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Safety of Long-term Large Doses of Aspartame

Safety of Long-term Large Doses of Aspartame Abstract • Safety of long-term administration of 75 mg/kg of aspartame per day was evaluated with the use of a randomized, double-blind, placebo-controlled, parallel-group design in 108 male and female volunteers aged 18 to 62 years. Subjects received either aspartame or placebo in capsule form three times daily for 24 weeks. No persistent changes over time were noted in either group in vital signs; body weight; results of standard laboratory tests; fasting blood levels of aspartame's constituent amino acids (aspartic acid and phenylalanine), other amino acids, and methanol; or blood formate levels and 24-hour urinary excretion of formate. There also were no statistically significant differences between groups in the number of subjects experiencing symptoms or in the number of symptoms per subject. These results further document the safety of the long-term consumption of aspartame at doses equivalent to the amount of aspartame in approximately 10 L of beverage per day. (Arch Intern Med. 1989;149:2318-2324) References 1. Aspartame: commissioner's final decision . Federal Register . (July 24) , 981;46:38285-38308. 2. Food additives permitted for direct addition to food for human consumption: aspartame . Federal Register . (July 8) , 1983;48:31376-31382. 3. Ranney RE, Oppermann JA, Muldoon E, McMahon FG. Comparative metabolism of aspartame in experimental animals and humans . J Toxicol Environ Health . 1976;2:441-451.Crossref 4. Food additives permitted for direct addition to food for human consumption: aspartame . Federal Register . (November 23) , 1983;48:52899-52901. 5. McMartin KE, Ambre JJ, Tephly TR. Methanol poisoning in human subjects: role of formic acid accumulation in the metabolic acidosis . Am J Med . 1980;68:414-418.Crossref 6. Martin-Amat G, McMartin KE, Hayreh SS, Tephly TR. Methanol poisoning: ocular toxicity produced by formate . Toxicol Appl Pharmacol . 1978;45:201-208.Crossref 7. American Medical Association's Council on Scientific Affairs. Aspartame: review of safety issues . JAMA . 1985;254:400-402.Crossref 8. Food additives permitted for direct addition to food for human consumption: aspartame . Federal Register . (February 22) , 1984;49:6672-6682. 9. Heybach JP, Allen SS. Resources for inferential estimates of aspartame intake in the United States . In: Wurtman RJ, Ritter-Walker E, eds. Dietary Phenylalanine and Brain Function . Cambridge, Mass: Birkhauser Boston Inc; 1988:365-372. 10. Leon AS, Hunninghake DB. Safety of long term aspartame administration in normal subjects . FASEB J . 1988;2:A633. Abstract. 11. Frey GH. Use of aspartame by apparently healthy children and adolescents . J Toxicol Environ Health . 1976;2:401-415.Crossref 12. Knopp RH, Brandt K, Arky RA. Effects of aspartame in young persons during weight reduction . J Toxicol Environ Health . 1976;2:417-428.Crossref 13. Koch R, Shaw KNF, Williamson M, Haber M. Use of aspartame in phenylketonuric heterozygous adults . J Toxicol Environ Health . 1976;2:453-457.Crossref 14. Stern SB, Bleicher SJ, Flores A, Gombos G, Recita SD, Shu J. Administration of aspartame in non-insulin-dependent diabetics . J Toxicol Environ Health . 1976;2:429-439.Crossref 15. Nehrling JK, Kobe P, McLane MP, Olson RE, Kamath S, Horwitz DL. Aspartame use by persons with diabetes . Diabetes Care . 1985;8:415-417.Crossref 16. Strathman I. Experience with the WHO adverse reaction terminology at Searle . Drug Info J . 1986;20:179-186. 17. Jacobs DR Jr, Hunninghake DB, Dempsey M, et al. Blood lipids and lipoproteins in a Minnesota urban population . J Chronic Dis . 1980;33:395-406.Crossref 18. Lipid Research Clinics Program Manual of Laboratory Operations . Lipid and Lipoprotein Analysis . Washington, DC: Department of Health, Education, and Welfare; 1982. Publication (NIH)75-628. 19. Denckla WD, Dewey HK. The determination of tryptophan in plasma, liver and urine . J Lab Clin Med . 1967;69:160-169. 20. Bloxam DL, Warren WH. Error in the determination of tryptophan by the method of Denckla and Dewey: a revised procedure . Anal Biochem . 1974;60:621-625.Crossref 21. Fernstrom JD, Wurtman RJ. Brain serotonin content: physiological regulation by plasma neutral amino acids . Science . 1972;178:414-416.Crossref 22. Baker RN, Alenty AL, Zack JF Jr. Simultaneous determination of lower alcohols, acetone, and acetaldehyde in blood by gas chromatography . J Chromatogr Sci . 1969;7:312-314.Crossref 23. Makar AB, Tephly TR. Improved estimation of formate in body fluids and tissues . Clin Chem . 1982;28:385. 24. O'Brien D, Ibbott FA, Rodgerson DO. Laboratory Manual of Pediatric Micro-biochem Techniques . 4th ed. New York, NY: Harper & Row Publishers Inc; 1968:114-116. 25. Fleiss JL. Statistical Methods for Rates and Proportions . 2nd ed. New York, NY: John Wiley & Sons Inc; 1981:19-27. 26. Zar JH. Biostatistical Analysis . 2nd ed. Englewood Cliffs, NJ: Prentice-Hall Inc; 1984:122-149. 27. Siegel S. Nonparametric Statistics for the Behavioral Sciences . New York, NY: McGraw-Hill International Book Co Inc; 1956:127-136. 28. Stegink LD, Filer LJ Jr, Baker GL. Plasma and erythrocyte concentrations of free amino acids in adult humans administered abuse doses of aspartame . J Toxicol Environ Health . 1981;7:291-305.Crossref 29. Fernstrom JD, Fernstrom MH, Gillis MA. Acute effects of aspartame on large neutral amino acids and monoamines in rat brain . Life Sci . 1983;32:1651-1658.Crossref 30. Yokogoshi H, Wurtman RJ. Acute effects of oral or parenteral aspartame on catecholamine metabolism in various regions of rat brain . J Nutr . 1986;116:356-364. 31. Coulombe RA Jr, Sharma RP. Neurobiochemical alterations induced by the artificial sweetener aspartame (NutraSweet) . Toxicol Appl Pharmacol . 1986;83:79-85.Crossref 32. Stegink LD, Brummel MC, McMartin K, et al. Blood methanol concentrations in normal adult subjects administered abuse doses of aspartame . J Toxicol Environ Health . 1981;7:281-290.Crossref 33. Blundell JE, Hill AJ. Paradoxical effects of an intense sweetener (aspartame) on appetite . Lancet . 1986;1:1092-1093.Crossref 34. Stellman SD, Garfinkel L. Artificial sweetener use and one-year weight change among women . Prev Med . 1986;15:195-202.Crossref 35. Ryan-Harshman M, Leiter LA, Anderson GH. Phenylalanine and aspartame fail to alter feeding behavior, mood and arousal in men . Physiol Behav . 1987;39:247-253.Crossref 36. Kanders BS, Lavin PT, Kowalchuk MB, Greenburg I, Blackburn GL. An evaluation of the effect of aspartame on weight loss . Appetite . 1988; 11( (suppl) ):73-84.Crossref 37. Maher TJ, Wurtman RJ. High doses of aspartame reduce blood pressure in spontaneously hypertensive rats . N Engl J Med . 1983;309:1125. 38. Walsh GM, Bittner SE, Mooney AK, Rozek LF. Absence of blood pressure lowering effects of aspartame in spontaneously hypertensive rats . In: Kaufman S, ed. Amino Acids in Health and Disease: New Perspectives . New York, NY: Alan R Liss Inc; 1987:469-486. 39. Bradstock MK, Serdula MK, Marks JS, et al. Evaluation of reactions to food additives: the aspartame experience . Am J Clin Nutr . 1986;43:464-469. 40. Schiffman SS, Buckley CE, Sampson HA, et al. Aspartame and susceptibility to headache . N Engl J Med . 1987;317:1181-1185.Crossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

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Publisher
American Medical Association
Copyright
Copyright © 1989 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinte.1989.00390100120026
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Abstract

Abstract • Safety of long-term administration of 75 mg/kg of aspartame per day was evaluated with the use of a randomized, double-blind, placebo-controlled, parallel-group design in 108 male and female volunteers aged 18 to 62 years. Subjects received either aspartame or placebo in capsule form three times daily for 24 weeks. No persistent changes over time were noted in either group in vital signs; body weight; results of standard laboratory tests; fasting blood levels of aspartame's constituent amino acids (aspartic acid and phenylalanine), other amino acids, and methanol; or blood formate levels and 24-hour urinary excretion of formate. There also were no statistically significant differences between groups in the number of subjects experiencing symptoms or in the number of symptoms per subject. These results further document the safety of the long-term consumption of aspartame at doses equivalent to the amount of aspartame in approximately 10 L of beverage per day. (Arch Intern Med. 1989;149:2318-2324) References 1. Aspartame: commissioner's final decision . Federal Register . (July 24) , 981;46:38285-38308. 2. Food additives permitted for direct addition to food for human consumption: aspartame . Federal Register . (July 8) , 1983;48:31376-31382. 3. Ranney RE, Oppermann JA, Muldoon E, McMahon FG. Comparative metabolism of aspartame in experimental animals and humans . J Toxicol Environ Health . 1976;2:441-451.Crossref 4. Food additives permitted for direct addition to food for human consumption: aspartame . Federal Register . (November 23) , 1983;48:52899-52901. 5. McMartin KE, Ambre JJ, Tephly TR. Methanol poisoning in human subjects: role of formic acid accumulation in the metabolic acidosis . Am J Med . 1980;68:414-418.Crossref 6. Martin-Amat G, McMartin KE, Hayreh SS, Tephly TR. Methanol poisoning: ocular toxicity produced by formate . Toxicol Appl Pharmacol . 1978;45:201-208.Crossref 7. American Medical Association's Council on Scientific Affairs. Aspartame: review of safety issues . JAMA . 1985;254:400-402.Crossref 8. Food additives permitted for direct addition to food for human consumption: aspartame . Federal Register . (February 22) , 1984;49:6672-6682. 9. Heybach JP, Allen SS. Resources for inferential estimates of aspartame intake in the United States . In: Wurtman RJ, Ritter-Walker E, eds. Dietary Phenylalanine and Brain Function . Cambridge, Mass: Birkhauser Boston Inc; 1988:365-372. 10. Leon AS, Hunninghake DB. Safety of long term aspartame administration in normal subjects . FASEB J . 1988;2:A633. Abstract. 11. Frey GH. Use of aspartame by apparently healthy children and adolescents . J Toxicol Environ Health . 1976;2:401-415.Crossref 12. Knopp RH, Brandt K, Arky RA. Effects of aspartame in young persons during weight reduction . J Toxicol Environ Health . 1976;2:417-428.Crossref 13. Koch R, Shaw KNF, Williamson M, Haber M. Use of aspartame in phenylketonuric heterozygous adults . J Toxicol Environ Health . 1976;2:453-457.Crossref 14. Stern SB, Bleicher SJ, Flores A, Gombos G, Recita SD, Shu J. Administration of aspartame in non-insulin-dependent diabetics . J Toxicol Environ Health . 1976;2:429-439.Crossref 15. Nehrling JK, Kobe P, McLane MP, Olson RE, Kamath S, Horwitz DL. Aspartame use by persons with diabetes . Diabetes Care . 1985;8:415-417.Crossref 16. Strathman I. Experience with the WHO adverse reaction terminology at Searle . Drug Info J . 1986;20:179-186. 17. Jacobs DR Jr, Hunninghake DB, Dempsey M, et al. Blood lipids and lipoproteins in a Minnesota urban population . J Chronic Dis . 1980;33:395-406.Crossref 18. Lipid Research Clinics Program Manual of Laboratory Operations . Lipid and Lipoprotein Analysis . Washington, DC: Department of Health, Education, and Welfare; 1982. Publication (NIH)75-628. 19. Denckla WD, Dewey HK. The determination of tryptophan in plasma, liver and urine . J Lab Clin Med . 1967;69:160-169. 20. Bloxam DL, Warren WH. Error in the determination of tryptophan by the method of Denckla and Dewey: a revised procedure . Anal Biochem . 1974;60:621-625.Crossref 21. Fernstrom JD, Wurtman RJ. Brain serotonin content: physiological regulation by plasma neutral amino acids . Science . 1972;178:414-416.Crossref 22. Baker RN, Alenty AL, Zack JF Jr. Simultaneous determination of lower alcohols, acetone, and acetaldehyde in blood by gas chromatography . J Chromatogr Sci . 1969;7:312-314.Crossref 23. Makar AB, Tephly TR. Improved estimation of formate in body fluids and tissues . Clin Chem . 1982;28:385. 24. O'Brien D, Ibbott FA, Rodgerson DO. Laboratory Manual of Pediatric Micro-biochem Techniques . 4th ed. New York, NY: Harper & Row Publishers Inc; 1968:114-116. 25. Fleiss JL. Statistical Methods for Rates and Proportions . 2nd ed. New York, NY: John Wiley & Sons Inc; 1981:19-27. 26. Zar JH. Biostatistical Analysis . 2nd ed. Englewood Cliffs, NJ: Prentice-Hall Inc; 1984:122-149. 27. Siegel S. Nonparametric Statistics for the Behavioral Sciences . New York, NY: McGraw-Hill International Book Co Inc; 1956:127-136. 28. Stegink LD, Filer LJ Jr, Baker GL. Plasma and erythrocyte concentrations of free amino acids in adult humans administered abuse doses of aspartame . J Toxicol Environ Health . 1981;7:291-305.Crossref 29. Fernstrom JD, Fernstrom MH, Gillis MA. Acute effects of aspartame on large neutral amino acids and monoamines in rat brain . Life Sci . 1983;32:1651-1658.Crossref 30. Yokogoshi H, Wurtman RJ. Acute effects of oral or parenteral aspartame on catecholamine metabolism in various regions of rat brain . J Nutr . 1986;116:356-364. 31. Coulombe RA Jr, Sharma RP. Neurobiochemical alterations induced by the artificial sweetener aspartame (NutraSweet) . Toxicol Appl Pharmacol . 1986;83:79-85.Crossref 32. Stegink LD, Brummel MC, McMartin K, et al. Blood methanol concentrations in normal adult subjects administered abuse doses of aspartame . J Toxicol Environ Health . 1981;7:281-290.Crossref 33. Blundell JE, Hill AJ. Paradoxical effects of an intense sweetener (aspartame) on appetite . Lancet . 1986;1:1092-1093.Crossref 34. Stellman SD, Garfinkel L. Artificial sweetener use and one-year weight change among women . Prev Med . 1986;15:195-202.Crossref 35. Ryan-Harshman M, Leiter LA, Anderson GH. Phenylalanine and aspartame fail to alter feeding behavior, mood and arousal in men . Physiol Behav . 1987;39:247-253.Crossref 36. Kanders BS, Lavin PT, Kowalchuk MB, Greenburg I, Blackburn GL. An evaluation of the effect of aspartame on weight loss . Appetite . 1988; 11( (suppl) ):73-84.Crossref 37. Maher TJ, Wurtman RJ. High doses of aspartame reduce blood pressure in spontaneously hypertensive rats . N Engl J Med . 1983;309:1125. 38. Walsh GM, Bittner SE, Mooney AK, Rozek LF. Absence of blood pressure lowering effects of aspartame in spontaneously hypertensive rats . In: Kaufman S, ed. Amino Acids in Health and Disease: New Perspectives . New York, NY: Alan R Liss Inc; 1987:469-486. 39. Bradstock MK, Serdula MK, Marks JS, et al. Evaluation of reactions to food additives: the aspartame experience . Am J Clin Nutr . 1986;43:464-469. 40. Schiffman SS, Buckley CE, Sampson HA, et al. Aspartame and susceptibility to headache . N Engl J Med . 1987;317:1181-1185.Crossref

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Oct 1, 1989

References