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Boldo

Scientific Name(s): Peumus boldus Molina
Common Name(s): Boldea, Boldo, Boldoa, Boldu, Boldus

Clinical Overview

Use

In vitro and animal studies suggest boldo leaf extract and its constituent, boldine, possess antioxidant, anti-inflammatory, and antimicrobial effects, as well as potential applications in diabetes, GI disorders, and cancer. However, clinical trials are lacking to support any therapeutic application.

Dosing

No quality clinical trials exist to support therapeutic dosing of boldo leaf extract. Traditional doses include 1 to 2 teaspoons (2 to 3 g) of dry leaf per cup of water; 0.1 to 0.3 mL of liquid extract (1:1 in 45% alcohol) 3 times a day. Commercial preparations may contain ascaridole, a toxic constituent.

Contraindications

Contraindicated in liver disease and diseases of the bile duct, including gallstones.

Pregnancy/Lactation

Avoid use. Adverse effects have been noted in animal studies.

Interactions

Boldo ingestion may enhance the anticoagulant effect of warfarin; caution is warranted.

Adverse Reactions

Boldo-related adverse events described in case reports included anaphylaxis, prolonged QT interval and ventricular tachycardia, and hepatotoxicity.

Toxicology

High doses are necessary for toxic effects; animal studies documented neurotoxicity, hepatotoxicity, and mutagenicity.

Botany

P. boldus is an evergreen shrub or small tree native to central Chile, Argentina, Ecuador, Bolivia, and Peru. The plant grows up to 6 m in height. The woody, bitter-smelling leaves are used medicinally. Small, green edible fruits are borne from small, pink-white flowers,1, 2, 3 which are also referred to as Boldu boldus (Molina) Lyons and Boldea fragrans Gay.

History

In Chile, the yellowish-green fruit is eaten, its bark is used in tanning, and its wood is used for charcoal. Explorers noticed that local South Americans used the leaves medicinally and introduced the herb to North America and Great Britain as a carminative for stomach, bladder, and liver complaints, and as a mild sedative. The name "boldu" has been attributed to the Mapuche words weltum (to sprout again) and volitum (to put out new roots). The plant is used in the treatment of digestive disorders, as a laxative, choleretic (a stimulant of bile secretion), diuretic, and for hepatic diseases. The leaves also have been used for worms, urogenital inflammations (eg, gonorrhea, syphilis), gout, rheumatism, head colds, and earaches. Boldo extract is also used as a flavoring for alcoholic beverages.2, 3, 4 A patent has been granted for the use of boldo in cosmetic or dermatological products.5

Chemistry

The leaves contain aporphine alkaloids (0.25% to 0.5%), volatile oil (2.5%), flavonol glycosides, resin, and tannins.

At least 17 benzylisoquinoline alkaloids are present in the leaves and include laurolitsine, reticuline, boldine, and isoboldine. Flavonoids include catechin, gallic, and tannic acids. Boldine is also present in the bark of the tree. Up to 46 compounds have been identified in the essential oil of boldo, with ascaridole, p-cymene, and 1,8-cineole as the main components.

Genetic variation of the essential oil and alkaloid content has been investigated. Variability is dependent upon season, location, sex, canopy height, leaf age, and light intensity. Various methods have been described for the analysis of boldo leaves and preparations.3, 4, 6, 7, 8, 9, 10, 11, 12

Uses and Pharmacology

Anti-inflammatory effects

Animal data

The dried hydroalcoholic extract of the plant reduced the inflammatory process in a carrageenan-induced edema model in rats.13 Boldine has also been shown to inhibit prostaglandin synthesis.3, 14

Clinical data

There are no clinical data regarding the use of boldo as an anti-inflammatory agent.

Antimicrobial

Animal data

Antifungal, herbicidal, and antihelminthic effects have been shown in vitro15, 16, 17, 18 and in animal studies.19 Efficacy may be due to ascaridole content.2, 3

Clinical data

There are no clinical data regarding the use of boldo for antimicrobial activity.

Antioxidant activity

Animal data

Antioxidant activity of boldine and blood leaf extracts has been demonstrated in multiple animal and in vitro studies.6, 20 Applications of the observed antioxidant effect include improved endothelial function, especially in diabetic rats,21, 22, 23 and protection against induced hepatic damage,24, 25 which may also be the mechanism of action in other observed effects.

Clinical data

There are no clinical data regarding the use of boldo as an antioxidant.

Cancer

Animal data

Both boldine alone and boldo leaf extracts have shown antiproliferative effects in vitro.6, 26, 27, 28 Protective effects against ultraviolet-mediated DNA damage has been demonstrated in melanoma cells.6, 29, 30

Clinical data

There are no clinical data regarding the use of boldo in cancer.

Diabetes/Metabolic syndrome

Animal data

Diabetic rats given boldine for 7 days showed slight decreases in plasma glucose levels, but no effect on the plasma lipid profile. A decrease in body weight was also observed.21 In rats administered boldine over 10 weeks, a protective effect was found against increases in glucose and blood pressure while markers of renal damage improved.23 Boldine may affect adipogenesis.31 Antihypertensive effects have been shown in spontaneously hypertensive rats.32

Clinical data

There are no clinical data regarding the use of boldo in diabetes or related conditions.

GI disorders

Animal data

Flavones boldoside and peumoside suppressed an induced excitation in mice and demonstrated a marked spasmolytic effect in rabbits experiencing gut spasm.33 Boldine demonstrated anti-inflammatory properties in experimental colitis models.34, 35

Clinical data

Dry boldo extract prolonged orocecal transit time in 12 volunteers in an older study.36 Clinical studies are lacking.

Other uses

An antipyretic effect has been shown in rabbits.3 Other studies performed with boldo/boldine demonstrated neuromuscular blockade in mouse phrenic nerve-diaphragm,37 sensitization of the ryanodine receptor, and induced calcium release from storage sites in isolated skeletal muscle.38 Boldo also has been studied in the radioactive labeling of blood cells and plasma proteins, tracing uptake by cells.39, 40

Dosing

No quality clinical trials exist to recommend therapeutic dosing of boldo leaf extract. Traditional doses include 1 to 2 teaspoons (2 to 3 g) of dry leaf per cup of water; 0.1 to 0.3 mL of liquid extract (1:1 in 45% alcohol) 3 times a day.4 Commercial preparations may contain ascaridole, a toxic constituent.2

Pregnancy / Lactation

Avoid use. Adverse effects have been noted in animal studies.

Hydroalcoholic extract of boldo and boldine demonstrated abortive and teratogenic actions in rats.41 Another report found no malformations in the fetus following short-term administration. At high doses, abortifacient and teratogenic effects were noted.6

Interactions

A case report exists of a potential interaction with warfarin, which returned on rechallenge with a combination herbal preparation.42 Inhibition of platelet aggregation has been shown in 1 in vitro study.6 As boldo has purported diuretic effects, increased effects of cardiac glycosides due to potassium depletion are theoretically possible.43

Adverse Reactions

Boldo-related adverse events described in case reports include anaphylaxis in an atopic individual.44 A combination preparation of dandelion, focus, and boldo was associated with a prolonged QT interval and ventricular tachycardia in another report,45, 46 while hepatotoxicity (increased liver enzymes) was noted following the use of boldo leaf extract as a component of a laxative preparation.47 The German Commission E cautions against the use of boldo leaf in severe liver disease and disease of the bile duct, including gallstones, and only approves the use of boldo preparations devoid of ascaridole.2

Data collected between 2004 and 2013 among 8 US centers in the Drug-induced Liver Injury Network revealed 15.5% (130) of hepatotoxicity cases was caused by herbals and dietary supplements whereas 85% (709) were related to medications. Of the 130 related cases of liver injury related to supplements, 65% were from non-bodybuilding supplements and occurred most often in Hispanic/Latinos compared to non-Hispanic whites and non-Hispanic blacks. Liver transplant was also more frequent with toxicity from non-bodybuilding supplements (13%) than with conventional medications (3%) (P<0.001). Overall, the number of severe liver injury cases was significantly higher from supplements than conventional medications (P=0.02). Of the 217 supplement products implicated in liver injury, boldo was among the 22% (116) of the single-ingredient products.51

Toxicology

High-dose boldine is necessary to produce adverse effects, toxicity, or death. The median lethal dose in mice was 250 mg/kg. Death in animals is from sequelae, leading to respiratory failure.6 Death in rats was also from neurotoxic effects, including depletion of dopaminergic neurons.48 Long-term administration resulted in increased liver enzymes in rats, but not histological evidence of hepatotoxicity.6 Mutagenicity tests have found equivocal results.3, 6, 49, 50

References

1. Peumus boldus. USDA, NRCS. 2014. The PLANTS Database (http://plants.usda.gov, 20 April 2014). National Plant Data Team, Greensboro, NC 27401-4901. USA.
2. Blumenthal M, Goldberg A, Brinckmann J, eds. Herbal Medicine: Expanded Commission E Monographs. Newton, MA: Integrative Medicine Communications; 2000.
3. Khan IA, Abourashed EA. Leung's Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics. 3rd ed. Hoboken, NJ: Wiley; 2009.
4. Duke JA. Handbook of Medicinal Herbs. 2nd ed. Boca Raton, FL: CRC Press; 2003.
5. Pauley G. Use of a boldo extract in a cosmetic or dermatological product. German patent application #WO 99-EP7261.
6. O'Brien P, Carrasco-Pozo C, Speisky H. Boldine and its antioxidant or health-promoting properties. Chem Biol Interact. 2006;159(1):1-17.
7. Vogel H, Razmilic I, Muñoz M, Doll U, Martin JS. Studies of genetic variation of essential oil and alkaloid content in boldo (Peumus boldus). Planta Med. 1999;65(1):90-91.17260243
8. Vogel H, et al. Variability of some active compounds in boldo (Peumus boldus Mol.). Zuechtungsforsch. 1996;2(1):364-367.
9. Simirgiotis MJ, Schmeda-Hirschmann G. Direct identification of phenolic constituents in Boldo Folium (Peumus boldus Mol.) infusions by high-performance liquid chromatography with diode array detection and electrospray ionization tandem mass spectrometry. J Chromatogr A. 2010;1217(4):443-449.20022332
10. Camara CI, Bornancini CA, Cabrera JL, Ortega MG, Yudi LM. Quantitative analysis of boldine alkaloid in natural extracts by cyclic voltammetry at a liquid-liquid interface and validation of the method by comparison with high performance liquid chromatography. Talanta. 2010;83(2):623-630.
11. Hroch M, Mičuda S, Cermanová J, Chládek J, Tomšik P. Development of an HPLC fluorescence method for determination of boldine in plasma, bile and urine of rats and identification of its major metabolites by LC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2013;936:48-56.23973534
12. Petigny L, Périno-Issartier S, Wajsman J, Chemat F. Batch and continuous ultrasound assisted extraction of boldo leaves (Peumus boldus Mol.). Int J Mol Sci. 2013;14(3):5750-5764.23481637
13. Lanhers M, Joyeux M, Soulimani R, et al. Hepatoprotective and anti-inflammatory effects of a traditional medicinal plant of Chile, Peumus boldus. Planta Med. 1991;57(2):110-115.1891491
14. Backhouse N, Delporte C, Givernau M, Cassels BK, Valenzuela A, Speisky H. Anti-inflammatory and antipyretic effects of boldine. Agents Actions. 1994;42(3-4):114-117.7879695
15. Passone MA, Etcheverry M. Antifungal impact of volatile fractions of Peumus boldus and Lippia turbinata on Aspergillus section Flavi and residual levels of these oils in irradiated peanut. Int J Food Microbiol. 2014;168-169:17-23.24211775
16. Bluma R, Amaiden MR, Daghero J, Etcheverry M. Control of Aspergillus section Flavi growth and aflatoxin accumulation by plant essential oils. J Appl Microbiol. 2008;105(1):203-214.18284488
17. Verdeguer M, García-Rellán D, Boira H, Pérez E, Gandolfo S, Blázquez MA. Herbicidal activity of Peumus boldus and Drimys winterii essential oils from Chile. Molecules. 2011;16(1):403-411.21221059
18. Vila R, Valenzuela L, Bello H, Cañigueral S, Montes M, Adzet T. Composition and antimicrobial activity of the essential oil of Peumus boldus leaves. Planta Med. 1999;65(2):178-179.10193210
19. van Krimpen MM, Binnendijk GP, Borgsteede FH, Gaasenbeek CP. Anthelmintic effects of phytogenic feed additives in Ascaris suum inoculated pigs. Vet Parasitol. 2010;168(3-4):269-277.19954891
20. Speisky H, Cassels BK. Boldo and boldine: an emerging case of natural drug development. Pharmacol Res. 1994;29(1):1-12.8202440
21. Lau YS, Tian XY, Huang Y, Murugan D, Achike FI, Mustafa MR. Boldine protects endothelial function in hyperglycemia-induced oxidative stress through an antioxidant mechanism. Biochem Pharmacol. 2013;85(3):367-375.23178655
22. Lau YS, Tian XY, Mustafa MR, et al. Boldine improves endothelial function in diabetic db/db mice through inhibition of angiotensin II-mediated BMP4-oxidative stress cascade. Br J Pharmacol. 2013;170(6):1190-1198.23992296
23. Hernández-Salinas R, Vielma AZ, Arismendi MN, Boric MP, Sáez JC, Velarde V. Boldine prevents renal alterations in diabetic rats. J Diabetes Res. 2013;2013:593672.24416726
24. Fernández J, Lagos P, Rivera P, Zamorano-Ponce E. Effect of boldo (Peumus boldus Molina) infusion on lipoperoxidation induced by cisplatin in mice liver. Phytother Res. 2009;23(7):1024-1027.19145575
25. Cordero-Pérez P, Torres-González L, Aguirre-Garza M, et al. Hepatoprotective effect of commercial herbal extracts on carbon tetrachloride-induced liver damage in Wistar rats. Pharmacognosy Res. 2013;5(3):150-156.23900881
26. Falé PL, Amaral F, Amorim Madeira PJ, et al. Acetylcholinesterase inhibition, antioxidant activity and toxicity of Peumus boldus water extracts on HeLa and Caco-2 cell lines. Food Chem Toxicol. 2012;50(8):2656-2662.22617353
27. Gerhardt D, Bertola G, Dietrich F, et al. Boldine induces cell cycle arrest and apoptosis in T24 human bladder cancer cell line via regulation of ERK, AKT, and GSK-3beta. Urol Oncol. 2014;32(1):36.e1-36.e9.24239461
28. Gerhardt D, Horn AP, Gaelzer MM, et al. Boldine: a potential new antiproliferative drug against glioma cell lines. Invest New Drugs. 2009;27(6):517-525.19050827
29. Russo A, Cardile V, Caggia S, Gunther G, Troncoso N, Garbarino J. Boldo prevents UV light and nitric oxide-mediated plasmid DNA damage and reduces the expression of Hsp70 protein in melanoma cancer cells. J Pharm Pharmacol. 2011;63(9):1219-1229.21827495
30. Hidalgo M, et al. Boldine as a sunscreen: its photoprotector capacity against UVB radiation. Cosmet Toiletries. 1998;113(9):59,60,62-64,66.
31. Yu B, Cook C, Santanam N. The aporphine alkaloid boldine induces adiponectin expression and regulation in 3T3-L1 cells. J Med Food. 2009;12(5):1074-1083.19857072
32. Lau YS, Machha A, Achike FI, Murugan D, Mustafa MR. The aporphine alkaloid boldine improves endothelial function in spontaneously hypertensive rats. Exp Biol Med (Maywood). 2012;237(1):93-98.22156043
33. Borkowski B, et al. Pharmacodynamic investigations on flavone derivatives from the leaves of Peumus boldus. Herba Pol. 1965;11(3):198-193.
34. Salati R, Lugli R, Tamborino E. Evaluation of the choleretic property of 2 preparations containing extracts of boldo and cascara. Minerva Dietol Gastroenterol. 1984;30(3):269-272.6504376
35. Gotteland M, Jimenez I, Brunser O, et al. Protective effect of boldine in experimental colitis. Planta Med. 1997;63(4)311-315.9270374
36. Gotteland M, Espinoza J, Cassels B, Speisky H. Effect of a dry boldo extract on oro-cecal intestinal transit in healthy volunteers. Rev Med Chil. 1995;123(8):955-960.8657963
37. Kang JJ, Cheng YW, Fu WM. Studies on neuromuscular blockade by boldine in the mouse phrenic nerve-diaphragm. Jpn J Pharmacol. 1998;76(2):207-212.9541284
38. Kang JJ, Cheng YW. Effects of boldine on mouse diaphragm and sarcoplasmic reticulum vesicles isolated from skeletal muscle. Planta Med. 1998;64(1):18-21.9491763
39. Reiniger IW, de Oliveira JF, Caldeira-de-Araújo A, Bernardo-Filho M. Effect of Peumus boldus on the labeling of red blood cells and plasma proteins with technetium-99m. Appl Radiat Isot. 1999;51(2):145-149.10376326
40. Braga AC, Oliveira MB, Feliciano GD, et al. The effect of drugs on the labeling of blood elements with technetium-99m. Curr Pharm Des. 2000;6(11):1179-1191.10903389
41. Almeida ER, Melo AM, Xavier H. Toxicological evaluation of the hydro-alcohol extract of the dry leaves of Peumus boldus and boldine in rats. Phytother Res. 2000;14(2):99-102.
42. Lambert JP, Cormier J. Potential interaction between warfarin and boldo-fenugreek. Pharmacotherapy. 2001;21(4):509-512.11310527
43. Vogel JH, Bolling SF, Costello RB, et al. American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (Writing Committee to Develop an Expert Consensus Document on Complementary and Integrative Medicine). Integrating complementary medicine into cardiovascular medicine. J Am Coll Cardiol. 2005;46(1):184-221.15992662
44. Monzón S, Lezaun A, Sáenz D, et al. Anaphylaxis to boldo infusion, a herbal remedy. Allergy. 2004;59(9):1019-1020.15291920
45. Agarwal SC, Crook JR, Pepper CB. Herbal remedies-how safe are they? A case report of polymorphic ventricular tachycardia/ventricular fibrillation induced by herbal medication used for obesity. Int J Cardiol. 2006;106(2):260-261.16321701
46. Izzo AA, Di Carlo G, Borrelli F, Ernst E. Cardiovascular pharmacotherapy and herbal medicines: the risk of drug interaction. Int J Cardiol. 2005;98(1):1-14.15676159
47. Piscaglia F, Leoni S, Venturi A, Graziella F, Donati G, Bolondi L. Caution in the use of boldo in herbal laxatives: a case of hepatotoxicity. Scand J Gastroenterol. 2005;40(2):236-239.15764158
48. Mejía-Dolores JW, Mendoza-Quispe DE, Moreno-Rumay EL, et al. Neurotoxic effect of aqueous extract of boldo (Peumus boldus) in an animal model. Rev Peru Med Exp Salud Publica. 2014;31(1):62-68.24718528
49. Moreno PR, Vargas VM, Andrade HH, Henriques AT, Henriques JA. Genotoxicity of the boldine aporphine alkaloid in prokaryotic and eukaryotic organisms. Mutat Res. 1991;260(2):145-152.2046695
50. Tavares DC, Takahashi CS. Evaluation of the genotoxic potential of the alkaloid boldine in mammalian cell systems in vitro and in vivo. Mutat Res. 1994;321(3):139-145.7513064
51. Navarro VJ, Barnhart H, Bonkovsky HL, et al. Liver injury from herbals and dietary supplements in the U.S. drug-induced liver injury network. Hepatology. 2014;60(4):1399-1408.25043597

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This information relates to an herbal, vitamin, mineral or other dietary supplement. This product has not been reviewed by the FDA to determine whether it is safe or effective and is not subject to the quality standards and safety information collection standards that are applicable to most prescription drugs. This information should not be used to decide whether or not to take this product. This information does not endorse this product as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this product. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this product. This information is not specific medical advice and does not replace information you receive from your health care provider. You should talk with your health care provider for complete information about the risks and benefits of using this product.

This product may adversely interact with certain health and medical conditions, other prescription and over-the-counter drugs, foods, or other dietary supplements. This product may be unsafe when used before surgery or other medical procedures. It is important to fully inform your doctor about the herbal, vitamins, mineral or any other supplements you are taking before any kind of surgery or medical procedure. With the exception of certain products that are generally recognized as safe in normal quantities, including use of folic acid and prenatal vitamins during pregnancy, this product has not been sufficiently studied to determine whether it is safe to use during pregnancy or nursing or by persons younger than 2 years of age.

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