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Direct and indirect cellular effects of aspartame on the brain

Abstract

The use of the artificial sweetener, aspartame, has long been contemplated and studied by various researchers, and people are concerned about its negative effects. Aspartame is composed of phenylalanine (50%), aspartic acid (40%) and methanol (10%). Phenylalanine plays an important role in neurotransmitter regulation, whereas aspartic acid is also thought to play a role as an excitatory neurotransmitter in the central nervous system. Glutamate, asparagines and glutamine are formed from their precursor, aspartic acid. Methanol, which forms 10% of the broken down product, is converted in the body to formate, which can either be excreted or can give rise to formaldehyde, diketopiperazine (a carcinogen) and a number of other highly toxic derivatives. Previously, it has been reported that consumption of aspartame could cause neurological and behavioural disturbances in sensitive individuals. Headaches, insomnia and seizures are also some of the neurological effects that have been encountered, and these may be accredited to changes in regional brain concentrations of catecholamines, which include norepinephrine, epinephrine and dopamine. The aim of this study was to discuss the direct and indirect cellular effects of aspartame on the brain, and we propose that excessive aspartame ingestion might be involved in the pathogenesis of certain mental disorders (DSM-IV-TR 2000) and also in compromised learning and emotional functioning.

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References

  • Anonymous (1984). Evaluation of consumer complaints related to aspartame use. MMWR 33, 605–607.

    Google Scholar 

  • Berger-Sweeney J, Hohmann CF (1997). Behavioral consequences of abnormal cortical development: insights into developmental disabilities. Behav Brain Res 86, 121–142.

    CAS  Article  Google Scholar 

  • Boutrel B, Franc B, Hen R, Hamon M, Adrien J (1999). Key role of 5-Ht1B receptors in the regulation of paradoxical sleep as evidenced in 5-HT1B knock-out mice. J Neurosci 19, 3204–3212.

    CAS  Article  Google Scholar 

  • Bowen J, Evangelista MA (2002). Brain cell damage from amino acid isolates: a primary concern from aspartame-based products and artificial sweetening agents. http://www.wnho.net/aspartame_brain_damage.htm.

  • Caballero B, Wurtman RJ (1988). Control of plasma phenylalanine levels. In: Wurtman RJ, Ritterwalker E (eds). Dietary phenylalanine and Brain Function. Birkhauser: Basal. pp 9–23.

    Google Scholar 

  • Choi DW, Rothman SM (1990). The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci 13, 171–182.

    CAS  Article  Google Scholar 

  • Chubakov AR, Gromova EA, Konovalov GV, Sarkisova EF, Chumasov EI (1986). The effects of serotonin on the morpho-functional development of rat cerebral neocortex in tissue culture. Brain Res 369, 285–297.

    CAS  Article  Google Scholar 

  • Chubakov AR, Tsyganova VG, Sarkisova EF (1993). The stimulating influence of the raphe nuclei on the morphofunctional development of the hippocampus during their combined cultivation. Neurosci Behav Physiol 23, 271–276.

    CAS  Article  Google Scholar 

  • Chugani DC (2004). Serotonin in autism and pediatric epilepsies. Mental RetardDev Disabil Res Rev 10, 112–116.

    Article  Google Scholar 

  • Clarke J (2000). Aspartame concerns: an overview for health professionals. Additive Survivors Network: UK.

    Google Scholar 

  • Cooper JR, Bloom FE, Roth RH (2003). The Biochemical Basis of Neuropharmacology, 8th edn. Oxford University Press: New York.

    Google Scholar 

  • Coulombe RA, Sharma RS (1986). Neurobiochemical alterations induced by the artificial sweetener aspartame. (Nutrasweet). Toxicol Appl Pharmacol 83, 79–85.

    CAS  Article  Google Scholar 

  • Dare E, Fetissov S, Hokfelt T, Hall H, Ogren SO, Ceccatelli S (2003). Effects of prenatal exposure to methylmercury on dopamine-mediated locomotor activity and dopamine D2 receptor binding. Naunyn Schmiedebergs Arch Pharmacol 367, 500–508.

    CAS  Article  Google Scholar 

  • Diamond A, Briand L, Fossella J, Gehlbach L (2004). Genetic and neurochemical modulation of prefrontal cognitive functions in children. Am J Psychiatry 161, 125–132.

    Article  Google Scholar 

  • Fernstorm JD, Fernstrom MH, Gillis MA (1983). Acute effects of aspartame on large neutral amino acid and mono-amines in rat brain. Life Sci 32, 1651–1658.

    Article  Google Scholar 

  • Fernstorm JD (1988). Effects of aspartame ingestion on large amino acids and monoamine neurotransmitters in the central nervous system. In: Wurtman RJ, Ritterwalker E (eds). Dietary Phenylalanine And Brain Function. Birkhauser: Basal. pp 87–94.

    Chapter  Google Scholar 

  • Fernstrom JD (1994). Dietary amino acids and brain function. J Am Diet Ass 94 (1), 71–77.

    CAS  Article  Google Scholar 

  • Filer LJ, Stegink LD (1988). Effect of aspartame on plasma phenylalanine concentration in humans. In: Wurtman RJ, Ritterwalker E (eds). Dietary Phenylalanine and Brain Function. Birkhauser: Basal. pp 18–40.

    Chapter  Google Scholar 

  • Fountain SB, Hennes SK, Teyler TJ (1988). Aspartame exposure and in vitro hippocampal slice excitability and plasticity. Fundam Appl Toxicol 11, 221–228.

    CAS  Article  Google Scholar 

  • Ganong WF (1997). Review of Medical Physiology, 18th edn. Appleton and Lange: Stanford, Connecticut.

    Google Scholar 

  • Gaspar P, Cases O, Maroteaux L (2003). The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci 4, 1002–1012.

    CAS  Article  Google Scholar 

  • Hawkins RA, Mans AM, Biebuyck JF (1988). Regional transport and other neutral amino acids across the blood-brain barrier. In: Wurtman RJ, Ritter-Walker E (eds). Dietary Phenylalanine and Brain Function. Birkhauser: Basal. pp 63–67.

    Chapter  Google Scholar 

  • Herlenius E, Langercrantz H (2004). Development of neurotransmitter systems during critical periods. Exp Neurol 190, 8–21.

    Article  Google Scholar 

  • Hidemitsu P-H, Yasuo S, Yasuhiro O, Masao S, Masanori Y (1990). Effect of aspartame on N-methyl-D-aspartate-sensitive L-[3H]glutamate binding sites in rat brain synaptic membranes. Brain Res 520, 351–353.

    Article  Google Scholar 

  • Johns DR (1986). Migraine provoked by aspartame. Natl Eng J Med 315, 456.

    CAS  Google Scholar 

  • Johnston MV, Silverstein FS (1998). Development of neurotransmitters. In: Polin RA, Fox WW (eds). Fetal and Neonatal Physiology. Saunders: Philadelphia. pp 2116–2117.

    Google Scholar 

  • Kolb B, Whishaw IQ (2003). Fundamentals of Human Neuropsychology 5th edn Worth Publishers: New York.

    Google Scholar 

  • Lauder JM (1990). Ontogeny of the serotonergic system in the rat: Serotonin as a developmental signal. Ann NY Acad Sci 600, 297–313.

    CAS  Article  Google Scholar 

  • Letinic K, Zoncu R, Rakic P (2002). Origin of GABAergic neurons in the human neocortex. Nature 417, 645–649.

    CAS  Article  Google Scholar 

  • Lipton SA, Nakanishi N (1999). Shakespeare in love—with NMDA receptors? Nat Med 5, 270–271.

    CAS  Article  Google Scholar 

  • Maher TJ, Wurtman RJ (1987). Possible neurologic effects of aspartame, a widely used food additive. Environ Health Perspect 75, 53–57.

    CAS  Article  Google Scholar 

  • McDonald JW, Johnston MV (1990). Physiological and pathophysiological roles of excitatory amino acids during central nervous system de-velopment. Brain Res Brain Res Rev 15, 41–70.

    Article  Google Scholar 

  • Mehl-Madrona L (2005). Autism an overview and theories on its causes. http://www.healingarts.org/mehl-madrona/autism accessed:17 December 2005.

  • Noctor SC, Flint AC, Weissman TA, Dammerman RS, Kriegstein AR (2001). Neurons derived from radial glial cells establish radial units in neocortex. Nature 409, 714–720.

    CAS  Article  Google Scholar 

  • Noctor SC, Martinez-Cerdeno V, Ivic L, Kriegstein AR (2004). Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci 7, 136–144.

    CAS  Article  Google Scholar 

  • Olney JW (1975). Letter to the editor. N Engl J Med 292 (23).

  • Owens DF, Kriegstein AR (2002). Is there more to GABA than synaptic inhibition? Nat Rev Neurosci 3, 715–727.

    CAS  Article  Google Scholar 

  • Panksepp J (1998). Affective Neuroscience: The Foundations of Human and Animal Emotions. Oxford University Press: New York.

    Google Scholar 

  • Qu Y, Vadivelu S, Choi L, Liu S, Lu A, Lewis B et al. (2003). Neurons derived from embryonic stem (ES) cells resemble normal neurons in their vulnerability to excitotoxic death. Exp Neurol 184, 326–336.

    CAS  Article  Google Scholar 

  • Sharma RP, Coulombe Jr RA (1987). Effects of repeated doses of aspartame on serotonin and its metabolite in various regions of the mouse brain. Food Chem Toxicol 25 (8), 565–568.

    CAS  Article  Google Scholar 

  • Stegink LD, Filer LJ, Baker CL (1988). Repeated ingestion of aspartame-sweetened beverage: effect on plasma amino acid concentrations in normal adults. Metabolism 37 (3), 246–251.

    CAS  Article  Google Scholar 

  • Stegink LD, Filer LJ, Bell EF, Ziegler EE, Tephly TR (1989). Effect of repeated ingestion of aspartame-sweetened beverage on plasma amino acid, blood methanol, and blood formate concentrations. Metabolism 34 (4), 357–363.

    Article  Google Scholar 

  • Stone TW, Burton NR (1988). NMDA receptors and ligands in the vertebrate CNS. Prog Neurobiol 30, 333–368.

    CAS  Article  Google Scholar 

  • Sundstrom E, Kolare S, Souverbie F, Samuelsson EB, Pschera H, Lunell NO et al. (1993). Neurochemical differenti-ation of human bulbospinal monoaminergic neurons during the first trimester. Brain Res Dev Brain Res 75, 1–12.

    CAS  Article  Google Scholar 

  • Sundstrom E (1996). First trimester development of the human nigros-triatal dopamine system. Exp Neurol 139, 227–237.

    Article  Google Scholar 

  • Trocho C, Pardo R, Rafecas I, Virgili J, Remesar X, Fernandez-Lopez JA et al. (1998). Formaldehyde derived from dietary aspartame binds to tissue components in vivo. Life Sci 63, 337–349.

    CAS  Article  Google Scholar 

  • Turlejski K (1996). Evolutionary ancient roles of serotonin: Long-lasting regulation of activity and development. Acta Neurobiol Exp 56, 619–636.

    CAS  Google Scholar 

  • Wang F, Lidow MS (1997). Alpha 2A-adrenergic receptors are expressed by diverse cell types in the fetal primate cerebral wall. J Comp Neurol 378, 493–507.

    CAS  Article  Google Scholar 

  • Watkins JC (1984). Excitatory amino acids and central synaptic transmission. Trends Pharmacol 5, 373–376.

    CAS  Article  Google Scholar 

  • Williams GV, Goldman-Rakic PS (1995). Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376, 572–575.

    CAS  Article  Google Scholar 

  • Whitaker-Azmitia PM (1991). Role of serotonin and other neurotrans-mitter receptors in brain development: Basis for developmental pharmacology. Pharmacol Rev 43, 553–561.

    CAS  PubMed  Google Scholar 

  • Whitaker-Azmitia PM, Druse M, Walker P, Lauder JM (1996). Serotonin as a developmental signal. Behav Brain Res 73, 19–29.

    CAS  Article  Google Scholar 

  • Whitaker-Azmitia PM (2001). Serotonin and brain development: Role in human developmental diseases. Brain Res Bull 56 (5), 479–485.

    CAS  Article  Google Scholar 

  • Young SN (1988). Facts and myths related to the regulation of phenylalanine and other amino ‘Dietary phenylalanine and brain function’. In: Wurtman RJ, Ritterwalker E (eds). Use and Aids. Birkhauser: Basal. pp 341–347.

    Google Scholar 

  • Zhou QY, Palmiter RD (1995). Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic. Cell 83, 1197–1209.

    CAS  Article  Google Scholar 

Download references

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Correspondence to E Pretorius.

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Humphries, P., Pretorius, E. & Naudé, H. Direct and indirect cellular effects of aspartame on the brain. Eur J Clin Nutr 62, 451–462 (2008). https://doi.org/10.1038/sj.ejcn.1602866

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  • DOI: https://doi.org/10.1038/sj.ejcn.1602866

Keywords

  • astrocytes
  • aspartame
  • neurotransmitters
  • glutamate
  • GABA
  • serotonin
  • dopamine
  • acetylcholine

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