Aspartame.jpg

Kimberley Anderson, Irene Chen, Vanessa Liang, Crystal Moran




Introduction
Neuroscientific Context
Critical Analysis
Search Strategy
References



Introduction

This clip is a broadcast news segment about the controversies surrounding aspartame. Aspartame is the world's most popular sugar substitute, and is found in a wide range of products, including diet sodas, confectionary foods, chewing gum, and medications. The individuals featured in this video claim to suffer from headaches, twitches, blindness, and seizures; all of which they attribute to aspartame. The media item is an expose by Fox 5 News, Washington DC, and was first aired on November 15th, 1999. Through a series of interviews and overhead narration, this clip explores the controversial FDA approval of aspartame, its subsequent saturation of the artificial sweetener market, and some of the adverse effects as described by consumers, researchers and physicians.

Our research demonstrated the lack of conclusive evidence as to the danger or safety of aspartame, and the necessity for more independent studies to ensure the health and wellbeing of consumers.

This topic is of significant interest because of the popularity of artificially-sweetened products within Western markets, and in particular the high consumption of aspartame in diet carbonated drinks within Australia. We chose this item as it had broad links to different areas studied within the course, including seizures, depression and pharmacological effects on the brain, but also because of its pertinence to our group: young women being the second highest consumers of aspartame-laden beverages (second only to sufferers of diabetes).

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Neuroscientific Context





Background
Aspartame is an white, odourless, powdered methyl ester comprised of aspartic acid and phenylalanine; hence its IUPAC name N-(L-α-Aspartyl)-L-phenylalanine,1-methyl ester (Figure 1). It is ~200 times sweeter than sucrose. While having a similar caloric profile to sucrose, its intensity of sweetness renders calorie intake negliable. It is slightly soluble in water (3x10-2 g mL-1 at ph 3 and 25oC). Solubility increases with high and low pH and heating, but various types of degredation also occur- in particularly strong acidic or alkaline conditions, aspartame may be used to produce methanol, or free amino acids via hydrolysis. (Ager et al 1998, p. 1806)

Aspartame_structure.jpg
Aspartame_structure.jpg

Figure 1. Aspartame is metabolised into aspartate, phenylalanine and methanol. (Butchko et al., 2002, p. S17)
Aspartame was 'discovered' in 1965 when chemist James Schattler, while using aspartame in the development of an anti-ulcer drug, found it had a sweet flavour (ibid, p. 1806). At the time, Schattler was working for the G.D. Searle & Co. (now owned pharmaceutical giant Pfizer), who quickly patented it and put it up for approval for the consumable market by the Food and Drug Administration. While made legal in 1974, it was not until 1981 that Searle were permitted to market Aspartame in dry goods, and then in carbonated drinks in 1983 (GOA 1987, p. 2).

During the delay in marketing-approval, the FDA assessed the quality of Searle's findings, as well as those of a 1975-1980 Public Board of Inquiry. While the PBI concluded that "aspartame did not cause brain damage... studies did not conclusively show that aspartame did not cause brain tumours" (ibid, p. 3). In the 1987 United States General Accounting Office's review of Aspartame's approval, scientists indicated "neurological function, brain tumours, seizures, headaches, and adverse effects on children and pregnant women" (ibid, p. 3) as being key areas which needed further investigation before approval could be given. While approval was given without addressing these concerns, research in all aforementioned issues continues.

Purported Negative Health Effects



Neurotoxicity:After consumption, aspartame metabolises into two common amino acids, aspartic acid and phenylalanine, and methanol. While these can be harmful in large amounts, they are also naturally occurring in many of the foods we eat. In fact, foods such as milk, tomato juice and chicken have much higher amounts of these chemicals than aspartame. The chemical which has had the most focus from a neuroscientific perspective is phenylalanine, which is a Large Neutral Amino Acid (LNAA). Studies have focused on how consumption of it impacts upon the ratio of phenylalanine to other LNAAs, and whether this leads to inhibition of other important LNAAs and enzymes in the brain, such as decreased catecholamine, serotonin and dopamine concentrations. There are two fates for phenylalanine: firstly, some is metabolized in the liver to tyrosine, essential for the synthesis of important neurotransmitters such as dopamine (Figure 2a); secondly, phenylalanine readily crosses the blood brain barrier (BBB) by competing for binding on the NAAT, a co-transporter of phenylalanine, tryptopahn (precursor for serotonin) and other amino acids (Figure 2b and 2c). At high concentrations, the competitive binding of phenylalanine results in lower concentrations of dopamine hence disturbing its negative feedback pathway (Figure 2d). However, studies such as those by Stegink et al. (1996), show that while consumption of aspartame leads to a small increase in phenylalanine to LNAA ratio, it is not significant enough to cause any adverse effects. (Humphries, Pretorius & Naude, 2008)

Phenylalanine.jpg
Phenylalanine.jpg
Figure 2. High concentrations of phenylalanine will bind more effectively to NAAT, rather than tyrosine, hence leading to lower concentrations of dopamine. There are two pathways of uptake of phenylalanine in the body: (a) firstly, some phenylalanine is hydrolysed into tyrosine in the liver; and (b) secondly, phenylalanine will compete with tyrosine, methionine and other amino acids for binding on the NAAT and transported across the BBB. (c) Tyrosine must enter the BBB via NAAT since it cannot be synthesized in the brain. (d) Inside the brain, tyrosine is converted to dopamine. (Humphries, Pretorius & Naude, 2008, p. 453)

Aspartame also releases aspartate during digestion, a type of excitatory amino acid and neurotransmitter used by the neurons in the brain. Aspartate is purported to act on the NMDA receptors on the glutamate binding sites, causing calcium ion influx into the cell (Figure 3), thereby promoting greater chances of depolarization or increased firing of action potentials. This high rate of neuron depolarization can potentiate neurodegeneration (Humphries, Pretorius & Naude, 2008). Therefore, when such excitatory neurotransmitters are in excess, the potential toxicity may lead to the neuronal death in the CNS. Additionally, excess aspartame in extracellular space will pump back into glial cells by using enormous amounts of ATP; as the level of ATP stores decrease, the synthesis of glutamate and GABA also falls, thus affecting the functionality of glutamate. In essence, disrupting the balance of neurotransmitters potentially affects a wide range processes in the CNS and the rest of the body, such as amino acid metabolism.


NMDA_receptor1.jpg
NMDA_receptor1.jpg

Figure 3. It is purported that aspartate may act directly on the glutamate binding sites on the NMDA receptor, causing calcium ion influx and hence excitation. ("Neuroactive steroids: Synthesis of positive and negative modulators of NMDA receptor", n.d.)


Headaches:A headache is a common ailment in the general population due to pain caused by structures within the cranium (e.g. blood vessels, meninges), or structures outside the cranium (e.g. nerves, muscles). Aspartame has been accused of being a precipitant of headaches in consumer reports and questionnaires (Butchko et al., 2002). Yet, the unreliability of these studies have prompted further research using a double-blind crossover method. A double-blind crossover study conducted by Schiffman et al. (1987) did not find significance in the incidence of headaches in subjects who took aspartame compared to placebo. On the contrary, another study showed a subset of the study group were indeed more vulnerable to headaches (Van Den Eeden et al., 1994). However, this study only comprised a small sample of 33 subjects leading to potential statistical issues. Therefore, the answer to whether aspartame provokes headaches is still unclear given such variable reports.

Depression:Depression is a mood disorder characterized by many symptoms, including: depressed mood, loss of interest or pleasure, guilt, loss of appetite or overeating, and cognitive problems affecting concentration, memory or decision making. The ingestion of aspartame is suggested to increase the ratio of phenylalanine to other large neutral amino acids, possibly altering central neurotransmitter concentrations (Butchko et al., 2002). These alterations might modify brain function, such as mood or cognition. Walton, Hudak and Green-Waite (1993) conducted a study which examined the effect of aspartame on subjects already suffering from mood disorders; however, this study was cancelled due to severity of reactions in the initial 13 subjects. On the contrary, a completed study on healthy volunteers showed no significant effects of aspartame on mood or cognitive function (Spiers et al., 1998).


Phenylketonuria:Phenylketonuria (PKU) is an autosomal recessive disease resulting in dysfunction in metabolism caused by deficiency of the enzyme, phenylalanine hydroxylase (PAH). PAH is essential for converting phenylalanine consumed in food to tyrosine, which is the precursor for dopamine, noradrenaline and adrenaline. As a consequence to deficient or inactive PAH, the concentration of phenylalanine in patients suffering from PKU can become toxic ("Pheylketonuria", n.d.) since phenylalanine is hydrophobic, and competes with large, neutral amino acids to cross the blood brain barrier. Some common symptoms of PKU are neurological comprising of seizures, behavioural problems, psychiatric disorders and mental retardation. Therefore, aspartame consumption is theorized to cause adverse effects on vulnerable individuals, such as the heterozygous parents of PKU sufferers (PKUH). Despite this studies have once more produced inconclusive evidence, as some studies found high phenylalanine concentrations caused generalized EEG slowing (Epstein et al., 1989); whereas other data show no medical and biochemical changes (Koch, Shaw, Williamson, & Haber, 1976); nor significant effects on cognitive performance and EEGs (Trefz, et al., 1994). Further, a review by Butchko et al. (2002) on the vulnerability of PKUH to aspartame shows that several studies have demonstrated the tolerance of high levels of aspartame in PKUH, and studies employing more sophisticated EEG analysis found no statistically significant differences.

Brain Tumours:A brain tumour is an abnormal growth of cells within the brain or the central canal of the spinal cord, causing neurologic symptoms which are focal or generalised (DeAngelis, 2001). Generalized symptoms are due to intracranial hypertension leading to headaches, nausea and vomiting. Focal symptoms indicate the location of the tumour and can include weakness on one side of the body (hemiparesis) and impairment of producing or comprehending language (aphasia). One of the most controversial purported adverse effects of aspartame use is that it causes brain tumours. Investigations conducted in the 1970s showed a high occurrence of brain tumours in rats exposed to aspartame (Reynolds, Butler & Lemkey-Johnston, 1976). A more recent rat study showed a statistically significant increase in malignant schwannomas (cancer of Schwann cells on peripheral nerves), in addition to other cancers (Soffritti et al., 2006). Thus, suggesting that aspartame is a potential carcinogenic agent, particularly affecting the central nervous system.

Consequently, there is much controversy regarding whether aspartame may be a causative factor in human brain tumours. The incidence of human brain tumours increased significantly in the United States within 1-2 years following the approval of aspartame by the FDA (Roberts, 1991). A comparison of total CNS tumour trends showed a substantial fluctuation pre- and post-aspartame introduction in the US (Olney, Farber, Spitznagel & Robins, 1996). Given results from rat studies and the correlation between aspartame approval and brain tumour incidences, it is highly suggestive that aspartame causes brain tumours.

However, the same experimental procedure which found hypothalamic lesions in neonatal mice had no effect on infant monkeys (Reynolds, Butler & Lemkey-Johnston, 1976), indicating that primates may manage high amino acid loads better than rats, metabolically or at the level of the blood brain barrier. Furthermore, recent research found no risk associated with aspartame and brain cancer (Lim et al., 2006).

Seizures:A seizure generally manifests in physical convulsions or other physical signs and the underlying mechanism is due to uncontrolled electrical activity in the brain. Given that aspartame is a purported excitotoxin, consumption may cause disturbance to the balance of central neurotransmitters, hence provoking seizures. In animal models aspartame promoted an increase in seizure frequency in those that were already at risk, yet it is unclear whether these results translate to humans (Maher & Wurtman, 1987). Although self reports of aspartame induced seizures may appear to be significant, a double-blind crossover model applied to such indivudals did not cause seizures even though phenylalanine concentrations were found to be significantly higher with aspartame consumption (Spiers et al, 1998).
A study by Helali et. al (1996) suggested that aspartame played an antagonistic role against anti-epileptic drugs possibly through decreased epinephrine and norepinephrine levels and increased GABA levels. Some studies (i.e. Sze, 1989) have shown that doses of 1000 mg aspartame/kg body weight (bw) or greater did enhance chemically induced seizures, however according to the review by Magnusson et. al. (2007), these results were not consistent, as another study (Reynolds et. al., 1984) claimed that doses of 2000 mg/kg bw had no effect on inducing seizures. There has been a general consensus amongst nearly all studies that doses of under 1000 mg/kg bw have no effect on inducing seizures. Considering that the average amount of aspartame consumed by the top-consuming 90th percentile of society is around 2-3 mg/kg bw, there should be very little concern for seizures as a symptom of aspartame consumption.

As becomes clearly apparent from our research, there is no conclusive evidence to suggest that aspartame is dangerous or safe for consumption. It would be our recommendation that more studies with improved methodologies commence so as to ensure the safety of the public.
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Critical Analysis

The media item comes from a local Fox News station, Fox News 5, D.C.. Fox is regularly rebuked for poor journalism, and typical braodcast practices such as sensationalism and non-objective language appear throughout this piece.

The expose references the many websites which speak out against aspartame to justify the segment, yet a quick search through an engine reveals that most of these sites are not endorsed by any scientific or professionals. There are also many references to studies which found in opposition to aspartame, but little investigation into those in favour. The interviewer also is very harsh and leading toward the 1981 FDA Commissioner- potentially sacrificing a interview that would make the story more two sided for the opportunity to be sensationalistic.

There is also a discrepancy during the interview with 'Edith Johnson'. Originally the woman tells us that she went completely blind, before suggesting rather that "[her] vision became quite blurred". The notion of blindness, as opposed to blurred vision, has a very intense emotional connection with the audience, and somewhat unfairly leads their opinion of aspartame.

The media item is however, not all bad. Though choosing to use opposing rather than affirmative studies, the fact remains that these studies are scientific, peer-reviewed studies instead of experiments conducted by the broadcasting station as seen in other current affairs exposes. These are relevant studies that are contributing to the current neuroscientific understanding of this topic.

Many of the researchers interviewed were contemporary scientists who participated in these studies- not other researchers describing someone else's findings- and were involved in the approval process. Their contextual knowledge provides an good amount of credibility to the piece.

The media item also highlights the economic and political climate that allowed a product that was not conclusively safe onto the market.

Ultimately, this piece was delivered during prime-time news, and thus had to reach a very wide local audience. Language is highly accessible, and studies are explained in a way that an uneducated person is likely to understand. In this way, it is an important addition to the world's reporting on aspartame.



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Search Strategy

Choosing the topic was ultimately a product of happenstance. While we each suggested many topics, there was no strong agreeance on any specific one. On the day of our self-imposed deadline, one of our group members was reading The Huffington Post (an online liberal newspaper) and happened upon an article about the neurotoxicity of aspartame with a related YouTube clip, and immediately suggested it.
Everyone was very interested in the topic, and set about locating clips. With so many to choose from- the controversial nature of aspartame created many options- it came down to Dr Vickery to choose one. Dr Vickery recommended the above media item, which we appreciated for its capacity to quickly synthesise vast amounts of information, and the use of contemporary scientists involved in the research and approval of aspartame.
The video comes from a 1999 Fox News 5 broadcast, which meant there was plenty of new studies to build upon, rather than simply repeating information within the clip. Many of the other YouTube videos came from amateurs, rival companies or news outlets with little scientific evidence for claims.
It was the interplay between these factors that made this media item a good choice.
Information within the report was chosen primarily for its relevance and academic integrity, and was compared to other sources before inclusion.
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References
Butchko, H.H., Stargel, W.W., Comer, C.P., Mayhew, D.A., Benninger, C., Blackburn, G.L., de Sonneville, L.M.J., Geha, R.S.,... Mendenhall, C.L. (2002). Aspartame: Review of Safety. Regulatory Toxicology and Pharmacology, 35, S1-S93.

Lim, U., Subar, A.F., Mouw, T., Hartge, P., Morton, L.M., Stolzenberg-Solomon, R., Campbell, D., Hollenbeck, A.R., Schatzkin, A. (2006). Consumption of Aspartame-Containing Beverages and Incidence of Hematopoietic and Brain Malignancies. Cancer Epidemiology, Biomarkers & Prevention, 15, 1654-1659.

DeAngelis, L.M. (2001). Brain Tumors. The New England Journal of Medicine, 344, 114-123.

Olney, J.W., Farber, N.B., Spitznagel, E., Robins, L.N. (1996). Increasing Brain Tumour Rates: Is There a Link to Aspartame? Journal of Neuropathology and Experimental Neurology, 55, 1115-1123.

European Food Safety Authority (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, 356: 1-44.

Koch, R., Shaw, K.N.F., Williamson, M., Haber, M. (1976). Use of aspartame in phenylketonuric heterozygous adults. Journal of Toxicology and Environmental Health Part A, 2, 453-457.

Helali N. Y., El Kashef H., Salem H., Gamiel N., Elmazar M. M.A. (1996). The effect of aspartame on seizure susceptibility and the anticonvulsant action of ethosuximde, valproate and phenytoin in mice. Saudi Pharmaceutical Journal, 4: 149–156.

Humphries, P., Pretorius, E., Naude, H. (2008). Direct and indirect cellular effects of aspartame on the brain. European Journal of Clinical Nutrition, 62, 451-462.

Magnuson, B. A., Burdock, G. A., Doull, J., Kroes, R.M., Marsh, G.M., Pariza, M.W., Spencer, P.S., Waddell, W.J., Walker, R., Williams, G.M. (2007). Aspartame: A Safety Evaluation Based on Current Use Levels, Regulations, and Toxicological and Epidemiological Studies. Critical Reviews in Toxicology, 37, No. 8, 629-727.

Maher, T.J., Wurtman, R.J. (1987). Possible Neurologic Effects of Aspartame, a Widely Used Food Additive. Environmental Health Perspectives, 75, 53-57.

Neuroactive steroids: Synthesis of positive and negative modulators of NMDA receptor (n.d.). Retrieved September 15, 2010, from Institute of Organic Chemistry and Biochemistry, site: http://www.uochb.cz/web/structure/409.html

Phenylketonuria (n.d.). Retrieved September 13, 2010, from National Center for Biotechnology Information, site: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gnd&part=phenylketonuria.

Reynolds, A.W., Butler, V., Lemkey-Johnston, N. (1976). Hypothalamic Morphology Following Ingestion of Aspartame or MSG in the Neonatal Rodent and Primate: A Preliminary Report. Journal of Toxicology and Environmental Health, 2, 471-480.

Roberts, H.J. (1991). Does Aspartame Cause Human Brain Cancer? Journal of Advancement in Medicine, 4, 231-241.

Schiffman, S.S., Buckley, E. III., Sampson, H.A., Massey, E.W., Baraniuk, J.N., Follett, J.V., Warwick, Z.S. (1987). Aspartame and Susceptibility to Headache. New England Journal of Medicine, 317, 1181-1185.

Spiers, P.A., Sabounjian, L., Reiner, A., Myers, D.K., Wurtman, J., Schomer, D.L. (1998). Aspartame: neuropsychologic and neurophysiologic evaluation of acute and chronic effects. American Journal of Clinical Nutrition, 68, 531-537.

Soffritti, M., Belpoggi, F., Esposti, D.D., Lambertini, L., Tibaldi, E., Rigano, A. (2006). First Experimental Demonstration of the Multipotential Carcinogenic Effects of Aspartame Administered in the Feed to Sprague-Dawley Rats. Environmental Health Perspectives, 114, 379-385.

Stegink, L.D., Filer, L.J. Jr. (1996). Effects of aspartame ingestion on plasma aspartate, phenylalanine and methanol concentrations in normal adults.The Clinical Evaluation of a Food Additive: Assessment of Aspartame, pp. 87-113, CRC Press, Boca Raton, FL.

Sze, P. Y. (1989). Pharmacological effects of phenylalanine on seizure susceptibility: An overview. Neurochemical Research, 14: 103–111.

Trefz, F., Sonneville, L., Matthis, P., Benninger, C., Lanz-Englert, B., Bickel, H. (1994). Neuropsychological and biochemical investigations in heterozygotes of phenylketonuria during ingestion of high dose aspartame (as sweetener containing phenylalanin). Human Genetics, 93, 369-374.

Van Den Eeden, S.K., Koepsell, T.D., Longstreth, W.T., van Belle, G., Daling, J.R., McKnight, B. (1994). Aspartame ingestion and headaches: A randomized crossover trial. Neurology, 44, 1787-1793.

Walton, R.G., Hudak, R., Green-Waite, R.J. (1993). Adverse reactions to aspartame: Double-blind challenge in patients from a vulnerable population. Biological Psychiatry, 34, 13-17.

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