Recent advances in chiral analytical chemistry have revealed that fermented and natural foods contain substantial amounts of D-amino acids (D-AAs), the mirror-image counterparts of L-amino acids, leading to their recognition as nutraceutical components with potential health relevance. Although clinical evidence provides only limited support for their therapeutic efficacy, commercial expectations have outpaced scientific validation, and recent safety concerns emphasize the need for critical evaluation. In this review, we integrate findings from food chemistry, microbiology, biochemistry, physiology, and clinical research to provide a critical overview of dietary D-AAs. We examine how dietary exposure, microbial metabolism, host clearance capacity, and redox status collectively shape their context-dependent biological effects. We highlight the mechanistic linkage between D-amino acid oxidase (DAAO)-mediated hydrogen peroxide (H2O2) generation and organ-specific vulnerability, thereby clarifying the molecular basis of their “double-edged sword” actions. Within this interdisciplinary framework, we propose that D-AAs function as context-dependent “contronymic” molecules in cellular communication. By distinguishing physiological regulation, experimental modulation, and clinical application, this review aims to support evidence-based nutraceutical strategies and safety assessments that harness the potential benefits of D-AAs while minimizing associated risks.
Yamasaki et al. (2026) studied this question.