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Red clover (Trifolium pratense)



Interactions

Red clover/Drug Interactions:
  • AndrogensAndrogens: Based on in vitro study, isoflavones in red clover may have antiandrogenic properties (31). Theoretically, red clover may alter the effects of androgens.
  • Anticoagulants and antiplateletsAnticoagulants and antiplatelets: Red clover contains coumarin and coumarin-like compounds. Genistein and raloxifene have been found to inhibit platelet aggregation in animal study (12; 13; 14). Flavones (apigenin and luteolin) and isoflavones (genistein) have been found to inhibit the binding to the thromboxane A2 receptor (12). A case report stated that a 53 year-old woman had spontaneous subarachnoid hemorrhage due to the use of an herbal supplement containing red clover, dong quai, and Siberian ginseng (32). Theoretically, concurrent use of anticoagulant or antiplatelet agents and red clover may increase the risk of bleeding.
  • Antidiabetic agentsAntidiabetic agents: In clinical study, red clover has been evaluated for its effects on blood sugar with inconclusive results; in healthy premenopausal women taking an isoflavone preparation from red clover, no significant changes were seen in insulin or glucose concentrations (17). The effects of red clover with antidiabetic agents are not well understood.
  • AntiestrogensAntiestrogens: Based on preliminary human study, red clover isoflavones possess varying affinity for estradiol receptors (estradiol-? and estradiol-?), and are capable of acting as both agonists and antagonists (29). Theoretically, red clover may alter the effects of antiestrogen therapy.
  • AntihypertensivesAntihypertensives: Based on human study, red clover may improve cardiovascular disease risk factors, including the flow of blood through arteries and veins and blood pressure control (22; 3; 7). In clinical study, systolic and diastolic blood pressure measurements were significantly lower with treatment with red clover isoflavones (3). Theoretically, concurrent use of red clover with antihypertensive agents may cause added blood pressure lowering.
  • Antilipemic agentsAntilipemic agents: Because estrogens have been reported to decrease low-density lipoproteins (LDL) and increase high-density lipoproteins (HDL), some effort has been undertaken to discern the effects of red clover isoflavones, which appear to possess estrogenic activity, on lipid metabolism. Available evidence of red clover's effects on lipid levels in humans remains inconclusive (33; 7; 34). Theoretically, concurrent use of red clover with antilipemic agents may cause added cholesterol lowering.
  • Antineoplastic agentsAntineoplastic agents: Based on in vitro study, isoflavones in red clover may inhibit cell proliferation, induce apoptosis, disrupt transcriptional processes, and may have antiandrogenic properties (35; 36; 37; 31; 38; 29; 39). The effects of red clover with antineoplastic agents are not well understood.
  • Cytochrome P450 metabolized agentsCytochrome P450 metabolized agents: Based on in vitro study, red clover, or more specifically, the isoflavone biochanin A, may inhibit cytochrome P450 enzymes, particularly CYP450 1A2, 2C19, 2C9, and 3A4 (40; 41; 42; 43). Theoretically, red clover may increase the levels of drugs metabolized by these enzymes.
  • Hormonal agentsHormonal agents: Based on preliminary human study, red clover isoflavones possess varying affinity for estradiol receptors (estradiol-? and estradiol-?), and are capable of acting as both agonists and antagonists (29). Preliminary evidence suggests a preferential binding to estrogen receptor ?, which is found in the vasculature, brain, bone, and heart, as opposed to estrogen receptor ? (found in the ovaries, breast, uterus, and adrenal glands). Based on in vitro study, isoflavones may affect levels of gonadotropin-releasing hormone (GrRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) via hormonal feedback mechanisms (10); however, there is controversy in this area (11), and high-quality human evidence is currently lacking. Theoretically, red clover may alter the effects of hormonal estrogen therapy.

Red clover/Herb/Supplement Interactions:
  • AndrogensAndrogens: Based on in vitro study, isoflavones in red clover may possess antiandrogenic properties (31). Theoretically, red clover may alter the effects of androgens.
  • Anticoagulants and antiplateletsAnticoagulants and antiplatelets: Red clover contains coumarin and coumarin-like compounds. Genistein and raloxifene have been found to inhibit platelet aggregation in animal study (12; 13; 14). Flavones (apigenin and luteolin) and isoflavones (genistein) have been found to inhibit the binding to the thromboxane A2 receptor (12). A case report stated that a 53 year-old woman had spontaneous subarachnoid hemorrhage due to the use of an herbal supplement containing red clover, dong quai, and Siberian ginseng (32). Theoretically, concurrent use of anticoagulant or antiplatelet agents and red clover may increase the risk of bleeding.
  • AntiestrogensAntiestrogens: Based on preliminary human study, red clover isoflavones possess varying affinity for estradiol receptors (estradiol-? and estradiol-?), and are capable of acting as both agonists and antagonists (29). Theoretically, red clover may alter the effects of antiestrogen therapy.
  • AntilipemicsAntilipemics: Because estrogens have been reported to decrease low-density lipoproteins (LDL) and increase high-density lipoproteins (HDL), some effort has been undertaken to discern the effects of red clover isoflavones, which appear to possess estrogenic activity, on lipid metabolism. Available evidence of red clover's effects on lipid levels in humans remains inconclusive (33; 7; 34). Theoretically, concurrent use of red clover with antilipemic agents may cause added cholesterol lowering.
  • AntineoplasticsAntineoplastics: Based on in vitro study, isoflavones in red clover may inhibit cell proliferation, induce apoptosis, disrupt transcriptional processes, and may have antiandrogenic properties (35; 36; 37; 31; 38; 29; 39). The effects of red clover with antineoplastic agents are not well understood.
  • AntioxidantsAntioxidants: Red clover's purported antioxidant properties have been attributed to the isoflavone genistein. Based on human and in vitro study, daidzein also appears to have antioxidant properties, although to a lesser extent (38). The effects of red clover with other antioxidants are not well understood.
  • Cytochrome P450 metabolized herbs and supplementsCytochrome P450 metabolized herbs and supplements: Based on in vitro study, red clover, or more specifically, the isoflavone biochanin A, may inhibit cytochrome P450 enzymes, particularly CYP450 1A2, 2C19, 2C9, and 3A4 (40; 41; 42; 43). Theoretically, red clover may increase the levels of drugs metabolized by these enzymes.
  • HypoglycemicsHypoglycemics: In clinical study, red clover has been evaluated for its effects on blood sugar, with inconclusive results; in healthy premenopausal women taking an isoflavone preparation from red clover, no significant changes were seen in insulin or glucose concentrations (17). The effects of red clover with hypoglycemic agents are not well understood.
  • HypotensivesHypotensives: Based on human study, red clover may improve cardiovascular disease risk factors, including the flow of blood through arteries and veins and blood pressure control (22; 3; 7). In clinical study, systolic and diastolic blood pressure measurements were significantly lower with treatment with red clover isoflavones (3). Theoretically, concurrent use of red clover with antihypertensive agents may cause added blood pressure lowering.
  • PhytoestrogensPhytoestrogens: Based on preliminary human study, red clover isoflavones possess varying affinity for estradiol receptors (estradiol-? and estradiol-?), and are capable of acting as both agonists and antagonists (29). Preliminary evidence suggests a preferential binding to estrogen receptor ?, which is found in the vasculature, brain, bone, and heart, as opposed to estrogen receptor ? (found in the ovaries, breast, uterus, and adrenal glands). Based on in vitro study, isoflavones may affect levels of gonadotropin-releasing hormone (GrRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) via hormonal feedback mechanisms (10); however, there is controversy in this area (11), and high-quality human evidence is lacking. Theoretically, red clover may alter the effects of phytoestrogen therapy.

Red clover/Food Interactions:
  • GeneralGeneral: Red clover is on the FDA's GRAS (Generally Recognized as Safe) list, and is included in many beverages and teas. It is believed that the amounts found in these beverages are too small to be of clinical relevance.

Red clover/Lab Interactions:
  • Blood glucoseBlood glucose: In clinical study, red clover has been evaluated for its effects on blood sugar, with inconclusive results; in healthy premenopausal women taking an isoflavone preparation from red clover, no significant changes were seen in insulin or glucose concentrations (17).
  • Blood pressureBlood pressure: In clinical study, systolic and diastolic blood pressure measurements were significantly lower with treatment with red clover isoflavones (3).
  • Coagulation panelCoagulation panel: Red clover contains coumarin and coumarin-like compounds. Genistein and raloxifene have been found to inhibit platelet aggregation in animal study (12; 13; 14). Flavones (apigenin and luteolin) and isoflavones (genistein) have been found to inhibit the binding to the thromboxane A2 receptor (12). A case report stated that a 53 year-old woman had spontaneous subarachnoid hemorrhage due to the use of an herbal supplement containing red clover, dong quai, and Siberian ginseng (32).
  • Hormonal levelsHormonal levels: Based on in vitro study, isoflavones may affect levels of gonadotropin-releasing hormone (GrH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) via hormonal feedback mechanisms (10). However, in a randomized trial of 205 women receiving Promensil® (40mg of red clover isoflavones per tablet) or placebo daily for one year, no significant differences in FSH or LH levels were detected between groups (9; 11).
  • Lipid profileLipid profile: Available evidence of red clover's effects on lipid levels in humans remains inconclusive (33; 7; 34). Reductions low-density lipoproteins (LDL) and increases high-density lipoproteins (HDL) may occur.

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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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