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. 2025 Aug;17(8):e70138.
doi: 10.1111/1753-0407.70138.

No Evidence of Metabolomic Disruptions From Real-World Intakes of Aspartame or Saccharin: The Coronary Artery Risk Development in Young Adults Study

Brian T Steffen  1 , Elizabeth R Lusczek  1 , David R Jacobs Jr  2 , Chi Chen  3 , Venkatesh L Murthy  4 , Linda Van Horn  5 , James G Terry  6 , John Jeffrey Carr  6 , Lyn M Steffen  2
Affiliations

No Evidence of Metabolomic Disruptions From Real-World Intakes of Aspartame or Saccharin: The Coronary Artery Risk Development in Young Adults Study

Brian T Steffen et al. J Diabetes. 2025 Aug.

Abstract

Background: Artificial sweeteners have become ubiquitous additives in the food supply, and yet the safety of their regular consumption remains controversial. The present study examined whether intakes of aspartame or saccharin are related to aberrations in the plasma metabolome indicating disruptions in metabolism.

Methods: A cohort of 2160 male and female participants, mean age 32.1 years, was included in the analysis. Liquid chromatography and mass-spectrometry assessed 549 unique plasma metabolites. Diet was assessed using a validated questionnaire that allowed for estimation of aspartame and saccharin intakes. A generalized linear regression model evaluated associations of saccharin or aspartame intake with plasma metabolites with adjustment for potential confounders and multiple comparisons. Multiple sensitivity analyses and propensity score matching were conducted.

Results: Heavy aspartame intake (≥ 5 servings/day) was associated with plasma levels (per SD) of saccharin (β = 0.90; q = 9.0E-36), myo-inositol (β = 0.27; q = 3.7E-04), caffeine (β = 0.31; q = 4.1E-04), and five metabolites of caffeine including 1,7-dimethyluric acid (β = 0.37; q = 7.1E-06), 1-methylurate (β = 0.36; q = 7.1E-06), 5-acetylamino-6-amino-3-methyluracil (β = 0.38; q = 3.2E-6), theophylline (β = 0.36; q = 9.1E-06), and 1-methylxanthine (β = 0.32; q = 2.0E-03). Saccharin intake was associated with plasma levels of saccharin alone (β = 0.29; q = 1.8E-10). No associations with sugars, carbohydrates, lipids, amino acids, or other metabolites that would suggest metabolic perturbations were observed with either artificial sweetener; sensitivity analyses supported these findings.

Conclusions: In the largest metabolomics study to date, no link was found between metabolic disruptions and either aspartame or saccharin intake. We cannot exclude the possibility that more extreme intakes may be related to metabolic disruptions among consumers of artificial sweeteners.

Keywords: artificial sweeteners; aspartame; diet; metabolomics; saccharin.

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Conflict of interest statement

V. Murthy owns stock in General Electric, Cardinal Health, Viatris, Pfizer, Amgen, Merck, and Johnson & Johnson and stock options in Ionetix. He is a paid consultant for INVIA Medical Imaging Solutions & Siemens Healthineers. V. Murthy has received research support through his institution from Siemens Healthineers. The remaining authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Volcano plots of plasma metabolites associated with intakes of (A) heavy aspartame (≥ 5 servings/day); and (B) saccharin (> 0 servings/day).
FIGURE 2
FIGURE 2
Results of propensity score matching analysis. Volcano plots of plasma metabolites associated with intakes of (A) heavy aspartame (≥ 5 servings/day); and (B) saccharin (> 0 servings/day).
See this image and copyright information in PMC

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