Stevia

Scientific Name(s): Stevia rebaudiana Bertoni. Asteraceae (daisies)

Common Name(s): Stevia , rebiana , sweet leaf of Paraguay , sweetleaf , sweetherb , honey leaf , candyleaf , honey yerba , caa-he-é , ca-a-yupi , eira-caa , capim doce , Truvia , PureVia

Uses

Stevia leaf is used as a sweetening agent and contains several sweet glycosides. The glycoside rebaudioside A is used in commercially available products in the United States and has not shown any pharmacologic effects. Stevioside and stevia preparations have shown conflicting data, indicating possible effects as hypotensive and hypoglycemic agents and possible bactericidal properties.

Dosing

Stevia leaf is used for sweetening foods.

Contraindications

Contraindications have not yet been identified.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

No major contraindications, warnings, or adverse reactions have been documented.

Toxicology

Stevioside, a main glycoside of stevia, was found to be nontoxic in acute toxicity studies in a variety of laboratory animals.

Botany

Stevia is a perennial shrub indigenous to northern South America and is commercially grown in Central America, Israel, Thailand, and China. The plant can grow to 1 m in height, with leaves 2 to 3 cm in length. The leaves are used for their sweet taste. 1

History

Stevia was historically used to sweeten tea by the Guarani tribe of South America. For hundreds of years, native Brazilians and Paraguayans have also used the leaves of the plant as a sweetening agent. Europeans discovered stevia in the 16th century, whereas North American researchers began investigating its sweetening properties in the 20th century. Paraguayan botanist Moises Bertoni described the plant S. rebaudiana in the early 1900s. Glycosides responsible for the plant's sweetness were discovered in 1931. Stevia extracts have been used for years in a few countries, including Japan and Paraguay, as a food and medicine. In December 2008, the US Food and Drug Administration recognized one of stevia's glycosides, rebaudioside A, as generally safe for use as a general purpose sweetener, opening the door for marketing in the United States. 2

Chemistry

The main glycosides of stevia include stevioside and rebaudioside. Eight of stevia's glycosides were discovered and named in 1931. 3 More recently, the glycosides have been analyzed by capillary electrophoresis. Rebaudioside A and steviobioside have been isolated by high performance liquid chromatography (HPLC) methods. 4 Stevioside determination has been reported. 5 Two glucosyl transferases acting on steviol and its glycosides have been isolated. 6 Stevioside (6% to 18% in leaves) is the sweetest glycoside and was tested and found to be 300 times sweeter than saccharose in one report. 7 Steviol hydroxylation has been reported. 8 Sterols in stevia include stigmasterol, beta-sitosterol, and campesterol. 9 Isolation of the principal sugars of stevia has also been studied. 10

Stevia also contains certain vitamins (A, B, C), minerals (iron, zinc, calcium), electrolytes (sodium, potassium), proteins, and other elements. 1

Cultivation studies have been performed, 11 , 12 as well as tissue culture experiments. 13

Uses and Pharmacology

Stevia has been used for centuries as a natural sweetener. 1 The plant contains sweet ent-kaurene glycosides, 14 with the most intense sweetness belonging to the species S. rebaudiana . 15 Stevia has been evaluated for sweetness in animal response testing. 16 In humans, stevia as a sweetening agent works well in weight-loss programs to satisfy sugar cravings and is low in calories. Japan is the largest consumer of stevia leaves and uses the plant to sweeten foods, such as soy sauce, confections, and soft drinks, and as a replacement for aspartame and saccharin. 1 Several studies have examined the pharmacologic effects of stevia in animals and humans. These studies were conducted on different stevia glycosides and contribute to the conflicting results. In addition, some of the earlier studies did not specify the glycoside content of the stevia used. Stevioside appears to have more pharmacologic effect than the commercially available sweeteners that primarily contain rebaudioside A.

Diabetes
Animal data

Stevia may be helpful in treating diabetes. Steviol, isosteviol, and glucosylsteviol decreased glucose production in rat renal cortical tubules. 17 Stevioside lowered blood glucose in type 2 diabetic fatty rats when given orally. 18 , 19 However, rebaudioside A did not affect glycemic control after 8 weeks of treatment in type 2 diabetic rats. 20 Oral use of stevia extract in combination with chrysanthemum to manage hyperglycemia has been discussed. 21

Clinical data

Studies with rebaudioside A indicate no effect on blood glucose. A 16-week study in patients (n = 122) with type 2 diabetes did not find any statistically significant changes from baseline versus placebo in hemoglobin A 1c (HbA 1c ), fasting glucose, insulin, or C-peptide when patients were administered rebaudioside A 500 mg twice a day with meals for 16 weeks. 22 Another study supports this lack of pharmacological effect of steviol glycosides. This study included 72 patients divided into 3 groups consisting of patients with type 1 diabetes, with type 2 diabetes, or without diabetes. After 3 months of the patients receiving steviol glycosides 250 mg 3 times a day, no change in HbA 1c was observed. 23 Commercially available rebaudioside A has not been shown to affect blood glucose; however, earlier studies, some conducted with the stevioside glycoside, indicate a potential effect on blood glucose. Aqueous extracts of the plant increased glucose tolerance in 16 healthy volunteers, as well as markedly decreasing plasma glucose levels. 24 When given 1 g capsules (consisting of 91% stevioside) orally along with a meal, postprandial blood glucose was decreased in a crossover study of 12 patients with type 2 diabetes. 25

Hypertension
Animal data

Stevia's effects on blood pressure have been reported. The plant may have cardiotonic actions, which normalize blood pressure and regulate heartbeat. 1 The plant displayed vasodilatory actions in both normotensive and hypertensive animals. 26 Stevia has also produced decreases in blood pressure and has increased diuretic and natriuretic effects in rats. 27 , 28 A study of stevioside in dogs indicated hypotensive effects. 29 However, a study with rebaudioside A indicated no effect on blood pressure in rats. 20

Clinical data

Several studies with rebaudioside A in normotensive and hypotensive patients indicated the agent had no effect on blood pressure. 22 , 23 , 30 Conflicting data exist concerning the effect of stevioside as an antihypertensive agent. A decrease in systolic and diastolic blood pressure has been observed in patients with hypertension when given stevioside 250 mg 3 times daily for 1 year. 31 In another study, stevioside administered at a dosage of up to 15 mg/kg/day for 6 weeks did not decrease blood pressure compared with placebo. 32

Other uses

Stevia extract has exhibited strong bactericidal activity against a wide range of pathogenic bacteria, including certain Escherichia coli strains. 33 Steviol was observed to be mutagenic toward Salmonella and other bacterial strains under various conditions and toward certain cell lines. 34 , 35 , 36 , 37 Stevia may also be effective against Candida albicans and has shown some antirotavirus activity. 1 , 38 Stevioside has shown promising immunomodulating effects in rats and cell lines. 39 , 40 , 41 In addition, stevia may have antiproliferative/antimutagenic/antioxidant properties. 42 , 43 , 44 One report addresses stevia's role in reducing dental plaque. 45

Certain metabolic aspects of stevioside have been described, including rat liver effects 46 , 47 , 48 and cell membrane transport. 49

Dosage

Stevia leaf is used for sweetening foods.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Rebaudioside A has been studied in rats for 2 generations, with no effects on gestation lengths or growth. 50

Interactions

None well documented.

Adverse Reactions

No major contraindications, warnings, or adverse reactions have been documented.

Toxicology

Stevia is not mutagenic or genotoxic. 1 One report found that constituents of stevioside and steviol were not mutagenic in vitro. 51 Stevioside was found to be nontoxic in acute toxicity studies in a variety of laboratory animals. 1 Chronic administration of stevia to male rats had no effect in fertility versus controls. 52 Another report concluded that stevioside in high doses did not affect growth or reproduction in hamsters of both sexes. 53 Rebaudioside A showed no toxic effects when given to rats at dosages of up to 2,000 mg/kg/day for 90 days. 54

Bibliography

1. Stevia. Raintree Nutrition Tropical Plant Database. http://www.rain-tree.com/stevia.htm . Updated January 22, 2007. Accessed January 5, 2010.
2. Tarantino LM. Agency Response Letter GRAS Notice No. GRN 000253. CFSAN/Office of Food Additive Safety. Food and Drug Administration web site. http: / / www.fda.gov / Food / FoodIngredientsPackaging / GenerallyRecognizedasSafeGRAS / GRASListings / ucm154989.htm . Published December 17, 2008. Updated June 18, 2009. Accessed November 20, 2009.
3. Bridel M, Lavielle R. Bull Soc Chim Biol . 1931;13:636-655.
4. Mauri P, Catalano G, Gardana C, Pietta P. Analysis of Stevia glycosides by capillary electrophoresis. Electrophoresis . 1996;17(2):367-371.
5. Mitsuhashi H, Ueno J, Sumita T. Studies on the cultivation of Stevia rebaudiana Bertoni. Determination of stevioside (author's transl) [in Japanese]. Yakugaku Zasshi . 1975;95(1):127-130.
6. Shibata H, Sawa Y, Oka T, Sonoke S, Kim KK, Yoshioka M. Steviol and steviol-glycoside: glucosyltransferase activities in Stevia rebaudiana Bertoni—purification and partial characterization. Arch Biochem Biophys . 1995;321(2):390-396.
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8. Kim KK, Sawa Y, Shibata H. Hydroxylation of ent-kaurenoic acid to steviol in Stevia rebaudiana Bertoni—purification and partial characterization of the enzyme. Arch Biochem Biophys . 1996;332(2):223-230.
9. D'Agostino M, De Simone F, Pizza C, Aquino R. Sterols in Stevia rebaudiana Bertoni [in Italian]. Boll Soc Ital Biol Sper . 1984;60(12):2237-2240.
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11. Mitsuhashi H, Ueno J, Sumita T. Studies on the cultivation of Stevia rebaudiana Bertoni. Determination of stevioside. II. (author's transl) [in Japanese]. Yakugaku Zasshi . 1975;95(12):1501-1503.
12. Miyazaki Y, Watanabe H, Watanabe T. Studies on the cultivation of Stevia rebaudiana Bertoni. III. Yield and stevioside content of 2-year-old plants (author's transl) [in Japanese]. Eisei Shikenjo Hokoku . 1978;(96):86-89.
13. Handro W, Hell KG, Kerbauy GB. Tissue culture of Stevia rebaudiana , a sweetening plant. Planta Med . 1977;32(2):115-117.
14. Kinghorn AD, Soejarto DD, Nanayakkara NP, et al. A phytochemical screening procedure for sweet ent-kaurene glycosides in the genus Stevia. J Nat Prod . 1984;47(3):439-444.
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16. Jakinovich W Jr, Moon C, Choi YH, Kinghorn AD. Evaluation of plant extracts for sweetness using the Mongolain gerbil. J Nat Prod . 1990;53(1):190-195.
17. Yamamoto NS, Kelmer Bracht AM, Ishii EL, Kemmelmeier FS, Alvarez M, Bracht A. Effect of steviol and its structural analogues on glucose production and oxygen uptake in rat renal tubules. Experientia . 1985;41(1):55-57.
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19. Dyrskog SE, Jeppensen PB, Colombo M, Abudula R, Hermansen K. Preventative effects of a soy-based diet supplemented with stevioside on the development of the metabolic syndrome and type 2 diabetes in Zucker diabetic fatty rats. Metabolism . 2005;54(9):1181-1188.
20. Dyrskog SE, Jeppensen PB, Chen J, Christensen LP, Hermansen K. The diterpene glycoside, rebaudioside A, does not improve glycemic control or affect blood pressure after eight weeks treatment in the Goto-Kakizaki rat. Rev Diabet Stud . 2005;2(2):84-91.
21. White JR Jr, Kramer J, Campbell RK, Bernstein R. Oral use of a topical preparation containing an extract of Stevia rebaudiana and the chrysanthemum flower in the management of hyperglycemia. Diabetes Care . 1994;17(8):940.
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23. Barriocanal LA, Palacios M, Benitez G, et al. Apparent lack of pharmacological effect of steviol glycosides used as sweeteners in humans. A pilot study of repeated exposures in some normotensive and hypotensive individuals and in type 1 and type 2 diabetics. Regul Toxicol Pharmacol . 2008:51(1);37-41.
24. Curi R, Alvarez M, Bazotte RB, Botion LM, Godoy JL, Bracht A. Effect of Stevia rebaudiana on glucose tolerance in normal adult humans. Braz J Med Biol Res . 1986;19(6):771-774.
25. Gregersen S, Jeppesen PB, Holst JJ, Hermansen K. Antihyperglycemic effects of stevioside in type 2 diabetic subjects. Metabolism . 2004:53(1):73-76.
26. Melis MS. A crude extract of Stevia rebaudiana increases the renal plasma flow of normal and hypertensive rats. Braz J Med Biol Res . 1996;29(5):669-675.
27. Melis MS, Sainati AR. Effect of calcium and verapamil on renal function of rats during treatment with stevioside. J Ethnopharmacol . 1991;33(3):257-262.
28. Melis MS. Chronic administration of aqueous extract of Stevia rebaudiana in rats: renal effects. J Ethnopharmacol . 1995;47(3):129-134.
29. Liu JC, Kao PK, Chan P, et al. Mechanism of the antihypertensive effect of stevioside in anesthetized dogs. Pharmacology . 2003;67(1):14-20.
30. Maki KC, Curry LL, Carakostas MC, et al. The hemodynamic effects of rebaudioside A in healthy adults with normal and low-normal blood pressure. Food Chem Toxicol . 2008;46(suppl 7):S40-S46.
31. Chan P, Tomlinson B, Chen YJ, Liu JC, Hsieh MH, Cheng JT. A double-blind placebo-controlled study of the effectiveness and tolerability of oral stevioside in human hypertension. Br J Clin Pharmacol . 2000;50(3):215-220.
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33. Tomita T, Sato N, Arai T, et al. Bactericidal activity of a fermented hot-water extract from Stevia rebaudiana Bertoni towards enterohemorrhagic Escherichia coli O157:H7 and other food-borne pathogenic bacteria. Microbiol Immunol . 1997;41(12):1005-1009.
34. Pezzuto JM, Compadre CM, Swanson SM, Nanayakkara D, Kinghorn AD. Metabolically activated steviol, the aglycone of stevioside, is mutagenic. Proc Natl Acad Sci U S A . 1985;82(8):2478-2482.
35. Pezzuto JM, Nanayakkara NP, Compadre CM, et al. Characterization of bacterial mutagenicity mediated by 13-hydroxy-ent-kaurenoic acid (steviol) and several structurally-related derivatives and evaluation of potential to induce glutathione S-transferase in mice. Mutat Res . 1986;169(3):93-103.
36. Matsui M, Matsui K, Kawasaki Y, et al. Evaluation of the genotoxicity of stevioside and steviol using six in vitro and one in vivo mutagenicity assays. Mutagenesis . 1996;11(6):573-579.
37. Klongpanichpak S, Temcharoen P, Toskulkao C, Apibal S, Glinsukon T. Lack of mutagenicity of stevioside and steviol in Salmonella typhimurium TA 98 and TA 100. J Med Assoc Thai . 1997;80(suppl 1):S121-S128.
38. Takahashi K, Matsuda M, Ohashi K, et al. Analysis of anti-rotavirus activity of extract from Stevia rebaudiana . Antiviral Res . 2001;49(1):15-24.
39. Boonkaewwan C, Toskulkao C, Vongsakul M. Anti-inflammatory and immunomodulatory activities of stevioside and its metabolite steviol on THP-1 cells. J Agric Food Chem . 2006;54(3):785-789.
40. Boonkaewwan C, Ao M, Toskulkao C, Rao MC. Specific immunomodulatory and secretory activities of stevioside and steviol in intestinal cells. J Agric Food Chem . 2008;56(10):3777-3784.
41. Sehar I, Kaul A, Bani S, Pal HC, Saxena AK. Immune up regulatory response of a non-caloric natural sweetener, stevioside. Chem Biol Interact . 2008;173(2):115-121.
42. Yasukawa K, Kitanaka S, Seo S. Inhibitory effect of stevioside on tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in two-stage carcinogenesis in mouse skin. Biol Pharm Bull . 2002;25(11):1488-1490.
43. Wong K, Lin JW, Liu JC, et al. Antiproliferative effect of isosteviol on angiotensin-II-treated rat aortic smooth muscle cells. Pharmacology . 2006;76(4):163-169.
44. Ghanta S, Banerjee A, Poddar A, Chattopadhyay S. Oxidative DNA damage preventative activity and antioxidant potential of Stevia rebaudiana (Bertoni) Bertoni, a natural sweetener. J Agric Food Chem . 2007;55(26):10962-10967.
45. Pinheiro CE, de Oliveira SS, da Silva SM, Poletto MI, Pinheiro CF. Effect of guaraná and Stévia rebaudiana Bertoni (leaves) extracts, and stevioside, on the fermentation and synthesis of extracellular insoluble polysaccharides of dental plaque [in Portuguese]. Rev Odontol Univ Sao Paulo . 1987;1(4):9-13.
46. Kelmer Bracht A, Alvarez M, Bracht A. Effects of Stevia rebaudiana natural products on rat liver mitochondria. Biochem Pharmacol . 1985;34(6):873-882.
47. Ishii EL, Bracht A. Stevioside, the sweet glycoside of Stevia rebaudiana , inhibits the action of atractyloside in the isolated perfused rat liver. Res Commun Chem Pathol Pharmacol . 1986;53(1):79-91.
48. Ishii-Iwamoto EL, Bracht A. Stevioside is not metabolized in the isolated perfused rat liver. Res Commun Mol Pathol Pharmacol . 1995;87(2):167-175.
49. Constantin J, Ishii-Iwamoto EL, Ferraresi-Filho O, Kelmer-Bracht AM, Bracht A. Sensitivity of ketogenesis and citric acid cycle to stevioside inhibition of palmitate transport across the cell membrane. Braz J Med Biol Res . 1991;24(8):767-771.
50. Curry LL, Roberts A, Brown N. Rebaudioside A: two-generation reproductive toxicity study in rats. Food Chem Toxicol . 2008;46(suppl 7):S21-S30.
51. Suttajit M, Vinitketkaumnuen U, Meevatee U, Buddhasukh D. Mutagenicity and human chromosomal effect of stevioside, a sweetener from Stevia rebaudiana Bertoni. Environ Health Perspect . 1993;101(suppl 3):53-56.
52. Oliveira-Filho RM, Uehara OA, Minetti CA, Valle LB. Chronic administration of aqueous extract of Stevia rebaudiana (Bert.) Bertoni in rats: endocrine effects. Gen Pharmacol . 1989;20(2):187-191.
53. Yodyingyuad V, Bunyawong S. Effect of stevioside on growth and reproduction. Hum Reprod . 1991;6(1):158-165.
54. Nikiforov AI, Eapen AK. A 90-day oral (dietary) toxicity study of rebaudioside A in Sprague-Dawley rats. Int J Toxicol . 2008;27(1):65-80.

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