Aspartame is the common name of the non-saccharide sweetener aspartyl-phenylalanine-1-methyl ester. Initially discovered by accident by James Schlatter, a chemist of G D Searle Co. in 1965, it was approved for use in carbonated drinks 1983 and is now used by over 50% of adults in the United States. Almost since its conception, aspartame has raised controversy; it has been implicated in increasing the risk of lymphomas, cancers of the bladder, brain and bowel, chronic fatigue syndrome, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, autism, and systemic lupus, depression, dementia, hair loss, behavioral disturbances, triggering migraines and affecting fetal development when ingested by mothers during pregnancy (Whitehouse et al., 2008). Now 27 years after it was launched, despite numerous studies on its effects, the potential hazards associated with aspartame remain controversial. This is worsened in part by problems of alleged conflicts of interest; many of the studies claiming to prove that aspartame is safe have been carried out by scientists funded by or associated with companies involved in its production. This review will provide an overview of the history of aspartame, its chemical structure, biological fate, physiological effects and critically assess the evidence accumulated from animal and human studies suggesting that aspartame can be hazardous to human health.
The allure of artificial sweeteners is that they provide the sweetness of sugar without the associated calories. Aspartame has approximately the same number of calories per gram as table sugar (sucrose), but is 180-200 times sweeter (Lean et al., 2004). Aspartame acts by binding to the the sweet taste receptor, a heterodimer of two G protein coupled receptors, T1R2 and T1R3 (Cui et al., 2006). As the incidence of obesity increases in both Europe and the United States more people are becoming drawn to the use of artificial sweeteners. Aspartame is used in more than 6000 products including soft drinks, chewing gum, candy and desserts and is known by the brand names, Nutrasweet, Equal, Spoonful and Equal Measure, while in the European Union it is known as the E number (additive code) E951 (Belpoggi et al., 2006). In Europe, approximately 2000 tonnes of aspartame is consumed annually (Lean et al., 2004), while aspartame is consumed by 54% of adults in the USA (Hill et al., 2003). The present review will focus on the following topics:
- Aspartame structure and metabolism
- Potential hazards of aspartame:
- Aspartame and cancer
- Aspartame and neurological disorders
- Aspartame involvement in oxidative stress, dermatitis and fetal development
Aspartame is a methyl ester of the dipeptide of the two amino acids aspartic acid and phenylalanine, composed of fifty percent phenylalanine, forty percent aspartic acid and ten percent methanol (Humphries et al., 2008), arranged as depicted below:
Once ingested, aspartame is metabolised back to phenylalanine, aspartic acid and methanol in the intestinal lumen and gastrointestinal tract mucosal cells, followed by the partial absorption of these components into the circulation (Butchko et al., 2002). In adults the intake of aspartic acid from aspartame containing foods vs. typical daily diets are 1.2 and 80 mg/kg body weight/day, respectively, while that of phenylalanine from aspartame containing foods vs. the typical daily dietary phenylalanine intake is 1.5 and 52 mg/kg body weight/day, suggesting that the daily intake of these two amino acids from aspartame is relatively small compared to the intake from common foods (Abegaz et al., 2008). Each of the breakdown products can have several effects; aspartic acid can act as an excitatory neurotransmitter itself or function as a precursor for the production of glutamate, asparagine and glutamine (Humphries et al., 2008). Methanol is converted within the body to formate. This can then either leave the body via excretion or be further metabolised to formaldehyde, diketopiperazine and other derivatives (Humphries et al., 2008). Phenylalanine functions in neurotransmitter regulation, but can be toxic to patients who have phenylketonuria, an autosomal recessive genetic disorder due to a deficiency in the enzyme phenylalanine hydroxylase (Harding, 2008). This enzyme is required to breakdown phenylalanine to tyrosine, when it is deficient excessive amounts of phenylalanine accumulate and are converted into phenylpyruvate which can affect neurological development, leading to retardation and seizures. In order to control this disorder patients must follow a diet low in phenylalanine (Harding, 2008).
2. Potential hazards of Aspartame:
Aspartame has been found to be safe for human consumption by more than ninety countries world-wide based on research reviews and recommendations from advisory bodies such as the European Commission’s Scientific Committee on Food and the Food and Agriculture Organization/World Health Organization Joint Expert Committee on Food Additives (Renwick et al., 2007). Indeed, the U.S. Food and Drug Administration states that aspartame is one of the most thoroughly tested food additives the agency has ever approved, while the WHO/FAO Joint Expert Committee on Food Additives (JECFA) concluded that aspartame had been more thoroughly evaluated than any other dietary constituent (Renwick et al., 2007). In order to limit any potential harmful effects of aspartame, the acceptable daily intake of this compound has been set at 40 mg/kg body weight, calculated by taking the no observed adverse effect level (NOAEL) from animal studies and dividing by an safety factor of 100 (Renwick et al., 2007). In order to reach this level, most adults would need to ingest at least 10 cans of a drink fully sweetened with aspartame alone. While aspartame has been judged by governmental food advisory bodies both in Europe and the United States to be safe to consume below 40mg/kg body weight, a number of studies have suggested that even within this acceptable range aspartame can have a deleterious effect on health. The most pertinent studies on the effects of aspartame on health will be discussed below.
Over the past two decades aspartame has often been associated in the media with an increased risk of developing certain cancers. A critical review of the literature reveals that there are a number of studies both implicating and exonerating aspartame as a carcinogen. A key trial carried out in 1989 in human subjects is often quoted in relation to the safety of aspartame. In this trial either a placebo or 75mg/kg body weight of aspartame was administered per day to human subjects for 24 weeks. No significant differences in health were detected between the two groups and since this intake of aspartame is equivalent to consuming 10 litres of aspartame sweetened beverages per day this trial was taken to document the safety of long term consumption of aspartame (Leon et al., 1989). However, this trial was restricted to healthy adults, and not other groups, such as children, or individuals heterozygous for phenylketonuria who may be at greater risk of adverse effects. Further evidence supporting the safety of aspartame comes from a number of case control studies were carried out in Italy between 1994 and 2001 examining a link between sweeteners such as aspartame and cancer in humans (Gallus et al., 2007). The consumption of aspartame was compared between men and women admitted to hospital for acute non-neoplastic disorders and those admitted due to cancer of the oral cavity, pharynx, oesophagus, colon, rectum, breast, larynx, prostate and kidney. This comparison of the incidence of these cancers and aspartame consumption found no correlation between the two (Gallus et al., 2007). The authors of this study therefore suggest that aspartame does not increase the incidence of several common neoplasms.
However, in 2006, a carcinogenicity study performed at the Ramazzini Institute reignited the debate that aspartame could increase the incidence of neoplasms (Soffritti et al., 2006). This study administered aspartame with food to 8-week-old Sprague-Dawley rats at a wide range of concentrations above and below the recommended daily intake. At the time of the rat’s natural death the animals underwent histopathologic evaluation of all tissues and organs. This revealed that aspartame under these experimental conditions increased the incidence of malignant-tumors, lymphomas, leukemias, carcinomas of the renal pelvis and ureter, and malignant schwannomas of peripheral nerves (Soffritti et al., 2006). These results were taken to indicate that aspartame could act as a multipotential carcinogenic agent, even at a daily dose equivalent to 20 mg/kg body weight, which is half the current acceptable daily intake. Experiments have also been carried out at the Ramazzini Foundation to characterise whether aspartame can bear a carcinogenic risk when administered during fetal life. Rodents were administered aspartame with feed from the 12th day of fetal life until natural death. These tests revealed an increase in malignant tumors, lymphomas and leukemias and a dose-related increase in mammary cancer in female animals, suggesting exposure to the acceptable daily intake of aspartame (for humans) during fetal life can increase its carcinogenic effects and the development of cancers may appear earlier in life (Soffritti et al., 2008; Soffritti et al., 2007).
Though the carcinogenicity study performed at the Ramazzini Institute (Belpoggi et al., 2006; Soffritti et al., 2006) drew much media attention, it has been heavily criticized by a number of groups, particularly those associated with the manufacturing of aspartame (Renwick et al., 2007). The study used animals from an inbred colony which it has been claimed had a high incidence of respiratory and other infections and, thus, did not comply with testing guidelines as the data accumulated is difficult to interpret. In addition it was claimed that the data could not be easily interpreted as it was carried out in rodents and thus there would be significant uncertainties associated with inter-species extrapolation (Renwick et al., 2007). The European Food Safety Authority evaluation of the study concluded that the data did not provide evidence of the carcinogenic potential of aspartame and thus the established acceptable daily intake for aspartame remained at 40 mg/kg body weight.
b. Aspartame and neurological disorders:
Several studies have noted a correlation between prolonged aspartame ingestions and the frequency of headaches and migraines in those who suffer from these conditions (Koehler et al., 1988; Lipton et al., 1989; Van den Eeden et al., 1994). In addition, a comparison of the effect of aspartame on a control group and individuals with a history of depression suggested that those with mood disorders may be more sensitive to its effects and should avoid its use (Walton et al., 1993). These effects of aspartame are suggested to be due to it changing the local concentration of the neurotransmitters norepinephrine, epinephrine and dopamine (Humphries et al., 2008). Another potential effect of aspartame in the nervous system is its action on the key enzyme acetylcholinesterase. Whilst low concentrations have no effect on this enzyme’s activity, high concentrations significantly decrease its ability to hydrolyse the neurotransmitter acetylcholine (Tsakiris et al., 2006). Aspartame has also been linked to Parkinson’s disease and in particular with worsening the symptoms of those who suffer from this disease. The rationale behind this suggestion is that aspartame is hydrolyzed to phenylalanine, which as a large neutral amino acid can compete with levodopa for uptake into the brain (Karstaedt et al., 1993). However, comparison of the effects of high doses of aspartame with a placebo has shown no adverse effect on Parkinsonian patients (Karstaedt et al., 1993).
Aspartame has also been suggested to be able to alter the neurochemical balance in the brain in order to induce seizure activity (Humphries et al., 2008; Zhi et al., 1989). In monkeys an intake of over 1g per day has been shown to alter the levels of neurotransmitters in the brain, inducing seizure states, however high doses in humans have not been shown to have any such effects on behavior (Butchko et al., 2001; Kanarek, 1994; Wolraich et al., 1994).
c. Aspartame involvement in oxidative stress, dermatitis and fetal development:
One of the breakdown products of aspartame, methanol can itself be broken down to the metabolites formaldehyde and formate. Application of formaldehyde to rat thymocytes has been shown to induce cell death and possibly increase cell susceptibility to oxidative stress (Oyama et al., 2002). However, these effects only occurred at relatively high levels of aspartame application (Oyama et al., 2002). Aspartame has also been reported to have several negative effects on the eye area including dryness and dermatitis of the eyelid, possibly due to the production of formaldehyde (Hill et al., 2003). However, such cases are rare. In addition, effects on fetal development have been suggested since the metabolites of aspartame; aspartic acid and phenylalanine may be able to cross the placenta in a concentration-dependent manner and possibly across blood-brain barrier entering the cerebrospinal fluid of the fetus (Simintzi et al., 2007). This has been disputed by scientists associated with aspartame production which claim that aspartame levels even in high users would not raise the blood plasma level of any aspartame metabolites enough to cross the placenta or the blood-brain barrier (Abegaz et al., 2008).
3. Potential benefits of aspartame:
Some research groups particularly those funded by industry associated with aspartame production have purported that it could potentially have benefits in reducing obesity and related diseases such as cardiovascular disease and diabetes type 2 (Renwick et al., 2007). Sugar provides approximately 200kcal or 10% of the total calories in most western diets. Therefore it has been argued that if this was entirely replaced by a sweetener such as aspartame which is non-caloric and the calories not replaced, this could significantly reduce obesity levels and encourage weight loss (Lean et al., 2004). However, this may not be a realistic way of reducing obesity since aspartame has been shown to increase appetite in some cases (Tordoff et al., 1990b). Indeed, the evidence that aspartame can reduce weight gain and obesity is inconclusive (Drewnowski, 1999; Tordoff et al., 1990a).
While the benefits of aspartame using in reducing the obesity pandemic remain equivocal, evidence does suggest that aspartame can have other beneficial effects. Studies on cultured cells that have been exposed to the mycotoxin Ochratoxin have shown that aspartame can provide a protective effect (Baudrimont et al., 1997). Ochratoxin is produced by several species of fungus, particularly those of the genera Aspergillus and Penicillum and as such is a common contaminant in foodstuffs, where it has been shown to be immunosuppressive, genotoxic, teratogenic and carcinogenic. Pretreatment of monkey kidney cells with aspartame was shown to reduce the toxicity of Ochratoxin by competitive binding, suggesting aspartame may have protective qualities (Baudrimont et al., 1997).
As previously stated aspartame is one of the most thoroughly tested additives (Renwick et al., 2007) and yet still remains one of the most controversial. Though its effects have been investigated numerous times, including in 2002 when the European Scientific Committee on Food reviewed 500 reports, the debate as to the safety of aspartame remains unabated. The difficulty in assessing the consequences of aspartame ingestion is increased by the conflicts of interest of several scientists who present data showing aspartame is safe. When the funding for such research comes from the company whose product is being tested, can the research really be unbiased? A review of the literature suggests that bias does indeed occur; while all studies funded in some portion by the aspartame industry determine that aspartame presents no risk, ninety two percent of independent studies have shown that aspartame has the potential to adversely affect health (Briffa, 2005). Though the current weight of evidence suggests that the acceptable daily intake level of aspartame will not be deleterious to general human health in the short term, those with particular susceptibilities such as phenylketonuria and mood disorders should exercise caution. In addition, given that over fifty percent of adults in the United States consume aspartame, and some will now have been consuming this product for two decades, it is now that the true effects of long-term aspartame ingestion in humans will become clear. Therefore a systematic review of the biochemical, clinical and behavioural effects of aspartame within the next decade may finally clarify the true consequences of aspartame on human health. Furthermore, despite two decades of use in the human diet, there has not been a single controlled study published to confirm that aspartame can aid weight loss, which begets the question, when the safety of aspartame is still equivocal, is it worth taking the risk?