Red Clover

Trifolium pratense L. belongs to Fabaceae (Leguminosae), the legume or pea family, and NCBI Taxonomy files it as taxon 57577. The genus name means three leaves, and pratense means of meadows. NCCIH describes it as native to Europe, central Asia, and northern Africa; the USDA plant guide places its origin in Asia Minor and south-eastern Europe, says it reached the British Isles from Germany in the 1600s, and notes that English colonists brought it to North America, where it is now grown and naturalized throughout the United States. It is a biennial or short-lived perennial with hollow, hairy stems, usually 45–75 cm long, growing from a crown. Each leaf has three oval leaflets, often marked with a pale chevron or V. The first-year taproot usually disintegrates in the second year and is replaced by branched secondary roots (USDA).

The flowers are borne in dense, rounded heads at the tips of the stems, usually rose-pink to purplish, each head made of up to 125 small pea-like florets (USDA). The long floral tubes suit long-tongued bees: the USDA notes that bumblebees are especially important pollinators, while honey bees tend to prefer white, alsike, and sweet clover when they are nearby. Seed pods are small, with kidney-shaped seeds ranging from yellow to violet. King’s American Dispensatory describes the leaflets as lighter coloured in the centre and the flowers as fragrant. Traditional medicine used the dried flower heads, while some modern isoflavone extracts are made from the flowering tops or wider aerial parts, so products are not interchangeable.

Red clover is the most widely grown of the true clovers and, according to the USDA, the most important legume hay crop in the north-eastern United States, with as much as 10 million acres grown in northern states in the 1940s. With the right Rhizobium bacteria in root nodules it fixes atmospheric nitrogen and needs little or no nitrogen fertilizer. The same chemistry that interests supplement makers matters on the farm: red clover contains isoflavones, chiefly biochanin A (PubChem CID 5280373, C16H12O5) and formononetin (CID 5280378, C16H12O4), with much smaller amounts of genistein and daidzein. The extract used by Atkinson and colleagues supplied 26 mg of biochanin A, 16 mg of formononetin, 1 mg of genistein, and 0.5 mg of daidzein a day. The USDA notes infrequent reproductive problems in sheep grazing pure stands of red clover, attributed to its oestrogenic compounds, and a risk of bloat in grazing livestock.

Red clover’s medical reputation is largely American and nineteenth-century. King’s American Dispensatory (1898), the standard text of the Eclectic physicians, calls the blossoms an excellent alterative, a term for remedies believed to purify the blood and gradually restore health, and one of the few remedies that favourably influence whooping cough. It recommends red clover for other spasmodic coughs, for leg ulcers, burns, and ill-conditioned sores, and claims that it unquestionably retards the growth of cancers when taken over long periods. MSKCC adds traditional uses for psoriasis, eczema, and mastitis. These were the claims of an era before controlled trials, and none has been confirmed.

The cancer claims carried into commercial products. King’s describes a Compound Extract of Trifolium sold by the Wm. S. Merrell Chemical Company of Cincinnati, combining red clover with stillingia, burdock, poke root, cascara amarga, Oregon grape, mayapple, prickly ash, and potassium iodide. The principal ‘brown’ tonic later promoted by Harry Hoxsey as a cancer cure has a strikingly similar recipe: MSKCC lists potassium iodide, licorice, red clover, burdock root, stillingia root, barberry, cascara, pokeweed, prickly ash bark, and buckthorn bark. MSKCC records that Hoxsey was convicted many times of practising medicine without a licence, that the US government found the 400 patients he claimed to have cured had never had cancer, were cured beforehand, still had cancer, or had died of it, and that the National Cancer Institute found no evidence of efficacy in 77 case reports he submitted. The treatment is illegal in the United States but has been offered at clinics in Tijuana, Mexico. No clinical data support it.

The modern phytoestrogen story began on Australian sheep farms. Bennetts and colleagues (Australian Veterinary Journal 1946) described a breeding problem in sheep on subterranean clover pastures in Western Australia, and Pool and colleagues (Frontiers in Endocrinology 2022) explain that this ovine clover disease was later traced to the high formononetin content of several cultivars of subterranean clover (Trifolium subterraneum), a different species from red clover. In the rumen, formononetin is converted to the oestrogenic compound equol, which damages the ewe’s reproductive tract and can cause lasting infertility. Pool and colleagues describe clover disease as the first evidence that plant oestrogens could act as endocrine disruptors. Isoflavone extracts of red clover such as Promensil were later marketed as a natural alternative to hormone therapy, and Tice and colleagues (JAMA 2003) noted that trials linking hormone therapy to heart disease and breast cancer had increased interest in such products. Red clover is also Vermont’s state flower, designated by an act of 1894 and still named in Vermont law; the state’s legislative manual calls it a symbol of the countryside and dairy farms, while noting that the plant is not native to Vermont.

Isoflavones are phytoestrogens: plant compounds similar enough in shape to oestradiol to bind oestrogen receptors, though far more weakly than the body’s own hormones. In the body, biochanin A and formononetin, the dominant isoflavones in red clover, are partly converted to genistein and daidzein, the main isoflavones of soy. In ruminants, formononetin is also converted to equol, a more strongly oestrogenic metabolite (Pool). The hope was that a weak plant oestrogen could ease oestrogen-withdrawal symptoms such as hot flashes and protect bone without the risks of hormone therapy; the fear is that the same activity could stimulate oestrogen-sensitive tissues such as breast and endometrium. That is why the safety of red clover in breast and womb tissue has been studied as closely as its benefits.

MSKCC summarizes the laboratory evidence as mixed in direction. Red clover extract acted as an oestrogen agonist and stimulated the growth of oestrogen-receptor-positive breast cancer cells in preclinical studies, while biochanin A inhibited aromatase, the enzyme that makes oestrogen, which might be protective. Formononetin induced cell death in breast cancer cells in other laboratory work. In vitro, red clover also inhibited the growth of normal prostate cells and made prostate cancer cells more resistant to high-dose radiation, a finding MSKCC calls a concern. None of this establishes what happens in people. Laboratory studies cited by MSKCC also show inhibition of several drug-metabolizing CYP enzymes, of unknown clinical relevance.

Bleeding has usually been explained by coumarins, compounds found in red clover and many other plants. Hall and colleagues (Surgical Neurology International 2018) point out that the coumarin-based bleeding risk is theoretical with very little supporting evidence, and in their case report the patient’s INR was normal and her clotting abnormality looked more like an antiplatelet effect, consistent with laboratory findings that red clover can reduce platelet adhesion. Plant coumarins are not the same as the drug warfarin.

Menopausal hot flashes are the main modern use, and the best evidence is negative or marginal. Lethaby and colleagues (Cochrane 2013) reviewed 43 randomized trials of phytoestrogens with 4,364 women. Five trials of Promensil could be pooled: hot flash frequency did not differ significantly from placebo (a mean difference of 0.93 fewer flashes a day, with a confidence interval running from 1.95 fewer to 0.10 more). Placebo effects were strong across the trials, reducing hot flash frequency by between 1% and 59%. The reviewers concluded that there is no conclusive evidence that phytoestrogen supplements reduce the frequency or severity of hot flashes and night sweats, although high-genistein extracts, typically from soy, deserved further study.

Two independent US trials anchor that conclusion. In the ICE study, Tice and colleagues (JAMA 2003) randomized 252 women with at least 35 hot flashes a week to Promensil (82 mg isoflavones a day), Rimostil (57 mg), or placebo for 12 weeks. Daily hot flashes fell by 5.1, 5.4, and 5.0 respectively; Promensil reduced flashes slightly faster, but neither product had a clinically important effect. Geller and colleagues (Menopause 2009), in an NIH-funded, four-arm, double-blind trial lasting 12 months, found that vasomotor symptoms fell by 57% with standardized red clover, 34% with black cohosh, 63% with placebo, and 94% with combined oestrogen and progestogen hormone therapy; only hormone therapy beat placebo, and there were generally no improvements in other menopausal symptoms.

Newer meta-analyses are somewhat more favourable. Kanadys and colleagues (Nutrients 2021) pooled eight trials and found that red clover reduced hot flashes by 1.73 a day more than placebo, with a wide confidence interval (0.18 to 3.28) and very high heterogeneity; effects looked larger in postmenopausal women with five or more flashes a day, at doses of at least 80 mg of isoflavones, and in 12-week studies. The authors called the relationship moderate and asked for well-designed trials to confirm it. NCCIH, citing this review, describes the results as inconsistent and notes that some studies had a high risk of bias. A small reduction is plausible; a large one is not supported.

Cholesterol: Kanadys and colleagues (Maturitas 2020) pooled 10 studies with 910 peri- and postmenopausal women taking a standardized red clover extract. Total cholesterol fell by an average of 0.29 mmol/L (about 11 mg/dL) compared with placebo, but changes in LDL cholesterol, HDL cholesterol, and triglycerides were not statistically significant, and heterogeneity between studies was extreme (I² of 88–98%). NCCIH says red clover may have a beneficial effect on cholesterol in postmenopausal women but that more research is needed. It is not a substitute for statins or other proven treatments in people at cardiovascular risk.

Bone: in a one-year trial in 205 women aged 49 to 65, Atkinson and colleagues (American Journal of Clinical Nutrition 2004) found less loss of lumbar spine bone mineral density with a red clover isoflavone supplement than with placebo, but no effect at the hip, the site most relevant to serious fractures. In the three-year Powles trial, bone mineral density did not differ from placebo. NCCIH notes that only a few bone studies exist and that their results are inconsistent; there is no evidence that red clover prevents fractures. Traditional uses for coughs, skin conditions, and cancer have not been tested in modern trials. MSKCC finds no clinical data supporting the Hoxsey formula, of which red clover is an ingredient, and notes that the American Cancer Society strongly urges cancer patients not to use it.

Most clinical research used standardized isoflavone extracts rather than the whole herb. Promensil, the product in most trials, was supplied as 40 mg isoflavone tablets in the Powles safety trial, and the ICE trial used 82 mg a day; Rimostil supplied 57 mg a day. The extract in the Atkinson bone trial provided about 43.5 mg of isoflavones daily, mostly biochanin A and formononetin. The Kanadys meta-analysis found larger hot flash effects at 80 mg a day or more and after about 12 weeks. Trials have lasted from three months to three years. Products differ in their isoflavone mix, and results from one extract may not apply to another.

Traditional preparations are teas, tinctures, and fluid extracts of the dried flower heads, and ointments for the skin. King’s American Dispensatory (1898) gives an infusion of about one ounce of flowers to a pint of water, taken freely, and a tincture in 50% alcohol. There is no modern standardized dose for these, and their isoflavone content is variable and generally far lower than that of concentrated tablets, so trial results do not apply to them. MSKCC notes that red clover is sold as tablets, capsules, tinctures, creams, and ointments.

Practical points: give any red clover product two to three months before judging it, and stop if there is no clear benefit; placebo responses in menopause trials are large, so a short-lived improvement may not be due to the supplement. Do not combine several phytoestrogen products, such as red clover, soy isoflavones, and combination menopause formulas, without advice. Stop red clover before surgery and tell the surgical team, given the bleeding case reports. Women with a uterus who have any vaginal bleeding after the menopause should see a doctor rather than assume a supplement is responsible.