Sugar Substitutes: What are the Healthiest Sweeteners?

packets of sweeteners in a jar

What are artificial sweeteners?

Artificial sweeteners aren’t found in nature. They’re sweet-tasting chemicals, created by synthesizing and modifying compounds. [1] The six synthetic FDA-approved artificial sweeteners include:

Artificial sweeteners are manufactured to taste sweet but contain negligible calories. Therefore, these artificial sweeteners are also known as “non-nutritive sweeteners”. [2] They are now emerging in a wide range of foods and beverages, taking over grocery stores.

The rapid development of artificial sweeteners began in 1879 with saccharin. [3] Aspartame and Ace-K were discovered in the 1960s, followed by sucralose in 1976, and neotame in the 1980s. [4] The most recent of the six is advantame in 2006. [5]

Many artificial sweeteners were banned for use as food additives throughout their development. The sweetener cyclamate got banned by the FDA in 1970 after investigations revealed it produced bladder tumors in lab rats. [6]

There's a lot of research on artificial sweeteners. It's important to note that many studies get funding from the companies that produce these products. [7] Some of these studies suggest that sweeteners have no link to health problems at all. Yet, there are plenty of independent studies that link artificial sweeteners to negative effects on our health.

How are artificial sweeteners made?

Aspartame, the most common artificial sweetener, is made by combining two amino acids: phenylalanine and aspartic acid. The resulting chemical compound is about 200 times sweeter than table sugar. [8]

Sucralose is made by chlorinating sucrose, or table sugar. The resulting compound is about 600 times sweeter than sugar. [9]

Saccharin is made by oxidizing a compound called o-toluene sulfonamide. The resulting compound is about 300 times sweeter than sugar. [10]

Acesulfame potassium, or Ace-K, is made by reacting acetoacetic acid with potassium. The resulting compound is about 200 times sweeter than sugar. [11]

After taking a look at a few of the “recipes,” it is safe to say that we can't make these in our kitchen. These sweeteners are even limited by the FDA in the amounts used in food and beverages, revealing their hesitancy. [12] As consumers, we face the question: are artificial sweeteners safe?

Are noncaloric sweeteners better than refined sugar?

Artificial sweeteners have been hotly debated in health circles. Some advocate for the use of non-nutritive sweeteners because unlike refined sugar, they don't contribute to our daily calorie intake. This perspective aligns with a trend in recent decades that focuses more on the number of calories rather than the quality of ingredients.

For marketing reasons, brands sell pseudo-foods with this persuading stipulation. Some people switch to artificial sweeteners to avoid the negative health effects of sugar. But research indicates artificial sweeteners aren’t the solution. In fact, they're creating a whole new set of problems.

The benefits of artificially-sweetened “diet” foods and beverages aren’t supported with evidence. Rather, they’re shown to increase weight, waist circumference, obesity, hypertension, metabolic syndrome, type 2 diabetes, and cardiovascular events. [13]

A major issue with artificial sweeteners is the lack of long-term human research we have on them. Without controlled trials, we have minimal confidence in their use. The evolving, adverse research shows that we should exercise caution here, and instead stick to time-tested, natural sweeteners.

Hunger signaling

Sweeteners that have no nutritional value can actually be more harmful than those that deliver calories. Our bodies get confused when we consume “food” that it doesn't recognize as food. It's like our bodies haven't caught up with the latest diet fads!

The feeling of satiation allows us control while eating. Satiation is crucial to regulating our appetite. After nourishing ourselves with a meal, we expect a feeling of satiation. After eating is over, satiety sets in and keeps us from eating more until our hunger strikes again. Hunger regulation is hijacked when we consume sweeteners without real energy content. [14]

Artificial sweeteners disrupt the body's ability to regulate energy intake, leading to overeating. The inconsistent pairing between a sweet taste and caloric content enhances our appetite. [15] Non-nutritive sweeteners can even interfere with the learned responses that control glucose and energy homeostasis. [16]

Substituting caloric sweeteners with noncaloric alternatives will lower the energy density of foods and beverages. However, there's a catch. This “benefit” doesn’t account for the change in metabolic and hormonal factors elicited by artificial sweeteners. [17] Diverse patterns of brain activation occur with these sweet-tasting products. [18] An impairment in energy regulation can override any caloric deficit set by choosing noncaloric sweeteners.

In animal studies, the lack of association between a sweet taste and energy content of foods using non-nutritive sweeteners leads to higher caloric intake, increased body weight, and reduced ability to compensate for the consumed calories. [19] Controlled human trials face various challenges when evaluating noncaloric sweeteners’ effectiveness for weight loss. The complex interplay of physiological, psychological, and behavioral factors makes it difficult to draw definitive conclusions. Factors such as genetics, diet, physical activity, and overall health status can influence the outcomes of these trials, further complicating the interpretation of results.

What about noncaloric “natural” extract sweeteners?

stevia leaf and refined powder

These natural sweeteners may be found in nature, but they are not natural for human consumption. Artificial sweeteners are typically synthetic compounds. However, there’s a category of high-intensity artificial sweeteners derived from natural sources. They’re considered to be “natural” alternatives to traditional sugar, but are classified as artificial by the FDA due to their manufacturing process or composition. [20] Two of the most common of these sweeteners are stevia extract and monk-fruit extract.

Many are led to believe that these extracts are healthy to consume. After all, they’re derived from nature, calorie-free, and cause little to no immediate side effects. However, these isolated substances are not of the same concentration as they are found in nature.

However, as we’ve seen, a food’s energy content plays a role in regulating our hunger signals. [21] Even with these “natural” noncaloric sweeteners, the presence of sweetness without nutritional value disrupts our body’s delicate balance of hunger regulation in the same way that synthetic noncaloric sweeteners do. [22] Avoiding the more detrimental effects of chemically manufactured sweeteners is a major priority, yet avoiding appetite confusion is just as important. For this reason, even natural noncaloric sweeteners may be problematic for our hunger homeostasis.

How do the noncaloric sweeteners stack up against each other?


One of the most used artificial sweeteners is aspartame – aka Equal®, NutraSweet®, and Sugar Twin®. Multiple mechanisms are at play to demonstrate the toxicity of aspartame.

Instead of metabolizing like refined sugar, aspartame gets metabolized into its three parts – the amino acids aspartic acid and phenylalanine, as well as methanol. [23] The two amino acids get absorbed in the small intestine and are metabolized by the liver. [24]

These amino acids are present in many natural foods and get used by the body in various processes. [25] When they’re naturally occurring in food, aspartic acid and phenylalanine are bound to a protein. Therefore they’re slowly digested and metabolized. When aspartame is consumed, these amino acids are in their free form, which are released directly into the bloodstream. [26]

Unlike dietary protein, consuming aspartame increases phenylalanine and aspartic acid levels in the brain. These compounds can inhibit the production and release of neurotransmitters like dopamine, norepinephrine, and serotonin, which are essential for regulating brain activity. [27]

Aspartame also produces a metabolite called aspartate, which acts as a neurotransmitter. [24] Aspartate serves as a precursor for the amino acid glutamate. Aspartate and glutamate in excess can be harmful to our central nervous system by exciting nerve cells to their death. [28] These excitotoxic effects are similar to the changes seen in neurodegenerative diseases like Alzheimer's disease, epilepsy, Huntington's disease, and multiple sclerosis. [23]


Sucralose, or Splenda®, has become as popular as table sugar. We can find this artificial sweetener on the table at restaurants in little yellow packets. This chlorinated sucrose derivative is “made from sugar so it tastes like sugar”, as implied in its slogan.

Unfortunately, this artificial sweetener is a little too similar to sugar. Sucralose has been shown to have negative effects on blood sugar and insulin levels. [29] Sucralose can ultimately increase insulin and blood sugar levels, causing insulin resistance – as shown by its decrease in insulin clearance rate. [29]

Ironically, avoiding these effects was the primary reason for a sugar alternative. To make matters worse, sucralose alters our gut microbiome by decreasing its beneficial bacteria by up to 50%. Animal studies suggest the beneficial bacteria in the gut can remain in these altered conditions for more than 12 weeks. [30]

Our gut microbiome plays a crucial role in maintaining our overall health by aiding in digestion, absorbing essential nutrients, and supporting our immune system. [31] A decrease in beneficial bacteria can even lead to mental health issues like mood disorders, anxiety, depression, and cognitive problems. [32]

Some of the more detrimental effects of sucralose are the chloropropanols and dioxins released while heated. Chloropropanols and dioxin are genotoxic, carcinogenic, and tumorigenic compounds. [33] Thermal decomposition takes place at temperatures used in baking. [34] [35] That said, we can expect all sucralose-containing foods to have carcinogenic potential.


One of the artificial sweeteners with the most troubling history is saccharin. Saccharin remains in our products today, even though it was initially banned in 1981 due to producing bladder tumors in rats. Since then, it’s been taken off of the US hazardous list. [36] Saccharin is found in little pink packets under the brand name Sweet ‘N Low®.

Foods containing saccharin, or Sweet ‘N Low®, used to require a warning label – “Use of this product may be hazardous to your health. This product contains saccharin, which has been determined to cause cancer in laboratory animals.”

Yet, saccharin got removed from the U.S. Department of Health and Human Services' list of substances that cause cancer in May 2000. [37] This decision was based on a reassessment of saccharin’s carcinogenic potential. Over 30 human studies were used to show that the effects observed in animals don’t apply to humans – implying safety in saccharin for human consumption. [38]

However, cancer isn’t the only health concern when it comes to saccharin, and more recent research has revealed additional areas of potential harm. For example, saccharin has been shown to contribute to impaired kidney and liver function, [39] hyperglycemia, [40] obesity, [41] and oxidative stress [42] – with some of this research conducted specifically in humans. All while ineffectively mitigating the effects of sugar. [40]

Despite the evident risks, saccharin is still in children’s medication, diet sodas, jelly, chewing gum, and salad dressings – to name a few.


Ace-K is a sweetener that is not metabolized by our body. Although this might seem like a benefit for people trying to regulate their blood sugar, it’s not that simple. This sweetener promotes insulin secretion, which makes reactive hypoglycemia (low blood sugar) worse. [43]

In vitro experiments show that Ace-K acts directly on pancreatic islets to heighten the release of insulin in response to glucose. [43] Alterations in our insulin release rate play a major role in our glucose utilization and metabolism. [44]

To make matters worse, Ace-K alters the gut microbiome and affects carbohydrate metabolism. Ace-K stimulates an abundance of pathogenic E. coli growth. [45] Through the consumption of Ace-K, evidence points to a decrease in the expression of genes involved in energy metabolism pathways. [46] While many of us already struggle with a sluggish metabolism, this is not a wise risk to take.

Sugar alcohols

Unlike artificial sweeteners, sugar alcohols are “nutritive sweeteners”. [47] However, nutritive doesn’t mean nutritious.

Sugar alcohols are generally recognized by the suffix “-itol”. The sugar alcohols approved for use internationally in food products are: [48]

We can find sugar alcohols on a nutrition label under Total Carbohydrate as “Sugar Alcohol”. We're told to subtract these from the Total Carbohydrates because the body doesn’t metabolize them. [49]

What’s interesting is that the chemical structure of sugar alcohols resembles that of both sugar and alcohol. [50] So, sugar alcohols get praised for their ability to replace sugar, often at a one-to-one ratio. The difference is that they lack the calories and possible health concerns of sugar.

Like artificial sweeteners, sugar alcohols aren’t metabolized by our bodies. Instead, sugar alcohols enter the bowels intact since they are not broken down in the stomach. This is when “passive diffusion” occurs in the intestines. Here, sugar alcohols cause the bowels to draw water in. This results in bacterial fermentation and minimal degradation of the sugar alcohols. The absorption of each sugar alcohol depends on its specific chemical structure. Each will have different gastrointestinal effects. [51]

The digestion of some sugar alcohols does in fact raise blood sugar levels – shown as they take the body out of ketosis. [50] The glycemic index values of sugar alcohols vary. Dependence on sugar alcohols for regulating blood sugar is an unreliable approach. Maltitol, for example, has a high glycemic index of 35-52. Yet erythritol has a glycemic index of 0. [1]

But this isn’t the only downside to these sweeteners. Their most detrimental effect is the impact on our digestion.

Sugar alcohol use contributes to abnormal gas and irritable bowel syndrome (IBS). [52] [53] It’s common to experience gas, bloating, and diarrhea from these sweeteners. [54]

The behavior of sugar alcohols in the gut lumen varies in effects. The molar mass and symmetry of each sugar alcohol will allow for different intestinal absorption. High permeation and intestinal uptake generates the most severe gastrointestinal disturbances.


The most commonly isolated compounds from the stevia plant are stevioside and rebaudioside A. [55] Stevia leaves and stevioside have little-to-no calories and do not cause blood glucose levels to rise. [56] This doesn’t make it devoid of health effects.

A study done on human sperm cells exposed to steviol demonstrated an ability to alter progesterone signaling at three different sites. This endocrine-disrupting potential is due to the steroidal structure of steviol glycosides (stevioside and rebaudioside A). [57] Additional research shows that stevia can negatively impact the gut microbiome, including in ways that could promote obesity and metabolic dysfunction. [58]

Monk-fruit extract

This sweetener is from a small, green fruit, with the species name Siraitia grosvenorii. The fruit contains chemical compounds called mogrosides that give a sweet taste. [59] Although mogrosides have antioxidant properties, no human studies have proven any benefits. [60]

We do know that mogrosides have the ability to stimulate the secretion of insulin. A study has shown pure mogroside isolates to trigger insulin secretion in pancreatic beta cells. [61] It’s vital for insulin secretion to be synchronized with glucose in the bloodstream to ensure proper blood glucose regulation. [62] Given the calorie-devoid nature of monk-fruit extract, we can expect physiological problems in the long run.

When it comes to sweeteners, there is no outsmarting nature. These isolated sweeteners derived from nature may seem promising, yet they give mixed signals to our bodies. This bears the question: What sweeteners are really natural to consume?


One of the newest sweeteners is Glyvia™, patented by BIOLOGIC PharmaMedical.

What is Glyvia?

Glyvia generally includes a blend of plant glycosides from Stevia rebaudiana (stevia), plant mogrosides from Siraitia grosvenorii (monk-fruit), amino acids, specifically glycine, and/or gymnemic acid from the Gymnemic sylvestre herb. [65] Glycosides are natural compounds in living organisms where sugar is bound to another functional group via a glycosidic bond. [66] The most well-known plant glycosides are the steviol glycosides, found in stevia, which are 250-300 times sweeter than sucrose. [67] Mogrosides are glycosides attached to a molecular backbone structure called a mogrol. The extract of Mogroside V from Siraitia grosvenorii is 250 times sweeter than sucrose. [68]

In the book The Glycemic Factor, Glyvia’s inventor claims it is a “zero carbohydrate, zero protein, zero-calorie, zero artificial ingredients, and zero aftertaste natural dietary supplement.” [69] While the sweetener is technically derived from natural ingredients (plant glycosides and amino acids), they are artificially combined to create a novel patented chemical.

How is Glyvia made?

According to the patent, the sweetener composition depends on the desired embodiment, such as the form (powder, capsule, tablet, or gel). Once decided, the formula is made with a combination of the four following main components:



Gymnemic acid:

Free glycine:

Glyvia is also subject to include standard binders that may be necessary, as in the formula for tablets. [65] While the individual molecules used to create Glyvia are found in nature, this novel combination of concentrated extracts is not and warrants further study.

What does Glyvia do?

This zero-carbohydrate sweetener is not digested the same way as sugar. Neither glycosides nor mogrosides have an impact on our blood glucose levels since they aren't absorbed in the upper gastrointestinal tract. The glycosidic linkage is resistant to human digestive enzymes. [74] In the colon, our gut microbes break down the glycosides into glucose and aglycones. Mogrosides are degraded by both digestive enzymes and intestinal microbiota, but not absorbed. [59] They are then broken down into the mogrol and its mono- and diglucosides. The glycoside and mogroside backbones are metabolized by our liver and excreted from the body.

There is no evidence that the glucose or glucosides are absorbed, as they’re presumed to be quickly utilized by colonic bacteria. [75] [76] [77] [78] These anaerobic bacteria generate short-chain fatty acids (SCFAs) with the carbohydrates through saccharolytic fermentation. [79] Glyvia’s glycosides and mogrosides are from Stevia rebaudiana and Siraitia grosvenorii, which significantly increase SCFAs acetate, valerate, propionate, and butyrate. [80] [81] Increased levels of SCFAs are associated with positive health outcomes related to appetite regulation, metabolic health, and body composition. [82] [83]

The gymnemic acid has two intentional roles within Glyvia. Firstly, the acid provides a slight anti-sweet effect. This seems counterintuitive, but it serves to mask the bitter aftertaste that often accompanies stevia. Next, gymnemic acid enhances insulin secretion and normalizes blood sugar levels. [84] [85] However, these effects are shown in studies administering upwards of 200-400 milligrams of gymnemic acid. [86] The dosage in Glyvia is about 25 milligrams per serving. [65]

To sweeten a 300-500 milliliter beverage, Glyvia contains approximately 4 grams of glycine. A common glycine supplement dosage is about 2-5 grams, so you're likely to notice the effects of glycine using Glyvia. This free glycine serves as a carrier for the glycoside component, but it also confers a sweet taste itself. With glycine as a carrier, less glycosides are required to deliver the same sweet taste. [65]

Additionally, glycine is a secretagogue of glucagon. [87] [88] In a study giving healthy subjects 1 mmol glycine per kilogram of lean body mass (≈4.6 grams) ingested alone, an increase in glucagon concentration was strongly stimulated. This increase persisted throughout the duration of the study. [87]

Glucagon has been shown to have an appetite-reducing effect. [89] Simultaneously, glucagon stimulates energy expenditure and thermogenic activity in brown adipose tissue. This combination of effects makes for a possible weight loss tool at the level of dosing likely in artificially sweetened drinks. [90]

Another selling point of this patented technology is that there is no glycemic response to follow its sweet taste. [91] Opting for a zero glycemic index sweetener, such as Glyvia, instead of sugar could improve chronically elevated blood glucose levels. Testing by the company revealed that after participants consumed 6 grams of Glyvia powder in water, with sweetness equivalent to table sugar, serum glucose levels remained at the low fasting level past a 75-minute test period. In contrast, consuming an equal sweetness of table sugar in water led to a significant and sustained rise in serum glucose levels lasting for nearly 70 minutes. [91]

Our stance on Glyvia?

Glyvia's advantage over table sugar lies in its lack of a glycemic response. However, it's worth noting that this short-term effect doesn't account for the potential effects of long-term consumption. As we’ve mentioned in the “Hunger signaling” section above, the body expects real energy and complex nutrients to accompany a sweet taste. Noncaloric sweeteners lead to a lack of satiation and further cravings down the line. [15] [14] Although Glyvia has not been specifically studied for this effect, the concept aligns with the nature of this noncaloric sweetener. This lack of satiation should be taken into account before considering Glyvia as a weight-loss tool.

How to avoid artificial sweeteners

The degree of risk when consuming artificial sweeteners varies, so it’s critical to be mindful of them. Be skeptical of products with the “sugar-free” or “no sugar added” label. This usually means they added artificial sweeteners. To know for sure, check the ingredients list on any food products you buy.

The following foods and beverages are likely to contain artificial sweeteners:


Natural sweetener options

There are amazing natural sweeteners used in place of artificial sweeteners. Not only are they healthier and safer, but they taste better than their artificial counterparts. These don’t confuse your appetite and satiation as artificial sweeteners do.

For example, the two following sweeteners provide us nutrition, alongside sweetness:

The recent fad that we should avoid natural sugars is not aligned with ancestral health. Unprocessed, whole-food carbohydrates are not to be confused with processed alternatives. These natural sweeteners provide us with sweetness and real energy.

Takeaway tips

The negative effects of artificial sweeteners and sugar alcohols are not worth the damage and confusion faced by our bodies. Sweeteners that are foreign to our bodies fail to compete with nature. We can easily avoid their effects with a switch to natural sweeteners.

There’s no need to panic if you’ve been using any of the harmful sweeteners mentioned long-term. It's also important not to stress or be overly critical of ourselves when future slip-ups occur. Instead, let’s focus on what we can control moving forward. Opting for natural sweeteners like honey and maple syrup is a step in the right direction. Natural sugars found in fruits provide sweetness along with beneficial nutrients and fiber, making them a perfect choice for satisfying our sweet cravings. By making mindful decisions, we can sustain a balanced approach to our healthful eating habits.


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