Creatine supplementation and brain health: Methodological challenges, current evidence, and translational perspectives

Abstract Although creatine supplementation holds promising translational value for supporting brain health and cognitive function, the current body of literature is small, incohesive, and critical knowledge gaps remain. Challenges related to the accuracy, reproducibility, and interpretability of brain creatine quantification have significantly impeded our understanding of the interplay between creatine supplementation, brain creatine availability, and cognitive function. A small body of evidence suggests that creatine supplementation may increase brain creatine and thereby support brain energetics, particularly under metabolically demanding conditions, such as sleep deprivation, hypoxia, or neurological disease. Optimal supplementation regimens remain unknown, however, and heterogeneity across cohort demographics, supplementation regimens, and cognitive assessments, combined with the widespread absence of brain creatine quantification, limits the translation of current evidence. This review will: a) provide an up-to-date standpoint on the efficacy for creatine supplementation to increase brain creatine contents, integrating critical appraisal of methodological rigour and reporting standards of existing literature; b) outline key considerations for the implementation and optimisation of magnetic resonance spectroscopy for quantifying brain creatine, including common error sources and practical recommendations to improve measurement quality and interpretability; and c) discuss the potential translational value of increasing brain creatine in health and disease, including discussion of key barriers that need to be overcome moving forward. By increasing awareness of the methodological and interpretative complexities underlying brain creatine research, we aim to strengthen scientific rigour, foster an improved understanding of current evidence, and advance knowledge surrounding the role of creatine supplementation to increase brain creatine contents and support cognitive function.