ARTIFICIAL SWEETENERS

Artificial sweeteners are sugar substitutes that provide high sweetening power associated
with low accompanied calories. They are also referred as “intense sweeteners” because they
provide a taste similar to that of table sugar but up to several thousand times sweeter. They’re
made by chemically combining different molecules in a lab as they are used to mimic the
flavor of sugar [1].

The use of artificial sweeteners has been increased constantly in recent years. Studies have
reported that almost 25% of children and more than 41% of adults have used artificial
sweeteners between 2010 and 2020 globally. However, studies have shown various side
effects associated with the use of these sweeteners including gastrointestinal symptoms,
neurologic and taste perception changes, allergic reactions, insulin and metabolic effects, and
cardiovascular effects [2]. There are six FDA (Food & Drug Administration) approved
artificial sweeteners. They include the following:

1. Saccharin
2. Aspartame
3. Sucralose
4. Acesulfame potassium
5. Neotame
6. Advantame

Figure 1: Different artificial sweeteners in packaging form [3].

Artificial vs Natural Sweeteners

Non-caloric artificial sweeteners or non-nutritional sweeteners are a heterogeneous group of

compounds with different chemical structures, which are popular substitutes for added sugars
in foods and beverages due to their low caloric content and sweetness. Non-nutritional

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sweeteners (NNSs) can be classified into artificial sweeteners (ASs) and natural sweeteners
(NSs). They are described below:

Table 1: Difference between Artificial and Natural sweeteners [4].

Artificial Sweeteners Natural Sweeteners

They are chemically produced in They are directly extracted from
laboratory. They include aspartame, plants. They include stevia which is
saccharin etc. extracted from intensely sweet plant
S. Rebaudiana.

Many taste buds cover the surface of tongue, with each containing several taste receptors that
detect different flavors. When a person eats, taste receptors encounter food molecules and
send a signal to brain, which allows a person to identify the taste. For example, the sugar
molecule binds to taste receptor for sweetness, allowing the brain to identify sweet taste.
However, artificial sweetener molecules are similar enough to sugar molecules to bind on
sweetness receptors but they are different from sugars in such a way that they are not broken
down into calories by the body [3, 4].

Figure 2: Sweetness intensity of sweeteners as compared to table sugar [2].

ASPARTAME
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Aspartame is an artificial sweetener and a popular sugar substitute sold under the brand
names NutraSweet. The Food and Drug Administration (FDA) first approved aspartame for
use as a sweetener in 1974. It can be used as a safe artificial sweetener [5].

It is a dipeptide having chemical formula C14H18N20, a molar mass of 294.3 g/mol and a
density of 1.3g/cm cube. Aspartame is made by joining L-phenylalanine or L-phenylalanine
methyl ester with L-aspartic acid. It is completely hydrolyzed in the gastrointestinal tract to
methanol, aspartic acid, and phenylalanine. Furthermore, aspartame does not elicit the same
response as sugar does in the brain or the pancreas. A magnetic resonance imaging study
showed a decline in activity of the hypothalamus part of the brain after ingestion of sucrose,
whereas aspartame does not show similar response. In pancreas, aspartame does not stimulate
an insulin response as sugar does [5].

Figure 3: Formation of Aspartame [6].

Significance & Food sources

As it is made from amino acids, it provides 4 kcal/g. Aspartame is 200 times sweeter than
sucrose and therefore very small amounts are required for sweetening foods, thus making its
caloric contribution insignificant. According to the FDA, the acceptable daily intake of
aspartame for humans is 50 mg/kg body weight, for both adults and children [6].

It is a common ingredient in diet sodas, soft drinks and other sugar-free products. Also, many
gum brands use aspartame as a sweetener because sugar-free gums frequently contain
aspartame as a primary ingredient. Moreover, some baked goods, including cookies, cakes,
muffins, and pastries, use aspartame to reduce sugar content while maintaining sweetness.

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These products are designed for individuals looking to reduce carbohydrate intake or manage
blood sugar levels.

Side effects

Following are the side effects of aspartame:

 Aspartame has been linked to behavioral and cognitive problems. Possible

neurophysiological symptoms include learning problems, headache, seizures and
migraines, irritable moods, anxiety, depression and insomnia.
 The consumption of aspartame can elevate the levels of phenylalanine and aspartic
acid in the brain. These compounds can inhibit the synthesis and release of
neurotransmitters, dopamine, norepinephrine, and serotonin which are known as
regulator of neurophysiological activity [5].
 Aspartame acts as a chemical stressor by elevating plasma cortisol levels and causing
the production of excess free radicals. High cortisol levels and excess free radicals
may increase the brain vulnerability to oxidative stress which may have adverse
effects on neurobehavioral health [5].
 Individuals with phenylketonuria (PKU), a rare genetic disorder, cannot metabolize
phenylalanine, a component of aspartame. High phenylalanine levels can accumulate
in blood and brain, leading to neurological symptoms and cognitive impairments. So,
excessive use of aspartame should be avoided by patients with phenylketonuria.
 It can also cause digestive discomfort in some individuals. Reported symptoms
include bloating, gas, diarrhea, and abdominal pain. These gastrointestinal issues are
thought to arise from the fermentation of undigested aspartame by gut bacteria, which
produces excess gas and upsets the stomach [6].

NEOTAME

Neotame was approved as artificial sweetener by the US Food and Drug Administration
(FDA) in 2002. It is marketed as a zero-calorie sweetener that does not affect blood sugar
levels, making it effective in reducing caloric intake or managing diabetes [7].

It is chemically very similar to aspartame but is much more stable and potent. It is between
7000 and 13000 times sweeter than sucrose sugar. Neotame (N- [N-(3, 3-dimethylbutyl)-L-
alpha-aspartyl]-L-phenylalanine 1-methyl ester) has a heat dependent stability. Its chemical
formula is C20H24N2O5 and it has a molar mass of 378.46 g/mol [7].

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 Figure 4: Chemical structure of Neotame [7].

Significance & Food Sources

Neotame is an important component of diet sodas, sugar-free puddings, gelatin desserts, ice
creams, sugar-free candies and chewing gums. It is also included in various low-calorie
snacks to offer sweetness without the added sugars in order to manage calorie consumption.
Moreover, it is also found in some condiments and sauces including sugar-free ketchup,
barbecue sauce, and salad dressings [6].

It can also be used in both cooking and baking applications because of its good heat
resistance. Neotame, along with many other artificial sweeteners, is often used in
combination with other sweeteners. It does not have a particularly strong aftertaste and
because of its high potency, is often used alone or with sweeteners such as aspartame or Ace-
K. Also, because of its potency, it is very desirable by mass manufacturers of food products
because large amounts can be produced cheaply and very large amounts are not needed for
sufficient sweetening purposes [6].

Side Effects

The side effects of neotame are mentioned below:

 Although neotame contains no calories, it has been linked to metabolic disorders.

Some studies suggest that regular consumption of neotame may disrupt the body's
ability to regulate appetite and calorie intake, potentially leading to weight gain and
metabolic dysfunction over time. This is due to neotame's high sweetness intensity,
which can alter taste perception and appetite control mechanisms [6, 7].
 Like other artificial sweeteners, it can affect the composition and function of gut
microbiota. Changes in the gut microbiota compounds have been associated with
various health issues, including obesity, insulin resistance, and inflammation [6].

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  Phenylalanine, present in neotame, can trigger allergic reactions in some individuals,
especially those with phenylketonuria (PKU). Symptoms of a phenylalanine allergy
may include rash, itching, swelling, difficulty breathing, and abdominal discomfort.
People with a known sensitivity to phenylalanine should avoid neotame-containing
products to prevent allergic reactions [6].
 Aspartic acid is a component of neotame. Studies have revealed that too much of this
substance is suspected to cause brain damage in fetuses, and high doses have been
found to destroy brain cells in experimental animals [6].
 Its component methanol is converted to formaldehyde and formic acid, which have a
toxic effect on the thymus gland. Formaldehyde is a known carcinogen, producing
cancer of pharynx and lung.
 Neotame also comprises of 3-di-methylbutyl, a neurotoxin and most hazardous
chemical which causes cell to die at a faster rate [7].

ADVANTAME

Advantame is a relatively new artificial sweetener, recognized for its high sweetness potency.
It was approved by the Food and Drug Administration (FDA) in 2014. Its chemical formula is
C16H18N2O5S, with a molar mass of 346.39 g/mol. Advantame is an N-substituted (aspartic
acid portion) derivative of aspartame that is similar in structure to neotame. Advantame is
intended for use as a non-nutritive sweetener. At a sweetness equivalent to 6% sucrose,
advantame has been demonstrated to be approximately 116 times sweeter than aspartame and
approximately 20,000 times sweeter than sucrose [8].

It is produced from aspartame and vanillin. In the first step, vanillin is converted into
hexamethylphosphoramide (HMPA). In the presence of metal, an alkyl is transferred from
HMPA to aspartame which then becomes advantame. This is called alkylation. The metal,
which is often platinum or palladium, acts as a landing site where an aspartame molecule and
an HMPA molecule can settle for the transfer of an alkyl group [8].

Figure 5: Chemical structure of Advantame [9].

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Significance & Food Sources

Advantame is a low-calorie sweetener. Because of its sweetness, only tiny amounts are
needed to achieve the right level of sweetness. The FDA has approved advantame as safe to
eat and has set a daily limit for consumption. The average intake of advantame is estimated
to be about 1.2 mg/person/day [9].

It is found as a very good sweetener in coffee, powdered beverage formulations, as a flavor

enhancer in beverages, chewing gum and yogurt. The stability of advantame indicates
potential functionality in a broad range of food and beverage applications, including low-pH
products and products that require high-temperature processing. It is also a suitable sweetener
alternative for diabetics as consumption of advantame was shown not to affect glucose
homeostasis. The flavor and sweetness qualities of advantame, coupled with good stability
characteristics can function as a multi-purpose low-calorie sweetener [9].

Side effects

There are no specific side effects linked with advantame. Few of them are:
 Overuse of advantame may cause gastrointestinal disturbances in some individuals,
including bloating and upset stomach, particularly due to its high sweetness intensity.
 There are ongoing discussions about the long-term metabolic effects of advantame,
particularly regarding its influence on insulin sensitivity and glucose metabolism.
 Though it has not been linked to specific health risks like some other sweeteners, its
excessive consumption is still discouraged [8, 9].

ACESULFAME POTASSIUM

Acesulfame potassium also known as acesulfame K or ace K is an artificial sweetener. It was

discovered in 1967 by a German scientist Hoechst AG. It is sold under the brand names
Sweet One and Sunett. It is formed by an initial reaction between 4-chlorophenol and sodium.
It has a white crystalline structure and is about 180-200 times sweeter than sucrose.
Acesulfame potassium has a molecular formula of C4H4KNO4S, molecular weight of 201.24
g/mol and a density of 1.81g/cm cube. It is stable under heated conditions and has a structural
likely to saccharin. The FDA recommends that acesulfame potassium is safe up to an
acceptable daily intake of 15 milligrams per kilogram (mg/kg) [10].

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 Figure 6: Chemical structure of Acesulfame Potassium [10].

Significance and food sources

Ace-K is stable in high-heat situations and is therefore often used in baked products.
Currently it can be found in many tabletop sweeteners, desserts, puddings, baked goods, soft
drinks, candies (including breath mints, cough drops and lozenges), dairy products, canned
foods and alcoholic beverages. Ace-K has an extraordinarily long shelf life therefore it is
considered ideal for use in candies, canned foods and alcoholic beverages. Another important
aspect of Ace-K is its ability to remain stable and retain its sweetness under pasteurizing
conditions which often exposes dairy products to a wide variety of temperatures and pH
values [2].

It has several health advantages including weight management. It benefits in losing weight or
maintaining a healthy weight when a person consumes fewer calories because it has no
calories as a sugar substitute. Also, it does not promote tooth decay making itself an ideal
candidate for ‘sugar free’ candies and diet drinks. Moreover, it does not elevate blood sugar
levels as that of sugar. However, when it is mixed with other non-nutritive sweeteners, it can
create a synergistic sweetening effect [10].

Side effects

Some of the side effects of Acesulfame potassium are described below:

 Some research says that acesulfame potassium may be harmful during pregnancy.
However, a 2014 research study indicated that people can eat small amount during
pregnancy. Despite these concerns, both the United States and Europe have declared
acesulfame potassium is safe for use in humans [10].
 Several studies have shown that acesulfame potassium can impose potential negative
effects on human health, including gut dysbiosis (an imbalance within the gut
microbiome), metabolic syndrome, obesity, and type 2 diabetes [3].

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  Neurometabolic effects have also been observed with the consumption of acesulfame
K. A series of in vivo and in vitro studies suggest that acute exposure to acesulfame K
may decrease intracellular ATP production and reduce cellular viability and protective
activity of neuronal cells affecting neurocognitive function [3, 10].

SUCRALOSE

Sucralose is a zero calorie artificial sweetener, and Splenda is the most common sucralose-
based product. Sucralose was discovered in 1976 and received FDA approval in 1998. It is
significantly more stable than aspartame thereby allowing it a significantly longer shelf life
without loss of sweetness. Sucralose (1', 4, 6’-Trichloro-galactosucrose) is a chlorinated
sugar with chemical formula C12H19Cl3O8 and a molar mass of 397.64 g/mol. It is a stable
molecule that maintains its sweetness property when exposed to high temperatures, making it
suitable for use in baking. Its synthesis is carried out by the selective chlorination of sucrose
(table sugar) which converts three of the hydroxyl groups to chlorides. The selective
chlorination is achieved by selective protection of the primary alcohol groups followed by
acetylation and then deprotection of the primary alcohol groups. In the course of the
chlorination, the stereochemistry at position 4 of the glucose ring gets inverted, so it becomes
a derivative of galacto-sucrose. Sucralose is approximately 600 times sweeter than sugar [11].

Figure 7: Synthesis of Sucralose by chlorination and deacetylation [11]

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Significance & Food Sources

It is one of the newer sweeteners however its demand is very high. The manufacturing of
sucralose is relatively time consuming and expensive causing prices of sucralose to be
significantly higher than those of its competitors. Sucralose is derived from sugar and is
therefore very similar to it in its chemical structure and reactivity. Essentially, it is used to
improve the taste or properties of a particular food or beverage containing other artificial
sweeteners. It is very soluble in different types of liquids making it one of the most versatile
artificial sweeteners today [2, 11].

Side effects

It has following side effects:

 A research study found that heating sucralose with glycerol, a compound found in fat
molecules, produced harmful substances called chloropropanols. These substances
may raise cancer risk.
 A study published in the journal Diabetes Care discovered that daily consumption of
diet soda containing sucralose was associated with a 36 percent greater risk of
metabolic syndrome and a 67 percent greater risk of type 2 diabetes. So, sucralose is
among the unexpected diabetes triggers [11].
 A study indicated that cooking at high temperatures with sucralose can generate
dangerous chloropropanols, a potentially toxic class of compounds. Although
sucralose is commonly used in baked goods, studies have shown that the stability of
this artificial sweetener decreases with the increase in temperature and pH [11].

SACCHARIN

Saccharin is one of the earliest sugar substitutes, commonly recognized under brand names
like Sweet'N Low. Saccharin (benzoic sulfimide) is a very stable organic acid with a pKa of
1.6. It was first discovered in 1879 and approved as a food additive by the Food and Drug
Administration (FDA) in the 1970s. It is approximately 300 to 400 times sweeter than
sucrose. The FDA has established an acceptable daily intake for saccharin at 5 mg/kg body
weight for adults and children [12].

Its chemical composition is 45.9% carbon, 2.7% hydrogen, 7.7% nitrogen, 26.2% oxygen,
and 17.5% sulfur. In acid form, saccharin is not soluble. Therefore, the form used as an
artificial sweetener in its sodium salt. Its chemical formula is C 7H5NO3S, with a molar mass

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of 183.18 g/mol. Saccharin is not metabolized by the body, which means it does not
contribute calories or carbohydrates, making it a popular choice for those seeking to reduce
sugar intake [12].

Figure 8: Saccharin in acidic and sodium salt form [13].

Significance & Food sources

Saccharin is a low-calorie sweetener made from a compound known as benzoic sulfonamide,

providing 0 kcal/g. It is frequently found in a variety of sugar-free products, including diet
sodas, beverages, and sugar-free snacks. Additionally, many brands of sugar-free candies and
baked goods, such as cookies and pastries, incorporate saccharin to offer sweetness. Unlike
sugar, saccharin does not stimulate insulin secretion and is not associated with the same
metabolic responses, such as changes in blood glucose levels. Despite past controversies
regarding its safety, extensive research has supported its safe use as a sweetener in foods and
beverages [12].

Side effects

Following are the side effects of Saccharin:

 Saccharin may cause gastrointestinal issues such as bloating, diarrhea, and abdominal
cramps, likely due to its effect on gut bacteria and digestion. Some individuals
experience headaches and a metallic taste, which can detract from food enjoyment.
 There are concerns regarding saccharin's potential impact on metabolic processes,
possibly affecting glucose regulation and insulin sensitivity [13].
 The use of saccharin as artificial sweetener has been the center of several
controversies regarding potential toxic effects, most recently focusing on the urinary
bladder carcinogenicity of sodium saccharin in rats which fed at high doses in two
generation studies. No carcinogenic effect has been observed in mouse, hamster, or
monkeys, and numerous epidemiological studies provide no clear evidence that
sodium saccharin increases the risk of bladder cancer in human population [12].

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  Unlike typical carcinogens which interact with DNA, sodium saccharin is not
genotoxic, but leads to an increase in cell proliferation of the urothelium, the only
target tissue. The effect of saccharin is modified by the salt form in which it is
administered.
 As with any food additive, moderation is advised, particularly for individuals with
specific sensitivities [13].

CYCLAMATES

Cyclamate (Cyclohexyl sulfamic acid) is the sodium or calcium salt of cyclamic acid. It is
prepared by the sulfonation of cyclohexylamine. It can be accomplished by reacting
cyclohexylamine with either sulfamic acid or sulfur trioxide [14].

Figure 9: Chemical structure of Cyclamate

Significance

Cyclamate is 30–50 times sweeter than sugar (depending on concentration), making it the
least potent of the commercially used artificial sweeteners. The recommended daily intake of
sodium and calcium cyclamate is up to 11mg/kg. It is often used synergistically with other
artificial sweeteners, especially saccharin: the mixture of 10 parts cyclamate to 1-part
saccharin is common and masks the off-tastes of both sweeteners. Cyclamate is stable under
heat conditions, making it ideal for baking. It is sparingly soluble in water, and is slowly
hydrolyzed in hot water. Sodium cyclamate and calcium cyclamate are both freely soluble in
water. Sodium cyclamate is a potent sweetening agent. Cyclamate is commercially available
in the sodium and calcium salt forms. Both of these are colorless and odorless solids.
Cyclamate in its acid form is a strong acid with pKa of 1.7141 [14].

Side effects

A research study linked the use of artificial sweeteners containing a mix of cyclamate and
saccharin to an increased risk of bladder cancer in lab animals. Other studies showed that
bacteria in the intestines may convert cyclamate to cyclohexamine, which is a carcinogen.

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However, there is no data from human populations indicating that consumption of
nonnutritive sweeteners are associated with increased risk of cancer [14].

PROPERTIES OF A GOOD SWEETENER

An artificial or non-nutritive sweeteners should fulfil following requirements:

 High solubilities and rapid dissolution rates are very desirable properties for non-
nutritive sweeteners.
 In addition, a commercially viable non-caloric sweetener must be sufficiently stable to
hydrolysis as well as to thermal and photochemical breakdown to be used in
beverages, baked goods and confectionery.
 It should be stable. Stability is critical for three reasons. First, the rate of degradation
must not be such that product shelf life is affected. Second, degradation must not
cause any ‘off’ taste or odor. And third, since non-caloric sweeteners are food
additives, any degradation products formed must also be safe [1, 4].

FUTURE PERSPECTIVES

Biochemists are finding new ways in order to create bioengineered sweeteners aiming to
produce zero calorie sweeteners with precision. However, new formulations are being tested
in order to improve the taste of artificial sweeteners, reducing bitterness or aftertaste when
used alone or in combination. Also, acceptable daily intake (ADI) levels of different artificial
sweeteners are being re-evaluated based on present research [15].

CONCLUSION

Artificial sweeteners offer a low-calorie alternative to sugar and are widely used in food and
drinks. However, they are generally considered safe, ongoing research is exploring their long-
term health effects as well as their association with different diseases. Artificial sweeteners
will continue to evolve as consumer’s demand healthier choices.

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