Aspartame is an artificial non-saccharide sweetener 200 times sweeter than sucrose, and is commonly used as a sugar substitute in foods and beverages. It is a methyl ester of the aspartic acid/phenylalanine dipeptide with the trade names NutraSweet, Equal, and Canderel. Aspartame was first made in 1965 and approved for use in food products by the U.S. Food and Drug Administration (FDA) in 1981.
|Pronunciation||// or //|
3D model (JSmol)
|E number||E951 (glazing agents, ...)|
CompTox Dashboard (EPA)
|Molar mass||294.307 g·mol−1|
|Melting point||246–247 °C (475–477 °F; 519–520 K)|
|Solubility||Slightly soluble in ethanol|
|NFPA 704 (fire diamond)|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|(what is ?)|
Aspartame is one of the most rigorously tested food ingredients. Reviews by over 100 governmental regulatory bodies found the ingredient safe for consumption at current levels. As of 2018, several reviews of clinical trials showed that using aspartame in place of sugar reduces calorie intake and body weight in adults and children.
Aspartame is around 180 to 200 times as sweet as sucrose (table sugar). Due to this property, even though aspartame produces 4 kcal (17 kJ) of energy per gram when metabolized, the quantity of aspartame needed to produce a sweet taste is so small that its caloric contribution is negligible. The taste of aspartame and other artificial sweeteners differs from that of table sugar in the times of onset and how long the sweetness lasts, though aspartame comes closest to sugar's taste profile among approved artificial sweeteners. The sweetness of aspartame lasts longer than that of sucrose, so it is often blended with other artificial sweeteners such as acesulfame potassium to produce an overall taste more like that of sugar.
Like many other peptides, aspartame may hydrolyze (break down) into its constituent amino acids under conditions of elevated temperature or high pH. This makes aspartame undesirable as a baking sweetener, and prone to degradation in products hosting a high pH, as required for a long shelf life. The stability of aspartame under heating can be improved to some extent by encasing it in fats or in maltodextrin. The stability when dissolved in water depends markedly on pH. At room temperature, it is most stable at pH 4.3, where its half-life is nearly 300 days. At pH 7, however, its half-life is only a few days. Most soft-drinks have a pH between 3 and 5, where aspartame is reasonably stable. In products that may require a longer shelf life, such as syrups for fountain beverages, aspartame is sometimes blended with a more stable sweetener, such as saccharin.
Descriptive analyses of solutions containing aspartame report a sweet aftertaste as well as bitter and off-flavor aftertastes. In products such as powdered beverages, the amine in aspartame can undergo a Maillard reaction with the aldehyde groups present in certain aroma compounds. The ensuing loss of both flavor and sweetness can be prevented by protecting the aldehyde as an acetal.
Safety and health effects
The safety of aspartame has been studied since its discovery and it is one of the most rigorously tested food ingredients. Aspartame has been deemed safe for human consumption by over 100 regulatory agencies in their respective countries, including the United States Food and Drug Administration, UK Food Standards Agency, the European Food Safety Authority (EFSA), Health Canada, Australia, and New Zealand.
As of 2017, reviews of clinical trials showed that using aspartame (or other non-nutritive sweeteners) in place of sugar reduces calorie intake and body weight in adults and children.
A 2017 review of metabolic effects by consuming aspartame found that it did not affect blood glucose, insulin, total cholesterol, triglycerides, calorie intake, or body weight. While high-density lipoprotein levels were higher compared to control, they were lower compared to sucrose.
High levels of the naturally occurring essential amino acid phenylalanine are a health hazard to those born with phenylketonuria (PKU), a rare inherited disease that prevents phenylalanine from being properly metabolized. Because aspartame contains a small amount of phenylalanine, foods containing aspartame sold in the United States must state: "Phenylketonurics: Contains Phenylalanine" on product labels.
In the UK, foods that contain aspartame are required by the Food Standards Agency to list the substance as an ingredient, with the warning, "Contains a source of phenylalanine". Manufacturers are also required to print '"with sweetener(s)" on the label close to the main product name on foods that contain "sweeteners such as aspartame" or "with sugar and sweetener(s)" on "foods that contain both sugar and sweetener".
Phenylalanine is one of the essential amino acids and is required for normal growth and maintenance of life. Concerns about the safety of phenylalanine from aspartame for those without phenylketonuria center largely on hypothetical changes in neurotransmitter levels as well as ratios of neurotransmitters to each other in the blood and brain that could lead to neurological symptoms. Reviews of the literature have found no consistent findings to support such concerns, and while high doses of aspartame consumption may have some biochemical effects, these effects are not seen in toxicity studies to suggest aspartame can adversely affect neuronal function. As with methanol and aspartic acid, common foods in the typical diet such as milk, meat, and fruits, will lead to ingestion of significantly higher amounts of phenylalanine than would be expected from aspartame consumption.
Reviews have found no association between aspartame and cancer. This position is supported by multiple regulatory agencies like the FDA and EFSA as well as scientific bodies such as the National Cancer Institute. The EFSA, FDA, and the US National Cancer Institute state that aspartame is safe for human consumption.
Neurological and psychiatric symptoms
Numerous allegations have been made via the Internet and in consumer magazines purporting neurotoxic effects of aspartame leading to neurological or psychiatric symptoms such as seizures, headaches, and mood changes. Review of the biochemistry of aspartame has found no evidence that low doses consumed would plausibly lead to neurotoxic effects. Comprehensive reviews have not found any evidence for aspartame as a cause for these symptoms. A review of studies on children did not show any significant findings for safety concerns with regard to neuropsychiatric conditions such as panic attacks, mood changes, hallucinations, ADHD, or seizures by consuming aspartame.
Headaches are the most common symptom reported by consumers. While one small review noted aspartame is likely one of many dietary triggers of migraines, in a list that includes "cheese, chocolate, citrus fruits, hot dogs, monosodium glutamate, aspartame, fatty foods, ice cream, caffeine withdrawal, and alcoholic drinks, especially red wine and beer," other reviews have noted conflicting studies about headaches and other studies lack any evidence and references to support this claim.
Mechanism of action
The perceived sweetness of aspartame (and other sweet substances like acesulfame K) in humans is due to its binding of the heterodimer G protein-coupled receptor formed by the proteins TAS1R2 and TAS1R3. Aspartame is not recognized by rodents due to differences in the taste receptors.
Aspartame is rapidly hydrolyzed in the small intestines. Even with ingestion of very high doses of aspartame (over 200 mg/kg), no aspartame is found in the blood due to the rapid breakdown. Upon ingestion, aspartame breaks down into residual components, including aspartic acid, phenylalanine, methanol, and further breakdown products including formaldehyde and formic acid. Human studies show that formic acid is excreted faster than it is formed after ingestion of aspartame. In some fruit juices, higher concentrations of methanol can be found than the amount produced from aspartame in beverages.
Aspartame's major decomposition products are its cyclic dipeptide (in a 2,5-diketopiperazine, or DKP, form), the non-esterified dipeptide (aspartylphenylalanine), and its constituent components, phenylalanine, aspartic acid, and methanol. At 180 °C, aspartame undergoes decomposition to form a diketopiperazine derivative.
Aspartic acid (aspartate) is one of the most common amino acids in the typical diet. As with methanol and phenylalanine, intake of aspartic acid from aspartame is less than would be expected from other dietary sources. At the 90th percentile of intake, aspartame provides only between 1% and 2% of the daily intake of aspartic acid. There has been some speculation that aspartame, in conjunction with other amino acids like glutamate, may lead to excitotoxicity, inflicting damage on brain and nerve cells. However, clinical studies have shown no signs of neurotoxic effects, and studies of metabolism suggest it is not possible to ingest enough aspartic acid and glutamate through food and drink to levels that would be expected to be toxic.
The methanol produced by the metabolism of aspartame is absorbed and quickly converted into formaldehyde and then completely oxidized to formic acid. The methanol from aspartame is unlikely to be a safety concern for several reasons. Fruit juices and citrus fruits contain methanol, and there are other dietary sources for methanol such as fermented beverages and the amount of methanol produced from aspartame-sweetened foods and beverages is likely to be less than that from these and other sources that are already in people's diets. With regard to formaldehyde, it is rapidly converted in the body, and the amounts of formaldehyde from the metabolism of aspartame are trivial when compared to the amounts produced routinely by the human body and from other foods and drugs. At the highest expected human doses of consumption of aspartame, there are no increased blood levels of methanol or formic acid, and ingesting aspartame at the 90th percentile of intake would produce 25 times less methanol than what would be considered toxic.
Aspartame is a methyl ester of the dipeptide of the natural amino acids L-aspartic acid and L-phenylalanine. Under strongly acidic or alkaline conditions, aspartame may generate methanol by hydrolysis. Under more severe conditions, the peptide bonds are also hydrolyzed, resulting in free amino acids.
While known aspects of synthesis are covered by patents, many details are proprietary. Two approaches to synthesis are used commercially. In the chemical synthesis, the two carboxyl groups of aspartic acid are joined into an anhydride, and the amino group is protected with a formyl group as the formamide, by treatment of aspartic acid with a mixture of formic acid and acetic anhydride. Phenylalanine is converted to its methyl ester and combined with the N-formyl aspartic anhydride; then the protecting group is removed from aspartic nitrogen by acid hydrolysis. The drawback of this technique is that a byproduct, the bitter-tasting β-form, is produced when the wrong carboxyl group from aspartic acid anhydride links to phenylalanine, with desired and undesired isomer forming in a 4:1 ratio. A process using an enzyme from Bacillus thermoproteolyticus to catalyze the condensation of the chemically altered amino acids will produce high yields without the β-form byproduct. A variant of this method, which has not been used commercially, uses unmodified aspartic acid, but produces low yields. Methods for directly producing aspartyl-phenylalanine by enzymatic means, followed by chemical methylation, have also been tried, but not scaled for industrial production.
The acceptable daily intake (ADI) value for aspartame, as well as other food additives studied, is defined as the "amount of a food additive, expressed on a body weight basis, that can be ingested daily over a lifetime without appreciable health risk." The Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the European Commission's Scientific Committee on Food has determined this value is 40 mg/kg of body weight for aspartame, while FDA has set its ADI for aspartame at 50 mg/kg.
The primary source for exposure to aspartame in the United States is diet soft drinks, though it can be consumed in other products, such as pharmaceutical preparations, fruit drinks, and chewing gum among others in smaller quantities. A 12 US fluid ounce (355 ml) can of diet soda contains 0.18 grams (0.0063 oz) of aspartame, and for a 75 kg (165 lb) adult, it takes approximately 21 cans of diet soda daily to consume the 3.7 grams (0.13 oz) of aspartame that would surpass the FDA's 50 milligrams per kilogram of body weight ADI of aspartame from diet soda alone.
Reviews have analyzed studies which have looked at the consumption of aspartame in countries worldwide, including the United States, countries in Europe, and Australia, among others. These reviews have found that even the high levels of intake of aspartame, studied across multiple countries and different methods of measuring aspartame consumption, are well below the ADI for safe consumption of aspartame. Reviews have also found that populations that are believed to be especially high consumers of aspartame such as children and diabetics are below the ADI for safe consumption, even considering extreme worst-case scenario calculations of consumption.
In a report released on 10 December 2013, the EFSA said that, after an extensive examination of evidence, it ruled out the "potential risk of aspartame causing damage to genes and inducing cancer," and deemed the amount found in diet sodas safe to consume.
Aspartame was discovered in 1965 by James M. Schlatter, a chemist working for G.D. Searle & Company. Schlatter had synthesized aspartame as an intermediate step in generating a tetrapeptide of the hormone gastrin, for use in assessing an anti-ulcer drug candidate. He discovered its sweet taste when he licked his finger, which had become contaminated with aspartame, to lift up a piece of paper. Torunn Atteraas Garin participated in the development of aspartame as an artificial sweetener.
In 1975, prompted by issues regarding Flagyl and Aldactone, a U.S. FDA task force team reviewed 25 studies submitted by the manufacturer, including 11 on aspartame. The team reported "serious deficiencies in Searle's operations and practices". The FDA sought to authenticate 15 of the submitted studies against the supporting data. In 1979, the Center for Food Safety and Applied Nutrition (CFSAN) concluded, since many problems with the aspartame studies were minor and did not affect the conclusions, the studies could be used to assess aspartame's safety.
In 1980, the FDA convened a Public Board of Inquiry (PBOI) consisting of independent advisors charged with examining the purported relationship between aspartame and brain cancer. The PBOI concluded aspartame does not cause brain damage, but it recommended against approving aspartame at that time, citing unanswered questions about cancer in laboratory rats.:94–96
In 1983, the FDA approved aspartame for use in carbonated beverages, and for use in other beverages, baked goods, and confections in 1993. In 1996, the FDA removed all restrictions from aspartame, allowing it to be used in all foods.
Several European Union countries approved aspartame in the 1980s, with EU-wide approval in 1994. The European Commission Scientific Committee on Food reviewed subsequent safety studies and reaffirmed the approval in 2002. The European Food Safety Authority reported in 2006 that the previously established Acceptable daily intake was appropriate, after reviewing yet another set of studies.
Under the trade names Equal, NutraSweet, and Canderel, aspartame is an ingredient in approximately 6,000 consumer foods and beverages sold worldwide, including (but not limited to) diet sodas and other soft drinks, instant breakfasts, breath mints, cereals, sugar-free chewing gum, cocoa mixes, frozen desserts, gelatin desserts, juices, laxatives, chewable vitamin supplements, milk drinks, pharmaceutical drugs and supplements, shake mixes, tabletop sweeteners, teas, instant coffees, topping mixes, wine coolers and yogurt. It is provided as a table condiment in some countries. Aspartame is less suitable for baking than other sweeteners, because it breaks down when heated and loses much of its sweetness.
In 1985, Monsanto Company bought G.D. Searle, and the aspartame business became a separate Monsanto subsidiary, the NutraSweet Company. In March 2000, Monsanto sold it to J.W. Childs Equity Partners II L.P. European use patents on aspartame expired starting in 1987, and the U.S. patent expired in 1992. Since then, the company has competed for market share with other manufacturers, including Ajinomoto, Merisant and the Holland Sweetener Company.
Many aspects of industrial synthesis of aspartame were established by Ajinomoto. In 2004, the market for aspartame, in which Ajinomoto, the world's largest aspartame manufacturer, had a 40 percent share, was 14,000 metric tons a year, and consumption of the product was rising by 2 percent a year. Ajinomoto acquired its aspartame business in 2000 from Monsanto for $67M.
In 2008, Ajinomoto sued British supermarket chain Asda, part of Wal-Mart, for a malicious falsehood action concerning its aspartame product when the substance was listed as excluded from the chain's product line, along with other "nasties". In July 2009, a British court found in favour of Asda. In June 2010, an appeals court reversed the decision, allowing Ajinomoto to pursue a case against Asda to protect aspartame's reputation. Asda said that it would continue to use the term "no nasties" on its own-label products, but the suit was settled in 2011 with Asda choosing to remove references to aspartame from its packaging.
Holland Sweetener Company
A joint venture of DSM and Tosoh, the Holland Sweetener Company manufactured aspartame using the enzymatic process developed by Toyo Soda (Tosoh) and sold as the brand Sanecta. Additionally, they developed a combination aspartame-acesulfame salt under the brand name Twinsweet. They left the sweetener industry in late 2006, because "global aspartame markets are facing structural oversupply, which has caused worldwide strong price erosion over the last five years", making the business "persistently unprofitable".
Because sucralose, unlike aspartame, retains its sweetness after being heated, and has at least twice the shelf life of aspartame, it has become more popular as an ingredient. This, along with differences in marketing and changing consumer preferences, caused aspartame to lose market share to sucralose. In 2004, aspartame traded at about $30/kg and sucralose, which is roughly three times sweeter by weight, at around $300/kg.
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