{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T23:48:16Z","timestamp":1792712896864,"version":"4.5.0"},"reference-count":45,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T00:00:00Z","timestamp":1751846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoX"],"abstract":"<jats:p>Aspartame, a widely used artificial sweetener, has been at the center of ongoing debates concerning its safety, particularly its potential role in cancer development. This review provides an overview and analysis of the current research exploring the carcinogenic effects of aspartame. It examines findings from in vitro studies, in vivo experiments, and epidemiological investigations to offer a comprehensive perspective on the controversy. The results from these studies remain inconsistent\u2014some suggest a possible association between high aspartame intake and increased cancer risk, while others fail to establish a conclusive link. Additionally, this review explores potential mechanisms by which aspartame could exert carcinogenic effects, focusing on its metabolic byproducts and their influence on cellular and molecular processes. Despite these investigations, the question of aspartame\u2019s safety remains unresolved. Continued research is essential to clarify its role in cancer risk and to inform evidence-based dietary guidelines.<\/jats:p>","DOI":"10.3390\/jox15040114","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T04:43:37Z","timestamp":1751863417000},"page":"114","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Aspartame and Human Health: A Mini-Review of Carcinogenic and Systemic Effects"],"prefix":"10.3390","volume":"15","author":[{"given":"Nour El","family":"Doueihy","sequence":"first","affiliation":[{"name":"Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli P.O. Box 100, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joya","family":"Ghaleb","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli P.O. Box 100, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Kfoury","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli P.O. Box 100, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6151-4182","authenticated-orcid":false,"given":"Katy Kaleen","family":"Khouzami","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli P.O. Box 100, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3526-6165","authenticated-orcid":false,"given":"Nicolas","family":"Nassif","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli P.O. Box 100, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8491-0790","authenticated-orcid":false,"given":"Philippe","family":"Attieh","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli P.O. Box 100, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilda E.","family":"Ghadieh","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli P.O. Box 100, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami","family":"Azar","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli P.O. Box 100, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amjad","family":"Kanaan","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli P.O. Box 100, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5882-1619","authenticated-orcid":false,"given":"Frederic","family":"Harb","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli P.O. Box 100, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,7]]},"reference":[{"key":"ref_1","unstructured":"Caballero, B. (2003). Aspartame. Encyclopedia of Food Sciences and Nutrition, Academic Press."},{"key":"ref_2","first-page":"311","article-title":"The Health Risks of Saccharin Revisited","volume":"38","author":"Ellwein","year":"2008","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1093\/nutrit\/nux035","article-title":"Revisiting the Safety of Aspartame","volume":"75","author":"Choudhary","year":"2017","journal-title":"Nutr. Rev."},{"key":"ref_4","unstructured":"Wexler, P. (2014). Aspartame. Encyclopedia of Toxicology, Academic Press. [3rd ed.]."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1002\/jnr.490230115","article-title":"Aspartate Neurotoxicity on Cultured Cortical Neurons","volume":"23","author":"Choi","year":"1989","journal-title":"J. Neurosci. Res."},{"key":"ref_6","unstructured":"Nill, A. (2000). The History of Aspartame, Chemical Heritage Foundation."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Shaher, S.A.A., Mihailescu, D.F., and Amuzescu, B. (2023). Aspartame Safety as a Food Sweetener and Related Health Hazards. Nutrients, 15.","DOI":"10.20944\/preprints202307.0384.v1"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5487\/TR.2011.27.1.001","article-title":"Lipid Peroxidation and Its Toxicological Implications","volume":"27","author":"Nam","year":"2011","journal-title":"Toxicol. Res."},{"key":"ref_9","unstructured":"National Toxicology Program (NTP) (2005). NTP Report on the Toxicology Studies of Aspartame in Genetically Modified Mice."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s12940-021-00725-y","article-title":"Aspartame and Cancer\u2014New Evidence for Causation","volume":"20","author":"Landrigan","year":"2021","journal-title":"Environ. Health"},{"key":"ref_11","first-page":"208","article-title":"Aspartame Safety and Health Implications: A Comprehensive Review","volume":"27","author":"Bayrak","year":"2025","journal-title":"Int. Food Res. J."},{"key":"ref_12","unstructured":"Knowledge Based Value (KBV) Research (2023). Global Aspartame Market Size, Share & Industry Trends Analysis Report (2023\u20132029), Market Research Firm. Available online: https:\/\/www.kbvresearch.com\/aspartame-market\/."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Hou, X., and Chen, D. (2024). Aspartame Carcinogenic Potential Revealed Through Network Toxicology and Molecular Docking Insights. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-62461-w"},{"key":"ref_14","unstructured":"Malkan, S. (2025, May 10). Aspartame: Decades of Science Point to Serious Health Risks, Environmental Health News, Available online: https:\/\/usrtk.org\/sweeteners\/aspartame_health_risks\/."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Liauchonak, I., Qorri, B., Dawoud, F., Riat, Y., and Szewczuk, M.R. (2019). Non-Nutritive Sweeteners and Their Implications on the Development of Metabolic Syndrome. Nutrients, 11.","DOI":"10.3390\/nu11030644"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kossiva, L., Karaglani, K., Christodouli, F., Soldatou, A., Karanasios, S., and Karavanaki, K. (2024). Chronic Use of Artificial Sweeteners: Pros and Cons. Nutrients, 16.","DOI":"10.3390\/nu16183162"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Naik, A.Q., Zafar, T., and Shrivastava, V.K. (2023). The Impact of Non-Caloric Artificial Sweetener Aspartame on Female Reproductive System in Mice Model. Reprod. Biol. Endocrinol., 21.","DOI":"10.1186\/s12958-023-01115-4"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Debras, C., Chazelas, E., Srour, B., Druesne-Pecollo, N., Esseddik, Y., de Edelenyi, F.S., Aga\u00ebsse, C., De Sa, A., Lutchia, R., and Gigandet, S. (2022). Artificial Sweeteners and Cancer Risk: Results from the NutriNet-Sant\u00e9 Population-Based Cohort Study. PLoS Med., 19.","DOI":"10.1371\/journal.pmed.1003950"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Griebsch, L.V., Theiss, E.L., Janitschke, D., Erhardt, V.K.J., Erhardt, T., Haas, E.C., Kuppler, K.N., Radermacher, J., Walzer, O., and Lauer, A.A. (2023). Aspartame and Its Metabolites Cause Oxidative Stress and Mitochondrial and Lipid Alterations in SH-SY5Y Cells. Nutrients, 15.","DOI":"10.3390\/nu15061467"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1080\/07315724.1991.10718153","article-title":"Acceptable Daily Intake vs Actual Intake: The Aspartame Example","volume":"10","author":"Butchko","year":"1991","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Pati, S., Irfan, W., Jameel, A., Ahmed, S., and Shahid, R.K. (2023). Obesity and Cancer: A Current Overview of Epidemiology, Pathogenesis, Outcomes, and Management. Cancers, 15.","DOI":"10.3390\/cancers15020485"},{"key":"ref_22","unstructured":"Stiepan, D. (2024, April 20). Mayo Clinic Expert Weighs in on WHO Labeling Aspartame Sweetener as Low, but Possible, Cancer Risk. Mayo Clinic News Network, 14 July 2023. Available online: https:\/\/newsnetwork.mayoclinic.org\/discussion\/mayo-clinic-expert-weighs-in-on-who-labeling-aspartame-sweetener-as-low-but-possible-cancer-risk\/."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e071204","DOI":"10.1136\/bmj-2022-071204","article-title":"Artificial Sweeteners and Risk of Cardiovascular Diseases: Results from the Prospective NutriNet-Sant\u00e9 Cohort","volume":"378","author":"Debras","year":"2022","journal-title":"BMJ"},{"key":"ref_24","unstructured":"Bressler, J. (2025, May 10). Histroy of the U.S. Food and Drug Administration, Available online: https:\/\/www.fda.gov\/media\/80995\/download\/."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Pang, M.D., Goossens, G.H., and Blaak, E.E. (2021). The Impact of Artificial Sweeteners on Body Weight Control and Glucose Homeostasis. Front. Nutr., 7.","DOI":"10.3389\/fnut.2020.598340"},{"key":"ref_26","unstructured":"International Agency for Research on Cancer (IARC) (2023). Carcinogenicity of Aspartame, Methyleugenol, and Isoeugenol, IARC Press. IARC Monographs."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Xiao, L., Xian, M., Zhang, C., Guo, Q., and Yi, Q. (2023). Lipid Peroxidation of Immune Cells in Cancer. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1322746"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/B978-0-444-63432-0.00004-9","article-title":"Overview of the Immune System","volume":"133","author":"Medina","year":"2016","journal-title":"Handb. Clin. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.psyneuen.2015.01.010","article-title":"Diurnal Cortisol and Survival in Epithelial Ovarian Cancer","volume":"53","author":"Schrepf","year":"2015","journal-title":"Psychoneuroendocrinology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1254\/jphs.91.83","article-title":"Formaldehyde-Induced Shrinkage of Rat Thymocytes","volume":"91","author":"Nakao","year":"2003","journal-title":"J. Pharmacol. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Kawanishi, M., Matsuda, T., and Yagi, T. (2014). Genotoxicity of Formaldehyde: Molecular Basis of DNA Damage and Mutation. Front. Environ. Sci., 2.","DOI":"10.3389\/fenvs.2014.00036"},{"key":"ref_32","first-page":"1410","article-title":"Artificial Food Sweetener Aspartame Induces Stress Response in Model Organism Schizosaccharomyces pombe","volume":"7","author":"Bayrak","year":"2020","journal-title":"Toxicol. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"154664","DOI":"10.1016\/j.prp.2023.154664","article-title":"Oxidative Stress Affects the Beginning of the Growth of Cancer Cells Through a Variety of Routes","volume":"248","author":"Saleh","year":"2023","journal-title":"Pathol. Res. Pract."},{"key":"ref_34","unstructured":"(2022). Novel L-Phenylalanine Dipeptide Inhibits Prostate Cancer Growth via Targeting DUSP1 and TNFSF9. Int. J. Mol. Sci., 23."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Czarnecka, K., Pilarz, A., Rogut, A., Maj, P., Szyma\u0144ska, J., Olejnik, \u0141., and Szyma\u0144ski, P. (2021). Aspartame\u2014True or False? Narrative Review of Safety Analysis of General Use in Products. Nutrients, 13.","DOI":"10.3390\/nu13061957"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1289\/ehp.8711","article-title":"First Experimental Demonstration of the Multipotential Carcinogenic Effects of Aspartame Administered in the Feed to Sprague-Dawley Rats","volume":"114","author":"Soffritti","year":"2006","journal-title":"Environ. Health Perspect."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1196\/annals.1371.075","article-title":"Results of a Long-Term Carcinogenicity Bioassay on Sprague-Dawley Rats Exposed to Sodium Arsenite Administered in Drinking Water","volume":"1076","author":"Soffritti","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1289\/ehp.10271","article-title":"Life-Span Exposure to Low Doses of Aspartame Beginning During Prenatal Life Increases Cancer Effects in Rats","volume":"115","author":"Soffritti","year":"2007","journal-title":"Environ. Health Perspect."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"EFSA Panel on Food Additives and Nutrient Sources Added to Food (ANS) (2013). Scientific Opinion on the Re-Evaluation of Aspartame (E 951) as a Food Additive. EFSA J., 11, 3496.","DOI":"10.2903\/j.efsa.2013.3496"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3267","DOI":"10.1021\/bi00634a001","article-title":"Formaldehyde as a Probe of DNA Structure. 3. Equilibrium Denaturation of DNA and Synthetic Polynucleotides","volume":"16","author":"McGhee","year":"1977","journal-title":"Biochemistry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.molcel.2015.08.020","article-title":"Endogenous Formaldehyde Is a Hematopoietic Stem Cell Genotoxin and Metabolic Carcinogen","volume":"60","author":"Pontel","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1080\/10408440701516184","article-title":"Aspartame: A Safety Evaluation Based on Current Use Levels, Regulations, and Toxicological and Epidemiological Studies","volume":"37","author":"Magnuson","year":"2007","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.tiv.2010.09.002","article-title":"In Vitro Effect of Aspartame in Angiogenesis Induction","volume":"25","author":"Alleva","year":"2011","journal-title":"Toxicol. Vitro"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Guercio, B.J., Zhang, S., Niedzwiecki, D., Li, Y., Babic, F.A., Morales-Oyarvide, V., Saltz, L.B., Mayer, R.J., Mowat, R.B., and Whittom, R. (2018). Associations of Artificially Sweetened Beverage Intake with Disease Recurrence and Mortality in Stage III Colon Cancer: Results from CALGB 89803 (Alliance). PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0199244"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s00394-014-0818-5","article-title":"Consumption of Soft Drinks and Juices and Risk of Liver and Biliary Tract Cancers in a European Cohort","volume":"55","author":"Stepien","year":"2016","journal-title":"Eur. J. Nutr."}],"container-title":["Journal of Xenobiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2039-4713\/15\/4\/114\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:05:41Z","timestamp":1760033141000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2039-4713\/15\/4\/114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,7]]},"references-count":45,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["jox15040114"],"URL":"https:\/\/doi.org\/10.3390\/jox15040114","relation":{},"ISSN":["2039-4713"],"issn-type":[{"value":"2039-4713","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,7]]}}}