Stevia is a non-caloric sweetener and belongs to a class of substances also known as Non-nutritive sweeteners (NNS), Non-caloric artificial sweeteners (NAS) or intense sweeteners (IS). The chief interest in this class of compounds is related to weight management, diabetes control and intervention on any disorder where a high serum glucose level can be detrimental.

As one of the few NNS that is extracted from a plant, stevia was welcomed and acclaimed as a “natural” sweetener, celebrated by those consumers who reject or feel suspicious about synthetic compounds.

Since there had been warnings concerning possible toxic effects caused by synthetic sweeteners, this segment of consumers was an important market for Stevia-derived sweeteners.

The acceptance of stevia-derived sweeteners still faces some problems: although powerfully sweet, some stevia-derived sweetener products leave an aftertaste and are slightly bitter. A lot of effort has been invested in making these products more palatable.

Another issue is that more educated consumers are aware that the carcinogenic effects of artificial sweeteners were highly overrated.

There was a radical change of perspective when some studies indicated that instead of helping to control the deleterious effects of high glucose serum levels, some artificial sweeteners, in spite of not being caloric, could be causing metabolic responses similar to sugar. Those allegations, combined with the previous alarm about their possible carcinogenic effect led to a search for alternative NNS with fewer side effects.

That is when stevia-derived products showed their value: apparently, they lacked the undesired side effects.

Let’s start with an overview of Non-nutritive sweeteners (NNS) and the health concerns about their possible biological action.

NNS – Effects on Health

NNS have no calories (non-nutritive) and were seen as a powerful tool against obesity, diabetes, and other disorders. There were some questions about their safety and effectiveness.

NNS were introduced as tools to control two main health threats: obesity (or unwanted weight gain) and diabetes. They would be useful in weight control because, unlike sucrose and glucose, they are non-caloric.

It was a straightforward rationale: if sucrose accounted for a certain percentage of daily calorie intake, its substitution by a non-caloric alternative would represent a caloric deficit. As for diabetes, NNS were adopted because they would not be recognized by glucose receptors, wouldn’t affect insulin production or cause hyperglycemia.

Since the beginning of their use, NNS were controversial. Although the weight of evidence suggests they are not only beneficial but potentially life-saving, controversy remains (Bellisle & Drewnowski 2007, Tandel 2011). For the purpose of this review, we will first address the claims concerning potential weight gain and metabolic adverse effects of NNS and the other harmful side effects (cancer and neurological damage).

According to Pepino (2015), there are two possible explanations (not mutually exclusive) for the paradoxical and controversial (not always reproduced) hypothetical metabolic effect NNS may have on weight gain: 1. Reverse causation (individuals already likely to develop metabolic disorders consume NNS therapeutically, but still exhibit the effects); 2. NNS actually are metabolically active.

According to this author, there are three possible mechanisms: 1. Behavioral; 2. Dysbiosis; 3. Direct endocrine action.

Let us have a look at the arguments and evidence:

Weight gain

Are NNS effective tools to lose weight or are the claims suggesting the opposite supported? Evidence suggests that as long as NNS are used to reduce the total amount of calories in a diet, they are effective tools. NNS do not cause weight loss: consuming fewer calories does.

Most studies concerning the connection between NNS use and weight gain are or rely on, epidemiological data. The epidemiology argument fails at the logical level: the fact that the obesity incidence is still rising and more NNS containing products are being commercialized have never shown to have a causal relation. In fact, figure 1 suggests a different conclusion:

NNS - effect on weight

Fig 1: from Anusha et al (2016).

According to Anusha and collaborators (2016), the curves suggest that the higher BMI (body mass index) is caused by NNS consumption. However, it could be the opposite: the obesity epidemic is uncontrolled and the percentage of people substituting sucrose by NNS is still too small and not growing fast enough.

The new products curve shows nothing except that manufacturers believe there is a market for them. Epidemiological curves may or may not be “by proxy” indicators of some phenomenon. As I hope to have shown, in this case, they don’t support the argument that NNS cause an increase in BMI.

Another argument focuses on central control of appetite and metabolism, as reviewed by Bellisle and Drewnowski (2007) and Pepino (2015). Current research has focused on the physiological responses to the sweetness content of the food supply: sweet-tasting foods with high-energy density are claimed to disrupt appetite regulation and overwhelm the body’s regulatory mechanisms.

Energy-dense diets cause insulin and leptin resistance in the central nervous system (CNS) and blunt responses to physiological signals of satiety. Diet-induced CNS insulin resistance is the suggested reason why the pleasure response to energy-dense foods does not diminish even in the face of caloric repletion.

Sweetness may also affect cortisol reactivity and compensate for feelings of stress. Studies in mice suggest that leptin modulates sweet taste responsiveness, with further implications for fatness and energy intake. This line of reasoning requires NNS consumption conditions without calorie restriction and concomitant to calorie-dense food.

Another possible mechanism of central control disruption would be the ability of NNS to interfere with learned responses that contribute to control glucose and energy homeostasis. As Pepino (2015) points out, many of these studies have only been carried out in animal models and the differences between humans and rodents in the hypothesized mechanisms are important.

Glucose homeostasis and metabolic syndrome

High blood sugar is dangerous to diabetic patients. Can NNS cause high blood sugar as some authors suggest? There is no clear evidence that they actually cause high blood sugar.

Studies concerning the effect of NNS on glucose homeostasis, insulin sensitivity, hormonal response to glucose intake and metabolic syndrome markers are controversial. The chief concern is how the consumption of NNS prior to a glucose stimulus affects insulin secretion or response. There are studies showing evidence of such an effect on healthy and obese subjects. There are other studies showing no effect.

According to Pepino (2015), the origin of these discrepancies is not clear but could be related to different adaptive responses to NNS among obese patients who habitually use the substances.

Again, we have the methodological issues of animal versus human studies, of human studies with subjects under diverse dietary regimes and several other factors that we know to interfere with the measured responses.

Considering that studies on healthy adults don’t seem to suggest hormonal effects, that the obese patient has different hormonal responses altogether, and that dietary NNS or glucose is one factor in the complex metabolic syndrome, at this point this subject is inconclusive.

Dysbiosis

Our gut has a few trillions of microbes, known as the “gut microbiota”. Many things can influence their number, diversity and how they interact with their host (us). Are NNS harmful to the gut microbiota? Can this hypothetical harmful effect lead to health problems?

One of the concerns about NNS with the strongest supporting evidence is dysbiosis: several studies have shown that all NNS, at some level, alter the gut microbiota (Suez et al 2014). In the past few years, research into gut microbiota and what is now known as the brain-gut-microbiome axis has shown that the diversity and composition of intestinal microbiota are far more important than previously thought (Lozupone et al 2012):

  1. Gut microbiota diversity, composition, and changes in species prevalence has been associated with obesity and other disorders (Stanislawski et al 2018, Abrahamsson et al 2014, Jakobsson et al 2014)
  2. Energy metabolism is highly affected by the gut microbiome (Liu et al 2017, John & Mullin 2016, Torres-Fuentes et al 2017)

However, a direct causal relationship between NNS consumption and energy metabolism disruption (metabolic syndrome, insulin resistance, weight gain) has not been established (Pepino 2015, Lozupone et al 2012):

  1. Most studies have been carried out in animal models or in vitro. It is still unclear what the precise effect on humans is;
  2. Studies on humans show an association between phenomena, but not cause;
  3. Too many substances, behaviors, and physiological phenomena cause changes in the gut microbiota and directly interfere with the brain-gut-microbiome. From the prevalence of processed food in the diet to neurological or psychiatric conditions, sleep deprivation and exercise, there are too many variables interfering with the delicate balance of the gut microbiological community;
  4. As a corollary to the previous item, we do know that too many factors affect the gut microbiome but we can’t positively identify which changes are negative. Since all subjects have probably been exposed to something that has potentially altered their microbiome, it is hard to make the case in favor of an important negative causal effect of NNS.

Up to now, the medical literature doesn’t provide a clear indication of the importance, magnitude or relevance of the microbiome-altering effect of NNS.

Carcinogenesis

Can NNS cause cancer? There is no evidence that it does in the doses that a human is capable of consuming.

Carcinogenesis was a concern since NNS became a widespread strategy for weight management (for example, Kamby & Jensen 1982, Kessler & Clark 1978). Although we could technically say there is still controversy (because a positive consensus is not confirmed by literature analysis), even older studies from the early 1990s when the most widely used sweeteners were saccharine and cyclamate, failed to provide evidence for in vivo carcinogenesis.

Ahmed & Thomas (1992) go as far as advise the discontinuation of this line of research. Some researchers still insist on the risk (Soffritti et al 2010) but most are skeptical about carcinogenesis (Magnuson et al 2008 ). A recent study (Dooley et al 2017) comparing aspartame and stevia on the development of pancreatic cancer showed no evidence of an effect on the course of the disease (in either direction).

Neurological disorders

You may have heard that NNS can cause long-term neurological disorders. There is no evidence that they actually do.

In the late 1980s, the association of aspartame with neurological damage hit the news through anecdotal evidence (Maher 1987). Three decades later little progress has been made: aspartame may elevate the levels of phenylalanine and aspartic acid in the brain, which may inhibit the synthesis and release of dopamine, norepinephrine, and serotonin, which are known regulators of neurophysiological activity.

Their decreased levels may cause problems (Choudhary & Lee 2018). Inflammatory effects were identified in animal models, as well as possible mechanisms to prevent them (Saleh 2015).

A few epidemiological studies suggest that there might be an actual human risk in the consumption of NNS. No causal mechanism was identified (Guo et al 2014, Gardener et al 2012).

Ironically, a virtual screening campaign to identify novel anticonvulsant agents indicated several widely-used artificial sweeteners as potential candidates:  Acesulfame potassium, cyclamate, and saccharin were tested in the Maximal Electroshock Seizure model and showed moderate anticonvulsant activity (Talevi et al 2012).

The authors suggest a possible relationship between the receptor responsible for sweet taste and anticonvulsant molecular targets.

Thirty years of research after the alarm, neurological risk is a vague and inconclusive possibility.

Possible alternatives to traditional NNS

In October 2018, The Wall Street Journal featured an Israeli startup https://www.amaiproteins.com/ developing a different class of “sweet molecules”: sweet proteins (Kamping-Carder 2018). The existence of sweet-tasting polypeptides is known. Whether the new product will be successful or not is to be seen.

The other novelty is a stevia product: Heylo https://www.heylosweet.com/revolution , developed in 2017 by also Israeli Unavoo, combines stevia with acacia fiber.

What is Stevia?

There is a lot of hype about stevia and the market for stevia products is growing.

Much of the interest in stevia is directly related to the bad reputation artificial NNS have acquired. Stevia has been looked at with optimism from the start because it is “natural” (as opposed to synthetic), it was consumed in one way or another by traditional populations for a long time and its introduction in Western culture, first among special lifestyle communities and then widely in industrialized form has been successful.

Regardless of new technologies and products that solve the bitterness/aftertaste problem, stevia is here to stay and has been so for a while.

Stevia global market size today is already significant. In 2015 it was estimated in USD 337.7 million and expected to grow from 5-8%/year in the following 5-7 years according to reputable market research companies (Statista https://www.statista.com/topics/2304/stevia-industry/ , BusinessWire https://www.businesswire.com/news/home/20181112005489/en/Global-Stevia-Market-2018-2022-Growing-Demand-Flavored, and Natural Products Insider https://www.naturalproductsinsider.com/specialty-nutrients/stevia-market-dominance ).

It is still small compared to the global market value of NNS as a product class, estimated in USD 3.2 billion in 2016 https://www.mordorintelligence.com/industry-reports/artificial-sweeteners-market .

The overall growth, however, is estimated in 3.25% for the 2019-2024 period. Forecasts vary according to each research institute’s methodology. In spite of discrepancies, it does seem that the stevia market is growing and will continue to grow more than other NNS https://purecircle.com/news/stevia-use-in-beverages-and-foods-continues-to-increase/ .

What will actually happen to this market depends also on the weight of new players, like Heylo and the sweet proteins mentioned above. In any scenario, stevia has a place in all types of products and technologies: diversity is business, and business is good.

Not only there are several stevia-based sweeteners, but there are many sugar-free stevia-based industrialized foods  https://traditionalcookingschool.com/food-preparation/stevia-sweetened-desserts/

To understand why there should be so many different stevia-based sweetener products and why their taste varies, we need to understand what stevia is.

Why are there so many different stevia-based products? Understand what stevia is.

Stevia is a natural (not synthetic) NNS extracted from the plant Stevia rebaudiana. The active sweet substances are steviol glycosides. These compounds are 100-300 sweeter than sucrose (table sugar). The use of their purified form in the USA is legal and does not require FDA “approval” (as other NNS require).

It has received an FDA GRAS: “generally recognized as safe”: “The use of a food additive must undergo premarket review and approval by FDA before it can be used in food. In contrast, use of a GRAS substance does not require premarket approval.” https://www.fda.gov/Food/IngredientsPackagingLabeling/FoodAdditivesIngredients/ucm397716.htm .

Stevia crude extract and leaf, however, have not received any FDA approval https://www.fda.gov/AboutFDA/Transparency/Basics/ucm194320.htm .

The plant is native to South America (the area today belonging to Paraguay and Brazil). The sweet leaf and traditional preparations made from it have been used for very long (Lemus-Mondaca 2012). There are no sources with evidence concerning when the many peoples that have lived there started using stevia preparations in their food.

What we do know is that there were people in the area for a long time and when some had contact with Europeans, stevia was already employed in food preparations.

The glycosides found in stevia are (Brandle et al 1998, Lemus-Mondaca 2012)

  • Stevioside (5–10%)
  • Rebaudioside A (2–4%)
  • Rebaudioside C (1–2%)
  • Dulcoside A (0.5–1%)
  • Rebaudioside B
  • Rebaudioside D
  • Rebaudioside E

Stevia

Figure 2: S. rebaudiana glycosides (Lemus-Mondaca 2012)

The two compounds with the highest relevance for stevia’s sweet taste are Stevioside and Rebaudioside A.

Less purified or manipulated stevia preparations are sometimes less accepted than other NNS because of the aftertaste or bitterness of the product. Of the two glycosides, the less bitter-tasting is rebaudioside, which is also less prevalent. The industry has focused on extraction and purification technology to optimize rebaudioside.

Purified rebaudioside A is called Rebiana and some of the biggest soda and food industries have already marketed their brands: Truvia is the Cargill-Coca-Cola brand for an erythritol and rebiana sweetener and PureVia is PepsiCo’s competitor brand.

There are many stevia sweetener products besides the big brands. The only concern the consumer must have is to make sure to read the ingredients. If in the added ingredient list are the following substances, the product may not be safe for diabetic patients or anyone who is avoiding hyperglycemia or insulinogenic carbohydrates: dextrose, glucose, sucrose, maltodextrin, high fructose corn syrup.

Other added ingredients such as inulin, gum Arabic (acacia fiber), erythritol or xylitol are harmless: they are either soluble fibers or other natural carbohydrates not convertible to glucose, with no insulinogenic action and much less sweet than the stevia glycosides.

These are the major fillers and alarmist reactions to these additives are unfounded. If there is another intense sweetener in the ingredient list, such as sucralose or aspartame, then the sweet effect is a combination of the stevia glycosides and the other NNS.

The stevia sweetener products available in the market today are obtained from S. rebaudiana’s leaf. It is also possible to purchase the crude extract, although it hasn’t been approved by the FDA as a food additive. Several studies suggest that substances with a biological activity other than sweeteners can be obtained from the plant (Lemus-Mondaca 2012).

Some important examples are the inulin-type fructooligosaccharides present in the roots and also leaves (de Oliveira et al 2011), with potentially relevant prebiotic activity, and the insulinotropic effect (important in anti-diabetic action) of the non-sweetener fraction of the plant (Piovan et al 2018).

Rebaudiana extracts, from the whole plant, have shown, whether in animal models or in vitro, to have more properties than the sweet taste of the chief glycosides. Some of the other effects, whether from other glycosides or other chemical substance classes include anti-hyperglycemic, antihypertensive, anti-inflammatory, anti-tumor, anti-diarrhoeal, diuretic, and immunomodulatory effects (Lemus-Mondaca 2012). There are still no drugs from these isolated substances available in the market.

Is There Any Research?

There is little research, both in absolute numbers and relative to the world scientific production.

NNS research is usually related as a sub-theme to the weight loss issue, where diabetes and obesity are the greatest health concerns. Here we show the absolute and relative trends in scientific production. The first image represents the number of published articles each year containing a certain word or expression in the title (absolute increase).

The second image represents the documents matching the query, divided by the total number of publications per year and corrects for the increasing number of total publications (relative increase).

Diabetes has been a major concern for a long time, as can be seen by both the relative and absolute scientific production increase (figs 3 and 4). Obesity has a more recent rise in interest, matching a greater public health awareness about it (figs 5 and 6).

Diabetes research

Fig 3. Diabetes research – absolute increase. The vertical axis represents the total number of published articles in each year. The horizontal axis represents the years.

Diabetes research – relative increase

Fig 4. Diabetes research – relative increase. The vertical axis represents the number of published articles in each year corrected by the total number of publications. The horizontal axis represents the years. Palidwor et al. (2010) J. Biomed. Discov. Collab. 5, 1-6.

Obesity research – absolute increase

Fig. 5. Obesity research – absolute increase. The vertical axis represents the total number of published articles in each year. The horizontal axis represents the years.

 Obesity research – relative increase

Fig 6. Obesity research – relative increase. The vertical axis represents the number of published articles in each year corrected by the total number of publications. The horizontal axis represents the years. Palidwor et al. (2010) J. Biomed. Discov. Collab. 5, 1-6.

Scientific production about NNS doesn’t follow either diabetes or obesity curves. The absolute number of publications shows a recent rise, but in relative terms, it remains a topic of small scientific interest (figs 7 and 8).

Sweeteners research – absolute increase

Fig. 7. Sweeteners research – absolute increase. The vertical axis represents the total number of published articles in each year. The horizontal axis represents the years.

Sweeteners research – relative increase

Fig 8. Sweeteners research – relative increase. The vertical axis represents the number of published articles in each year corrected by the total number of publications. The horizontal axis represents the years. Palidwor et al. (2010) J. Biomed. Discov. Collab. 5, 1-6.

Stevia exhibits a recent rise both in absolute and relative terms, but it is still a small volume of research (figs 9 and 10). It does seem to be the focus of more attention than other NNS, now the object of research as a class of compounds that may cause dysbiosis and other deleterious effects (figs 11 and 12).

Research on Stevia shows up in reputable outlets, such as Molecular and Cellular Endocrinology (H index 120) or Food Chemistry (H index 193). The H index is a measure of both the impact and productivity of the journal. Topics of interest in Stevia research, have, however, diverged from obesity and weight control, into other topics such as antinociceptive properties, antioxidant, renal and hepatoprotection, among others.

tevia research – absolute increase

Fig. 9. Stevia research – absolute increase. The vertical axis represents the total number of published articles in each year. The horizontal axis represents the years.

Stevia research – relative increase.

Fig 10. Stevia research – relative increase. The vertical axis represents the number of published articles in each year corrected by the total number of publications. The horizontal axis represents the years. Palidwor et al. (2010) J. Biomed. Discov. Collab. 5, 1-6.

Aspartame research – absolute increase

Fig. 11. Aspartame research – absolute increase. The vertical axis represents the total number of published articles in each year. The horizontal axis represents the years.

Aspartame research – relative increase

Fig 12. Aspartame research – relative increase. The vertical axis represents the number of published articles in each year corrected by the total number of publications. The horizontal axis represents the years. Palidwor et al. (2010) J. Biomed. Discov. Collab. 5, 1-6.

Stevia versus Cancer

Some studies show that stevia has anti-cancer activity. Can you prevent cancer by consuming stevia (or more stevia)? Can you treat cancer by consuming more stevia? Unfortunately, there is still no stevia-based product in the market that can do that.

Stevia compounds have shown potential anti-tumor activity both in vitro and in animal models. Stevioside was shown to inhibit skin carcinogenesis in mice (Kanoshima & Takasaki 2002) and four Stevia leaf solvent extracts showed cytotoxic effects against cancer cell lines in vitro (Jayaraman et al 2008). Studies have also shown antiproliferative effects in cervix (HeLa), pancreatic (MiaPaCa-2) and colonic (HCT116) cancer cells (López et al. 2016). The mechanisms of action are still unclear.

Because certain stevia compounds have shown anti-oxidant activity (they scavenge reactive oxygen species), that alone is suggestive of tumor-protective action (Shivana et al 2013, Lemus-Mondaca et al. 2012, Goodman et al 2011).

Will Stevia Help You Lose Weight?

Stevia may be a powerful tool for weight loss as long as you use it as a sugar substitute because, this way, you will consume less calories.

Although most people looking for solutions to their real or perceived weight excess refer to their goal as “weight loss”, I will follow public health guidelines and adjust our nomenclature. I will start by calling it “weight management” since both epidemiologically (at the population level) and individually, the goal is not only to reduce weight or body fat but maintain it (Ryan & Kahan 2018).

In 2013, the American College of Cardiology/American Heart Association Task Force on Practice Guidelines reviewed the available evidence and I am adopting their report to offer a scientifically sound and medically official perspective on the subject (Yannakoulia et al 2019).

Weight gain (whether intentional or not) is a result of energy imbalance: energy intake is greater than energy expenditure (Doucet & Tremblay 1997). Weight loss (intentional or not) is the opposite: energy expenditure is greater than energy intake. There are many hormonal, neurologic and social factors that influence energy expenditure and what happens to the energy (food) that comes in is also regulated by several factors. That complexity is what makes the obesity epidemic/inactivity epidemic so hard to fix (Wing & Hill 2001, Donnelly et al. 2009, Church 2016).

In the end, whatever else is manipulated (hormones, adjustment of the brain-gut-microbiome, drugs, physical activity, social and urban interventions), weight and fat loss are achieved by a negative energy balance.

Therefore, there is one general and a few specific answers to the question (“will stevia help you lose weight?”): weight loss is always a result of negative calorie balance. Even when we consider the links between obesity and dysbiosis, or the several metabolic disorders that may result in weight gain, weight loss involves a negative calorie balance.

Stevia can help you lose weight and fat as long as it is used as a sugar substitute and its introduction in your diet results in a calorie deficit. In other words, if you use stevia and stevia-sweetened food instead of their sugar-sweetened alternative. Let’s simulate this. Suppose overweight Joe takes 2 portions of sweetened drink each day (soda, iced tea, juice, among others).

Their calorie content varies from 150-270 calories so let’s assume 150 for convenience. Suppose Joe drinks 2 portions of coffee with sugar each day. That will add an extra 100 calories from sugar. That is not an unrealistic scenario: the CDC estimates an average of 145 calories from sweet beverages among USA adults and the overweight population consumes more than that https://www.cdc.gov/nutrition/data-statistics/sugar-sweetened-beverages-intake.html .

If we substitute Joe’s sugar-sweetened beverages by stevia-sweetened beverages, Joe will ingest approximately 400 calories less if he doesn’t change anything else in his diet or physical activity pattern. If Joe’s bodyweight is 260, and he is inactive, his isocaloric diet (energy intake = expenditure) is around 3000 calories.

If he ingests 400 less than that just by using stevia instead of sugar, he will be adopting a 13% hypocaloric diet. This is close to the ideal deficit according to health organizations.

Stevia seems to have some added benefits for weight loss and management. In animal experiments, among several biochemical indicators changes, Elnaga and collaborators (2016) observed spontaneous decreased energy intake (decreased appetite).

As a final note, like all NNS, the results concerning weight loss are inconclusive and lack methodological comparability (Rojas et al. 2018). What we can positively say is that if stevia is used as a sugar substitute in a hypocaloric diet strategy, it will contribute to weight loss.

Is Stevia Helpful for Diabetics?

Can stevia help you control your diabetes? Yes, as a sugar substitute. The pharmacological anti-diabetic effects are promising but are still being studied. It is, therefore, not yet an anti-diabetic medication.

Any sweet substance that does not elevate blood glucose levels (Cantley & Ashcroft 2015), does not have an insulinogenic effect (Weyer et al 2001, Modan et al 1985, Luchsinger 2008) and is not metabolically active in any other way will, by definition, be helpful for diabetics. Diabetes mellitus is not one, but a group of metabolic disorders (Cantley & Ashcroft 2015) characterized by sustained high blood glucose levels and impaired insulin production.

Hyperinsulinemia is a symptom in the development of diabetes because it is the compensatory response to hepatic and muscle insulin resistance (Verhaeghe & Bouillon 2008, Van Buren & LeWinter 2011).

In that respect, any NNS will be not only helpful but necessary (depending on the type and stage of the disease) to diabetics.

It is possible, however, that stevia may have anti-diabetic biological action through other mechanisms (Philippaert et al 2017, Piovan et al 2018). Jeppesen and collaborators (2000) have found that stevioside and steviol stimulate insulin secretion via a direct action on pancreatic beta cells. This suggests that these compounds “may have a potential role as antihyperglycemic agents in the treatment of type 2 diabetes mellitus” (Jeppesen et al. 2000).

Bhasker and collaborators (Bhasker et al 2015), 15 years later, offered an explanation to the mechanism of action of the observed effect: stevioside and steviol have an insulinomimetic property: they have a functional similarity to insulin in controlling the level of glucose, as shown  in vitro studies.

Philippaert and collaborators (2017) have shown that these glycosides affect taste receptors and pancreatic beta cells because they share a Ca++ activated cation channel, TRPM5, which is potentiated by stevioside, rebaudioside A and their aglycon steviol.

More recent studies focused on the non-sweet fraction of stevia extracts. The insulinotropic, anti-oxidant and renal protective properties of stevia’s polyphenols are the focus of attention now (Shivanna et al 2013, Piovan 2018).

The takeaway for the diabetic patient is that the regular consumption of stevia-based sweeteners may be helpful in managing their illness but for advanced pharmacological therapies, they will have to wait until stevia-derived drugs from other fractions of the plant are developed. The obvious question is: can diabetics consume the crude extract or the whole plant, which contains all fractions?

First, the plant and the crude extract are not FDA approved. We have no positive confirmation about their safety. Second, by using a crude extract or a part of the plant, the compounds or fractions that showed biological activity when purified will not necessarily display the same effect.

Does It Reduce Cholesterol?

Can you count on stevia to control your high cholesterol? Not yet.

Among the potential health benefits of stevia consumption, here we have positive results in human experiments. Savita and collaborators (2004) used stevia leaf powder in selected recipes as a sugar substitute with 14 subjects, ages 35-55, of which eight were hypertensives (2 men and 6 women) and 6 were diabetics (4 men and 2 women).

The initial mean total serum cholesterol, HDL cholesterol, and LDL cholesterol were, respectively, 215.8, 54.7 and 134.7 mg/dl. After 30 days of consumption of stevia, the mean levels were 167.28, 34.78 and 102.94 mg/dl respectively. The experiment showed a decrease in the mean levels of total serum cholesterol, HDL cholesterol, and LDL cholesterol.

Another, more recent study (Sharma et al. 2009) with 20 hypercholesterolemic women reported slightly better results: the consumption of stevia extract reduced the levels of cholesterol, triglyceride, LDL-C significantly while an increased in HDL-C. Partial or comprehensive results on cholesterol reduction keep being confirmed in human and animal studies (Kassi et al 2016, Elnaga et al 2016, Ahmad et al 2018).

None of the studies reviewed here tested the cholesterol-lowering effect of commercially available stevia sweeteners. While research strongly suggests stevia might be a tool in cholesterol management, it doesn’t mean that consuming the commercial products available will have that effect.

Does It Lower Blood Pressure?

Can you use stevia products as an anti-hypertensive (a medication that reduces high blood pressure)? Not yet.

The anti-hypertensive properties of stevia were tested on humans, with positive results, in the early 2000s in China. Chan and collaborators carried out a study with 106 Chinese hypertensive patients (Chan et al 2001). The experimental group received a 250mg stevioside capsule each day for three months and had significant systolic and diastolic blood pressure decrease.

The effect persisted for a year. Also in China, a two-year randomized study with 174 patients taking 500mg stevioside powder three times daily showed a significant decrease in blood pressure in the experimental group (Hsieh et al. 2003). Two more recent studies showed no antihypertensive effect using doses between those employed in the first two studies (Ferri et al. 2006, Barriocanal et al. 2008).

The recent reviews used in this article all cite these same studies (Abbas Momtazi-Borojeni et al. 2017, Rojas et al. 2018). At this point, research is inconclusive concerning the anti-hypertensive properties of stevia.

Is Stevia Safe?

Stevia is safer than other NNS: this much seems to be possible to infer from published research. Also, the actual side effect risks of other NNS are still controversial, as mentioned before. But whether stevia is 100% safe and risk-free, there is no way to answer now.

If we consider the deleterious side effects of NNS derived from dysbiosis, a study presented at the IAFP 5th Latin American Symposium in Food Safety – 7th Food Science, Biotechnology and Safety Meeting (Álvarez et al 2016) showed evidence that stevia has a mild effect on the growth of certain gut bacteria. They are even less evidenced if corrected by the estimated daily intake.

Some concern was raised about recent data demonstrating that steviol and stevioside might act as glucocorticoid receptor (GR) agonists, producing adverse effects on metabolism.

Panagiotou and collaborators (2018) tested this hypothesis and concluded that although their study provides strong evidence that steviol and steviol glycosides exert GR-mediated effects in cancer Jurkat cells, the same effect is not observed in normal human cells.

The use of stevia sweetener products has been considered safe for a long time and the medical and research consensus have not changed (Geuns 2002, Sekihashi et al 2002, Ashwell 2015, Serra-Majem et al. 2018, Abbas Momtazi-Borojeni 2017, Zhang et al 2017).

Conclusion

Most NNS, in spite of the controversy, are considered safe for human consumption as reviewed by Chattopadhyay et al (2014). There will be increased concern about their effect on gut microbiota and you will be exposed to this debate. You will feel safer consuming stevia than other NNS and certainly safer than consuming a high content of other sweet sugars such as sucrose, glucose or fructose.

Whether you choose to substitute table sugar (sucrose) for NNS for weight control or for any other reason, such as the risks of a high sugar diet for cancer patients, for certain neurological disorders or whatever it is the leads you to this decision, stevia may be your safest choice.

As I explained here, although there may be promising results concerning other pharmacologically active compounds extracted from stevia addressing different health conditions, today stevia preparations must be considered a non-caloric sweetener option. It is not a good idea to use stevia for anything else like cancer treatment or hypertension.

Whatever is your reason for choosing a non-caloric sugar substitute, however, you may want to consider that it is just one item in the health toolbox for your strategy, whatever is your objective.

Using NNS in combination with a diet rich in high glycemic index carbohydrates, processed foods, low in fiber, consuming therapeutic or recreational substances, inactivity, neurological and psychiatric conditions all potentially contribute to the things you want to avoid. Some of these items will cause more damage than others and that also depends on the individual.

Stevia and all the technology being used to developed better food products and new pharmaceutical ones are a good thing. As always, however, there is no magic bullet.

Remember: individuality, effect magnitude, and lifestyle/health context. It all boils down to this.

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