Herb-Drug Interactions: Red clover

Trifolium pratense L. (Fabaceae)

Synonym(s) and related species

Cow clover, Meadow clover, Purple clover, Trefoil.

Trifolium borysthenicum Gruner, Trifolium bracteatum Schousb., Trifolium lenkoranicum (Grossh.) Rosk., Trifolium ukrainicum Opp.

Not to be confused with melilot, which is known as sweet clover.

Pharmacopoeias

Powdered Red Clover (US Ph 32); Powdered Red Clover extract (US Ph 32); Red Clover (US Ph 32); Red Clover Tablets (The United States Ph 32).

Constituents

Red clover flowers contain isoflavones, to which they may be standardised. The major isoflavones are biochanin A and formononetin, with small amounts of genistein and daidzein and others, and their glycoside conjugates. Other constituents include clovamides, coumestrol, and the natural coumarins medicagol and coumarin.

Use and indications

Red clover was traditionally used for skin conditions, such as eczema and psoriasis. However, the isoflavone fraction is now more commonly used as a form of HRT in women to reduce the symptoms of the menopause, although randomised controlled studies show only a slight benefit at best. It is also used for mastalgia, premenstrual syndrome and cancer prevention.

Pharmacokinetics

In an in vitro study, an extract of red clover reduced the activity of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. The effects on CYP2C8 and CYP2C9 were the most significant. Biochanin A, a major component of red clover, can inhibit P-glycoprotein and OATP, see Isoflavones + Digoxin and Isoflavones + Paclitaxel.

For further information on the pharmacokinetics of the specific isoflavones genistein, daidzein and biochanin A, see isoflavones. Note that biochanin A is metabolised to genistein and formononetin to daidzein.

Interactions overview

It has been suggested that red clover may interact with anticoagulants, but evidence for this is largely lacking. Potential interactions of isoflavone constituents of red clover are covered under isoflavones; see antibacterials, digoxin, fexofenadine, paclitaxel and tamoxifen.

Red clover + Antibacterials

No data for red clover found. For the theoretical possibility that broad-spectrum antibacterials might reduce the metabolism of the isoflavone constituents of red clover, such as daidzin, by colonic bacteria, and so alter their efficacy, see Isoflavones + Antibacterials.

Red clover + Anticoagulants

The interaction between red clover and anticoagulants is based on a prediction only.

Evidence, mechanism, importance and management

Some reviews list red clover as having the potential to increase the risk of bleeding or potentiate the effects of warfarin, based on the fact that red clover contains natural coumarins. Although red clover contains coumarin, it is not itself an active anticoagulant. With melilot, which has a high content of coumarin, the action of moulds on the herb can result in the formation of an active anticoagulant, dicoumarol, from the coumarin, and bleeding disorders have occurred in animals fed spoiled hay containing melilot. There appears to be no published evidence of haemorrhagic disorders in animals fed red clover silage or hay. It might be that the coumarin content of red clover is too low to be a problem. Note that mouldy red clover hay has caused poisoning in animals, but this is because of mycotoxins such as slaframine. However, there is one case report of spontaneous subarachnoid haemorrhage in a 53-year-old woman, which was attributed to a herbal supplement containing red clover, and also wild yam, black cohosh, Chinese angelica, raspberry leaf, agnus castus, Siberian ginseng, partridge berry and nettle leaf, which she had been taking for 4 months. With case reports, it is not possible to say, conclusively, which, if any, of these constituents might have contributed to the adverse effect. However, of the constituents in this preparation, Chinese angelica has been associated with bleeding events, see Chinese angelica + Warfarin and related drugs.

Taken together, the evidence suggests that no special precautions are likely to be required when red clover supplements are used with anticoagulants.

Red clover + Digoxin

No data for red clover found. For the possibility that high-dose biochanin A, an isoflavone present in red clover, might increase digoxin levels, see Isoflavones + Digoxin.

Red clover + Fexofenadine

No data for red clover found. For the possibility that high-dose biochanin A, a major isoflavone in red clover, has been shown to slightly decrease fexofenadine levels in rats, see Isoflavones + Fexofenadine.

Red clover + Food

No interactions found.

Red clover + Herbal medicines

No interactions found.

Red clover + Paclitaxel

No data for red clover found. For the possibility that biochanin A and genistein present in red clover might markedly increase paclitaxel levels, see Isoflavones + Paclitaxel. Note that paclitaxel is used intravenously, and the effect of biochanin A on intravenous paclitaxel does not appear to have been evaluated.

Red clover + Tamoxifen

No data for red clover found. Data relating to the use of the isoflavone constituents of red clover, such as biochanin A, daidzein and genistein, with tamoxifen are covered under Isoflavones + Tamoxifen.