Red Clover

Purported Benefits, Side Effects & More
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Red Clover

Common Names

  • Cow clover
  • Wild clover
  • Purple clover beebread
  • Cow grass
  • Meadow clover
  • Purple clover

For Patients & Caregivers

Tell your healthcare providers about any dietary supplements you’re taking, such as herbs, vitamins, minerals, and natural or home remedies. This will help them manage your care and keep you safe.


What is it?

Red clover is an herb that belongs to the same family as peas and beans. It contains nutrients known as isoflavones (i-so-FLAY-vones) that help treat hot flashes.

Red clover is used in traditional medicine for many health issues. You can take red clover supplements as tablets, capsules, and tinctures (concentrated herbal liquid). It also comes as creams and ointments that you can put on your skin.

What are the potential uses and benefits?

Red clover is used to:

  • Manage symptoms caused by menopause (permanent end of menstrual cycles), such as hot flashes.
  • Treat osteoporosis (thinning of your bones).
  • Lower high cholesterol.

Red clover also has other uses that have not been studied by doctors to see if they work.

Talk with your healthcare provider before taking red clover supplements. Herbal supplements are stronger than the herbs you would use in cooking.

Some supplements can also affect how medications work. For more information, read the “What else do I need to know?” section below.

What are the side effects?

Side effects have not been reported.

What else do I need to know?
  • Talk with your healthcare provider if you’re taking blood thinners such as warfarin (Jantoven® or Coumadin®). Red clover may increase your risk of bleeding.
  • Avoid red clover if you’re pregnant or breastfeeding. It may not be safe for you.
  • Talk to your healthcare provider if you have a hormone-sensitive cancer (like some breast cancers). Red clover may worsen your condition.
  • The safety of using red clover over a long period of time is not known.
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For Healthcare Professionals

Brand Name
Promensil®
Scientific Name
Trifolium pratense
Clinical Summary

Red clover is a perennial herb traditionally used to treat skin disorders such as psoriasis and eczema, whooping cough, and mastitis. It contains compounds known as isoflavones that act as phytoestrogens. An isoflavone extract is widely promoted as a dietary supplement to relieve menopausal symptoms.

Preclinical studies suggest red clover extract may act as an estrogen agonist and stimulate proliferation of ER-positive breast cancer cells (1). However, the isoflavone Biochinin A inhibited aromatase activity and expression (2) and may therefore confer a protective effect. Isoflavone-enriched extracts have shown neuroprotective effects in human cortical neurons (3) (4) and reduced skin aging in mice by increasing collagen (5).

Clinical data show that supplementation with red clover isoflavones improves menopausal symptoms compared with placebo (7) (8), but systematic reviews are mixed (9) (24) (10). In postmenopausal women, supplementation alleviated vasomotor and menopausal symptoms (18) (25). A meta-analysis of a standardized extract suggests potential reductions in total cholesterol in peri- and postmenopausal women, but studies were heterogeneous (29). Isoflavones may also improve bone loss (11). In a trial involving osteopenic postmenopausal women, a red clover extract rich in isoflavones, aglycones, and probiotics attenuated bone mineral density loss caused by estrogen deficiency and improved bone turnover (26).

Of concern are findings that red clover inhibits the growth of normal prostate cells and increases resistance of prostate cancer cells to high-dose radiation in vitro (15). Patients should consult with their physicians before taking red clover supplements.

Purported Uses and Benefits
  • Menopause support
  • Osteoporosis
  • High cholesterol
Mechanism of Action

Formononetin, an isoflavone, induced apoptosis in human breast cancer cells by activating the Ras-p38 mitogen-activated protein kinase in ER-positive breast cancer cells (23). It also inhibited proliferation of human osteosarcoma U2SO cells by decreasing expression of miR-375 and Bcl-2, an apoptotic repressor, while increasing Bax, a pro-apoptotic protein  (27). The isoflavone Biochanin A inhibited activity and gene expression of aromatase, an enzyme that catalyzes the conversion of androgen to estrogen (2). In addition, it protected dopaminergic neurons against lipopolysaccharide-induced damage by inhibiting microglial activation and proinflammatory factors (3). An isoflavone-enriched fraction showed neuroprotective activity in human cortical neurons as well, possibly due to antioxidant and estrogenic effects (4).

In a murine model, red clover isoflavones reduced skin aging induced by estrogen deprivation following ovariectomy (5).

Contraindications
  • Patients with hormone-sensitive cancers should avoid red clover because it has estrogenic activity (21).
  • Red clover may increase effects of anticoagulants and antiplatelet drugs (20).
  • Red clover was associated with toxic effects when used by a patient receiving methotrexate injections for severe psoriasis (19).
Adverse Reactions

Case reports

Subdural hematoma: In a 65-year-old woman with no other risk factors for bleeding except long-term use of red clover supplements for postmenopausal symptoms (6).

Subarachnoid hemorrhage: In a 53-year-old woman following use of an herbal supplement containing red clover, dong quai, and Siberian ginseng for perimenopausal hot flashes. Symptoms resolved after supplement discontinuation (16).

Herb-Drug Interactions

Anticoagulants / Antiplatelets: Preclinical studies suggest red clover may increase their effects (20). Clinical relevance has yet to be determined.
CYP450 enzymes: Preclinical studies suggest red clover can inhibit 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4, and may interact with substances metabolized by these enzymes (17) (28). Clinical relevance has yet to be determined.
Methotrexate: Red clover was reported to cause toxicity, resulting in severe vomiting and epigastric pain, when used along with methotrexate injections (19).

Dosage (OneMSK Only)
References
  1. Le Bail JC, Champavier Y, Chulia AJ, Habrioux G. Effects of phytoestrogens on aromatase, 3beta and 17beta-hydroxysteroid dehydrogenase activities and human breast cancer cells. Life Sci. 2000;66(14):1281-1291.
  2. Wang Y, Man Gho W, Chan FL, Chen S, Leung LK. The red clover (Trifolium pratense) isoflavone biochanin A inhibits aromatase activity and expression. Br J Nutr 2008;99(2):303-310.
  3. Chen HQ, Jin ZY, Li GH. Biochanin A protects dopaminergic neurons against lipopolysaccharide-induced damage through inhibition of microglia activation and proinflammatory factors generation. Neurosci Lett 2007;417(2):112-117.
  4. Occhiuto F, Zangla G, Samperi S, et al. The phytoestrogenic isoflavones from Trifolium pratense L. (Red clover) protects human cortical neurons from glutamate toxicity. Phytomedicine 2008.
  5. Circosta C, De Pasquale R, Palumbo DR, Samperi S, Occhiuto F. Effects of isoflavones from red clover (Trifolium pratense) on skin changes induced by ovariectomy in rats. Phytother Res 2006;20(12):1096-1099.
  6. Hall S, Walshe E, Ajayi C, et al. Acute-on-chronic subdural hematoma in a patient taking Red Clover herbal supplement: A case report. Surg Neurol Int. 2018;9:43.
  7. Hidalgo LA, Chedraui PA, Morocho N, Ross S, San Miguel G. The effect of red clover isoflavones on menopausal symptoms, lipids and vaginal cytology in menopausal women: a randomized, double-blind, placebo-controlled study. Gynecol Endocrinol 2005;21(5):257-264.
  8. van de Weijer PH, Barentsen R. Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas 2002;42(3):187-193.
  9. Coon JT, Pittler MH, Ernst E. Trifolium pratense isoflavones in the treatment of menopausal hot flushes: a systematic review and meta-analysis. Phytomedicine 2007;14(2-3):153-159.
  10. Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev 2007(4):CD001395.
  11. Atkinson C, Compston JE, Day NE, Dowsett M, Bingham SA. The effects of phytoestrogen isoflavones on bone density in women: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr 2004;79(2):326-333.
  12. Nestel PJ, Pomeroy S, Kay S, et al. Isoflavones from red clover improve systemic arterial compliance but not plasma lipids in menopausal women. J Clin Endocrinol Metab 1999;84(3):895-898.
  13. Brandli A, Simpson JS, Ventura S. Isoflavones isolated from red clover (Trifolium pratense) inhibit smooth muscle contraction of the isolated rat prostate gland. Phytomedicine. 2010 Sep;17(11):895-901.
  14. Tava A, Ramella D, Grecchi M, et al.Volatile constituents of Trifolium pratense and T. repens from N.E. Italian alpine pastures. Nat Prod Commun. 2009 Jun;4(6):835-8.
  15. Hasan Y, Schoenherr D, Martinez AA, et al. Prostate-specific natural health products (dietary supplements) radiosensitize normal prostate cells. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3):896-904.
  16. Friedman JA, Taylor SA, McDermott W, Alikhani P. Multifocal and recurrent subarachnoid hemorrhage due to an herbal supplement containing natural coumarins. Neurocrit Care. 2007;7(1):76-80.
  17. Unger M, Frank A. Simultaneous determination of the inhibitory potency of herbal extracts on the activity of six major cytochrome P450 enzymes using liquid chromatography/mass spectrometry and automated online extraction. Rapid Commun Mass Spectrom. 2004;18(19):2273-81.
  18. Lipovac M, Chedraui P, Gruenhut C, et al. The effect of red clover isoflavone supplementation over vasomotor and menopausal symptoms in postmenopausal women. Gynecol Endocrinol. 2012 Mar;28(3):203-7.
  19. Orr A, Parker R. Red clover causing symptoms suggestive of methotrexate toxicity in a patient on high-dose methotrexate. Menopause Int. 2013 Sep;19(3):133-4.
  20. Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm. 2000 Jul 1;57(13):1221-7.
  21. Booth NL, Overk CR, Yao P, et al. The chemical and biologic profile of a red clover (Trifolium pratense L.) phase II clinical extract. J Altern Complement Med. 2006 Mar;12(2):133-9.
  22. Howes J, Waring M, Huang L, Howes LG. Long-term pharmacokinetics of an extract of isoflavones from red clover (Trifolium pratense). J Altern Complement Med. 2002 Apr;8(2):135-42.
  23. Chen J, Sun L. Formononetin-induced apoptosis by activation of Ras/p38 mitogen-activated protein kinase in estrogen receptor-positive human breast cancer cells. Horm Metab Res. 2012 Dec;44(13):943-8.
  24. Myers SP, Vigar V. Effects of a standardised extract of Trifolium pratense (Promensil) at a dosage of 80mg in the treatment of menopausal hot flushes: A systematic review and meta-analysis. Phytomedicine. 2017 Jan 15;24:141-147.
  25. Shakeri F, Taavoni S, Goushegir A, Haghani H. Effectiveness of red clover in alleviating menopausal symptoms: a 12-week randomized, controlled trial. Climacteric. 2015;18(4):568-73.
  26. Lambert MNT, Thybo CB, Lykkeboe S, et al. Combined bioavailable isoflavones and probiotics improve bone status and estrogen metabolism in postmenopausal osteopenic women: a randomized controlled trial. Am J Clin Nutr. 2017 Sep;106(3):909-920.
  27. Hu W, Xiao Z. Formononetin induces apoptosis of human osteosarcoma cell line U2OS by regulating the expression of Bcl-2, Bax and MiR-375 in vitro and in vivo. Cell Physiol Biochem. 2015;37(3):933-9.
  28. Arora S, Taneja I, Challagundla M, Raju KS, Singh SP, Wahajuddin M. In vivo prediction of CYP-mediated metabolic interaction potential of formononetin and biochanin A using in vitro human and rat CYP450 inhibition data. Toxicol Lett. 2015 Nov 19;239(1):1-8.
  29. Kanadys W, Baranska A, Jedrych M, et al. Effects of red clover (Trifolium pratense) isoflavones on the lipid profile of perimenopausal and postmenopausal women-A systematic review and meta-analysis. Maturitas. Feb 2020;132:7-16.
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