Black cohosh

Black cohosh/Drug Interactions:

  • AnalgesicsAnalgesics: According to traditional use, black cohosh may have additive effects with analgesics (167).
  • AnestheticsAnesthetics: The authors of a systematic review indicated that black cohosh may interact with anesthetics, according to the Clinical Practice Guideline of the Canadian Society of Obstetricians and Gynecologists (86). According to traditional use, black cohosh may have additive effects with anesthetics (167).
  • AntiandrogensAntiandrogens: 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 (168). Another in vivo study in mice demonstrated inhibited PC3 prostate cancer tumor growth with black cohosh and other herbal extracts (53).
  • AntiarthriticsAntiarthritics: In humans, Reumalex? has been reported to have significant improvements in arthritis pain (169).
  • Anticoagulants and antiplateletsAnticoagulants and antiplatelets: The authors of a systematic review indicated that black cohosh may contain anticoagulant coumarins, although an effect on prothrombin times was lacking (86). However, in a clinical trial of postmenopausal women, changes in markers of coagulation were lacking (98). Native black cohosh contains small amounts of salicylic acid and may potentiate the antiplatelet effects of other agents. It is unclear 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 (11; 13; 8). A study in ovariectomized rats demonstrated strong binding to serotonin receptors 5-HT(1A), 5-HT(1D), and 5-HT(7) subtypes (11).
  • AntiestrogensAntiestrogens: The estrogenic activity of black cohosh remains debated. Specific estrogenic constituents have not been identified, and it is unclear how (or if) black cohosh interacts with estrogens, estrogen receptors, and/or progestins. Publications suggest that there may be no direct effects on estrogen receptors, although this is an area of controversy (10; 14; 15; 16; 17; 13; 12; 11). In animals and in vitro, initial reports of estrogen receptor-binding activity (139) stand in contrast with data suggesting a lack of significant estrogen receptor-binding activity or estrogenic activities (140; 141; 142; 80). One in vitro study found no effects of black cohosh alone on estrogen receptors, but it reported that black cohosh antagonized proliferative effects on cells induced by estradiol (143). Several studies have aimed to assess estrogenic activity by measuring luteinizing hormone (LH), follicle-stimulating hormone (FSH), or prolactin levels (144; 145). 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 (144). Results from other trials have found no effects on these hormone levels after up to six months of black cohosh therapy (146; 60; 78). When administered to female infantile mice, black cohosh could not precipitate premature onset of estrus (147). Estrogenic effects on vaginal epithelium were noted in one three-month trial of black cohosh (148), while a six-month trial reported no effects on vaginal cytology (62). In a systematic review, with relevance to cancer patients, black cohosh also seemed to lack phytoestrogenic activity and may inhibit tumor growth (29).
  • AntihistaminesAntihistamines: In vitro, black cohosh extract showed inhibitory potential for histamine release (49).
  • AntihypertensivesAntihypertensives: The authors of a systematic review mentioned that black cohosh may interact with antihypertensives, according to the Clinical Practice Guideline of the Canadian Society of Obstetricians and Gynecologists (86). Due to theoretical hypotensive effects, black cohosh should be used cautiously with other hypotensive agents (87; 48). There have been reports of hypotension in animals, although human data are limited in this area; increased peripheral blood flow has been associated with black cohosh administration in a 1962 study (87).
  • Anti-inflammatory agentsAnti-inflammatory agents: In animal research, a phytoestrogen compound containing genistein, daidzein, glycitein, black cohosh, Angelica, licorice, and Vitex agnus-castus lowered levels of proinflammatory cytokines and increased levels of TGF-beta (170).
  • Antilipemic agentsAntilipemic agents: In a case report, black cohosh has been reported to interact with atorvastatin, resulting in an increase in liver enzymes, possibly due to inhibition of CYP3A4 (171). In a clinical trial of black cohosh, changes in total, HDL, and LDL cholesterol were lacking in postmenopausal women, but an increase in triglycerides was reported (98). In women, Cimicifuga racemosa caused a statistically significant increase in high-density lipoprotein (HDL) cholesterol and a statistically significant decrease in low-density lipoprotein (LDL) cholesterol from baseline (107). In human research, a combination of black cohosh (Cimicifuga racemosa) and St. John's wort (Hypericum perforatum) significantly increased HDL levels (159), although other studies have not found the same results (111). In postmenopausal women, three months of therapy with Cimicifuga racemosa was reported to be well tolerated and did not alter the lipid profile (100).
  • Antineoplastic agentsAntineoplastic agents: In vitro, relatively low concentrations of actein or the methanol/water fraction of black cohosh caused synergistic inhibition of human breast cancer cell proliferation when combined with different classes of chemotherapy agents (172). In vitro, black cohosh has been shown to inhibit the intestinal breast cancer resistant protein, which may lead to increased absorption of certain drugs (173). However, black cohosh may not interact with all chemotherapy agents, according to an animal study using high doses of black cohosh with low doses of formestane (174).
  • Cytochrome P450-metabolized agentsCytochrome P450-metabolized agents: Unlike that observed for rifampin and clarithromycin, midazolam pharmacokinetics was unaffected by black cohosh, and black cohosh did not appear to have a clinically relevant effect on CYP2D6 or CYP3A activity in vivo (175; 176). In a systematic review, the authors indicated that the effect of black cohosh on human cytochrome activity may be small (86). However, another systematic review suggested that laboratory studies have shown that black cohosh may interact with CYP3A4 (73). In a clinical trial of 16 healthy volunteers, supplementation of black cohosh for 14 days did not demonstrate an effect on CYP2D6 (177). In vitro, strong inhibition of all CYP isoenzymes was documented due to cimicifugic acids A and B and fukinolic acid at median inhibitory concentrations (IC50) of 1.8-12.6mcM (115; 178). Triterpene glycosides were reported to be weakly active (IC50: 25-100mcM). In addition, Hep-G2 cell growth was not shown to be inhibited by any black cohosh extracts (cimicifugic acids A and B, fukinolic acid, and triterpene glycosides in concentrations as high as 50mcg/mL) (115). However, in vitro, seven black cohosh products were not shown to inhibit CYP3A4 in the human liver (179). In vitro, methanolic extracts of black cohosh were shown to inhibit CYP2B6, (5)2C19, and (D)2C19 in human liver cells (180). In vitro, black cohosh has been reported to lack an effect on CYP450-catalyzed 4-hydroxylation of estradiol in human mammary epithelial cells (181). In mice, black cohosh at a dose of 500mg/kg was reported to induce liver CYP3A11 sevenfold after 28 days of treatment (182; 178). This induction was reported to be both time- and dose-dependent. A change in the kidney and small intestine CYP3A11was lacking. In further research, mouse pregnane X receptor (PXR) was reported to be activated by black cohosh, but human PXR was not (182). In a case report, black cohosh has been reported to interact with atorvastatin, resulting in an increase in liver enzymes, possibly due to inhibition of CYP3A4 (171).
  • Disulfiram (Antabuse?)Disulfiram (Antabuse?): Tinctures may have 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 (11; 13; 8).
  • 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 (11; 13; 8).
  • 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, and who also consumed alcohol (85). The relative contribution of each agent or risk of combination is unclear.
  • EstrogensEstrogens: The estrogenic activity of black cohosh remains debated. Specific estrogenic constituents have not been identified, and it is unclear how (or if) black cohosh interacts with estrogens, estrogen receptors, and/or progestins. Studies suggest that there may be no direct effects on estrogen receptors, although this is an area of active controversy (10; 14; 15; 16; 17; 13; 12; 11). 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 (139) stand in contrast with data suggesting no significant estrogen receptor-binding activity or estrogenic activities (140; 141; 142; 80). One in vitro study found no effects of black cohosh alone on estrogen receptors, but it reported that black cohosh antagonized proliferative effects on cells induced by estradiol (143). Several studies have aimed to assess estrogenic activity by measuring luteinizing hormone (LH), follicle-stimulating hormone (FSH), or prolactin levels (144; 145). 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 (144). Results from other trials have found no effects on these hormone levels after up to six months of black cohosh therapy (146; 60; 78). When administered to female infantile mice, black cohosh could not precipitate the premature onset of estrus (147). Estrogenic effects on vaginal epithelium were noted in one three-month trial of black cohosh (148), while a six-month trial reported no effects on vaginal cytology (62). In a systematic review, with relevance to cancer patients, black cohosh also seemed to lack phytoestrogenic activity and may inhibit tumor growth (29).
  • 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, and who also consumed alcohol (85). The relative contribution of each agent or risk of combination is unclear.
  • Gastrointestinal agentsGastrointestinal agents: According to traditional use, black cohosh may have additive effects with gastrointestinal agents.
  • Hepatotoxic agentsHepatotoxic agents: Several cases of liver damage have been reported following use of black cohosh (88; 89; 26; 25; 90). However, animal studies and human exposure have not been definitive (116; 117; 120; 121; 122; 123; 124; 29; 30; 31; 32; 33; 34; 35; 36; 125; 126; 127; 128; 64; 98; 70).
  • Hormonal agentsHormonal agents: The estrogenic activity of black cohosh remains debated. Specific estrogenic constituents have not been identified, and it is unclear how (or if) black cohosh interacts with estrogens, estrogen receptors, and/or progestins. Studies suggest that there may be a lack of direct effects on estrogen receptors, although this is an area of controversy (10; 14; 15; 16; 17; 13; 12; 11). 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 (139) stand in contrast with data suggesting no significant estrogen receptor-binding activity or estrogenic activities (140; 141; 142; 80). One in vitro study found no effects of black cohosh alone on estrogen receptors, but it reported that black cohosh antagonized proliferative effects on cells induced by estradiol (143). Several studies have aimed to assess estrogenic activity by measuring luteinizing hormone (LH), follicle-stimulating hormone (FSH), or prolactin levels (144; 145). 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 (144). Results from other trials have found no effects on these hormone levels after up to six months of black cohosh therapy (146; 60; 78). Administered to female infantile mice, premature onset of estrus could not be precipitated by black cohosh (147). Estrogenic effects on vaginal epithelium were noted in one three-month trial of black cohosh (148), while a six-month trial reported no effects on vaginal cytology (62). In vitro, black cohosh has been reported to lack an effect on CYP450-catalyzed 4-hydroxylation of estradiol in human mammary epithelial cells (181).
  • Metronidazole (Flagyl?)Metronidazole (Flagyl?): A disulfiram reaction may 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.
  • Neurologic agentsNeurologic agents: In a clinical trial, the frequency of menstrual migraines was decreased with a combination of soy, dong quai, and black cohosh (183). 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, and who also consumed alcohol (85). The relative contribution of each agent or risk of combination is unclear.
  • 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 (184). In vitro, black cohosh has been shown to inhibit the intestinal breast cancer-resistant protein, which may lead to increased absorption of certain drugs (173).
  • Osteoporosis agentsOsteoporosis agents: In postmenopausal women, three months of therapy with Cimicifuga racemosa resulted in increased alkaline phosphatase and a decrease in the concentration of N-telopeptides in the urine (100). In postmenopausal women, CR BNO 1055 was reported to increase osteoblast activity and decrease osteoclast activity (97). An increase in bone-specific collagen-1alpha1 was lacking with CR administration, and bone-specific alkaline phosphatase increased significantly with CR administration when compared to placebo after 12 weeks of treatment (98). According to animal and in vitro research, black cohosh may increase osteogenesis (185; 17; 186).
  • Salicylate-containing agents (e.g., aspirin)Salicylate-containing agents (e.g., aspirin): Native black cohosh contains small amounts of salicylic acid, but it is unclear 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 (19; 78). The influence of black cohosh alone or in combination with tamoxifen is unclear in these cases. It is unclear if tamoxifen antagonized the effects of black cohosh or if hot flashes induced by tamoxifen are refractory to black cohosh therapy. The authors of a systematic review suggested that black cohosh may augment the antiproliferative effects of tamoxifen in clinical trials. However, some studies included in the review advised against using black cohosh during chemotherapy or radiotherapy (86). In vitro research suggests possible additive antiproliferative effects of black cohosh and tamoxifen (187; 143).
  • VasodilatorsVasodilators: Laboratory research on cimicifugic acids C and D, and fukinolic acid in the rhizome of black cohosh has shown vasoactive effects (188).

    • 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 may increase toxicity and death. There is a case report of a 24 year-old woman who took 48-56% pennyroyal herb in an alcohol base and an unknown amount of black cohosh root for two weeks in an attempt to induce abortion (189). Following a single subsequent dose of this combination, the patient died within 48 hours.
  • AnalgesicsAnalgesics: According to traditional use, black cohosh may have additive effects with analgesics (167).
  • AnestheticsAnesthetics: The authors of a systematic review mentioned that black cohosh may interact with anesthetics, according to the Clinical Practice Guideline of the Canadian Society of Obstetricians and Gynecologists (86). According to traditional use, black cohosh may have additive effects with anesthetics (167).
  • AntiandrogensAntiandrogens: 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 (168). Another in vivo study in mice demonstrated inhibited PC3 prostate cancer tumor growth with black cohosh and other herbal extracts (53).
  • AntiarthriticsAntiarthritics: In humans, Reumalex? has been reported to have significant improvements in arthritis pain (169).
  • Anticoagulants and antiplateletsAnticoagulants and antiplatelets: In a systematic review, the authors of the review indicated that black cohosh may contain anticoagulant coumarins, although an effect on prothrombin times was lacking (86). In a clinical trial of postmenopausal women, changes in markers of coagulation were lacking (98). Native black cohosh contains small amounts of salicylic acid and may potentiate the antiplatelet effects of other agents, such as ginkgo or garlic. It is unclear 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 (11; 13; 8). A study in ovariectomized rats demonstrated strong binding to serotonin receptors 5-HT(1A), 5-HT(1D), and 5-HT(7) subtypes (11).
  • AntihistaminesAntihistamines: In vitro, black cohosh extract showed inhibitory potential for histamine release (49).
  • AntihypertensivesAntihypertensives: The authors of a systematic review mentioned that black cohosh may interact with antihypertensives, according to the Clinical Practice Guideline of the Canadian Society of Obstetricians and Gynecologists (86). Due to theoretical hypotensive effects, black cohosh should be used cautiously with other hypotensive agents (87; 48). 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 (87).
  • Anti-inflammatory herbs and supplementsAnti-inflammatory herbs and supplements: In animal research, a phytoestrogen compound containing genistein, daidzein, glycitein, black cohosh, Angelica, licorice, and Vitex agnus-castus lowered levels of proinflammatory cytokines and increased levels of TGF-beta (170).
  • AntilipemicsAntilipemics: In a case report, black cohosh has been reported to interact with atorvastatin resulting in an increase in liver enzymes, possibly due to inhibition of CYP3A4 (171). In a clinical trial of black cohosh, changes in total, HDL, and LDL cholesterol were lacking in postmenopausal women, but an increase in triglycerides was reported (98). In women, Cimicifuga racemosa caused a statistically significant increase in high-density lipoprotein (HDL) cholesterol (51.6 ? 1.8 to 53.1 ? 1.7mg/dL, respectively; p=0.04) and a statistically significant decrease in low-density lipoprotein (LDL) cholesterol (153.8 ? 39.0 to 146.1 ? 34.4mg/dL, respectively; p=0.003) from baseline (107). In human research, it is unclear whether a combination of black cohosh (Cimicifuga racemosa) and St. John's wort (Hypericum perforatum) increased HDL levels (159) or leaves lipid levels unchanged (111). In postmenopausal women, three months of therapy with Cimicifuga racemosa was reported to be well tolerated and did not cause a change in the lipid profile (100).
  • AntineoplasticsAntineoplastics: According to the authors of a systematic review, black cohosh may augment the antiproliferative effects of tamoxifen, based on clinical trials. However, some studies included in the review advised against using black cohosh during chemotherapy or radiotherapy (86). In vitro, relatively low concentrations of actein or the methanol/water fraction of black cohosh caused synergistic inhibition of human breast cancer cell proliferation when combined with different classes of chemotherapy agents (172). In vitro, black cohosh has been shown to inhibit the intestinal breast cancer-resistant protein, which may lead to increased absorption of certain drugs (173). However, black cohosh may not interact with all chemotherapy agents, according to an animal research using high doses of black cohosh with low doses of formestane (174).
  • AntioxidantsAntioxidants: According to in vitro research, black cohosh may have antioxidant properties (40; 190; 41).
  • 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 (83). There is a report of severe multiorgan hypoxic injury in a child delivered with the aid of both blue and black cohosh, who was not breathing at the time of birth (81; 82; 83). 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 they are used internationally, few safety and efficacy data are available for homeopathic preparations of blue and black cohosh (162).
  • 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, and who also consumed alcohol (85). The relative contribution of each agent or risk of combination is unclear.
  • Cytochrome P450-metabolized herbs and supplementsCytochrome P450-metabolized herbs and supplements: In vivo, black cohosh did not appear to have a clinically relevant effect on CYP2D6 or CYP3A activity (175; 176). The authors of a systematic review indicated that the effect of black cohosh on human cytochrome activity may be small (86). However, another systematic review suggested that laboratory studies have shown that black cohosh may interact with CYP3A4 (73). In a clinical trial of 16 healthy volunteers, supplementation of black cohosh for 14 days did not demonstrate an effect on CYP2D6 (177). In vitro, strong inhibition of all CYP isoenzymes was documented, due to cimicifugic acids A and B and fukinolic acid at median inhibitory concentrations (IC50) of 1.8-12.6mcM (115; 178). Triterpene glycosides were reported to be weakly active (IC50: 25-100mcM). In addition, Hep-G2 cell growth was not shown to be inhibited by any black cohosh extracts (cimicifugic acids A and B, fukinolic acid, and triterpene glycosides in concentrations as high as 50 mcg/mL) (115). However, in vitro, seven black cohosh products were not shown to inhibit CYP3A4 in human liver (179). In vitro, methanolic extracts of black cohosh were shown to inhibit CYP2B6, (5)2C19, and (D)2C19 in human liver cells (180). In vitro, black cohosh has been reported to lack an effect on CYP450-catalyzed 4-hydroxylation of estradiol in human mammary epithelial cells (181). In mice, black cohosh at a dose of 500mg/kg was reported to induce liver CYP3A11 sevenfold after 28 days of treatment (182; 178). This induction was reported to be both time- and dose-dependent. A change in the kidney and small intestine CYP3A11 was lacking. In further research, mouse pregnane X receptor (PXR) was reported to be activated by black cohosh, but human PXR was not (182). In a case report, black cohosh has been reported to interact with atorvastatin, resulting in an increase in liver enzymes, possibly due to inhibition of CYP3A4 (171).
  • 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 (11; 13; 8).
  • 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 (11; 13; 8).
  • 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, and who also consumed alcohol (85). The relative contribution of each agent or risk of combination is unclear.
  • Gastrointestinal herbs and supplementsGastrointestinal herbs and supplements: According to traditional use, black cohosh may have additive effects with gastrointestinal agents.
  • Hepatotoxic agentsHepatotoxic agents: Several cases of liver damage have been reported following use of black cohosh (88; 89; 26; 25; 90). However, animal studies and human exposure have not been definitive (116; 117; 120; 121; 122; 123; 124; 29; 30; 31; 32; 33; 34; 35; 36; 125; 126; 127; 128; 64; 98; 70).
  • 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, and who also consumed alcohol (85). The relative contribution of each agent or risk of combination is unclear.
  • 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 unclear 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 controversy (10; 14; 15; 16; 17; 13; 12; 11).
  • Hormone replacement therapyHormone replacement therapy: The estrogenic activity of black cohosh remains debated. Specific estrogenic constituents have not been identified, and it is unclear 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 controversy (10; 14; 15; 16; 17; 13; 12; 11).
  • HypotensivesHypotensives: The authors of a systematic review mentioned that black cohosh may interact with antihypertensives, according to the Clinical Practice Guideline of the Canadian Society of Obstetricians and Gynecologists (86). Due to theoretical hypotensive effects, black cohosh should be used cautiously with other hypotensive agents (87; 48). There have been reports of hypotension in animals, although human data are limited in this area; increased peripheral blood flow has been associated with black cohosh administration in a 1962 study (87).
  • Neurologic herbs and supplementsNeurologic herbs and supplements: In a clinical trial, the frequency of menstrual migraines was decreased with a combination of soy, dong quai, and black cohosh (183). 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, and who also consumed alcohol (85). The relative contribution of each agent or risk of combination is unclear.
  • 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 (184). In vitro, black cohosh has been shown to inhibit the intestinal breast cancer-resistant protein, which may lead to increased absorption of certain drugs (173).
  • Osteoporosis agentsOsteoporosis agents: In postmenopausal women, three months of therapy with Cimicifuga racemosa resulted in a significant increased alkaline phosphatase and a decrease in the concentration of N-telopeptides in the urine compared to placebo (100). However, the mechanism to decrease bone remodeling is not known. In postmenopausal women, CR BNO 1055 was reported to increase osteoblast activity and decrease osteoclast activity (97). An increase of bone-specific collagen-1alpha1 was lacking with CR administration, and bone-specific alkaline phosphatase increased significantly with CR administration when compared to placebo after 12 weeks of treatment (98). According to in vitro and animal studies, black cohosh may increase osteogenesis (185; 17; 186).
  • PhytoestrogensPhytoestrogens: The estrogenic activity of black cohosh remains debated. Specific estrogenic constituents have not been identified, and it is unclear if black cohosh interacts with other estrogenic compounds. Studies suggest that there may be no direct effects on estrogen receptors, although this is an area of active controversy (10; 11; 62; 14; 15; 16; 17; 13; 12; 144; 78; 139; 145; 60; 146; 141; 142; 80; 147; 148; 29; 140). 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 unclear how much (if any) is present in commercially available or standardized extracts.
  • St. John's wortSt. John's wort: According to 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 (132).
  • Vasodilator herbs and supplementsVasodilator herbs and supplements: Laboratory research on cimicifugic acids C and D and fukinolic acid in the rhizome of black cohosh has shown vasoactive effects (188).

    • Black cohosh/Food Interactions:

  • Insufficient available evidence.

    • Black cohosh/Lab Interactions:

  • Allergy testsAllergy tests: In vitro, black cohosh extract showed inhibitory potential for histamine release (49).
  • 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 (185). In postmenopausal women, three months of therapy with Cimicifuga racemosa resulted in increased alkaline phosphatase and decreased concentration of N-telopeptides in the urine (100). However, the mechanism to decrease bone remodeling is not known. In postmenopausal women, CR BNO 1055 was reported to increase osteoblast activity and decrease osteoclast activity (97). An increase of bone-specific collagen-1alpha1 was lacking with CR administration, and bone-specific alkaline phosphatase increased significantly with CR administration when compared to placebo after 12 weeks of treatment (98).
  • Coagulation panelCoagulation panel: In a systematic review, the authors indicated that black cohosh may contain anticoagulant coumarins, although an effect on prothrombin times was lacking (86). In a clinical trial of postmenopausal women, changes in markers of coagulation were lacking (98). Native black cohosh contains small amounts of salicylic acid and may potentiate the antiplatelet effects of other agents. It is unclear if therapeutic amounts of salicylates are present in commercial or processed black cohosh products.
  • Liver function testsLiver function tests: A prospective longitudinal clinical study of 87 postmenopausal women that received 40mg of a dry extract of Cimicifuga racemosa (Klimadyon) to treat menopausal symptoms for 12 months did not report alterations in liver function tests or hepatic perfusion (70).
  • Serum glucoseSerum glucose: In a randomized trial in 351 peri- or postmenopausal women, black cohosh lacked demonstrable effects on lipids, glucose, insulin, or fibrinogen (111).
  • Serum insulinSerum insulin: In a randomized trial in 351 peri- or postmenopausal women, black cohosh lacked demonstrable effects on lipids, glucose, insulin, or fibrinogen (111).
  • Serum levels of cytochrome P450-metabolized agents: Serum levels of cytochrome P450-metabolized agents: In vivo, black cohosh did not appear to have a clinically relevant effect on CYP2D6 or CYP3A activity (175; 176). In a systematic review, the authors indicated that the effect of black cohosh on human cytochrome activity may be small (86). However, another systematic review suggested that laboratory studies have shown that black cohosh may interact with CYP3A4 (73). In a clinical trial of 16 healthy volunteers, supplementation of black cohosh for 14 days did not demonstrate an effect on CYP2D6 (177). In vitro, strong inhibition of all CYP isoenzymes was documented, due to cimicifugic acids A and B and fukinolic acid at median inhibitory concentrations (IC50) of 1.8-12.6mcM (115; 178). Triterpene glycosides were reported to be weakly active (IC50: 25-100mcM). In addition, Hep-G2 cell growth was not shown to be inhibited by any black cohosh extracts (cimicifugic acids A and B, fukinolic acid, and triterpene glycosides in concentrations as high as 50mcg/mL (115). However, in vitro seven black cohosh products were not shown to inhibit CYP3A4 in the human liver (179). In vitro, methanolic extracts of black cohosh were show to inhibit CYP2B6, (5)2C19, and (D)2C19 in human liver cells (180). In vitro, black cohosh has been reported to lack an effect on CYP450-catalyzed 4-hydroxylation of estradiol in human mammary epithelial cells (181). In mice, black cohosh at a dose of 500mg/kg was reported to induce liver CYP3A11 sevenfold after 28 days of treatment (182; 178). This induction was reported to be both time- and dose-dependent. A change in the kidney and small intestine CYP3A11 was lacking. In further research, mouse pregnane X receptor (PXR) was reported to be activated by black cohosh, but human PXR was not (182). In a case report, black cohosh has been reported to interact with atorvastatin, resulting in an increase in liver enzymes, possibly due to inhibition of CYP3A4 (171).
  • 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 (184). In vitro, black cohosh has been shown to inhibit the intestinal breast cancer-resistant protein, which may lead to increased absorption of certain drugs (173).
  • Serum lipidsSerum lipids: In human research, there is controversy about whether black cohosh alters serum lipid levels (159; 111). In postmenopausal women, three months of therapy with Cimicifuga racemosa was reported to be well tolerated and did not show a change in lipid profile (100). In a clinical trial of black cohosh, changes in total, HDL, and LDL cholesterol were lacking in postmenopausal women, but an increase in triglycerides was reported (98). In women, Cimicifuga racemosa caused a statistically significant increase in high-density lipoprotein (HDL) cholesterol and a statistically significant decrease in low-density lipoprotein (LDL) cholesterol from baseline (107).