Family

Fabaceae.

Parts Used

Flowers (traditional); “leaf” (standardized isoflavone preparations).

Common Forms

Dried flowering tops.

• Tincture, Fluid Extract:   Flowers, ethanol 25% to 35%, typically 1:2 to 1:5.

• Standardized Extract:   Standardized to 40 mg total isoflavones (Promensil, Trinovin); note: these are not red clover flowers (see following discussion).

Strategic Considerations

Current mainstream perceptions of red clover are dominated by the view of the herb as a source of phytoestrogenic isoflavones. This contrasts with traditional medicine's view of red clover flowers as having “alterative” (i.e., normalizing and “blood cleansing”) properties. Historically, red clover flowers have been used internally as an alterative, antiscrofulous, antispasmodic, expectorant, and topically as a poultice for acne, ulcers, and cancerous growths.

Red clover flowers were a key ingredient of a famous Eclectic medical formulation “Trifolium Compound.” Other ingredients included compound fresh extracts of Stillingia sylvatica, Lappa minor, Phytolacca decandra, Cascara amarga, Berberis aquifolium, Podophyllum peltatum, Xanthoxylum carolinianum, and potassium iodide. It was intended for administration “in syphilis, scrofula, chronic rheumatism, glandular and various skin affections.” ¹ The popularization of red clover as a cancer treatment in the first half of the twentieth century derived from various sources, including Jethro Kloss and the controversial Harry Hoxsey, whose anticancer “Hoxsey Formula” incorporated most of the herbs of the original Trifolium Compound, including red clover flowers. ² Hoxsey formula–type products persist in the retail marketplace today. Red clover flowers remain in widespread use by modern herbalists, particularly in women's health care, despite the rise of interest in standardized leaf extracts, based on isoflavones. ³

Interactions reports for red clover flower are not available. Extrapolations from the available pharmacological literature encounter difficulties. First, there is the difference between traditional red clover flower preparations and isoflavone standardized extracts. Bone ⁴ suggests that the traditional 25% alcohol extracts of red clover flowers have a very different constituent profile than the leaf-based standardized extracts. Analytical data suggest that the isoflavone content of clover flowers is 25% that of the leaves. Thus the flower heads have relatively small quantities of isoflavones, and only formononetin has been positively demonstrated. ⁵ In addition, the traditional pharmacopoeial remedy Trifollii flos is based on Trifolium pratense inflorescence (flowers). The literature on red clover flowers itself is not extensive. The herb is monographed in the British Herbal Compendium ⁵ and British Herbal Pharmacopoeia ⁶ but has received scant attention from other pharmacopoeial sources.

Second, much of the related research and literature focuses on the two soy-derived isoflavones, genistein and daidzein. These occur naturally as free compounds and as glycosides, genistin and daidzin. Red clover primarily contains biochanin A and formononetin, which are not present in soy. For example, a recent patent registered by Novogen Research Pty., the manufacturers of Promensil, for “therapy of estrogen associated disorders,” cites the use of “clovers” ( Trifolium spp.) and “chick peas” ( Cicer arietinum L., Fabaceae) as sources of isoflavones. The clover species in the patent include Trifolium repens and T. subterranean, as well as “any clover related species or chick pea variety.” The use of multiple leguminous sources for the isoflavone content of standardized extracts is controversial from a traditional pharmacopeial perspective, and such extracts are likely to include high concentrations of materials not present in red clover flowers. However, significant differences in effect are likely with the different proportions of different isoflavone ingredients.

Booth et al. ⁷ analyzed the estrogenicity and estrogen receptor (ER)–binding properties of different isoflavone compounds in a “preformulated red clover clinical extract.” All the isoflavones, except formononetin, showed binding activity to one or other recombinant ER type. Analytical methods have been developed that allow accurate characterization of the isoflavone content of clover products. ^8,9Given the use of semipurified extracts containing isoflavones from multiple sources in commercial preparations used in controlled trials on “red clover” and available commercially for menopausal symptom relief, the interactions relating to these products are closer to those relating to soy isoflavones, isolates that are not a food, nutrient, or herb in any commonly accepted sense, than to red clover.

Pharmacokinetics and Effects on Drug Metabolism

Setchell et al. ¹⁰ reviewed the complex metabolism of these compounds and analyzed 33 commercial isoflavone-containing supplements. They concluded that the ingredients showed considerable variation and demonstrated that pharmacokinetics of different preparations were not at all equivalent. The naturally occurring form of the isoflavones is glycosidic, as genistin and daidzin. In vivo, the glycosides undergo bacterial hydrolysis in the large bowel to release the aglycones genistein and daidzein. Availability of appropriate bacterial enzymes for hydrolysis of glycosidic isoflavones may also vary widely based on varying endogenous bacterial ecologies, which may lead to large variations in biovailability of the aglycone forms.

The red clover isoflavones include biochanin A and formononetin, which are not present in soy; these are partially metabolized in vivo to the estrogenic metabolite equol. Polymorphisms between “fast” and “slow” equol producers have been described, and equol also undergoes enterohepatic recirculation. ¹¹ Biochanin A and formononetin may also be metabolized in hepatocytes to genistein and daidzein. ¹² The modulation of cytochrome P450 (CYP450) enzymes by isoflavones has been a topic of research interest; the inhibition of CYP450 1A2 partly explains the chemopreventive properties of the compounds. ¹³ Biochanin A and formononetin may also modulate P-glycoprotein. ¹⁴ Budzinski et al. ¹⁵ showed that an unidentified commercial ethanolic red clover extract was a potential inhibitor of CYP3A4 in a high-throughput in vitro screening assay of various compounds and commercial extracts. However, no reports of interactions with CYP3A4-metabolized pharmaceuticals have been made to date. Meanwhile, Kroyer ¹⁶ established that the total polyphenolic content and antioxidant activity of ethanolic extracts of red clover leaf were significantly higher than those of comparable soybean-based extracts.

A double caveat must therefore be applied in evaluating the literature pertaining to red clover. Not only are red clover flower extracts significantly different from standardized red clover preparations, but data derived from isolated soy isoflavones such as genistein and daidzein are not directly applicable to red clover isoflavone extracts.

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