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Stevia

Scientific Name(s): Stevia rebaudiana Bertoni
Common Name(s): Azucacaa, Ca-a-jhei, Ca-a-yupi, Caa-he-é, Candyleaf, Capim doce, Eira-caa, Erva doce, Honey leaf, Honey yerba, Ka'a he'ȇ, Kaa jheeé, PureVia, Rebiana, Stevia, Sweet herb of Paraguay, Sweet leaf of Paraguay, Sweetherb, Sweetleaf, Truvia, Yaa waan

Clinical Overview

Use

Stevia and its extracts contain sweetening constituents known as steviol glycosides that have been evaluated for their antioxidant, antidiabetic, antimicrobial, and antihypertensive effects. However, clinical trials are lacking to support any uses of stevia, except as a sweetening agent.

Dosing

The acceptable daily intake of stevia is 4 mg/kg.

Note: 1/4 tsp of ground stevia leaves is equal to 1 tsp of sugar.

A standard stevia leaf infusion (1 cup taken 2 to 3 times daily) has been used as a natural aid for diabetes and hypertension. Stevioside 250 to 500 mg capsules administered 3 times daily for 1 to 2 years has been used in clinical studies evaluating antihypertensive effects. A dosage of 1 g of stevia leaf powder for 60 days was used in a small study of patients with type 2 diabetes to reduce postprandial glucose levels.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

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

Interactions

Coadministration of stevia with drugs that inhibit organic anion transporter 3 (OAT3) uptake of stevia (eg, diclofenac, quercetin, telmisartan, mulberrin) may alter the renal clearance of stevia.

Adverse Reactions

No major adverse reactions have been documented.

Toxicology

Steviol glycosides have "generally recognized as safe" (GRAS) status according to the US Food and Drug Administration (FDA). However, stevia leaf and crude stevia extracts do not have GRAS status and are not FDA-approved for use in food.

Botany

Stevia is a branched, perennial shrub indigenous to northern South America and commercially grown in Central America, Israel, Thailand, and China.Lemus-Mondaca 2012, Taylor 2005 The plant can grow to 1 m in height; the leaves are 3 to 4 cm in lengthLemus-Mondaca 2012 and are used for their sweet taste.Taylor 2005 The stem is woody, and the flowers are small and white with a pale purple hue. The fruit is a spindle-shaped achene. The plant does not tolerate cold weather, particularly temperatures below 9°C (48°F).Lemus-Mondaca 2012

History

Stevia was historically used by the Guarani tribe of South America to sweeten tea. Native Brazilians and Paraguayans used the leaves of the plant as a sweetening agent. Europeans discovered stevia in the 16th century, and North American researchers began investigating its sweetening properties in the 20th century. Paraguayan botanist Moises Santiago de Bertoni described stevia in the late 1800s to early 1900s. It was not until 1905 that the plant was officially named S. rebaudiana.Momtazi-Borojeni 2017 Eight glycosides responsible for the plant's sweetness (eg, stevioside, rebaudioside) were discovered in 1931 by the French chemists M. Bridel and R. Lavieille.Bridel 1931, Carrera-Lanestosa 2017 Stevia extracts have been used in a few countries, including Japan and Paraguay, as a food and in medicine.

Chemistry

There are 220 to 230 species under the genus Stevia, but only S. rebaudiana and Stevia phlebophylla produce steviol glycosides.Ceunen 2013, Lemus-Mondaca 2012 The main glycosides of stevia include stevioside and rebaudioside. The glycosides have been analyzed by capillary electrophoresis. Rebaudioside A and steviolbioside have been isolated by high-performance liquid chromatography methods.Mauri 1996 Stevioside determination has been reported.Mitsuhashi 1975 Two glucosyl transferases acting on steviol and its glycosides have been isolated.Shibata 1995 Stevioside (6% to 18% in leaves) is the sweetest glycoside and was found to be 300 times sweeter than saccharose (sucrose) in one report.Samuelsson 1992 Stevioside contains 3 glucose molecules attached to an aglycone, the steviol moiety.Lemus-Mondaca 2012 All steviosides contain a common chemical core known as diterpene steviol, which is the final product of bacterial metabolism in the colon.Magnuson 2016 Steviosides are water soluble, heat stable, nonfermentable, and pH stable.Ferrazzano 2015, Momtazi-Borojeni 2017 Steviol contains a hydrophobic ring and a negative charge in the carboxylic group.Carrera-Lanestosa 2017 Steviol hydroxylation has been reported.Kim 1996 Sterols in stevia include stigmasterol, beta-sitosterol, and campesterol.D'Agostino 1984 Isolation of the principal sugars of stevia has also been reported.Aquino 1985 The leaves of stevia contain essential fats, tannins, and flavonoids, which are associated with a bitter aftertaste.Momtazi-Borojeni 2017

Stevia also contains certain vitamins (A, B, C), minerals (iron, zinc, calcium), electrolytes (sodium, potassium), proteins, and other elements.Lemus-Mondaca 2012, Taylor 2005 Additionally, it contains 9 essential amino acids (glutamic acid, aspartic acid, lysine, serine, isoleucine, alanine, proline, tyrosine, and methionine) and 6 fatty acids (palmitic, palmitoleic, stearic, oleic, linoleic, and linolenic acids).Momtazi-Borojeni 2017

Cultivation studies have been performed,Mitsuhashi 1975, Miyazaki 1978 as well as tissue culture experiments.Handro 1977

Uses and Pharmacology

Stevia has been used as a natural sweetener.Taylor 2005 The plant contains sweet ent-kaurene glycosides,Kinghorn 1984 with the most intense sweetness belonging to the species S. rebaudiana.Soejarto 1982 Stevia has been evaluated for sweetness in animal response testing.Jakinovich 1990 Stevioside, considered a high-intensity sweetener, has been reported to taste between 200 and 300 times sweeter than a sucrose 0.4% solution on a gram-for-gram basis.Brambilla 2014, Magnuson 2016 Approximately 80 to 125 mg of stevia would replace 25 g of sugar.Magnuson 2016 Stevia, a low-calorie natural sweetener, is used as a weight-loss aid to satisfy sugar cravings. In Japan, which is the largest consumer of stevia leaves, the plant is used to sweeten foods such as soy sauce, confections, and soft drinks, and as a replacement for aspartame and saccharin.Taylor 2005 Several animal and clinical studies examining the pharmacologic effects of stevia have used different stevia glycosides, which may contribute to conflicting study results. In addition, some earlier studies did not specify the glycoside content used. Stevioside appears to have more pharmacologic effect than commercially available sweeteners that primarily contain rebaudioside A.

Antihypertensive effects

Animal and in vitro data

The stevia plant may have cardiotonic actions, which normalize blood pressure and regulate heartbeat.Taylor 2005 The plant displayed vasodilatory actions in both normotensive and hypertensive animals.Melis 1996 Stevia has also produced decreases in blood pressure and has increased diuretic and natriuretic effects in rats.Melis 1991, Melis 1995 A study of stevioside in dogs indicated hypotensive effects.Liu 2003 However, a study with rebaudioside A indicated no effect on blood pressure in rats.Dyrskog 2005 Findings from an in vitro study suggest that isosteviol may inhibit angiotensin-II cell proliferation.Wong 2006

Clinical data

Data regarding antihypertensive effects of stevioside are conflicting. Several studies in normotensive and hypotensive patients indicate that rebaudioside A has no effect on blood pressure.Barriocanal 2008, Maki 2008, Maki 2008 However, a decrease in systolic and diastolic blood pressure was observed in patients with hypertension when given stevioside 250 mg 3 times daily for 1 year.Chan 2000 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.Ferri 2006 In a randomized, double-blind, placebo-controlled trial in 168 Chinese men and women, the effects of stevioside (500 mg 3 times daily for 2 years) on mild essential hypertension (defined as systolic blood pressure 140 to 159 mm Hg and diastolic blood pressure 90 to 99 mm Hg) were assessed. Significant reductions in mean systolic blood pressure (from 150 [standard deviation, 7.3] to 140 [6.8] mm Hg) and diastolic blood pressure (from 95 [4.2] to 89 [3.2] mm Hg) compared with baseline (P<0.05) and with placebo (P<0.05) were noted in patients receiving stevioside. These effects were noted around the first week of therapy and continued throughout the study. Stevioside was associated with significant improvements in quality-of-life scores compared with placebo (P<0.001).Hsieh 2003

Anti-inflammatory effects

Animal and in vitro data

In a study of mice, stevioside exerted anti-inflammatory effects against lipopolysaccharide-induced acute lung injury, possibly due to its ability to inhibit the NF-KB pathway.Yingkun 2013 In a similar study, a hydroalcoholic extract of stevia leaves (500 mg/kg) and stevioside (250 mg/kg) reduced hepatic levels of tumor necrosis factor alpha, interleukin 1 beta (IL-1beta), and IL-6 associated with lipopolysaccharide-induced acute liver injury in rats.Latha 2017

Antimicrobial effects

Animal and in vitro data

Stevia extract has exhibited strong bactericidal activity against a wide range of pathogenic bacteria, including certain Escherichia coli strains.Tomita 1997 An acetone extract of stevia exerted antibacterial effects against E. coli, Klebsiella pneumoniae, Bacillus cereus, Salmonella typhimurium, and Staphylococcus aureus.Moselhy 2016 Steviol was mutagenic toward Salmonella and other bacterial strains under various conditions and toward certain cell lines.Klongpanichpak 1997, Matsui 1996, Pezzuto 1985, Pezzuto 1986 Stevia may also be effective against Candida albicans and has shown some antirotavirus activity.Alfajaro 2014, Takahashi 2001, Taylor 2005 Stevia reduced the hemolytic capability of Listeria monocytogenes.Sansano 2017 Stevioside and rebaudioside A had varying effects on different strains of Lactobacillus reuteri.Deniņa 2014 A derivative of steviol was found to exert antituberculosis activity against Mycobacterium tuberculosis (strain H37Rv).Khaybullin 2012 A whole leaf extract of stevia was found to eliminate Borrelia burgdorferi spirochetes, the organism that causes Lyme disease.Theophilus 2015

Stevia has been evaluated for its effects against bacteria that cause tooth decay, as well as for nonacidogenic potential.Ruiz-Ruiz 2017 In an in vitro study, bacterial colonization with Streptococcus mutans was higher in a sucrose solution compared with stevioside and rebaudioside A solutions.Brambilla 2014 Stevia leaf extracts exerted antimicrobial effects against various strains of Streptococcus and Lactobacillus.Gamboa 2012

Clinical data

In an in vivo study of 20 healthy volunteers, rinsing with a solution of sucrose produced a lower pH value compared with rinses containing either stevioside or rebaudioside A. The stevia extract rinses were not fermented by S. mutans biofilm. The authors concluded that stevia extracts can be considered nonacidogenic, which can be helpful in the prevention of dental caries.Brambilla 2014

Antioxidant effects

In vitro data

In vitro results indicate S. rebaudiana may be useful as a potential source of natural antioxidants.Ghanta 2007 In one study, steviol glycosides counteracted oxidative stress by increasing reduced glutathione intracellular levels and upregulating expression and activity of superoxide dismutase and catalase.Prata 2017 Stevia's potential antioxidant properties have been attributed to its ability to scavenge free radicals.Lemus-Mondaca 2012, López 2016 In one study, an ethanolic extract of stevia exerted radical scavenging properties while stevioside did not.López 2016

Cardioprotective effects

Animal data

Both oral and direct perfusion of stevioside conferred cardioprotection following stunning of the hearts of rats. Specifically, there was an improvement in postischemic contractile recovery and total muscle economy with stevioside administration after severe stunning, whereas only total muscle economy improved after moderate stunning. Additionally, stevioside improved left ventricular end-diastolic pressure during both stunning models. These effects were suggested to be the result of stevioside's regulation of myocardial calcium homeostasis.Ragone 2017

Cytotoxic effects

Animal and in vitro data

In in vitro studies, steviol and isosteviol derivatives exerted antiproliferative effects against various cancer cell lines.Khaybullin 2014, Ukiya 2013, Yasukawa 2002 The ethanolic extract of stevia induced dose-dependent cell death in cervical (HeLa), pancreatic (Mia-PaCa-2), and colonic (HCT116) cell lines, with most activity occurring against cervical cancer cells. Stevioside exerted antiproliferative effects, but higher doses were needed compared with the ethanolic extract.López 2016 Steviol was associated with G2/M-phase arrest and induction of apoptosis in a dose-dependent fashion in MCF-7 human breast cancer cells.Gupta 2017

Conversely, in a murine study, stevia was not associated with any effects on pancreatic acinar carcinoma development, growth, or mortality.Dooley 2017 An in vitro study demonstrated that stevioside and steviol did not exert cytotoxic effects against human colon carcinoma cell lines (Caco-2).Boonkaewwan 2013

An ethanolic extract of stevia and stevioside given 48 hours after cisplatin resulted in attenuation of cisplatin-induced nephrotoxicity through suppression of oxidative stress, inflammation, and apoptosis. This mechanism involved suppression of extracellular signal-regulated kinases 1 and 2, signal transducer and activator of transcription 3, and nuclear factor kappa B (NF-KB).Potočnjak 2017

Diabetes

Rebaudioside A undergoes metabolism to stevioside by colonic bacteria and then further decomposes to glucose and steviol. The resulting glucose is consumed by the gut bacteria and not absorbed into circulation, and therefore does not raise blood glucose. Reports suggest that steviosides stimulate the release of insulin.Momtazi-Borojeni 2017

Animal, in vitro, and in vivo data

Steviol, isosteviol, and glucosylsteviol decreased glucose production in rat renal cortical tubules.Yamamoto 1985 Stevioside given orally lowered blood glucose in type 2 diabetic fatty rats.Dyrskog 2005, Lailerd 2004 However, rebaudioside A did not affect glycemic control after 8 weeks of treatment in type 2 diabetic rats.Dyrskog 2005 Oral use of stevia extract in combination with chrysanthemum to manage hyperglycemia has been discussed.White 1994 In a study of rats, stevia 400 mg/kg/day for 28 days resulted in significant reductions in fasting blood sugar, triglycerides, malondialdehyde, and liver function tests in treated rats (P<0.05). There was also an increase in PPAR-gamma and insulin mRNA levels associated with stevia administration (P<0.05).Assaei 2016 A study in hyperglycemic rabbits found an aqueous extract of stevia lowered total cholesterol and low-density lipoprotein cholesterol, as well as increased high-density lipoprotein cholesterol.Aghajanyan 2017

In another study of mice, an aqueous stevioside solution administered as 20 mg/kg orally significantly inhibited the rise in glucose following an oral glucose tolerance test (P<0.05).Ilić 2017 An in vivo study suggests that similar to insulin, stevia might be capable of modulating glucose transporter–type translocation through the PI3K/Akt pathway.Rizzo 2013 Another study in mice showed reductions in blood glucose with administration of stevia leaf powder and its polyphenol extract, but not with stevia fiber. In the same study, stevia exerted both renoprotective and hepatoprotective effects.Shivanna 2013

In a study of rats, minor steviol glycosides (ie, dulcoside A; rebaudioside B, C, or D; steviolbioside) did not reduce glucose levels after 28 days of administration, as measured using the intraperitoneal glucose tolerance test.Aranda-González 2016

Clinical data

Studies with rebaudioside A indicate no effect on blood glucose. In a 16-week study in 122 patients with type 2 diabetes, rebaudioside A 500 mg twice a day with meals did not produce statistically significant changes from baseline versus placebo in hemoglobin A1c (HbA1c), fasting glucose, insulin, or C-peptide.Maki 2008 In another study, a lack of pharmacological effect of steviol glycosides was demonstrated when 72 patients were divided into 3 groups: patients with type 1 diabetes, those with type 2 diabetes, and those without diabetes. After receiving steviol glycosides 250 mg 3 times a day for 3 months, no change in HbA1c was observed.Barriocanal 2008 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. In a small study of patients with type 2 diabetes, 1 g of stevia leaf powder reduced fasting and postprandial glucose levels after 60 days of administration.Ritu 2016 In as study of 16 healthy volunteers, aqueous extracts of the plant increased glucose tolerance and markedly decreased plasma glucose levels.Curi 1986 In an acute crossover study of 12 patients with type 2 diabetes, postprandial blood glucose was decreased following oral supplementation with 1 g capsules (consisting of 91% stevioside) with a meal.Gregersen 2004 In a study of 10 healthy males, replacing one sweetened beverage per day with one containing a nonnutritive sweetener such as stevia did not result in differences in 24-hour glucose profile, incremental area under the curve, or total area under the curve for glucose.Tey 2017

Hepatic effects

Animal data

Certain metabolic aspects of stevioside have been described, including rat liver effectsIshii 1986, Ishii-Iwamoto 1995, Kelmer Bracht 1985 and cell membrane transport.Constantin 1991

An acetone extract of stevia was found to suppress AST and ALT elevations in rats injected with carbon tetrachloride.Moselhy 2016

Immunomodulating effects

Animal and in vitro data

Stevioside has demonstrated immunomodulating effects in rats and in cell lines.Boonkaewwan 2006, Boonkaewwan 2008, Boonkaewwan 2013, Sehar 2008

Dosing

The acceptable daily intake of stevia is 4 mg/kg.Ashwell 2015, Fitch 2012

Note: 1/4 tsp of ground stevia leaves is equal to 1 tsp of sugar.Taylor 2005

A standard stevia leaf infusion (1 cup taken 2 to 3 times daily) has been used as a natural aid for diabetes and hypertension.Taylor 2005 Stevioside 250 to 500 mg capsules administered 3 times daily for 1 to 2 years has been used in clinical studies evaluating antihypertensive effects.Chan 2000, Hsieh 2003 A dosage of 1 g of stevia leaf powder for 60 days was used in a small study of patients with type 2 diabetes to reduce postprandial glucose levels.Ritu 2016

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 observed.Curry 2008 Similarly, an aqueous extract of stevia at varying concentrations (0.2%, 1%, or 10%) for 60 days did not negatively impact pregnancies of female rats, as noted by the number of corpus lutea, implanted versus dead fetuses, and size of the fetuses.Saenphet 2006 In hamsters, doses of stevioside up to 2.5 g/kg/day did not have any impact on growth, fertility, or pregnancy.Yodyingyuad 1991

Interactions

One study found that steviol glucuronide was not a substrate of the human efflux transporters P-glycoprotein, breast cancer resistance protein, multidrug resistance protein 2, or multidrug and toxin extrusion protein 1, and therefore would not have any anticipated interactions with drugs impacted by these transporters. However, OAT3, an uptake transporter in the kidney, plays an important role in the uptake of steviol glucuronide. Drugs like quercetin, telmisartan, diclofenac, and mulberrin were found to inhibit the OAT3-mediated uptake of steviol glucuronide, potentially altering its renal clearance.Wang 2015 Theoretically, given stevia's potential blood glucose– and blood pressure–lowering effects, coadministration of glucose-lowering drugs or antihypertensives could have additive effects.Taylor 2005

Adverse Reactions

No major contraindications, warnings, or adverse reactions have been documented. Some sources have suggested a potential for hypersensitivity or allergic reactions with products belonging to the Asteraceae family. However, a review of the literature reveals little documented scientific evidence linking stevia to hypersensitivity or allergic reactions.Urban 2015

Toxicology

Stevia is not mutagenic or genotoxic.Taylor 2005 Steviol glycosides have been assigned GRAS status by the FDA. However, stevia leaf and crude stevia extracts are not considered GRAS and are not FDA-approved for use in food.FDA 2017, Fitch 2012 In one report, constituents of stevioside and steviol were not mutagenic in vitro.Suttajit 1993 Stevioside has been found to be nontoxic in acute toxicity studies in a variety of laboratory animals.Taylor 2005 Long-term administration of stevia to male rats had no effect on fertility compared to controls.Oliveira-Filho 1989 Another report concluded that stevioside in daily doses up to 2.5 g/kg did not affect growth or reproduction in hamsters of both sexes.Yodyingyuad 1991 An ethanolic extract of stevia leaves, when given at varying concentrations daily for 90 days, did not cause behavioral, hematological, clinical, or histopathological changes in rats.Zhang 2017 Rebaudioside A showed no toxic effects when given to rats at dosages up to 2,000 mg/kg/day for 90 days.Nikiforov 2008 In one study, the no-observed-adverse-effect level in rats receiving rebaudioside A for 4 weeks was determined to be 100,000 ppm. Body weight gains were lower at higher doses. In another similar 13-week study, the no-observed-adverse-effect level was determined to be 50,000 ppm or 4,161 mg/kg/day in male rats and 4,645 mg/kg/day in female rats.Curry 2008

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