​Melilotus officinalis (Yellow Melilot / Sweet Clover)

Melilotus officinalis (Yellow Melilot / Sweet Clover)

Product Name: Донник лекарственный, Melilotus officinalis, Echter Steinklee, Meliloto amarillo, Mélilot officinal, حندقوق أصفر, โคลเวอร์เหลือง, Sariq beda, Сары беде, Sarı yonca, Зардюз, Vaistinis barkūnas, Dzeltenais amoliņš, Буркун лікарський, Sarı yonca, תלתן רפואי.

Synonyms: Буркун лекарственный, донник жёлтый, буркун жёлтый, yellow sweet clover, sweet clover, yellow melilot, common melilot, Echter Steinklee, Steinklee gelb, meliloto amarillo, mélilot jaune, حندقوق بري, โคลเวอร์หวาน, honey clover.

Parts used: aerial part, herb, flowers.

Main indications for the use of Melilotus officinalis: Chronic venous insufficiency of the lower extremities, varicose veins of the lower extremities, post-thrombotic syndrome, thrombophlebitis of superficial veins, lymphedema, hemorrhoids, phlebitis, peripheral edema of inflammatory and congestive origin, neurocirculatory dystonia of the hypertensive type, spastic conditions of smooth muscles, neurotic insomnia.

Indications for the use of Melilotus officinalis in mixtures and complexes: Stage I arterial hypertension, atherosclerosis of the arteries of the lower extremities, ischemic heart disease, migraine, climacteric syndrome, chronic prostatitis, chronic inflammatory diseases of the pelvic organs, allergic dermatitis, chronic eczema, chronic bronchitis.

Main pharmacological properties of Melilotus officinalis: venotonic, angioprotective, lymphatic drainage, anticoagulant, antiplatelet, anti-inflammatory, antispasmodic, sedative, hypotensive, antioxidant, capillary-stabilizing.

Dosage of Pharmaceutical Forms — Melilotus officinalis

Powder — Melilotus officinalis

Indications (Powder): Chronic venous insufficiency of the lower extremities, varicose veins of the lower extremities, post-thrombotic syndrome, hemorrhoids, lymphedema, peripheral edema of congestive origin, neurotic insomnia.

Standard Dosage (Powder): 1–2 grams of powder orally 2 times a day after meals, course duration — 21 days.

Enhanced Dosage (Powder): 3 grams 2 times a day for pronounced chronic venous insufficiency and post-thrombotic syndrome, course duration — up to 30 days under specialist supervision.

Maximum Dosage (Powder): Up to 8 grams per day for severe congestive peripheral edema, short-term no more than 10 days.

Preventive Dosage (Powder): 1 gram once a day for a tendency to venous congestion, prolonged static load, and chronic venous insufficiency in the compensation stage, course — 14 days every 3 months.

Pediatric Dosage (Powder): Permissible from 12 years with a body weight of more than 40 kilograms, 0.5 grams once a day, course duration — no more than 10 days.

Contraindications (Powder): Contraindicated in hemorrhagic diathesis, decreased blood clotting, gastric ulcer in the acute phase, pregnancy, pronounced hepatic insufficiency, and individual hypersensitivity.

Side Effects (Powder): In case of overdose, headache, nausea, drowsiness, and hemorrhagic manifestations may occur.

Adjustment for Patient Body Weight (Powder): For body weight below 60 kilograms, the daily dose is reduced by 25 percent; for body weight above 90 kilograms, an increase in the standard dose by 20 percent is permissible.

Preparation method (Powder): Prepared from dried herb. To prepare 100 grams of product, 100 grams of dried aerial part of the plant are used. The raw material is ground to a finely dispersed state at a temperature not exceeding +40 °C, followed by sieving through a sieve with a mesh size of 0.5 millimeters. No additional ingredients are used.

Storage Conditions and Shelf Life (Powder): Store in a dry place at a temperature of +5 °C to +25 °C, in an airtight container, protected from direct sunlight and electromagnetic radiation. Shelf life — 24 months. After opening, use within 3 months.

Dry Extract — Melilotus officinalis

Indications (Dry Extract): Chronic venous insufficiency of the lower extremities, varicose veins of the lower extremities, post-thrombotic syndrome, thrombophlebitis of superficial veins, lymphedema, hemorrhoids, peripheral edema of inflammatory and congestive origin.

Standard Dosage (Dry Extract): Dry extract in terms of raw material 300–600 milligrams 2 times a day after meals, course duration — 21 days.

Enhanced Dosage (Dry Extract): Dry extract 900 milligrams per day for pronounced chronic venous insufficiency and post-thrombotic syndrome, course — up to 30 days under specialist supervision.

Maximum Dosage (Dry Extract): Dry extract up to 1200 milligrams per day short-term no more than 10 days for severe congestive peripheral edema.

Preventive Dosage (Dry Extract): Dry extract 300 milligrams once a day for a tendency to venous congestion and prolonged static load, course — 14 days every 3 months.

Pediatric Dosage (Dry Extract): Dry extract is permissible from 12 years with a body weight of more than 40 kilograms, 150 milligrams once a day, course duration — no more than 10 days.

Contraindications (Dry Extract): Contraindicated in hemorrhagic diathesis, decreased blood clotting, thrombocytopenia, gastric ulcer in the acute phase, pregnancy, pronounced hepatic insufficiency, and individual hypersensitivity.

Side Effects (Dry Extract): In case of overdose, headache, nausea, drowsiness, and bleeding of mucous membranes may occur.

Adjustment for Patient Body Weight (Dry Extract): For body weight below 60 kilograms, the daily dose is reduced by 25 percent; for body weight above 90 kilograms, an increase in the standard dose by 20 percent is permissible.

Preparation method (Dry Extract): Prepared by aqueous-alcoholic extraction. To prepare 100 grams of finished product, 300 grams of dry herb and 1500 milliliters of 70 percent ethanol are used. Ethanol is used only for extraction and is not a component of the finished preparation. The raw material is infused at a temperature not exceeding +40 °C for 72 hours with periodic stirring. Then filtration and evaporation in a water bath at a temperature not exceeding +50 °C are carried out until complete removal of the solvent. Control of removal — complete disappearance of the ethanol odor. The permissible residual ethanol content is no more than 500 ppm in accordance with pharmacopoeial standards. The use of an intermediate product containing liquid solvent as a medicinal product is not allowed. The resulting thick extract is dried at a temperature not exceeding +45 °C to a residual moisture content of less than 5 percent.

Storage Conditions and Shelf Life (Dry Extract): Store at a temperature of +5 °C to +25 °C in an airtight container, protected from light and electromagnetic radiation. Shelf life — 24 months. After opening, use within 6 months.

Alcohol-Based Tincture — Melilotus officinalis

Indications (Tincture): Chronic venous insufficiency of the lower extremities, varicose veins of the lower extremities, post-thrombotic syndrome, hemorrhoids, lymphedema, neurotic insomnia, neurocirculatory dystonia of the hypertensive type.

Standard Dosage (Tincture): 20 drops 2 times a day after meals, course duration — 21 days.

Enhanced Dosage (Tincture): 30 drops 2 times a day for pronounced chronic venous insufficiency and post-thrombotic syndrome, course — up to 30 days under specialist supervision.

Maximum Dosage (Tincture): Up to 90 drops per day short-term no more than 10 days for severe congestive peripheral edema.

Preventive Dosage (Tincture): 15 drops once a day for a tendency to venous congestion and prolonged static load, course — 14 days every 3 months.

Pediatric Dosage (Tincture): Permissible from 14 years with a body weight of more than 45 kilograms, 10 drops once a day, course duration — no more than 10 days.

Contraindications (Tincture): Contraindicated in hemorrhagic diathesis, decreased blood clotting, thrombocytopenia, pregnancy, pronounced hepatic insufficiency, individual hypersensitivity, and alcohol dependence.

Side Effects (Tincture): In case of overdose, drowsiness, headache, nausea, and hemorrhagic manifestations may occur.

Adjustment for Patient Body Weight (Tincture): For body weight below 60 kilograms, the daily dose is reduced by 25 percent; for body weight above 90 kilograms, an increase in the standard dose by 20 percent is permissible.

Preparation method (Tincture): Prepared from 200 grams of dry herb and 1000 milliliters of 70 percent ethanol to obtain 1000 milliliters of finished tincture. Ethanol is used exclusively for the extraction of active substances and is a component of the dosage form. The raw material is placed in a glass container, poured with ethanol, and infused in a dark place at a temperature of +18...+25 °C for 14 days with daily shaking. After infusion, filtration through a dense filter is performed. The residual content of foreign impurities is absent; quality control is carried out organoleptically and by the transparency of the solution.

Storage Conditions and Shelf Life (Tincture): Store at a temperature of +5 °C to +25 °C in a tightly closed glass container, protected from light and electromagnetic radiation. Shelf life — 36 months. After opening, use within 12 months.

Oil Infusion — Melilotus officinalis

Indications (Oil Infusion): Varicose veins of the lower extremities, thrombophlebitis of superficial veins, lymphedema, hemorrhoids, allergic dermatitis, chronic eczema, superficial inflammatory processes of the skin.

Standard Dosage (Oil Infusion): Apply a thin layer to the affected area 2 times a day, course duration — 14 days.

Enhanced Dosage (Oil Infusion): Apply 3 times a day for pronounced inflammatory process and congestive phenomena, course — up to 21 days.

Maximum Dosage (Oil Infusion): Application up to 4 times a day is permissible short-term no more than 10 days for pronounced lymphedema.

Preventive Dosage (Oil Infusion): Apply once a day for a tendency to venous congestion and prolonged static load, course — 10 days quarterly.

Pediatric Dosage (Oil Infusion): External use is permissible from 7 years in the absence of individual hypersensitivity, apply once a day, course — no more than 7 days.

Contraindications (Oil Infusion): Contraindicated in violation of the integrity of the skin with bleeding, hemorrhagic diathesis, and individual hypersensitivity.

Side Effects (Oil Infusion): In case of overdose, local hyperemia and allergic reactions may occur.

Adjustment for Patient Body Weight (Oil Infusion): Dose adjustment for external use is not required.

Preparation method (Oil Infusion): Prepared from 30 grams of dry ground herb and 70 grams of unrefined coconut oil to obtain 100 grams of product. The mixture is kept in a water bath at a temperature of up to +50 °C for 3 hours, followed by infusion for 48 hours at a temperature of +20...+25 °C. After this, filtration through a dense fabric is performed. Residual moisture is not allowed.

Storage Conditions and Shelf Life (Oil Infusion): Store at a temperature of +5 °C to +20 °C in a dark glass container, protected from light and electromagnetic radiation. Shelf life — 12 months. After opening, use within 3 months.

Rectal Suppositories — Melilotus officinalis

Indications (Rectal Suppositories): Chronic internal hemorrhoids, external hemorrhoids, thrombophlebitis of hemorrhoidal veins, chronic proctitis, venous congestion of the pelvic organs.

Standard Dosage (Rectal Suppositories): 1 suppository weighing 2 grams once a day after hygiene procedure, course duration — 10 days.

Enhanced Dosage (Rectal Suppositories): 1 suppository 2 times a day for pronounced inflammatory process and pain syndrome, course — up to 14 days under specialist supervision.

Maximum Dosage (Rectal Suppositories): Up to 2 suppositories per day short-term no more than 10 days for thrombosis of hemorrhoidal nodes.

Preventive Dosage (Rectal Suppositories): 1 suppository every other day for 10 days for chronic venous insufficiency of the pelvic organs, repeat the course 2 times a year.

Pediatric Dosage (Rectal Suppositories): Permissible from 14 years with a body weight of more than 45 kilograms, 1 suppository every other day, course duration — no more than 7 days.

Contraindications (Rectal Suppositories): Contraindicated in hemorrhagic diathesis, active bleeding, decreased blood clotting, ulcerative-necrotic lesions of the rectum, pregnancy, and individual hypersensitivity.

Side Effects (Rectal Suppositories): In case of overdose, increased bleeding and local irritation of the mucous membrane may occur.

Adjustment for Patient Body Weight (Rectal Suppositories): For body weight below 60 kilograms, use every other day is recommended; for body weight above 90 kilograms, the standard regimen without correction is permissible.

Preparation method (Rectal Suppositories): Prepared on the basis of 10 grams of dry extract and 90 grams of coconut oil to obtain 100 grams of suppository mass. The coconut oil is melted in a water bath at a temperature not exceeding +40 °C, the dry extract is added with uniform stirring until a homogeneous mass is obtained. The mixture is poured into molds weighing 2 grams and cooled at a temperature of +4...+8 °C until completely solidified.

Storage Conditions and Shelf Life (Rectal Suppositories): Store at a temperature of +4 °C to +8 °C in airtight packaging, protected from light and electromagnetic radiation. Shelf life — 12 months. After opening, use within 1 month.

Nasal Drops — Melilotus officinalis

Indications (Nasal Drops): Vasomotor rhinitis, allergic rhinitis, chronic sinusitis, edema of the nasal mucosa, impaired venous outflow in the nasopharynx.

Standard Dosage (Nasal Drops): 1–2 drops into each nostril 2 times a day, course duration — 7 days.

Enhanced Dosage (Nasal Drops): 2 drops 3 times a day for pronounced edema of the mucosa, course — up to 10 days.

Maximum Dosage (Nasal Drops): Up to 6 instillations per day short-term no more than 7 days.

Preventive Dosage (Nasal Drops): 1 drop once a day for a tendency to vasomotor reactions of the mucosa, course — 5 days during seasonal changes.

Pediatric Dosage (Nasal Drops): Permissible from 12 years, 1 drop once a day, course duration — no more than 5 days.

Contraindications (Nasal Drops): Contraindicated in a tendency to nosebleeds, hemorrhagic diathesis, decreased blood clotting, pregnancy, and individual hypersensitivity.

Side Effects (Nasal Drops): In case of overdose, dryness of the mucous membrane and bleeding may occur.

Adjustment for Patient Body Weight (Nasal Drops): Dose adjustment is not required.

Preparation method (Nasal Drops): Prepared from 5 grams of dry extract, 94 grams of purified water, and 1 gram of sea salt to obtain 100 grams of solution. The water is heated to a temperature of +36...+38 °C, salt and extract are added with constant stirring until complete dissolution. The solution is filtered through a sterile filter and poured into sterile bottles.

Storage Conditions and Shelf Life (Nasal Drops): Store at a temperature of +4...+8 °C, protect from light and electromagnetic radiation. Shelf life — 10 days. After opening, use within 5 days.

Toxicity and Biosafety of Melilotus officinalis

Sweet clover contains coumarin and its derivatives, including dicoumarol, which, during metabolic transformation, can exert an anticoagulant effect. The acute toxicity of aqueous-alcoholic extracts of the aerial part in experiments on laboratory animals is assessed as low or moderate. In studies on mice with oral administration of the extract, the LD₅₀ exceeded 2000 mg/kg body weight, which allows the raw material to be classified as a low-toxicity substance according to the WHO classification. With chronic administration of high doses, hemorrhagic manifestations have been described in animals, due to impaired synthesis of blood clotting factors.

With prolonged feeding of moldy raw material containing dicoumarol, a syndrome of hemorrhagic diathesis associated with vitamin K antagonism has been described in cattle. These changes were reversible upon withdrawal of the toxic factor and correction of coagulation status. Data on the genotoxicity and mutagenicity of coumarin in phytoraw materials indicate the absence of a pronounced mutagenic effect at therapeutic doses, however, at high concentrations, hepatotoxicity is possible in experimental models.

In general, when dosages are observed and high-quality, non-fermented raw material is used, Melilotus officinalis is assessed as a low-toxicity phytopreparation with a potential risk of hemorrhagic complications in case of overdose or combination with anticoagulants.

References:
- Egan D., O'Kennedy R., Moran E. et al. (1990). The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compounds. Drug Metabolism Reviews, 22(5), 503–529. (https://pubmed.ncbi.nlm.nih.gov/2192182/)
- Link K.P. (1959). The discovery of dicumarol and its sequels. Circulation, 19(1), 97–107. (https://pubmed.ncbi.nlm.nih.gov/13629420/)

Pharmacodynamics — Melilotus officinalis

The pharmacodynamic properties of Melilotus officinalis are due to the presence of coumarins, flavonoids, phenolic compounds, and triterpene components, which form a multicomponent effect on the vascular, lymphatic, and nervous systems. Coumarin and its derivatives affect the hemostasis system through modulation of the synthesis of clotting factors associated with vitamin K metabolism, which is manifested by a moderate anticoagulant and antiplatelet effect. This mechanism is realized predominantly at the systemic level with oral use of standardized forms.

The flavonoid complex contributes to the stabilization of the vascular wall by reducing capillary permeability and suppressing lipid peroxidation. The antioxidant effect is associated with the neutralization of reactive oxygen species and modulation of the activity of enzymatic antioxidant systems. An effect on endothelial function through regulation of nitric oxide synthesis and a decrease in the expression of pro-inflammatory mediators is noted.

The anti-inflammatory effect is realized through a decrease in the activity of enzymes of the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism, which leads to a reduction in the synthesis of prostaglandins and leukotrienes. Additionally, a decrease in the expression of pro-inflammatory cytokines and modulation of signaling cascades involved in the cellular inflammatory response are observed.

The lymphatic drainage effect is associated with an effect on the tone of lymphatic vessels and improvement of microcirculation. Sweet clover demonstrates the ability to reduce interstitial edema by optimizing venous return and normalizing the microcirculatory bed. The venotonic effect is manifested by an increase in the tone of the venous wall and a decrease in venous stasis.

The sedative and moderate antispasmodic effect is due to an effect on the central nervous system, including modulation of neurotransmitter systems, which is manifested by a decrease in the level of nervous excitability and normalization of the autonomic balance. These effects are mild in nature and are manifested predominantly with course use.

Thus, the pharmacodynamics of Melilotus officinalis is characterized by angioprotective, venotonic, lymphatic drainage, anti-inflammatory, antioxidant, and moderate sedative effects, realized through a complex effect on the vascular endothelium, the hemostasis system, and cellular mediator mechanisms.

References:
- Egan D., O'Kennedy R., Moran E. et al. (1990). The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compounds. Drug Metabolism Reviews, 22(5), 503–529. (https://pubmed.ncbi.nlm.nih.gov/2192182/)
- Bruneton J. (1999). Pharmacognosy, Phytochemistry, Medicinal Plants. Lavoisier Publishing.

Pharmacokinetics — Melilotus officinalis

The pharmacokinetic characteristics of Melilotus officinalis are determined mainly by the properties of coumarins, flavonoids, and accompanying phenolic compounds. With oral use of powder or dry extract, active components are released in the upper parts of the gastrointestinal tract. Coumarin has high lipophilicity and is rapidly absorbed in the small intestine by passive diffusion. Flavonoids, presented in glycoside form, are partially hydrolyzed under the action of intestinal microflora with the formation of aglycones, which are then absorbed through enterocytes.

After absorption, coumarin is transported with the blood flow to the liver, where it undergoes intensive metabolism with the participation of microsomal enzyme systems. The main biotransformations include hydroxylation and subsequent conjugation with glucuronic acid. Metabolites are excreted primarily by the kidneys with urine, and partially with bile. With systematic use, accumulation in tissues is not pronounced, however, when doses are exceeded, an increase in the load on hepatic detoxification mechanisms is possible.

Flavonoid compounds after absorption are distributed in the vascular bed and bind to plasma proteins. Their metabolism is also carried out in the liver with the formation of conjugated forms excreted by the kidneys. Some metabolites may undergo enterohepatic circulation.

With external use of the oil infusion, active components penetrate the epidermal barrier predominantly by the transdermal route. Lipophilic fractions of coumarins demonstrate the ability to penetrate the surface layers of the dermis, exerting a local effect on microcirculation. Systemic absorption with external use is minimal.

With rectal administration of suppositories, absorption occurs through the venous network of the rectum with partial bypass of the primary hepatic metabolism. This ensures faster entry of active compounds into the systemic circulation compared to the oral route.

Nasal forms provide local effect on the mucous membrane with limited systemic absorption. Penetration occurs through the rich vascular network of the nasal cavity, while the main effect is local in nature.

Thus, the pharmacokinetics of Melilotus officinalis is characterized by effective oral absorption of coumarins, hepatic metabolism with subsequent renal excretion, limited systemic bioavailability with external use, and predominantly local action when using mucosal forms.

References: Lake B.G. (1999). Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessment. Food and Chemical Toxicology, 37(4), 423–453. (https://pubmed.ncbi.nlm.nih.gov/10418958/)

Mechanisms of Action and Scientific Rationale — Melilotus officinalis

The pharmacological activity of Melilotus officinalis is due to the presence of coumarins, primarily coumarin and its derivatives, as well as flavonoids and phenolic compounds. Coumarin in the body undergoes biotransformation with the formation of compounds capable of indirectly affecting the hemostasis system through mechanisms related to vitamin K metabolism. This effect is realized through changes in the activity of liver enzyme systems involved in the γ-carboxylation of clotting factors, which is reflected in the coagulation cascade. Coumarin derivatives have demonstrated the ability to interfere with vitamin-K-dependent enzyme processes, affecting the functional state of the prothrombin complex.

Reference: Egan D., O'Kennedy R., Moran E. et al. (1990). The pharmacology, metabolism, analysis, and applications of coumarin and coumarin-related compounds. Drug Metabolism Reviews, 22(5), 503–529. (https://pubmed.ncbi.nlm.nih.gov/2192182/)

Angioprotective and lymphotropic action is associated with the effect of coumarin on macrophage cells and endothelial structures. In experimental models, it has been demonstrated that coumarin is able to modulate the activity of macrophages and enhance the proteolytic degradation of protein components of interstitial fluid, which is accompanied by a decrease in tissue edema. Participation in the regulation of cytokine synthesis and growth factors affecting vascular permeability and lymphatic vessel tone is assumed.

Reference: Piller N.B., Thelander A., Wedin B. (1984). The effect of coumarin on macrophages and lymphatic flow. Lymphology, 17(3), 114–121. (https://pubmed.ncbi.nlm.nih.gov/6473077/)

Anti-inflammatory action is realized through suppression of the activity of cyclooxygenase and lipoxygenase enzymes involved in arachidonic acid metabolism. Sweet clover flavonoids demonstrate the ability to reduce the production of prostaglandins and leukotrienes, as well as to decrease the expression of pro-inflammatory cytokines through effects on nuclear transcription factors that regulate the synthesis of inflammatory mediators. In cellular models, a decrease in the activation of signaling cascades associated with the inflammatory response has been noted.

Reference: Kontogiorgis C.A., Hadjipavlou-Litina D.J. (2003). Biological evaluation of several coumarin derivatives designed as possible anti-inflammatory agents. Journal of Enzyme Inhibition and Medicinal Chemistry, 18(1), 63–69. (https://pubmed.ncbi.nlm.nih.gov/12739814/)

The antioxidant potential of sweet clover is associated with the presence of phenolic structures capable of acting as electron donors and neutralizing reactive oxygen species. Flavonoid components participate in the stabilization of cell membranes, reducing the intensity of lipid peroxidation. An effect on enzymatic antioxidant systems, including superoxide dismutase and catalases, has also been described, which contributes to a decrease in oxidative stress at the cellular level.

Reference: Borges F., Roleira F., Milhazes N. et al. (2005). Simple coumarins and analogues in medicinal chemistry: occurrence, synthesis and biological activity. Current Medicinal Chemistry, 12(8), 887–916. (https://pubmed.ncbi.nlm.nih.gov/15853713/)

Thus, the mechanisms of action of Melilotus officinalis include modulation of vitamin-K-dependent enzyme systems, effects on macrophage and endothelial cells, suppression of pro-inflammatory enzyme pathways, and realization of antioxidant potential, which forms a complex angioprotective and anti-inflammatory action at the tissue and cellular levels.

Synergy — Melilotus officinalis

Pharmacological synergy of Melilotus officinalis has been most studied in combinations with taxa possessing angioprotective and venotonic activity. Sweet clover coumarins demonstrate additive and potentiating interaction with flavonoid complexes of plants such as Aesculus hippocastanum and Vitis vinifera, through combined effects on the vascular endothelium, reduction of capillary permeability, and modulation of venous tone. In microcirculation models, an enhancement of the capillary-stabilizing effect has been noted in combination of coumarins with triterpene saponins and proanthocyanidins, which is explained by effects on common links of the inflammatory and oxidative cascade.

Reference: Pittler M.H., Ernst E. (1998). Horse-chestnut seed extract for chronic venous insufficiency. The Cochrane Database of Systematic Reviews. (https://pubmed.ncbi.nlm.nih.gov/10796625/)

In combination with Ruscus aculeatus, potentiation of the venotonic effect is observed due to the simultaneous effect on alpha-adrenergic mechanisms of the vascular wall and lymphatic drainage. Coumarin compounds enhance the lymphotropic component, while steroid saponins of butcher's broom increase the tone of the venous wall, forming a functionally complementary effect at the level of microcirculation.

Reference: Beltramino R., Penenory A. (2000). Metaanalysis of double-blind clinical trials of Ruscus aculeatus in chronic venous insufficiency. Phytomedicine, 7(1), 1–7. (https://pubmed.ncbi.nlm.nih.gov/10782484/)

Antioxidant synergy of sweet clover has been described in combination with polyphenolic plants such as Camellia sinensis and Curcuma longa. Phenolic compounds of these taxa are able to enhance the neutralization of reactive oxygen species and reduce the expression of pro-inflammatory mediators through common regulatory pathways of the cellular response. In in vitro experiments, additive suppression of lipid peroxidation has been demonstrated with combined use of coumarins and catechins.

Reference: Borges F., Roleira F., Milhazes N. et al. (2005). Simple coumarins and analogues in medicinal chemistry: occurrence, synthesis and biological activity. Current Medicinal Chemistry, 12(8), 887–916. (https://pubmed.ncbi.nlm.nih.gov/15853713/)

In combination with flavonoid-containing taxa such as Ginkgo biloba, functional synergy is possible with respect to microcirculation and antioxidant protection through effects on endothelial function and a decrease in the aggregation activity of blood cells. The combined effect is realized at the level of the vascular endothelium and cellular signaling cascades regulating the inflammatory response and vascular tone.

Reference:
- Smith J.V., Luo Y. (2004). Studies on molecular mechanisms of Ginkgo biloba extract. Applied Microbiology and Biotechnology, 64(4), 465–472. (https://pubmed.ncbi.nlm.nih.gov/14740166/)
- Thus, Melilotus officinalis demonstrates confirmed pharmacological synergy with angioprotective, venotonic, and polyphenolic taxa, realized through additive or potentiating effects on endothelial structures, the lymphatic system, oxidative stress, and mediator mechanisms of inflammation.

Geography of Use and Traditional Medicine — Melilotus officinalis

Sweet clover is widespread in Europe, Western and Central Asia, the Caucasus, Siberia, and North Africa. Subsequently, the plant was introduced to North and South America, where it became naturalized and became part of meadow ecosystems. Ethnobotanical sources indicate its wide use in Slavic, Balkan, Germanic, and Caucasian traditions of folk medicine.

In the Slavic tradition, sweet clover was used as a plant "for blood and vessels," used in the form of infusions and poultices. The herb was included in collections aimed at improving venous outflow and reducing edema. In village practice, a decoction of the herb was used to wash the limbs for congestive phenomena, and compresses were applied to areas of induration. Sweet clover was also used as a mild sedative, used in evening infusions.

In the Germanic phytotherapeutic tradition, Echter Steinklee was mentioned in herbals of the 16th–17th centuries as a remedy for external applications and compresses. In medieval sources, the plant was recommended for the preparation of ointments and poultices. Its use in monastic medicine of Central Europe is noted.

In the Caucasian regions, sweet clover was included in herbal mixtures used in the form of decoctions and infusions. In some ethnocultural practices, the herb was used in fumigations as a cleansing agent for rooms. In the traditions of folk medicine of Central Asia, the plant was used externally in the form of lotions and compresses.

Historical references to sweet clover are found in European herbals of the late Middle Ages. The plant was considered "honey-bearing and favorable," associated with purification and renewal. In the ritual practices of some regions, the herb was used as a component of aromatic collections for fumigating dwellings.

Non-medical use included the use of the plant as a forage crop and honey plant. The aroma of dried herb, due to the content of coumarins, contributed to its use for flavoring rooms and storing linen.

Thus, sweet clover has a wide geography of traditional use and a stable presence in European and Asian ethnomedical practices, mainly in the form of infusions, decoctions, poultices, and aromatic collections.