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Three artificial sweeteners in paper packets, coded by color: Equal (aspartame; blue), Sweet'N Low (saccharin, pink),[note 1] and Splenda (sucralose, yellow). Other colors used are green for stevia.[1]

A sugar substitute or artificial sweetener[2] is a food additive that provides a sweetness like that of sugar while containing significantly less food energy than sugar-based sweeteners, making it a zero-calorie (non-nutritive)[3] or low-calorie sweetener. Artificial sweeteners may be derived from plant extracts or processed by chemical synthesis. Sugar substitute products are commercially available in various forms, such as small pills, powders and packets.

Common sugar substitutes include aspartame, monk fruit extract, saccharin, sucralose, stevia, acesulfame potassium (ace-K) and cyclamate. These sweeteners are a fundamental ingredient in diet drinks to sweeten them without adding calories. Additionally, sugar alcohols such as erythritol, xylitol and sorbitol are derived from sugars.

No links have been found between approved artificial sweeteners and cancer in humans.[4] Reviews and dietetic professionals have concluded that moderate use of non-nutritive sweeteners as a relatively safe replacement for sugars that can help limit energy intake and assist with managing blood glucose and weight.

Types

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Artificial sweeteners may be derived through manufacturing of plant extracts or processed by chemical synthesis.

High-intensity sweeteners—one type of sugar substitute—are compounds with many times the sweetness of sucrose (common table sugar). As a result, much less sweetener is required and energy contribution is often negligible. The sensation of sweetness caused by these compounds is sometimes notably different from sucrose, so they are often used in complex mixtures that achieve the most intense sweet sensation.

In North America, common sugar substitutes include aspartame, monk fruit extract, saccharin, sucralose and stevia. Cyclamate is prohibited from being used as a sweetener within the United States, but is allowed in other parts of the world.[5]

Sorbitol, xylitol and lactitol are examples of sugar alcohols (also known as polyols). These are, in general, less sweet than sucrose but have similar bulk properties and can be used in a wide range of food products. Sometimes the sweetness profile is fine-tuned by mixing with high-intensity sweeteners.

Allulose

[edit]
Main article: Allulose

Allulose is a sweetener in the sugar family, with a chemical structure similar to fructose. It is naturally found in figs, maple syrup and some fruit. While it comes from the same family as other sugars, it does not substantially metabolize as sugar in the body.[6] The FDA recognizes that allulose does not act like sugar, and as of 2019, no longer requires it to be listed with sugars on U.S. nutrition labels.[7] Allulose is about 70% as sweet as sugar, which is why it is sometimes combined with high-intensity sweeteners to make sugar substitutes.[8]

Acesulfame potassium

[edit]
Main article: Acesulfame potassium

Acesulfame potassium (Ace-K) is 200 times sweeter than sucrose (common sugar), as sweet as aspartame, about two-thirds as sweet as saccharin, and one-third as sweet as sucralose. Like saccharin, it has a slightly bitter aftertaste, especially at high concentrations. Kraft Foods has patented the use of sodium ferulate to mask acesulfame's aftertaste. Acesulfame potassium is often blended with other sweeteners (usually aspartame or sucralose), which give a more sucrose-like taste, whereby each sweetener masks the other's aftertaste and also exhibits a synergistic effect in which the blend is sweeter than its components.

Unlike aspartame, acesulfame potassium is stable under heat, even under moderately acidic or basic conditions, allowing it to be used as a food additive in baking or in products that require a long shelf life. In carbonated drinks, it is almost always used in conjunction with another sweetener, such as aspartame or sucralose. It is also used as a sweetener in protein shakes and pharmaceutical products, especially chewable and liquid medications, where it can make the active ingredients more palatable.

Aspartame

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Main article: Aspartame

Aspartame was discovered in 1965 by James M. Schlatter at the G.D. Searle company. He was working on an anti-ulcer drug and accidentally spilled some aspartame on his hand. When he licked his finger, he noticed that it had a sweet taste. Torunn Atteraas Garin oversaw the development of aspartame as an artificial sweetener. It is an odorless, white crystalline powder that is derived from the two amino acids aspartic acid and phenylalanine. It is about 180–200 times sweeter than sugar,[9][10] and can be used as a tabletop sweetener or in frozen desserts, gelatins, beverages and chewing gum. When cooked or stored at high temperatures, aspartame breaks down into its constituent amino acids. This makes aspartame undesirable as a baking sweetener. It is more stable in somewhat acidic conditions, such as in soft drinks. Though it does not have a bitter aftertaste like saccharin, it may not taste exactly like sugar. When eaten, aspartame is metabolized into its original amino acids. Because it is so intensely sweet, relatively little of it is needed to sweeten a food product, and is thus useful for reducing the number of calories in a product.

The safety of aspartame has been studied extensively since its discovery with research that includes animal studies, clinical and epidemiological research, and postmarketing surveillance,[11] with aspartame being a rigorously tested food ingredient.[12] Although aspartame has been subject to claims against its safety,[13] multiple authoritative reviews have found it to be safe for consumption at typical levels used in food manufacturing.[11][13][14][15] Aspartame has been deemed safe for human consumption by over 100 regulatory agencies in their respective countries,[15] including the UK Food Standards Agency,[9] the European Food Safety Authority (EFSA),[10] and Health Canada.[16]

Cyclamate

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Main article: Cyclamate
Cyclamate-based sugar substitute sold in Canada (Sweet'N Low)

In the United States, the Food and Drug Administration banned the sale of cyclamate in 1969 after lab tests in rats involving a 10:1 mixture of cyclamate and saccharin (at levels comparable to humans ingesting 550 cans of diet soda per day) caused bladder cancer.[17] This information, however, is regarded as "weak" evidence of carcinogenic activity,[18] and cyclamate remains in common use in many parts of the world, including Canada, the European Union and Russia.[19][20]

Mogrosides (monk fruit)

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Main article: Siraitia grosvenorii

Mogrosides, extracted from monk fruit (which is commonly also called luǒ hán guò), are recognized as safe for human consumption and are used in commercial products worldwide.[21][22] As of 2017, it is not a permitted sweetener in the European Union,[23] although it is allowed as a flavor at concentrations where it does not function as a sweetener.[22] In 2017, a Chinese company requested a scientific review of its mogroside product by the European Food Safety Authority.[24] It is the basis of McNeil Nutritionals's tabletop sweetener Nectresse in the United States and Norbu Sweetener in Australia.[25]

Saccharin

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Main article: Saccharin
Saccharin, historical wrapping – Sugar Museum, Berlin

Apart from sugar of lead (used as a sweetener in ancient through medieval times before the toxicity of lead was known), saccharin was the first artificial sweetener and was originally synthesized in 1879 by Remsen and Fahlberg. Its sweet taste was discovered by accident. It had been created in an experiment with toluene derivatives. A process for the creation of saccharin from phthalic anhydride was developed in 1950, and, currently, saccharin is created by this process as well as the original process by which it was discovered. It is 300 to 500 times sweeter than sucrose and is often used to improve the taste of toothpastes, dietary foods and dietary beverages. The bitter aftertaste of saccharin is often minimized by blending it with other sweeteners.

Fear about saccharin increased when a 1960 study showed that high levels of saccharin may cause bladder cancer in laboratory rats. In 1977, Canada banned saccharin as a result of the animal research. In the United States, the FDA considered banning saccharin in 1977, but Congress stepped in and placed a moratorium on such a ban. The moratorium required a warning label and also mandated further study of saccharin safety.

Subsequently, it was discovered that saccharin causes cancer in male rats by a mechanism not found in humans. At high doses, saccharin causes a precipitate to form in rat urine. This precipitate damages the cells lining the bladder (urinary bladder urothelial cytotoxicity) and a tumor forms when the cells regenerate (regenerative hyperplasia). According to the International Agency for Research on Cancer, part of the World Health Organization, "This mechanism is not relevant to humans because of critical interspecies differences in urine composition".[26]

In 2001, the United States repealed the warning label requirement, while the threat of an FDA ban had already been lifted in 1991. Most other countries also permit saccharin, but restrict the levels of use, while other countries have outright banned it.

The EPA has removed saccharin and its salts from their list of hazardous constituents and commercial chemical products. In a 14 December 2010 release, the EPA stated that saccharin is no longer considered a potential hazard to human health.

Steviol glycosides (stevia)

[edit]
Main article: Stevia

Stevia is a natural non-caloric sweetener derived from the Stevia rebaudiana plant, and is manufactured as a sweetener.[27] It is indigenous to South America, and has historically been used in Japanese food products, although it is now common internationally.[27] In 1987, the FDA issued a ban on stevia because it had not been approved as a food additive, although it continued to be available as a dietary supplement.[28] After being provided with sufficient scientific data demonstrating safety of using stevia as a manufactured sweetener, from companies such as Cargill and Coca-Cola, the FDA gave a "no objection" status as generally recognized as safe (GRAS) in December 2008 to Cargill for its stevia product, Truvia, for use of the refined stevia extracts as a blend of rebaudioside A and erythritol.[29][30][31] In Australia, the brand Vitarium uses Natvia, a stevia sweetener, in a range of sugar-free children's milk mixes.[32]

In August 2019, the FDA placed an import alert on stevia leaves and crude extracts—which do not have GRAS status—and on foods or dietary supplements containing them, citing concerns about safety and potential for toxicity.[33]

Sucralose

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Main article: Sucralose

The world's most commonly used artificial sweetener,[19] sucralose is a chlorinated sugar that is about 600 times sweeter than sugar. It is produced from sucrose when three chlorine atoms replace three hydroxyl groups. It is used in beverages, frozen desserts, chewing gum, baked goods and other foods. Unlike other artificial sweeteners, it is stable when heated and can therefore be used in baked and fried goods. Discovered in 1976, the FDA approved sucralose for use in 1998.[34]

Most of the controversy surrounding Splenda, a sucralose sweetener, is focused not on safety but on its marketing. It has been marketed with the slogan, "Splenda is made from sugar, so it tastes like sugar." Sucralose is prepared from either of two sugars, sucrose or raffinose. With either base sugar, processing replaces three oxygen-hydrogen groups in the sugar molecule with three chlorine atoms.[35] The "Truth About Splenda" website was created in 2005 by the Sugar Association, an organization representing sugar beet and sugar cane farmers in the United States,[36] to provide its view of sucralose. In December 2004, five separate false-advertising claims were filed by the Sugar Association against Splenda manufacturers Merisant and McNeil Nutritionals for claims made about Splenda related to the slogan, "Made from sugar, so it tastes like sugar." French courts ordered the slogan to no longer be used in France, while in the U.S., the case came to an undisclosed settlement during the trial.[35]

There are few safety concerns pertaining to sucralose[37] and the way sucralose is metabolized suggests a reduced risk of toxicity. For example, sucralose is extremely insoluble in fat and, thus, does not accumulate in fatty tissues; sucralose also does not break down and will dechlorinate only under conditions that are not found during regular digestion (i.e., high heat applied to the powder form of the molecule).[38] Only about 15% of sucralose is absorbed by the body and most of it passes out of the body unchanged.[38]

In 2017, sucralose was the most common sugar substitute used in the manufacture of foods and beverages; it had 30% of the global market, which was projected to be valued at $2.8 billion by 2021.[19]

Sugar alcohol

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Main article: Sugar alcohol

Sugar alcohols, or polyols, are sweetening and bulking ingredients used in the manufacturing of foods and beverages, particularly sugar-free candies, cookies and chewing gums.[39][40] As a sugar substitute, they typically are less-sweet and supply fewer calories (about a half to one-third fewer calories) than sugar. They are converted to glucose slowly, and do not spike increases in blood glucose.[39][40][41]

Sorbitol, xylitol, mannitol, erythritol and lactitol are examples of sugar alcohols.[40] These are, in general, less sweet than sucrose, but have similar bulk properties and can be used in a wide range of food products.[40] The sweetness profile may be altered during manufacturing by mixing with high-intensity sweeteners.

Sugar alcohols are carbohydrates with a biochemical structure partially matching the structures of sugar and alcohol, although not containing ethanol.[40][42] They are not entirely metabolized by the human body.[42] The unabsorbed sugar alcohols may cause bloating and diarrhea due to their osmotic effect, if consumed in sufficient amounts.[43] They are found commonly in small quantities in some fruits and vegetables, and are commercially manufactured from different carbohydrates and starch.[40][42][44]

Production

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The majority of sugar substitutes approved for food use are artificially synthesized compounds. However, some bulk plant-derived sugar substitutes are known, including sorbitol, xylitol and lactitol. As it is not commercially profitable to extract these products from fruits and vegetables, they are produced by catalytic hydrogenation of the appropriate reducing sugar. For example, xylose is converted to xylitol, lactose to lactitol, and glucose to sorbitol.

Use

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Reasons for use

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Sugar substitutes are used instead of sugar for a number of reasons, including:

Dental care

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Carbohydrates and sugars usually adhere to the tooth enamel, where bacteria feed upon them and quickly multiply.[45] The bacteria convert the sugar to acids that decay the teeth. Sugar substitutes, unlike sugar, do not erode teeth as they are not fermented by the microflora of the dental plaque. A sweetener that may benefit dental health is xylitol, which tends to prevent bacteria from adhering to the tooth surface, thus preventing plaque formation and eventually tooth decay. A Cochrane review, however, found only low-quality evidence that xylitol in a variety of dental products actually has any benefit in preventing tooth decay in adults and children.[45]

Dietary concerns

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Sugar substitutes are a fundamental ingredient in diet drinks to sweeten them without adding calories. Additionally, sugar alcohols such as erythritol, xylitol and sorbitol are derived from sugars. In the United States, six high-intensity sugar substitutes have been approved for use: aspartame, sucralose, neotame, acesulfame potassium (Ace-K), saccharin and advantame.[5] Food additives must be approved by the FDA,[5] and sweeteners must be proven as safe via submission by a manufacturer of a GRAS document.[46] The conclusions about GRAS are based on a detailed review of a large body of information, including rigorous toxicological and clinical studies.[46] GRAS notices exist for two plant-based, high-intensity sweeteners: steviol glycosides obtained from stevia leaves (Stevia rebaudiana) and extracts from Siraitia grosvenorii, also called luo han guo or monk fruit.[5]

Glucose metabolism
[edit]
  • Diabetes mellitus – People with diabetes limit refined sugar intake to regulate their blood sugar levels. Many artificial sweeteners allow sweet-tasting food without increasing blood glucose. Others do release energy but are metabolized more slowly, preventing spikes in blood glucose. A concern, however, is that overconsumption of foods and beverages made more appealing with sugar substitutes may increase risk of developing diabetes.[47] A 2014 systematic review showed that a 330ml/day (an amount little less than the standard U.S can size) consumption of artificially sweetened beverages lead to increased risks of type 2 diabetes.[48] A 2015 meta-analysis of numerous clinical studies showed that habitual consumption of sugar sweetened beverages, artificially sweetened beverages, and fruit juice increased the risk of developing diabetes, although with inconsistent results and generally low quality of evidence.[47] A 2016 review described the relationship between non-nutritive sweeteners as inconclusive.[48] A 2020 Cochrane systematic review compared several non-nutritive sweeteners to sugar, placebo and a nutritive low-calorie sweetener (tagatose), but the results were unclear for effects on HbA1c, body weight and adverse events.[49] The studies included were mainly of very low certainty and did not report on health-related quality of life, diabetes complications, all-cause mortality or socioeconomic effects.[49]
  • Reactive hypoglycemia – Individuals with reactive hypoglycemia will produce an excess of insulin after quickly absorbing glucose into the bloodstream. This causes their blood glucose levels to fall below the amount needed for proper body and brain function. As a result, like diabetics, they must avoid intake of high-glycemic foods like white bread, and often use artificial sweeteners for sweetness without blood glucose.

Cost and shelf life

[edit]

Many sugar substitutes are cheaper than sugar in the final food formulation. Sugar substitutes are often lower in total cost because of their long shelf life and high sweetening intensity. This allows sugar substitutes to be used in products that will not perish after a short period of time.[50]

Acceptable daily intake levels

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In the United States, the FDA provides guidance for manufacturers and consumers about the daily limits for consuming high-intensity sweeteners, a measure called acceptable daily intake (ADI).[5] During their premarket review for all of the high-intensity sweeteners approved as food additives, the FDA established an ADI defined as an amount in milligrams per kilogram of body weight per day (mg/kg bw/d), indicating that a high-intensity sweetener does not cause safety concerns if estimated daily intakes are lower than the ADI.[51] The FDA states: "An ADI is the amount of a substance that is considered safe to consume each day over the course of a person's lifetime." For stevia (specifically, steviol glycosides), an ADI was not derived by the FDA, but by the Joint Food and Agricultural Organization/World Health Organization Expert Committee on Food Additives, whereas an ADI has not been determined for monk fruit.[51]

For the sweeteners approved as food additives, the ADIs in milligrams per kilogram of body weight per day are:[51]

Mouthfeel

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If the sucrose, or other sugar, that is replaced has contributed to the texture of the product, then a bulking agent is often also needed. This may be seen in soft drinks or sweet teas that are labeled as "diet" or "light" that contain artificial sweeteners and often have notably different mouthfeel, or in table sugar replacements that mix maltodextrins with an intense sweetener to achieve satisfactory texture sensation.

Sweetness intensity

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The FDA has published estimates of sweetness intensity, called a multiplier of sweetness intensity (MSI) as compared to table sugar.

Plant-derived

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The sweetness levels and energy densities are in comparison to those of sucrose.

Name Relative sweetness
to sucrose by weight 		Sweetness by food energy Energy density Notes
Brazzein 1250 Protein
Curculin 1250 Protein; also changes the taste of water and sour solutions to sweet
Erythritol 0.65 14 0.05
Fructooligosaccharide 0.4
Glycyrrhizin 40
Glycerol 0.6 0.55 1.075 E422
Hydrogenated starch hydrolysates 0.65 0.85 0.75
Inulin 0.1
Isomalt 0.55 1.1 0.5 E953
Isomaltooligosaccharide 0.5
Isomaltulose 0.5
Lactitol 0.4 0.8 0.5 E966
Mogroside mix 300
Mabinlin 100 Protein
Maltitol 0.825 1.7 0.525 E965
Maltodextrin 0.15
Mannitol 0.5 1.2 0.4 E421
Miraculin A protein that does not taste sweet by itself but modifies taste receptors to make sour foods taste sweet temporarily
Monatin 3,000 Sweetener isolated from the plant Sclerochiton ilicifolius
Monellin 1,400 Sweetening protein in serendipity berries
Osladin 500
Pentadin 500 Protein
Polydextrose 0.1
Psicose 0.7
Sorbitol 0.6 0.9 0.65 Sugar alcohol, E420
Stevia 250 Extracts known as rebiana, rebaudioside A, a steviol glycoside; commercial products: Truvia, PureVia, Stevia In The Raw
Tagatose 0.92 2.4 0.38 Monosaccharide
Thaumatin 2,000 Protein; E957
Xylitol 1.0 1.7 0.6 E967

Artificial

[edit]
Name Relative sweetness to
sucrose by weight 		Trade name Approval Notes
Acesulfame potassium 200[51] Nutrinova FDA 1988 E950 Hyet Sweet
Advantame 20,000[51] FDA 2014 E969
Alitame 2,000 approved in Mexico, Australia, New Zealand and China Pfizer
Aspartame 200[51] NutraSweet, Equal FDA 1981, EU-wide 1994 E951 Hyet Sweet
Salt of aspartame-acesulfame 350 Twinsweet E962
Carrelame 200,000
Sodium cyclamate 40 FDA banned 1969, approved in EU and Canada E952, Abbott
Dulcin 250 FDA banned 1950
Glucin 300
Lugduname 220,000–300,000
Neohesperidin dihydrochalcone 1650 EU 1994 E959
Neotame 7,000–13,000[51] NutraSweet FDA 2002 E961
P-4000 4,000 FDA banned 1950
Saccharin 200–700[51] Sweet'N Low FDA 1958, Canada 2014 E954
Sucralose 600[51] Kaltame, Splenda Canada 1991, FDA 1998, EU 2004 E955, Tate & Lyle

Sugar alcohols

[edit]
Sugar alcohols relative sweetness[42][52]
Name Relative sweetness
to sucrose by weight 		Food energy (kcal/g) Sweetness per food energy,

relative to sucrose

Food energy for equal

sweetness, relative to sucrose

Arabitol 0.7 0.2 14 7.1%
Erythritol 0.8 0.21 15 6.7%
Glycerol 0.6 4.3 0.56 180%
HSH 0.4–0.9 3.0 0.52–1.2 83–190%
Isomalt 0.5 2.0 1.0 100%
Lactitol 0.4 2.0 0.8 125%
Maltitol 0.9 2.1 1.7 59%
Mannitol 0.5 1.6 1.2 83%
Sorbitol 0.6 2.6 0.92 108%
Xylitol 1.0 2.4 1.6 62%
Compare with:

Sucrose

1.0 4.0 1.0 100%

Research

[edit]

Body weight

[edit]

Reviews and dietetic professionals have concluded that moderate use of non-nutritive sweeteners as a safe replacement for sugars may help limit energy intake and assist with managing blood glucose and weight.[53][54][55] Other reviews found that the association between body weight and non-nutritive sweetener usage is inconclusive.[48][56][57] Observational studies tend to show a relation with increased body weight, while randomized controlled trials instead show a little causal weight loss.[48][56][57] Other reviews concluded that use of non-nutritive sweeteners instead of sugar reduces body weight.[53][54]

Obesity

[edit]

There is little evidence that artificial sweeteners directly affect the onset and mechanisms of obesity, although consuming sweetened products is associated with weight gain in children.[58][59] Some preliminary studies indicate that consumption of products manufactured with artificial sweeteners is associated with obesity and metabolic syndrome, decreased satiety, disturbed glucose metabolism, and weight gain, mainly due to increased overall calorie intake, although the numerous factors influencing obesity remain poorly studied, as of 2021.[58][59][60][61]

Cancer

[edit]

Multiple reviews have found no link between artificial sweeteners and the risk of cancer.[48][62][63][64] FDA scientists have reviewed scientific data regarding the safety of aspartame and different sweeteners in food, concluding that they are safe for the general population under common intake conditions.[65]

Mortality

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High consumption of artificially sweetened beverages was associated with a 12% higher risk of all-cause mortality and a 23% higher risk of cardiovascular disease (CVD) mortality in a 2021 meta-analysis.[66] A 2020 meta-analysis found a similar result, with the highest consuming group having a 13% higher risk of all-cause mortality and a 25% higher risk of CVD mortality.[67] However, both studies also found similar or greater increases in all-cause mortality when consuming the same amount of sugar-sweetened beverages.

Non-nutritive sweeteners vs sugar

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Further information: Sugar § Health effects

The World Health Organization does not recommend using non-nutritive sweeteners to control body weight, based on a 2022 review that could only find small reductions in body fat and no effect on cardiometabolic risk.[68] It recommends fruit or non-sweetened foods instead.[69]

See also

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Notes

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References

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Sugar substitute

View on Grokipedia
from Grokipedia
Sugar substitutes are additives that provide a sweet with substantially fewer calories than , enabling their use in products aimed at reducing , managing , or catering to low-carbohydrate diets. These include high-intensity artificial sweeteners such as , , , and ; plant-derived options like glycosides and monk fruit extract; and polyols or sugar alcohols such as , , and , which contribute partial calories but resist full . Regulatory bodies including the U.S. deem most sugar substitutes safe for consumption within established limits based on toxicological reviews, yet empirical evidence from cohort studies and meta-analyses indicates associations with adverse outcomes like disrupted , impaired glucose metabolism, heightened cardiovascular risk, no sustained benefit for or prevention, and accelerated cognitive decline and brain aging. Observational data link regular to elevated incidences of , coronary events, and , while mechanistic studies in animals and humans suggest causal pathways involving appetite dysregulation, , and microbial , challenging assumptions of inertness despite industry-backed approvals. These findings underscore ongoing debates, with peer-reviewed syntheses recommending caution over promotion as healthy alternatives, particularly for long-term use.

History

Early Discoveries and Development

![Saccharin in Zucker-Museum][float-right] , the first artificial sweetener, was discovered on February 27, 1879, by Russian chemist Constantin Fahlberg while experimenting with derivatives in Ira Remsen's laboratory at . Fahlberg noticed the sweet taste accidentally after contaminating his food with an oxidized derivative of o-toluenesulfonamide, leading to its identification as benzoic sulfimide, approximately 300-400 times sweeter than without caloric value. Fahlberg patented the compound in 1884 and began commercial production, initially marketing it as a non-nutritive sugar substitute for cost efficiency in an era when refined sugar remained expensive. Although saw limited early adoption in pharmaceuticals and products for flavor enhancement due to its intense sweetness and stability, its rudimentary commercialization focused on bulk production from derived from . Widespread use accelerated during amid acute shortages and rationing, as governments promoted it to conserve supplies for military needs, with U.S. consumption surging as prices escalated. This empirical driver—scarcity-induced cost pressures rather than health considerations—propelled from laboratory curiosity to industrial staple, with production scaling via to meet demand. Cyclamate, another early synthetic substitute, emerged in 1937 when University of Illinois graduate student Michael Sveda accidentally identified the sweet taste of cyclohexylsulfamic acid while synthesizing potential anti-infective agents. Initially explored for industrial applications, its non-caloric sweetness prompted a shift toward uses in the 1950s, with introducing cyclamate tablets for diabetics seeking sugar alternatives without caloric intake. Approximately 30-50 times sweeter than , 's development emphasized economic viability in low-calorie products, building on saccharin's precedent amid post-war interest in affordable sweetening amid fluctuating sugar costs.

20th Century Milestones

The post-World War II era witnessed rising obesity prevalence in developed nations, attributed to increased caloric consumption including from sugars, which heightened demand for low-calorie alternatives to traditional sugar. In 1969, the U.S. Food and Drug Administration (FDA) banned cyclamates, artificial sweeteners widely used since the 1950s, following studies in rats showing bladder tumors at high doses, often when combined with saccharin. Subsequent evaluations determined that the carcinogenic mechanism observed in rodents, involving bladder stones, did not apply to humans due to physiological differences. Despite petitions and further research in the 1970s and 1980s demonstrating no human cancer risk, the FDA maintained the ban, citing insufficient proof of absolute safety, though cyclamates remained approved in over 50 countries. Aspartame was discovered in 1965 by chemist James Schlatter at G.D. Searle & Company during synthesis of an anti-ulcer peptide, when he accidentally tasted its intense sweetness. Initial safety concerns arose from 1970s animal studies suggesting possible brain tumor links, prompting FDA to revoke a provisional 1974 approval and convene a public board of inquiry. After additional testing resolved these issues, the FDA approved aspartame in 1981 for use in dry foods, expanding approvals later for beverages and other products. Sucralose emerged in 1976 from efforts by researchers in the UK to modify via selective chlorination, yielding a compound 600 times sweeter than . Over 110 studies confirmed its safety, including no or carcinogenicity, and highlighted its unique heat and acid stability, enabling use in cooking and baking unlike many predecessors. The FDA granted approval in 1998 for 15 food and beverage categories, marking a major advancement in versatile non-caloric sweeteners.

Post-2000 Expansions and Innovations

In response to escalating global prevalence, which reached 422 million cases by and continued to rise, demand for natural sugar substitutes intensified post-2000, prompting regulatory approvals and product innovations emphasizing plant-derived options over synthetic alternatives. The U.S. Food and Drug Administration issued a "no questions" letter in 2008 affirming the Generally Recognized as Safe (GRAS) status for highly purified steviol glycosides derived from stevia leaves, enabling their widespread use as a zero-calorie sweetener with 200-300 times the sweetness of sucrose. Similarly, monk fruit extracts rich in mogrosides received GRAS designation in 2010, supporting their incorporation into beverages and confections due to their natural origin and intense sweetness profile, up to 250 times that of sugar. These approvals aligned with consumer preferences for "natural" labeling, spurring market entries by companies seeking to replace high-fructose corn syrup in low-sugar formulations. Allulose, a rare sugar with 70% of sucrose's sweetness and minimal caloric impact, gained expanded regulatory footing in 2019 when the FDA issued guidance permitting its exclusion from total and added sugars counts on nutrition labels, facilitating broader adoption in baked goods and . Production advancements followed, with enzymatic conversion methods scaling up by 2023 through engineered microbial systems achieving over 60% yield from glucose substrates, improving cost-efficiency and sensory mimicry of sugar's bulking properties. Ingredion introduced a breakthrough stevia solution in April 2024 under its PureCircle brand, featuring rebaudioside M with 100 times greater solubility than standard forms, allowing seamless integration into clear beverages without crystallization or aftertaste issues. Concurrently, consumption expanded in sugar-free products despite emerging alerts from cardiovascular association studies starting in 2023, reflecting its established role as a with cooling and heat stability for cooking applications.

Classification

Natural and Plant-Derived

, the primary sweetening compounds in leaves, are glycosides that occur naturally in this South American herb. These glycosides, including and , impart a intensity of 250–300 times that of while providing zero calories, as they pass through the digestive system largely unabsorbed and unmetabolized. These properties also render them non-cariogenic, as they are not fermented by oral bacteria such as Streptococcus mutans, thereby supporting dental health by reducing the risk of tooth decay, similar to certain sugar alcohols. Mogrosides, extracted from the fruit of (monk fruit), are triterpenoid glycosides such as mogroside V, which deliver sweetness 100–300 times greater than depending on purity, with no caloric contribution due to non-digestibility. These compounds also exhibit activity, attributed to their cucurbitacin-like structure, and have received (GRAS) status from the U.S. for use in products without associated fermentation byproducts in direct extracts. They are likewise non-cariogenic, not fermented by oral bacteria, thereby supporting dental health by reducing caries risk, akin to the benefits observed with select sugar alcohols. Allulose, also known as D-psicose, is a rare of found in trace amounts (typically less than 1 g/kg) in natural sources including figs, raisins, and other dried fruits. It offers about 70% of sucrose's sweetness and approximately 0.4 kcal/g, with most ingested allulose excreted unmetabolized, resulting in negligible net caloric impact; emerging evidence suggests potential prebiotic effects through selective fermentation by .

Sugar Alcohols

Sugar alcohols, also known as polyols, are carbohydrates produced by the of , resulting in reduced caloric availability due to incomplete absorption in the via passive . They provide approximately 2-3 kcal/g, compared to 4 kcal/g for , as a portion passes undigested to the , where it exerts osmotic effects. This partial digestibility distinguishes them from fully fermentable , contributing to their use in low-calorie products. Common sugar alcohols include , derived from or corncobs through extraction and ; , produced by hydrogenating glucose from ; and , obtained via microbial fermentation of glucose followed by purification. is not fermented by oral bacteria such as , reducing acid production and plaque formation, which confers dental benefits including up to 30-60% caries reduction in studies using gum. offers about 2.6 kcal/g and 50-60% sweetness relative to but is poorly absorbed, with excess leading to fermentation by . , in contrast, is rapidly absorbed (up to 90%) and excreted unchanged in , yielding near-zero net calories (0 kcal/g for labeling purposes) with minimal metabolic impact. High intake of sugar alcohols can cause effects, including osmotic , , and abdominal discomfort, due to unabsorbed s drawing into the intestines and serving as substrates for bacterial fermentation. Tolerance varies, but doses exceeding 20-50 g/day often trigger symptoms in healthy individuals. , another , exemplifies osmotic properties historically exploited in as a to reduce by drawing fluid from tissues, though it risks from renal osmotic stress. Overall, their non-fermentability by oral pathogens supports reduced cariogenic potential across types.

Synthetic and Artificial

Aspartame, chemically N-(L-α-aspartyl)-L-phenylalanine methyl , is a composed of and linked as a methyl , providing approximately 200 times the of while metabolizing into its constituent and in the body. Its molecular design enhances receptor binding for intense but renders it susceptible to at elevated temperatures above 100°C, preventing effective use in or prolonged heating processes. Acesulfame potassium, the potassium salt of 6-methyl-1,2,3-oxathiazine-4(3H)-one 2,2-dioxide, delivers about 200 times the sweetness of sucrose with high heat stability up to 200°C, allowing incorporation into cooked and processed foods without degradation. Sucralose, produced by selective chlorination of sucrose at the 4-, 6-, and 1'-positions to replace hydroxyl groups with chlorine atoms, achieves 600 times the sweetness potency of sucrose and exhibits robust thermal and pH stability, passing through the digestive system with over 85% excretion unchanged due to poor absorption and metabolism. Post-2000 innovations include , an N-[3-(3-hydroxy-4-methoxyphenyl)propyl] derivative of featuring a 3,3-dimethylbutyl on the nitrogen, which amplifies sweetness to 7,000–13,000 times that of by strengthening interactions with the sweet while reducing off-notes like bitterness through altered and minimal breakdown. Advantame, approved by the FDA in , further refines this approach with an N-(2,2-dimethylpropyl)-L-aspartyl-L-phenylalanine 1-methyl structure incorporating an isovaleryl group, yielding up to 37,000 times 's sweetness and engineered resistance to metabolic enzymes, thereby minimizing aftertaste and enabling ultra-low usage levels in formulations.

Production

Natural Extraction Processes

Steviol glycosides, the primary sweet compounds in Stevia rebaudiana leaves, are extracted through a process beginning with drying the leaves to preserve bioactive components, followed by steeping in hot water or ethanol to solubilize the glycosides. The crude extract undergoes purification via ion exchange resins, adsorption chromatography, or alcohol precipitation to isolate rebaudioside A (Reb A), which constitutes a smaller fraction of total glycosides (typically 2-4% in leaves) and exhibits reduced bitterness compared to stevioside. This selective purification yields high-purity Reb A (>95%), but low natural abundance limits overall efficiency, with extraction yields around 5-10% of leaf dry weight, necessitating large-scale cultivation and contributing to higher costs despite stevia's relatively sustainable growth in subtropical regions. Mogrosides from monk fruit (Siraitia grosvenorii), native to southern , are obtained by drying the and extracting with hot , which efficiently solubilizes these cucurbitane glycosides due to their water solubility. The extract is then clarified and concentrated, often via resin adsorption to enrich mogroside V, the sweetest component (300 times ), achieving purities up to 50% but with overall fruit yields limited by the plant's small-scale cultivation—average farms produce about 200,000 fruits per harvest on 4-acre plots. Low global supply, primarily from , results in extraction yields below 1% mogrosides per fruit weight, driving imports and sustainability concerns from intensive harvesting and variable weather impacts on this perennial vine. D-allulose, a rare monosaccharide occurring trace amounts in figs and wheat, is produced industrially via enzymatic isomerization of D-fructose derived from corn starch hydrolysis, using D-tagatose 3-epimerase (DTEase) or similar ketose 3-epimerases to catalyze the C-3 epimerization. Fructose is first obtained by enzymatic liquefaction and saccharification of corn starch, yielding high-fructose syrups, then converted to allulose at rates of 20-30% under optimized conditions (e.g., 60°C, pH 7-8). This biological mimicry enables scalability beyond natural sources, but enzyme immobilization and recycling address yield limitations, as raw conversion efficiencies remain below 50% without enhancements, tying sustainability to corn monoculture's environmental footprint including water use and pesticide reliance.

Chemical Synthesis and Fermentation

Saccharin, the simplest synthetic non-nutritive sweetener, is produced industrially through oxidation of o-toluenesulfonamide, an intermediate derived from sulfonation and amidation. The process typically involves treating o-toluenesulfonamide with an like in an alkaline at 25–35°C, followed by acidification to yield the cyclic structure of . This chemical route enables efficient, large-scale production without reliance on natural precursors, minimizing variability and costs compared to extraction methods. Sucralose synthesis starts with and employs selective chlorination to replace three hydroxyl groups—specifically at positions 4, 6, and 1'—with atoms across a five-step process, often involving protection of the 6-position as an to direct reactivity. The chlorination uses reagents like or derivatives in non-aqueous solvents, yielding with about 600 times the sweetness of and minimal gastrointestinal absorption due to its modified structure. This targeted chemical modification achieves high specificity and yield, bypassing biological limitations for a stable, zero-calorie product. Fermentation-based production dominates for certain sugar alcohols, such as , where glucose serves as the carbon source fermented by osmotolerant yeasts like lipolytica or Trichosporonoides sp. under high osmotic stress (e.g., 200–400 g/L sugar) and controlled pH around 5. The yeast reduces glucose via the , excreting erythritol extracellularly, with subsequent purification through ion-exchange and to exceed 99% purity. This microbial method offers scalability and lower energy input than purely chemical routes, producing erythritol at rates up to 2.8 g/L/h in optimized fed-batch systems. In contrast, production relies on catalytic of from , using or catalysts at 100–140°C and 10–125 pressure. This older chemical process generates alongside byproducts, requiring separation via or , but achieves near-complete conversion (95–99%) in continuous fixed-bed reactors for industrial . alternatives for thus provide a complementary biological , reducing 's high-pressure demands while targeting lower-calorie polyols.

Quality Control and Scalability Challenges

(HPLC) is routinely employed in the manufacturing of synthetic sugar substitutes like to detect and quantify impurities, including residual solvents and byproducts from chlorination processes, with detection limits as low as 0.02 mg/kg in complex matrices. Regulatory agencies such as the FDA enforce strict limits on these impurities, often at parts per million (ppm) levels, under guidelines like ICH Q3C for residual solvents, classifying substances like (a potential solvent in synthesis) as Class 2 with permitted daily exposures to minimize risks from carryover. These controls ensure batch consistency but demand advanced analytical validation to differentiate from degradation products or unreacted . Scalability poses significant hurdles for rare sugars such as allulose, historically limited by inefficient enzymatic conversion from , which drove high production costs and constrained commercial viability. In 2023, a breakthrough collaboration between UC Davis and Mars Edge introduced a streamlined microbial pathway using engineered , bypassing multiple purification steps in traditional methods and enabling large-scale output at reduced costs. This innovation addressed stability and yield limitations, facilitating broader adoption in food formulations, though ongoing challenges include optimizing conditions for consistent high-purity yields above 90%. Natural plant-derived substitutes, such as glycosides or monk fruit extracts, exhibit pronounced batch-to-batch variability stemming from factors like conditions, harvest timing, and genetic differences in source plants, leading to fluctuations in active compound concentrations and incidental impurities. protocols, including solvent extraction followed by chromatographic purification and sensory profiling, are essential to mitigate off-flavors from polyphenolic contaminants or inconsistent profiles, with regulatory bodies like EFSA requiring compositional data from at least five batches to verify uniformity. Adulteration risks further complicate , necessitating forensic methods like NMR to confirm authenticity and purity levels exceeding 95% for key sweetening components.

Properties

Sweetness Intensity and Mechanisms

The perception of sweetness from sugar substitutes arises primarily from their interaction with the human , a heterodimeric composed of TAS1R2 and TAS1R3 subunits expressed on type II cells in the and . Upon binding, these induce conformational changes in the receptor's domain (primarily in TAS1R2), leading to activation, intracellular signaling via Cβ2, and release of neurotransmitters that transmit the sweet signal to the . This mechanism parallels sucrose's activation but varies in potency based on affinity, , and structural fit to the receptor's multiple pharmacophores, including hydrogen-bonding AH/B units and hydrophobic interactions. High-intensity sugar substitutes, often synthetic or plant-derived glycosides, achieve sweetness potencies of 100 to over 1,000 times that of through enhanced receptor binding efficiency. , for example, structurally mimics as a trichlorinated analog, allowing it to occupy the TAS1R2 binding pocket with high affinity via strengthened electrostatic and hydrogen-bonding interactions, resulting in approximately 600 times the sweetness of . Similarly, elicits about 200 times 's intensity by forming key hydrogen bonds and hydrophobic contacts at the receptor's orthosteric site, while (300–500 times) and (200 times) leverage distinct sulfonamide-based pharmacophores that stabilize the active receptor conformation despite lacking 's scaffold. from Stevia rebaudiana, such as , provide 200–400 times the sweetness through structures that engage TAS1R2's extracellular domain, though with potential off-tastes from weaker allosteric modulation. Lower-intensity substitutes, including sugar alcohols and rare monosaccharides, exhibit reduced potency relative to due to suboptimal interactions with the TAS1R2/TAS1R3 receptor. Sugar alcohols like (approximately 70% as sweet as sucrose) and (90–100%) feature chains with multiple hydroxyl groups that form internal bonds, diminishing their ability to precisely align with the receptor's AH/B/X glycophore requirements for maximal activation, as originally proposed in physiology models emphasizing vicinal diol configurations. This structural deviation leads to lower binding affinity and weaker compared to sucrose's optimized furanose/ ring system. Allulose (D-psicose), a of , confers approximately 70% of sucrose's intensity through partial mimicry of binding but with altered that reduces hydrogen-bonding efficiency at key receptor residues, positioning it as a lower-potency bulking alternative rather than a high-intensity agent. Both allulose and erythritol provide a clean taste similar to sucrose, although erythritol may impart a mild cooling sensation.
SubstituteRelative Sweetness (vs. Sucrose)Key Mechanism Note
Sucralose600xChlorinated sucrose mimic; high-affinity H-bonding in TAS1R2 pocket
200x pharmacophore; orthosteric site engagement
300–500x interactions; multiple binding modes
200–400x glycoside; extracellular domain binding
0.7x internal H-bonding reduces receptor fit
0.9–1.0xAltered diol configuration vs. sucrose
Allulose0.7x epimer; suboptimal stereochemical alignment

Stability and Sensory Attributes

Aspartame exhibits limited thermal stability, decomposing into , , and at elevated temperatures, which restricts its use to cold beverages and formulations below approximately 60–100°C to preserve sweetness. In contrast, demonstrates greater heat resistance, retaining sweetness during typical cooking and baking processes up to around 180°C, though some studies indicate potential degradation and formation of chlorinated byproducts at very high temperatures under low-moisture conditions. and maintain stability across a broad and temperature range, enabling their incorporation into heat-processed foods without significant loss of potency. Sensory profiles of sugar substitutes often include off-tastes that deviate from sucrose's clean sweetness. imparts a metallic or bitter aftertaste, attributed to activation of bitter receptors such as TAS2R43 and TAS2R44. Similarly, elicits a delayed bitter and metallic sensation, varying by individual influencing TAS2R31 receptor sensitivity. in extracts contributes a licorice-like or bitter lingering note, stemming from interactions with receptors, though purified minimizes this. Erythritol, a common sugar alcohol, imparts a mild cooling sensation due to its negative heat of solution (approximately -23 kcal/g), which deviates from sucrose's sensory profile. In contrast, allulose provides a clean taste similar to sucrose without a cooling effect, with a sweetness decay curve closely resembling that of sucrose. Additionally, erythritol may crystallize upon cooling in certain applications such as baking, resulting in a gritty texture, whereas allulose more effectively mimics sucrose's smooth mouthfeel, browning, and caramelization properties. These off-flavors are frequently mitigated through blending multiple substitutes, which synergistically masks bitterness while approximating sucrose's temporal profile. Sugar substitutes generally lack the bulking and provided by , resulting in thinner in liquids and reduced body in semi-solids, which can affect perceived quality. This deficit is commonly addressed by combining high-intensity sweeteners with bulking agents like or sugar alcohols, or through formulation adjustments such as added hydrocolloids to restore texture and sensory fullness.

Caloric Content and Metabolic Impact

High-intensity synthetic sweeteners, such as and , contribute zero calories because they resist by and are not metabolized for energy. , chlorinated at three hydroxyl groups, passes through the intact, with approximately 85% excreted unchanged in and the remainder eliminated via urine without contributing to energy yield. This non-absorptive pathway ensures no net caloric intake, unlike , which is fully hydrolyzed to glucose and for complete glycolytic yielding 4 kcal/g. Sugar alcohols, or polyols, exhibit 50-100% caloric reduction relative to through partial small-intestinal absorption followed by colonic bacterial of the unabsorbed fraction into , which provide about 2 kcal/g via host utilization. , for instance, is nearly completely absorbed (~90% excreted unchanged in urine), resulting in ~0.24 kcal/g, while and are absorbed at 50-75%, with the remainder fermented, yielding 2.4-3.0 kcal/g overall. This hybrid pathway contrasts with 's exclusive small-intestinal and hepatic processing, limiting polyols' but introducing variable gastrointestinal tolerance based on rates. Rare sugars like D-allulose demonstrate low caloric impact (0.2–0.4 kcal/g) due to rapid absorption in the but inefficient phosphorylation by fructokinase, which sequesters it from full glycolytic flux, leading to ~70-90% urinary excretion as unmetabolized allulose. Unlike , where fructose phosphorylation enables complete ATP generation via or , allulose's blocked downstream metabolism minimizes energy extraction, with human studies confirming without proportional caloric assimilation. Allulose and erythritol are popular low-calorie sugar substitutes with comparable metabolic profiles. Both are minimally metabolized and primarily excreted in urine, resulting in negligible blood sugar impact. They are generally well-tolerated, but high doses may cause gastrointestinal issues such as bloating or nausea, with allulose often easier on the gut than erythritol.
Substitute TypeExampleCaloric Content (kcal/g)Primary Metabolic Fate
High-Intensity Synthetic0Excreted unchanged (/)
Sugar Alcohol~0.24Urinary post-nearly complete absorption; limited
Sugar Alcohol∼2.4Partial absorption; colonic to SCFAs
Rare SugarAllulose0.2–0.4Phosphorylation block; urinary (majority)
Reference (Disaccharide)4Full and

Applications

Food and Beverage Formulation

Formulating food and beverage products with substitutes requires addressing 's multifaceted roles, including providing bulk volume, texture, , , and alongside . High-intensity sweeteners (HIS), which deliver intense with minimal volume, often necessitate bulking agents like polyols (sugar alcohols) to replicate 's physical properties, while blends mitigate sensory drawbacks such as bitterness or lingering aftertaste. Challenges include poor heat stability in , variable in liquids, and potential off-flavors that can alter product appeal, demanding precise combinations and processing techniques to maintain consumer acceptance. In beverages, blends of and acesulfame-K (Ace-K) are commonly employed for synergistic sweetness enhancement and improved stability, as Ace-K's longer compensates for aspartame's limitations under heat or acidic conditions. These combinations support flavor profiles, such as bolstering fruitiness in or orange variants, and are standard in major diet sodas like Coke Zero Sugar and reformulated . Artificial sweeteners, including such blends, dominate low-calorie beverage formulations, holding over 80% market share in the segment as of 2024 due to their established efficacy in reducing caloric content without fully compromising taste. For solid and semi-solid products like chewing gums and baked goods, sugar alcohols serve as bulking agents to provide the necessary volume and texture absent in HIS. Erythritol, often paired with maltitol, enhances humectancy and sweetness while providing structural support, though it imparts a mild cooling sensation and may crystallize upon cooling, resulting in a gritty texture in some baked goods. In contrast, allulose, a low-calorie rare sugar, excels in baking by mimicking sucrose's texture, browning, and caramelization without crystallization or cooling effects, enabling superior performance in achieving tender, moist, and well-colored bakery items. These substitutes replace sugar's bulk with significantly reduced caloric content, though their sweetness intensity (typically 60-70% of ) requires supplemental HIS for balanced profiles. Post-2010s reformulation trends emphasize natural substitutes like for clean-label appeal, particularly in products such as , where advancements in Reb M —over 100 times higher than earlier forms—facilitate seamless integration without metallic notes. By 2024, manufacturers increasingly substituted sugar with blends to lower added sugars while preserving creaminess, driven by consumer demand for transparent ingredients and regulatory pushes for clearer labeling of content per serving. These shifts address formulation hurdles like 's inherent bitterness through enzymatic modifications and flavor masking, enabling broader adoption in no-added-sugar variants.

Therapeutic and Medical Uses

Sugar substitutes, particularly non-nutritive sweeteners such as , have been investigated for their role in glycemic control among individuals with . A 2024 meta-analysis of randomized controlled trials indicated that stevia supplementation significantly reduced fasting blood glucose levels, with effects more pronounced in interventions lasting less than 120 days, though evidence certainty was rated low due to heterogeneity in study designs. Similarly, in a 12-week randomized trial involving 200 participants with , replacing with led to significant HbA1c reductions, supporting its use as a caloric substitute without elevating postprandial glucose excursions. However, broader meta-analyses of acute effects from low-energy sweeteners, including , have shown minimal impacts on postprandial glucose and insulin responses in healthy and diabetic populations, underscoring that benefits may derive primarily from calorie displacement rather than direct metabolic modulation. Sugar alcohols like xylitol demonstrate established therapeutic utility in oral health, specifically for caries prevention. Multiple systematic reviews and meta-analyses of randomized controlled trials confirm that regular xylitol consumption, often via chewing gum or lozenges, reduces dental caries incidence by 30-60% in children and adults, attributable to its non-fermentability and inhibition of Streptococcus mutans biofilm formation and acid production. For instance, a 2024 systematic review found statistically significant caries-reducing effects from daily xylitol gum use, with optimal dosing at 5-10 grams spread across multiple intakes to maximize salivary flow and bacterial suppression. This mechanism positions xylitol as an adjunct in preventive dentistry, particularly in high-risk populations, without contributing to enamel demineralization seen with fermentable sugars. Erythritol, a used in low-carbohydrate therapeutic formulations such as ketogenic diets for management, warrants caution following observational and interventional evidence of cardiovascular risks. A 2023 associating elevated plasma with major adverse cardiovascular events (MACE) risk, including and , prompted mechanistic investigations revealing that oral intake acutely enhances platelet reactivity and formation in healthy volunteers. While 's negligible glycemic impact supports its inclusion in glucose-restricted protocols, these findings—replicated in subsequent 2024 analyses—suggest potential prothrombotic effects that may offset benefits in patients with preexisting or clotting predispositions.

Industrial and Non-Food Applications

is utilized in as a cost-effective to improve , leveraging its thermal and for processing under extreme conditions. It also functions as a brightener in baths, where its addition enhances deposit brightness and reduces internal stress in metal coatings. In and , masks bitter tastes and provides sweetness without contributing calories, with concentrations typically below 0.5% in formulations like lotions and shampoos. Sucralose serves as an in , particularly in chewable tablets and syrups, due to its high stability across ranges (3–7) and temperatures up to 120°C, minimizing degradation during production and storage. This non-reactivity prevents interactions with active ingredients, enabling its use in pediatric and geriatric medications where is critical without caloric addition. Sugar alcohols, including , , and , are common in oral care products such as and , acting as humectants to retain moisture and prevent drying while exhibiting anti-cariogenic effects by inhibiting biofilm formation. , in particular, promotes enamel remineralization and reduces caries incidence by up to 30–60% in habitual users, as evidenced by clinical trials evaluating daily exposures of 6–10 grams. These polyols are deemed safe for cosmetic applications at concentrations up to 25% for and 35% for , providing viscosity control and a non-sticky texture in formulations.

Health Effects

Benefits for Weight Management and Metabolic Health

Randomized controlled trials provide causal evidence that substituting non-nutritive sweeteners for caloric sugars promotes modest weight loss through calorie displacement. A 2020 meta-analysis of 37 randomized controlled trials involving diverse populations found that replacing sugar with non-nutritive sweeteners under ad libitum conditions led to statistically significant body weight reductions, averaging greater effects in individuals with overweight or obesity compared to normal-weight participants. Similarly, a 2014 meta-analysis of 15 randomized controlled trials reported that low-calorie sweetener substitution for sugar reduced body weight by approximately 0.4 kg and body fat by 0.5 kg on average, with effects accumulating over 6-12 month durations in beverage-focused interventions including aspartame. These findings counter associational data from observational studies by isolating substitution effects in controlled settings, demonstrating sustained advantages of 0.5-1 kg greater loss versus sugar equivalents in trials exceeding six months. In metabolic health, certain sugar substitutes enhance glycemic control and insulin dynamics, particularly in . A 2024 meta-analysis of clinical trials on allulose supplementation in patients showed significant reductions in postprandial glucose levels (mean difference -1.2 mmol/L) and time above range, indicating improved insulin sensitivity without adverse . and monk fruit extracts have similarly demonstrated acute improvements in insulin response and glycemic excursions in obese individuals with impaired glucose tolerance, as per randomized crossover studies measuring post-ingestion insulin indices, offering zero calories, low glycemic index, and suitability for diabetes and weight management despite potential slight aftertaste. Allulose further provides 0.4 kcal/g with taste closest to sucrose, good baking properties, potential antioxidant benefits, and good tolerance. These effects stem from minimal by non-nutritive sweeteners, enabling substitution without elevating blood glucose or insulin demands beyond baseline. Sugar substitutes also mitigate dental caries risk through non-fermentability by oral bacteria, offering benefits orthogonal to caloric content. A 2024 meta-analysis of intervention studies confirmed that low-intensity non-nutritive sweeteners significantly reduced levels of cariogenic bacteria such as Streptococcus mutans in plaque and saliva, independent of energy intake differences. Polyol-based substitutes like xylitol further decrease caries incidence by 28-53% in long-term trials versus fermentable sugars, via inhibition of bacterial adhesion and acid production. This empirical reduction persists even in caloric polyols, underscoring a direct antimicrobial mechanism rather than mere dilution of fermentable substrate.

Risks and Associations with Disease Outcomes

Observational studies and mechanistic investigations have identified potential associations between certain sugar substitutes and adverse cardiovascular outcomes, particularly , which exhibits dose-dependent enhancement of platelet reactivity. A 2023 study found that erythritol consumption elevates plasma levels dramatically—up to 1,000-fold after ingesting 30 grams—promoting platelet activation and clot formation in human blood samples and mouse models, with higher endogenous plasma erythritol correlating to doubled risk of (MACE) like heart attack and in cohort analyses of over 1,000 patients. A follow-up 2024 intervention trial in healthy volunteers confirmed that erythritol ingestion heightens platelet responsiveness to agonists, increasing potential , though effects were transient and not directly linked to clinical events in short-term settings. Randomized controlled trials (RCTs) remain sparse and small-scale, often showing minimal or reversible platelet changes without overt harm at typical doses, underscoring the need for longer-term human data to establish causality beyond correlative plasma elevations. Similar prothrombotic effects and associations with cardiovascular risk have been reported for xylitol, another sugar alcohol. In contrast, stevia, monk fruit, and allulose are regarded as relatively safer alternatives lacking clear cardiovascular risks. Sucralose has been linked to gut microbiota alterations primarily in preclinical models, with limited and inconsistent human evidence precluding causal inference for disease outcomes. Mouse studies demonstrate that chronic sucralose exposure induces dysbiosis, expanding Proteobacteria phyla and Escherichia coli populations while impairing carbohydrate metabolism and immune responses, such as reduced T-cell proliferation at high doses equivalent to heavy human intake. Human fecal and short-term intervention studies yield mixed results: a 2023 meta-analysis of sucralose effects on microbiota composition reported shifts like decreased Firmicutes/Bacteroidetes ratios in some cohorts, potentially tied to modest glucose homeostasis changes, but a 7-day RCT in healthy adults found no significant microbiome disruption or metabolic shifts at doses up to 200 mg daily. These discrepancies highlight dose-response variability and potential confounders like baseline diet, with no direct mechanistic pathway to clinical dysbiosis-driven diseases in humans established. Artificial sweeteners like aspartame share similar gut microbiome concerns. Potential concerns with artificial sweeteners like aspartame include effects on the gut microbiome, metabolism, or increased cravings, though studies yield mixed results and remain inconclusive without definitive causal evidence in humans. Some observational studies associate long-term use with higher risks of stroke, heart disease, or metabolic issues, but these do not prove causation and likely reflect confounding factors, including reverse causation in at-risk populations. Observational evidence has also linked higher consumption of low- and no-calorie artificial sweeteners to accelerated cognitive decline. A 2025 prospective cohort study published in Neurology, conducted by researchers from the University of São Paulo, Brazil, followed over 12,000 adults for 8 years and found that participants in the highest tertile of intake (average 191 mg/day) experienced a 62% faster rate of global cognitive decline compared to the lowest tertile (average 20 mg/day), equivalent to approximately 1.6 years of additional brain aging. This association was more pronounced in individuals under 60 years of age and in those with diabetes, with specific sweeteners including aspartame, saccharin, acesulfame-K, erythritol, xylitol, and sorbitol associated with faster declines in domains such as memory and verbal fluency. As an observational study, these findings indicate association rather than causation, and further research is needed to confirm the results and explore underlying mechanisms. Large prospective cohorts and meta-analyses indicate neutral to modestly elevated all-cause mortality risks with non-nutritive sweeteners overall, in contrast to sugar's robust dose-dependent associations with , , and . A analysis of artificially sweetened beverage (ASB) intake across cohorts exceeding 500,000 participants linked higher consumption to 10-26% increased all-cause and CVD mortality hazards, yet risks were attenuated compared to sugar-s (SSBs), where each daily serving elevates odds by 20-30% via caloric surplus and insulin dynamics. WHO-commissioned reviews of observational data similarly report hazard ratios around 1.09 for CVD events with total intake, but emphasize reverse causation—wherein at-risk individuals preferentially consume substitutes—and lack of dose-response clarity in RCTs, which prioritize short-term metabolic neutrality over long-term endpoints. Unlike caloric sugars, where meta-analyses confirm linear risk escalation (e.g., 1.18-fold incidence per 150 kcal/day increment), associations often plateau at high intakes without proportional mechanistic escalation, suggesting by factors rather than inherent toxicity.

Specific Controversies and Debunked Claims

In July 2023, the International Agency for Research on Cancer (IARC) classified aspartame as "possibly carcinogenic to humans" (Group 2B), citing limited evidence from human observational studies linking it to hepatocellular carcinoma and limited mechanistic evidence involving oxidative stress, but relying heavily on animal data from doses far exceeding typical human exposure. Concurrently, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) reaffirmed aspartame's acceptable daily intake (ADI) at 40 mg/kg body weight, concluding no convincing evidence of harm at levels below this threshold, as the classification reflects hazard identification rather than quantified risk assessment. The U.S. Food and Drug Administration (FDA) maintained its ADI of 50 mg/kg, emphasizing that methanol produced as a metabolite from aspartame hydrolysis yields blood levels orders of magnitude below those from natural dietary sources like fruit juice, rendering purported carcinogenic risks from this pathway physiologically implausible at approved doses. This divergence highlights IARC's focus on potential mechanisms without dose-response context, contrasting with regulatory bodies' integration of exposure data showing negligible risk for average consumers, who ingest far below the ADI equivalent to 9-14 cans of diet soda daily. Cyclamate faced scrutiny in the late 1960s after high-dose rodent studies linked its metabolite to bladder tumors in s, prompting a U.S. ban in 1969 despite prior approval. Subsequent analyses revealed these effects as species-specific artifacts: s excrete urinary proteins forming precipitates that promote tumorigenesis only under chronic high-dose conditions irrelevant to , where is poorly absorbed and lacks such . epidemiological data, including large cohort studies, found no association with , confirming the findings do not extrapolate due to differences in urinary , protein handling, and dose scaling—over 100 times human-equivalent levels used in trials. Re-evaluations, such as those by JECFA, upheld 's safety in approved regions like the and , with an ADI of 11 mg/kg, attributing early alarms to flawed interspecies generalization without causal validation in primates or humans. A 2025 prospective study published in Neurology by researchers from the University of São Paulo, Brazil, involving 12,772 adults (mean age 52 years), found that higher consumption of low- and no-calorie sweeteners (LNCS), including aspartame, saccharin, acesulfame-K, erythritol, xylitol, and sorbitol, was associated with an accelerated rate of cognitive decline over eight years. Participants in the highest consumption tertile exhibited a 62% faster decline in global cognition compared to those in the lowest tertile, equivalent to approximately 1.6 years of additional brain aging, with stronger associations observed in individuals under 60 years of age and those with diabetes. However, as an observational analysis reliant on self-reported dietary data, it cannot disentangle causation from confounders such as reverse causality—wherein individuals with emerging cognitive impairments or (itself a driver of decline) preferentially adopt sweeteners for weight control—or residual factors like and baseline health. Industry responses noted the absence of evidence linking LNCS to cognition, with prior meta-analyses showing no such effects, underscoring how in sweetener users (often those with metabolic disorders) inflates apparent risks without establishing temporal or mechanistic precedence. First-principles evaluation reveals these claims falter on : sweeteners lack plausible neurotoxic pathways at dietary doses, unlike 's established inflammatory effects, suggesting artifactual correlations rather than direct harm.

Regulation

Approval Processes and Safety Assessments

In the United States, the (FDA) regulates high-intensity sugar substitutes as food additives unless they qualify for (GRAS) status, which can be achieved through expert consensus via self-affirmation or by submitting a GRAS notice with supporting data. The GRAS evaluation requires comprehensive toxicological testing, including assays and at least 90-day subchronic oral toxicity studies in (and often non-rodents) to identify potential adverse effects at various doses, forming the basis for determining no-observed-adverse-effect levels (NOAELs). These animal studies emphasize dose-response relationships but incorporate inherent limitations in extrapolating to humans, such as differences in and body scaling, addressed through uncertainty factors rather than direct equivalence. Internationally, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) conducts assessments for non-nutritive sweeteners, deriving provisional acceptable daily intakes (ADIs) from the lowest NOAEL in long-term animal studies divided by a composite margin typically of 100—comprising factors of 10 for interspecies differences (animal to human) and 10 for intraspecies variability (within humans). This margin acknowledges uncertainties in scaling toxicological endpoints from high-dose exposures to typical human consumption, prioritizing conservative estimates over precise mechanistic alignment, while evaluations also integrate , reproductive, and carcinogenicity data from multiple species. Post-market surveillance complements pre-approval testing, with agencies like the FDA and (EFSA) reviewing emerging human data for potential risks. For instance, following 2023 publications associating consumption with elevated cardiovascular event markers in observational and acute human studies, the FDA evaluated the evidence in 2023 and reaffirmed its GRAS status, citing insufficient causation from the data, while EFSA's 2024 assessment similarly found no established link between dietary and risk despite the signals. Such reviews highlight the challenges of reconciling animal-derived safety margins with real-world epidemiological findings, often requiring additional mechanistic studies to resolve discrepancies.

Acceptable Daily Intake and Labeling Requirements

The acceptable daily intake (ADI) for sugar substitutes represents the estimated amount of a substance in or drink, expressed in milligrams per kilogram of body weight per day (mg/kg bw/d), that can be ingested daily over a lifetime without appreciable health risk, based on toxicological data with a safety margin. Regulatory bodies like the U.S. Food and Drug Administration (FDA) and the (EFSA) derive ADIs from animal and human studies, often incorporating a 100-fold safety factor applied to the no-observed-adverse-effect level (NOAEL). For , the FDA establishes an ADI of 50 mg/kg bw/d, equivalent to approximately 3,500 mg daily for a 70 kg adult or 18-19 cans of assuming typical content of 180-200 mg per 355 ml serving; EFSA sets a slightly lower ADI of 40 mg/kg bw/d based on refined intake modeling and neurodevelopmental considerations. has an FDA ADI of 5 mg/kg bw/d, while (Ace-K) is 15 mg/kg bw/d under FDA guidelines, with EFSA aligning closely but applying stricter exposure assessments that can result in more conservative effective limits for high consumers. Saccharin lacks a formal FDA ADI due to its long history of safe use but aligns with international values around 15 mg/kg bw/d from joint expert committees.
SweetenerFDA ADI (mg/kg bw/d)EFSA ADI (mg/kg bw/d)
5040
515
Acesulfame K159
(stevia)GRAS, no numerical ADI; aligns with 4 mg/kg steviol equivalents4 (steviol equivalents)
No ADI (sugar alcohol, safe at typical intakes)0.5 g/kg (2023 update based on cardiovascular data)
Natural-derived substitutes like from and sugar alcohols such as generally permit higher or unlimited intakes relative to synthetic options due to endogenous metabolism and lower toxicity profiles, though EFSA's 2023 reduction for reflects emerging associations with cardiac events in vulnerable populations exceeding prior estimates. Allulose, a rare sugar, has no ADI as it is (GRAS) by the FDA, with minimal caloric contribution (0.4 kcal/g) and rapid excretion. Labeling requirements mandate disclosure of sugar substitutes in ingredient lists, with specific warnings for in both the U.S. and EU due to its component, which can exacerbate (PKU) in affected individuals; U.S. law requires the statement "Phenylketonurics: Contains " on products containing , while EU regulations demand indication by name or E-number (E951) and PKU advisories in package leaflets for medicinal products. For allulose, FDA guidance finalized in 2020 (effective through 2025) permits exclusion from "Total Sugars" and "Added Sugars" declarations on Facts labels, treating it instead as a non-digestible contributing 0.4 kcal/g, to reflect its low metabolic impact without misleading consumers on caloric content. EU labeling aligns sweeteners under general additives rules but lacks equivalent allulose exemptions, requiring inclusion in carbohydrates unless proven otherwise.

Global Variations and Recent Updates

Regulatory approaches to sugar substitutes exhibit significant global variations, often reflecting differing interpretations of safety data, historical usage patterns, and public health priorities. , for instance, remains banned since 1969 following animal studies linking it to in rats, despite subsequent reviews questioning the relevance to humans. In contrast, it is permitted in the with an (ADI) of 7 mg/kg body weight, as established by the based on re-evaluations confirming no genotoxic or carcinogenic risks at typical exposure levels. Many Asian countries, including and , also authorize at similar ADI levels, influenced by its long-standing use in low-calorie products and alignment with Joint FAO/WHO Expert Committee on Food Additives (JECFA) assessments deeming it safe. In , -derived sweeteners benefit from accelerated approvals amid the country's dominant role in global production and export, supplying over 90% of the world's supply through specialized cultivation in regions like . Recent regulatory updates include the approval of stevia leaf polyphenols as a new food in June 2024 by the , enabling novel blends with enhanced stability and flavor profiles for beverages and confections. This reflects cultural preferences for plant-based alternatives rooted in traditional herbal practices, contrasting with stricter scrutiny in Western markets over purity standards. India's regulatory landscape is evolving rapidly in response to its prevalence, affecting over 100 million adults and driving demand for low-glycemic options. The and Standards Authority of India (FSSAI) is reviewing scientific on allulose, a rare sugar with minimal metabolic impact, with a potential approval decision anticipated by late 2025 to bolster domestic production and reduce import reliance. This proactive stance diverges from more conservative approaches in several African nations, where regulators like South Africa's Department of Health have proposed mandatory warning labels for products containing artificial sweeteners alongside high sugar content, citing insufficient long-term in local populations and prioritizing natural dietary patterns over synthetic substitutes. Such variations underscore how epidemiological burdens and cultural dietary norms shape approval timelines and restrictions.

Comparison to Sugar

Nutritional and Physiological Differences

, a composed of equal parts glucose and , undergoes hydrolysis in the intestine to its components, with glucose primarily stimulating insulin secretion and peripheral while is predominantly metabolized in the liver, bypassing key regulatory steps like phosphofructokinase-1 and promoting de novo lipogenesis through rapid conversion to triglycerides. This hepatic load contributes to and potential accumulation, independent of insulin-mediated pathways triggered by glucose. In contrast, non-nutritive sugar substitutes such as , , , and are not significantly metabolized for energy; they pass through the largely unabsorbed or are excreted unchanged, providing negligible caloric contribution and avoiding both glycemic excursions and acute insulin responses observed with . Most non-nutritive substitutes exhibit a of zero, as they do not elevate blood glucose levels, unlike with a of approximately 65, which directly impacts postprandial glycemia. Sugar alcohols, a of substitutes like and , provide partial caloric value (about 2-3 kcal/g) and elicit a modest glycemic response due to incomplete absorption and in the gut, yielding around 7 for compared to . This distinction underscores substitutes' general circumvention of carbohydrate-driven metabolic pathways, though polyols impose a minor hepatic and osmotic load absent in fully non-nutritive options. Neither refined nor synthetic substitutes supply meaningful s, as sucrose offers only without vitamins, minerals, or , and non-nutritive alternatives similarly lack these elements by design. However, substitutes facilitate achievement without the bulk volume required for equivalent sweetness from sucrose, enabling reduced overall energy intake while preserving dietary density from other sources.

Functional Equivalence and Limitations

Sugar provides bulk and structural volume in formulations, aiding in texture through its crystalline form and ability to trap air during creaming or whipping processes. High-intensity sugar substitutes, such as or , possess far greater sweetness per unit mass—up to 600 times for sucralose—necessitating bulking agents like polyols (e.g., or ) or (e.g., ) to approximate 's volume and prevent overly dense or watery consistencies in baked goods. These fillers, however, often fail to replicate 's precise control over kinetics, leading to challenges in confections where rapid or fine grain size is required, such as in or hard candies, potentially resulting in gritty textures without formulation tweaks. Non-reducing substitutes like cannot participate in the due to the absence of free or groups on their molecules, which are essential for reacting with in proteins under to form melanoidins responsible for desirable and flavor compounds. Polyols similarly do not engage in this reaction, yielding lighter-colored products compared to sugar-containing counterparts. , involving the of sugar molecules above 160°C to generate nutty aromas and golden hues, is also absent in most substitutes, as their structures resist the necessary thermal breakdown pathways inherent to or . To mitigate these limitations, hybrid systems blending high-intensity sweeteners with polyols or small amounts of reducing sugars are commonly employed in formulations, enabling partial emulation of and textural properties through synergistic interactions, though full equivalence remains elusive without residual sugar.

Long-Term Substitution Outcomes

Meta-analyses of randomized controlled trials indicate that substituting sugar-sweetened beverages with low- and no-calorie sweetened beverages (LNCSBs) results in modest reductions in body weight and BMI among adults, particularly those or obese. In a network of 17 RCTs involving 1,733 participants (median duration 12 weeks), LNCSBs versus sugar-sweetened beverages yielded a mean difference of -1.06 kg in body weight (95% CI: -1.71 to -0.41) and -0.32 kg/m² in BMI (95% CI: -0.58 to -0.07). Prospective cohort studies further support sustained benefits, with substitution of LNCSBs for sugar-sweetened beverages associated with -0.12 kg/year weight change across three cohorts totaling 165,579 participants (95% CI: -0.14 to -0.10). These findings align with broader reviews of long-term RCTs (up to 40 months), where artificial sweeteners reduced energy intake compared to caloric sugars, contributing to lower body weight in individuals without evidence of reversal over time. Blinded trials refute claims of compensatory overeating triggered by non-nutritive sweeteners, such as cephalic phase responses decoupling from calories. A double-blind randomized crossover trial in 53 /obese adults compared biscuits sweetened with , , or over three 2-week periods; both sweeteners produced reductions and hormonal responses (e.g., , GLP-1) equivalent to , with no increase in subsequent intake. This nutritional displacement mechanism—replacing ~200-300 kcal per sugary drink without caloric offset—underpins the observed deficits, as confirmed in substitution-focused interventions exceeding 6 months. At the population level, widespread adoption of substitutes has correlated with reduced caloric intake from beverages, paralleling rate stabilizations. U.S. caloric intake from sugar-sweetened sodas declined by over 20% between 2001 and 2010 amid rising low-calorie alternative consumption, coinciding with adult prevalence plateauing after rapid increases in prior decades. Cohort data reinforce this, showing habitual low-calorie sweetener users maintain lower trajectories versus consumers, attributing outcomes to net reduction rather than behavioral compensation.

Economic Drivers and Consumption Patterns

The global market for sugar substitutes was valued at approximately USD 23.56 billion in , with projections indicating growth to USD 29.90 billion by 2029 at a (CAGR) of around 4.8%. This expansion is driven primarily by surging demand for low-calorie alternatives amid the global epidemic, which affected an estimated 589 million adults aged 20-79 in , equivalent to one in nine individuals in that demographic. Supply-side factors include scaled production of high-intensity sweeteners like and , enabling cost efficiencies for food and beverage manufacturers seeking to reduce content without compromising sweetness or volume in products such as soft drinks and . Demand is further propelled by economic incentives for producers, including lower formulation costs over time and consumer premiums for zero-calorie options in weight management-focused markets. In established markets like the and , consumption patterns reflect mature adoption in diet beverages and processed foods, collectively accounting for a substantial portion of global volume—Europe alone held about 18.5% of the market share in 2023, with similarly prominent due to high intake of low-sugar products. These regions exhibit steady demand growth tied to regulatory pressures for sugar reduction and consumer shifts toward functional foods, though saturation limits explosive expansion. Conversely, demonstrates the fastest regional growth, fueled by rising disposable incomes, , and local sourcing advantages for natural substitutes; for instance, production in countries like and supports a regional market CAGR exceeding 8% through 2030, leveraging abundant raw materials and export-oriented supply chains. Production economics underscore varying competitiveness: prices have stabilized at USD 2.25-2.70 per kg in 2024, approaching functional parity with refined 's wholesale costs of around USD 0.50 per kg in bulk global trade, allowing broader substitution in high-volume applications despite higher upfront synthesis expenses. Natural substitutes like , however, maintain a structure—often 5-10 times that of —due to extraction complexities and supply variability from agricultural yields, which constrains their penetration in cost-sensitive emerging markets but bolsters margins in premium segments. Overall, these dynamics reflect a supply-demand equilibrium increasingly tilted toward artificial high-potency options for , while natural variants gain traction in Asia via localized production efficiencies.

Innovations and Emerging Products

In 2024, introduced a breakthrough clean-label stevia extract that achieves over 100 times greater solubility than rebaudioside M (Reb M) while delivering superior taste performance with reduced bitterness in consumer testing. This innovation leverages advanced extraction and purification techniques to enhance ' functionality, enabling broader application in beverages and foods where traditional stevia's aftertaste limits use. Fermentation-based has accelerated production of high-purity Reb M, a next-generation prized for its sugar-like sweetness without calories or bitterness. In May 2025, Cargill's EverSweet, a Reb M/Reb D blend produced via , received and approval, facilitating up to 90% sugar reduction in formulations while preserving sensory qualities. Peer-reviewed analyses confirm Reb M's clean taste profile outperforms earlier glycosides, positioning it for projected market dominance by 2030 through scalable microbial synthesis. Amid 2024-2025 studies associating with elevated risks of cardiovascular events and neuronal damage—via mechanisms like impaired and clot formation—developers are blending or allulose with prebiotic fibers to support . ZBiotics launched a 2024 probiotic mix employing engineered enzymes to convert ingested sugars into fibers in the gut, promoting without caloric absorption and countering microbiome disruptions from polyols. These hybrids target health claims for improved glycemic control, though long-term human trials remain limited.

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