Aspartame

Uses

Aspartame is about 180 to 200 times sweeter than sucrose (table sugar). Due to this property, even though aspartame produces roughly the same energy per gram when metabolized as sucrose does, 4 kcal, the quantity of aspartame needed to produce the same sweetness is so small that its caloric contribution is negligible.

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.

Acceptable levels of consumption

The acceptable daily intake (ADI) value for food additives, including aspartame, 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 (later becoming EFSA) have determined this value is 40 mg/kg of body weight per day for aspartame, while the FDA has set its ADI for aspartame at 50 mg/kg per day an amount equated to consuming 75 packets of commercial aspartame sweetener per day to be within a safe upper limit.

The primary source for exposure to aspartame in the US 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.

Reviews have analyzed studies which have looked at the consumption of aspartame in countries worldwide, including the US, 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.

Safety and health effects

The safety of aspartame has been studied since its discovery, and it is a rigorously tested food ingredient. Aspartame has been deemed safe for human consumption by over 100 regulatory agencies in their respective countries, including the US Food and Drug Administration (FDA), UK Food Standards Agency, the European Food Safety Authority (EFSA), Health Canada, and Food Standards Australia New Zealand.

Metabolism and body weight

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.

In 2023, the World Health Organization recommended against the use of common non-sugar sweeteners (NSS), including aspartame, to control body weight or lower the risk of non-communicable diseases, stating: "The recommendation is based on the findings of a systematic review of the available evidence which suggests that use of NSS does not confer any long-term benefit in reducing body fat in adults or children. Results of the review also suggest that there may be potential undesirable effects from long-term use of NSS, such as an increased risk of type 2 diabetes, cardiovascular diseases, and mortality in adults."

Phenylalanine

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 phenylalanine, foods containing aspartame sold in the US 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".

In Canada, foods that contain aspartame are required to list aspartame among the ingredients, include the amount of aspartame per serving, and state that the product contains phenylalanine.

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.

Cancer

regulatory agencies, including the FDA and EFSA, These conclusions are based on various sources of evidence, such as reviews and epidemiological studies finding no association between aspartame and cancer.

In July 2023, scientists for the International Agency for Research on Cancer (IARC) concluded that there was "limited evidence" for aspartame causing cancer in humans, classifying the sweetener as Group 2B (possibly carcinogenic). The lead investigator of the IARC report stated that the classification "shouldn't really be taken as a direct statement that indicates that there is a known cancer hazard from consuming aspartame. This is really more of a call to the research community to try to better clarify and understand the carcinogenic hazard that may or may not be posed by aspartame consumption."

The Joint FAO/WHO Expert Committee on Food Additives (JECFA) added that the limited cancer assessment indicated no reason to change the recommended acceptable daily intake level of 40 mg per kg of body weight per day, reaffirming the safety of consuming aspartame within this limit.

The FDA responded to the report by stating:

Neurological safety

Reviews found no evidence that low doses of aspartame had neurotoxic effects.

Headaches

Reviews have found little evidence to indicate that aspartame induces headaches, although certain subsets of consumers may be sensitive to it.

Water quality

Aspartame passes through wastewater treatment plants mainly unchanged.

Mechanism of action

The perceived sweetness of aspartame (and other sweet substances like acesulfame potassium) in humans is due to its binding of the heterodimer G protein-coupled receptor formed by the proteins TAS1R2 and TAS1R3. Rodents do not experience aspartame as sweet-tasting, due to differences in their taste receptors.

Metabolites

Aspartame is rapidly hydrolyzed in the small intestine by digestive enzymes which break aspartame down into methanol, phenylalanine, aspartic acid, and further metabolites, such as formaldehyde and formic acid. Due to its rapid and complete metabolism, aspartame is not found in circulating blood, even following ingestion of high doses over 200 mg/kg.

Aspartic acid

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.

Methanol

The methanol produced by aspartame metabolism is unlikely to be a safety concern for several reasons. The amount of methanol produced from aspartame-sweetened foods and beverages is likely to be less than that from food sources already in 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.

Chemistry

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.

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.

History

Aspartame was discovered by accident in 1965 by James M. Schlatter, a chemist working for G.D. Searle & Company in Skokie, Illinois. 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, an 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.

In 1983, the FDA approved aspartame for use in carbonated beverages and for use in other beverages, baked goods, and confections in 1993. As of May 2023, the FDA stated that it regards aspartame as a safe food ingredient when consumed within the acceptable daily intake level of 50 mg per kg of body weight per day.

Several European Union countries approved aspartame in the 1980s, with EU-wide approval in 1994. The Scientific Committee on Food (SCF) reviewed subsequent safety studies and reaffirmed the approval in 2002. The European Food Safety Authority (EFSA) reported in 2006 that the previously established Acceptable daily intake (ADI) was appropriate, after reviewing yet another set of studies.

Compendial status

• British Pharmacopoeia
• United States Pharmacopeia

Commercial uses

Under the brand 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.

NutraSweet Company

In 1985, Monsanto bought G.D.Searle, and the aspartame business became a separate Monsanto subsidiary, NutraSweet. In March 2000, Monsanto sold it to J.W. Childs Associates Equity Partners II L.P. European use patents on aspartame expired beginning in 1987, with the US patent following suit in 1992.

Ajinomoto

In 2004, the market for aspartame, in which Ajinomoto, the world's largest aspartame manufacturer, had a 40% share, was 14000 t a year, and consumption of the product was rising by 2% a year. Ajinomoto acquired its aspartame business in 2000 from Monsanto for $67 million (equivalent to $ in ).

In 2007, Asda was the first British supermarket chain to remove all artificial flavorings and colors in its store brand foods. In 2008, Ajinomoto sued Asda, part of Walmart, 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 ruled in favor 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.

In November 2009, Ajinomoto announced a new brand name for its aspartame sweetener — AminoSweet.

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 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".

Competing products

Because sucralose, unlike aspartame, retains its sweetness after being heated, and has at least twice the shelf life of aspartame, it has become more commonly used as an ingredient. This, along with differences in marketing and changing consumer preferences, caused aspartame to lose market share to sucralose during the early 21st century.

References

References

1. (1989). "The Merck Index". Merck & Co..
2. (2016). "[[CRC Handbook of Chemistry and Physics]]". [[CRC Press]].
3. (2009). "Handbook of Pharmaceutical Excipients". Pharmaceutical Press.
4. (27 May 2023). "Aspartame". PubChem, National Library of Medicine, US National Institutes of Health.
5. (February 2022). "Natural sweeteners: Sources, extraction and current uses in foods and food industries". Food Chemistry.
6. (30 May 2023). "Timeline of Selected FDA Activities and Significant Events Addressing Aspartame". US Food and Drug Administration.
7. (14 July 2023). "Aspartame and Other Sweeteners in Food". US Food and Drug Administration.
8. Kay O'Donnel. (2012). "Sweeteners and sugar alternatives in food technology". Wiley-Blackwell.
9. (2007). "Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies". Critical Reviews in Toxicology.
10. "Food Standards Australia New Zealand: Aspartame – what it is and why it's used in our food".
11. (April 2002). "Aspartame: review of safety". Regulatory Toxicology and Pharmacology.
12. (12 April 2022). "Health effects of the use of non-sugar sweeteners: a systematic review and meta-analysis". [[World Health Organization]] (WHO).
13. (4 May 2007). "New Products Weigh In". foodproductdesign.com.
14. (May 2007). "Fountain Beverages in the US". [[The Coca-Cola Company]].
15. (February 1998). "Sensory evaluation of mixtures of maltitol or aspartame, sucrose and an orange aroma". Chemical Senses.
16. WHO. (1987). "Principles for the safety assessment of food additives and contaminants in food". Environmental Health Criteria 70.
17. (April 2006). "The intake of intense sweeteners – an update review". Food Additives and Contaminants.
18. (29 August 2023). "Artificial Sweeteners and Cancer".
19. (6 July 2023). "Aspartame and Cancer Risk".
20. "Aspartame in Soda is Safe: European Review".
21. EFSA National Experts. (May 2010). "Report of the meetings on aspartame with national experts". EFSA.
22. (2006). "Sweeteners and sugar alternatives in food technology". Wiley-Blackwell.
23. (1 April 2018). "CFR – Code of Federal Regulations, Title 21, Part 172: Food additives permitted for direct addition to food for human consumption. Subpart I – Multipurpose Additives; Sec. 172.804 Aspartame". US Food and Drug Administration.
24. (17 June 2008). "Aspartame". UK FSA.
25. (10 December 2013). "Scientific Opinion on the re-evaluation of aspartame (E 951) as a food additive". EFSA Journal.
26. "Aspartame". EFSA.
27. (5 November 2002). "Aspartame". Health Canada.
28. (July 2017). "Nonnutritive sweeteners and cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies". CMAJ.
29. (March 2016). "Does low-energy sweetener consumption affect energy intake and body weight? A systematic review, including meta-analyses, of the evidence from human and animal studies". International Journal of Obesity.
30. (September 2014). "Low-calorie sweeteners and body weight and composition: a meta-analysis of randomized controlled trials and prospective cohort studies". The American Journal of Clinical Nutrition.
31. (April 2017). "Metabolic effects of aspartame in adulthood: A systematic review and meta-analysis of randomized clinical trials". Critical Reviews in Food Science and Nutrition.
32. (15 May 2023). "WHO advises not to use non-sugar sweeteners for weight control in newly released guideline". [[World Health Organization]] (WHO).
33. (15 May 2023). "Use of non-sugar sweeteners: WHO guideline". [[World Health Organization]] (WHO).
34. (27 May 2023). "Phenylalanine". PubChem, National Library of Medicine, US National Institutes of Health.
35. . (19 March 2015). ["Aspartame"](https://www.food.gov.uk/science/additives/aspartame).
36. (11 May 2018). "Mandatory Labelling of Sweeteners". Canadian Food Inspection Agency, Health Canada.
37. (October 2013). "Aspartame, low-calorie sweeteners and disease: regulatory safety and epidemiological issues". Food and Chemical Toxicology.
38. (October 2015). "Aspartame: A review of genotoxicity data". Food and Chemical Toxicology.
39. (1 April 2019). "Evaluation of aspartame cancer epidemiology studies based on quality appraisal criteria". Regulatory Toxicology and Pharmacology.
40. (August 2023). "Carcinogenicity of aspartame, methyleugenol, and isoeugenol". The Lancet Oncology.
41. (13 July 2023). "Aspartame hazard and risk assessment results released (news release)". World Health Organization.
42. "Aspartame hazard and risk assessment results released".
43. (14 July 2023). "Aspartame is a possible carcinogen: the science behind the decision". Nature.
44. (June 2009). "Foods and supplements in the management of migraine headaches". The Clinical Journal of Pain.
45. (February 2018). "Removal of artificial sweeteners and their effects on microbial communities in sequencing batch reactors". Scientific Reports.
46. (July 2012). "Artificial sweeteners – a recently recognized class of emerging environmental contaminants: a review". Analytical and Bioanalytical Chemistry.
47. (April 2002). "Human receptors for sweet and umami taste". Proceedings of the National Academy of Sciences of the United States of America.
48. (March 2002). "An amino-acid taste receptor". Nature.
49. (October 2000). "Simultaneous formation and detection of the reaction product of solid-state aspartame sweetener by FT-IR/DSC microscopic system". Food Additives and Contaminants.
50. "Process for producing N-formylamino acid and use thereof".
51. (5 April 2016). "The Saccharin Saga – Part 6". ChemViews Magazine.
52. (November 2008). "Synthesis and application of dipeptides; current status and perspectives". Applied Microbiology and Biotechnology.
53. (1974). "Symposium: sweeteners". AVI Publishing.
54. (1 May 2002). "Torunn A. Garin, 54, Noted Food Engineer". The New York Times.
55. (18 June 1987). "Food additive approval process followed for Aspartame". US Food and Drug Administration.
56. Testimony of Dr. Adrian Gross, Former FDA Investigator to the US Senate Committee on Labor and Human Resources, 3 November 1987. Hearing title: "NutraSweet Health and Safety Concerns." Document # Y 4.L 11/4:S.HR6.100, pp. 430–39.
57. In 1996, the FDA removed all restrictions from aspartame, allowing it to be used in all foods.[https://web.archive.org/web/20041128020903/https://www.fda.gov/bbs/topics/answers/ans00772.html FDA Statement on Aspartame], 18 November 1996
58. Panel on Food Additives and Nutrient Sources added to Food. (2006). "Opinion of the Scientific Panel on food additives, flavourings, processing aids and materials in contact with food (AFC) related to a new long-term carcinogenicity study on aspartame". The EFSA Journal.
59. British Pharmacopoeia Commission Secretariat. "Index (BP)".
60. United States Pharmacopeia. "Food Ingredient Reference Standards".
61. (17 July 2013). "How Sugar Substitutes Stack Up".
62. (2014). "Sugar replacement in sweetened bakery goods". International Journal of Food Science & Technology.
63. (18 July 1985). "Monsanto to Acquire G.D. Searle". The New York Times.
64. [http://www.findarticles.com/p/articles/mi_m0EUY/is_22_6/ai_62920821 J.W. Childs Equity Partners II, L.P] {{webarchive. link. (14 May 2007 , ''Food & Drink Weekly'', 5 June 2000)
65. (28 March 2000). "JW Childs Acquires Monsanto's NutraSweet Sweetener Business".
66. (19 November 1989). "Nutrasweet's Bitter Fight". [[The New York Times]].
67. (18 November 2004). "Ajinomoto May Exceed Full-Year Forecasts on Amino Acid Products". Bloomberg L.P.access-date=23 June 2010.
68. "Sweetener sale-05/06/2000-ECN". icis.com.
69. (12 April 2012). "Asda becomes first supermarket to axe all artificial flavourings and colours in own brand foods". [[Evening Standard]].
70. (15 July 2009). "Asda wins fight over 'nasty' sweetener". [[The Independent]].
71. "Asda claims victory in aspartame 'nasty' case". foodanddrinkeurope.com.
72. (2 June 2010). "Radical new twist in Ajinomoto vs Asda 'nasty' battle". [[William Reed Ltd]].
73. (3 June 2010). "FoodBev.com".
74. (2 June 2010). "Radical new twist in Ajinomoto vs Asda 'nasty' battle". [[William Reed Ltd]].
75. (18 May 2011). "Asda settles 'nasty' aspartame legal battle with Ajinomoto". [[William Reed Ltd.
76. Bouckley, Ben. (16 May 2011). "Asda settles 'nasty' legal spat with Ajinomoto over sweetener aspartame". William Reed.
77. (25 November 2009). "Ajinomoto brands aspartame AminoSweet". [[William Reed Ltd]].
78. (2007). "Kirk-Othmer Encyclopedia of Chemical Technology". Wiley.
79. (19 November 2003). "Holland Sweetener rolls out Twinsweet". William Reed Business Media.
80. [https://www.sec.gov/Archives/edgar/vprr/06/9999999997-06-013522 "Holland Sweetener Company to exit from aspartame business"] {{webarchive. link. (7 May 2013 . DSM press release, [[US Securities and Exchange Commission]]. 30 March 2006.)