Family

Ranunculaceae.

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.

Overview

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.

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

• 1.BHMA. Black cohosh. In: Bradley P, ed. British Herbal Compendium. 1 vol. Bournemouth, UK: British Herbal Medical Association; 1992:34-36.
• 2.Blumenthal M, Busse W, Goldberg A et al. Black cohosh root. The Complete German Commission E Monographs. Austin, TX: American Botanical Council: Integrative Medicine Communications; 1998:90.
• 3.WHO. Rhizoma cimicifugae racemosae. WHO Monographs on Selected Medicinal Plants. 2 vol. Geneva: World Health Organization; 2002:55-65.
• 4.Upton R. Black cohosh rhizome. American Herbal Pharmacopoeia. Santa Cruz, CA; 2002.
• 5.ESCOP. Cimicifugae rhizoma. ESCOP Monographs: the Scientific Foundation for Herbal Medicinal Products. 2nd ed. Exeter, UK: European Scientific Cooperative on Phytotherapy and Thieme; 2003:79-91.
• 6.Duke JA. The CRC Handbook of Medicinal Herbs. Boca Raton, FL: CRC Press; 1985.
• 7.Millspaugh CF. Cimicifuga. American Medicinal Plants. New York: Dover Edition, 1974; 1892:37-40.
• 8.Felter H, Lloyd J. Cimicifuga. King’s American Dispensatory. 1 vol. 1983 Reprint ed. Sandy, OR: Eclectic Medical Publications; 1898:529-533.
• 9.Felter H. Macrotys. The Eclectic Materia Medica, Pharmacology and Therapeutics. Eclectic Medical Publications, Portland, OR; 1985 ed. Cincinnati, OH; 1922:466-470.
• 10.Ellingwood F, Lloyd J. Macrotys. The American Materia Medica, Therapeutics, and Pharmacognosy. Eclectic Medical Publications, Portland, OR; 1983 ed. Cincinnati, OH; 1919:144-147.
• 11.Leyel CF. A Modern Herbal by Mrs M Grieve. Penguin Reprint Edition, 1976 ed. London: Jonathan Cape; 1931.
• 12.Boericke W. Cimicifuga racemosa. Homeopathic Materia Medica and Repertory. 9th ed. Reprinted 1994 ed. New Delhi: B Jain; 1927.
• 13.Chen SN, Li W, 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;65:601-605.View Abstract
• 14.Kennelly EJ, Baggett S, Nuntanakorn P et al. Analysis of thirteen populations of black cohosh for formononetin. Phytomedicine 2002;9:461-467.View Abstract
• 15.Jiang B, Kronenberg F, Balick MJ, Kennelly EJ. Analysis of formononetin from black cohosh (Actaea racemosa). Phytomedicine 2006;13:477-486.View Abstract
• 16.Nuntanakorn P, Jiang B, Einbond LS et al. Polyphenolic constituents of Actaea racemosa. J Nat Prod 2006;69:314-318.View Abstract
• 17.Mills S, Bone K. Black cohosh. Principles and Practice of Phytotherapy. Edinburgh: Churchill Livingstone; 2000:303-309.
• 18.Low Dog T, Powell KL, Weisman SM. Critical evaluation of the safety of Cimicifuga racemosa in menopause symptom relief. Menopause 2003;10:299-313.View Abstract
• 19.Huntley A, Ernst E. A systematic review of the safety of black cohosh. Menopause 2003;10:58-64.View Abstract
• 20.Thomsen M, Schmidt M. Hepatotoxicity from Cimicifuga racemosa? Recent Australian case report not sufficiently substantiated. J Altern Complement Med 2003;9:337-340.View Abstract
• 21.National Institutes of Health: Workshop on the Safety of Black Cohosh in Clinical Studies, Nov 22, 2004. Bethesda, MD: NCCAM, ODS; 2004.
• 22.Day R, Ganz PA, Costantino JP et al. Health-related quality of life and tamoxifen in breast cancer prevention: a report from the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Clin Oncol 1999;17:2659-2669.View Abstract
• 23.Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371-1388.View Abstract
• 24.Ibrahim NK, Hortobagyi GN. The evolving role of specific estrogen receptor modulators (SERMs). Surg Oncol 1999;8:103-123.View Abstract
• 25.Rostom AY. The management of menopausal sequelae in patients with breast cancer. Clin Oncol (R Coll Radiol) 2001;13:174-180.View Abstract
• 26.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 2002;62:3448-3452.View Abstract
• 27.Bodinet C, Freudenstein J. Influence of Cimicifuga racemosa on the proliferation of estrogen receptor–positive human breast cancer cells. Breast Cancer Res Treat 2002;76:1-10.View Abstract
• 28.Hernandez Munoz G, Pluchino S. Cimicifuga racemosa for the treatment of hot flushes in women surviving breast cancer. Maturitas 2003;44 Suppl 1:S59-65.View Abstract
• 29.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;19:2739-2745.
• 30.Nisslein T, Freudenstein J. Synergistic effects of black cohosh and tamoxifen in an animal model of mammary carcinoma. Maturitas 2003;44 Suppl 2:S128.
• 31.Brinker F. Herb Contraindications and Drug Interactions. 3rd ed. Sandy, OR: Eclectic Medical Publications; 2001.
• 32.Borrelli F, Ernst E. Cimicifuga racemosa: a systematic review of its clinical efficacy. Eur J Clin Pharmacol 2002;58:235-241.View Abstract
• 33.Borrelli F, Izzo AA, Ernst E. Pharmacological effects of Cimicifuga racemosa. Life Sci 2003;73:1215-1229.View Abstract
• 34.Zierau O, Bodinet C, Kolba S et al. Antiestrogenic activities of Cimicifuga racemosa extracts. J Steroid Biochem Mol Biol 2002;80:125-130.View Abstract
• 35.Mahady GB. Is black cohosh estrogenic? Nutr Rev 2003;61:183-186.
• 36.Einer-Jensen N, Zhao J, Andersen KP, Kristoffersen K. Cimicifuga and Melbrosia lack oestrogenic effects in mice and rats. Maturitas 1996;25:149-153.View Abstract
• 37.Seidlova-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:S39-50.View Abstract
• 38.Wuttke W, Jarry H, Becker T et al. Phytoestrogens: endocrine disrupters or replacement for hormone replacement therapy? Maturitas 2003;44 Suppl 1:S9-20.
• 39.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;44 Suppl 1:S67-77.View Abstract
• 40.Liske E, Hanggi W, Henneicke-von Zepelin HH et al. Physiological investigation of a unique extract of black cohosh (Cimicifugae racemosae rhizoma): a 6-month clinical study demonstrates no systemic estrogenic effect. J Womens Health Gend Based Med 2002;11:163-174.View Abstract
• 41.Liu Z, Yang Z, Zhu M, Huo J. [Estrogenicity of black cohosh (Cimicifuga racemosa) and its effect on estrogen receptor level in human breast cancer MCF-7 cells]. Wei Sheng Yan Jiu 2001;30:77-80.View Abstract
• 42.Kruse SO, Lohning 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 1999;65:763-764.View Abstract
• 43.Zava DT, Dollbaum CM, Blen M. Estrogen and progestin bioactivity of foods, herbs, and spices. Proc Soc Exp Biol Med 1998;217:369-378.View Abstract
• 44.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;49:2472-2479.View Abstract
• 45.Davis V, Jayo M, Hardy M et al. Effects of black cohosh on mammary tumor development and progression in MMTV-neu transgenic mice. Abstract R910. Proceedings of the AACR, Vol 44, 2nd ed, July 2003.
• 46.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;71:495-500.View Abstract
• 47.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;51:5661-5670.View Abstract
• 48.Jarry H, Metten M, Spengler B et al. In vitro effects of the Cimicifuga racemosa extract BNO 1055. Maturitas 2003;44 Suppl 1:S31-38.View Abstract
• 49.Weitzner MA, Moncello J, Jacobsen PB, Minton S. A pilot trial of paroxetine for the treatment of hot flashes and associated symptoms in women with breast cancer. J Pain Symptom Manage 2002;23:337-345.View Abstract
• 50.Loprinzi CL, Kugler JW, Sloan JA et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 2000;356:2059-2063.View Abstract
• 51.Loprinzi CL, Sloan JA, Perez EA et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002;20:1578-1583.View Abstract
• 52.O’Malley BW, Schrader WT, Mani S et al. An alternative ligand-independent pathway for activation of steroid receptors. Recent Prog Horm Res 1995;50:333-347.
• 53.Yoon K, Pallaroni L, Stoner M et al. Differential activation of wild-type and variant forms of estrogen receptor alpha by synthetic and natural estrogenic compounds using a promoter containing three estrogen-responsive elements. J Steroid Biochem Mol Biol 2001;78:25-32.View Abstract
• 54.Bramlett KS, Burris TP. Target specificity of selective estrogen receptor modulators within human endometrial cancer cells. J Steroid Biochem Mol Biol 2003;86:27-34.
• 55.Igaz P, Pap E, Patocs A et al. Genomics of steroid hormones: in silico analysis of nucleotide sequence variants (polymorphisms) of the enzymes involved in the biosynthesis and metabolism of steroid hormones. J Steroid Biochem Mol Biol 2002;82:359-367.View Abstract
• 56.Calabrese EJ. Estrogen and related compounds: biphasic dose responses. Crit Rev Toxicol 2001;31:503-515.View Abstract
• 57.Almstrup K, Fernandez MF, Petersen JH et al. Dual effects of phytoestrogens result in U-shaped dose-response curves. Environ Health Perspect 2002;110:743-748.View Abstract
• 58.Uebelhack R, Blohmer J-U, Graubaum H-J et al. Black cohosh and St. John’s wort for climacteric complaints: a randomized trial. Obstet Gynecol 2006;107:247-255.View Abstract
• 59.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;50:7022-7028.View Abstract
• 60.Gurley BJ, Gardner SF, Hubbard MA et al. In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes. Clin Pharmacol Ther 2005;77:415-426.View Abstract
• 61.Gurley B, Hubbard MA, Williams DK et al. Assessing the clinical significance of botanical supplementation on human cytochrome P450 3A activity: comparison of a milk thistle and black cohosh product to rifampin and clarithromycin. J Clin Pharmacol 2006;46:201-213.View Abstract
• 62.Cozza K, Armstrong S, Oesterheld J. Drug Interaction Principles for Medical Practice. 2nd ed. Washington, DC: American Psychiatric Publishing; 2003.
• 63.Gurley B, 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 2005;34:69-74.View Abstract
• 64.Fuchikami H, Satoh H, Tsujimoto M et al. Effects of herbal extracts on the function of human organic anion transporting polypeptide, OATP-B. Drug Metab Dispos 2006;34:577-582.View Abstract
• 65.Moyad MA. Complementary/alternative therapies for reducing hot flashes in prostate cancer patients: reevaluating the existing indirect data from studies of breast cancer and postmenopausal women. Urology 2002;59:20-33.View Abstract
• 66.Strum S, Pogliano D. A Primer on Prostate Cancer. Hollywood, FL: Life Extension Foundation; 2002:151-153.
• 67.McKenna DJ, Jones K, Humphrey S, Hughes K. Black cohosh: efficacy, safety, and use in clinical and preclinical applications. Altern Ther Health Med 2001;7:93-100.View Abstract
• 68.Gokhale L, Sturdee DW, Parsons AD. The use of food supplements among women attending menopause clinics in the West Midlands. J Br Menopause Soc 2003;9:32-35.
• 69.Kam IW, Dennehy CE, Tsourounis C. Dietary supplement use among menopausal women attending a San Francisco health conference. Menopause 2002;9:72-78.
• 70.Newton KM, Buist DS, Keenan NL et al. Use of alternative therapies for menopause symptoms: results of a population-based survey. Obstet Gynecol 2002;100:18-25.View Abstract
• 71.Ma J, Drieling R, Stafford RS. US women desire greater professional guidance on hormone and alternative therapies for menopause symptom management. Menopause 2006;13:506-516.View Abstract
• 72.Ness J, Aronow WS, Beck G. Menopausal symptoms after cessation of hormone replacement therapy. Maturitas 2006;53:356-361.View Abstract
• 73.Nisslein T, Freudenstein J. Concomitant administration of an isopropanolic extract of black cohosh and tamoxifen in the in vivo tumor model of implanted RUCA-I rat endometrial adenocarcinoma cells. Toxicol Lett 2004;150:271-275.View Abstract
• 74.Pockaj BA, Loprinzi CL, Sloan JA et al. Pilot evaluation of black cohosh for the treatment of hot flashes in women. Cancer Invest 2004;22:515-521.View Abstract
• 75.Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998;158:2200-2211.View Abstract
• 76.Harkness R, Bratman S. Mosby’s Handbook of Drug-Herb and Drug-Supplement Interactions. St Louis: Mosby; 2003.