Behaviour, Cognition and Mood
Some years ago, it was hypothesised that aspartame, primarily due to its content of Phe, could have an effect on human behaviour, cognition, and possibly on measures of physiological function (Wurtman, 1985). However, no consistent and reproducible effects were observed in a number of older animal studies investigating the effects of aspartame on neurotransmitter levels.
Only a limited number of studies on behavioural aspects in animals have been published in the last ten years. A proportion of these focused on seizure activity but a causal link with aspartame could not be established; no adverse effects on other aspects of behaviour and cognition were reported in experimental animals when aspartame was given at oral dose levels of up to 2000 mg/kg bw/day (Yirmiya et al., 1989; Tilson et al., 1991; Mullenix et al., 1991; Vitulli et al., 1996; LaBuda and Hale, 2000; Goerss et al., 2000).
A number of anecdotal reports in humans were received by the manufacturers of aspartame in early to mid 1980's relating to a variety of symptoms following the marketing of aspartame in the USA. About two-thirds of these symptoms fell into the neurobehavioural category (Butchko and Stargel, 2001). These consisted mostly of headaches (see below), mood alterations, insomnia, and dizziness. More than 500 reports were received by CDC, and almost half underwent follow-up and evaluation. A post-marketing surveillance system was developed by the NutraSweet company (Butchko and Kotsonis, 1994; Butchko et al., 1996), which was followed by scientific research on these neurological symptoms (see below).
A number of scientific studies were carried out in healthy and potentially sensitive individuals, including children, to test whether the consumption of aspartame was associated with behavioural and cognitive changes. The potentially sensitive individuals studied were, heterozygotes for PKU, individuals suffering from depression, Attention Deficit Disorder (ADD), Parkinson’s Disease, epilepsy or other suspected seizures. They included double-blind studies in children (Saravis et al., 1990; Shaywitz et al., 1994) in which no effects were observed on behaviour, mood or learning when aspartame was given as a drink at single and multiple doses of 34 mg/kg bw/day for up to two weeks. The longer term study of Shaywitz et al. (1994) examined the effect of aspartame in children with ADD and included an assessment of liver function as well as measurement of plasma levels of amino acids, serotonin and monoamine metabolites. Treatment-related effects were also absent in a study of pre- school children who were given aspartame at 32 mg/kg bw/day and described as sugar sensitive by their parents (Wolraich et al., 1994).
A number of double-blind behavioural studies of variable quality in healthy adults, involving single and repeated administrations of aspartame have also been conducted. No treatment-related effects were noted in tests on a range of cognitive parameters in studies employing single administrations of aspartame at doses of up to 60 mg/kg bw/day (Lieberman et al., 1988; Lapierre et al., 1990; Pivonka and Grunewald, 1990; Stokes et al., 1991, 1994). However, it can be argued that single dosing studies employing high amounts of aspartame do not reflect typical consumption patterns.
A number of longer term studies with a double-blind design involving multiple dosing in healthy individuals also failed to highlight any treatment-related adverse effects on behaviour (Spiers et al., 1998; Leon et al., 1989). As noted with shorter-term studies, no treatment-related effects on behaviour were noted even when aspartame was tested at 74 mg/kg bw/day for periods extending up to 24 weeks. Although Phe concentrations increased significantly as a result of treatment with aspartame, there were no significant effects noted on behaviour, mood or electroencephalogram (EEG) patterns, nor on a comprehensive battery of clinical laboratory tests. Headache was the most frequently reported adverse effect in placebo- and aspartame-treated groups but there were no significant differences noted between groups.
Several subpopulations of individuals who may potentially be sensitive to aspartame have also been studied. From a double-blind study with a cross-over design in 13 depressed patients, Walton et al. (1993) concluded that aspartame (30 mg/kg bw/day for 7 days) increased the frequency and severity of adverse experiences in these individuals. These authors concluded that the use of aspartame in individuals with mood disorder should be discouraged. However, it is difficult to interpret this study since the authors numerically combined unrelated adverse effects to show a statistically significant result in depressed patients and only a limited number of subjects were available for evaluation due to premature termination of the study.
The effect of aspartame on behaviour, cognition and EEG patterns has also been investigated in PKU heterozygotes. Older studies in PKU homozygotes and those heterozygous for the condition have been reviewed elsewhere (de Sonneville and Benninger, 1996, and references therein). Overall, the authors concluded that aspartame did not affect cognitive function and EEG profiles in either the general population or those heterozygous for PKU. In a more recent double-blind study, which included assessment of plasma amino acid levels and EEG patterns (Trefz et al., 1994), the subjects ingested aspartame (15 or 45 mg/kg bw/day) and placebo for 12 weeks. The battery of behavioural tests included tests for short-term memory, reaction time and various attention tasks. Although headaches were among the mild adverse symptoms reported, there was no statistically significant difference between treatments. There was a significant rise in Phe in the high-dose group in contrast to the low-dose group and this was also the case for the ratio of Phe to LNAA. However, aspartame had no significant effect on cognitive function or EEG profiles.