Creatine Monohydrate: Meta-Analysis Data on Strength, Hypertrophy, and Safety

How does creatine work?

During brief, high-intensity efforts - a resistance set, sprint, or jump - muscle cells deplete ATP faster than aerobic resynthesis can keep up. The first reserve is phosphocreatine (PCr): it immediately donates a phosphate group to ADP via the creatine kinase reaction, restoring ATP. The endogenous PCr store provides approximately 8-10 seconds of maximal effort.

According to the ISSN (Kreider et al., Journal of the International Society of Sports Nutrition, 2017), creatine monohydrate supplementation raises phosphocreatine content in muscles by 20-40% above baseline. The practical implication: 2-4 additional reps at the end of a heavy set - precisely at peak effort, where the greatest mechanical stimulus for hypertrophy accumulates.

Strength and muscle mass: what do meta-analyses show?

The most comprehensive current meta-analysis on strength is Kazeminasab et al. (Nutrients, 2025; 69 RCTs, 1,937 participants, ages 18-80). Key results:

• Bench press: WMD = +1.43 kg (95% CI: 0.53-2.34; p=0.002; 49 studies).
• Squat: WMD = +5.64 kg (95% CI: 3.87-7.40; p<0.001; 17 studies).
• Vertical jump: WMD = +1.48 cm (95% CI: 0.30-2.66; p=0.01; 23 studies).
• Peak anaerobic power (Wingate test): WMD = +47.81 W (95% CI: 15.18-80.45; p=0.004; 12 studies).

An important caveat from this meta-analysis: in participants over 50 years old, no significant strength gains were detected, indicating an age-dependent nature of the effects.

For lean body mass, Ashtary-Larky et al. (JISSN, 2025; 61 RCTs, 1,457 participants; studies from 1997-2024) showed: lean mass +1.39 kg (95% CI: 1.07-1.70; p<0.001), total body mass +0.89 kg, fat mass - non-significant gain (+0.15 kg). GRADE evidence quality - high. The effect was reproduced in both untrained individuals (+1.23 kg) and experienced athletes (+1.82 kg).

Delpino et al. (Nutrition, 2022; 35 RCTs, 1,192 participants) clarify: when combined with resistance training, lean mass +1.10 kg (95% CI: 0.56-1.65); without training - no significant gain. The supplement amplifies the training stimulus, not replaces it.

Does creatine affect cognitive function?

Xu et al. (Frontiers in Nutrition, 2024; 16 RCTs, 492 participants, ages 20.8-76.4) conducted the first comprehensive meta-analysis of cognitive effects. Results by domain:

• Memory: SMD = 0.31 (95% CI: 0.18-0.44; I²=21%; p<0.00001) - GRADE confidence moderate. This is the most robust cognitive finding.
• Overall cognitive score: SMD = 0.34 (95% CI: -0.20 to 0.88; p=0.22) - not statistically significant.
• Executive function: SMD = 0.32 (95% CI: -0.08 to 0.71) - not significant.
• Reaction speed and information processing: significant improvement only in specific subgroups (ages 18-60, presence of disease) - confidence low.

Conclusion: the memory effect is real and moderately reliable; overall cognitive performance cannot be confirmed from existing data. Interpret with caution.

Safety: kidney data

Concerns about nephrotoxicity are widespread in public discussions but are not supported by peer-reviewed literature.

The meta-analysis by Naeini et al. (BMC Nephrology, 2025; 12 studies, 177 participants in the supplementation group): serum creatinine rose by +0.07 umol/L (95% CI: 0.01-0.12; p=0.03) - statistically significant but clinically negligible. The mechanism is clear: exogenous creatine increases its turnover to creatinine; the rise in serum concentration is a consequence of substrate metabolism, not a sign of kidney damage. The authors conclude: "Creatine supplements are safe and do not cause kidney disease."

Longobardi et al. (Frontiers in Nutrition, 2025) examined safety data at doses of 1-80 g/day for durations ranging from 5 days to 60 months and assigned renal safety a level of evidence of Grade I (high) in healthy individuals. Exception: clinical monitoring is necessary with pre-existing kidney pathology.

How to take it: two equivalent protocols

The 2017 ISSN position statement describes two regimens with identical final muscle saturation:

• Loading protocol: 20 g/day split across doses (4 x 5 g per day) for 5-7 days, then 3-5 g/day. Muscles saturate in approximately one week.
• Gradual protocol: 3 g/day without a loading phase. Saturation is reached in approximately 28 days. Final phosphocreatine level is identical to the loading approach.

The loading protocol is justified when rapid effect is needed by a specific date. In all other cases, both approaches are equivalent. The only reproducible side effect is an initial body weight gain (~0.5-1.0 kg) due to water retention in muscle; gastrointestinal discomfort is minimal when a single dose does not exceed 5 g (ISSN, 2017).