Written by Sarah Vadeboncoeur and the CAM-Cancer Consortium.
Updated February 8, 2017

Red clover (Trifolium pratense)

Is it safe?

Safety data in women with cancer is generally lacking; the information below refers to women without cancer.

Adverse events

Red clover is generally well tolerated but has been reported to cause minor adverse effects, some occurring at doses as low as 40 mg per day. Adverse effects include: headaches, myalgia, arthralgia, nausea, and diarrhoea2, breast tenderness, swollen neck glands, dizziness, vertigo, tremor, hypertension, acne, rash, pruritis, psoriasis, bloating, constipation, mouth ulcer, sore throat, osteoarthritis, bronchitis, low platelets, reflux, epistaxis, menstrual bleeding, urinary tract infection, and vaginal thrush. Compounds and mechanisms responsible for triggering adverse events are currently unknown33. A large trial of a red clover extract (Promensil) versus placebo reported no differences in the proportion of women who experienced any adverse events and no differences in the rate of specific adverse events between groups33.

Interactions

There are no reports of clinically significant drug interactions with red clover in the published literature. Red clover isoflavones can inhibit CYP IA1, CYP IBI and CYP 2C9 metabolic liver enzymes and may increase plasma levels of drugs metabolised through these pathways34.

Use of red clover concomitantly with herbs that have constituents that might affect platelet aggregation could theoretically increase the risk of bleeding in some people. These herbs include angelica, clove, danshen, garlic, ginger, ginkgo, Panax ginseng, horse chestnut, turmeric, and others5.

Use of red clover with oestrogenic herbs and drugs, including tamoxifen, are theoretically contraindicated as red clover may have additive or antagonistic effects5.

Contraindications

Some suggest testing prothrombin time and/or partial thromboplastin time prior to initiating therapy34 and avoiding its use in those with bleeding disorders2. Individuals with thyroid conditions should use caution when consuming phytooestrogens as one animal study reported higher concentrations of some thyroid hormones with red clover use1. Red clover is contraindicated during pregnancy33.

Contamination issues

There are some concerns about the potential presence of coumarins in some products or specific species of red clover which can affect bleeding time. It is therefore contraindicated in those with bleeding disorders.

Citation

Sarah Vadeboncoeur, CAM-Cancer Consortium. Red clover (Trifolium pratense) [online document]. http://cam-cancer.org/The-Summaries/Herbal-products/Red-clover-Trifolium-pratense. February 8, 2017.

Document history

Assessed as up to date in February 2017 by Barbara Wider.
Assessed as up to date in January 2015 by Barbara Wider.
Summary first published in February 2013 by Sarah Vadeboncoeur.

References

  1. Osoki L, Kennelly E. Phytoestrogens: A Review of the Present State of Research. Phytother. Res. 2003; 17: 845–869
  2. Cheema D, Coomarasamy A, El-Toukhy T. Non-hormonal therapy of post-menopausal vasomotor symptoms: a structured evidence-based review. Arch Gynecol Obstet, 2007 ; 276:463–469.
  3. Maul R & Kulling S. Absorption of red clover isoflavones in human subjects: results from a pilot study. British Journal of Medicine. 2010;103(11):1569-72.
  4. Fugate SE, Church CO Nonestrogen Treatment Modalities for Vasomotor Symptoms Associated with Menopause. The Annals of Pharmacotherapy. 2004; 38:1482-99.
  5. Natural Medicine Comprehensive Database [Online]. Red Clover. Available from https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=308 [Accessed 8 February 2017]
  6. Bodinet C, Freudenstein J. Influence of marketed herbal menopause preparations on MCF-7 cell proliferation. Menopause. 2004; 11( 3):281-289.
  7. Medjakovic S, Jungbauer A. Red clover isoflavones biochanin A and formononetin are potent liagands of the human aryl hydrocarbon receptor. Journal of Steroid Biochemistry & Molecular Biology. 2008;108:171-177.
  8. Lam A, Demasi M, James M, Husband A, Walker C. Effect of Red Clover Isoflavones on Cox-2 Activity in Murine and Human Monocye/Macrohpage Cells. Nutrition and Cancer. 2004;49(1):89-93.
  9. Kreen L & Paper DH. Inhibition of Angiogenesis and Inflammation by an extract of red clover (Trifolium pratense L.) Phytomedicine. 2009;16:1083-88.
  10. Ma H, Sullivan-Halley J, Smith A, Neuhouser M, Alfano C, Meeske K, George S, McTiernan A, McKean-Cowdin R, Baumgartner K, Ballard-Barbash R, Bernstein L. Estrogenic Botanical Supplements, health related quality of life, and hormone related symptoms in breast cancer survivors: a HEAL study report. BMC Complementary and Alternative Medicine. 2011;11:109.
  11. Hooper L, Madhavan G, Tice J, Leinster S, Cassidy A. Effects of Isoflavones on breast density in pre- and post-menopausal women: a systematic review and meta-analysis of randomized control trials. Human Reproduction Update. 2010;16(6):745-760.
  12. Tempfer C, Bentz E-K, Leodolter, S, Tcsherne G, Reuss F, Cross H, Huber J. Phytoestrogens in Clinical Practice: a review of the literature. Fertil Steril. 2007; 87: 1243-9.
  13. Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev 2007;(4): CD001395.
  14. Thompson Coon J, Pittler M, Ernst E. Trifolium pratense isoflavones in the treatment of menopausal hot flushes: A systematic review and meta-analysis. Phytomedicine. 2006; 14:153-159.
  15. Booth N, Piersen C, Banuvar S, Geller S, Shulman L, Farnsworth, N. Clinical studies of red clover (Trifolium pratense) dietary supplements in menopause: a literature review. Menopause: Journal of the North American Menopause Society. 2006; 13(2):251-264.
  16. Hale G, Hughes C, Robboy S, Agarwal S, Bievre M. A double-blind randomized study on the effects of red clover isoflavones on the endometrium. Menopause: The Journal of the North American Menopause Society. 2011;8(5):338-346.
  17. Song W, Chun OK, Hwang I, Shin HS, Kim B-G, Kim KS, Lee S-Y, Shin D, Lee S. Soy Isoflavones as safe functional ingredients. Journal of Medicinal Food. 2007; 10(4): 571-580.
  18. Atkinson C, Warren R, Sala E, Dowsett M, Dunning A, Healey C, Runswick S, Day N, Bingham S. Red clover-derived isoflavones and mammographic breast density: a double-blind, randomized, placebo-controlled trial. Breast Cancer Research. 2004; 6(3): R1 70-79.
  19. Vrieling A, Rookus M, Kampman E, Bonfrer J, Korse C, van Doorn J, Lampe J, Cats A, Witteman B, van Leeuwen F, van’t Veer L, Voskuil D. Isolated Isoflavones Do Not Affect the Circulating Insulin-Like Growth Factor System in Men at Increased Colorectal Cancer Risk. The Journal of Nutrition. 2007; 137:379-383.
  20. Jarred R, Keikha M, Dowling C et al. Induction of Apoptosis in Low to Moderate-Grade Human Prostate Carcinoma by Red-Clover Derived Dietary Isoflavones. Cancer Epidemiology, Biomarkers & Prevention. 2002;11:1689-96.
  21. Stephens, F. Phytoestrogens and prostate cancer: possible preventive role. Medical Journal of Australia. 1997; 167: 138-40.
  22. Chan H, Wang H, Leung L. The red clover (Trifolium pratense) isoflavone biochanin A modulates the biotransformation pathways of 7,12-dimethylbenz[a]anthracene. British Journal of Nutrition. 2003;90(1):87-92.
  23. Han E, Kim J & Jeong H. Effect of Biochanin A on the Aryl Hydrocarbon Receptor and Cytochrome P450 1A1 in MCF-7 Human Breast Carcinoma Cells. Arch Pharm Res. 2006;29(7):570-576.
  24. Boué S, Wiese T, Nehls S, Burow M, Elliott S, Carter-Wientjes C, Shih B, McLachlan J, Cleveland T. Evaluation of the Estrogenic Effects of Legume Extracts Containing Phytoestrogens. Journal of Agricultural and Food Chemistry. 2003;51:2193-2199.
  25. Fokialakis N, Alexi X, Aligiannis N, Siriani D, Meligova A, Pratsinis H, Mitakou S, Alexis M. Ester and carbamate ester derivatives of Biochanin A: Synthesis and in vitro evaluation of estrogenic and antiproliferative activities. Bioorganic & Medicinal Chemistry. 2012;20:2962-2970.
  26. Rice L, Samedi V, Medrano T, Sweeney C, Baker H, Stenstrom A, Furman J, Shiverick K. Mechanism of Growth Inhibitory Effects of the Isoflavonoid Biochanin A on LNCaP Cells and Xenografts. The Prostate. 2002;52:201-212.
  27. Szliszka E, Czuba Z, Mertas MD, Paradysz A, Krol W. The dietary isoflavone biochanin-A sensitizes prostate cancer cells to TRAIL-induced apoptosis. Urologic Oncology. 2011.
  28. Wang Y, Gho WM, Chan F, Chen S, Leung L. The red clover (Trifolium pratense) isoflavone biochanin A inhibits aromatase activity and expression. British Journal of Nutrition. 2008;99(2):303-310.
  29. Liu J, Burdette J, Xu H, Chungang G, van Breernen R, Bhat K, Booth N, Constantinou A, Pezzuto J, Fong H, Farnsworth N, Bolton J. Evaluation of Estrogenic Activity of Plant Extracts for the Potential Treatment of Menopausal Symptoms. J. Agric Food Chem. 2001; 49:2472-79.
  30. Jarred R, McPherson S, Jones M, Simpson E, Risbridger G. Anti-Androgenic Action by Red Clover-Derived Deitary Isoflavones reduces Non-Malignant Prostate Enlargement in Aromatase Knockout (ArKO) Mice. The Prostate. 2003;56:54-64.
  31. Gray N, Liu X, Choi R et al. Endocrine-Immune Paracrine Interactions in Prostate Cells as Targeted by Phytomedicines. Cancer Prev Res. 2009;2:134-42.
  32. Liu X, Piao Y, Arnold J. Transforming gowth factor B1 increase of hydroxysteroid dehydrogenase proteins is partly suppressed by red clover isoflavones in human primary prostate cancer-derived stromal cells. Carcinogenesis. 2011;32(11):1648-54.
  33. Booth N, Overk C, Yao P, Totura S, Deng Y, Hedayat AS, Bolton J, Pauli G, Farnsworth N. Seasonal Variation of Red Clover (Trifolium pratense L., Fabaceae) Isoflavones and Estrogenic Activity. Journal of Agricultural and Food Chemistry. 2006;54:1277-82.
  34. Roberts H. Safety of herbal medicinal products in women with breast cancer. Maturitas. 2010; 66:363-369.Moyad M. Complementary/Alternative Therapies for reducing hot flashes in prostate cancer patients: re-evaluating the existing indirect data from studies of breast cancer and postmenopausal women. Urology. 2002; 59(Supplement 4A):20-33.
  35. Moyad M. Complementary/Alternative Therapies for reducing hot flashes in prostate cancer patients: re-evaluating the existing indirect data from studies of breast cancer and postmenopausal women. Urology. 2002; 59(Supplement 4A):20-33.
  36. Pfitscher A, Reiter E, Jungbauer A. Receptor binding and transactivation activities of red clover isoflavones and their metabolites. J Steroid Biochem Mol Biol 2008 Nov;112(1-3):87-94)