Stevioside safety and benefits
A natural extract from the leaves of Stevia rebaudiana Bertoni, what is the right dosage and which product is best?
February 1 2017 by Dr. Ray Sahelian, M.D.

Stevioside is a natural sweetener extract from the stevia leaf becoming more popular since the FDA allowed it to be called a sweetener in 2008. The metabolism of stevioside leads to the formation of steviol. Stevioside is quite safe. Fertility and teratogenicity studies have not shown any major concerns for safety. Stevioside is of benefit for diabetics, PKU patients, as well as for obese persons intending to consume fewer calories by avoiding sugar supplements in the diet. No allergic reactions to it seem to exist. Stevioside is present in the stevia plant at levels up to 13%.

Safety, risk, caution, allergy and danger
As of 2017 no major side effects, allergies, physical or mental harm has been reported in medical journals from the use of stevioside. Two decades of research proove this natural sweetener is safe based on evaluation of the published research on animals and humans.

Consumers want to know
I keep reading conflicting reports in magazines regarding the safety of stevia. In your opinion, is it safe?
   Stevia has been available to the consumer in the USA since the mid 1990s and many people have used it daily for more than a decade with absolutely no safety concerns. Based on a thorough evaluation of published animal and human studies, we are confident that stevioside is safe and significantly safer than practically all of the artificial sweeteners currently on the market. Stevia extracts have been given in massive doses to three generations of rodents with no harmful effects noted and it has been used in Japan for more than 3 decades with no adverse reactions reported.

Weight loss, Does it help with weight loss?
It's difficult to say. One would think that consuming a substance that is sweet and replaces sugar in some instances would lead to fewer calories consumed, but this has not been the case with artificial sweeteners and we do not know if it applies to stevia, also.

Used worldwide
Stevioside has been used for a number of years as a sweetener in South America, Asia, Japan and China. It started becoming popular in the United States in the mid 1990s.

Artificial sweeteners
There are many artificial sweeteners on the market, including aspartame, saccharin, acesulfame-K, neotame, sucralose, cyclamate, and alitame. Since stevia derived stevioside became available to the public in the late 1990s, more people are using this natural sweetener. Rebaudioside A and stevioside are steviol glycosides extracted from the plant Stevia rebaudiana Bertoni and are used in several countries as food and beverage sweeteners.

Frequently asked questions regarding the benefits, uses, and safety

How sweet is stevioside compared to sugar?
It is 200 to 300 times sweeter than sucrose.

Can stevioside be used in cooking and baking?
Yes, it is heat stable.

Would stevioside use influence pregnancy and childbirth?
There is no evidence in humans that it has a negative effect on pregnancy or cause genetic defects or difficulties with labor.

How many milligrams of stevioside is safe to ingest daily?
Human studies are not available to determine how many milligrams or grams of stevioside can be consumed safely each day. However, rather than worrying about the specific amounts, as long as you are reasonable in your intake of stevia products there is little or nothing to worry about. It takes a very, very high amount of stevioside to cause any toxicity. A dosage of 15 grams per kilogram is about 1000 grams per human each day. Most people will ingest less than 1 gram a day of stevioside even if they ingest a lot of stevia products. The study below suggest stevioside and steviol are very safe. If aspirin, acetaminophen or another medication is given at these dosages fatality would occur quite quickly.

Acute toxicity of stevioside, a natural sweetener, and its metabolite, steviol, in several animal species.
Drug Chem Toxicol. 1997; Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
The acute toxicity of stevioside and steviol (a product of enzymatic hydrolysis) was investigated in three animal species including rat, mouse and hamster. The animals were treated intragastrically with stevioside or steviol and general signs and symptoms were observed. The numbers of dead animals were recorded within a period of 14 days after administration for estimation of LD50. Stevioside at a dose as high as 15 g/kg body weight was not lethal to either mice, rats or hamsters. Hamsters were found to be more susceptible to steviol than rats or mice. LD50 values of steviol in hamsters were 5.20 and 6.10 g/kg BW for males and females, respectively. In rats and mice, LD50 values of steviol were higher than 15 g/kg BW in both sexes. Histopathological examination in the kidney of hamsters induced by steviol revealed severe degeneration of the proximal tubular cells. These structural alterations were correlated with the increases in serum blood urea nitrogen (BUN) and creatinine. Therefore, the possible cause of death induced by steviol might be due to acute renal failure.

How many calories are in stevioside?
It has no calories.

Benefit
A number of studies have suggested that, beside sweetness, stevioside along with related compounds, which include rebaudioside A (second most abundant component of S. rebaudiana leaf), steviol and isosteviol (metabolic components of stevioside) may also offer therapeutic benefits, as they have anti-hyperglycemic, anti-hypertensive, anti-inflammatory, anti-tumor, diuretic, and immune influencing properties. However, more human research in varying dosages needs to be published before we have a better understanding.

Stevioside and related compounds: therapeutic benefits beyond sweetness. Pharmacol Ther. 2009. Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Stevioside, an abundant component of Stevia rebaudiana leaf, has become well-known for its intense sweetness (250-300 times sweeter than sucrose) and is used as a non-caloric sweetener in several countries. A number of studies have suggested that, beside sweetness, stevioside along with related compounds, which include rebaudioside A (second most abundant component of S. rebaudiana leaf), steviol and isosteviol (metabolic components of stevioside) may also offer therapeutic benefits, as they have anti-hyperglycemic, anti-hypertensive, anti-inflammatory, anti-tumor, anti-diarrheal, diuretic, and immunomodulatory actions. 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. As steviol can interact with drug transporters, its role as a drug modulator is proposed. This review summarizes the current knowledge of the pharmacological actions, therapeutic applications, pharmacokinetics and safety of stevioside and related compounds.

Use by patients with kidney disease, influence on renal function
Q. There is an internet web site that those with kidney disease should not use stevioside products. They were basing their conclusion on a study in rodents that found stevioside was harmful to the kidneys. I read a few reports on Stevia that reference the same study referred to below as footnote. I copied excerpts below form an article I recently read. All of the reports state that there is an issue of nephrotoxicity and that people with damaged kidneys are advised to stay away from stevia until more research is available. I love the soft drinks made by Zevia, including its cola, root beer and other flavors. And other than the nephrotoxicity, it seems perfectly safe. I am not a medical person, so I did not understand the study when I read it. My guess is that the rats in the study were given exceptionally large dosages of stevia, a lot more than my 500 mgs a day. I have 1-kidney, which is not 100% (if provides about 50% of what 2-kidneys did for me) but it is stable and improving over time So if I am concerned about losing nephrons if I continue consuming 500 mgs of stevia on a regular if not daily basis. Can you comment on this?
   A. Whenever researchers do studies in rodents, they often give massive doses of the drugs or nutrients they are evaluating. The results they obtain in many cases may not be relevant to humans. In the case of stevioside, the intake in most humans will be a tiny fraction of what is given to the animals. Over several decades of stevia and stevioside use by humans in Japan and other countries, we have not seen reports of this natural sweetener extract to cause kidney damage. It is up to you and your physician to review the published studies and decide whether this sweetener is appropriate for your condition. The stevioside study mentioned below refers to rats given an injection of 1500 mg of stevioside per kilogram of body weight.

Chaivat Toskulkao, Deechakawan, “The Low Calorie Natural Sweetener Stevioside: Nephrotoxicity and its Relationship to Urinary Enzyme Excretion in the Rat”. Phytotherpy Research. Keywords: stevioside • stevia • sweetener • nephrotoxicity • lipid peroxidation • urinary enzymes • glucosuria
The relationships between urinary enzyme levels and changes in blood urea nitrogen (BUN) and plasma creatinine levels, along with simultaneous ultrastructural changes of the kidney, were studied in rats treated with stevioside. BUN levels increased at 3 h onward after subcutaneous injection (s.c.) with stevioside (1.5 g/kg BW). The maximum increases in BUN and creatinine were approximately 180% and 132% at 9 h after stevioside injection, respectively. At this time, stevioside also caused significant increases in glucosuria, alkaline phosphatase (AP) and -glutamyl transpeptidase (-GTP) but no significant changes in proteinuria, N-acetyl--D-glucuronidase (NAG) or glutathione-S-transferase (GSH-S-TF). Histopathological examination of the kidney induced by stevioside revealed degeneration of the proximal convoluted tubule cells but no relation to lipid peroxide formation was detected. These results suggest that stevioside induced nephrotoxicity at the proximal convoluted tubules rather than at the glomeruli and other tubules presumably by a defect of cell volume regulation due to depletion of intracellular ATP and disruption of microvilli, and nuclear dysfunction.

Stevioside effect on renal function of normal and hypertensive rats.
J Ethnopharmacol. 1992. Departamento de Biologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Brazil.
Physiological and pharmacological experiments have suggested that stevioside from the leaves of Stevia rebaudiana acts as a typical systemic vasodilator. The effect of stevioside on renal function in both normal and with experimental renal hypertension rats was evaluated. Stevioside provoked hypotension, diuresis and natriuresis in both the normal and hypertensive rats. Normal rats presented an increase in renal plasma flow and glomerular filtration rate constant following stevioside administration. The last effect is in part due to vasodilation of both the afferent and efferent arterioles. Moreover, stevioside infusion in hypertensive rats caused an increase in renal plasma flow and glomerular filtration rate. These data are consistent with impairment of a renal autoregulation mechanism in this experimental hypertensive model.

Blood pressure 
Does stevioside increase or decrease blood pressure?
    Studies thus far do not show stevioside to have a significant effect on blood pressure, particularly since the amounts used are so small.

Blood sugar, insulin response, diabetes
Mechanism of the hypoglycemic effect of stevioside, a glycoside of Stevia rebaudiana.
Planta Med. 2005.
We have studied the effects of stevioside on the glucose and insulin metabolism in 2 models of diabetes in rats, STZ-induced diabetic rats and NIDDM diabetic rats induced by feeding with fructose. Stevioside (0.5 mg/kg), lowered the blood glucose levels in STZ-induced diabetic rats, peaking at 90 min. Administered twice daily also demonstrated dose-dependent effects in lowering the glucose levels in both diabetic rat models. It reduced the rise in glucose during glucose tolerance testing in normal rats. In conclusion, stevioside was able to regulate blood glucose levels by enhancing not only insulin secretion, but also insulin utilization in insulin-deficient rats.

Stevioside inhibits atherosclerosis by improving insulin signaling and antioxidant defense in obese insulin-resistant mice.
Int J Obes. Atherosclerosis and Metabolism Unit, Department of Cardiovascular Diseases and Leuven Food Science and Nutrition Research Centre, Leuven, Belgium.
Stevioside is a non-caloric natural sweetener that does not induce a glycemic response, making it attractive as sweetener to diabetics and others on carbohydrate-controlled diets. Obesity is frequently associated with insulin resistance and increased inflammation and oxidative stress. Therefore, we investigated its effects on insulin resistance, inflammation and oxidative stress related to atherosclerosis in obese insulin-resistant mice. Twelve-week-old mice were treated with stevioside or placebo for 12 weeks.Results:Stevioside had no effect on weight and triglycerides, but lowered glucose and insulin. Stevioside treatment improved adipose tissue maturation, and increased glucose transport, insulin signaling and antioxidant defense in white visceral adipose tissues. Together, these increases were associated with a twofold increase of adiponectin. In addition, stevioside reduced plaque volume in the aortic arch by decreasing the macrophage, lipid and oxidized low-density lipoprotein (ox-LDL) content of the plaque. The higher smooth muscle cell-to-macrophage ratio was indicative for a more stable plaque phenotype. The decrease in ox-LDL in the plaque was likely due to an increase in the antioxidant defense in the vascular wall, as evidenced by increased Sod1, Sod2 and Sod3. Circulating adiponectin was associated with improved insulin signaling and antioxidant defense in both the adipose tissue and the aorta of stevioside-treated mice. Stevioside treatment was associated with improved insulin signaling and antioxidant defense in both the adipose tissue and the vascular wall, leading to inhibition of atherosclerotic plaque development and inducing plaque stabilization.

Is it safe for a person with diabetes?
Stevioside is a safe alternative to artificial sweeteners in those who have diabetes.

Cancer
Cancer preventive agents. Part 8: Chemopreventive effects of stevioside and related compounds.
Bioorg Med Chem. 2009. Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Choshi, Chiba, Japan.
In a search for potential cancer chemopreventive agents from natural resources, stevioside, a sweetener, and six related compounds, including two aglycones steviol and isosteviol, were screened in an in vitro assay for inhibitory effects on Epstein-Barr virus early antigen activation. Stevioside, steviol and isosteviol showed significant activity in this assay and also exhibited strong inhibitory effects in a two-stage carcinogenesis test using mouse skin induced by 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). The inhibitory effects of these three compounds were greater than that of glycyrrhizin. Furthermore, these three compounds significantly inhibited mouse skin carcinogenesis initiated by peroxynitrite and promoted by TPA. Their activities were comparable to that of curcumin. These results suggested that stevioside, steviol and isosteviol could be valuable as chemopreventive agents for chemical carcinogenesis.

Metabolism and excretion of stevioside
Comparative toxicokinetics and metabolism of rebaudioside A, stevioside, and steviol in rats.
Food Chem Toxicol. 2008.
The toxicokinetics and metabolism of rebaudioside A, stevioside, and steviol were examined in rats for comparative purposes to determine whether toxicological studies conducted previously with stevioside would be applicable to the structurally-related glycoside, rebaudioside A. Single, oral doses of the radiolabelled compounds were extensively and rapidly absorbed with plasma concentration-time profiles following similar patterns for stevioside and rebaudioside A. Elimination of radioactivity from plasma was essentially complete within 72h. All plasma samples had similar metabolite profiles; the predominant radioactive component in all samples was steviol, with lower amounts of steviol glucuronide(s) and low levels of one or two other metabolites. Rebaudioside A, stevioside, and steviol were metabolized and excreted rapidly, with the majority of the radioactivity eliminated in the feces within 48h. Urinary excretion accounted for less than 2% of the administered dose for all compounds in both intact and bile duct-cannulated rats, and the majority of the absorbed dose was excreted via the bile. After administration of the compounds to intact and bile duct-cannulated rats, radioactivity in the feces was present primarily as steviol. The predominant radioactive compound detected in the bile of all cannulated rats was steviol glucuronide(s), indicating de-conjugation in the lower intestine. Overall, the data on toxicokinetics and metabolism indicate that rebaudioside A and stevioside are handled in an almost identical manner.

Pharmacokinetics of rebaudioside A and stevioside after single oral doses in healthy men.
Food Chem Toxicol. 2008. Medical Consultant, Northborough, MA, United States.
This study assessed the comparative pharmacokinetics of steviol following single oral doses of rebaudioside A and stevioside in healthy adult male subjects. Steviol glucuronide appeared in the plasma of all subjects after administration of rebaudioside A or stevioside. Steviol glucuronide was eliminated from the plasma, with similar t1/2 values of approximately 14h for both compounds. Administration of rebaudioside A resulted in a significantly (approximately 22%) lower steviol glucuronide geometric mean Cmax value than administration of stevioside. Steviol glucuronide was excreted primarily in the urine of the subjects during the 72h collection period, accounting for 59% and 62% of the rebaudioside A and stevioside doses, respectively. No steviol glucuronide was detected in feces. Pharmacokinetic analysis indicated that rebaudioside A and stevioside underwent similar metabolic and elimination pathways in humans with steviol glucuronide excreted primarily in the urine and steviol in the feces. No safety concerns were noted as determined by reporting of adverse events, laboratory assessments of safety or vital signs.