Traditionally used for cancer and currently promoted for menopausal symptoms, there is no convincing evidence of efficacy for either claim.

[LFODPKM ] Letter Key

Latin Name

Trifolium pratense L.

Family

Leguminosae

Other Common Names

Purple clover, trefoil, cowgrass, and pavine clover

Description

• Red clover is a nitrogen-fixing perennial that grows up to 2 ft tall. It has red or purple globular "flowers" (actually collections of tiny florets).

Part Used

Flowers

Known Active Constituents

• Red clover contains notable amounts of at least four estrogenic isoflavones: formononetin, biochanin A, daidzein, and genistein. Flowers also contain salicylic acid, p-coumaric acid, isorhamnetin glucosides (including trifolianol, a phytosterol glucoside), trifolin, trifolitin, rhamnose, isotrofilin, pratol, pratensol, trans and cis-cloramide, and phaseolic acid (1).

Mechanism/Pharmacokinetics

• Formononetin, biochanin A, daidzein, and genistein are phytoestrogens, capable of stimulating estrogen receptors and inducing biologic responses.

[Outline]

• LLatin Name
• FFamily
• OOther Common Names
• DDescription
• PPart Used
• KKnown Active Constituents
• MMechanism/Pharmacokinetics

[CO ] Letter Key

Clinical Trials

• Hot flashes and other menopausal symptoms
  • Two double-blind, placebo-controlled trials of a standardized red clover extract found no benefit of red clover extract on hot flashes. In one crossover trial study of red clover extract, 51 women (whose last menses was at least 6 months past) having at least three hot flashes a day were randomized to one daily tablet of placebo or red clover extract (containing 40 mg total isoflavones, including genistein 4 mg, daidzein 3.5 mg, biochanin 24.5 mg, and formononetin 8.0 mg) (2). The first phase of the trial lasted for 3 months, followed by a 1-month washout period, after which they were crossed over to the other arm for 14 weeks (3 months plus an additional 2 weeks, to accommodate the possibility of change in reporting habits that might occur at the end of a trial). Symptom diaries using the Greene Menopause Score (a validated symptom self-assessment scale) were kept by the participants. At the beginning of the trial, and at the conclusion of each treatment arm, participants underwent a medical examination and blood tests [complete blood count (CBC), liver function tests, and levels of follicle-stimulating hormone (FSH), estradiol, and sex hormone binding globulin (SHBG)]. A 24-hour urine sample was also collected for analysis of genistein, daidzein, formononetin, and biochanin A. A vaginal smear (for vaginal maturation index) was collected, and transvaginal ultrasound was performed to assess endometrial thickness.
    Forty-three women completed the study. Hot flush frequency decreased in both placebo and active groups at 12 weeks (about 18% and 20%, respectively), but there were no statistically significant differences between groups in Greene Scores at any timepoint. No significant differences were seen between groups in SHBG levels, blood counts, serum electrolytes, urea, creatinine, or liver function tests. No change in body weight was observed in either group. There were no differences between groups in endometrial thickness or vaginal epithelium in the vaginal maturation index between treatment groups at the beginning and end of the trial. Information on adverse events was not reported.
  • In another trial of the effects of red clover extract on menopausal symptoms (3), 37 postmenopausal women having at least three hot flushes per day were randomized to placebo or one of two doses of red clover extract (40 mg or 160 mg) for 12 weeks. Endpoints were similar to the previous trial. Hot flush frequency decreased in all groups over the 12 weeks (35%, 29%, 34%); there was no significant difference among the three groups. There were no significant differences from baseline in any group in FSH, SHBG, vaginal maturation scores, or vaginal pH (the latter two are biologic indicators of estrogenicity). Serum high density lipoprotein (HDL)-cholesterol levels increased significantly by 18% (p = 0.038) in participants taking the 40-mg dose; HDL levels for those taking 160 mg were not different from the placebo group. These data are not possible to evaluate without the total cholesterol levels. The ratio of HDL to total cholesterol is important; if the increase in HDL is due to an increase in total cholesterol, this may not be a benefit. In addition, because the higher dose did not result in a beneficial effect on HDL, it is questionable whether this effect will stand up in future trials. Nowhere in the paper is there a report of adverse events.
• Arterial compliance and lipids
  • A third double-blind trial with an unusual design compared the effects of two doses of standardized red clover extract on arterial compliance and plasma lipids in the same group; a much smaller group took placebo. After a 3 to 4 week run-in followed by a 5-week placebo phase, 26 women were randomized either to one tablet of red clover extract (40 mg) or placebo, in a 4:1 ratio (4). After 5 weeks, those on red clover extract had their doses doubled to 80 mg for another 5 weeks, while those receiving placebo continued on placebo. The dropout rate was very high. Nineteen women underwent lipid assessment; 17 underwent measurements of arterial compliance at the end of the first intervention; and only 16 women (including 3 in the placebo group) completed the study. Because the placebo group was so small, those results were not statistically analyzed; comparisons were made among the treatment group at different phases (placebo, 40 mg, 80 mg).
    In those who completed the study, a significant increase in arterial compliance was found during the 40- and 80-mg phases, compared with the placebo phase, with no significant difference between 40- and 80-mg doses. There were no significant changes in plasma lipoprotein levels. This trial suffers from problems in blinding and placebo control and, furthermore, had a high dropout rate.

Other Claimed Benefits/Actions

• Cancer treatment
• Cancer prevention
• Heart disease prevention
• Expectorant
• Bronchitis
• Burns, ulcers, sores, athlete’s foot (external washes)
• Constipation
• Diuretic
• Rheumatism
• Asthma (smoked)

[Outline]

• CClinical Trials
  • Hot flashes and other menopausal symptoms
  • Arterial compliance and lipids
• OOther Claimed Benefits/Actions

[ADT ] Letter Key

Adverse Reactions

• No adverse reactions have been reported; however, none of the published clinical trials have reported adverse effects (in most studies it is unclear whether this information was gathered). There are theoretical concerns about estrogenic effects on endometrium or breast (see questions and answers).

Drug Interactions

• None reported.

Animal Toxicity

• Clovers may be eaten by grazing animals and can be associated with significant toxicity; white clover (T. repens) contains a cyanogenic glycoside and is the species most commonly associated with poisonings (5). Subterranean clover (T. subterraneum), like red clover, contains large amounts of phytoestrogens, and its consumption by sheep in Australia in the 1940s resulted in what has come to be known as "clover disease"; infertility, abnormal lactation, dystocia, and prolapsed uterus were attributed to estrogenic effects (6). In ovariectomized sheep, red clover silage causes clear estrogenic effects, including enlargement of the vulva, uterus, udder, and teats, as well as secretion of a milky fluid (6).

[Outline]

• AAdverse Reactions
• DDrug Interactions
• TAnimal Toxicity

Common Dosage Forms

• Tablets containing solid extract (usually 40 mg)
• Dried flowerheads: 2 to 4 g t.i.d.
• Infusion made with 2 to 4 g herb taken t.i.d.
• Fluid extract: (1:1, 25% ethanol) 1.5 to 4 mL t.i.d.
• Tincture: (1:10, 45% ethanol) ½ to 2 mL t.i.d.
• Topical use: Infusion, liquid extract, or ointment containing 10% to 15% of flowerheads

• Does red clover cause estrogenic stimulation of breast or endometrium?
• Isn’t clover used as human food?
• Where do the anticancer claims for red clover come from?

Q: Does red clover cause estrogenic stimulation of breast or endometrium?

A: Two studies have found no increased endometrial thickness by ultrasound; however, one of these studies was only 8 weeks long (7) and the other 14 weeks long (2). Neither was long enough to adequately assess estrogenic effects on endometrium. This is definitely of concern, especially given known estrogenic effects in grazing animals; admittedly sheep are particularly sensitive to phytoestrogens in fodder, but humans manifest biologic responses to phytoestrogens as well.

Breast cancer cell stimulation is also a concern. In one bioactivity assay, red clover was in the top 5% of 150 herbs tested in a binding assay for both estradiol and progesterone binding (8).

Q: Isn’t clover used as human food?

A: Clover is edible, but is consumed only in small quantities, and is not commonly eaten. Unlike soybeans (also rich in phytoestrogens), clover has never been a dietary staple of humans. Clovers are occasionally consumed in small quantities as a tea or flavoring, and even that use is among limited populations. In parts of Asia, powdered leaves and flower heads are sprinkled onto rice (9); clover leaves may be put into soups (10). Aztec clover (Trifolium amabile) is used in Latin America and mixed with white corn and other herbs by Peruvian Indians, and leaves and stems of Trifolium ciliatum are used by the Luisena Indians of California (11). Flower heads and sprouts may be eaten; red clover is considered generally recognized as safe (GRAS). Solid extract may be used in food products, usually at less than 20 ppm, but jams and jellies may contain 525 ppm (1). Most of these uses are uncommon today.

Q: Where do the anticancer claims for red clover come from?

A: It was included in Harry Hoxsey’s anticancer formula, a famous cancer remedy popular in the 1940s. The formula contained barberry, buckthorn, burdock, cascara, red clover, licorice, poke, prickly ash, and stillingia (along with topically applied bloodroot). The story goes that the originator of the formula was Hoxsey’s great grandfather, who observed a horse with cancer put out to pasture who recovered after eating herbs in the field (Duke, personal communication, 2001). Red clover’s anticancer properties are also touted in Jethro Kloss’ Back to Eden, which states that "Red clover is one of God’s greatest blessings to man ... Combined with equal parts of blue violet, burdock, yellow dock, dandelion root, rock rose and goldenseal, it is a most powerful remedy for cancerous growths ..." (12).

1. Duke JA. CRC handbook of medicinal herbs. Boca Raton, FL: CRC Press, 1985.
2. Baber RJ, Templeman C, Morton T et al. Randomized placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women. Climacteric 1999;2:85–92.
3. Knight DC, Howes JB, Eden JA. The effect of Promensil, an isoflavone extract, on menopausal symptoms. Climacteric 1999;2:79–84.
4. 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 Endo Metab 1999;84:895–898.
5. Lewis RA. Lewis’ dictionary of toxicology. Boca Raton: CRC Press, 1998.
6. Nwannenna AI, Lundh TJ-O, Madej A et al. Clinical changes in ovariectomized ewes exposed to phytoestrogens and 17-estradiol implants. Proc Soc Exp Biol Med 1995;208:92–97.
7. Nachtigal LE, Nachtigal LB. The effects of isoflavones derived from red clover on vasomotor symptoms and endometrial thickness. 9th International World Congress on the Menopause, Oct 1999, Yokohama, Japan (abst P. 128).
8. Zava DT, Dollbaum CM, Blen M. Estrogen and progestin bioactivity of foods, herbs, and spices. Proc Soc Exp Biol Med 1998;217:369–378.
9. Facciola S. Cornucopia II: a source book of edible plants. Vista CA: Kampong Publications, 1998.
10. Tanaka T. In Nakao S, ed. Tanaka’s cyclopedia of edible plants of the world. Tokyo: Keigaku, 1976.
11. Uphof JC Th. Dictionary of economic plants. New York: Stechert-Hatner Service Agency, 1968.
12. Kloss J. Back to Eden. Coalmont, TN: Longview, 1971:301.