Creatine Supplementation: Evidence-Based Benefits and Latest Research Findings
Creatine has evolved from a niche athletic supplement into one of the most scientifically validated nutritional compounds, with research extending well beyond muscle performance to encompass brain health, cardiovascular function, and therapeutic applications for various medical conditions. The body of scientific evidence now comprises over 1,000 peer-reviewed studies, establishing creatine as a safe and effective supplement with applications across diverse populations and health scenarios.
Understanding Creatine: Mechanism and Function
Creatine is an organic compound naturally synthesised by the body from three amino acids—glycine, arginine, and methionine primarily in the liver and kidneys, with approximately half of daily requirements also obtained from dietary sources, particularly red meat and fish. Once ingested, creatine is transported through the bloodstream where approximately 95 percent is stored in skeletal muscle tissue, with about 67 percent converted to phosphocreatine (PCr) and 33 percent remaining as free creatine.
The fundamental mechanism through which creatine works involves the phosphocreatine energy system. Phosphocreatine combines with adenosine diphosphate (ADP) and is catalysed by creatine kinase to rapidly regenerate adenosine triphosphate (ATP), the primary energy currency of cells. This system is particularly critical during high-intensity exercise and in tissues with high energy demands, including the brain. By facilitating faster ATP resynthesis and buffering hydrogen ion accumulation, creatine effectively extends performance capacity during intense activity and supports cellular energy production under demanding conditions.
Muscle Growth and Athletic Performance
The most established benefit of creatine supplementation is its ability to enhance muscle strength, power, and lean mass, particularly when combined with resistance training. Research demonstrates that creatine supplementation can double strength and lean muscle gains compared to training alone, with improvements visible within relatively short timeframes.
A comprehensive scoping review examining multiple clinical trials revealed that creatine supplementation produced positive effects on muscle strength across diverse exercise modalities. Studies show improvements in bench press strength, leg press performance, and cycling sprints, with one 4-week investigation demonstrating a 17 percent improvement in cycling sprints, an 18-pound increase in bench press one-repetition maximum, and 20 percent greater work capacity at lower weights. These benefits extend to both beginners and advanced weight lifters, making creatine valuable across fitness experience levels.
The mechanisms underlying muscle hypertrophy involve multiple pathways. Creatine increases intracellular energy availability, enhances insulin-like growth factor 1 (IGF-1) signalling, activates the mechanistic target of rapamycin (mTOR) pathway, a critical regulator of protein synthesis, increases cellular hydration through osmotic effects, stimulates satellite cell activation, reduces muscle damage, and improves recovery processes. The increase in muscle cell water content creates osmotic stress that serves as a signal for anabolic processes, triggering the formation of new proteins and ultimately increasing muscle mass.
Cognitive Function and Brain Health
Recent research has significantly expanded our understanding of creatine's role in brain function, revealing benefits that extend far beyond athletic performance. A 2024 meta-analysis examining 24 studies with approximately 1,000 participants found that creatine monohydrate supplementation produced significant positive effects on memory function, with improvements in attention time and information processing speed. The analysis demonstrated standardised mean differences of 0.31 for memory benefits, indicating a meaningful enhancement of cognitive performance.
The mechanisms underlying cognitive benefits involve creatine's enhancement of cerebral energy metabolism. Creatine increases phosphocreatine and ATP levels in the brain, preventing pH drops and supporting cellular energy homeostasis, particularly in energy-demanding regions like the cerebellum, hippocampus, and cerebral cortex. A 2024 study on sleep deprivation demonstrated that a high single dose of creatine (0.35 g/kg body weight) improved cognitive performance and processing speed during sleep loss by inducing changes in phosphocreatine-to-inorganic phosphate ratios and ATP levels, reducing fatigue-related cognitive deterioration.
Among the most promising recent findings is creatine's potential application in neurodegenerative diseases and mental health conditions. A pilot study from the University of Kansas Medical Centre examining creatine supplementation in Alzheimer's patients, the first study of its kind, found moderate improvements in working memory and executive function. Researchers theorise that by supplying additional energy directly to brain cells, creatine may enhance cognitive processes that rely on adequate ATP availability.
Depression and mood disorders represent another emerging area of research. A 2024 review revealed that creatine supplementation reduces depressive symptoms, particularly when combined with selective serotonin reuptake inhibitors (SSRIs), potentially through enhancement of brain energy metabolism and modulation of neurotransmitter systems regulating mood, including serotonin and dopamine pathways. Neuroimaging studies indicate that creatine boosts phosphocreatine levels in brain regions linked to mood regulation, with doses above the standard 5 grams daily showing additional increases in brain creatine levels.
Benefits for Ageing and Sarcopenia
The ageing population represents a critical area where creatine supplementation demonstrates significant therapeutic potential. Sarcopenia—age-related loss of muscle mass, strength, and functional ability—affects an estimated 200 million older adults aged 65 and above globally and is projected to increase dramatically by 2050, increasing risks of falls, fractures, and disability.
Creatine monohydrate supplementation at doses of 5 grams or greater daily, combined with resistance training, produces significant improvements in measures of muscle strength, lean body mass, and functional ability in older adults. A meta-analysis demonstrated that this combination effectively addresses sarcopenia, the key diagnostic factor of which is reduced muscle strength. Beyond muscle, emerging evidence shows that older individuals consuming adequate dietary creatine (greater than 0.95 grams daily) demonstrate superior cognitive function compared to those with lower intake.
The mechanism involves creatine's ability to maintain high local ATP/ADP ratios, particularly important for energy-demanding processes like the sarcoplasmic reticulum calcium pump, and to reduce reactive oxygen species production in mitochondria. This mitochondrial support is crucial, as chronic reduction in cellular energy status can lead to pathological calcium overload characteristic of ageing-related muscle diseases.
Cardiovascular and Vascular Health
Recent pilot research suggests creatine may support cardiovascular health through multiple pathways. A 2025 study from Florida State University examined creatine's effects on vascular ageing in 12 healthy older adults, revealing that creatine improved flow-mediated dilation (FMD), a key measure of artery health, comparable to the effects achieved with blueberries, coenzyme Q10, and blood pressure medications. Additionally, creatine enhanced microvasculature function, as evidenced by faster oxygen perfusion into muscles, and significantly reduced both blood glucose and blood triglyceride concentrations, both cardiovascular risk factors.
In patients with heart failure and reduced ejection fraction, a prospective study of 43 patients found that 5 grams daily of creatine monohydrate for three months was safe and produced statistically significant improvements in the six-minute walk test, reduced perceived exertion, decreased heart rate during exercise, and improved health-related quality of life. Whilst additional research with larger sample sizes is needed, these findings suggest creatine may support functional capacity in cardiovascular disease.
Emerging Applications: Cancer Cachexia and Immunity
Preclinical research has revealed creatine's potential in combating cancer cachexia, devastating muscle and fat wasting associated with malignancy. Studies in cancer cachexia mouse models demonstrate that creatine supplementation alleviated cachectic weight loss, protected against skeletal muscle atrophy, increased grip strength, and improved muscle regeneration. These protective effects were mediated through restoration of mitochondrial bioenergetics function, blocking abnormal activation of protein degradation pathways, and reducing cellular energy deficiency.
Clinical trials examining creatine combined with curcumin in patients with early-stage cachexia from upper gastrointestinal tumours are currently underway to evaluate effects on inflammatory markers, metabolic parameters, and nutritional status. Additionally, research indicates creatine supplementation enhances immune function by increasing cellular ATP in neutrophils, thereby enhancing antibacterial immunity.
Dosing Protocols and Safety Profile
Standard supplementation protocols involve either a loading phase or steady-state dosing. The most common loading approach consists of 20 grams daily for 4–7 days divided into multiple doses, followed by a maintenance dose of 2–5 grams daily. Alternatively, individuals can bypass the loading phase and take 3–5 grams daily (approximately 0.1 g/kg body weight), which reaches saturation levels within about 4 weeks.
For athletes performing intense training, recommendations range from 5–10 grams daily, whilst general recommendations for the non-athletic population range from 3–5 grams daily or 0.1 g/kg body weight daily.
Creatine monohydrate remains the gold standard despite numerous proprietary forms claiming enhanced absorption and effectiveness. Creatine monohydrate has been subjects of over 1,000 peer-reviewed studies, demonstrating unmatched research validation. Whilst alternative forms like creatine hydrochloride (HCl) claim to require smaller doses due to improved solubility, comparative studies show no significant advantage in muscle creatine content accumulation. Micronised creatine monohydrate, mechanically processed into smaller particles, offers potential digestive benefits for sensitive individuals whilst maintaining equivalent effectiveness.
Regarding safety, creatine supplementation is extraordinarily well-tolerated. A comprehensive 2025 analysis examining 685 human clinical trials found that creatine supplementation does not increase the prevalence or frequency of side effects when compared to placebo, effectively refuting anecdotal claims of adverse effects. Studies document that creatine taken at 25 grams daily for 14 days is safe, supplementation at 4–5 grams daily for 18 months produces no side effects, and even 10 grams daily for 5 years causes no adverse effects.
Concerns about kidney damage are largely unfounded. Whilst creatine is metabolised to creatinine, a waste product filtered by kidneys, this causes a harmless increase in blood creatinine levels without indicating actual kidney damage. Numerous investigations demonstrate that healthy individuals taking recommended doses show no signs of kidney harm, though individuals with pre-existing kidney conditions should consult healthcare professionals before supplementing.
Minor digestive issues occasionally occur, particularly during loading phases. A 2008 study found that a 5-gram dose taken twice daily caused diarrhoea in 29 percent of participants, comparable to placebo, whilst a 10-gram single daily dose increased diarrhoea risk by 56 percent. These issues typically resolve by reducing dosage, skipping the loading phase, or choosing micronised forms.
Special Populations: Vegetarians and Vegans
Vegetarians and vegans typically have muscle creatine stores approximately 20–30 percent lower than omnivores, since plant-based foods contain no creatine and dietary sources are limited to meat and fish. Whilst the body synthesises about 1 gram daily endogenously, plant-based eaters lack exogenous dietary sources to supplement this amount, resulting in lower steady-state muscle creatine concentrations.
Remarkably, research demonstrates that vegetarian and vegan athletes often respond more robustly to creatine supplementation than omnivores. A 2020 review comparing creatine responses between vegetarians and meat eaters showed that vegetarian groups achieved larger increases in muscle creatine content and greater improvements in lean tissue mass. This enhanced responsiveness likely reflects their baseline deficit, as starting from a lower creatine baseline provides greater potential for improvement.
Creatine monohydrate supplements are naturally vegan, as the manufacturing process synthesises creatine from non-animal sources in laboratories. For plant-based athletes, taking 3–5 grams of creatine daily can help match or exceed the muscle creatine levels of omnivorous athletes, providing substantial performance and cognitive benefits.
Latest Research Findings and Future Directions
The research landscape continues to expand rapidly, with 2024–2025 investigations revealing new applications and mechanisms. A 2025 comprehensive review on safety across the lifespan demonstrated that creatine monohydrate supplementation possesses health benefits during pregnancy and infancy, for children and adolescents, for women, for exercise-trained adults, and for older populations. Evidence indicates creatine can enhance immunity, promote heart health, support vascular function, and maintain brain health.
Therapeutic applications under investigation include type 2 diabetes management, sarcopenia treatment, osteoporosis intervention, rehabilitation for neuromuscular diseases, and even potential roles in slowing cancer progression and maintaining muscle mass during chemotherapy.
The convergence of evidence across these diverse domains, athletic performance, cognitive function, cardiovascular health, ageing, mental health, and disease management, establishes creatine as one of the most comprehensively studied and broadly beneficial nutritional supplements available. As research continues to elucidate mechanisms and optimise applications across specific populations and conditions, creatine's role in supporting health and performance will likely continue to expand.
