Unveiling the Sweet Truth about Aspartame

Aspartame is a common artificial sweetener used as a sugar substitute in many beverages and foods. The sugar substitute is not at all structurally similar to other known saccharides, but has been found to be 200 times sweeter. It was discovered in 1965 by American chemist James M. Schlatter, while working for G.D. Searle & Company [Figure 1]. The properties of aspartame were discovered accidentally by Schlatter while working towards an anti-ulcer drug candidate. While synthesizing aspartame, Schlatter licked his finger, which had been contaminated with the compound in the process, and discovered its sweet properties (Mazur, 2020). The sweetener (methyl L-α-aspartyl-L-phenylalaninate) is synthesized by adding two different naturally occurring amino acids, the methyl ester of phenylalanine and aspartic acid.

Figure 1: James M. Schlatter (The Hindu, 2019).

The History of Aspartame

Aspartame was approved by the Food and Drug Administration (FDA) in 1974, however, its introduction to the market was put on hold after many concerns were raised against Searle & Company. These concerns involved reports of serious allegations against the company’s operations and procedures. Following these concerns, several hearings were conducted by the FDA in order to authenticate the investigational studies and research data submitted by Searle. The data submitted from fifteen pivotal studies were thoroughly audited to determine its authenticity. Records from the FDA show that three of these studies were audited by the FDA themselves and twelve by the Universities Associated for Research and Education in Pathology (UAREP). Evaluation of the data took over two years and the FDA and UAREP concluded that the fifteen studies reviewed were indeed authentic. Aspartame was finally approved for market in 1981 (Choudhary & Pretorius, 2017).

Several concerns were raised by Dr. John Olney [Figure 2], a medical doctor and professor of psychiatry, pathology, and immunology at the Washington University School of Medicine. He was known for his research focusing on the toxic effects of certain amino acids on the brain. This included aspartic acid. He claimed that aspartame might cause brain damage resulting in mental retardation, endocrine dysfunction, or both. He also raised issues against the apparent relationship between aspartame and brain cancer, and the use of aspartame in people who suffer from phenylketonuria (PKU), a disorder that prevents the metabolism of phenylalanine. Following these concerns, the FDA assembled a group of independent advisors, called the Public Board of Inquiry (PBOI) to examine these concerns. The PBOI concluded that aspartame does not cause brain damage (Butchko et al., 2002).

Figure 2: Dr. John Olney (St Louis Post Dispatch, n.d.).

In 1983, aspartame was approved for use in carbonated drinks as well as other beverages, baked goods and confectionary by the FDA. All restrictions against aspartame were lifted in 1996, allowing it to be used in all foods.

Several other European Union (EU) countries approved aspartame for use in the 1980s, and by 1994 the whole of the EU approved its use as well. The Scientific Committee on Food (SCF) reviewed the safety studies in 2002 and reaffirmed its approval. To date, Aspartame remains one of the most tested food additive substances in the world, and is considered safe to consume at the ADI level.

The Chemistry

Aspartame is a synthetic combination of two amino acids, namely phenylalanine methyl ester and aspartic acid. A peptide bond is formed when they are combined; this is also known as an amide bond, which is a covalent bond formed between the a-amino group of one amino acid and the a-carboxylic acid group of another amino acid when condensed (two molecules condense into a single molecule with the removal of a water molecule in the process). In the case of aspartame, the a-amino group comes from phenylalanine and the a-carboxylic acid group from aspartic acid. Aspartame is hydrolyzed under strong acidic or alkaline conditions, generating methanol as a by-product [Figure 3]. Under stronger conditions, the peptide bond may also be hydrolyzed forming the individual free amino acids. The N-terminal of the molecule has a free alpha-amino group on it and, as indicated in Figure 3, this is called the aspartyl residue. The C-terminal from the phenylalanine residue has a methyl ester derivative. Common table sugar has a completely different structure to aspartame, as seen in Figure 4.

Figure 3: Aspartame hydrolysis (Quizlet, n.d.).

Aspartame is synthesized commercially in two different ways. The synthesis is not as straightforward as one would expect it to be. Due to the structure of aspartic acid, the coupling of the two amino acids can occur in two different ways as shown in Figure 4. Therefore, aspartic acid needs to be protected before the coupling occurs, so as to ensure that the correct product aspartame is made and not the by-product. The by-product of aspartame is known as beta aspartame and it has opposite properties to aspartame, resulting in a bitter taste. Protecting aspartic acid during the production of aspartame ensures a lower ratio of the β-form by-product. The second process involves using an enzyme to catalyze the condensation of the protected amino acids (Stoineva et al., 1992), which have proven to form high yields of the desired aspartame with limited yields of the β-form by-product [Figure 4].

Figure 4: Aspartame (left), β-aspartame (right) and table sugar (bottom) (Wikipedia, 2011).

Extensive Usage

Aspartame is found in more than 5000 foods and drinks, and is far sweeter than sugar (O'Mullane et al., 2014). Some of the most common foods and drinks with aspartame include:

• Tabletop sweeteners, including NutraSweet, Canderel [Figure 5], Equal and Sugar Twin;

• Beverages and drinks such as Diet Coke, Coke Zero, Fanta Zero, Wyler’s Light and many more;

• Sugar-free gum;

• Gelatin products such as sugar-free Jeel-O and Royal’s sugar-free dessert products;

• Sugar-free syrups.

For food additives, including aspartame, the acceptable daily intake (ADI) refers to the maximum amount of the additive consumed daily without appreciable health effects over a lifetime. According to the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the Scientific Committee on Food of the European Commission which later became the EFSA), aspartame has a safe upper limit of 40 mg/kg of body weight per day. However, the FDA has set the ADI for aspartame at 50 mg/kg per day. To reach the ADI about 75 packets of commercially available aspartame sweetener would need to be consumed daily. Recent reports from the FDA stated that it considers aspartame safe to be used within the daily intake level of 50 mg per kg of body weight. After reviewing yet another set of safety and daily intake limits in 2006, the European Food Safety Authority (EFSA) affirmed that the Acceptable Daily Intake (ADI) of 50 mg per kg of body weight was appropriate.

Figure 5: Canderel contains 8% aspartame (Canderel, n.d.).

In the US, diet soft drinks are the primary source of aspartame exposure, though it can also be found in pharmaceutical preparations, fruit drinks, and chewing gums. A standard can of diet soda (350mL) contains 0.18 grams of aspartame. This would mean that for a 75-kilogram adult, approximately 21 cans or 7.35 L of diet soda would equate to a consumption of 3.7 grams, which would surpass the FDA’s 50 mg/kg of body weight ADI of aspartame from diet soda alone. Several studies have been performed looking at the consumption of aspartame in various countries such as the United States of America, England and several more in Europe. The results have shown that even at high levels of aspartame intake, the levels are still well below ADI's limits for safe consumption. Even in studies on populations of children and diabetics, where the intake is assumed to be high, data are still shown to be below the ADI level (Butchko et al., 2002; Magnuson et al., 2007).

Health and Safety

Phenylketonuria

Phenylketonuria (known as PKU) is an inherited genetic disorder in which phenylalanine levels in the blood are increased. The disorder is characterized by a PAH gene mutation, resulting in a dysfunctional enzyme called phenylalanine hydroxylase. This causes a halt in the metabolism of phenylalanine in the body. Phenylalanine is found in many foods, including proteins (such as meat, eggs, nuts and milk) and in some artificial sweeteners such as Canderel. In the absence of treatment, phenylalanine accumulation in the body leads to cognitive difficulties (intellectual disability). People suffering from phenylketonuria often have paler skin and a smaller head [Figure 6]. In many countries such as the UK, foods that contain aspartame are required by the Food Standard Agency (FDA) to list it as an ingredient and with warnings such as “Contains a source of phenylalanine”. In Canada, food suppliers are required to list aspartame as an ingredient along with the quantity of aspartame found in the food (Butchko et al., 2002; Newbould et al., 2021).

Figure 6: Phenylketonuria genetic hereditary and a patient with PKU (Wikipedia, 2008).

Phenylalanine is an essential amino acid that plays a crucial role in the growth and maintenance of life. Furthermore, some scientists have expressed concern about phenylalanine's safety for individuals living without phenylketonuria. These concerns are mainly based on hypothetical changes in neurotransmitter levels and the ratio of neurotransmitters in the brain that could cause neurological symptoms.

Cancer

In July 2023, researchers from the International Agency for Research and Cancer (IARC), concluded that there was limited evidence that suggested that aspartame is a cancer-causing agent in humans. They classified the sweetener as a Group 2B carcinogen, which is defined as possibly carcinogenic. Figure 7 below shows classifications of common foods that are considered carcinogenic according to the WHO. This report suggests the research community should take the Group 2B classification as an opportunity to clarify and understand the carcinogenic risks posed by aspartame consumption. However, as of 2023, authoritative bodies like the FDA, EFSA, and the US National Cancer Institute have affirmed that the consumption of aspartame remains safe when kept within acceptable daily intake limits. Their assessments, drawn from a range of evidence including reviews and epidemiological studies, have found no link between aspartame consumption and the development of cancer (Magnuson et al., 2007).

The FDA also responded to the report by the IARC by stating that aspartame being labeled as possibly carcinogenic to humans does not mean that it is actually linked to cancer. The FDA disagreed with the classification made by the IARC. The report by IARC was reviewed by scientists from the FDA in 2021 when it was first published and identified significant shortcomings to the studies by the IARC.

Figure 7: WHO classification of red and processed meats (United Nations Associations Coventry Branch, n.d.).

Following these reports the World Health Organisation (WHO) placed aspartame in two separate risk categories, namely; carcinogenic to humans and probably carcinogenic. Research on aspartame's link to cancer has not yielded conclusive evidence, and many of the conclusions of these studies have been derived from animal studies. A 2020 study, for example, found an increased incidence of leukemia and lymphoma in mice that consumed aspartame, but the doses were almost quadruple the weight of the mice, which is not a fair representative to correlate with human risk (Riboli et al., 2023). Meanwhile, studies in the 1980s found aspartame did not cause brain tumors or bladder cancer (Urothelial carcinoma) in rats. In another study conducted in France in 2022 consisting of more than 100,000 adults, large amounts of artificial sweeteners were linked to a slightly higher risk of cancer.

According to a report released by the EFSA on 10 December 2013, the EFSA ruled out the "potential risk of aspartame damaging genes and causing cancer" and considered the amount of aspartame in diet sodas to be safe. [Figure 8].

Figure 8: Coca Cola and Diet Coca Cola (Marketing Week, n.d.).

Conclusion

Aspartame is a widely used artificial sweetener that has been thoroughly studied and assessed for its safety by regulatory agencies around the world. Individuals seeking to reduce their calorie intake and manage their weight, find it to be an attractive alternative to sugar due to its low-calorie content and intense sweetness. A series of decades of research has consistently demonstrated that aspartame is safe to consume at the levels established by regulatory authorities for acceptable daily consumption. In spite of concerns about anecdotal reports of adverse effects, extensive scientific reviews and studies have repeatedly confirmed its safety for pregnant women and children.

As with any food additive, individual sensitivity can vary, and some individuals may experience mild adverse reactions to aspartame. Nevertheless, these instances are relatively rare and do not indicate widespread harm. Moderation and awareness of personal health considerations are important when it comes to any dietary choice. It is important to note that scientific understanding evolves over time, and ongoing research and assessments are crucial to ensure the continued safety of aspartame use and other food additives. According to the scientific community, aspartame, when consumed within the recommended limits, is a safe alternative for those looking to reduce their daily sugar intake without sacrificing taste. However, it is always recommended to consult with healthcare professionals and regulatory authorities to stay informed on the latest updates.

Bibliographical References

Butchko, H. H., Stargel, W. W., Comer, C. P., Mayhew, D. A., Benninger, C., Blackburn, G. L., de Sonneville, L. M., Geha, R. S., Hertelendy, Z., & Koestner, A. (2002). Aspartame: review of safety. Regulatory Toxicology and Pharmacology, 35(2), 1–93.

Choudhary, A. K., & Pretorius, E. (2017). Revisiting the safety of aspartame. Nutrition reviews, 75(9), 718–730.

Magnuson, B., Burdock, G., Doull, J., Kroes, R., Marsh, G., Pariza, M., Spencer, P., Waddell, W., Walker, R., & Williams, G. (2007). Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies. Critical reviews in toxicology, 37(8), 629–727.

Mazur, R. H. (2020). Discovery of aspartame. In Aspartame (3–9).

Newbould, E., Pinto, A., Evans, S., Ford, S., O’Driscoll, M., Ashmore, C., Daly, A., & MacDonald, A. (2021). Accidental consumption of aspartame in phenylketonuria: patient experiences. Nutrients, 13(2), 707.

O'Mullane, M., Fields, B., & Stanley, G. (2014). Food Additives: Sweeteners. In Y. Motarjemi (Ed.), Encyclopedia of Food Safety (477– 484).

Riboli, E., Beland, F. A., Lachenmeier, D. W., Marques, M. M., Phillips, D. H., Schernhammer, E., Afghan, A., Assunção, R., Caderni, G., & Corton, J. C. (2023). Carcinogenicity of aspartame, methyleugenol, and isoeugenol. The Lancet Oncology, 24(8), 848–850.

Stoineva, I. B., Galunsky, B. P., Lozanov, V. S., Ivanov, I. P., & Petkov, D. D. (1992). Enzymic synthesis design and enzymic synthesis of aspartame. Tetrahedron, 48(6), 1115–1122.

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