Creatine supplementation for brain metabolic stress: a narrative review

The brain accounts for approximately 2% of the total body mass yet it consumes about 20% of the daily energy expenditure. These energetic demands are further elevated during periods of metabolic stress, including sleep deprivation, hypoxia, forced mental fatigue, mood disorders, and traumatic brain injury (TBI). Creatine monohydrate supplementation (CrM) plays a critical role in brain bioenergetics via the phosphocreatine (PCr) energy system, which acts as a spatial and temporal buffer by rapidly regenerating adenosine triphosphate (ATP) from adenosine diphosphate (ADP). Accordingly, CrM has been proposed as a potential neuroprotective intervention, particularly under conditions of metabolic stress. This narrative review examines both the mechanistic rationale and empirical evidence supporting this role. CrM has been shown to increase brain creatine content by 3–10%, enhance PCr availability, stabilize intracellular pH, and support mitochondrial function. These physiological effects are associated with attenuated cognitive declines during acute sleep deprivation and hypoxia, improved executive function under forced mental fatigue, and reduced depressive symptoms, especially when used adjunctively with standard therapies. In the context of TBI, preclinical studies in rodents demonstrate reduced cortical damage and improved bioenergetics, while limited but promising pediatric clinical data suggest improved recovery outcomes with CrM supplementation. Collectively, the existing body of research indicates that CrM can enhance brain creatine content and bioenergetic capacity, which is associated with improvements in cognitive function. Despite these promising findings, the current body of evidence remains limited. Large, well-designed randomized controlled trials are needed to establish optimal dosing strategies, determine population-specific efficacy, and evaluate long-term neurological outcomes associated with CrM supplementation.