Bugleweed

Scientific Name(s): Lycopus europaeus L. Family: Lamiaceae (mint). Other members of the Lycopus (water horehound), including Lycopus asper Greene, Lycopus unifloris Michx., and Lycopus virginicus L., are also broadly termed bugleweed.

Common Name(s): Bitter bugle , bugleweed , carpenter's herb , green archangel , gypsywort , northern bugleweed , Paul's betony , purple archangel , rough bugleweed , sweet bugle , Thyreo-loges N tablets, Virginia water horehound , water bugle , water horehound , wolf foot , wolfstrappkraut

Uses

Bugleweed is used to treat mild hyperthyroidism, premenstrual syndrome, and breast pain; however, there are few clinical studies to support these uses.

Dosing

Clinical trials are lacking regarding dosages for specific clinical applications. A daily dosage of 2 Thyreo-loges N tablets ( Lycopi europaei herba 40 mg/day) taken in divided doses was used for 3 months in an open-label clinical study for mild hyperthyroidis.

Contraindications

None specifically identified except pregnancy. Exercise caution in patients with hypothyroidism.

Pregnancy/Lactation

Contraindicated in pregnancy and lactation because of the potential for antigonadotropic and antithyrotropic effects; however, clinical data are lacking.

Interactions

None well documented.

Adverse Reactions

Clinical trials and case reports are lacking. Bugleweed taken in high amounts or stopped suddenly has the potential to cause thyroid enlargement.

Toxicology

Information is lacking.

Botany

Bugleweed is an herbaceous perennial mint that grows in wet habitats. The leaves are toothed, and the small white flowers surround the square stem at the leaf axils in dense clusters. The plant has little odor; the European species has a bitter taste, but the American species is not bitter. The whole herb is used medicinally. 1

History

Traditional uses of bugleweed include treatment of nosebleeds, heavy menstrual bleeding, and coughs. It has also been used as a sedative, astringent, and mild narcotic, and for tuberculosis characterized by bleeding from the lungs. More current uses are primarily for mild hyperthyroid conditions and for premenstrual syndrome, including breast pain (mastodynia). 2 , 3

Chemistry

The phenolic compounds lithospermic acid, rosmarinic acid, chlorogenic acid, and caffeic acid have been identified in both L. europaeus and L. virginicus . 4 , 5 , 6 , 7 , 8 The metabolism of these phenolics in rat liver has been analyzed by high-performance liquid chromatography (HPLC) and capillary electrophoresis. 6 The flavonoids luteolin 7-glucoside, luteolin 3′,7-diglucoside, luteolin 7-glucuronide, and apigenin 7-glucoside have also been isolated from L. europaeus , L. virginicus , and Lycopus lucidus . 9 , 10 , 11 , 12 , 13 , 14 Several isopimarane diterpenes have been isolated as well. 15 , 16 , 17 , 18 Triterpenes (eg, ursolic, oleanolic, betulinic acid) have been identified primarily from L. asper . 8 , 19 An automated thin-layer chromatography method for analysis of Lycopus and other plants has been published. 20

Uses and Pharmacology

Mild hyperthyroidism

The majority of studies on L. europaeus and thyroid activity arise from a small pool of researchers. A review of the thyroid pharmacology of Lycopus has been published. 5 Antithyroid activity initially was attributed to lithospermic acid 4 ; however, a more complex mechanism has developed since that early work. It has been proposed that the oxidation of phenolics to unstable orthoquinones by plant enzymes is required for antithyroid activity. Thus, caffeic acid, rosmarinic acid, and lithospermic acid are inactive without some form of oxidation. 21 , 22

Animal data

Extracts of L. europaeus administered to healthy rats reduced the weight of the thyroid, decreased thyroid hormone activity, and increased absorption and storage of iodine. The extract retarded goiter formation in propylthiouracil-treated rats. All animals treated with the extract demonstrated reduced metabolism. 23 Other studies in rats have shown inhibition of serum thyrotropic hormone and thyroxine after oral administration. 24 Cardiac signs of hyperthyroidism were reduced in an experiment in rats treated with L. europaeus extract. 3

Freeze-dried extracts of bugleweed and other related plants showed a dose-dependent inhibition of bovine thyroid-stimulating hormone (TSH) binding to human thyroid membranes, with simultaneous inhibition of TSH-stimulated adenyl cyclase activity. 25 , 26 Formation of covalent adducts with TSH amino acid residues was postulated; however, the evidence for this is not conclusive. 21

Clinical data

Few clinical studies have been reported, and the methodology in these studies limits the findings. Randomized, placebo-controlled clinical trials are lacking.

Humans treated with Lycopus extracts showed inhibition of serum thyrotropic hormone and thyroxine, 27 while a reduction in the thyroid-stimulating effect of thyroid antibodies in Graves disease has been demonstrated. 22

Low-dose powdered L. europaeus equivalent to 2 × 5 mg Lycopus extract administered in an observational study produced no changes in thyroid hormone levels but demonstrated improved cardiac symptoms. 2 , 3

A prospective open study (N = 62) was conducted in patients with mild hyperthyroidism. 2 Patients in the treatment arm of the study were given Lycopus herb 40 mg/day, while those in the control arm were managed in a different naturopathic manner. No difference was found in excretion of tri-iodothyronine in the urine; however, an increase was found for thyroxine excretion in the Lycopus -treated patients. Free thyroxine and TSH serum levels also remained unchanged. A renal mechanism has been proposed for the observed effects. 2

Antigonadotropic effect

Clinical studies are lacking; however, one small clinical trial measured no changes in plasma estradiol, testosterone, follicle-stimulating hormone, or luteinizing hormone levels. 2

Flavonoids and phenolics from Lycopus species exert antigonadotropic activity in animal and in vitro experiments. 9 , 28 , 29 , 30 , 31 , 32 , 33 , 34 Activation of the phenolic compounds appears to be required for effect and may be limited to glycoprotein hormones, including TSH and gonadotropin. 35 Extracts showed inhibition of human chorionic gonadotropin binding to rat testis membranes. 25 Lycopus extract administration in rats reduced prolactin levels and is thought to be secondary to reduction in TSH because thyroid status influences prolactin production. 36

Other effects

The antioxidant potential of extracts of Lycopus has been demonstrated in vitro and is attributed in part to the phenolic content of the plant. 14 , 37 , 38

Vascular inflammation induced by high glucose levels in human cells was inhibited by an aqueous extract of the leaves of L. lucidus . 38 Triterpenes from the plant also inhibited cholesterol acyltransferase, 19 suggesting a potential role in the prevention of atherosclerosis.

Immune-modulating effects have been demonstrated by extracts of the leaves of L. lucidus , as well as betulinic acid extracted from the aerial plant parts. A reduction in histamine released from mast cells because of membrane stabilization, as well as both increased and decreased secretion of tumor necrosis factor, has been shown. 8 , 39

Inhibition of xanthine oxidase (key to the production of uric acid in gout) by an extract of the leaves of L. europaeus has been demonstrated in vitro. 40 Diterpenes extracted from L. europaeus were effective against multidrug resistant Staphylococcal aureus when used in combination with tetracycline or erythromycin. 18

Dosage

A commercially available preparation, Thyreo-loges N tablets, contains Lycopi europaei 20 mg per tablet. A dosage of 40 mg/day in divided doses was used for 3 months in an open-label clinical study. 2 Low-dose powdered L. europaeus equivalent to 2 × 5 mg Lycopus extract used in an observational study produced no changes in thyroid hormone levels but was associated with improved cardiac symptoms. 2 , 3

Pregnancy/Lactation

Contraindicated in pregnancy and lactation because of the potential for antigonadotropic and antithyrotropic effects, as demonstrated in animal experiments. 41 , 42 Data on secretion of bugleweed compounds in human breast milk are not available. A reduction of prolactin levels in rats following Lycopus extract administration has been observed, 36 while no effect on plasma levels of prolactin was found in a clinical study. 2

Interactions

None well documented. The potential for interaction with thyroid medications exists, as well as interference in laboratory values.

Adverse Reactions

In a clinical study (N = 62), 6 adverse events were recorded, one of which (subjective feelings of cardiac rhythm disturbance) was attributed to the active bugleweed preparation. 2

A review of natural preparations with the potential to have adverse renal effects included bugleweed; however, the level of evidence is low. 43

Bugleweed taken in high amounts or stopped suddenly has the potential to cause thyroid enlargement. 5

Toxicology

The potential for serious toxicity appears to be low; however, data are lacking. 5

Bibliography

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3. Vonhoff C, Baumgartner A, Hegger M, Korte B, Biller A, Winterhoff H. Extract of Lycopus europaeus L. reduces cardiac signs of hyperthyroidism in rats. Life Sci . 2006;78(10):1063-1070.
4. Wagner H, Hörhammer L, Frank U. Lithospermic acid, the antihormonally active principle of Lycopus europaeus L. and Symphytum officinale . 3. Ingredients of medicinal plants with hormonal and antihormonal-like effect [in German]. Arzneimittelforschung . 1970;20(5):705-713.
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18. Gibbons S, Oluwatuyi M, Veitch NC, Gray AI. Bacterial resistance modifying agents from Lycopus europaeus . Phytochemistry . 2003;62(1):83-87.
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22. Auf'mkolk M, Ingbar JC, Kubota K, Amir SM, Ingbar SH. Extracts and auto-oxidized constituents of certain plants inhibit the receptor-binding and the biological activity of Graves' immunoglobulins. Endocrinology . 1985;116(5):1687-1693.
23. Hiller E, Girod E. Experimental studies on the effect of concentrates from Lycopus europaeus on the thyroid gland with special reference to the histology of iodine metabolism [in German]. Arzneimittelforschung . 1954;4(6):380-388.
24. Winterhoff H, Gumbinger HG, Vahlensieck U, Kemper FH, Schmitz H, Behnke B. Endocrine effects of Lycopus europaeus L. following oral application. Arzneimittelforschung . 1994;44(1):41-45.
25. Auf'mkolk M, Ingbar JC, Amir SM, et al. Inhibition by certain plant extracts of the binding and adenylate cyclase stimulatory effect of bovine thyrotropin in human thyroid membranes. Endocrinology . 1984;115(2):527-534.
26. Kleeman S, Winterhoff H. Rosmarinic acid and freeze-dried extract (FDE) of Lycopus virginicus are able to inhibit forskolin-induced activation of adenylate cyclase in cultured rat thyroid cells. Planta Med . 1990;56(6):683.
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30. Nahrstedt A, Albrecht M, Wray V, et al. Structures of compounds with antigonadotropic activity obtained by in vitro oxidation of caffeic acid. Planta Med . 1990;56(4):395-398.
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32. John M, Gumbinger HG, Winterhoff H. The oxidation of caffeic acid derivatives as model reaction for the formation of potent gonadotropin inhibitors in plant extracts. Planta Med . 1993;59(3):195-199.
33. Rompel A, Fischer H, Meiwes D, et al. Purification and spectroscopic studies on catechol oxidases from Lycopus europaeus and Populus nigra : evidence for a dinuclear copper center of type 3 and spectroscopic similarities to tyrosinase and hemocyanin. J Biol Inorg Chem . 1999;4(1):56-63.
34. Rompel A, Fischer H, Meiwes D, et al. Substrate specificity of catechol oxidase from Lycopus europaeus and characterization of the bioproducts of enzymic caffeic acid oxidation. FEBS Lett . 1999;445(1):103-110.
35. Thotakura NR, Blithe DL. Glycoprotein hormones: glycobiology of gonadotrophins, thyrotrophin and free alpha subunit. Glycobiology . 1995;5(1):3-10.
36. Sourgens H, Winterhoff H, Gumbinger HG, Kemper FA. Antihormonal effects of plant extracts. TSH- and prolactin-suppressing properties of Lithospermum officinale and other plants. Planta Med . 1982;45(2):78-86.
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38. Lee YJ, Kang DG, Kim JS, Lee HS. Lycopus lucidus inhibits high glucose-induced vascular inflammation in human umbilical vein endothelial cells. Vascul Pharmacol . 2008;48(1):38-46.
39. Shin TY, Kim SH, Suk K, et al. Anti-allergic effects of Lycopus lucidus on mast cell-mediated allergy model. Toxicol Appl Pharmacol . 2005;209(3):255-262.
40. Kong LD, Cai Y, Huang WW, Cheng CH, Tan RX. Inhibition of xanthine oxidase by some Chinese medicinal plants used to treat gout. J Ethnopharmacol . 2000;73(1-2):199-207.
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43. Voss D. Complementary medicines in predialysis patients. Nephrology . 2005;10(s5):S201-S203.

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