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Aspartame and seizures

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Summary

It has been hypothesized that the dietary sweetener aspartame (L-aspartyl-L-phenylalanine methyl ester) might promote seizures and this hypothesis has been argued in the published literature. The current manuscript reviews the biochemical, neurochemical and behavioral experiments that have been carried out in order to assess the hypothesis linking aspartame with seizure promotion. We conclude that convulsive seizures are not caused by orally administered aspartame in rodents or in primates, including humans. Early reports of seizure facilitation by aspartame in several rodent models were not confirmed by later and more careful experimentation. Proconvulsive effects were absent in humans and other mammals with epilepsy and those without epilepsy. Lack of convulsive liability was evident, even when doses many fold higher than those consumed in the human diet, were used in experimental paradigms. Studies of aspartame in absence seizures are not as complete as those in convulsive seizures, but available evidence in humans does not document an association between absence seizure incidence and aspartame usage.

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References

  • Abraham R, Dougherty W, Goldberg L, Coulston F (1971) The response of the hypothalamus to high doses of monosodium glutamate in mice and monkeys. Exp Mol Pathol 15: 43–60

    Google Scholar 

  • Abraham R, Swart J, Golberg L, Coulston F (1975) Electron microscopic observations of hypothalami in neonatal rhesus monkeys (Macaca mulatta) after administration of monosodium L-glutamate. Exp Mol Pathol 23: 203–213

    Google Scholar 

  • Arauz-Contreras J, Feria-Velasco A (1984) Monosodium-L-glutamate-induced convulsions — I. Differences in seizure pattern and duration of effect as a function of age in rats. Gen Pharmacol 15: 391–395

    Google Scholar 

  • Axelrod J, Daly J (1965) Pituitary gland: Enzymic formation of methanol from S-adenosylmethionine. Science 150: 892–893

    Google Scholar 

  • Beas-Zarate C, Arauz-Contreras J, Velazquez A, Feria-Velasco A (1985) Monosodium L-glutamate-induced convulsions. II. Changes in catecholamine concentrations in various brain areas of adult rats. Gen Pharmacol 16: 489–493

    Google Scholar 

  • Beas-Zarate C, Schliebs R, Morales-Villagran A, Feria-Velasco A (1989) Monosodium L-glutamate-induced convulsions: Changes in uptake and release of catecholamines in cerebral cortex and caudate nucleus of adult rats. Epilepsy Res 4: 20–27

    Google Scholar 

  • Benninger Ch, Matthis P, de Sonneville LMJ, Lenz-Englert B, Trefz FK, Bickel H (1991) High dose aspartame has no effect on EEG spectral parameters in phenylketonuric heterozygotes (PKUH). Neurosci Abstr 17: 504

    Google Scholar 

  • Bettendorf AF, Dailey JW, Lasley SM, Jobe PC (1989) Aspartame fails to facilitate bicuculline-induced seizures in DBA/2 mice. Neurosci Abstr 15: 47

    Google Scholar 

  • Bhagavan HN, Coursin DF, Stewart CN (1971) Monosodium glutamate induces convulsive disorders in rats. Nature 232: 275–276

    Google Scholar 

  • Bickel H, Trefz FK (1986) Aspartame: ein Süssstoff mit hohem Phenylalaningehalt. Monatsschr Kinderheilkd 134: 478–480

    Google Scholar 

  • Blasberg R, Lajtha A (1965) Substrate specificity of steady-state amino acid transport in mouse brain slices. Arch Biochem Biophys 112: 361–377

    Google Scholar 

  • Bradford HF, Dodd PR (1977) Convulsions and activation of epileptic foci induced by monosodium glutamate and related compounds. Biochem Pharmacol 26: 253–254

    Google Scholar 

  • Bradstock MK, Serdula MK, Marks JS, Barnard RJ, Crane NT, Remington PL, Trowbridge FL (1986) Evaluations of reactions to food additives: the aspartame experience. Am J Clin Nutr 43: 464–469

    Google Scholar 

  • Browning RA (1987a) The role of neurotransmitters in electroshock seizure models. In: Jobe PC, Laird HE (eds) Neurotransmitters and epilepsy. Humana Press, Clifton, NJ, pp 277–320

    Google Scholar 

  • Browning RA (1987b) Effect of lesions on seizures in experimental animals. In: Fromm GH, Faingold CL, Browning RA, Burnham WM (eds) Epilepsy and the reticular formation: The role of the reticular core in convulsive seizures. Alan R. Liss, New York, pp 137–162

    Google Scholar 

  • Browning RA (1991) Overview of neurotransmission: relationship to the action of antiepileptic drugs. In: Faingold CL, Fromm GH (eds) Drugs for the control of epilepsy: Actions on neuronal networks involved in seizure disorders. CRC Press, Boca Raton, FL, pp 23–56

    Google Scholar 

  • Browning RA, Maynert EW (1978) Effect of intracisternal 6-hydroxydopamine on seizure susceptibility in rats. Eur J Pharmacol 50: 97–101

    Google Scholar 

  • Browning RA, Wang C, Jobe PC (1989) Effect of regional CNS norepinephrine (NE) depletion on seizure severity in the genetically epilepsy-prone rat (GEPR). Epilepsia 30: 651

    Google Scholar 

  • Burns TS, Stargel WW, Tschanz C, Kotsonis FN, Hurwitz A (1991) Aspartame and sucrose produce a similar increase in the plasma phenylalanine to large neutral amino acid ratio in healthy subjects. Pharmacology 43: 210–219

    Google Scholar 

  • Butchko HH, Kotsonis FN (1989) Aspartame: review of recent research. Comm Toxicol 3: 253–278

    Google Scholar 

  • Butchko HH, Kotsonis FN (1991) Acceptable daily intake vs actual intake: The aspartame example. J Am Coll Nutr 10: 258–266

    Google Scholar 

  • Cain DP, Boon F, Bevan M (1989) Failure of aspartame to affect seizure susceptibility in kindled rats. Neuropharmacology 28: 433–435

    Google Scholar 

  • Camfield PR, Camfield CS, Dooley JM, Gordon K, Jollymore S, Weaver DF (1992) Aspartame exacerbates EEG spike-wave discharge in children with generalized absence epilepsy: A double-blind controlled study. Neurology 42: 1000–1003

    Google Scholar 

  • Chapman AG, Meldrum BS (1987) Epilepsy-prone mice: genetically determined soundinduced seizures. In Jobe PC, Laird HE (eds) Neurotransmitters and epilepsy. Human Press, Clifton, NJ, pp 9–40

    Google Scholar 

  • Chiu P, Woodbury DM (1988) Effects of aspartame (ASM) and its metabolites on seizure susceptibility in mice. Pharmacologist 30: A119

  • Clough RW, Browning RA, Maring ML, Jobe PC (1991) Intracerebral grafting of fetal dorsal pons in genetically epilepsy-prone rats: Effects on audiogenic-induced seizures. Exp Neurol 112: 195–199

    Google Scholar 

  • Corcoran ME (1988) Characteristics and mechanisms of kindling. In: Kalivas P, Barnes C (eds) Sensitization of the nervous system. The Telford Press, Caldwell, NJ, pp 81–116

    Google Scholar 

  • Daabees TT, Finkelstein MW, Stegink LD, Applebaum AE (1985) Correlation of glutamate plus aspartate dose, plasma amino acid concentration and neuronal necrosis in infant mice. Food Chem Toxicol 23: 887–895

    Google Scholar 

  • Dailey JW, Lasley SM, Frasca J, Jobe PC (1987) Aspartame (ASM) is not pro-convulsant in the genetically epilepsy-prone rat (GEPR). Pharmacologist 29: 142

    Google Scholar 

  • Dailey JW, Lasley SM, Bettendorf AF, Burger RL, Jobe PC (1988) Aspartame does not facilitate pentylenetetrazol-induced seizures in genetically epilepsy-prone rats. Epilepsia 29: 651

    Google Scholar 

  • Dailey JW, Lasley SM, Mishra PK, Bettendorf AF, Burger RL, Jobe PC (1989a) Aspartame fails to facilitate pentylenetetrazol-induced convulsions in CD-1 mice. Toxicol Appl Pharmacol 98: 475–486

    Google Scholar 

  • Dailey JW, Reigel CE, Mishra PK, Jobe PC (1989b) Neurobiology of seizure predisposition in the genetically epilepsy-prone rats. Epilepsy Res 3: 3–17

    Google Scholar 

  • Dailey JW, Bettendorf AF, Lasley SM, Jobe PC (1989c) Aspartame does not facilitate bicuculline-induced seizures in C57 mice. Pharmacologist 31: 187

    Google Scholar 

  • Dailey JW, Lasley SM, Burger RL, Bettendorf AF, Mishra PK, Jobe PC (1991) Amino acids, monoamines and audiogenic seizures in genetically epilepsy-prone rats: effects of aspartame. Epilepsy Res 8: 122–133

    Google Scholar 

  • Dailey JW, Mishra PK, Ko KH, Penny JE, Jobe PC (1992a) Serotonergic abnormalities in the central nervous system of seizure naive genetically epilepsy-prone rats. Life Sci 50: 319–326

    Google Scholar 

  • Dailey JW, Yan QS, Mishra PK, Burger RL, Jobe PC (1992b) Effects of fluoxetine on convulsions and on dialyzable brain serotonin in genetically epilepsy-prone rats. J Pharmacol Exp Ther 260: 533–540

    Google Scholar 

  • Davis WM, King WT (1966) Pharmacogenetic factor in the convulsive responses of mice to flurothyl. Experientia 23: 214–215

    Google Scholar 

  • Delgado-Escueta AV, Ward Jr AA, Woodbury DM, Porter RJ (1986) New wave of research in the epilepsies. In: Delgado-Escueta AV, Ward AA Jr, Woodbury DM, Porter RJ (eds) Advances in neurology, vol 44. Raven Press, New York, pp 3–55

    Google Scholar 

  • Dreisbach RH (1983) Handbook of poisoning: Prevention diagnosis and treatment, 11th edn. Lange Medical Publications, Los Altos CA, pp 452–467

    Google Scholar 

  • Eriksen SP, Kulkarni AB (1963) Methanol in normal human breath. Science 141: 639–640

    Google Scholar 

  • Faingold CL, Meldrum BS (1990) Excitant amino acids in epilepsy. In: Avoli M, Gloor P, Kostopoulos G, Naquet R (eds) Generalized epilepsy: Neurobiological approaches. Birkhäuser, Boston, pp 102–117

    Google Scholar 

  • Faingold CL, Naritoku DK (1991) The genetically epilepsy-prone rat: neuronal networks and actions of amino acid neurotransmitters. In: Faingold CL, Fromm GH (eds) Drugs for the control of epilepsy: Actions on neuronal networks involved in seizure disorders. CRC Press Boca Raton, FL, pp 277–308

    Google Scholar 

  • Fernstrom JD (1983) Role of precursor availability in the control of monoamine biosynthesis in brain. Physiol Rev 63: 484–546

    Google Scholar 

  • Fernstrom JD (1989) Oral aspartame and plasma phenylalanine: pharmacokinetic difference between rodents and man, and relevance to CNS effects of phenylalanine. J Neural Transm 75: 159–164

    Google Scholar 

  • Fernstrom JD, Wurtman RJ, Hammarstrom-Wiklund B, Rand WM, Munro HN, Davidson CS (1979) Diurnal variations in plasma concentrations of tryptophan, tyrosine and other neutral amino acids: Effect of dietary protein intake. Am J Clin Nutr 32: 1912–1922

    Google Scholar 

  • Fernstrom JD, Fernstrom MH, Gillis MA (1983) Acute effects of aspartame on large neutral amino acids and monoamines in rat brain. Life Sci 32: 1651–1658

    Google Scholar 

  • Fishbein DH, Thatcher RW, Cantor DS (1990) Ingestion of carbohydrates varying in complexity produce differential brain responses. Clin Electroencephalogr 21: 5–11

    Google Scholar 

  • Fisher RS (1989) Aspartame, neurotoxicity, and seizures: A review. J Epilepsy 2: 55–64

    Google Scholar 

  • Fisher RS (1991) Glutamate and epilepsy. In Fisher RS, Coyle JT (eds) Neurotransmitters and epilepsy. John Wiley & Sons, New York, pp 131–145

    Google Scholar 

  • Fisher RS, Coyle JT (1991) Summary: neurotransmitters and epilepsy. In: Fisher RS, Coyle JT (eds) Neurotransmitters and epilepsy. John Wiley & Sons, New York, pp 247–252

    Google Scholar 

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

    Google Scholar 

  • Frasca MA, Aldag JC (1988) The single-patient clinical trial. Am Fam Physician 37: 195–199

    Google Scholar 

  • Gagnon C (1979) Presence of a protein methylesterase in mamalian tissues. Biochem Biophys Res Commun 88: 847–853

    Google Scholar 

  • Gagnon C, Heisler S (1979) Protein carboxy-methylation: Role in exocytosis and chemotaxis. Life Sci 25: 993–1000

    Google Scholar 

  • Garattini S, Caccia S, Romano M, Diomede L, Guiso G, Vezzani A, Salmona M (1988) Studies on the susceptibility to convulsions in animals receiving abuse doses of aspartame. In: Wurtman RJ, Rittar-Walker E (eds) Dietary phenylalanine and brain function. Birkhäuser, Boston, pp 131–143

    Google Scholar 

  • Gibbs FA, Gibbs EL, Lennox WG (1939) Influence of the blood sugar level on the wave and spike formation in petit mal epilepsy. Arch Neurol Psychiat 41: 1111–1116

    Google Scholar 

  • Giroud M, Duman R, Dauvergne M, D'Athis P, Rochette P, Beley L, Bralet J (1990) 5-Hydroxyindoleacetic acid and homo-vanillic acid in cerebrospinal fluid of children with febrile convulsions. Epilepsia 31: 178–181

    Google Scholar 

  • Goddard GV (1967) Development of epileptic seizures through brain stimulation at low intensity. Nature 214: 1020–1021

    Google Scholar 

  • Goddard GV, McIntyre DC, Leech CK (1969) A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol 25: 295–330

    Google Scholar 

  • Green MC, Sidman RL (1962) Tottering — a neuromuscular mutation in the mouse. J Hered 53: 233–237

    Google Scholar 

  • Guiso G, Caccia S, Vezzani A, Stasi MA, Salmona M, Romano M, Garattini S (1988) Effect of aspartame on seizures in various models of experimental epilepsy. Toxicol Appl Pharmacol 96: 485–493

    Google Scholar 

  • Guey J, Bureau M, Dravet C, Roger J (1969) A study of the rhythm of petit mal absences in children in relation to prevailing situations. Epilepsia 10: 441–451

    Google Scholar 

  • Guyatt G, Sackett D, Taylor DW, Chong J, Robers R, Pugsley S (1986) Determining optimal therapy — randomized trials in individual patients. N Eng J Med 314: 889–892

    Google Scholar 

  • Harper AE (1984) Phenylalanine metabolism. In: Stegink LD, Filer LJ Jr (eds) Aspartame physiology and biochemistry. Marcel Dekker, New York, pp 509–553

    Google Scholar 

  • Heatherbell DA, Wrolstad RE, Libbey LM (1971) Carrot volatiles: Characterization and effects of canning and freeze drying. J Food Sci 36: 219–224

    Google Scholar 

  • Heywood R, James RW (1979) An attempt to induce neurotoxicity in an infant rhesus monkey with monosodium glutamate. Toxicol Lett 4: 285–286

    Google Scholar 

  • Hjelle JJ, Dudley RE, Marietta MP, Sanders PG, Dickie BC, Brisson J, Kotsonis FN (1992) Plasma concentrations and pharmacokinetics of phenylalanine in rats and mice administered aspartame. Pharmacology 44: 48–60

    Google Scholar 

  • Jimenez-Rivera CA, Waterhouse BD (1991) The role of central noradrenergic systems in seizure disorders. In: Fisher RS, Coyle JT (eds) Neurotransmitters and epilepsy. John Wiley & Sons, New York, pp 109–129

    Google Scholar 

  • Jobe PC, Laird H (1987) Neurotransmitter systems and the epilepsy models: distinguishing features and unifying principles. In: Jobe PC, Laird HE (eds) Neurotransmitters and epilepsy. Humana Press, Clifton NJ, pp 339–366

    Google Scholar 

  • Jobe PC, Picchioni AL, Chin L (1973a) Role of 5-hydroxytryptamine in audiogenic seizure in the rat. Life Sci 13: 1–13

    Google Scholar 

  • Jobe PC, Piccioni AL, Chin L (1973b) Role of brain norepinephrine in audiogenic seizure in the rat. J Pharmacol Exp Ther 184: 1–10

    Google Scholar 

  • Jobe PC, Laird HE, Ko KH, Ray T, Dailey JW (1982) Abnormalities in monoamine levels in the central nervous system of the genetically epilepsy-prone rat. Epilepsia 23: 359–366

    Google Scholar 

  • Jobe PC, Ko KH, Dailey JW (1984) Abnormalities in norepinephrine turnover rate in the central nervous system of the genetically epilepsy-prone rat. Brain Res 290: 357–360

    Google Scholar 

  • Jobe PC, Bettendorf AF, Lasley SM, Dailey JW (1989a) Audiogenic seizures in DBA/2 mice are not facilitated by aspartame. Neurosci Abstr 15: 47

    Google Scholar 

  • Jobe PC, Bettendorf AF, Lasley SM, Dailey JW (1989b) Multiple exposures to audiogenic stimuli in DBA/2 mice: lack of effect of aspartame. Epilepsia 30: 653

    Google Scholar 

  • Jobe PC, Mishra PK, Dailey JW (1991a) Genetically epilepsy-prone rats: Actions of antiepileptic drugs and monoaminergic neurotransmitters. In: Faingold CL, Fromm GH (eds) Drugs for the control of epilepsy: Actions on neuronal networks involved in seizure disorders. CRC Press, Boca Raton, FL, pp 253–276

    Google Scholar 

  • Jobe PC, Mishra PK, Ludvig N, Dailey JW (1991b) Scope and contribution of genetic models to an understanding of the epilepsies. CRC Crit Rev Neurobiol 6: 183–220

    Google Scholar 

  • Jobe PC, Mishra PK, Bettendorf AF, Burger RL, Dailey JW, Wang C, Browning RA (1991c) Noradrenergic system also regulates forebrain seizures in the genetically epilepsy-prone rat (GEPR). Epilepsia 32: 31

    Google Scholar 

  • Jobe PC, Lasley SM, Burger RL, Bettendorf AF, Mishra PK, Dailey JW (1992a) Absence of an effect of aspartame on seizures induced by electroshock in epileptic and nonepileptic rats. Amino Acids 3: 155–172

    Google Scholar 

  • Jobe PC, Mishra PK, Ludvig N, Dailey JW (1992b) Genetic models of the epilepsies. In: Schwartzkroin PA (ed) Concepts and models in epilepsy research. Cambridge University Press (In press)

  • Johnston GAR (1973) Convulsions induced in 10-day-old rats by intraperitoneal injection of monosodium glutamate and related excitant amino acids. Biochem Pharmacol 22: 137–140

    Google Scholar 

  • Kazdin AE (1982) Single-case research designs: Methods for clinical and applied settings. Oxford University Press, New York

    Google Scholar 

  • Kazeniac SJ, Hall RM (1970) Flavor chemistry of tomato volatiles. J Food Sci 35: 519–530

    Google Scholar 

  • Killam EK (1976) Measurement of anticonvulsant activity in thePapio papio model of epilepsy. Fed Proc 35: 2264–2269

    Google Scholar 

  • Killam EK, Killam KF (1984) Evidence for neurotransmitter abnormalities related to seizure activity in the epileptic baboon. Fed Proc 43: 2510–2515

    Google Scholar 

  • Killam KF, Killam EK, Naquet R (1966a) Etudes pharmacologiques realisees chez des singes presentant une activite EEG paroxystique particuliere a la stimulation lumineuse intermittente. J Physiol (Paris) 58: 543–544

    Google Scholar 

  • Killam KF, Naquet R, Bert J (1966b) Paroxysmal responses to intermittent light stimulation in a population of baboons (Papio papio). Epilepsia 7: 215–219

    Google Scholar 

  • Killam KF, Killam EK, Naquet R (1967) An animal model of light sensitive epilepsy. Electroencephalograph Clin Neurophysiol 22: 497–513

    Google Scholar 

  • Kim KC, Tasch MD, Kim SH (1988) The effect of aspartame on 50% convulsion doses of lidocaine. In: Wurtman RJ, Ritter-Walker E (eds) Dietary phenylalanine and brain function. Birkhäuser, Boston, pp 127–130

    Google Scholar 

  • Kim S (1973) Purification and properties of protein methylase II. Arch Biochem Biophys 157: 476–484

    Google Scholar 

  • Kirchner JG, Miller JM (1957) Volatile water-soluble and oil constituents of Valencia orange juice. J Agric Food Chem 5: 283–291

    Google Scholar 

  • Laird II HE (1989) The genetically epilepsy-prone rat. A valuable model for the study of the epilepsies. Mol Chem Neuropathol 11: 45–59

    Google Scholar 

  • Larsson BT (1965) Gas chromatography of organic volatiles in human breath and saliva. Acta Chem Scand 19: 159–164

    Google Scholar 

  • Lemkey-Johnston N, Reynolds WA (1974) Nature and extent of brain lesions in mice related to ingestion of monosodium glutamate. A light and electron microscope study. J Neuropathol Exp Neurol 33: 74–97

    Google Scholar 

  • Leon AS, Hunninghake DB, Bell C, Rassin DK, Tephly TR (1989) Safety of long-term large doses of aspartame. Arch Intern Med 149: 2318–2324

    Google Scholar 

  • Levitt P, Noebels JL (1981) Mutant mouse tottering: selective increase of locus ceruleus axons in a defined single-locus mutation. Proc Nat Acad Sci 78: 4630–4634

    Google Scholar 

  • Loscher W, Schmidt D (1988) Which models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations. Epilepsy Res 2: 145–181

    Google Scholar 

  • Loscher W, Nolting B, Fassbender CP (1990) The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. I. The influence of administration vehicles. Epilepsy Res 7: 173–181

    Google Scholar 

  • Loscher W, Fassbender CP, Nolting B (1991a) The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. II. Maximal electroshock seizure models. Epilepsy Res 8: 79–94

    Google Scholar 

  • Loscher W, Honack D, Fassbender CP, Nolting B (1991b) The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. III. Pentylenetetrazole seizure models. Epilepsy Res 8: 171–189

    Google Scholar 

  • Ludvig N, Gyorgy L, Folly G, Vizi ES (1985) Yohimbine can not exert its anticonvulsant action in genetically audiogenic seizure-prone mice. Eur J Pharmacol 115: 123–124

    Google Scholar 

  • Lund ED, Kirkland CL, Shaw PE (1981) Methanol, ethanol, and acetaldehyde contents of citrus products. J Agric Food Chem 29: 361–366

    Google Scholar 

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

    Google Scholar 

  • Maynert EW, Marczynski TJ, Browning RA (1975) The role of neurotransmitters in the epilepsies. In: Friedlander WJ (ed) Advances in neurology vol 13. Raven Press, New York, pp 79–147

    Google Scholar 

  • Marley RJ, Gaffney D, Wehner JM (1986) Genetic influences on GABA-related seizures. Pharmacol Biochem Behav 24: 665–672

    Google Scholar 

  • Martin-Du Pan R, Mauron C, Glaeser B, Wurtman RJ (1982) Effect of various oral glucose doses on plasma neutral amino acid levels. Metabolism 31: 937–943

    Google Scholar 

  • McGeer PL, McGeer EG (1989) Amino acid neurotransmitters. In: Siegel GJ, Agranoff BW, Albers RW, Molinoff PB (eds) Basic neurochemistry: Molecular, cellular, and medical aspects. Raven Press, New York, pp 311–332

    Google Scholar 

  • McLeod RS, Taylor DW, Cohen Z, Cullen JB (1986) Single-patient randomised clinical trial. Use in determining optimum treatment for patient with inflammation of Kock continent ileostomy reservoir. Lancet (8483): 726–728

    Google Scholar 

  • McMartin KE, Martin-Amat G, Makar AB, Tephly TR (1977) Methanol poisoning. V. Role of formate metabolism in the monkey. J Pharmacol Exp Therap 201: 564–572

    Google Scholar 

  • McNamara JO, Bonhaus DW, Shin C, Crain BJ, Gellman RL, Giacchino JL (1985) The kindling model of epilepsy: a critical review. CRC Crit Rev Clin Neurobiol 1: 341–392

    Google Scholar 

  • McNamara JO, Byrne MC, Dasheiff RM, Fitz JG (1980) The kindling model of epilepsy: a review. Progr Neurobiol 15: 139–159

    Google Scholar 

  • Meldrum BS (1991) Anticonvulsant drugs with new mechanisms of action. In: Faingold CL, Fromm GH (eds) Drugs for control of epilepsy: Actions on neuronal networks involved in seizure disorders. CRC Press, Boca Raton, pp 485–495

    Google Scholar 

  • Meldrum BS, Nanji N, Cornell RG (1989) Lack of effect of aspartame or of L-phenylalanine on photically induced myoclonus in the baboon,Papio papio. Epilepsy Res 4: 1–7

    Google Scholar 

  • Micheletti G, Warter J-M, Marescaux C, Depaulis A, Tranchant C, Rumbach L, Vergnes M (1987) Effects of drugs affecting noradrenergic neurotransmission in rats with spontaneous petit mal-like seizures. Eur J Pharmacol 135: 397–402

    Google Scholar 

  • Mishra PK, Burger RL, Yan QS, Dailey JW, Jobe PC (1989) Characteristics of extracellular norepinephrine: A microdialysis study in genetically epilepsy-prone rats. FASEB J 3: A747

  • Mishra PK, Bettendorf AF, Burger RL, Dailey JW, Eldadah MK, Wang C, Browning RA, Jobe PC (1991) Noradrenergic regulation of forebrain and brainstem seizures in nonepileptic and genetically epilepsy-prone rats (GEPRs). Neurosci Abstr 17: 172

    Google Scholar 

  • Morin AM, Lis M (1973) Evidence for a methylated protein intermediate in pituitary methanol formation. Biochem Biophys Res Commun 52: 373–378

    Google Scholar 

  • Mushahwar IK, Koeppe RE (1971) The toxicity of monosodium glutamate in young rats. Biochim Biophys Acta 244: 318–321

    Google Scholar 

  • Neame KD (1968) A comparison of the transport systems for amino acids in brain, intestine, kidney and tumor. Prog Brain Res 29: 185–199

    Google Scholar 

  • Nemeroff CB, Crisley FD (1975) Monosodium L-glutamate-induced convulsions: temporary alteration in blood-brain barrier permeability to plasma proteins. Environ Physiol Biochem 5: 389–395

    Google Scholar 

  • Newman AJ, Heywood R, Palmer AK, Barry DH, Edwards FP, Worden AN (1973) The administration of monosodium L-glutamate to neonatal and pregnant rhesus monkeys. Toxicology 1: 197–204

    Google Scholar 

  • Nevins ME, Arnolde SM, Haigler HJ (1986a) Aspartame: lack of effect on convulsant thresholds in mice. Fed Proc 45: 1096

    Google Scholar 

  • Nevins ME, Arnolde SM, Haigler JJ (1986b) Aspartame: lack of effect on convulsant thresholds in mice. In: Kaufman S (Ed) Amino acids in health and diseases: New perspectives. Alan R. Liss, New York, pp 437–449

    Google Scholar 

  • Noebels JL, Sidman RL (1979) Inherited epilepsy: spike-wave and focal motor seizures in the mutant mouse tottering. Science 204: 1334–1336

    Google Scholar 

  • Okaniwa, A, Hori M, Masuda M, Takeshita M, Hayashi N, Wada I, Doi K, Ohara Y (1979) Histopathological study on effects of potassium aspartate on the hypothalamus of rats. J Toxicol Sci 4: 31–45

    Google Scholar 

  • Olney JW (1969) Brain lesions, obesity and other disturbances in mice treated with monosodium glutamate. Science 164: 719–721

    Google Scholar 

  • Olney JW, Sharpe LG (1969) Brain lesions in an infant rhesus monkey treated with monosodium glutamate. Science 166: 386–388

    Google Scholar 

  • Olney JW, Sharpe LG, Feigin RD (1972) Glutamate-induced brain damage in infant primates. Neuropathol Exp Neurol 31: 464–488

    Google Scholar 

  • Perego C, De Simoni MG, Fodritto F, Raimondi L, Diomede L, Salmona M, Algeri S, Garattini S (1988) Aspartame and the rat brain monoaminergic system. Toxicol Lett 44: 331–339

    Google Scholar 

  • Pinto JMB, Maher TJ (1988) Administration of aspartame potentiates pentylenetetrazoleand fluorothyl-induced seizures in mice. Neuropharmacology 27: 51–55

    Google Scholar 

  • Porszasz J, Worum I (1971) Seasonal variations of electroshock seizure susceptibility in the rat. Acta Physiol Acad Sci Hungar 40: 93–100

    Google Scholar 

  • Porta MS (1986) The search for more clinical meaningful research designs: single-patient random-mized clinical trials. J Gen Intern Med 1: 418–419

    Google Scholar 

  • Racine RJ (1972) Modification of seizure activity by electrical stimulation: II. motor seizure. Electroencephalogr Clin Neurophysio 32: 281–294

    Google Scholar 

  • Racine R (1978) Related disciplines. Kindling: the first decade. Neurosurgery 3: 234–252

    Google Scholar 

  • Racine R, Okujava V, Chipashvili S (1972) Modification of seizure activity by electrical stimulation: III. mechanisms. Electroencephalogr Clin Neurophysiol 32: 295–299

    Google Scholar 

  • Rall TW, Schleifer LS (1990) Drugs effective in the therapy of the epilepsies. In: Gilman AG, Rall TW, Nies AS, Taylor P (eds) Goodman and Gilman's the pharmacological basis of therapeutics, 8th edn. Pergamon Press, New York, pp 436–462

    Google Scholar 

  • Ranney RE, Opperman JA, Muldoon E (1976) Comparative metabolism of aspartame in experimental animals and humans. J Toxicol Environ Health 2: 441–451

    Google Scholar 

  • Reynolds WA, Lemkey-Johnston N, Filer LJ Jr, Pitkin RM (1971) Monosodium glutamate: Absence of hypothalamic lesions after ingestion by newborn primates. Science 172: 1342–1344

    Google Scholar 

  • Reynolds WA, Lemkey-Johnston N, Stegink LD (1979) Morphology of the fetal monkey hypothalamus after in utero exposure to monosodium glutamate. In: Filer LJ Jr, Garattini S, Kare MR, Reynolds WA, Wurtman RJ (eds) Glutamic acid: Advances in biochemistry and physiology. Raven Press, New York, pp 217–229

    Google Scholar 

  • Reynolds WA, Parsons L, Stegink LD (1984) Neuropathology studies following aspartame ingestion by infant nonhuman primates. In: Stegink LD, Filer LJ Jr., (eds) Aspartame: Physiology and biochemistry. Marcel Dekker, New York, pp 363–378

    Google Scholar 

  • Roberts HJ (1988) Aspartame (NutraSweet)-associated epilepsy. Clin Res 36: 349A

  • Rowan AJ, Shaywitz BA (1992) Aspartame has no effect on seizure incidence or EEG epileptiform discharges in children and adults who reportedly had seizures due to aspartame consumption. J Clin Neurophysiol (In press)

  • Segal M (1991) Serotonin and epilepsy. In: Fisher RS, Coyle JT (eds) Neurotransmitters and epilepsy. John Wiley & Sons, New York, pp 103–108

    Google Scholar 

  • Shaywitz BA, Novotny EJ, Ebersole JS, Anderson GM, Sullivan CM, Gillespie SM (1992) Aspartame does not provoke seizures in children with epilepsy. Pediatr Res 31: 354A

  • Smialowski A (1983) Excitatory effect of intrahippocampal injection of glutamic acid on rabbit EEG. J Neural Transm 58: 205–211

    Google Scholar 

  • Snead OC (1988) Gamma-hydroxybutyrate model of generalized absence seizures: Further characterization and comparison with other absence models. Epilepsia 29/4: 361–368

    Google Scholar 

  • Statnick MA, Dailey JW, Jobe PC, Browning RA (1991) Abnormalities in brain serotonin uptake and steady state concentration in the genetically epilepsy-prone rat (GEPR). Soc Neurosci Abstr 17: 171

    Google Scholar 

  • Stegink LD (1984) Aspartame metabolism in humans: Acute dosing studies. In: Stegink LD, Filer LJ Jr (eds) Aspartame: Physiology and biochemistry. Marcel Dekker, New York, pp 509–553

    Google Scholar 

  • Stegink LD, Brummel MC, McMartin K, Martin-Amat G, Filer LJ Jr, Baker GL, Tephly TR (1981) Blood methanol concentrations in normal adult subjects administered abuse doses of aspartame. J Toxicol Environ Health 7: 281–290

    Google Scholar 

  • Stegink LD, Filler LJ, Baker GL (1977) Effect of aspartame and aspartate loading upon plasma and erythrocyte free amino acid levels in normal adult volunteers. J Nutr 107: 1837–1845

    Google Scholar 

  • Stegink LD, Filer LJ Jr, 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 in normal adults. Metabolism 38: 357–363

    Google Scholar 

  • Stegink LD, Filer LJ Jr, Bell EF, Ziegler EE, Tephly TR, Krause WL (1990) Repeated ingestion of aspartame-sweetened beverages: Further observations in individuals heterozygous for phenylketonuria. Metabolism 39: 1076–1081

    Google Scholar 

  • Stegink LD, Reynolds WA, Filer LJ Jr, Pitkin RM, Boaz DP, Brummel MC (1975) Monosodium glutamate metabolism in the neonatal monkey. Am J Physiol 229: 246–250

    Google Scholar 

  • Stewart CN, Coursin DB, Bhagavan HN (1972) Electroencephalographic study of L-glutamate induced seizures in rats. Toxicol Appl Pharmacol 23: 635–639

    Google Scholar 

  • Stone WE (1972) Systemic chemical convulsants and metabolic derangements. In: Purpura DP, Penry JK, Tower DB, Woodbury DM, Walter RD (eds) Experimental models of epilepsy — A manual for the laboratory worker. Raven Press, New York, pp 407–432

    Google Scholar 

  • Swinyard EA (1972) Electrically induced convulsions. In: Purpura DP, Penry JK, Tower DB, Woodbury DM, Walter RD (eds) Experimental models of epilepsy — A manual for the laboratory worker. Raven Press, New York, pp 433–458

    Google Scholar 

  • Sze PY (1989) Pharmacological effects of phenylalanine on seizure susceptibility: an overview. Neurochemical Res 14: 103–111

    Google Scholar 

  • Tephly TR, McMartin KE (1984) Methanol metabolism and toxicity. In: Stegink LD, Filer LJ Jr (eds) Aspartame physiology and biochemistry. Marcel Dekker, New York, pp 111–140

    Google Scholar 

  • Tilson HA, Thai L, Zhao D, Sobotka TJ, Hong JS (1989) Oral administration of aspartame is not proconvulsant in rats. Neurotoxicology 10: 229–238

    Google Scholar 

  • Tollefson L, Barnard RJ, Glinsmann HW (1988) Monitoring of adverse reactions to aspartame reported to the US Food and Drug Administration. In: Wurtman RJ, Ritter-Walker E (eds) Dietary phenylalanine and brain function. Birkhäuser, Boston, pp 317–337

    Google Scholar 

  • Vergnes M, Marescaux Ch, Depaulis A, Micheletti G, Warter JM (1990) Spontaneous spike-and-wave discharges in wistar rats: A model of genetic generalized nonconvulisve epilepsy. In: Avoli M, Gloor P, Kostopoulos G, Naquet R (eds) Generalized epilepsy: Neurobiological approaches. Birkhäuser, Boston, pp 238–253

    Google Scholar 

  • Walton RG (1986) Seizure and mania after high intake of aspartame. Psychosomatics 27: 218–219

    Google Scholar 

  • Wang C, Jobe PC, Browning RA (1990) Effect of 6-OHDA-induced lesions of the medial forebrain bundle (MFB) on audiogenic seizures in genetically epilepsy-prone rats (GEPR-3s). Soc Neurosci Abstr 16: 781

    Google Scholar 

  • Ward AA (1972) Topical convulsant metals. In: Purpura DP, Penry JK, Tower DB, Woodbury DM, Walter RD (eds) Experimental models of epilepsy: A manual for the laboratory worker. Raven Press, New York, pp 14–35

    Google Scholar 

  • Wasterlain C (1988) Epileptic seizures. In: Siegel GJ, Agranoff B, Albers RW, Molinoff P (eds) Basic neurochemistry: Molecular, cellular, and medical aspects, 4th edn. Raven Press, New York, pp 797–810

    Google Scholar 

  • Wen C, Hayes KC, Gershoff SN (1973) Effects of dietary supplementation of monosodium glutamate on infant monkeys, weanling rats and suckling mice. Am J Clin Nutr 26: 803–813

    Google Scholar 

  • Wolf-Novak LC, Stegink LD, Brummel MC, Persoon TJ, Filer LJ Jr, Bell EF, Ziegler EE, Krause WL (1990) Aspartame ingestion with and without carbohydrate in phenylketonuric and normal subjects: Effect on plasma concentrations of amino acids, glucose, and insulin. Metabolism 39: 391–396

    Google Scholar 

  • Wurtman RJ (1985) Aspartame: possible effect on seizure susceptibility. Lancet November 9: 1060

    Google Scholar 

  • Wurtman RJ, Maher TJ (1987) Effects of oral aspartame on plasma phenylalanine in humans and experimental rodents. J Neural Transm 70: 169–173

    Google Scholar 

  • Yan QS, Jobe PC, Dailey JW (1992a) Effects of desipramine and yohimbine on convulsions and onin vivo norepinephrine release in genetically epilepsy-prone rats. FASEB J 6: A1879

  • Yan QS, Mishra PK, Burger RL, Bettendorf AF, Jobe PC, Dailey JW (1992b) Evidence that carbamazepine and antiepilepsirine may produce a component of their anticonvulsant effects by activating serotonergic neurons in genetically epilepsy-prone rats. J Pharmacol Exp Ther 261: 652–659

    Google Scholar 

  • Yokogoshi H, Roberts CH, Caballero B, Wurtman RJ (1984) Effects of aspartame and glucose metabolism on brain and plasma levels of large neutral amino acids and brain 5-hydroxyindoles. Am J Clin Nutr 40: 1–7

    Google Scholar 

  • Zhi J, Levy G (1989) Aspartame and phenylalanine do not enhance theophylline-induced seizures in rats. Res Commun Chem Path Pharmacol 66: 171–174

    Google Scholar 

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Jobe, P.C., Dailey, J.W. Aspartame and seizures. Amino Acids 4, 197–235 (1993). https://doi.org/10.1007/BF00805824

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