Aspartame Metabolism
Aspartame consists of two amino acids (L-phenylalanine and L-aspartic acid). It is hydrolyzed and absorbed in the gastrointestinal tract (GI) through the action of esterase and peptidases. Digestion releases methanol (10%), aspartic acid (40%) and phenylalanine (50%) (
Table 1), which are absorbable in the intestinal mucosa [
10]. These metabolites can be harmful at high doses and hence prolonged aspartame consumption may be a risk factor [
11,
12]. Indeed, the metabolism products of aspartame are believed to be more toxic than the original substance itself [
13,
14]. Methanol is firstly oxidized in the liver to formaldehyde and again to formic acid; however, while methanol is known to damage the liver, formaldehyde and formate are also responsible for the destruction of liver cells. In addition, during the process the formation of superoxide anions and hydrogen peroxide occur, which lead to protein denaturation and subsequent enzymatic changes [
15,
16,
17]. According to the study on the impact of aspartame administration on trans-sulfuration pathway, decrease of most metabolites of the trans-sulphuration pathway in the liver was observed during experiment. Levels of cysteine, homocysteine, S-adenosyl-homocysteine, and S-adenosyl-methionine were increased. There was no significant change in methionine and cystathionine level [
18]. All mentioned aspartame metabolites are toxic to the brain. Furthermore, rhenylalanine is mainly metabolized to tyrosine and smaller amounts of phenylethylamine and phenylpyruvate, while aspartic acid is metabolized into alanine and oxaloacetate [
10]. It has been suggested that in human beings consuming large amounts, aspartame may be a significant source of formate, which can contribute to serious physiological changes. The role of aspartame in several disorders affecting human body remains to be investigated. Most importantly, people with phenylketonuria, a genetic disorder in which patients cannot convert phenylalanine to tyrosine, must avoid aspartame. Due to the harmful effects of aspartame on phenylketonuria patients, according to the FDA requirements all products containing aspartame must have a label informing about the presence of phenylalanine
Diabetes Mellitus
Aspartame has also been blamed for causing type 2 diabetes mellitus (T2DM) and may not meet the expectation of being healthy alternative to sugar in sweetened beverages [
35]. A recent study investigating the effect of sucrose-sweetened and artificially (aspartame) sweetened food and drinks on inflammatory markers in overweight subjects found that consumption of sweetened items significantly increased plasma haptoglobin and transferrin but did not significantly increase the C-reactive protein level. This study corroborates findings from others that suggest that the pro-inflammatory process underlying the greater risk of diabetes may be exacerbated by a high intake of rapidly digested and absorbed carbohydrates and artificial sweetene
Impact of Aspartame on Children and Fetuses
A healthy diet is particularly important during pregnancy to allow the proper development of both mother and fetus [
41,
42]. Many prospective cohort studies note a relationship between artificial sweeteners (ASWs) consumption and putting on weight in children [
43,
44,
45]. Low-calorie sweeteners (LCS) are regarded as safe to consume during pregnancy and lactation if recommended levels are not exceeded [
9,
46,
47,
48,
49]. However, some reports have associated preterm delivery and allergic diseases in offspring with consumption of ASWs in beverages [
50,
51,
52]. Despite this, a review of papers found no such association between ASW and preterm delivery [
53]. While a recent study found aspartame metabolism products to cross into the placenta [
46], a dose of 200 mg/kg of bodyweight of aspartame, i.e., four to five times higher than recommended daily intake, was not found to result in methanol poisoning or mental retardation caused by increased Phe level in the blood of offspring [
54], suggesting that consumption within recommended levels should not cause adverse effects to the fetus [
46,
49]. Another study on fish embryos from medaka (Oryzias latipes) found that aspartame treatment increased embryo heart rate, gently decreased head growth, and caused anxiety-like behavior; interestingly, aspartame in combination with caffeine demonstrated a lower increase than caffeine alone and caused advanced eye development and decreased hatchling body length. The authors ranked aspartame in second place for developmental toxicity
