The Emerging Role of Citrulline and Theanine in Health and Disease: A Comprehensive Review.

Non-proteinogenic amino acids, such as L-citrulline and L-theanine, have garnered attention for their potential health benefits, including enhanced immunity, antioxidant activity, and cardiovascular support. The application of natural amino acids in disease treatment and health supplementation is and will remain a research hotspot in pharmaceutics. Plant-derived L-citrulline and L-theanine have demonstrated multifaceted benefits, primarily through mechanisms involving nitric oxide (NO) bioavailability (for L-citrulline) and mitochondrial regulation or immune modulation (for both). Critical gaps are identified: (1) the role of D-amino acids (e.g., D-citrulline and D-theanine) in health and metabolism remains underexplored, particularly regarding chiral-specific bioactivity; (2) derivatives and co-administration strategies of L-forms warrant systematic evaluation for drug. However, while these compounds show promise, evidence is predominantly from animal and cell studies, with limited long-term human data on efficacy and safety. Potential side effects, dosing limitations, and sourcing challenges are discussed. This review emphasizes the need for cautious interpretation of their benefits, acknowledging that while promising, some effects, such as those on muscle protein synthesis, require further validation compared to established nutrients like branched-chain amino acids. By bridging mechanistic insights with translational challenges, this work aims to guide future research toward sustainable nutraceutical production.