Translational Nutritional Neuropharmacology: A Review Bridging Dietary Modulation, Molecular Mechanisms, and Advanced Therapeutic Strategies For CNS Disorders

Neurological and psychiatric disorders, including Alzheimer’s disease, Parkinson’s disease, and major depressive disorder, are multifactorial conditions that necessitate therapeutic approaches extending beyond the constraints of single-target pharmacology. The emerging discipline of translational nutritional neuropharmacology focuses on elucidating the molecular synergy between bioactive dietary constituents (neuronutrients) and neuroactive pharmacological agents. This integrative framework is grounded in the convergence of core CNS pathologies, most notably chronic oxidative stress and neuroinflammation, which are amenable to modulation through targeted nutritional interventions. Bioactive compounds such as polyphenols and omega-3 fatty acids function as disease-modifying agents by activating endogenous protective pathways, including nuclear factor erythroid 2–related factor 2, and by promoting neurogenesis. Importantly, neuropharmacological efficacy is shaped by complex bidirectional interactions, wherein pharmacological treatments may induce clinically significant nutrient deficiencies (e.g., folate depletion associated with antiseizure medications), while dietary patterns and the gut microbiome critically influence drug metabolism and disposition. Evidence from pharmacomicrobiomics demonstrates that gut microbial enzymes can biotransform neuroactive drugs, thereby altering their pharmacokinetics, efficacy, and toxicity. Clinically, combination strategies such as omega-3 fatty acid supplementation alongside selective serotonin reuptake inhibitors in inflammatory depression, or ketogenic dietary therapy combined with antiseizure medications in refractory epilepsy have demonstrated enhanced therapeutic outcomes by simultaneously targeting inflammatory, metabolic, and electrophysiological mechanisms. Future progress in this field will depend on integrated, precision-based care models that combine pharmacogenomics and pharmacomicrobiomics to achieve sustained disease modification.