RED CLOVER

BACKGROUND

Ingredient Type: Botanical

Also Known As: Trifolium pratense, Honeysuckle clover, Meadow clover, Peavine clover, Purple clover, Rotklee

Trifolium pretense, also known as red clover, is a perennial herb that is part of the Fabaceae family of flowering plants known as the legume, pea, or bean family. The genus name Trifulium derives from the Latin tres meaning “three,” referring to the three-parted palmate leaf that grows in groups of three (10) and folium meaning “leaf.” Pratense is Latin for “growing in meadows” indicative of the native habitat of red clover as it is readily found growing in meadows (1).

This perennial herb can grow one to two feet high and produces purplish-red tubular edible flowers (1), which also possess a sweet fragrance. The flowers readily attract honeybees and provide a resource for the making of clover honey (10). The leaves also are edible and often used as a culinary garnish to any dish. For medicinal purposes, the flowering tops of the red clover plant are necessary to prepare extracts used in teas or capsule form. (6) The flowers also are used for essiac recipes, jelly, and tisanes. The flowers can be ground into a flour, and the essential oil used in aromatherapy. Red clover’s blossoming beauty makes it a popular plant for the garden (3).

Whereas red clover is native to central Europe, Asia Minor, and Africa (1), it also grows in Iran, India, and in Russia from the Arctic to east Siberia (2). In the Mediterranean region and Asia, red clover grows wild in meadows (4). It spread to England around 1650 but it’s unknown exactly when it was carried to America by British colonists, but reportedly has been used as a cover crop in America for approximately 200 years—dating its arrival to around 1726 (2). Red clover has been naturalized to grow in the United States and has become an agriculture cornerstone in conserving the productivity of the soil (10).

In addition to America, red clover has become naturalized in the South American countries of Argentina and Chile. How it arrived in the South American countries over 100 years ago is unknown; however, red clover now has become an increasingly vital source of economic stability in Chile. This has increased its need for pollinators such as the Bombus ruderatus, also known as the bumblebee, a known red clover pollinator in other countries like New Zealand (3).

Red clover is so popular and widely used that it is now the national flower of Denmark and the state flower of Vermont (3).

TRADITIONAL USES

There is not a lot of recorded historical data on the medicinal uses of red clover, and any reference to the herb is lacking in many early seminal works of botanical medicine. Even the most authoritative medical text of Dioscorides lacked any writings about red clover. The earliest recording of the red clover used as a medicinal herb is found in Physica by Hildegard von Bingen (1098-1179). She recommended using the herb to clear vision by anointing the eyes and eyelids with oil made from the flowers (10).

The earliest European reports on red clover for use in the aid of female health is reported in De Historia Stirpium Commenatrii Insignes by Leonhart Fuchs (1542). He writes that the herb benefits treating white discharges in women. Another commentary on the herb’s benefit in treating the female reproductive system is by the Renaissance herbal writer, Mattioli (1626), who wrote that in addition to using red clover water as an enema to heal the bowels, that eating the white flowers makes menses flow regularly (10).

In traditional Chinese medicine, infused red clover flowers are used to support bronchial-respiratory health (2), as an internal expectorant (1), and as a fundamental herb for treating carcinoma (15). The Europeans utilized the medicinal herb as a liver and digestive aid, and the Russians used the floral tea to treat bronchial asthma and other chest issues (9). In India, red clover is used in traditional medicine as a sedative, anti-inflammatory, antispasmodic, and expectorant (3).

It has been reported that despite being newly introduced to the Americas, multiple Native American tribes used the entire plant for both medicinal and culinary uses, using the leaves for food and treating sore eyes and burns with a salve made from the herb. They also used it to treat fevers, coughs, and menopause (9). The Cherokee used the plant to reduce fever, for a remedy for leucorrhea—vaginal discharge—and kidney disease (also known as Bright’s disease), and the Shinnecocks used it to treat cancer, specifically stomach cancer. The Iroquois were reported to use the blossoms to remedy blood disorders, and they used an infusion of the blossoms to assist women with their ‘change of life’—one of the first historical recordings of red clover being used for menopause (10). Today’s medicine continues to look towards red clover in the treatment of menopause symptoms (9). The Native tribes in California cooked the red clover plant between hot stones, and the Apaches in Arizona boiled red clover with other greens (10).

Red clover is now primarily cultivated for agricultural use as a fodder crop for grazing livestock (2). Its nitrogen-rich and nutrient-dense compounds increase soil fertility making its use as a green manure crop increasingly important (3). Red clover also has been widely recognized for its importance in crop rotation and soil conservation (1).

The active ingredients in fresh red clover leaves include isoflavonoids, flavonoids, phenolic acids, minerals—magnesium and potassium—saponins (2), and other nutrients, including vitamin C and thiamine (4).

Red clover has a high concentration of isoflavonoids—secondary metabolites that are divisible into isoflavones. These isoflavone preparations are readily available as nutritional supplements. The main isoflavones in red clover are biochanin A and formononetin. These are found in abundance in the leaves of red clover alongside the other well-known isoflavones, daizden and genistein (11). Due to these compounds having estrogen-like activities, potential cancer-preventative abilities, cardio-protective elements, and anti-osteoporosis effects (9), they have been subject to multiple studies and intense research over the past twenty years (15).

These compounds display weak estrogenic activity due to their ability to bind to one or both estrogen receptors (9). They also modulate several of the enzymes that help regulate sex hormones (10). Formononetin is one of the main bioactive components of red clover. It is a principal compound that has been found to have therapeutic effects. It is extracted from the roots of the plant, and due to its similar structure to estrogen, its bioactivity mimics the effect of estrogen resulting in it being considered to be a phytoestrogen (15).

The antioxidant activity of red clover is due to the presence of the phenolic acids (caffeic, rosmarinic, and chlorogenic acid), flavonoids (quercetin and kaempferol) and saponins (11).

The saponins and isoflavones have multiple biological and pharmacological properties. As secondary metabolites, they possess anti-cancer, anti-inflammatory, and antioxidant benefits (14).

WHAT DOES SCIENCE TELL US?

Red Clover Might Help Relieve Menopausal Symptoms:

Historically, red clover has been used by women to help alleviate their menopausal symptoms, specifically hot flashes. This traditional remedy is still in use today. In addition to the history of traditional use, the premise supporting red clover for menopausal relief is found in the isoflavones. The isoflavones act as a natural estrogen replacement for older women that have low endogenous estradiol levels—thus, alleviating hot flashes. Some research indicates that an effort needs to be made to increase the quality of the botanicals available in supplement form, as the level of quality has made accurate research difficult (5).

In multiple surveys of postmenopausal women, 79% of the participants used red clover as a dietary supplement specifically to reduce their hot flashes (5). In another study done by the Women’s Health Initiative, it was deduced that more and more women are decreasing their use of conventional hormone therapy and increasing their interests in the alternative, botanical supplements (7).

In one randomized, double-blind placebo trial that investigated the effect of isoflavones in red clover on menopausal symptoms, lipids and vaginal cytology in menopausal women. Sixty postmenopausal women over the age of forty were studied. They were randomized into placebo and supplement groups. The supplement group was given 80 mg a day of standard commercial red clover isoflavone supplement for ninety days. After ninety days, the participants took a seven-day “washout” period, and then they switched to receive the opposite treatment for another ninety days. Fifty-three of the sixty original participants completed the study. Seventy percent were age fifty or older. The results, compared to the placebo group, indicate that red clover isoflavone supplementation significantly decreases menopausal symptoms and had a positive effect on vaginal cytology and triglyceride levels (7).

Two trials were conducted in different hospitals in Sydney, Australia to investigate the clinical effects of red clover on perimenopausal women suffering from acute menopausal symptoms. The first double-blind, placebo-controlled trial was conducted at the Royal Hospital for Women. The women were given a standardized red clover isoflavonoid extract (SRCE) that contained a 40 mg tablet of the four main isoflavonoids in the ratio of 20:12:1:1 biochanin: formononetin: daidzein: genistein. This trial compared the placebo with two groups: 1) the first group took one SRCE tablet per day, and 2) the second group took two SRCE tablets per day for a total of three months. The second double-blind, placebo-controlled crossover trial was conducted at the Royal North Shore Hospital. The patients were given one SRCE tablet per day for three months and then crossed over for three months—patients did self-reporting of their outcomes.

Both trials reported no significant differences in the incident or severity of their hot flashes. However, both groups did have a decrease of 32-45% (9).

Other studies have shown similar outcomes, with one study on the isoflavones and their effect on menopausal hot flashes resulting in reducing the effects, while another study showed a decrease in bone loss in postmenopausal women (1). Several reviews and meta-analyses have concluded that red clover extract can reduce the frequency of hot flashes due to menopause. While these results indicate red clover’s potential benefits in treating menopausal symptoms, most of the reviews and studies concluded more studies are needed to fully assess red clover’s potential for reducing menopausal symptoms (3).

In a placebo-controlled, crossover trial of postmenopausal women, secondary outcomes were investigated for red clover’s effects on central nervous system symptoms—depression and anxiety. The trial included 109 women that were divided into two groups; one group was given 80 mg of red clover isoflavones, the other group was given a placebo. After ninety days, the decrease of depression and anxiety was 70% compared to the baseline. The placebo group had a 22% reduction (20).

Another randomized, triple-blind, placebo-controlled trial investigated red clover for its effect on menopausal symptoms, specifically hot flashes, sleeping disorders, heart discomfort. Seventy-two postmenopausal Iranian women participated in the trial and documented significant improvements in their menopausal symptom scores. They received 80 mg dried red clover leaf capsules daily for 12 weeks compared to the placebo group. The results showed a total score improvement of 10.33 points in the red clover group compared to 3.52 in the placebo group (P = 0.0001). The differences between their mean vegetative somatic scores and their mean psychological scores were significant showing the hot flashes, heart discomfort and sleeping disorders improving over their anxiety, irritability and mental exhaustion (P = 0.0002, P = 0.0001 respectively). No side effects were observed (21).

Multiple placebo-controlled studies have investigated changes in sexual symptoms in postmenopausal women taking red clover with no significant changes found between the red clover supplement groups and the placebo groups (this was three out of four studies that were reviewed). However, in another placebo study, the herbal supplement group that was administered red clover had a significant decrease in dyspareunia and low libido when compared to the placebo group (P <0.05) (22).

Red clover has been reported to significantly reduce vaginal dryness in menopausal women. In one placebo-controlled study, the red clover supplement group had 41% fewer symptomatic patients when compared to the placebo group that had 5% fewer symptomatic patients (P<0.05) (22).

Red Clover Might Help in the Lifecycles of Healthy Cells:

One of red clover’s legacies is its association as an ingredient in the famous Hoxsey cancer formula. Harry Hoxsey announced the formula in 1924, claiming that his great grandfather observed that a horse with cancer cured itself by eating various plants. However, this story is most likely fabricated due to the impossibility that all of the herbs necessary for anti-cancer benefits were growing in the same meadow. Additionally, horses do not dig up roots. The Hoxley formula is considered almost identical to another well-known anti-cancer formula that also includes red clover, the Fluidextractum Trifolii Compositum. Despite these trivialities of a horse curing itself, throughout medical literature, red clover has maintained a long-endured history as a potential anti-cancer agent (10).

Multiple species of Trifolium, including red clover, have shown to exhibit biological activities that include anti-inflammatory and antioxidant activity. Also included are anticestodal—drugs used to combat tapeworm infections—and cytotoxic activity that has been used as a type of chemoprotective action against the growth of numerous prominent cancers (12) including breast cancer, colorectal and prostate cancer (15). It has also been shown to inhibit the growth of cancer cells and cancer cell adhesion (9).

The formononetin found in red clover has been shown to have multiple pharmacological attributes including anticancer, anti-inflammatory, and antioxidant properties. In one review of multiple studies on formononetin’s pharmacological potential as a possible cancer treatment, it was determined that it has various biological properties including that of arresting cancer cell progression. Uncontrolled divisions of cells are the key cycle of the progression of cancer cells. Formononetin fights this progression of cancer cells by inducing apoptosis, arresting the cell cycle, and halting metastasis by targeting various pathways of several types of cancer. The arresting cell cycle attribute included human ovarian cancer, OV 90 cell lines, HepG2 cancerous cells and lung cancer cells (14).

An analytical review of both in vivo and in vitro studies done on formononetin investigated the evidence that it promotes apoptosis and that it might be used as an anticancer agent. The cells observed in this study included cancer cell models from breast, colorectal, non-small cell lung, and prostate cancer. Formononetin attenuated cancer cell proliferation through inducing cell cycle arrest in these cancer cell lines. It was found that formononetin also regulates various oncogenic pathways, which helps alleviate the possible causes of chronic inflammation. Inflammation is linked to the survival of cancer cells and their resistance to chemotherapy (15).

Evidence gathered from this review of both the in vivo and in vitro studies and current clinical studies, showed promise of formononetin’s potential anti-cancer properties (17), its promise as an adjunct therapy, and prospective drug development for cancer patients. The review details the process of antitumorigenic properties in the compound—through numerous molecular targets and mechanisms of actions—by primary inhibiting cell proliferation and induction of cell apoptosis and confirms the safety and efficacy of the herb (and its metabolites) in biological systems, specifically for anti-tumor and anti-cancer purposes. In addition to having tumor-inhibitory effects, formononetin is also found to be compatible with chemotherapeutic drugs. It has shown to have additive and synergistic effects with these drugs. While these significant antitumor properties of formononetin make it a promising candidate for anticancer drug development, it is recommended that other derivatives and metabolites of formononetin are fully investigated to ensure their pharmacokinetic properties are safe for clinical developmental drugs used in biological systems (15).

Red clover has become one of China’s fundamental herbs for treating carcinoma. This is due to formononetin’s protective effects against malignant tumors. Similar results were found in multiple in vivo studies where formononetin was able to reduce metastasis and tumor growth of cancer cells (15).

Although the results show formononetin as a possible pharmacological agent against cancer, more investigations need to be conducted to deduce the full array of its pharmacological and biological potential (14).

The biochanin A found in red clover has been studied for its effect as a possible chemo-preventative agent against cancer. No clarification has been made on biochanin A and its effect on human osteosarcoma cells. In this study, it was found that biochanin A inhibited osteosarcoma cancer cell colony formation and cell growth in a dose-dependent process with no adverse toxic effects on normal cells. The cancer cells were exposed to a combination of doxorubicin (a form of chemotherapy) and biochanin A. The results suggested that biochanin A induces apoptosis and inhibits cell growth in osteosarcoma cells (18).

One study on red clover extract and its role in the treatment of breast cancer showed promise for its anticancer properties. For this study, two breast cancer cell lines were tested, MCF-7 and MDA-MB-231. Both sets of cells were treated with T. pratense extract. After exposure, cell viability was evaluated and measured. The results indicated T. pratense extract increased apoptosis and autophagy and reduced nitric oxide production in a dose and time-dependent manner. It was even suggested that breast cancer patients who receive conventional chemotherapy might benefit from taking T. pratense as a dietary supplement (16).

Red Clover Might Have Antioxidant Properties:

Formononetin has also been investigated for its possible antioxidant properties. It is known for being a naturally potent and effective antioxidant that promotes the activity of antioxidant enzymes that can protect cells from free radicals (9). This is the foundation for formononetin as an anticancer agent because free radicals can lead to cancer development (15).

In one study, the extracts of red clover in vivo and in vitro grown plants and callus tissues were tested for their antioxidant capabilities. The total flavonoid content was investigated to determine if there was a correlation with the antioxidant activity of the extracts. The tested samples showed that the highest amount of total flavonoids content was found in methanol extract of in vivogrown plants. The highest reducing power, chelating power, and radical scavenging were found in methanol extract of the in vivo grown plant. The results of the study showed that there is a significant correlation between the total flavonoid content and antioxidant activity. The study results showed that the extract of red clover can be a safe and effective source of natural antioxidants with beneficial properties (11).

Another in vivo study examined the antioxidant activity of extracts of T. pratense leaves as a possible source for natural pharmaceuticals. The results showed that the extracts provided sufficient protection from oxidative stress for both tissues and cells through free radical scavenging and electron donation. Additionally, the antioxidant activities were higher than the comparable standard. The study concluded that the leaf extracts exhibited their potential as a valuable source of antioxidant protection from free radicals (12).

A third study looked at three species of clover, including T. pratense, for their free radical scavenging properties. They also investigated the ferric reducing abilities and antioxidant effects of the extracts. The antioxidant capacity was measured by assessing the antioxidant activities of T. pratense extract in human blood plasma going through oxidative stress (exposure to the oxidant, peroxynitrite). T. pratense was shown to exhibit the highest level of radical scavenging effects by protecting blood plasma from the peroxynitrite. It provided defense against the harmful action of oxidative stress by enhancing its non-enzymatic antioxidant defense.  The extracts promoted the activity of antioxidant enzymes that protected the blood plasma’s defense against the harmful action of oxidative stress exposure (13).

SAFETY

After being evaluated for its effect on various health conditions in multiple clinical trials (6), few adverse reactions have been reported in clinical trials at doses up to 160 mg isoflavones per day (19). However, it is reported that high doses of isoflavones (4 or 8 mg/kg) (24) have been associated with loss of appetite, pedal edema, and abdominal tenderness (19). The free and total genistein and daidzein did not accumulate (they disappeared rapidly from the plasma) and are unlikely to accumulate in the body with regular use (two to three times a day) (24).

Interactions:

Major

• Due to the concentration of coumarin in the blossoms, red clover can cause thinning of the blood. This may be beneficial in cases of thrombosis and other conditions in which thick blood obstructs vessels. However, those who are taking blood-thinning medications should take caution before taking red clover to avoid possible excess bleeding (8).
• More specifically, due to the coumarin derivatives in red clover, it should be used with caution in individuals with coagulation disorders or currently undergoing anticoagulation therapy (3). Additionally, due to its blood thinning properties, red clover should be avoided before surgery, as it may exacerbate surgical bleeding (8).

Moderate

• Red clover is considered safe in regular culinary use, but there are a few reactions that may occur when consuming supplement extracts. The extracts may cause muscle ache, headache, slow blood-clotting, rash-like reactions, and possible vaginal bleeding in women (3).
• It is metabolized by CYP3A4—the enzyme that oxidizes foreign organic molecules like drugs and toxins—and therefore, caution should be used when taking it with other drugs using this metabolic pathway (3).

• The genistein content found in red clover may negate the effects of the drug tamoxifen and aromatase inhibitors such as the hormone-based chemotherapy, letrozole (23).

Minor

• While there are no studies to show if isoflavones interact with steroid therapeutics, it has been recommended to take caution supplementing the diet with red clover if other steroids are being used. This includes estrogens, progestins, and androgens (9).
• The safety of isoflavones for pregnant women has not been established, however, studies done on pregnant rats produced offspring with delayed onset of puberty and decreased birthweights. Isoflavones have not been indicated to contribute to fetal abnormalities in communities where they are consumed through diet. It is still recommended that supplementation with isoflavones be discontinued during pregnancy (9).

• Red clover supplementation is not considered safe for children younger than twelve years of age (25), and in one study, it is not recommended for children under the age of two (9).

Side-Effects:

In addition to its estrogenic isoflavones that support older women with low estradiol levels during menopause, red clover contains several minor components as well. Many of these minor components have not been investigated for their estrogenic effects—especially whether they will convert to active estrogenic metabolites. Isolating these minor compounds in their over-the-counter supplement form in order to research their effects in the biological system is suggested (5).

Because red clover contains estrogen-like compounds, there’s a possibility that long-term use would increase the risk of women developing cancer of the endometrium (the lining of the uterus). However, short-term studies of women who have taken red clover have not shown harmful changes in the uterine lining (6).

There are some concerns about the phytoestrogens in red clover increasing the incidence of endometrial, ovarian, and breast cancers. It is unresolved whether phytoestrogens are beneficial or harmful to human health (26). The activity of the phytoestrogen coumestrol on estrogen receptors might be contraindicated in patients with a history of breast cancer, endometriosis, ovarian cancer, uterine cancer and other estrogen-sensitive conditions. Some authors have indicated that high isoflavone content can provide benefits to these conditions by counteracting the adverse effects (10).

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