Black cohosh (Cimicifuga racemosa)

• Constituents: Constituents of black cohosh with proposed or demonstrated pharmacological activity include triterpine glycosides (23-epi-26-deoxyactein, actein, 27-deoxyactein, cimicifugoside A, cimicifugoside M, cimiracemoside A-H)^{21,45,46,47,48,12,49,50,51}, cyclolanostanol xylosides ⁵², isoflavonone formononetin ⁵³, hydroxytyrosol ⁵⁴, actaeaeposcide ⁵⁵, phenylpropanoids (cimiracemate A, cimiracemate B)^8,56, organic acids (caffeic acid, cimicifugic acid A, cimicifugic acid B, cimicifugic acid E, cimicifugic acid F, cinnamic acid ester dehydrocimicifugic A, dehydrocimicifugic acid B, dihydroxyphenyl lactic acid, ferulic acid, fukinolic acid, isoferulic acid, methyl caffeate acid, salicylic acid)^8,57,54,58, phenols⁵⁷, quinoid metabolites of caffeic acid, cimiracemate B, fukinolic acid, fukiic acid, and.hydroxytyrosol⁵⁴. Actaea racemosa specifically contains lignans (e.g., actaealactone), phenylpropanoid ester derivatives (e.g., cimicifugic acid), polyphenols (0.36-2.92% (w/w) in dried root and rhizome), protocatechuic acid, protocatechualdehyde, p-coumaric acid, caffeic acid, methyl caffeate, ferulic acid, ferulate-1-methyl ester, isoferulic acid, 1-isoferuloyl-beta-d-glucopyranoside, fukinolic acid, and cimicifugic acids A, B, and D-F.^9,59. Methods of extracting active ingredients from black cohosh have been described.⁶⁰
• Anti-climacteric effects: According to in vitro study, black cohosh was found to be consistent with a human mu opiate receptor (hMOR) agonist, with an EC₅₀ of 68.8 ± 7.7mcg/mL, which may explain its purported beneficial role in alleviating menopausal symptoms.⁶¹
• Anti-coagulation effects: Native black cohosh contains small amounts of salicylic acid, but it is not clear how much (if any) is present in commercially available or standardized extracts. A popular combination product, Reumalex^®, contains black cohosh, white willow bark, sarsaparilla, poplar bark, and guaiacum resin. Notably, several constituents contain salicylates, and it has been estimated that each Reumalex® tablet may include up to 10-20mg of salicylates.
• Anti-inflammatory activity: Ovariectomized Wistar rats administered a phytoestrogen compound (genistein, daidzein, glycitein, black cohosh, Angelica, licorice, and Vitex agnus-castus) orally showed a significantly lower level of proinflammatory cytokines and a higher level of TGF-beta.³⁸ The constituent isoferulic acid has also been reported to have anti-inflammatory effects and may decrease muscular spasm.¹¹ Furthermore, salicylic acid is found in small quantities in black cohosh, and it is presumed that the salicylic acid contributes to the anti-inflammatory and analgesic properties of black cohosh.
• Antineoplastic effects: Based on a systematic review, there is laboratory evidence of antiproliferative properties of black cohosh but a lack of confirmation from clinical studies for a protective role in cancer prevention.¹⁹ In vitro studies have reported black cohosh to possess inhibitory effects on estrogen responsive cancer cell lines/breast cancer cells.^{37,45,62,63,22,21} Furthermore, in a cell line study, relatively low concentrations of actein or the methanol/water fraction of black cohosh may cause synergistic inhibition of human breast cancer cell proliferation when combined with different classes of chemotherapy agents.¹² Acetein may activate genes that respond to DNA damage and unfolded protein responses, and enhance apoptosis and repressed cell cycle genes.^64,65 Actaealactone and cimicifugic acid may also have a small stimulating effect on the growth of breast cancer cell proliferation.⁹ In an in vitro study conducted on human prostate cancer cells with black cohosh extract, the extract killed hormone-responsive or hormone-unresponsive prostate cancer cells by induction of apoptosis and activation of caspases.¹³ Another in vivo study in mice demonstrated inhibited PC3 prostate cancer tumor growth with black cohosh and other herbal extracts.¹⁴ The mechanism behind tumor inhibition appeared to be anti-angiogenic by decreasing intratumoral microvessel density.
• Antioxidant effects: Extracts of black cohosh have protected against induced DNA damage through scavenging of reactive oxygen species in vitro.⁸ A sample of black cohosh collected in 1919 by the physician and plant explorer Henry Hurd Rusby, was recently identified in the collections of The New York Botanical Garden and analyzed. A comparison of the triterpene glycosidic and phenolic constituents of the 85 year-old plant sample with those of a modern collection of Actaea racemosa showed the similarity of the two samples, and both extracts showed similar antioxidant activity. This confirms the stability of the older sample, despite curation.⁴⁴ In laboratory study, the constituents, actaealactone, cimicifugic acid, and fukinolic acid may display antioxidant activity in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free-radical assay with IC₅₀ values of 26 and 37mcM, respectively.^9,59
• Bone metabolism effects: An isopropanolic extract of black cohosh has been shown to significantly diminish the urinary content of pyridinoline and deoxypyridinoline, specific markers for bone loss, and the morphometric correlates of bone loss associated with ovariectomy in rats.¹⁵ Ovariectomized rats treated with Cimicifuga racemosa extract had slightly stimulated gene expression of IGF-I, collagen-lαl, osteoprotegerin and osteocalcin (all osteoblast products), and of tartrate-resistant acid phophatas (TRAP, an osteoclast product) in the metaphysic of the femur.⁶ In an in vitro study, an isopropanolic extract (iCR) from the rhizomes of black cohosh stimulated osteoblastic osteoprotegerin protein secretion by 3- to 5-fold as early as 12h without affecting receptor activator for nuclear factor κB ligand (RANKL) expression.⁴²
• CNS effects: Recent studies suggest that the mechanism of action of black cohosh may be centrally mediated, with possible action at the level of serotonin or dopamine receptors.^2,3 A study in ovariectomized rats demonstrated strong binding to serotonin receptors 5-HT(1A), 5-HT(1D), and 5-HT(7) subtypes.²
• Cytochrome P450 (CYP) effects: In a clinical trial of 12 healthy volunteers (six women), black cohosh daily for 28 days had a statistically significant inhibition of CYP2D6 (difference, -0.046; 95% CI, -0.085 to -0.007), but the magnitude of the effect (approximately 7%) did not appear to be clinically relevant.⁴⁰ In another trial by the same authors, healthy volunteers taking black cohosh 80mg daily for 14 days did not have a clinically relevant effect on their CYP3A activity.³⁹
• Endocrine effects: Cimicifugoside contained in black cohosh is believed to affect hypothalamus-pituitary function.
• Estrogenic effects: It is not clear what constituent(s) of black cohosh, if any, possesses estrogenic properties. In animals and in vitro, initial reports of estrogen receptor binding activity.^27,30 stand in contrast with more recent data suggesting no significant estrogen receptor binding activity or estrogenic activities.^{66,1,4,29,30,20,5,67,68,46,28,10} Two in vitro studies found no effects of black cohosh alone on estrogen receptors, but reported that black cohosh antagonized proliferative effects on cells induced by estradiol.^31,31 A similar in vitro study on estrogen sensitive breast cancer cells (MCF-7) reported isopropanolic black cohosh extract did not stimulate MCF-7 growth and exerted inhibitory effects on cellular proliferation, indicating strong estrogen-antagonist effects.⁶⁹ The proliferation-inhibiting effect of tamoxifen has been enhanced by black cohosh extract.³¹ Several studies have aimed to assess estrogen activity by measuring luteinizing hormone (LH), follicle stimulating hormone (FSH), or prolactin levels.^32,33 One study reported lower FSH levels (but not LH) in patients treated with black cohosh vs. placebo (N=110), although baseline hormone levels were not known in either group.³² Results from other trials have found no effects on these hormone levels after up to six months of black cohosh therapy.^34,17,23 Administered to female infantile mice, premature onset of estrus could not be precipitated by black cohosh.³⁵ Estrogenic effects on vaginal epithelium were noted in one three-month trial of black cohosh³⁶, while a more recent six-month trial reported no effects on vaginal cytology¹⁸. Cimicifuga racemosa ethanolic extract, Ze 450, may inhibit cell proliferation and show antiestrogenic activity.⁷⁰ The Cimicifuga racemosa extract bound to the progesterone receptor B1 but did not show progestin-like activity in the T-47D cell line. In an in vitro study using healthy breast tissue of pre- and postmenopausal women, incubation in vitro with black cohosh extract decreased local estrogen formation.⁷¹
• Gastrointestinal effects: In an in vitro study, black cohosh extracts moderately (but significantly) inhibited estrone-3-sulfate (a typical organic anion-transporting polypeptide B (OATP-B) substrate) uptake by 47.2% (p<0.05).⁴¹ As OAT-B is involved in the intestinal absorption of various drugs, black cohosh may decrease the absorption of orally administered substrates of OATP-B.
• Neuropharmacologic effects: Black cohosh has been shown to exhibit an action on the central endogenous opioid system in postmenopausal women as evidenced by suppression of mean luteinizing hormone pulse frequency following opioid receptor blockade.⁷²
• Serum glucose level altering effects: In a randomized trial in 351 peri- or post-menopausal women, black cohosh had no demonstrable effects on lipids, glucose, insulin, or fibrinogen.²⁴
• Serum insulin level altering effects: In a randomized trial in 351 peri- or post-menopausal women, black cohosh had no demonstrable effects on lipids, glucose, insulin, or fibrinogen.²⁴
• Serum lipid level altering effects: In a double-blind randomized, placebo controlled, study in 89 peri- or postmenopausal women experiencing climacteric symptoms, a combination of black cohosh (Cimicifuga racemosa) and St. John's wort (Hypericum perforatum) significantly increased HDL levels (from 58.32 ± 11.64 to 59.74 ± 10.54; p=0.04) compared to the control (from 60.20 ± 16.37 to 56.63 ± 12.67).²⁵ However, in a randomized trial in 351 peri- or post-menopausal women, black cohosh had no demonstrable effects on lipids, glucose, insulin, or fibrinogen.²⁴
• Vascular effects: In a 1962 study, acteina, a constituent of black cohosh, was found to cause peripheral vasodilation, and has been noted to elicit hypotension in animals.²⁶ Additional supporting data in humans is lacking.
• Vasoactive effects: Laboratory study of cimicifugic acids C and D, and fukinolic acid in the rhizome of black cohosh show vasoactive effects.⁴³
• Other: In vivo oral administration of black cohosh extract inhibited the anti-IgE-induced passive cutaneous anaphylaxis reaction.⁷ Black cohosh extract also showed inhibitory potential on histamine release. Cimicifugoside from Cimicifuga simplex has been found to inhibit cellular thymidine-³H uptake, and to act as a selective inhibitor of nucleoside transport into mammalian cells.^73,74,16,73

Pharmacokinetics/Pharmacodynamics:

• According to in vitro study, black cohosh was found to be consistent with a human mu opiate receptor (hMOR) agonist, with an EC₅₀ of 68.8 ± 7.7mcg/mL, which may explain its purported beneficial role in alleviating menopausal symptoms.⁶¹
• In a clinical trial, oral black cohosh administration for 14 days did not significantly affect digoxin's area under the serum concentration time curves from 0-3 hours (AUC(0-3)), AUC(0-24), C_max, apparent oral clearance of digoxin (CL/F), and elimination half-life.⁷⁵ Digoxin is a known P-glycoprotein (P-gp) substrate, which suggests that black cohosh is not a potent modulator of P-gp in vivo.