Trifolium pratense

Red clover/Drug Interactions:

  • AnalgesicsAnalgesics: In human research in patients with cyclical mastalgia, 40mg of red clover-derived isoflavones (Promensil?) decreased self-reported ratings of breast pain and demonstrated a higher treatment response rate compared to placebo (9).
  • AndrogensAndrogens: In vitro, isoflavones in red clover demonstrated antiandrogenic properties (64). Theoretically, red clover may alter the effects of androgens. However, in a meta-analysis, red clover- and soy-derived isoflavones (Promensil?) lacked an effect on circulating reproductive hormone levels, specifically testosterone, free testosterone, sex hormone-binding globulin (SHBG), or free androgen index (FAI) (65; 26).
  • AntiandrogensAntiandrogens: In vitro, isoflavones in red clover have demonstrated antiandrogenic properties (64). Theoretically, red clover may alter the effects of androgens. However, in a meta-analysis, red clover- and soy-derived isoflavones (Promensil?) lacked an effect on circulating reproductive hormone levels, specifically testosterone, free testosterone, sex hormone-binding globulin (SHBG), or free androgen index (FAI) (65; 26).
  • 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 research (11; 12; 13). Flavones (apigenin and luteolin) and isoflavones (genistein) have been found to inhibit the binding to the thromboxane A2 receptor (11). 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 (62).
  • AntidiabeticsAntidiabetics: In clinical research, red clover has been evaluated for its effects on blood sugar, with inconclusive results; in healthy premenopausal and postmenopausal women taking an isoflavone preparation from red clover (e.g., Promensil?), significant changes were lacking in insulin or glucose concentrations (25; 26). In human research, Promensil? unfavorably reduced the quantitative insulin sensitivity check index (QUICKI) compared to transdermal estrogen therapy (26).
  • AntiestrogensAntiestrogens: According to preliminary human research, red clover isoflavones possess varying affinity for estradiol receptors (estradiol-alpha and estradiol-beta) (66; 67) and are capable of acting as both agonists and antagonists (60).
  • Antigout agentsAntigout agents: According to secondary sources, red clover may interact with agents used for gout.
  • AntihypertensivesAntihypertensives: In human research, red clover improved cardiovascular disease risk factors, including the flow of blood through arteries and veins and blood pressure control (38; 15; 21). In clinical research, systolic and diastolic blood pressure measurements were significantly lower with treatment with red clover isoflavones (15).
  • 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 (68; 21; 69; 44; 56; 47).
  • AntineoplasticsAntineoplastics: In vitro, isoflavones in red clover have been shown to inhibit cell proliferation, induce apoptosis, disrupt transcriptional processes, and may have antiandrogenic properties (70; 71; 72; 64; 73; 60; 74). In human research, red clover isoflavone supplementation lacked a significant effect on the serum concentration or tissue mRNA expression of various insulin-like growth factor (IGF) system components, including total IGF-I, IGF-II, and IGF binding proteins (IGFB)-1, -2, or -3 (75).
  • Aromatase inhibitorsAromatase inhibitors: Literature review findings have suggested that antagonistic effects are plausible following the coadministration of aromatase inhibitors and phytoestrogens, including red clover (67).
  • Aryl hydrocarbon receptor (AhR) agonistsAryl hydrocarbon receptor (AhR) agonists: In vitro, red clover isoflavones, namely biochanin A and formononetin, demonstrated potent aryl hydrocarbon receptor (AhR) agonist activity, which was 10 times stronger than established AhR agonists, indole-3-carbinol and diindolylmethane (EC50 biochanin A: 2.5 x 10-7mol/L; formononetin: 1.3 x 10-7mol/L; indole-3-carbinol: 5.8 x 10-6mol/L; diindolylmethane: 1.1 x 10-6mol/L) (76).
  • Cardiovascular agentsCardiovascular agents: Because estrogens have been reported to decrease low-density lipoproteins (LDL) and increase high-density lipoproteins (HDL), the possible mechanism by which isoflavones protect against atherosclerosis may be related to estrogen agonist effects. The available evidence of red clover's effects on lipid levels in humans remains inconclusive (68; 21; 69). In human research, increases in HDL cholesterol and decreases in both total and LDL cholesterol levels have been reported with red clover isoflavone supplementation (44); however, results have been inconsistent among studies, with others noting a lack of difference in total cholesterol, LDL, HDL, or triglyceride levels compared to placebo (56). Lipid-lowering effects have also been observed in a post-hoc analysis of T. pratense isoflavone (Menoflavon?) supplementation, but were limited to individuals with a body mass index (BMI) ?25kg/m2; changes in lipid profile were lacking for individuals with a BMI <25kg/m2 (47). In human research, red clover improved cardiovascular disease risk factors, including the flow of blood through arteries and veins and blood pressure control, although it is unclear if the isoflavones in red clover are responsible for these effects (38; 15; 21; 77).
  • Cognitive improvement agentsCognitive improvement agents: In human research, red cover isoflavones (e.g., Rimostil?) lacked a compelling, overall treatment effect on the cognitive function of postmenopausal women compared to placebo, in spite of isolated improvements in certain tests (7; 8).
  • Cytochrome P450 metabolized agentsCytochrome P450 metabolized agents: In vitro, red clover, or more specifically, the isoflavone biochanin A, inhibited cytochrome P450 enzymes, particularly CYP450 1A2, 2C19, 2C9, and 3A4 (27; 28; 29; 30).
  • Dermatologic agentsDermatologic agents: In human research, topical coadministration of Trifolium pratense flower extract and biomimetic peptide positively altered the proportion of anagen and telogen hair growth in individuals with alopecia; both anagen hair growth and the anagen:telogen hair ratio increased, whereas telogen hair density decreased (78). In human research, mild cases of psoriasis and thrush have been reported following supplementation with red clover isoflavones (Promensil?), although the relatedness of these incidences to red clover treatment were unable to be determined by investigators (9).
  • Gastrointestinal agentsGastrointestinal agents: According to secondary sources, red clover may interact with gastrointestinal agents.
  • Genitourinary tract agentsGenitourinary tract agents: As a phytoestrogen, red clover possesses both estrogen receptor agonist and antagonist properties. In theory, menstrual changes and endometrial hyperplasia may occur due to estrogenic activity unopposed by progesterone, of which the latter may increase the risk of uterine (endometrial) cancer. In human research, 80mg but not 40mg of red clover isoflavones (Promensil?) increased the duration of menstrual cycles in women with mastalgia (9). However, preliminary short-term (less than six-month) studies have not found increases in endometrial thickness on ultrasound examination (40; 42). It remains unclear if phytoestrogens such as red clover affect these risks. In human research, purified isoflavones extracted from red clover (P-07) lacked an effect on endometrial proliferation vs. placebo, as measured by change in Ki-67 proliferative antigen index (56).
  • Hormonal agentsHormonal agents: According to preliminary human research, red clover isoflavones possess varying affinity for estradiol receptors (estradiol-alpha and estradiol-beta), and are capable of acting as both agonists and antagonists (60). Preliminary evidence suggests a preferential binding to estrogen receptor-beta, which is found in the vasculature, brain, bone, and heart, as opposed to estrogen receptor-alpha (found in the ovaries, breast, uterus, and adrenal glands) (66; 67). According to in vitro research, isoflavones may affect levels of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) via hormonal feedback mechanisms (24); however, there is controversy in this area (6) and high-quality human evidence is lacking. In human research, red clover isoflavones (Promensil?) increased the duration of menstrual cycles in women with mastalgia (9) but lacked an effect on the follicular and luteal phases of the menstrual cycle (43). The majority of evidence from meta-analyses and clinical trials has suggested that red clover isoflavones (e.g., Promensil?, Rimostil?) lack an effect on menopause-related vasomotor symptoms vs. placebo (2; 3; 52; 4; 5; 31; 8).
  • Hormone replacement therapy (HRT)Hormone replacement therapy (HRT): According to preliminary human research, red clover isoflavones possess varying affinity for estradiol receptors (estradiol-alpha and estradiol-beta), and are capable of acting as both agonists and antagonists (60). Preliminary evidence suggests a preferential binding to estrogen receptor beta, which is found in the vasculature, brain, bone, and heart, as opposed to estrogen receptor alpha (found in the ovaries, breast, uterus, and adrenal glands) (66; 67). According to in vitro research, isoflavones may affect levels of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) via hormonal feedback mechanisms (24); however, there is controversy in this area (6) and high-quality human evidence is lacking. In human research, red clover isoflavones (Promensil?) increased the duration of menstrual cycles in women with mastalgia (9), but lacked an effect on the follicular and luteal phases of the menstrual cycle (43). The majority of evidence from meta-analyses and clinical trials has suggested that red clover isoflavones (e.g., Promensil?, Rimostil?) lack an effect on menopause-related vasomotor symptoms vs. placebo (2; 3; 52; 4; 5; 31; 8).
  • Non-steroidal anti-inflammatory drugs (NSAIDs)Non-steroidal anti-inflammatory drugs (NSAIDs): In human research, an unexpectedly lower analgesic effect was observed following the impromptu coadministration of NSAIDs and red clover isoflavones (Promensil?) (9). Investigators therefore purported that NSAIDs possibly inhibit the analgesic activity of isoflavones (9).
  • Osteoporosis agentsOsteoporosis agents: In animal research, the isoflavones genistein and daidzein stimulated osteoblastic function (79). According to human research conducted in menopausal and postmenopausal women (22; 6; 46; 40; 19), it is unclear to what extent bone loss is affected by dietary isoflavones such as those present in red clover. In a randomized controlled trial, red clover isoflavones (Rimostil?) lacked an effect on bone resorption and fractional calcium absorption and reduced the level of serum alkaline phosphatase vs. baseline (54).
  • Selective estrogen receptor modulators (Tamoxifen)Selective estrogen receptor modulators (Tamoxifen): Literature review findings have suggested that antagonistic effects are plausible following the coadministration of tamoxifen and phytoestrogens, including red clover (67).

    • Red clover/Herb/Supplement Interactions:

  • AnalgesicsAnalgesics: In human research in patients with cyclical mastalgia, 40mg of red clover-derived isoflavones (Promensil?) decreased self-reported ratings of breast pain and demonstrated a higher treatment response rate compared to placebo (9).
  • AndrogensAndrogens: In vitro, isoflavones in red clover demonstrated antiandrogenic properties (64). In a meta-analysis, red clover- and soy-derived isoflavones (Promensil?) lacked an effect on circulating reproductive hormone levels, specifically testosterone, free testosterone, SHBG, or FAI (65; 26).
  • AntiandrogensAntiandrogens: In vitro, isoflavones in red clover demonstrated antiandrogenic properties (64). Theoretically, red clover may alter the effects of androgens. However, in a meta-analysis, red clover- and soy-derived isoflavones (Promensil?) lacked an effect on circulating reproductive hormone levels, specifically testosterone, free testosterone, sex hormone-binding globulin (SHBG), or free androgen index (FAI) (65; 26).
  • 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 research (11; 12; 13). Flavones (apigenin and luteolin) and isoflavones (genistein) have been found to inhibit the binding to the thromboxane A2 receptor (11). 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 (62).
  • AntiestrogensAntiestrogens: According to preliminary human research, red clover isoflavones possess varying affinity for estradiol receptors (estradiol-alpha and estradiol-beta) (66; 67) and are capable of acting as both agonists and antagonists (60).
  • Antigout agentsAntigout agents: According to secondary sources, red clover may interact with agents used for gout.
  • Anti-inflammatoriesAnti-inflammatories: In human research, an unexpectedly lower analgesic effect was observed following the impromptu coadministration of NSAIDs and red clover isoflavones (Promensil?) (9). Investigators therefore purported that NSAIDs possibly inhibit the analgesic activity of isoflavones (9).
  • AntilipemicsAntilipemics: Because estrogens have been reported to decrease LDL and increase 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 (68; 21; 69; 44; 56; 47).
  • AntineoplasticsAntineoplastics: In vitro, isoflavones in red clover have been shown to inhibit cell proliferation, induce apoptosis, and disrupt transcriptional processes, and they may have antiandrogenic properties (70; 71; 72; 64; 73; 60; 74). In human research, red clover isoflavone supplementation lacked a significant effect on the serum concentration or tissue mRNA expression of various IGF system components, including total IGF-I, IGF-II, and IGFB-1, -2, or -3 (75).
  • AntioxidantsAntioxidants: Red clover's purported antioxidant properties have been attributed to the isoflavone genistein. In human and in vitro research, daidzein has also demonstrated antioxidant properties, although to a lesser extent (73).
  • Cardiovascular agentsCardiovascular agents: Because estrogens have been reported to decrease low-density lipoproteins (LDL) and increase high-density lipoproteins (HDL), the possible mechanism by which isoflavones protect against atherosclerosis may be related to estrogen agonist effects. The available evidence of red clover's effects on lipid levels in humans remains inconclusive (68; 21; 69). In human research, increases in HDL cholesterol and decreases in both total and LDL cholesterol levels have been reported with red clover isoflavone supplementation (44); however, results have been inconsistent among studies, with others noting a lack of difference in total cholesterol, LDL, HDL, or triglyceride levels compared to placebo (56). Lipid-lowering effects have also been observed in a post-hoc analysis of T. pratense isoflavone (Menoflavon?) supplementation but were limited to individuals with a body mass index (BMI) ?25kg/m2; changes in lipid profile were lacking for individuals with a BMI <25kg/m2 (47). In human research, red clover improved cardiovascular disease risk factors, including the flow of blood through arteries and veins and blood pressure control, although it is unclear if the isoflavones in red clover are responsible for these effects (38; 15; 21; 77).
  • Cognitive improvement agentsCognitive improvement agents: In human research, red cover isoflavones (e.g., Rimostil?) lacked a compelling, overall treatment effect on the cognitive function of postmenopausal women compared to placebo, in spite of isolated improvements in certain tests (7; 8).
  • Cytochrome P450 metabolized herbs and supplementsCytochrome P450 metabolized herbs and supplements: In vitro, red clover, or more specifically, the isoflavone biochanin A, inhibited cytochrome P450 enzymes, particularly CYP450 1A2, 2C19, 2C9, and 3A4 (27; 28; 29; 30).
  • Dermatologic agentsDermatologic agents: In human research, topical coadministration of Trifolium pratense flower extract and biomimetic peptide positively altered the proportion of anagen and telogen hair growth in individuals with alopecia; both anagen hair growth and the anagen:telogen hair ratio increased, whereas telogen hair density decreased (78). In human research, mild cases of psoriasis and thrush have been reported following supplementation with red clover isoflavones (Promensil?), although the relatedness of these incidences to red clover treatment were unable to be determined by investigators (9).
  • Gastrointestinal agentsGastrointestinal agents: According to secondary sources, red clover may interact with gastrointestinal agents.
  • Genitourinary tract agentsGenitourinary tract agents: As a phytoestrogen, red clover possesses both estrogen receptor agonist and antagonist properties. In theory, menstrual changes and endometrial hyperplasia may occur due to estrogenic activity unopposed by progesterone, of which the latter may increase the risk of uterine (endometrial) cancer. In human research, 80mg but not 40mg of red clover isoflavones (Promensil?) increased the duration of menstrual cycles in women with mastalgia (9). However, preliminary short-term (less than six-month) studies have not found increases in endometrial thickness on ultrasound examination (40; 42). It remains unclear if phytoestrogens such as red clover affect these risks. In human research, purified isoflavones extracted from red clover (P-07) lacked an effect on endometrial proliferation vs. placebo, as measured by change in Ki-67 proliferative antigen index (56).
  • Hormonal agentsHormonal agents: According to preliminary human research, red clover isoflavones possess varying affinity for estradiol receptors (estradiol-alpha and estradiol-beta) and are capable of acting as both agonists and antagonists (60). Preliminary evidence suggests a preferential binding to estrogen receptor-beta, which is found in the vasculature, brain, bone, and heart, as opposed to estrogen receptor-alpha (found in the ovaries, breast, uterus, and adrenal glands) (66; 67). According to in vitro research, isoflavones may affect levels of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) via hormonal feedback mechanisms (24); however, there is controversy in this area (6) and high-quality human evidence is lacking. In human research, red clover isoflavones (Promensil?) increased the duration of menstrual cycles in women with mastalgia (9) but lacked an effect on the follicular and luteal phases of the menstrual cycle (43). The majority of evidence from meta-analyses and clinical trials has suggested that red clover isoflavones (e.g., Promensil?, Rimostil?) lack an effect on menopause-related vasomotor symptoms vs. placebo (2; 3; 52; 4; 5; 31; 8).
  • Hormone replacement therapy (HRT)Hormone replacement therapy (HRT): According to preliminary human research, red clover isoflavones possess varying affinity for estradiol receptors (estradiol-alpha and estradiol-beta) and are capable of acting as both agonists and antagonists (60). Preliminary evidence suggests a preferential binding to estrogen receptor-beta, which is found in the vasculature, brain, bone, and heart, as opposed to estrogen receptor-alpha (found in the ovaries, breast, uterus, and adrenal glands) (66; 67). According to in vitro research, isoflavones may affect levels of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) via hormonal feedback mechanisms (24); however, there is controversy in this area (6) and high-quality human evidence is lacking. In human research, red clover isoflavones (Promensil?) increased the duration of menstrual cycles in women with mastalgia (9) but lacked an effect on the follicular and luteal phases of the menstrual cycle (43). The majority of evidence from meta-analyses and clinical trials has suggested that red clover isoflavones (e.g., Promensil?, Rimostil?) lack an effect on menopause-related vasomotor symptoms vs. placebo (2; 3; 52; 4; 5; 31; 8).
  • HypoglycemicsHypoglycemics: In clinical research, red clover has been evaluated for its effects on blood sugar, with inconclusive results; in healthy premenopausal and postmenopausal women taking an isoflavone preparation from red clover (e.g., Promensil?), significant changes were lacking in insulin or glucose concentrations (25; 26). In human research, Promensil? unfavorably reduced the quantitative insulin sensitivity check index (QUICKI) compared to transdermal estrogen therapy (26).
  • HypotensivesHypotensives: In human research, red clover improved cardiovascular disease risk factors, including the flow of blood through arteries and veins and blood pressure control (38; 15; 21). In clinical research, systolic and diastolic blood pressure measurements were significantly lower with treatment with red clover isoflavones (15).
  • Osteoporosis agentsOsteoporosis agents: In animal research, isoflavones, genistein and daidzein, stimulated osteoblastic function (79). According to human research conducted in menopausal and postmenopausal women (22; 6; 46; 40; 19), it is unclear to what extent bone loss is affected by dietary isoflavones such as those present in red clover. In a randomized controlled trial, red clover isoflavones (Rimostil?) lacked an effect on bone resorption and fractional calcium absorption and reduced the level of serum alkaline phosphatase vs. baseline (54).
  • PhytoestrogensPhytoestrogens: According to preliminary human research, red clover isoflavones possess varying affinity for estradiol receptors (estradiol-alpha and estradiol-beta) and are capable of acting as both agonists and antagonists (60). Preliminary evidence suggests a preferential binding to estrogen receptor-beta, which is found in the vasculature, brain, bone, and heart, as opposed to estrogen receptor-alpha (found in the ovaries, breast, uterus, and adrenal glands) (66; 67). According to in vitro research, isoflavones may affect levels of GnRH, FSH, and LH via hormonal feedback mechanisms (24); however, there is controversy in this area (6) and high-quality human evidence is lacking. In human research, red clover isoflavones (Promensil?) have been shown to increase the duration of menstrual cycles in women with mastalgia (9) but lacked an effect on the follicular and luteal phases of the menstrual cycle (43). The majority of evidence from meta-analyses and clinical trials has suggested that red clover isoflavones (e.g., Promensil?, Rimostil?) lack an effect on menopause-related vasomotor symptoms vs. placebo (2; 3; 52; 4; 5; 31; 8).
  • Selective estrogen receptor modulatorsSelective estrogen receptor modulators: Literature review findings have suggested that antagonistic effects are plausible following the coadministration of tamoxifen and phytoestrogens, including red clover (67).

    • Red clover/Food Interactions:

  • GeneralGeneral: Solid extracts from red clover (Trifolium pratense) tops are listed on the Everything Added to Food in the United States (EAFUS) list. It is believed that the amounts typically found in foods, particularly teas and beverages, are too small to be of clinical relevance.

    • Red clover/Lab Interactions:

  • Blood glucoseBlood glucose: In clinical research, red clover has been evaluated for its effects on blood sugar with inconclusive results; in healthy premenopausal and postmenopausal women taking an isoflavone preparation from red clover (e.g., Promensil?), significant changes were lacking in insulin or glucose concentrations (25; 26). In human research, Promensil? unfavorably reduced the quantitative insulin sensitivity check index (QUICKI) compared to transdermal estrogen therapy (26).
  • Blood pressureBlood pressure: In clinical research, systolic and diastolic blood pressure measurements were significantly lower with treatment with red clover isoflavones (15).
  • Coagulation panelCoagulation panel: Red clover contains coumarin and coumarin-like compounds. Genistein and raloxifene have been found to inhibit platelet aggregation in animal research (11; 12; 13). Flavones (apigenin and luteolin) and isoflavones (genistein) have been found to inhibit the binding to the thromboxane A2 receptor (11).
  • Homocysteine levelsHomocysteine levels: In human research, red clover isoflavone supplementation lacked an effect on the serum concentrations of homocysteine and folate compared to placebo (43).
  • Hormonal levelsHormonal levels: According to in vitro research, isoflavones may affect levels of GnRH, FSH, and LH via hormonal feedback mechanisms (24). However, in a randomized trial of 205 women receiving Promensil? (40mg of red clover isoflavones per tablet) or placebo daily for one year, significant differences in FSH or LH levels were lacking between groups (23; 6). In a meta-analysis, red clover- and soy-derived isoflavones (Promensil?) lacked an effect on circulating levels of testosterone, free testosterone, SHBG, or FAI (65; 26).
  • Lipid profileLipid profile: Available evidence of red clover's (e.g., Menoflavon?) effects on lipid levels in humans remains inconclusive (68; 21; 69). Reductions in total cholesterol and LDL, as well as increases in HDL, have been observed (47; 44).