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Black cohosh (Cimicifuga racemosa [L.] Nutt.)



Interactions

Black cohosh/Drug Interactions:
  • AnalgesicsAnalgesics: Based on traditional use, black cohosh may have additive effects with analgesics (105).
  • AnestheticsAnesthetics: Based on traditional use, black cohosh may have additive effects with anesthetics (105).
  • Anticoagulants and antiplateletsAnticoagulants and antiplatelets: Native black cohosh contains small amounts of salicylic acid, and may potentiate the anti-platelet effects of other agents. This is a theoretical concern, as it is not clear if therapeutic amounts of salicylates are present in commercial or processed black cohosh products.
  • Antidepressant agents, selective serotonin reuptake inhibitors (SSRIs)Antidepressant agents, selective serotonin reuptake inhibitors (SSRIs): 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 (4; 6). A study in ovariectomized rats demonstrated strong binding to serotonin receptors 5-HT(1A), 5-HT(1D), and 5-HT(7) subtypes (4).
  • AntihistaminesAntihistamines: Based on in vitro study, black cohosh extract may inhibit histamine release (15).
  • AntihypertensivesAntihypertensives: Due to theoretical hypotensive effects, black cohosh should be used cautiously with other hypotensive agents (80; 27). There have been reports of hypotension in animals, although human data are limited in this area; increased peripheral blood flow was associated with black cohosh administration in a 1962 study (80).
  • Anti inflammatory agentsAnti inflammatory agents: Based on animal study, a phytoestrogen compound containing genistein, daidzein, glycitein, black cohosh, Angelica, licorice, and Vitex agnus-castus may lower levels of proinflammatory cytokines and increase levels of TGF-beta (106).
  • Antilipemic agentsAntilipemic agents: Based on randomized clinical studies, a combination of black cohosh (Cimicifuga racemosa) and St. John's wort (Hypericum perforatum) may significantly increase HDL levels (67), although other studies have not found the same results (62).
  • Antineoplastic agentsAntineoplastic agents: Based on 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 (22).
  • Cytochrome P450 metabolized agentsCytochrome P450 metabolized agents: Unlike those observed for rifampin and clarithromycin, midazolam pharmacokinetics was unaffected by black cohosh, and black cohosh does not appear to have a clinically relevant effect on CYP2D6 or CYP3A activity in vivo (107; 108).
  • Disulfiram (Antabuse®)Disulfiram (Antabuse®): Tinctures may contain high alcohol content, and theoretically may elicit a disulfiram reaction.
  • Dopamine agonistsDopamine agonists: 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 (4; 6).
  • Dopamine antagonistsDopamine antagonists: 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 (4; 6).
  • Drugs that may lower seizure thresholdDrugs that may lower seizure threshold: Tonic-clonic seizures have been reported in a 45 year-old woman who had been taking black cohosh, chaste tree (berries and seeds), and primrose oil for four months, who also consumed alcohol (100). The relative contribution of each agent or risk of combination is not clear.
  • EstrogensEstrogens: The estrogenic activity of black cohosh remains debated. Specific estrogenic constituents have not been identified, and it is not clear how (or if) black cohosh interacts with estrogens/estrogen receptors and/or progestins. Recent publications suggest that there may be no direct effects on estrogen receptors, although this is an area of active controversy (3; 7; 8; 9; 10; 6; 5; 4). Therefore, caution is warranted in individuals taking both black cohosh and estrogens due to unknown effects, and interactions data in this area are lacking. In animals and in vitro, initial reports of estrogen receptor binding activity (84) stand in contrast with more recent data suggesting no significant estrogen receptor binding activity or estrogenic activities (85; 86; 87; 46). One in vitro study found no effects of black cohosh alone on estrogen receptors, but reported that black cohosh antagonized proliferative effects on cells induced by estradiol (88). Several studies have aimed to assess estrogenic activity by measuring luteinizing hormone (LH), follicle stimulating hormone (FSH), or prolactin levels (89; 90). 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 (89). Results from other trials have found no effects on these hormone levels after up to six months of black cohosh therapy (91; 37; 49). Administered to female infantile mice, premature onset of estrus could not be precipitated by black cohosh (92). Estrogenic effects on vaginal epithelium were noted in one three-month trial of black cohosh (93), while a more recent six-month trial reported no effects on vaginal cytology (39). Based on a systematic review, with relevance to cancer patients, black cohosh also seems not to exhibit phytoestrogenic activity and may inhibit tumor growth (43).
  • EthanolEthanol: Tonic-clonic seizures have been reported in a 45 year-old woman who had been taking black cohosh, chaste tree (berries and seeds), and primrose oil for four months, who also consumed alcohol (100). The relative contribution of each agent or risk of combination is not clear.
  • Hepatotoxic agentsHepatotoxic agents: Several cases of liver damage have been reported following use of black cohosh (95; 96; 76; 54; 97). The USP notes that black cohosh may "possibly" cause liver damage (54).
  • Hormonal agentsHormonal agents: The estrogenic activity of black cohosh remains debated. Specific estrogenic constituents have not been identified, and it is not clear how (or if) black cohosh interacts with estrogens/estrogen receptors and/or progestins. Recent publications suggest that there may be no direct effects on estrogen receptors, although this is an area of active controversy (3; 7; 8; 9; 10; 6; 5; 4). Therefore, caution is warranted in individuals taking both black cohosh and estrogens due to unknown effects, and interactions data in this area are lacking. In animals and in vitro, initial reports of estrogen receptor binding activity (84) stand in contrast with more recent data suggesting no significant estrogen receptor binding activity or estrogenic activities (85; 86; 87; 46). One in vitro study found no effects of black cohosh alone on estrogen receptors, but reported that black cohosh antagonized proliferative effects on cells induced by estradiol (88). Several studies have aimed to assess estrogenic activity by measuring luteinizing hormone (LH), follicle stimulating hormone (FSH), or prolactin levels (89; 90). 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 (89). Results from other trials have found no effects on these hormone levels after up to six months of black cohosh therapy (91; 37; 49). Administered to female infantile mice, premature onset of estrus could not be precipitated by black cohosh (92). Estrogenic effects on vaginal epithelium were noted in one three-month trial of black cohosh (93), while a more recent six-month trial reported no effects on vaginal cytology (39).
  • Metronidazole (Flagyl®)Metronidazole (Flagyl®): A disulfiram reaction can occur when metronidazole and alcohol are used concomitantly. Due to the high alcohol content in some tinctures, this combination theoretically may cause such a reaction.
  • Oral agentsOral agents: Extracts of black cohosh moderately (but significantly) inhibited estrone-3-sulfate uptake, which suggests that coadministration may decrease the absorption of orally administered substrates of organic anion-transporting polypeptide B, which is considered to be involved in the intestinal absorption of various drugs (109).
  • Osteoporosis agentsOsteoporosis agents: Based on in vitro and animal studies, black cohosh may increase osteogenesis (31; 10; 110).
  • Salicylate-containing agents (e.g., aspirin)Salicylate-containing agents (e.g., aspirin): 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.
  • Tamoxifen, raloxifeneTamoxifen, raloxifene: Controversy surrounds the use of black cohosh in combination with tamoxifen. In a 2003 randomized, open-label controlled trial of black cohosh for the prevention of hot flashes in women survivors of breast cancer taking tamoxifen, 136 women, ages 36-52, received either black cohosh (CR BNO 1055, Menofem/Klimadynon, 20mg daily) with their tamoxifen, or tamoxifen alone (12). After 12 months, 24.4% of black cohosh subjects experienced hot flashes, compared to 73.9% in the tamoxifen-only group (p<0.01). These results are promising, although the introduction of bias due to the open-label design is possible. Long-term follow-up of disease-free interval was not conducted, therefore, the safety of black cohosh in breast cancer patients was not established. In a 2001 trial of 85 breast cancer survivors, endometrial hyperplasia was noted in one patient taking both black cohosh and tamoxifen (out of 42 subjects receiving black cohosh), and one instance each was noted of vaginal bleeding, weight gain, dilation and curettage, hysterectomy, and breast cancer recurrence (49). The influence of black cohosh alone or in combination with tamoxifen is not clear in these cases, although these complications were not reported among 43 non-black cohosh subjects. In this study, no improvements in hot flashes, other menopausal symptoms, or overall well being were noted over a two-month period (in contrast to other preliminary research suggesting efficacy of black cohosh for menopausal symptoms). It is not clear if tamoxifen antagonized the effects of black cohosh or if hot flashes induced by tamoxifen are refractory to black cohosh therapy. Although this trial suggests black cohosh may not be useful in the short-term treatment of tamoxifen-related hot flashes, due to methodological weaknesses, further study is warranted. Also in this trial, constipation was noted in one subject, and indigestion in one subject (49). Recent in vitro study suggests possible additive anti-proliferative effects of black cohosh and tamoxifen (111; 88).
  • VasodilatorsVasodilators: Laboratory study of cimicifugic acids C and D, and fukinolic acid in the rhizome of black cohosh show vasoactive effects (112).

Black cohosh/Herb/Supplement Interactions:
  • American pennyroyalAmerican pennyroyal: Pennyroyal (Hedeoma pulegioides L.) and black cohosh are sometimes taken together to induce abortion, although the use of these herbs together cannot be recommended due to the possibility of increased toxicity and death. There is a case report of a 24 year-old woman who took 48-56% of pennyroyal herb in an alcohol base and an unknown amount of black cohosh root for two weeks in an attempt to induce abortion (113). Following a single subsequent dose of this combination, the patient died within 48 hours.
  • AnalgesicsAnalgesics: Based on traditional use, black cohosh may have additive effects with analgesics (105).
  • AnestheticsAnesthetics: Based on traditional use, black cohosh may have additive effects with anesthetics (105).
  • Anticoagulants and antiplateletsAnticoagulants and antiplatelets: Native black cohosh contains small amounts of salicylic acid, and may potentiate the anti-platelet effects of other agents, such as ginkgo or garlic. This is a theoretical concern, as it is not clear if therapeutic amounts of salicylates are present in commercial or processed black cohosh products.
  • Antidepressants, selective serotonin reuptake inhibitors (SSRIs)Antidepressants, selective serotonin reuptake inhibitors (SSRIs): 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 (4; 6). A study in ovariectomized rats demonstrated strong binding to serotonin receptors 5-HT(1A), 5-HT(1D), and 5-HT(7) subtypes (4).
  • AntihistaminesAntihistamines: Based on in vitro study, black cohosh extract may inhibit histamine release (15).
  • Anti inflammatory herbs and supplementsAnti inflammatory herbs and supplements: Based on animal study, a phytoestrogen compound containing genistein, daidzein, glycitein, black cohosh, Angelica, licorice, and Vitex agnus-castus may lower levels of proinflammatory cytokines and increase levels of TGF-beta (106).
  • AntilipemicsAntilipemics: Based on randomized clinical studies, it is unclear whether a combination of black cohosh (Cimicifuga racemosa) and St. John's wort (Hypericum perforatum) increases HDL levels (67) or leaves lipid levels unchanged (62).
  • AntineoplasticsAntineoplastics: Based on 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 (22). However, black cohosh may not interact with all chemotherapy agents, as an animal study using high doses of black cohosh with low doses of formestane indicated (114).
  • AntioxidantsAntioxidants: Based on in vitro study, black cohosh may have antioxidant properties (16; 115; 17).
  • Blue cohosh (Caulophyllum thalictroides)Blue cohosh (Caulophyllum thalictroides): Both black cohosh and blue cohosh (Caulophyllum thalictroides) are commonly used by nurse-midwives in the United States to assist birth (52). There is a report of severe multi-organ hypoxic injury in a child delivered "naturally" with the aid of both blue and black cohosh, who was not breathing at the time of birth (50; 51; 52). The child survived with permanent central nervous system damage. Notably, blue cohosh possesses a vasoconstrictive glycoside, which may have been responsible for the adverse effects. Although used internationally, little safety and efficacy data is available for homeopathic preparations of blue and black cohosh (103).
  • ChasteberryChasteberry: Tonic-clonic seizures had been reported in a 45 year-old woman who had been taking black cohosh, chaste tree (berries and seeds), and primrose oil for four months, who also consumed alcohol (100). The relative contribution of each agent or risk of combination is not clear.
  • Cytochrome P450 metabolized herbs and supplementsCytochrome P450 metabolized herbs and supplements: Black cohosh does not appear to have a clinically relevant effect on CYP2D6 or CYP3A activity in vivo (107; 108).
  • Dopamine agonistsDopamine agonists: 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 (4; 6).
  • Dopamine antagonistsDopamine antagonists: 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 (4; 6).
  • Evening primrose oilEvening primrose oil: Tonic-clonic seizures had been reported in a 45 year-old woman who had been taking black cohosh, chaste tree (berries and seeds), and primrose oil for four months, who also consumed alcohol (100). The relative contribution of each agent or risk of combination is not clear.
  • Hepatotoxic agentsHepatotoxic agents: Several cases of liver damage have been reported following use of black cohosh (95; 96; 76; 54; 97). The USP notes that black cohosh may "possibly" cause liver damage (54).
  • Herbs and supplements that lower seizure thresholdHerbs and supplements that lower seizure threshold: Tonic-clonic seizures had been reported in a 45 year-old woman who had been taking black cohosh, chaste tree (berries and seeds), and primrose oil for four months, who also consumed alcohol (100). The relative contribution of each agent or risk of combination is not clear.
  • Hormonal herbs and supplementsHormonal herbs and supplements: The estrogenic activity of black cohosh remains debated. Specific estrogenic constituents have not been identified, and it is not clear if black cohosh interacts with other estrogenic compounds, such as soy or evening primrose oil (Oenothera biennis). Publications suggest that there may be no direct effects on estrogen receptors, although this is an area of active controversy (3; 7; 8; 9; 10; 6; 5; 4).
  • HypotensivesHypotensives: Due to theoretical hypotensive effects, black cohosh should be used cautiously with other hypotensive agents (80; 27). There have been reports of hypotension in animals, although human data are limited in this area; increased peripheral blood flow was associated with black cohosh administration in a 1962 study (80).
  • Oral herbs and supplementsOral herbs and supplements: Extracts of black cohosh moderately (but significantly) inhibited estrone-3-sulfate uptake, which suggests that coadministration may decrease the absorption of orally administered substrates of organic anion-transporting polypeptide B, which is considered to be involved in the intestinal absorption of various drugs (109).
  • Osteoporosis agentsOsteoporosis agents: Based on in vitro and animal studies, black cohosh may increase osteogenesis (31; 10; 110).
  • PhytoestrogensPhytoestrogens: The estrogenic activity of black cohosh remains debated. Specific estrogenic constituents have not been identified, and it is not clear if black cohosh interacts with other estrogenic compounds. Recent publications suggest that there may be no direct effects on estrogen receptors, although this is an area of active controversy (3; 4; 39; 7; 8; 9; 10; 6; 5; 89; 49; 84; 90; 37; 91; 86; 87; 46; 92; 93; 43; 85). Therefore, caution is warranted in subjects taking both black cohosh and herbs containing phytoestrogens due to unknown effects, and interaction data in this area are lacking.
  • Salicylate-containing herbs and supplements (e.g., willowbark)Salicylate-containing herbs and supplements (e.g., willowbark): 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.
  • St. John's wortSt. John's wort: Based on an open observational study of 6,141 menopausal women, black cohosh combined with St. John's wort may alleviate climacteric mood symptoms more than black cohosh alone (77).
  • Vasodilator herbs and supplementsVasodilator herbs and supplements: Laboratory study of cimicifugic acids C and D, and fukinolic acid in the rhizome of black cohosh show vasoactive effects (112).

Black cohosh/Food Interactions:
  • Insufficient available evidence.

Black cohosh/Lab Interactions:
  • Allergy testsAllergy tests: Based on in vitro study, black cohosh extract may inhibit histamine release (15).
  • Bone markersBone markers: 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 (31).
  • Coagulation panelCoagulation panel: Native black cohosh contains small amounts of salicylic acid, and may potentiate the anti-platelet effects of other agents. This is a theoretical concern, as it is not clear if therapeutic amounts of salicylates are present in commercial or processed black cohosh products.
  • Serum glucoseSerum glucose: In a randomized trial in 351 peri- or post-menopausal women, black cohosh had no demonstrable effects on lipids, glucose, insulin, or fibrinogen (62).
  • Serum insulinSerum insulin: In a randomized trial in 351 peri- or post-menopausal women, black cohosh had no demonstrable effects on lipids, glucose, insulin, or fibrinogen (62).
  • Serum levels of cytochrome P450 metabolized agentsSerum levels of cytochrome P450 metabolized agents: Unlike those observed for rifampin and clarithromycin, midazolam pharmacokinetics was unaffected by black cohosh, and black cohosh does not appear to have a clinically relevant effect on CYP2D6 or CYP3A activity in vivo (107; 108).
  • Serum levels of oral agentsSerum levels of oral agents: Extracts of black cohosh moderately (but significantly) inhibited estrone-3-sulfate uptake, which suggests that coadministration may decrease the absorption of orally administered substrates of organic anion-transporting polypeptide B, which is considered to be involved in the intestinal absorption of various drugs (109).
  • Serum lipidsSerum lipids: Based on human studies, there is controversy about whether black cohosh alters serum lipid levels (67; 62).

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The information in this monograph is intended for informational purposes only, and is meant to help users better understand health concerns. Information is based on review of scientific research data, historical practice patterns, and clinical experience. This information should not be interpreted as specific medical advice. Users should consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.

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