Modulating the Brain with D-Amino Acids: Exploring D-Tryptophan and D-Phenylalanine in CNS Disorders

D-amino acids are increasingly recognized as modulators of Central Nervous System (CNS) function, with growing interest in their therapeutic potential for neurodegenerative and psychiatric disorders. Among them, D-tryptophan and D-phenylalanine have emerged as promising candidates for the management of Alzheimer’s Disease (AD) and related conditions. Preclinical and emerging clinical findings suggest that these compounds may influence neural plasticity and cognitive processes through modulation of NMDA receptor activity, glutamatergic neurotransmission, and neurotrophic factor release. Beyond cognitive domains, potential benefits may extend to behavioral and mood regulation, highlighting their multifaceted role in CNS health. However, challenges remain regarding their bioavailability and ability to cross the blood–brain barrier, emphasizing the importance of advanced drug delivery strategies such as nanoparticle or liposomal formulations. Longitudinal studies that assess their impact on disease progression, along with the identification of predictive biomarkers, will be essential for evaluating their clinical relevance and enabling personalized therapeutic approaches. Furthermore, exploration of their utility beyond AD, particularly in other neurodegenerative disorders, such as Parkinson’s and Huntington’s disease, could broaden their therapeutic scope. This review summarizes current knowledge of D-tryptophan and D-phenylalanine in the context of neurodegeneration, highlights mechanistic insights, and outlines future directions aimed at translating these molecules into clinically viable interventions.