Creatine and cognitive function: Why has physiological plausibility not translated into convincing clinical evidence?

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Creatine is among the most extensively studied and widely used nutritional supplements in sports and exercise science. Over the past two decades, however, interest has expanded well beyond skeletal muscle, driven by growing recognition of the central role played by the creatine-phosphocreatine system in cerebral bioenergetics. Experimental evidence indicates that creatine contributes to neuronal energy homeostasis, mitochondrial function, membrane stability and potentially neuroprotection. This has fuelled growing enthusiasm for the idea that creatine supplementation might enhance cognitive function and benefit individuals with compromised cerebral metabolism. Yet, despite strong physiological plausibility, clinical findings remain inconsistent and often difficult to interpret. In this review, it is argued that the gap between proposed mechanisms and available clinical evidence reflects two distinct challenges: biological constraints on cerebral creatine availability after supplementation, and persistent methodological weaknesses in the clinical literature. We contend that the central challenge for the coming decade is not to identify new mechanisms of creatine action in the brain, but to establish, unequivocally, whether measurable changes in cerebral bioenergetics translate into meaningful cognitive benefit - whether as enhanced performance in healthy individuals or as clinically significant improvement in patient populations.