orchalgia and spermatorrhea as well as infections such as smallpox. 8-10Grieve includes the indication of St. Vitus’ dance (Sydenham’s chorea) in children. 11 Boericke 12 emphasized depression as a key mental indication for Cimicifuga as a homeopathic medicine.

Known or Potential Therapeutic Uses

Antirheumatic, antispasmodic, uterine tonic; treatment of climacteric symptoms and ovarian insufficiency, especially associated with iatrogenically induced menopause; mild depression, especially associated with cyclical or climacteric changes; fibromyalgia.

Key Constituents

  • Triterpene glycosides: More than 20 identified, including 23-epi-26 deoxyactein, which is often incorrectly labeled as “27-deoxyactein” on commercial standardized product labels. 13
  • Flavonoids: Early reports of the presence of the phytoestrogenic isoflavones formononetin and biochanin A have not been substantiated by recent analytical data and are not present in the standardized isopropanolic extract Remifenin. 14,15
  • Aromatic acids: Hydroxycinnamic acid esters of fukiic and piscidic acid; fukinolic and cimicifugic acids, along with ferulic isoferulic and caffeic acids.
  • Novel polyphenolics have recently been described. 16
  • Other components include up to 20% resin (“cimicifugin”). 17

Therapeutic Dosing Range

From 0.2 to 4.0 mL/day (1:1 equivalent) hydroethanolic extracts.

Recent clinical trials using isopropanolic extracts average a modest daily dose of 40 to 80 mg-equivalent dried herb.

interactions review

Strategic Considerations

Black cohosh therapeutic monographs typically do not identify any drug interactions. 2,3,5The herb appears to be relatively safe and is well tolerated with minimal toxicity at therapeutic doses.

A recent comprehensive safety review by Low Dog et al. 18 analyzed uncontrolled reports, postmarketing surveillance, and human clinical trials of more than 2800 patients involving black cohosh. The trials demonstrated a low incidence (5.4%) of adverse events, of which 97% were minor, and none resulted in discontinuation of therapy. No severe events were attributable to the herb. The authors concluded that black cohosh was safe when used for menopausal symptoms and is a safe alternative for women in whom estrogen therapy is contraindicated. 18 However, both this and other safety reviews 19 mainly examined isopropanolic extracts as used in clinical trials, and the data do not necessarily apply to traditional preparations, which are often used at higher doses. According to the manufacturers of Remifemin, animal tests suggest that higher equivalent doses, up to 500 times the 40-mg oral dose of isopropanolic preparations, are well tolerated over 6 months.

Despite the apparently benign toxicity of the herb according to clinical trial data, there have been persistent anecdotal reports of hepatotoxicity linked to black cohosh consumption. A recent National Institutes of Health (NIH) workshop discussed such reports and concluded that at present, hepatoxicity has not been conclusively demonstrated, although vigilance, including liver function monitoring, may be appropriate when higher doses are used. 20,21

The absence of published interactions data and reports requires integrative practitioners to make the best possible assessments about potential interactions in light of the known pharmacology of the herb. Given increasing concerns about the risks of breast cancer associated with female HRT, arguably one of the more common clinical settings for use of the herb is the coadministration of black cohosh with HRT. Related concerns are potential interactions between black cohosh and drugs used for other aspects of menopause, such as the bisphosphonates for osteoporosis.

Hormone-dependent malignancies are another important area where drug-herb interactions must be considered. Premenopausal patients with reproductive malignancies are likely to experience more severe menopausal symptoms, especially vasomotor effects, as a result of chemotherapy-induced menopause than are postmenopausal patients. 22,23The use of HRT in either population is contraindicated because of the proliferative activity of estrogens and the increased risk of renewed tumorigenesis. 24,25The possible efficacy of black cohosh for symptom relief in these populations has not been the subject of systematic long-term studies, although some data are available; nevertheless, anecdotally the use of black cohosh is widespread in this setting. 26 The potential interaction between adjunctive tamoxifen and black cohosh in this population has been subject of small number of preclinical and clinical investigations. 27-30(See SERMs later.)

Related adjuvant endocrine pharmacotherapies, such as aromatase inhibitors, including the more selective third-generation drugs, are restricted in use to postmenopausal patients. 24 Black cohosh does not contain the isoflavones with known in vitro aromatase inhibition (e.g., red clover, soy) and has no known aromatase inhibitory activity. Currently, no data relate coadministration of black cohosh with aromatase inhibitors.

Women for whom estrogen therapy is contraindicated and those with a history of estrogen-dependent malignancies should avoid black cohosh, according to some sources. 31 Recent studies on the pharmacology and clinical effects of black cohosh have been reviewed by Borrelli et al. 32,33The current consensus is that the herb is primarily antiestrogenic, with receptor-binding tests negative for alpha or beta estrogen receptor (ER), and that it lacks estrogenic effects on uterine tissue. 34-40Despite the predominant evidence for nonestrogenicity, as evidenced by assays on immortal ER-positive lines such as the MCF7 (breast) and Ishihara (endometrial) cell lines, data on cell proliferation are conflicting, with a few studies suggesting proliferation at low doses, although not at higher doses. 41-44In contrast, a recent poster report suggested that MMT-neu transgenic rats (in which mammary tumors develop through spontaneous activation of the HER-2/neu oncogene), when treated with equivalent oral doses of isopropanolic black cohosh, show increased metastatic progression to the lung at necropsy. 45 However, the black cohosh–treated animals did not differ from controls in latency or incidence of mammary tumor formation. Publicity about this poster report suggesting that black cohosh is unsafe for breast cancer patients would appear premature given that the weight of emerging evidence is against proliferative effects of the herb. 46 Further evidence is needed to establish safety definitively, and use of black cohosh in oncological settings should be restricted to health care professionals with appropriate clinical expertise in the use of botanicals in reproductive malignancies.

Evidence that both serotonergic and dopaminergic pathways may be involved in the mediation of some of the clinical effects of black cohosh on menopausal symptom reduction is gathering weight from initial experimental studies on serotonin receptor binding of the extract. 47 Borrelli et al. 33 hypothesized that serotonin may account for the apparent low-dose estrogenic effects, and this hypothesis has also been adopted by experienced researchers in the field such as Jarry et al. 48 Significantly, recent clinical evidence exists for the effectiveness of selective serotonin reuptake inhibitors (SSRIs; e.g., paroxetine, venlafaxine, fluoxetine) in reducing hot flashes in breast cancer patients. 49-51Circumstantial support for this theory is also found in ER research which suggests possible activation effect of ER transcription by serotonin. 52

The ER itself is an intensive focus of ongoing study, and the complexities of coactivation factors and pharmacogenomic variation within the alpha and beta receptor subtypes continue to expand the picture. 53-55The complexity of ER biology may account for some of the earlier contradictory research findings; for instance, the biphasic nature of dose-response curves exhibited by estrogens and phytoestrogens has been studied as an example of the general phenomenon of hormesis (biphasic or U -shaped dose response curves), adding a further explanatory dimension to the multifactorial mechanisms involved. 56,57

In clinical practice, combination prescriptions of herbs are often employed, but these are rarely studied in trials. An exception is a recent positive trial of the paired combination of St. John’s wort (Hypericum perforatum) and black cohosh for climacteric symptoms. 58 The study indirectly lends further support to the thesis that menopausal symptoms are caused by neurotransmitter imbalances, given the known pharmacology of St. John’s wort, which is devoid of phytoestogenic effects. (See St. John’s Wort monograph.)

Overall, the pharmacodynamics of black cohosh are complex and not fully understood. The focus on menopause may have detracted from wider considerations; for example, black cohosh compounds are chemoprotective against menadione-induced deoxyribonucleic acid (DNA) damage. 59 The model of black cohosh emerging from current research in many ways is more coincident with the traditional picture of the remedy as a neuroendocrine rather than a hormonal agent.

Effects on Drug Metabolism and Bioavailability

Pharmacokinetic interactions between black cohosh and prescription drugs have not been recorded to date. Preliminary clinical data suggest a potential for interactions with drugs metabolized by cytochrome P4502D6 (CYP2D6), following a probe drug study with desobriquin on 12 healthy volunteers by Gurley et al. 60 This study failed to find any effect of black cohosh extracts on CYP1A2, CYP2E1, and CYP3A4, despite significant inhibition of CYP2D6. The preparation was a commercial black cohosh extract standardized to 0.2% triterpene glycosides administered at 1090 mg orally twice daily for 28 days. An in vitro study tested separate black cohosh triterpene compounds for inhibitory activity against recombinant CYP3A4 oxidation of nifedipine. Separate isolated triterpenes demonstrated moderate IC50(median inhibitory concentration) effects, but the whole extract demonstrated a notable inhibition, with IC50of 0.027 mg/mL. The authors suggested potential for interactions with 3A4-metabolized drugs; however, this conflicts with the available clinical evidence from Gurley’s group, who established that black cohosh extracts had no effect in vivo on the 3A4 substrate midazolam. 61

Drugs metabolized by CYP2D6 include important tricyclic antidepressants, SSRIs, antipsychotics, stimulants (e.g., risperidone), analgesics, and tamoxifen. CYP2D6 is a narrow-band (high-affinity) low-throughput cytochrome, and many of the drugs metabolized by 2D6 can also be oxidized by 3A4. Polymorphisms of 2D6 are well known, and “poor metabolizers” have been shown to exhibit higher adverse effect levels with several drugs that are 2D6 substrates. Genotyping of patients for whom for prescription of 2D6 substrate drugs is indicated has been proposed as advisable. 62 Coadministration of black cohosh with drugs that are substrates of 2D6 should be avoided, or related drugs that are not 2D6 substrates should be selected, but interactions with 3A4 substrates are unlikely.

Modulation of drug transporters by black cohosh has received little study. Gurley et al. 63 found no effect of the herb (40 mg/day for 14 days) on digoxin pharmacokinetics, suggesting a negligible action on P-glycoprotein (P-gp). An experimental model of the human organic anion-transporting polypeptide B (OATP-B) revealed a moderate inhibitory effect on estrone-3-sulfate uptake after black cohosh addition; however, the number of known OATP-B substrates in humans is limited at present, although it does include DHEA-S and estrone. 64

herb-drug interactions
Androgen Blockade Chemotherapies
Hormone Replacement Therapy (HRT): Estrogen-Containing and Synthetic Estrogen and Progesterone Analog Medications
Selective Estrogen Response Modulators (SERMs)
theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Estrogen Replacement Therapy (ERT)
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