Stevia Health Benefits and Side Effects |
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Introduction
Stevia rebaudiana (Stevia) originally came from the rain forests of Brazil and Paraguay, and
now we also find it in South East Asia. The use of Stevia as a food sweetener is popular in
Asia and North America. Stevia accounts for about 40% of the sweetener market in Japan
and is widely used in South America. [5]
Stevia is believed to benefit people suffered from high blood pressure and help control
glucose levels; it has been used as a non-sugar sweetener for food and drinks and as
remedy for diabetes [1-3]. Its ingredient, stevoside, is about 100-200 times sweeter than
sugar, while, rebaudioside A, a steviol glycoside, sweetener is reported to be 250-450 times
sweeter than sucrose. [A2]
Active Ingredients [7, 12]
Stevia leave contains various glycosides including stevoside. Stevoside is a natural
sweetener. It is a a diterpenic carboxylic alcohol with three glucose molecules.
The sterol fraction of Stevia rebaudiana Bertoni contains, essentially, the following sterols:
stigmasterol (45,8%), beta-sitosterol (39,4%) and campesterol (13,1%).
Rebaudioside A (CAS Reg. No. 58543-16-1), a glycoside of steviol, is identified as 13-[(2-O-
β-D-glucopyranosyl-3-O-β-D-glucopyranosyl-β-D-glucopyranosyl)oxy] kaur-16-en-18-oic acid
β-D-glucopyranosyl ester. (See, section “Is Stevia rebaudiana (Bertoni) Bertoni a GRAS
substance?)
Specifications:
Whole Earth’s Specfications
Whole Earth provides specifications for rebaudioside A that include the content of
rebaudioside A (≥95% by weight (w/w)) and limits for stevioside (<2% w/w), steviol (<0.005%
w/w), moisture (<5%), lead (<1 mg/kg), arsenic (<1 mg/kg), cadmium (<1 mg/kg), residual
methanol (<300 mg/kg), residual ethanol (<1g/kg), and microbial contaminants (within
specified limits).
Stability
An earlier study suggested rebaudioside A to be unstable to sunlight exposure, while the
structurally homologous stevioside is stable. Researchers from Coca-Cola Company and
Cargill, Inc. replicated the earlier study and found no significant photodegradation
for either rebaudioside A or stevioside. In fact, the Coca-Cola Company and Cargill, Inc. have
initiated the commercialization of the Stevia rebaudiana (Bertoni) derived sweetener
rebaudioside A. Efforts were focused on photo-stability of a high purity rebaudioside A
(>97% by HPLC; also known as rebiana) in rebiana-sweetened beverages. [A5]
Cargill’s Specifications
Cargill provides specifications for rebaudioside A that include the content of rebaudioside A
(≥97% by weight (w/w)) and limits for other steviol glycosides (≤3% w/w), lead (≤1
milligrams per kilogram (mg/kg)), residual methanol (≤0.02% w/w), residual ethanol (≤0.5%
w/w), and microbial contaminants (within specified limits).
Extraction Methods
Jaitak V, Bikram Singh B, Kaul VK. from Institute of Himalyan Bioresource Technology, India,
extracted active ingredients from dried and powdered leaves of Stevia rebaudiana by
conventional, ultrasound and microwave-assisted techniques using methanol, ethanol and
water as single solvents as well as in binary mixtures.
Conventional cold extraction was performed at 25 degrees C for 12 h; this method yielded
6.54 and 1.20% of stevioside and rebaudioside-A.
Ultrasound extraction was carried out at temperature of 35 +/- 5 degrees C for 30 min. This
method yielded 4.20 and 1.98% of stevioside and rebaudioside-A.
Microwave-assisted extraction was carried out at a power level of 80 W for 1 min at 50
degrees C. This method yielded 8.64 and 2.34% of stevioside and rebaudioside-A,
respectively. [A3]
Whole Earth’s Method
Rebaudioside A (CAS Reg. No. 58543-16-1) is obtained from the leaves of S. rebaudiana
(Bertoni) Bertoni by extraction with water, ethanol, or methanol and is concentrated with an
adsorption resin to trap the desired steviol glycosides. The resin is washed with ethanol or
methanol to release the glycosides. The elutant is de-colorized and de-salted by ion
exchange and microfiltration to improve the purity of rebaudioside A. Recrystallization with
alcohol (methanol or ethanol) and water mixtures results in a final product with a purity of
greater than 95 percent. The residual ethanol or methanol is removed and the product is
then spray-dried or granulated.
Cargill’s Method
Rebaudioside A is obtained from the leaves of S. rebaudiana (Bertoni) Bertoni. The leaves
are dried, crushed and extracted with water, followed by precipitation and filtration of the
extract. An adsorption resin is used to trap the steviol glycosides of the leaf extract. The resin
is washed with methanol or ethanol to release the glycosides. The elutant is then
concentrated by evaporation or with an adsorption resin, followed by drying to yield a "steviol
glycoside primary extract." The primary extract is dissolved in a water-ethanol solvent mixture
and further processed by filtration, crystallization, and centrifugation steps. The resulting
preparation of crystals is rinsed with ethanol and vacuum-dried to yield the final
rebaudioside A product.
How may stevia affect our health? - Benefits and Side Effects
Chatsudthipong V and Muanprasat C., Mahidol University, Thailand, stated that stevioside
along with related compounds, which include rebaudioside A,steviol and isosteviol may offer
therapeutic benefits, as they have anti-hyperglycemic, anti-hypertensive, anti-inflammatory,
anti-tumor, anti-diarrheal, diuretic, and immunomodulatory actions in their review article. [A4]
Antioxidative Activities
Ethanolic leaf extract of Stevia rebaudiana was found to be a strong antioxidant. [A1] One
may expect that Stevia may carry a lot of health benefits for us.
Blood Pressure
Physiological and pharmacological experiments have suggested that stevioside from the
leaves of Stevia rebaudiana acts as a typical systemic vasodilator. Researchers found that
stevioside (from Stevia rebaudiana leaves) mediated vaso-relexation effect through Ca(2+)
influx inhibition. [11]
Rat Studies
Melis MS. demonstrated that stevioside (from Stevia rebaudiana leaves) provoked
hypotension (blood pressure lowering effect), diuresis and natriuresis in both the normal
and hypertensive rats. Normal rats presented an increase in renal plasma flow (RPF) and
glomerular filtration rate (GFR) constant following stevioside administration. The
last effect is in part due to vasodilation of both the afferent and efferent arterioles. [8]
Chan P et al demonstrated the blood pressure lowering effect of stevioside (from Stevia
rebaudiana leaves) on both systolic and diastolic blood pressure of rats. It is in a dose-
proportional fashion. They found no significant changes in serum dopamine,
norepinephrine and epinephrine levels 60 min after intravenous injection of stevioside
100 mg/kg in anesthetized rats. [10]
Drinking of 0.1% stevioside (from Stevia rebaudiana) solution in mature spontaneously
hypertensive rats could have antihypertensive (blood pressure lowering) effect and also
prevented hypertension (high blood pressure) in immature spontaneously hypertensive rats.
[12]Stevioside (from Stevia rebaudiana leaves) caused vasorelaxation via an inhibition of Ca
(2+) influx into the blood vessel in a study of normal rats. [11]
Dog Studies
Stevioside (from the leaves of Stevia rebaudiana) also showed significant hypotensive
effects in renal hypertensive dogs, in a dose-dependent manner and its hypotensive (blood
pressure lowering effect) mechanism may be probably due to inhibition of the Ca(2+) influx.
[13]
Clinical Studies
Chan P et al demonstrated the antihypertensive (blood pressure lowering) effect of
stevioside (from Stevia rebaudiana leaves) in a 3-month, multi-center, randomized, double-
blinded, placebo-controlled study. [9]
A 2-year study of 168 patients suffered from hypertension (aged 20-75) demonstrated that
oral stevioside (from Stevia rebaudiana Bertoni) decreased systolic and diastolic blood
pressure without significant adverse effects [14]
Glucose Tolerance
In vitro Study
Jeppesen PB and co-workers at Aarhus University Hospital, Denmark demonstrated that
stevioside and steviol stimulated insulin secretion via a direct action on beta cells. [16]
Animal Studies
In 2002, Jeppesen PB et al reportedthat stevioside had antihyperglycaemic, insulinotropic,
and glucagonostatic activities from a study of type 2 diabetic rat. [17]
Chen TH and co-workers found that stevioside was able to regulate blood glucose levels by
enhancing not only insulin secretion, but also insulin utilization in insulin-deficient rats; the
latter was due to decreased phosphoenol pyruvate carboxykinase gene expression in rat
liver by stevioside's action of slowing down gluconeogenesis. [19]
Clinical Studies
In 1986, Curi R et al, Universidade de Maringa, Brasil, demonstrated that aqueous extracts
of Stevia rebaudiana leaves could increase glucose tolerance in a study of 16 healthy
human subjects. [15]
In 2004, Jeppesen PB et al finally studied the anti-hyperglycaemic properties of stevioside
(from stevia) in human subjects. They recruited 12 patients suffered from Type 2 diabetes
and successfully demonstrated that stevioside reduces postprandial blood glucose levels in
the patients. [18]
Chatsudthipong V and Muanprasat C., Mahidol University, Thailand, stated, “It is of interest to
note that their effects on plasma glucose level and blood pressure are only observed when
these parameters are higher than normal.” [A4]
Whole Earth Sweetener Company LCC filed a GRAS application for rebaudioside A in 2008
(GRN No. 252). In the application, Whole Earth discusses published clinical studies of
stevioside, other steviol glycosides and crude stevia extracts in diabetics and nondiabetics
and in hypertensive and normotensive subjects. Whole Earth concludes that stevioside, at
levels up to 30 mg/kg bw/day, does not affect blood glucose levels. Whole Earth also
concludes that, although stevioside administration was associated with clinically relevant
reductions in blood pressure for individuals with moderately severe hypertension who were
not on antihypertensive therapy, such reductions in blood pressure were not observed in
individuals with normal blood pressure or in individuals with hypertension receiving
antihypertensive medication.
Cancer
Stevia may have anti-cancer activities, but the evidence is very limited. Yasukawa K and his
co-workers isolated four steviol (ent-kaurene-type diterpenoid) glycosides, stevioside,
rebaudiosides A and C, and dulcoside A) from Stevia rebaudiana BERTONI and they found a
strong inhibitory effect of these steviols on 12-O-tetradecanoylphorbol-13-
acetate (TPA)-induced inflammation in mice. [20]
Infection
Stevia may have anti-microbial activities, the scientific evidence is very limited. Amaro-Luis et
al isolated ombuoside from aerial parts of Stevia triflora and prepared derivatives of it- octa-
acetylombuoside, ombuine and retusine. They found these compounds were against a few
types of gram positive bacteria. [21]
Pharmacokinetics
Rats received a single oral administration of either steviol or stevia mixture; a peak steviol
plasma concentration appeared 15 min after its oral administration. However, after oral
administration of stevia mixture, the steviol concentration in plasma increased steadily over
8 h, [22]
Dosage and Side Effects --- Is Stevia safe?
Within the normal range, Stevia probably is safe, without serious adverse or toxic side
effects [4,6,9]. However, most studies are actually done with rebaudioside A.
Curry LL and Roberts A, Cargill Inc., evaluated the safety of rebaudioside A in two oral toxicity
studies of Wistar rats. One is 4 weeks long with a dosing range of 25,000 to 100,000 ppm
and the other is 13 weeks long with a dosing range of 25,000 and 50,000ppm. They found
reductions in body weight gains, overall normal hepatic functions, no significantly changes
in organs. [A6]
Rebaudioside A was non-mutagenic in an Ames test using Salmonella typhimurium and
Escherichia coli, in a chromosomal aberration test using Chinese Hamster V79 cells and in
a mouse lymphoma assay using L5178Y+/- cells, all studies were conducted at
concentrations up to 5000 microg/ml, with and without metabolic activation. Also,
Rebaudioside A was non-genotoxic in a bone marrow micronucleus test in mice at doses
up 750 mg/kg bw and in an unscheduled DNA synthesis test in rats at 2000 mg/kg bw. [A2]
Whole Earth provides an estimated daily intake (EDI) of rebaudioside A, based on the
intended food categories and use levels and data from the most recent National Health and
Nutrition Examination Survey (NHANES 2003-2004), which includes table top sweeteners.
Whole Earth calculates the total mean and 90th percentile EDI for eaters only, aged 2 years
and older, as 2 mg/kg body weight per day (mg/kg bw/d) and 5 mg/kg bw/d, respectively. The
range of exposures among population subgroups (age, gender and sex) is similar, ranging
from 1.2 to 2.4 mg/kg bw/day (mean) and 2.4 to 5.6 mg/kg bw/day (90th percentile). Whole
Earth states that the use of rebaudioside A is self-limiting in that high levels cause a food to
be unpalatable (GRN No. 252).
But, you may also see there are tons of complains on the side effects of Stevia, especially,
when it is combined with certain kinds of drinks and medicine. Do not overdose yourself.
Discuss with your doctor before taking any supplement including stevia, rebaudioside A etc.
Is Stevia rebaudiana (Bertoni) Bertoni a GRAS substance?
No, only one of its active ingredients is considered as a GRAS substance and it is
rebaudioside A. (GRN No. 252, 253 and 278). In addition, there is a limitation of its use and
amounts in products. Here is a summary:
1. GRN 000252 (Applicant: Whole Earth Sweetener Company LCC, Chicago, Date of Filing:
5/13/2008, Date of Closure: December 17, 2008)
Rebaludioside A is used as a sweetener in a variety of food categories-- cereals (oatmeal,
cold cereal, cereal bars) 150 mg/kg, ready-to-drink teas 90 – 450 mg/kg, fruit juice drinks
150 – 500 mg/kg, diet soft drinks 150 – 500 mg/kg, energy drinks 150 mg/kg and flavored
waters 150 mg/kg. And, it is also used a sweetener, formulated to provide 30 milligrams of
rebaudioside A per gram of finished product.
As part of its notice, Whole Earth includes the report of a panel of individuals (Whole Earth's
GRAS panel) who evaluated the data and information that are the basis for Whole Earth's
GRAS determination. Whole Earth considers the members of its GRAS panel to be qualified
by scientific training and experience to evaluate the safety of substances added to food.
Whole Earth's GRAS panel evaluated the identity, method of manufacture, product
specifications, and the potential exposure resulting from the intended uses of rebaudioside
A as well as published and unpublished studies on rebaudioside A and related substances.
Based on this review, Whole Earth's GRAS panel concluded that rebaudioside A, produced
consistent with good manufacturing practice and meeting appropriate purity and food grade
specifications, is GRAS, by scientific procedures, under the conditions of its intended use.
2. GRN 000253 (Applicant: Cargill, Inc., MN 55345, Date of Filing: 5/20/2008, Date of
Closure: December 17, 2008)
Rebaludioside A is used as a general-purpose sweetener in foods, excluding meat and
poultry products, provided that food standards of identity do not preclude such use, at levels
determined by current good manufacturing practices.
This article is not a medical advice; it is for reference only. Discuss with your doctor before taking any
supplements, herbs, medicine. Overdose of supplements can cause serious side effects. All rights
reserved.
References
[1] Leung AY, Foster S. Encyclopedia of Common Natural Ingredients Used in Foods, Drugs, and
Cosmetics, 2d ed. New York: John Wiley & Sons, 1996, 478–80.[2] Curi R, Alvarez M, Bazotte RB, et al.
Effect of Stevia rebaudiana on glucose tolerance in normal adult humans. Braz J Med Biol Res 1986;19:
771–4. [3] 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;17:940.[4] Leung AY, Foster S. Encyclopedia of Common Natural Ingredients Used in
Foods, Drugs, and Cosmetics, 2d ed. New York: John Wiley & Sons, 1996, 478–80. [5] Blumenthal M.
FDA rejects AHPA stevia petition. Whole Foods 1994:Apr;61–4. [6] Geuns JM. Stevioside.
Phytochemistry. 2003 Nov;64(5):913-21. [7] D'Agostino M, De Simone F, Pizza C, Aquino R. Sterols in
Stevia rebaudiana Bertoni. Boll Soc Ital Biol Sper. 1984 Dec 30;60(12):2237-40.[8] Melis MS Stevioside
effect on renal function of normal and hypertensive rats. J Ethnopharmacol. 1992 Jun;36(3):213-7.[9]
Chan P et al A double-blind placebo-controlled study of the effectiveness and tolerability of oral stevioside
in human hypertension. Br J Clin Pharmacol. 2000 Sep;50(3):215-20.[10] Chan P et al, The effect of
stevioside on blood pressure and plasma catecholamines in spontaneously hypertensive rats. Life Sci.
1998;63(19):1679-84. [11] Lee CN et al Inhibitory effect of stevioside on calcium influx to produce
antihypertension. Planta Med. 2001 Dec;67(9):796-9].[12] Hsu YH et al, Antihypertensive effect of
stevioside in different strains of hypertensive rats. Zhonghua Yi Xue Za Zhi (Taipei). 2002 Jan;65(1):1-6. [13]
Liu JC et al Mechanism of the antihypertensive effect of stevioside in anesthetized dogs. Pharmacology.
2003 Jan;67(1):14-20.[14] Hsieh MH et al Efficacy and tolerability of oral stevioside in patients with mild
essential hypertension: a two-year, randomized, placebo-controlled study. Clin Ther. 2003 Nov;25(11):
2797-808.[15] Curi R et al, Effect of Stevia rebaudiana on glucose tolerance in normal adult humans.
Braz J Med Biol Res. 1986;19(6):771-4.[16] Jeppesen PB et al, Stevioside acts directly on pancreatic beta
cells to secrete insulin: actions independent of cyclic adenosine monophosphate and adenosine
triphosphate-sensitive K+-channel activity. Metabolism. 2000 Feb;49(2):208-14.[17] Jeppesen PB et al,
Stevioside induces antihyperglycaemic, insulinotropic and glucagonostatic effects in vivo: studies in the
diabetic Goto-Kakizaki (GK) rats. Phytomedicine. 2002 Jan;9(1):9-14. 18] Gregersen S, Jeppesen PB, Holst
JJ, Hermansen K. Antihyperglycemic effects of stevioside in type 2 diabetic subjects. Metabolism. 2004
Jan;53(1):73-6.[19] Chen TH et al Mechanism of the hypoglycemic effect of stevioside, a glycoside of
Stevia rebaudiana. Planta Med. 2005 Feb;71 (2):108-13.[20] Yasukawa K et al Inhibitory effect of
stevioside on tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in two-stage carcinogenesis in
mouse skin. Pharm Bull. 2002 Nov;25(11):1488-90.[21] Amaro-Luis et al Isolation, identification and
antimicrobial activity of ombuoside from Stevia triflora. Ann Pharm Fr. 1997;55(6):262-8[22] Koyama E et
al. Absorption and metabolism of glycosidic sweeteners of stevia mixture and their aglycone, steviol, in rats
and humans. Food Chem Toxicol. 2003 Jun;41(6):875-83. [23] Sekihashi K et al Genotoxicity studies of
stevia extract and steviol by the comet assay, J Toxicol Sci. 2002 Dec;27 Suppl 1:1-8.[24] Melis MS.
Effects of chronic administration of Stevia rebaudiana on fertility in rats. J Ethnopharmacol. 1999 Nov 1;67
(2):157-61. [A1] Shukla S, Mehta A, Bajpai VK, Shukla S. In vitro antioxidant activity and total phenolic
content of ethanolic leaf extract of Stevia rebaudiana Bert. Food Chem Toxicol. 2009 Sep;47(9):2338-43.
Epub 2009 Jun 21. [A2] Williams LD, Burdock GA. Genotoxicity studies on a high-purity rebaudioside A
preparation. Food Chem Toxicol. 2009 Aug;47(8):1831-6. Epub 2009 May 8. [A3] Jaitak V, Bikram Singh
B, Kaul VK. An efficient microwave-assisted extraction process of stevioside and rebaudioside-A from
Stevia rebaudiana (Bertoni). Phytochem Anal. 2009 May;20(3):240-5. [A4] Chatsudthipong V, Muanprasat
C. Stevioside and related compounds: therapeutic benefits beyond sweetness. Pharmacol Ther. 2009 Jan;
121(1):41-54. Epub 2008 Oct 27. [A5] Clos JF, DuBois GE, Prakash I. Photostability of rebaudioside A and
stevioside in beverages. J Agric Food Chem. 2008 Sep 24;56(18):8507-13. Epub 2008 Aug 22. [A6] Curry
LL, Roberts A. Subchronic toxicity of rebaudioside A. Food Chem Toxicol. 2008 Jul;46 Suppl 7:S11-20.
Epub 2008 May 16.
Stevia rebaudiana (Stevia) originally came from the rain forests of Brazil and Paraguay, and
now we also find it in South East Asia. The use of Stevia as a food sweetener is popular in
Asia and North America. Stevia accounts for about 40% of the sweetener market in Japan
and is widely used in South America. [5]
Stevia is believed to benefit people suffered from high blood pressure and help control
glucose levels; it has been used as a non-sugar sweetener for food and drinks and as
remedy for diabetes [1-3]. Its ingredient, stevoside, is about 100-200 times sweeter than
sugar, while, rebaudioside A, a steviol glycoside, sweetener is reported to be 250-450 times
sweeter than sucrose. [A2]
Active Ingredients [7, 12]
Stevia leave contains various glycosides including stevoside. Stevoside is a natural
sweetener. It is a a diterpenic carboxylic alcohol with three glucose molecules.
The sterol fraction of Stevia rebaudiana Bertoni contains, essentially, the following sterols:
stigmasterol (45,8%), beta-sitosterol (39,4%) and campesterol (13,1%).
Rebaudioside A (CAS Reg. No. 58543-16-1), a glycoside of steviol, is identified as 13-[(2-O-
β-D-glucopyranosyl-3-O-β-D-glucopyranosyl-β-D-glucopyranosyl)oxy] kaur-16-en-18-oic acid
β-D-glucopyranosyl ester. (See, section “Is Stevia rebaudiana (Bertoni) Bertoni a GRAS
substance?)
Specifications:
Whole Earth’s Specfications
Whole Earth provides specifications for rebaudioside A that include the content of
rebaudioside A (≥95% by weight (w/w)) and limits for stevioside (<2% w/w), steviol (<0.005%
w/w), moisture (<5%), lead (<1 mg/kg), arsenic (<1 mg/kg), cadmium (<1 mg/kg), residual
methanol (<300 mg/kg), residual ethanol (<1g/kg), and microbial contaminants (within
specified limits).
Stability
An earlier study suggested rebaudioside A to be unstable to sunlight exposure, while the
structurally homologous stevioside is stable. Researchers from Coca-Cola Company and
Cargill, Inc. replicated the earlier study and found no significant photodegradation
for either rebaudioside A or stevioside. In fact, the Coca-Cola Company and Cargill, Inc. have
initiated the commercialization of the Stevia rebaudiana (Bertoni) derived sweetener
rebaudioside A. Efforts were focused on photo-stability of a high purity rebaudioside A
(>97% by HPLC; also known as rebiana) in rebiana-sweetened beverages. [A5]
Cargill’s Specifications
Cargill provides specifications for rebaudioside A that include the content of rebaudioside A
(≥97% by weight (w/w)) and limits for other steviol glycosides (≤3% w/w), lead (≤1
milligrams per kilogram (mg/kg)), residual methanol (≤0.02% w/w), residual ethanol (≤0.5%
w/w), and microbial contaminants (within specified limits).
Extraction Methods
Jaitak V, Bikram Singh B, Kaul VK. from Institute of Himalyan Bioresource Technology, India,
extracted active ingredients from dried and powdered leaves of Stevia rebaudiana by
conventional, ultrasound and microwave-assisted techniques using methanol, ethanol and
water as single solvents as well as in binary mixtures.
Conventional cold extraction was performed at 25 degrees C for 12 h; this method yielded
6.54 and 1.20% of stevioside and rebaudioside-A.
Ultrasound extraction was carried out at temperature of 35 +/- 5 degrees C for 30 min. This
method yielded 4.20 and 1.98% of stevioside and rebaudioside-A.
Microwave-assisted extraction was carried out at a power level of 80 W for 1 min at 50
degrees C. This method yielded 8.64 and 2.34% of stevioside and rebaudioside-A,
respectively. [A3]
Whole Earth’s Method
Rebaudioside A (CAS Reg. No. 58543-16-1) is obtained from the leaves of S. rebaudiana
(Bertoni) Bertoni by extraction with water, ethanol, or methanol and is concentrated with an
adsorption resin to trap the desired steviol glycosides. The resin is washed with ethanol or
methanol to release the glycosides. The elutant is de-colorized and de-salted by ion
exchange and microfiltration to improve the purity of rebaudioside A. Recrystallization with
alcohol (methanol or ethanol) and water mixtures results in a final product with a purity of
greater than 95 percent. The residual ethanol or methanol is removed and the product is
then spray-dried or granulated.
Cargill’s Method
Rebaudioside A is obtained from the leaves of S. rebaudiana (Bertoni) Bertoni. The leaves
are dried, crushed and extracted with water, followed by precipitation and filtration of the
extract. An adsorption resin is used to trap the steviol glycosides of the leaf extract. The resin
is washed with methanol or ethanol to release the glycosides. The elutant is then
concentrated by evaporation or with an adsorption resin, followed by drying to yield a "steviol
glycoside primary extract." The primary extract is dissolved in a water-ethanol solvent mixture
and further processed by filtration, crystallization, and centrifugation steps. The resulting
preparation of crystals is rinsed with ethanol and vacuum-dried to yield the final
rebaudioside A product.
How may stevia affect our health? - Benefits and Side Effects
Chatsudthipong V and Muanprasat C., Mahidol University, Thailand, stated that stevioside
along with related compounds, which include rebaudioside A,steviol and isosteviol may offer
therapeutic benefits, as they have anti-hyperglycemic, anti-hypertensive, anti-inflammatory,
anti-tumor, anti-diarrheal, diuretic, and immunomodulatory actions in their review article. [A4]
Antioxidative Activities
Ethanolic leaf extract of Stevia rebaudiana was found to be a strong antioxidant. [A1] One
may expect that Stevia may carry a lot of health benefits for us.
Blood Pressure
Physiological and pharmacological experiments have suggested that stevioside from the
leaves of Stevia rebaudiana acts as a typical systemic vasodilator. Researchers found that
stevioside (from Stevia rebaudiana leaves) mediated vaso-relexation effect through Ca(2+)
influx inhibition. [11]
Rat Studies
Melis MS. demonstrated that stevioside (from Stevia rebaudiana leaves) provoked
hypotension (blood pressure lowering effect), diuresis and natriuresis in both the normal
and hypertensive rats. Normal rats presented an increase in renal plasma flow (RPF) and
glomerular filtration rate (GFR) constant following stevioside administration. The
last effect is in part due to vasodilation of both the afferent and efferent arterioles. [8]
Chan P et al demonstrated the blood pressure lowering effect of stevioside (from Stevia
rebaudiana leaves) on both systolic and diastolic blood pressure of rats. It is in a dose-
proportional fashion. They found no significant changes in serum dopamine,
norepinephrine and epinephrine levels 60 min after intravenous injection of stevioside
100 mg/kg in anesthetized rats. [10]
Drinking of 0.1% stevioside (from Stevia rebaudiana) solution in mature spontaneously
hypertensive rats could have antihypertensive (blood pressure lowering) effect and also
prevented hypertension (high blood pressure) in immature spontaneously hypertensive rats.
[12]Stevioside (from Stevia rebaudiana leaves) caused vasorelaxation via an inhibition of Ca
(2+) influx into the blood vessel in a study of normal rats. [11]
Dog Studies
Stevioside (from the leaves of Stevia rebaudiana) also showed significant hypotensive
effects in renal hypertensive dogs, in a dose-dependent manner and its hypotensive (blood
pressure lowering effect) mechanism may be probably due to inhibition of the Ca(2+) influx.
[13]
Clinical Studies
Chan P et al demonstrated the antihypertensive (blood pressure lowering) effect of
stevioside (from Stevia rebaudiana leaves) in a 3-month, multi-center, randomized, double-
blinded, placebo-controlled study. [9]
A 2-year study of 168 patients suffered from hypertension (aged 20-75) demonstrated that
oral stevioside (from Stevia rebaudiana Bertoni) decreased systolic and diastolic blood
pressure without significant adverse effects [14]
Glucose Tolerance
In vitro Study
Jeppesen PB and co-workers at Aarhus University Hospital, Denmark demonstrated that
stevioside and steviol stimulated insulin secretion via a direct action on beta cells. [16]
Animal Studies
In 2002, Jeppesen PB et al reportedthat stevioside had antihyperglycaemic, insulinotropic,
and glucagonostatic activities from a study of type 2 diabetic rat. [17]
Chen TH and co-workers found that stevioside was able to regulate blood glucose levels by
enhancing not only insulin secretion, but also insulin utilization in insulin-deficient rats; the
latter was due to decreased phosphoenol pyruvate carboxykinase gene expression in rat
liver by stevioside's action of slowing down gluconeogenesis. [19]
Clinical Studies
In 1986, Curi R et al, Universidade de Maringa, Brasil, demonstrated that aqueous extracts
of Stevia rebaudiana leaves could increase glucose tolerance in a study of 16 healthy
human subjects. [15]
In 2004, Jeppesen PB et al finally studied the anti-hyperglycaemic properties of stevioside
(from stevia) in human subjects. They recruited 12 patients suffered from Type 2 diabetes
and successfully demonstrated that stevioside reduces postprandial blood glucose levels in
the patients. [18]
Chatsudthipong V and Muanprasat C., Mahidol University, Thailand, stated, “It is of interest to
note that their effects on plasma glucose level and blood pressure are only observed when
these parameters are higher than normal.” [A4]
Whole Earth Sweetener Company LCC filed a GRAS application for rebaudioside A in 2008
(GRN No. 252). In the application, Whole Earth discusses published clinical studies of
stevioside, other steviol glycosides and crude stevia extracts in diabetics and nondiabetics
and in hypertensive and normotensive subjects. Whole Earth concludes that stevioside, at
levels up to 30 mg/kg bw/day, does not affect blood glucose levels. Whole Earth also
concludes that, although stevioside administration was associated with clinically relevant
reductions in blood pressure for individuals with moderately severe hypertension who were
not on antihypertensive therapy, such reductions in blood pressure were not observed in
individuals with normal blood pressure or in individuals with hypertension receiving
antihypertensive medication.
Cancer
Stevia may have anti-cancer activities, but the evidence is very limited. Yasukawa K and his
co-workers isolated four steviol (ent-kaurene-type diterpenoid) glycosides, stevioside,
rebaudiosides A and C, and dulcoside A) from Stevia rebaudiana BERTONI and they found a
strong inhibitory effect of these steviols on 12-O-tetradecanoylphorbol-13-
acetate (TPA)-induced inflammation in mice. [20]
Infection
Stevia may have anti-microbial activities, the scientific evidence is very limited. Amaro-Luis et
al isolated ombuoside from aerial parts of Stevia triflora and prepared derivatives of it- octa-
acetylombuoside, ombuine and retusine. They found these compounds were against a few
types of gram positive bacteria. [21]
Pharmacokinetics
Rats received a single oral administration of either steviol or stevia mixture; a peak steviol
plasma concentration appeared 15 min after its oral administration. However, after oral
administration of stevia mixture, the steviol concentration in plasma increased steadily over
8 h, [22]
Dosage and Side Effects --- Is Stevia safe?
Within the normal range, Stevia probably is safe, without serious adverse or toxic side
effects [4,6,9]. However, most studies are actually done with rebaudioside A.
Curry LL and Roberts A, Cargill Inc., evaluated the safety of rebaudioside A in two oral toxicity
studies of Wistar rats. One is 4 weeks long with a dosing range of 25,000 to 100,000 ppm
and the other is 13 weeks long with a dosing range of 25,000 and 50,000ppm. They found
reductions in body weight gains, overall normal hepatic functions, no significantly changes
in organs. [A6]
Rebaudioside A was non-mutagenic in an Ames test using Salmonella typhimurium and
Escherichia coli, in a chromosomal aberration test using Chinese Hamster V79 cells and in
a mouse lymphoma assay using L5178Y+/- cells, all studies were conducted at
concentrations up to 5000 microg/ml, with and without metabolic activation. Also,
Rebaudioside A was non-genotoxic in a bone marrow micronucleus test in mice at doses
up 750 mg/kg bw and in an unscheduled DNA synthesis test in rats at 2000 mg/kg bw. [A2]
Whole Earth provides an estimated daily intake (EDI) of rebaudioside A, based on the
intended food categories and use levels and data from the most recent National Health and
Nutrition Examination Survey (NHANES 2003-2004), which includes table top sweeteners.
Whole Earth calculates the total mean and 90th percentile EDI for eaters only, aged 2 years
and older, as 2 mg/kg body weight per day (mg/kg bw/d) and 5 mg/kg bw/d, respectively. The
range of exposures among population subgroups (age, gender and sex) is similar, ranging
from 1.2 to 2.4 mg/kg bw/day (mean) and 2.4 to 5.6 mg/kg bw/day (90th percentile). Whole
Earth states that the use of rebaudioside A is self-limiting in that high levels cause a food to
be unpalatable (GRN No. 252).
But, you may also see there are tons of complains on the side effects of Stevia, especially,
when it is combined with certain kinds of drinks and medicine. Do not overdose yourself.
Discuss with your doctor before taking any supplement including stevia, rebaudioside A etc.
Is Stevia rebaudiana (Bertoni) Bertoni a GRAS substance?
No, only one of its active ingredients is considered as a GRAS substance and it is
rebaudioside A. (GRN No. 252, 253 and 278). In addition, there is a limitation of its use and
amounts in products. Here is a summary:
1. GRN 000252 (Applicant: Whole Earth Sweetener Company LCC, Chicago, Date of Filing:
5/13/2008, Date of Closure: December 17, 2008)
Rebaludioside A is used as a sweetener in a variety of food categories-- cereals (oatmeal,
cold cereal, cereal bars) 150 mg/kg, ready-to-drink teas 90 – 450 mg/kg, fruit juice drinks
150 – 500 mg/kg, diet soft drinks 150 – 500 mg/kg, energy drinks 150 mg/kg and flavored
waters 150 mg/kg. And, it is also used a sweetener, formulated to provide 30 milligrams of
rebaudioside A per gram of finished product.
As part of its notice, Whole Earth includes the report of a panel of individuals (Whole Earth's
GRAS panel) who evaluated the data and information that are the basis for Whole Earth's
GRAS determination. Whole Earth considers the members of its GRAS panel to be qualified
by scientific training and experience to evaluate the safety of substances added to food.
Whole Earth's GRAS panel evaluated the identity, method of manufacture, product
specifications, and the potential exposure resulting from the intended uses of rebaudioside
A as well as published and unpublished studies on rebaudioside A and related substances.
Based on this review, Whole Earth's GRAS panel concluded that rebaudioside A, produced
consistent with good manufacturing practice and meeting appropriate purity and food grade
specifications, is GRAS, by scientific procedures, under the conditions of its intended use.
2. GRN 000253 (Applicant: Cargill, Inc., MN 55345, Date of Filing: 5/20/2008, Date of
Closure: December 17, 2008)
Rebaludioside A is used as a general-purpose sweetener in foods, excluding meat and
poultry products, provided that food standards of identity do not preclude such use, at levels
determined by current good manufacturing practices.
This article is not a medical advice; it is for reference only. Discuss with your doctor before taking any
supplements, herbs, medicine. Overdose of supplements can cause serious side effects. All rights
reserved.
References
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