Creatine

Pharmacology & Research

Creatine is a nitrogenous organic acid the body makes from glycine, arginine and methionine and stores mostly in skeletal muscle as phosphocreatine, a rapidly mobilised reservoir for regenerating ATP during short, intense effort. It is the most-studied sports supplement, and for strength, power and lean-mass gains alongside resistance training the human evidence is deep and consistent. Nearly all of that evidence is for one cheap form — creatine monohydrate — so the “advanced” forms sold at a premium are marketing, not a bioavailability upgrade. The important distinction elsewhere is between correcting a low baseline (vegetarians, older adults, the sleep-deprived, whose muscle and brain creatine start lower) and adding more on top of an already-replete system: the muscle benefits appear in replete people, but the cognitive claims lean heavily on stressed or depleted states and thin out in healthy, well-fed young adults.

0. Evidence by application

Support is an experimental score I’m building — a composite weighted by study type (human > animal > in vitro > review) and study volume. It’s a beta: a fast way to rank strength of evidence at a glance, not a validated metric. Each application links down to its write-up.

Application	Support	Rests on
Muscle strength (with resistance training)	█████████░ 91%	Multiple meta-analyses, hundreds of RCT participants; consistent strength gains
Lean body mass & hypertrophy	█████████░ 88%	Meta-analyses incl. direct MRI/CT/ultrasound imaging of muscle
High-intensity & power performance	████████░░ 84%	Consistent ergogenic effect on short, repeated max efforts
Muscle & strength in older adults	████████░░ 76%	Several meta-analyses of creatine + RT in aging adults
Memory & cognition	█████░░░░░ 54%	RCT meta-analyses; small effect, larger in stressed/lower-baseline groups
Cognition under sleep deprivation	████░░░░░░ 44%	Single high-dose RCT + small earlier trial; mechanism plausible
Depression (SSRI augmentation)	████░░░░░░ 40%	A few small RCTs, mostly in women; needs replication

1. Muscle strength (with resistance training)

When combined with resistance training, creatine monohydrate produces meaningfully larger strength gains than training alone. A 2024 meta-analysis in adults under 50 found weighted mean differences of +4.4 kg upper-body and +11.4 kg lower-body strength versus placebo (both p < 0.001), with somewhat greater effects in males ^{1Reference 1Wang et al. · 2024Meta-analysisEffects of Creatine Supplementation and Resistance Training on Muscle Strength Gains in Adults <50 Years of Age — systematic review and meta-analysisView study →}. Older-adult meta-analyses show the same direction — greater chest-press and leg-press 1-RM gains — over ~12 weeks of training ^{4Reference 4Devries et al. · 2014Meta-analysisCreatine supplementation during resistance training in older adults — meta-analysisView study →}. This is a replete-population effect (it does not require a low baseline) and uses the standard 3–5 g/day monohydrate dose ^{11Reference 11Kreider et al. · 2017ReviewInternational Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation — reviewView study →}.

Gap: Benefit is contingent on actually doing resistance training; creatine alone, without a training stimulus, does little for strength.

2. Lean body mass & hypertrophy

Creatine plus resistance training increases fat-free mass more than training alone, confirmed with direct imaging rather than just bioimpedance. A 2023 meta-analysis restricted to MRI/CT/ultrasound measures of site-specific hypertrophy found a small but consistent added effect of creatine on muscle growth across 44 outcomes ^{2Reference 2Burke et al. · 2023Meta-analysisCreatine Supplementation Combined with Resistance Training on Regional Measures of Muscle Hypertrophy — systematic review with meta-analysisView study →}. Part of the early “gain” is intracellular water (creatine draws water into muscle cells), but the imaging and longer-term data support genuine added lean tissue with training ^{3,11Reference 3Delpino et al. · 2022Meta-analysisInfluence of age, sex, and type of exercise on the efficacy of creatine supplementation on lean body mass — systematic review and meta-analysis of RCTsView study →Reference 11Kreider et al. · 2017ReviewInternational Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation — reviewView study →}.

Gap: The added hypertrophy is modest on top of training, and some short-term scale change is water weight rather than contractile tissue.

3. High-intensity & power performance

For short, repeated bouts of maximal effort — sprints, jumps, repeated sets — creatine raises intramuscular phosphocreatine and improves performance and training adaptations, the core finding of the ISSN position stand ^{11Reference 11Kreider et al. · 2017ReviewInternational Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation — reviewView study →}. Sport-specific meta-analyses (e.g. in soccer players) report improved sprint and power measures ^{6Reference 6Mielgo-Ayuso et al. · 2019Meta-analysisEffects of Creatine Supplementation on Athletic Performance in Soccer Players — systematic review and meta-analysisView study →}. The effect is on the phosphagen energy system, so it fades for prolonged endurance work.

Gap: No meaningful benefit for steady-state endurance; the ergogenic window is anaerobic, high-intensity efforts.

4. Muscle & strength in older adults

In aging adults, creatine added to resistance training augments lean tissue mass and strength and improves functional measures such as the 30-second chair-stand and sit-to-stand ^{4,5Reference 4Devries et al. · 2014Meta-analysisCreatine supplementation during resistance training in older adults — meta-analysisView study →Reference 5Forbes et al. · 2021Meta-analysisImportance of Creatine Ingestion Strategies on Lean Tissue Mass and Strength in Older Adults — meta-analysisView study →}. This overlaps with the repletion theme — older muscle tends toward lower creatine stores — and dosing strategy (daily maintenance vs loading) matters less than consistent intake alongside training ^{5Reference 5Forbes et al. · 2021Meta-analysisImportance of Creatine Ingestion Strategies on Lean Tissue Mass and Strength in Older Adults — meta-analysisView study →}.

Gap: Benefits are tied to concurrent resistance training; creatine is an adjunct to exercise in sarcopenia, not a standalone treatment.

5. Memory & cognition

Meta-analyses of RCTs find a small positive effect of creatine on memory (SMD ≈ 0.31) and processing speed, with the largest effects in people who are older or have a disease/lower baseline, and no clear benefit for overall cognitive or executive function ^{7,9Reference 7Prokopidis et al. · 2023Meta-analysisEffects of creatine supplementation on memory in healthy individuals — systematic review and meta-analysis of RCTsView study →Reference 9Xu et al. · 2024Meta-analysisThe effects of creatine supplementation on cognitive function in adults — systematic review and meta-analysisView study →}. All trials used monohydrate. A skeptical systematic review argues that because supplementation raises brain creatine only modestly, the mechanistic basis for a general cognitive boost is weak once baseline is adequate ^{12Reference 12McMorris et al. · 2024Systematic reviewCreatine supplementation research fails to support the theoretical basis for an effect on cognition — systematic reviewView study →} — so this reads as a real-but-small, largely repletion-dependent effect rather than a nootropic for the already well-nourished.

Gap: Effect is small, driven by lower-baseline groups (vegetarians, older adults), and absent for executive function in healthy young adults.

6. Cognition under sleep deprivation

A 2024 crossover RCT found that a single high dose (~0.35 g/kg, ~25 g) of creatine improved cognitive performance and shifted cerebral high-energy phosphates during ~21 hours of sleep deprivation — notable because normal doses take weeks to change brain creatine ^{8Reference 8Gordji-Nejad et al. · 2024RCTSingle dose creatine improves cognitive performance and induces changes in cerebral high energy phosphates during sleep deprivation — RCTView study →}. An earlier small trial also reported reduced decrements under sleep deprivation with exercise ^{8Reference 8Gordji-Nejad et al. · 2024RCTSingle dose creatine improves cognitive performance and induces changes in cerebral high energy phosphates during sleep deprivation — RCTView study →}. This is an acute, stress-state effect using doses far above the 3–5 g/day maintenance range.

Gap: Rests on a single high-dose crossover plus small earlier work; the effective acute dose is much larger than the standard maintenance dose and needs independent replication.

7. Depression (SSRI augmentation)

In a randomized, double-blind trial in women with major depressive disorder, adding creatine monohydrate (5 g/day) to an SSRI produced faster and greater improvement in depression scores than SSRI plus placebo, with no excess adverse events ^{10Reference 10Lyoo et al. · 2012RCTOral creatine monohydrate augmentation for enhanced response to an SSRI in women with major depressive disorder — randomized double-blind placebo-controlled trialView study →}. Small dose-finding and neuroimaging studies support a brain-bioenergetic mechanism ^{10Reference 10Lyoo et al. · 2012RCTOral creatine monohydrate augmentation for enhanced response to an SSRI in women with major depressive disorder — randomized double-blind placebo-controlled trialView study →}. The signal is promising but limited to small trials, largely in women.

Gap: Few, small trials concentrated in female patients; not established as a general antidepressant augmentation strategy pending larger replication.

Mechanisms

Target / pathway	Effect	Relevant to
Phosphocreatine → ATP (creatine kinase system)	Rapid ATP regeneration during short intense effort	Strength, power, high-intensity performance
Intracellular osmolyte / cell hydration	Draws water into muscle cells	Early lean-mass change, muscle cell volumization
Brain phosphocreatine / bioenergetic buffer	Supports neuronal energy under demand/stress	Cognition, sleep deprivation, depression
Satellite-cell / training-adaptation support	Enhances resistance-training adaptations	Hypertrophy, older-adult muscle

Pharmacokinetics

Oral creatine monohydrate is well absorbed; muscle stores rise over ~1 week whether by a loading phase (~20 g/day split into 4 doses for 5–7 days) or by a simple 3–5 g/day that reaches the same saturation more slowly (~3–4 weeks). Muscle uptake is transporter-mediated and saturable, so above ~3–5 g/day the excess is largely excreted — more is not better once stores are full. Co-ingestion with carbohydrate/insulin modestly aids uptake. Brain creatine changes far more slowly and less completely than muscle, which is why cognitive effects are small at standard doses and why the sleep-deprivation work used a single very large dose ^{8,11Reference 8Gordji-Nejad et al. · 2024RCTSingle dose creatine improves cognitive performance and induces changes in cerebral high energy phosphates during sleep deprivation — RCTView study →Reference 11Kreider et al. · 2017ReviewInternational Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation — reviewView study →}. The molecule is not “used up” like a drug with a classic half-life; unused creatine is converted to creatinine and cleared renally, raising measured serum creatinine without indicating kidney harm ^{16Reference 16Naeini et al. · 2025Meta-analysisEffect of creatine supplementation on kidney function — systematic review and meta-analysisView study →}.

Clinical trials

Creatine is off-patent and cheap, so most trials are academic or sports-science rather than industry drug-development; registered activity is substantial for performance and growing for clinical uses (cognition, depression, aging, neurological conditions).

Completed	Planned	Terminated	Preclinical
Many (100s across performance & clinical)	Ongoing (cognition, aging, neuro)	Few	Extensive

Last checked: July 2026.

Dietary Sources

Creatine is not an essential nutrient — the body synthesises about 1 g/day from glycine, arginine and methionine, mostly in the liver and kidneys. The rest of a typical omnivore’s ~1–2 g/day turnover comes from animal foods, since creatine is concentrated in the muscle tissue of animals. There is essentially no creatine in plant foods, which is why vegetarians and vegans run lower muscle and brain creatine stores and tend to show the largest responses to supplementation.

Food (cooked, ~100 g)	Approx. creatine
Herring	~0.6–1.0 g
Pork	~0.5 g
Beef	~0.4–0.5 g
Salmon / tuna	~0.4 g
Chicken	~0.3–0.4 g
Milk / dairy	trace
Plant foods (grains, legumes, vegetables)	~none

Cooking degrades some creatine to creatinine, so real-world food intake is modest — reaching a supplemental 3–5 g/day from meat alone would mean roughly 1 kg of it per day. Supplemental creatine monohydrate is therefore made industrially (from sarcosine and cyanamide), not extracted from food.

Dosage

Creatine has no RDA, AI or UL — it is not a vitamin or essential mineral, so official reference intakes don’t apply. The doses below are those studied in research, not a personal recommendation.

• Maintenance: 3–5 g/day of creatine monohydrate, taken any time of day, every day (including rest days). This reaches full muscle saturation in roughly 3–4 weeks.
• Optional loading: ~20 g/day split into 4 × 5 g doses for 5–7 days saturates stores faster (~1 week), after which 3–5 g/day maintains them. Loading is optional — it only speeds up the timeline and can increase transient GI upset and water-weight gain.
• Form: creatine monohydrate is the studied standard; “advanced” forms (hydrochloride, buffered/Kre-Alkalyn, magnesium chelate, ethyl ester, liquid) have not shown better outcomes and generally cost more.
• Uptake notes: muscle uptake is saturable — beyond ~3–5 g/day (once stores are full) the surplus is excreted, so higher daily doses don’t add benefit. Co-ingestion with carbohydrate or a mixed meal modestly aids uptake. The acute cognitive work under sleep deprivation used a one-off ~25 g dose, which is a research setting, not a maintenance recommendation.

Safety

Creatine monohydrate is among the most-studied supplements and is very well tolerated in healthy people at 3–5 g/day, with long-term trials (up to several years) showing no reliable harm. The most common effects are mild water retention / weight gain (from intracellular water) and occasional gastrointestinal upset, both more likely during high-dose loading and eased by splitting doses and staying well hydrated.

The most important practical caveat is a lab-test artefact: creatine is metabolised to creatinine, so supplementing raises measured serum creatinine, which can make estimated kidney function (eGFR) look worse without any actual decline in kidney health. A meta-analysis found only a small rise in serum creatinine and no significant change in glomerular filtration rate ^{16Reference 16Naeini et al. · 2025Meta-analysisEffect of creatine supplementation on kidney function — systematic review and meta-analysisView study →}. Tell your clinician you take creatine before kidney lab work.

Interactions: No well-established serious drug interactions in healthy people. Caution is warranted when combining creatine with other agents that stress the kidneys (e.g. high-dose NSAIDs, nephrotoxic drugs), and anyone with pre-existing kidney disease should consult a clinician before use. Combining with caffeine is common; some older data hinted caffeine might blunt creatine’s ergogenic effect, but this is not firmly established.

Pregnancy & lactation

Verdict: not established — discuss with a clinician. There is active research interest in creatine during pregnancy (for fetal energy metabolism), but supplemental creatine has not been adequately studied for safety in pregnancy or breastfeeding, so a specific safe dose cannot be given here. This is not evidence of harm — it is absence of data. Decisions in pregnancy or lactation should be made with an obstetric clinician.

References

1. Wang, Z., Qiu, B., Li, R., et al. (2024). Effects of Creatine Supplementation and Resistance Training on Muscle Strength Gains in Adults <50 Years of Age — systematic review and meta-analysis. Nutrients. https://pubmed.ncbi.nlm.nih.gov/39519498/
2. Burke, R., Piñero, A., Coleman, M., et al. (2023). Creatine Supplementation Combined with Resistance Training on Regional Measures of Muscle Hypertrophy — systematic review with meta-analysis. Nutrients. https://pubmed.ncbi.nlm.nih.gov/37432300/
3. Delpino, F. M., Figueiredo, L. M., Forbes, S. C., Candow, D. G., & Santos, H. O. (2022). Influence of age, sex, and type of exercise on the efficacy of creatine supplementation on lean body mass — systematic review and meta-analysis of RCTs. Nutrition. https://pubmed.ncbi.nlm.nih.gov/35986981/
4. Devries, M. C., & Phillips, S. M. (2014). Creatine supplementation during resistance training in older adults — meta-analysis. Medicine & Science in Sports & Exercise. https://pubmed.ncbi.nlm.nih.gov/24576864/
5. Forbes, S. C., Candow, D. G., Ostojic, S. M., et al. (2021). Importance of Creatine Ingestion Strategies on Lean Tissue Mass and Strength in Older Adults — meta-analysis. Nutrients. https://pubmed.ncbi.nlm.nih.gov/34199420/
6. Mielgo-Ayuso, J., et al. (2019). Effects of Creatine Supplementation on Athletic Performance in Soccer Players — systematic review and meta-analysis. Nutrients. https://pubmed.ncbi.nlm.nih.gov/30935142/
7. Prokopidis, K., Giannos, P., Triantafyllidis, K. K., et al. (2023). Effects of creatine supplementation on memory in healthy individuals — systematic review and meta-analysis of RCTs. Nutrition Reviews. https://pubmed.ncbi.nlm.nih.gov/35984306/
8. Gordji-Nejad, A., Matusch, A., Kleedörfer, S., et al. (2024). Single dose creatine improves cognitive performance and induces changes in cerebral high energy phosphates during sleep deprivation — RCT. Scientific Reports. https://pubmed.ncbi.nlm.nih.gov/38418482/
9. Xu, C., et al. (2024). The effects of creatine supplementation on cognitive function in adults — systematic review and meta-analysis. Frontiers in Nutrition. https://pubmed.ncbi.nlm.nih.gov/39070254/
10. Lyoo, I. K., Yoon, S., Kim, T. S., et al. (2012). Oral creatine monohydrate augmentation for enhanced response to an SSRI in women with major depressive disorder — randomized double-blind placebo-controlled trial. American Journal of Psychiatry. https://pubmed.ncbi.nlm.nih.gov/22864465/
11. Kreider, R. B., Kalman, D. S., Antonio, J., et al. (2017). International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation — review. Journal of the International Society of Sports Nutrition. https://pubmed.ncbi.nlm.nih.gov/28615996/
12. McMorris, T., Hale, B. J., Pine, B. S., & Williams, T. B. (2024). Creatine supplementation research fails to support the theoretical basis for an effect on cognition — systematic review. Behavioural Brain Research. https://pubmed.ncbi.nlm.nih.gov/38582412/
13. Chilibeck, P. D., Candow, D. G., Gordon, J. J., et al. (2023). A 2-yr Randomized Controlled Trial on Creatine Supplementation during Exercise for Postmenopausal Bone Health. Medicine & Science in Sports & Exercise. https://pubmed.ncbi.nlm.nih.gov/37144634/
14. Sandkühler, J. F., Kersting, X., Faust, A., et al. (2023). The effects of creatine supplementation on cognitive performance — randomised controlled study. BMC Medicine. https://pubmed.ncbi.nlm.nih.gov/37968687/
15. Antonio, J., Candow, D. G., Forbes, S. C., et al. (2021). Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show? — review. Journal of the International Society of Sports Nutrition. https://pubmed.ncbi.nlm.nih.gov/33557850/
16. Naeini, E. K., Eskandari, M., Mortazavi, M., et al. (2025). Effect of creatine supplementation on kidney function — systematic review and meta-analysis. BMC Nephrology. https://pubmed.ncbi.nlm.nih.gov/41199218/