Stevia as a Natural Sweetener, Hypoglycemic, and Antihypertensive
February 2000; Volume 3: 13-17
By Michael D. Cirigliano, MD, FACP and Philippe O. Szapary, MD
The united states is the leading consumer of synthetic nonnutritive sweeteners, accounting for approximately 50% of world demand.1 Agents such as Nutrasweet (aspartame) have attained significant popularity in soft drinks and are currently added to more than 6,000 foods, personal care products, and pharmaceuticals. Many people use them in their efforts to control their weight and blood sugar levels.
Questions of personal cost, safety, and potential risk to long-term, heavy users of chemical sweeteners have recently resurfaced. Possible links to cancer, mutagenesis, multiple sclerosis, Gulf War syndrome, and chronic fatigue syndrome have been noted-.2,3 Although controversial, these concerns have led many to seek alternative natural agents possessing noncaloric sweetening properties.
One such natural alternative is the leaves of the plant stevia (Stevia rebaudiana). Although accepted for general use in Japan and Brazil as a natural sweetening agent, its use in the United States is currently limited to that of a dietary supplement only.
History and Worldwide Consumption
A member of the Asteraceae family, stevia is a perennial shrub indigenous to South America that is commercially grown in Central America, Israel, Thailand, and China.4 Used for centuries in Paraguay, its country of origin, to sweeten beverages and other foods, stevia’s popularity continues to rise—both as a sweetener, and for the treatment of hyperglycemia.4,5 In Paraguay, stevia was used by the Guarani Indians to sweeten various beverages before that country’s colonization by the Spaniards in the 16th century. European interest in stevia began around that time.
The use of stevia as a natural sweetener for widespread use has been approved in Japan since 1975. In Japan, it is used as a noncaloric sweetener in a variety of foods including seafood, pickled vegetables, desserts, ice cream, soft drinks, and confectionery. It is also sold as a table sweetener, as it is in the United States, to be mixed with tea and coffee.4 Sales figures for 1997 estimated that 700-1000 tons of stevia were imported to Japan alone; one company reported producing two to three tons of stevioside per month.6
Stevia rebaudiana represents a:
a. nutritive natural sweetener.
b. nonnutritive natural sweetener.
c. natural glucose sweetener.
Pharmacology
Stevia leaf contains a number of sweet ent-kaurene glycosides including stevioside and rebaudioside A. These represent the most significant natural sweeteners contained in the plant.4
Stevioside comprises 5% of the dry weight of the leaves7 and is formed by three glucose molecules and steviol, a diterpenic carboxylic alcohol. Other related compounds found in the plant include rebaudioside A-E, steviolbioside, steviol, and dulcoside A, several of which are also sweet.
Stevioside administered orally is excreted into the feces but most of it is decomposed by bacterial flora in the cecum to steviolbioside, steviol, and glucose. Steviol then becomes conjugated in the liver and is excreted into the intestinal tract through the bile.
Stevioside has been noted to be 300 times as sweet as sucrose. Stevioside itself offers particular advantages over other noncaloric sucrose substitutes in that it is heat-stable, somewhat resistant to acid hydrolysis, and nonfermentable.8
Mechanism of Action
Stevia and its major active constituents exhibit a number of pharmacological properties. Although mainly known for its noncaloric sweetening properties, components of stevia have also been shown to have hypoglycemic as well as antihypertensive activity.
Further studies have found that steviol inhibits gluconeogenesis, thereby possibly explaining the hypoglycemic effects seen with its use.9 It has been shown, however, to have no direct action on pancreatic A and B cells.10
Stevia is also noted to possess some hypotensive activity, possibly secondary to a diuretic and/or vasodilatory effect, modulated via prostaglandin activity.11 Other investigators believe that steviol’s diuretic activity may derive from its ability to inhibit sodium reabsorption in the renal tubular cells. Increased water and solute excretion result, with no effect on the glomerular filtration rate.7 Several other studies have implicated calcium channel blockade as a cause of stevia’s hypotensive effects. Stevia may inhibit calcium influx by blocking excitation-coupling in smooth muscle, and therefore may promote vasodilatation.12
Animal Studies
Studies have evaluated the hypoglycemic effects of stevia. In one small animal study, an unstandardized preparation containing stevia and the chrysanthemum flower were administered orally to nondiabetic dogs over a three-day period.13 The animals underwent a five-day pretreatment phase with normal dietary intake and then were administered daily dosages of stevia for three days using an escalating regimen of 3 drops, 1/2 ml, 1 ml, and 3 ml. This was followed by a one-time dose of 6 ml. The animals were maintained on their regular diets throughout the experiment. Laboratory studies including plasma glucose were measured daily with no reductions in blood glucose.
The authors determined that the product utilized had no effect on blood sugar levels but noted that the study was small and uncontrolled.
Clinical Trials
Despite its widespread use by the public and use as a food additive in Japan and Brazil, there is a surprising lack of human clinical trials evaluating the safety and efficacy of stevia.
In an often quoted Brazilian study,14 the effect of Stevia rebaudiana on glucose tolerance was studied in 22 nondiabetic adult volunteers receiving aqueous extracts of stevia leaves (20 g/d) during a three-day period. Aqueous extracts of Stevia rebaudiana were prepared by immersing the leaves in boiling water for 20 minutes. Sixteen subjects were nonrandomly assigned to receive stevia in a dose roughly corresponding to 5 g of extracted leaves, administered orally at six-hour intervals over three days. Each subject had a baseline glucose tolerance test (GTT) and then a follow-up GTT after three days of stevia treatment. A control group of six patients received 13 doses of 250 mg of arabinose (a sugar used as an active placebo). During the experimental period, the volunteers ate their usual diets.
Findings revealed that the plasma glucose levels measured after stevia treatment were significantly lower than the control at each of the times tested (P < 0.05-0.01). Of note, no test subjects developed hypoglycemia. In one volunteer, the renal threshold for glycosuria was exceeded during the first 90 minutes. After stevia administration, his glycosuria was completely abolished. In the control group, no differences in serum glucose were noted. The authors concluded that in every period studied, serum glucose levels were diminished after treatment with stevia. However, no generalizable conclusions can be drawn from this study as it was small, of short duration, nonrandomized, and used a nonstandardized preparation. Additionally, no mention was made of blinding subjects or investigators. Other small studies have also noted a decrease in blood sugars after ingestion of stevia.15
Stevia rebaudiana is thought to have hypotensive effects secondary to:
a. calcium channel blockade.
b. sodium reabsorption in renal tubular cells resulting in diuresis.
c. modulation of prostaglandin.
d. All of the above.
Adverse Effects and Contraindications
Stevia is not listed in the German Commission E Monographs. It is, however, categorized as a Class 1 agent by the American Herbal Products Association’s Botanical Safety Handbook indicating that stevia can be safely consumed when used appropriately.16
In May of 1991, the FDA issued an import alert identifying stevia as an "unsafe food additive."17 This ruling was later amended in 1995 to allow entry of stevia into the United States "explicitly labeled as a dietary supplement or for use as a dietary ingredient in a dietary supplement." The FDA reasoning for this initial import alert was the absence of extensive toxicological data on stevia. This lack of long-term human data was felt to be important enough to prohibit widespread U.S. consumption of stevioside. Of note, stevia is not currently allowed as a nonnutritional ingredient in Canada.
Several studies have attempted to evaluate the safety of stevia. One study in animals revealed no adverse effects on growth or reproduction in hamsters given dosages of stevioside as high as 2.5 g/kg body weight per day.18 In a report published by the Proceedings of the National Academy of Science,6 stevioside and the crude product used as a sweetening agent revealed no mutagenic activity on a variety of bacterial strains. Carcinogenicity was not detected in hamsters given stevioside orally for six months or in rats fed stevioside for two years.19,20
However, several animal studies indicating possible nephrotoxicity in hamsters given steviol intravenously have been noted.21 Found both in the stevia leaf and as a metabolite of stevioside, steviol has been found to be highly mutagenic in several in vitro studies.6
Despite these early reports, no recent information has appeared indicating that adverse effects have resulted from human use of stevia products. Neither stevia extract nor stevioside has been shown to be toxic or teratogenic in mice, rats, hamsters, and guinea pigs by oral administration at low doses.22 Unlike saccharin, no evidence has been reported that stevioside and its metabolites are carcinogenic.
Given the noted hypoglycemic and hypotensive properties of stevia, a theoretical concern exists in diabetic and hypertensive patients who might consume stevia. Patients with known sensitivities to plants of the Asteraceae/Compositae family, such as ragweed, should avoid stevia. Insufficient human data exist regarding safety in pregnancy and lactation: There, its use should be avoided.
Formulations and Dosage
Stevioside is classified as a nontoxic compound when given by an oral route (LD50 >15 g/kg) according to a toxicity rating chart.23 Despite this, no universally accepted method of standardization and dosing exists. Stevia is mainly consumed by mouth either in powder or liquid form and is most often used as an additive to foods and beverages. (See Table 1 for price/formulation comparison.)
| Table 1-Stevia cost and formulation comparison | |||
| Manufacturer/Product Name | Formulation | Manufacturer's Recommended Dose | Price |
| Only Natural, Inc. | 100% pure stevia extract 4:1 in water base | 2-5 drops, | $18.95/2 oz |
| Stevia Alcohol Free | not less than 4 lbs pure Paraguayan leaves used to make 1 liter of extract | 3-6 times daily | |
| NuNaturals Pure Liquid | Standardized to contain a minimum of 85% | 5-10 drops to favorite | $10.99/2 oz |
| Clear Stevia Extract | steviosides | food or beverage | |
| Nature's Herbs | Each capsule contains 57 mg certified potency | 1-2 capsules with | $8.69/60 capsules |
| Stevia Power | stevia extract concentrated and standardized | beverage | |
| for a minimum of preferred 85% steviosides | |||
| Optimum Nutrition | Stevia rebaudiana (leaf) extract standardized | 1-3 drops to tea, water | $6.99/2 oz |
| Alcohol-Free Stevia | to contain 90% steviosides | or beverage | |
| Liquid Extract | |||
| Source: Online mail-order companies | |||
Conclusion
Despite extensive use of stevia in Japan and South America as a food additive and nonnutritive sweetener, a remarkable lack of significant human data regarding safety and efficacy precludes recommending its use in the clinical setting. Despite a lack of significant human toxicity reports in the literature, animal reports of nephrotoxicity and possible mutagenicity with long-term use do exist. Randomized controlled trials investigating its long-term safety in humans are certainly needed before broad recommendations can be made regarding the use of stevia.
Recommendation
Historical and widespread use in low doses as a natural sweetener does not appear to be associated with any morbidity. Patients using these products, however, should be counseled regarding the potential risks and benefits of their use: Pregnant and lactating patients should avoid stevia.
Because of the scant published scientific data supporting the use of stevia in the treatment of hyperglycemia, its widespread use by diabetic patients as an adjunctive hypoglycemic agent cannot be recommended currently.
Although animal studies suggest a possible hypotensive effect from use of stevia, use in humans for control of high blood pressure also cannot be recommended.
Dr. Cirigliano and Dr. Szapary are Assistant Professors of Medicine at the University of Pennsylvania School of Medicine in Philadelphia.
Extensive human clinical data exist regarding the safety and efficacy of Stevia rebaudiana.
a. True
b. False
References
1. Bizzari S, et al. High intensity sweeteners. In: Chemical Economics Handbook. Menlo Park, CA: SRI Consulting; 1996.
2. Roberts HJ. Aspartame and brain cancer. Lancet 1997;349:362.
3. Zehetner A, McLean M. Aspartame and the internet. Lancet 1999;354:78.
4. Stevia. In: The Review of Natural Products. St. Louis, MO: Facts and Comparisons; 1999.
5. Das S, et al. Evaluation of the cariogenic potential of the intense natural sweeteners stevioside and rebaudioside A. Caries Res 1992;26:363-366.
6. Pezzuto JM, et al. Metabolically activated steviol, the aglycone of stevioside, is mutagenic. Proc Natl Acad Sci USA 1985:82:2478-2482.
7. Melis MS. Effects of steviol on renal function and mean arterial pressure in rats. Phytomedicine 1996;3:349-352.
8. Kinghorn AD, Soejarto DD. Stevioside. In: Alternative Sweeteners. Vol. 2. New York: Dekker; 1991:157-171.
9. Yamamoto NS, et al. Effect of steviol and its structural analogues on glucose production and oxygen uptake in rat renal tubules. Experientia 1985;41:55-57.
10. Usami M, et al. Effect of cyclamate sodium, saccharin sodium and stevioside on arginine-induced insulin and glucagon secretion in the isolated perfused rat pancreas. Horm Metab Res 1980;12:705-706.
11. Melis MS, Sainati AR. Participation of prostaglandins in the effect of stevioside on renal function and arterial pressure. Braz J Med Biol Res 1991;24:1269-1276.
12. Melis MS, et al. Effects of indomethacin on the action of stevioside on mean arterial pressure and on renal function in rats. IRCS Med Sci 1985;13:1230-1231.
13. White JR, et al. 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.
14. Curi R, et al. Effect of Stevia rebaudiana on glucose tolerance in normal adult humans. Braz J Med Biol Res 1986;19:771-774.
15. Oviedo CA, et al. Hypoglycaemic action of Stevia rebaudiana Bertoni. Excerpta Medica 1970;209:92.
16. Stevia rebaudiana. In: McGuffin M, et al. American Herbal Products Association’s Botanical Safety Handbook. Boca Raton, FL: CRC Press; 1997.
17. Food and Drug Administration. Revision of Import Alert #45-06, "Automatic detention of stevia leaves, extract of stevia leaves, and foods containing stevia." September 18, 1995.
18. Yodyingyuad V, Bunyawong S. Effect of stevioside on growth and reproduction. Hum Reprod 1991;6:158-165.
19. Glinsukon T, et al. Stevioside: A natural sweetener from Stevia rebaudiana Bertoni: Toxicological evaluation. Thai J Toxicol 1988;4:1-22.
20. Panichkul T, et al. The plasma levels of urea nitrogen, creatinine and uric acid and urine volume in rats and hamsters treated with stevioside. Thai J Toxicol 1988;4:47-52.
21. Toskulkao C, et al. Acute toxicity of stevioside, a natural sweetener, and its metabolite, steviol, in several animal species. Drug Chem Toxicol 1997;20:31-44.
22. Lee SJ, et al. A study of the safety of stevioside as a new sweetening source. Hanguk Sikpum Kwahakhoe Khi 1979;11:224-231.
23. Klaassen C, Doull J. Evaluation of safety: Toxicological evaluation. In: Cassarett and Doull’s Toxicology. 2nd ed. New York: Macmillan Publishing Co.; 1986.
February 2000; Volume 3: 13-17
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