A Comprehensive Review of Creatine Supplementation: From Foundational Bioenergetics to Evolving Therapeutic Applications and Clinical Safety

Abstract Creatine is a naturally occurring nitrogenous compound that plays a central role in cellular energy metabolism by facilitating rapid ATP resynthesis in tissues with high energetic demands, notably skeletal muscle and the brain. Although best known for enhancing exercise performance, contemporary evidence points to broader clinical potential across neurological conditions, muscle-wasting disorders, chronic diseases, and age-related loss of muscle mass. Supplementation increases creatine availability in muscle and brain, thereby sustaining energy flux, limiting oxidative stress, and supporting recovery, plasticity, and tissue repair. Populations with lower baseline stores, such as children, older adults, women, and individuals following vegan diets, may derive significant benefits. Importantly, creatine has been investigated extensively and demonstrates a strong safety profile, with no consistent evidence of kidney injury or serious adverse effects in healthy individuals or medically supervised clinical cohorts. Taken together, creatine should be considered not merely a sports supplement but a safe, versatile adjunct with relevance to health and function across the lifespan.