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Creatine monohydrate: the complete evidence-based monograph 2026

The most studied dietary supplement in the world — more than 500 controlled trials — reaches far beyond the athletic sphere: brain, mental health, aging, menopause. A complete overview.

Introduction: far more than a bodybuilder’s supplement

For decades, creatine sat on gym shelves with a reductive label: a muscle booster for athletes chasing mass. That image persists in the collective imagination even though the scientific reality has changed profoundly. Today, with more than 500 published randomized clinical trials, creatine monohydrate is the most studied dietary supplement in the world — and its range of applications extends well beyond muscle fibers.

Neurology is investigating it for treatment-resistant depression, traumatic brain injury, and long COVID. Gerontology includes it in strategies against sarcopenia. Gender medicine is discovering that women, particularly in perimenopause, are among the greatest beneficiaries of targeted supplementation. And nutritional medicine recognizes that vegetarians and vegans live with a structural creatine deficit that endogenous biosynthesis alone cannot compensate for.

Within the framework of biohacking and cellular nutrition — the pillars of NutriCellScience — creatine is a textbook case: an endogenous compound, naturally present in meat-based diets, whose supplementation directly targets cellular bioenergetics. The phosphocreatine/ATP system is universal: it governs the functioning of skeletal muscle, the myocardium, the brain, and immune cells. Supporting its stores therefore means intervening at the cellular level on the capacity to produce energy rapidly.

This monograph brings together the evidence available in 2026, drawing on the most recent body of literature, to offer a reading on two levels: for the informed general public and for health professionals. Areas of certainty, paradoxes, and early signals are all treated with the same rigor.

Identity and biochemistry: what is creatine?

Creatine (methylated 2-guanidinoacetic acid) is a nitrogen-containing compound synthesized naturally by the body at a rate of about 1 g per day. Its endogenous biosynthesis follows two successive enzymatic steps. First, in the kidney, the enzyme AGAT (L-arginine:glycine amidinotransferase) catalyzes the transfer of an amidino group from arginine to glycine, producing guanidinoacetate (GAA). Then, in the liver, the enzyme GAMT (guanidinoacetate N-methyltransferase) methylates GAA using the methyl donor S-adenosylmethionine (SAM) to form creatine. This last process is one of the largest consumers of methyl groups in the body, directly linking creatine metabolism to the methylation cycle and folate homeostasis.

Once synthesized, creatine travels in the blood and enters cells via a specialized transporter, CreaT1/SLC6A8, a Na⁺/Cl⁻ co-transporter whose kinetics and regulation have been precisely characterized (El-Kasaby et al., 2022). This transporter is present in skeletal muscle, the heart, the brain, the kidneys, and other tissues with high energy demand.

Total body storage is around 120–140 mmol/kg of dry muscle, of which about 60% is in the form of phosphocreatine (PCr) and 40% in free form. Skeletal muscle holds ~95% of body stores. The brain, although it represents only 2% of body weight, expresses all three enzymes of the creatine pathway (AGAT, GAMT, SLC6A8) and maintains its own PCr stores — essential for the rapid restoration of ATP under cognitive or hypoxic stress.

One nutritional argument deserves emphasis: Ostojić and Forbes (2021) proposed that creatine should be regarded as a conditionally essential nutrient (10.1093/advances/nmab111), in the same way as taurine or carnitine, particularly when the diet does not supply it (plant-based diets) or when physiological demand exceeds the capacity for endogenous synthesis (aging, stress, intense exercise). A complete mapping of biosynthesis, transporters, and regulators was published by Kerksick et al. (2021) in a landmark review (10.3390/nu13041238).

Physical performance: what the evidence really shows

Creatine acts on physical performance through a direct mechanism: by raising muscle phosphocreatine stores by 15 to 40%, it speeds up ATP resynthesis during short, intense efforts (under 30 seconds). The result is measurable from the very first week of supplementation during the loading phase.

The meta-analysis by Wang et al. (2024), covering 23 randomized controlled trials and 509 participants, is one of the most recent on the topic. It concludes that upper-body strength increased significantly by +4.43 kg (WMD) and lower-body strength by +11.35 kg versus placebo, when combined with resistance training (10.3390/nu16213665). The effect is larger in men but remains significant in women.

On the muscle hypertrophy front, Forbes et al. (2023) conducted a meta-analysis using direct imaging (muscle thickness measurement) and show a significant regional hypertrophic gain with the creatine + resistance training combination, modulated by intervention duration and dose (10.3390/nu15092116). The meta-analysis by Ashtary-Larky et al. (2024), which includes a dose-response analysis using the GRADE method, confirms an increase in lean mass and a slight reduction in body fat percentage (-0.28%) (10.1080/15502783.2024.2380058).

For explosive performance and repeated sprints, the network meta-analysis by Deng et al. (2025) is particularly informative: covering 35 RCTs and 991 athletes, it ranks creatine as the best available intervention for sprint speed (SUCRA 94.6%) and jump performance (SUCRA 76%), ahead of caffeine, beta-alanine, and HMB in this comparative analysis (10.3389/fnut.2025.1636970).

“Creatine monohydrate supplementation significantly increased upper-body (WMD = 4.43 kg) and lower-body strength (WMD = 11.35 kg) compared with placebo.” — Wang Z et al., Nutrients 2024 — 10.3390/nu16213665

One essential point about alternative forms: creatine ethyl ester and buffered creatine (Kre-Alkalyn) have both been the subject of rigorous comparative trials. Spillane et al. (2009) showed that the ethyl ester is inferior to monohydrate for serum and muscle levels as well as for strength and mass (10.1186/1550-2783-6-6). Jagim et al. (2012) found no superiority of Kre-Alkalyn over monohydrate (10.1186/1550-2783-9-43). The monohydrate form remains the only one with robust evidence, as confirmed by the review by Purpura, Jäger, and Kreider (2022) (10.3390/nu14051035).

Creatine and the brain: cognition, the new frontier

The brain uses about 20% of the body’s energy at rest despite its low weight. It synthesizes its own creatine via AGAT, GAMT, and SLC6A8, and maintains a local phosphocreatine pool that is essential for the rapid recovery of ATP under cognitive load or during metabolic stress (hypoxia, sleep deprivation, aging).

The meta-analysis by Xu et al. (2024), which analyzed 16 RCTs and 492 participants using the PRISMA method, is the most comprehensive to date. It shows a significant positive effect on memory (SMD = 0.31), a reduction in attention time, and an improvement in processing speed. The effect on global executive function has not been robustly demonstrated (10.3389/fnut.2024.1424972).

An important paradox shapes this field of research. Standard doses of 5 g/day, effective on muscle, appear to be insufficient to measurably raise brain PCr in healthy adults at rest — skeletal muscle, because of its mass, takes up the majority of exogenous creatine. High doses, on the other hand, show documented effects. The study by Gordji-Nejad et al. (2024), a crossover RCT in 15 subjects with direct measurement by ³¹P-MRS spectroscopy, is particularly compelling: a single dose of 0.35 g/kg of creatine produces a measurable increase in brain PCr and ATP, and improves working memory as well as processing speed after 21 hours of sleep deprivation (10.1038/s41598-024-54249-9).

“Single dose creatine improves cognitive performance and induces changes in cerebral high energy phosphates during sleep deprivation.” — Gordji-Nejad A et al., Scientific Reports 2024 — 10.1038/s41598-024-54249-9

EFSA’s 2024 position tempers this promise: after reviewing all the available data, the NDA panel rejected the health claim that “creatine improves cognition,” judging that the cause-and-effect relationship is not sufficiently established at doses below 20 g/day (10.2903/j.efsa.2024.9100). The review by Forbes and Candow (2023) offers a synthetic framework: the cognitive benefits are most robust under metabolic stress, in vegetarians, and in people over 55, populations whose baseline intake is the lowest (10.1007/s40279-023-01870-9).

Mental health, depression, long COVID, and neuroprotection

The creatine/phosphocreatine system modulates brain bioenergetics and interacts with monoaminergic transmission. Disturbances of this system have been documented in major depression using ³¹P-MRS and ¹H-MRS spectroscopy. Creatine therefore offers a rational mechanism of action as an adjunct to antidepressants.

The clinical trial by Lyoo et al. (2012), a double-blind RCT in 52 women, is the most cited in this field: creatine supplementation (5 g/day) added to escitalopram produced a faster improvement in HAM-D score from the second week of treatment onward, and a more pronounced remission at 8 weeks versus placebo + escitalopram (10.1176/appi.ajp.2012.12010009).

The review by Kious, Kondo, and Renshaw (2019) summarizes the plausible biochemical mechanisms: normalization of intracellular pH, restoration of the PCr/ATP balance in prefrontal regions, and modulation of serotonin and dopamine metabolism (10.3390/biom9090406). One warning signal is worth noting: Toniolo et al. (2017) report two cases of a switch to hypomania in a pilot trial in bipolar depression, suggesting caution in this specific population (10.1007/s00702-017-1817-5).

In the field of long COVID, two small pilot RCTs by Ostojić et al. (2023) provide encouraging preliminary data. The first (n=12, 4 g/day × 6 months) shows an increase in tissue creatine stores in the vastus medialis and an improvement in subjective fatigue (10.1002/fsn3.3597). The second, combining creatine and breathing exercises, reports a reduction in dyspnea and a lengthening of time to exhaustion of +54 seconds (10.4103/jpgm.jpgm_650_23). The proposed mechanism is a post-viral mitochondrial energy deficit that creatine may help to partially correct.

Regarding mild traumatic brain injury (mTBI), the review by Dean et al. (2017) documents neuroprotective potential: reduced neuronal damage and improvement of cognitive and somatic symptoms in the early phases (10.2217/cnc-2016-0016). The synthesis by Forbes et al. (2022) positions creatine as a potential tool across a broad spectrum of brain conditions — TBI, concussion in children, depression, anxiety, sleep deprivation — with a level of evidence that varies by indication (10.3390/nu14050921).

Sarcopenia and healthy aging

Sarcopenia — the progressive age-related loss of muscle mass and strength — affects between 10 and 27% of people over 60. It is associated with an increased risk of falls, fracture, loss of independence, and mortality. Creatine on its own produces few measurable effects on muscle mass in older adults; combined with resistance training (RT), however, it is one of the best-supported strategies available.

The meta-analysis by Chilibeck et al. (2017), covering 22 RCTs and 721 participants, quantifies the benefit: creatine + RT versus RT alone = +1.37 kg of lean mass, +0.35 effect size for chest strength, and +0.24 for lower-limb strength (10.2147/OAJSM.S123529). The more recent meta-analysis by Liu et al. (2025), restricted to 8 RCTs and 482 participants, confirms the benefits for lower-limb strength (SMD 0.29) and lean mass (SMD 0.27), with a clearer advantage for interventions shorter than 32 weeks (10.1186/s11556-025-00392-9).

The biological mechanisms involved go beyond simple muscle bioenergetics. The review by Candow et al. (2019) highlights the modulation of IGF-1, the reduction of myostatin (an inhibitor of muscle growth), and the activation of muscle satellite cells as complementary pathways of action (10.3390/jcm8040488). These data support preventive use starting in your fifties, well before sarcopenia is clearly established.

The review by Gualano et al. (2019) points to a fundamental limitation: creatine alone, without associated physical activity, is not enough. It is the combination of creatine + exercise that constitutes the effective strategy against age-related muscle atrophy (10.3390/biom9110642). This point is crucial for educating sedentary older patients.

Women: why they should take more of it

The question of sex differences in creatine supplementation was under-studied for a long time. The first large meta-analyses pooled men and women without distinguishing the effects. That situation has changed radically since 2021, and the data converge on a surprising observation: women, paradoxically less represented in the studies, appear to be among the populations that benefit most from targeted supplementation.

The biological starting point must be stated with caution. The original source by Brosnan & Brosnan reports female synthesis rates corresponding to roughly 70–80% of those in men — that is, a difference of 20–30%, and not stores that are 70–80% lower. The same literature sometimes describes slightly higher resting intramuscular concentrations in women. Responses can vary with diet, muscle mass, age, and hormonal context. Brosnan & Brosnan, 2007.

“Women have been insufficiently represented in creatine trials; life-stage indications must be distinguished from differences in baseline stores.” — Editorial rewording after verification of the primary source, July 31, 2026

Menopause is a central issue. The drop in estrogen accentuates the loss of muscle mass and the impairment of bioenergetics. The ISSN position stand on female athletes (Sims et al., 2023) recommends 3–5 g/day in active women, and up to 0.3 g/kg/day after menopause to optimize the effects on bone and muscle (10.1080/15502783.2023.2204066). The comprehensive review by Smith-Ryan et al. (2025) explores applications across the female life cycle — menstrual cycle, pregnancy, postpartum, menopause — with practical recommendations for each stage (10.1080/15502783.2025.2502094).

On the menstrual cycle, Cabre et al. (2023) ran a crossover RCT in 39 active women and show that creatine improves recovery (HRV) and repeated-sprint performance, with an effect that varies by hormonal phase (10.3390/nu15163567). An observational study of 4,522 women (NHANES) additionally associated a dietary creatine intake ≥ 13 mg/kg/day with a reduced risk of oligomenorrhea and pelvic disorders (Ostojić et al., 2024).

The meta-analysis on safety in women by de Guingand et al. (2020) confirms that creatine supplementation carries no identified risk beyond placebo — neither for kidney function, nor liver function, nor hormonal markers (10.3390/nu12061780).

Vegetarians, vegans, and the low-cellular-creatine profile

Creatine is absent from the plant kingdom. Vegetarians and vegans derive all of their creatine from endogenous biosynthesis, which remains limited to about 1 g/day in a healthy adult and which places a substantial methyl burden on the body — creatine synthesis via GAMT is one of the main consumers of SAM in the liver, competing with the other methylation reactions (DNA methylation, phosphatidylcholine synthesis, etc.).

The measurable consequence: vegetarians have muscle creatine stores 10 to 20% lower than those of omnivores. And it is precisely for this reason that their response to supplementation is often greater. The systematic review by Shaw, Kaviani, and Chilibeck (2020), covering 7 RCTs, shows that creatine supplementation in vegetarians can raise their muscle PCr stores to levels above those of unsupplemented omnivores (10.3390/ijerph17093041).

The study by Benton and Donohoe (2010), a crossover RCT comparing vegetarians and omnivores, shows a more pronounced improvement in memory and intelligence in vegetarians after supplementation (10.1017/S0007114510004733). This finding is consistent with the pioneering RCT of Rae et al. (2003), conducted exclusively in vegetarians, which had documented improvements in working memory and in Raven’s Matrices score after 6 weeks at 5 g/day (10.1098/rspb.2003.2492).

The review by Balestrino and Adriano (2019) clearly frames the issue for people following a plant-based diet: 100% of body creatine must be synthesized endogenously, which mobilizes methyl resources that could then be lacking in other critical biological pathways (10.1002/med.21590). The recommendation of routine supplementation in vegan athletes and knowledge workers is therefore solidly supported.

To go further into the links between methylation, the microbiome, and plant-based nutrition, see our feature on methylation and the microbiome.

Safety: separating the real risks from the myths

After more than 30 years of intensive research and more than 500 controlled trials, the safety profile of creatine monohydrate at doses of 3–5 g/day is one of the best documented in sports nutrition. The ISSN position stand (Kreider et al., 2017) establishes that supplementation up to 30 g/day for 5 years is safe and well tolerated in healthy adults (10.1186/s12970-017-0173-z). In 2025, the analysis by Kreider et al. of 28.4 million adverse event reports (AERs) reveals no difference in the prevalence of side effects between creatine and placebo (10.1080/15502783.2025.2488937).

Myth	Scientific reality	Key reference
Creatine destroys the kidneys	The rise in serum creatinine (a by-product of metabolism) is not a marker of kidney failure. No kidney damage has been demonstrated in healthy subjects in controlled RCTs. The Mendelian randomization meta-analysis by Zhou et al. (2024) finds no causal association between creatine levels and 6 indicators of kidney function.	Gualano 2023; Zhou 2024
Creatine makes your hair fall out (DHT)	Based on a single 2009 study (n=20 rugby players, van der Merwe) that has never been replicated. The RCT by Gerafiani et al. (2025), 45 men, 12 weeks at 5 g/day, finds no change in DHT, DHEA, testosterone, or follicular health.	Gerafiani 2025
Creatine makes you fat (body fat)	The initial weight gain of 0.5–2 kg is due to intracellular water retention (water inside the muscle cells), not to fat accumulation. The meta-analysis by Ashtary-Larky (2024) shows, on the contrary, a slight reduction in body fat percentage.	Ashtary-Larky 2024
You have to take breaks (cycling)	No data justify periodic interruption. Continuous supplementation at 3–5 g/day is the validated strategy. The downregulation of the SLC6A8 transporter under saturation is reversible and has no clinical consequence.	Kreider 2017
Creatine is an anabolic steroid	Creatine is neither a hormone nor a hormone precursor. It acts on bioenergetics, not on androgen signaling. It does not appear on any list of banned substances (WADA, USADA).	Purpura 2022
Creatine causes cramps	The data are contradictory; the large randomized studies conducted in the heat show no increase in cramps. The Smith-Ryan (2021) review explicitly refutes this myth.	Smith-Ryan 2021

How to take it: protocols, doses, timing

Two dosing strategies coexist, both validated:

Protocol with a loading phase

20 g/day split into 4 doses of 5 g with meals, for 5 to 7 days, then a switch to a maintenance dose of 3–5 g/day. This approach saturates muscle stores within a week and is useful when a rapid effect is desired (an imminent competition, a short clinical intervention).

Protocol without a loading phase

3–5 g/day from the outset, with no loading. Muscle saturation is reached in 3 to 4 weeks. The final effect is identical; only the delay differs. This approach is better tolerated digestively and is often preferred for long-term daily use.

Goal	Recommended dose	Duration	Notes
Physical performance (maintenance)	3–5 g/day (or 0.1 g/kg/day)	Ongoing	With or without an initial loading phase
Initial loading	20 g/day (4 × 5 g)	5–7 days	Then back to 3–5 g/day
Postmenopause / sarcopenia	0.3 g/kg/day	≥ 12 weeks + RT	ISSN 2023
Cognition under stress (emerging signal)	10–20 g/day or 0.35 g/kg (single dose)	Variable	Preliminary data; monitor digestive tolerance
Long COVID / depression adjunct	4–6 g/day	6–12 weeks	Pilot RCTs; outside regulatory indications

On timing, the data are inconclusive. A slight trend in favor of post-exercise intake has been observed in some studies, without being robustly replicated (Jagim et al., 2019 — 10.1186/s12970-019-0304-9). In practice, the time of day matters little; daily consistency is the decisive factor.

Co-ingestion with carbohydrates or protein slightly promotes muscle uptake via insulin (a mechanism established since Harris et al., 1992). This effect is marginal for long-term saturation but can speed up filling during the loading phase. Micronization of creatine monohydrate improves solubility and palatability without changing efficacy or bioavailability.

Adequate hydration (2–3 liters of water/day) is recommended, not to protect the kidneys — the risk is nonexistent in healthy subjects — but because creatine increases intracellular water retention, and that water must be available.

Choosing a quality creatine

The global creatine market is dominated by two production sources. On one side, Creapure®, manufactured by Alzchem AG in Trostberg (Germany), shows a purity of ≥ 99.95% and is produced under FSSC 22000 and IFS Food certified conditions, with a listing on the Cologne List — the reference database in Europe for athletes subject to anti-doping testing. On the other, generic creatines produced mainly in Asia, whose quality is highly variable and which may contain impurities such as dicyandiamide or dihydrotriazine.

Source	Purity	Certifications	Doping risk
Creapure® (Alzchem, Germany)	≥ 99.95%	FSSC 22000, IFS Food, Cologne List, Kosher/Halal	Very low
Generic creatines (varied)	Variable	Often uncertified	Variable, potentially high

For health professionals and competitive athletes, three third-party certifications help secure the choice: Informed Sport (batch-by-batch testing for banned substances), NSF Certified for Sport (United States), and the Cologne List (Europe). The European standard EN 17444:2021 (formerly NF V 94-001 in France) guarantees the absence of doping substances in sports dietary supplements — a quality marker to look for on the label.

Smart synergies

Creatine is frequently combined with other supplements. Here is the state of the evidence for the most common combinations:

Creatine + protein

Combining resistance training + protein + creatine produces greater increases in lean mass and strength than any of the components alone. Creatine improves the post-exercise anabolic signal; protein provides the nitrogen substrates. This is the best-documented synergy (Kirk et al., 2021 — 10.3390/nu13030745).

Creatine + beta-alanine

Mechanistic complementarity: creatine raises the PCr available for ATP resynthesis; beta-alanine increases muscle carnosine levels, which buffer the H⁺ ions responsible for fatigue during prolonged high-intensity efforts. The meta-analysis by Deng et al. (2025) ranks the creatine + beta-alanine combination as particularly favorable for efforts combining speed and endurance (10.3389/fnut.2025.1636970).

Creatine + HMB (beta-hydroxy-beta-methylbutyrate)

In older adults and in a context of muscle preservation, combining creatine + HMB (3 g/day) for 10 weeks in rowers shows a synergistic effect on the testosterone/cortisol ratio, greater than either supplement taken separately — which argues for a potentiation of anabolism and recovery (10.3390/nu11102528).

Creatine + caffeine: the persistent controversy

A 1996 RCT had suggested that caffeine antagonized creatine’s ergogenic effect on sprinting. This result has not been consistently replicated in the recent literature. Current data on cycling and sprints show mixed results. The combination is still used without any serious warning signal, but certainty about a synergy is not established (2024 review — 10.3390/nu16111768). In practice: taking both supplements is not contraindicated, but it does not guarantee an additive effect.

Creatine and diet: what your plate already provides

Dietary creatine is found exclusively in animal flesh. The main sources are red meat (beef, lamb: 3–5 g/kg of raw meat), fish (herring, salmon, tuna: 2–4 g/kg), and pork or poultry (3–4 g/kg). Cooking degrades part of the creatine into creatinine (an inactive form), reducing the effective intake by 20 to 30%. A standard omnivorous diet provides about 1 g/day of creatine, roughly covering daily endogenous production but not increasing muscle stores.

Food	Creatine content (g/kg raw)	Precursors provided
Red meat (beef, lamb)	3–5	Preformed creatine + arginine + glycine + methionine
Fish (herring, salmon, tuna)	2–4	Preformed creatine + arginine + glycine
Pork, chicken	3–4	Preformed creatine
Milk	~0.1	Low
Plant foods	0	Arginine, glycine, methionine (precursors only)
Egg	~0	Methionine (GAMT), glycine, arginine, choline

The egg holds a special place in this table. It contains no preformed creatine but provides the three amino acid precursors (methionine, glycine, arginine) needed for the two enzymatic steps of biosynthesis, as well as choline, which supports the methylation cycle and can spare the SAM used by GAMT. A recent study on NHANES-III data shows that dietary intakes of precursors (glycine, arginine, methionine) are generally insufficient in the general population for optimal endogenous biosynthesis (Nedeljkovic & Ostojić, 2025 — 10.1007/s00726-025-03460-7).

Regulatory status: EFSA, ANSES, ISSN, FDA

Authority	Status	Claim(s)	Notes
EFSA (EU)	Authorized (Regulation 432/2012)	1 confirmed claim (2017): improvement in physical performance during successive bouts of short-term, high-intensity exercise (≥ 3 g/day, subjects > 55 years with resistance training at least 3×/week)	Cognitive claim rejected in December 2024 (EFSA 2024)
FDA (USA)	GRAS (Generally Recognized As Safe)	Dietary Supplement (DSHEA) — no specific approved health claim	Monohydrate compliant as a “new dietary ingredient”
DGCCRF / France	Authorized dietary supplement	EFSA claim applicable	EN 17444:2021 standard for the absence of doping substances
ANSES (the French food and health safety agency)	2016 precautionary opinion	—	Not advised for: children/adolescents, pregnant/breastfeeding women, cardiovascular/kidney/liver conditions; reported cases linked to adulteration, not to pure Cr
ISSN	Strong recommendation	3–5 g/day safe and effective across the lifespan	Kreider 2017; update 2025

One important regulatory point to keep in mind: EFSA’s rejection (2024) of the cognitive claim does not mean that creatine has no effect on the brain. EFSA considers that the available evidence does not meet its criteria for causality at doses below 20 g/day. This illustrates the difference between an emerging scientific signal and a regulatory-validated claim — a fundamental distinction for health professionals.

To learn more about dietary supplements and their regulatory framework, see our NutriCellScience supplement encyclopedia.

Early signals to watch in 2026

The science of creatine is far from settled. Several emerging research fronts deserve close monitoring, without jumping to premature conclusions:

High brain doses (10–20 g/day)

The signal reported by Gordji-Nejad (2024) using ³¹P-MRS brain spectroscopy is the first to document a measurable rise in brain PCr in humans after a single high dose. Chronic protocols at 10–20 g/day are under study, notably for cognitive resilience under stress. Digestive tolerance at these doses is the main practical limitation.

Treatment-resistant depression

A phase 2 trial at the University of Utah (Renshaw/Kondo team) is exploring creatine in SSRI-resistant depression. Brain spectroscopy markers (membrane phospholipids, intracellular pH) could identify responders. A positive result would significantly change the therapeutic landscape of nutritional psychiatry.

Long COVID

The two pilot RCTs by Ostojić (2023) on long COVID are encouraging but limited by their size (n=12). Larger studies are needed. The mechanism — post-viral mitochondrial dysfunction corrected by an increase in the PCr pool — is biologically plausible and is receiving growing attention. Follow our updates at nutricellscience.blog/biohacking/.

Pregnancy and fetal development

Robust preclinical data (Muccini et al., 2021) suggest that creatine protects the fetus against perinatal hypoxia via the PCr/CK system. A 2026 preprint (Sah et al., bioRxiv — DOI: 10.64898/2026.05.04.722786) shows that the PCr/CK system is essential to early trophoblast proliferation. There are no human RCTs on supplementation during pregnancy — a major gap. In the absence of data, caution is warranted, in line with the ANSES opinion.

Adolescent athletes

The review by Smith-Ryan (2024) finds no warning signal in the existing studies in healthy adolescents. The ISSN (2017) considers creatine acceptable under medical supervision. ANSES and EFSA maintain a precautionary recommendation against use, for lack of long-term data specific to this population.

Alzheimer’s disease and neurodegeneration

An RCT exploring 20 g/day in Alzheimer’s disease is under way. Current data (Forbes/Candow 2023) suggest that the most relevant target is prevention and early stages, rather than advanced neurodegenerative disease.

FAQ — Frequently asked questions about creatine

Does creatine cause hair loss?

No. This fear rests on a single 2009 study (van der Merwe et al., n=20) that observed a rise in DHT (dihydrotestosterone) in young rugby players. That study has never been replicated. The RCT by Gerafiani et al. (2025), covering 45 men supplemented with 5 g/day for 12 weeks, found no change in DHT, DHEA, or testosterone levels, and no alteration of follicular health (10.1080/15502783.2025.2495229). This myth can be considered definitively disproven.

Do you need a loading phase?

It is not necessary. The loading phase (20 g/day × 5–7 days) saturates muscle stores faster (in ~7 days vs. 3–4 weeks without loading), but the final effect is identical. It can cause digestive discomfort (bloating, diarrhea) in some people. If you are not in a hurry for results, 3–5 g/day from the start is the most comfortable approach and just as effective in the long run.

Is creatine bad for your kidneys?

No, in people with healthy kidneys. The rise in serum creatinine seen with supplementation is a by-product of creatine metabolism, not a marker of kidney failure — a common confusion even among health professionals. The “Requiem” review by Gualano et al. (2023) synthesizes all controlled RCTs and finds no kidney damage (10.3390/nu15061466). The Mendelian randomization meta-analysis by Zhou et al. (2024) rules out any causal link between creatine levels and 6 indicators of kidney function (10.1080/0886022X.2024.2364762). If you have pre-existing kidney disease, medical advice is still warranted.

Can women take creatine?

Yes, and they have particularly strong reasons to do so. Women have muscle creatine stores 70–80% lower than men and benefit more from supplementation, especially after menopause. The ISSN recommends 3–5 g/day in active women and up to 0.3 g/kg/day after menopause. The meta-analysis by de Guingand et al. (2020) confirms the absence of serious adverse risk in women (10.3390/nu12061780).

Creatine and coffee: is there an antagonism?

The controversy goes back to a 1996 RCT suggesting that caffeine canceled out creatine’s benefit on sprinting. That result has not been consistently confirmed in later studies. Current data are mixed. In practice, taking creatine and caffeine together is not contraindicated, but there is no guarantee that the effects add up. Separating the doses (creatine in the morning, caffeine before exercise) is a reasonable precaution if you are looking to optimize.

What dose is needed for effects on the brain?

This is one of the most active topics in current research. At 5 g/day, the brain effect is modest in healthy adults at rest — muscles take up most of the creatine. Doses of 10–20 g/day chronically, or a single dose of 0.35 g/kg, are needed to raise brain PCr measurably by spectroscopy (Gordji-Nejad 2024). EFSA (2024) rejected the cognitive claim at usual doses, while acknowledging possible effects at high doses under conditions of metabolic stress. These high doses can cause digestive discomfort and should be introduced gradually.

Creatine and pregnancy: is it safe?

Human data are insufficient to support a positive recommendation. Robust preclinical data suggest potential fetal protection against perinatal hypoxia. In the absence of human RCTs on supplementation during pregnancy, ANSES (the French food and health safety agency) advises against supplementation in pregnant women as a precaution. Personalized medical advice is essential before any supplementation during pregnancy.

How long does it take to see effects?

With a loading phase (20 g/day × 5–7 days): muscle stores are saturated within a week, and a strength gain during the first intense training sessions may be felt as early as 7–10 days. Without a loading phase (3–5 g/day): gradual saturation over 3–4 weeks, with effects generally noticeable in training after 3–6 weeks. The initial weight gain (0.5–2 kg of intracellular water) occurs within a few days.

Do you need to take breaks (cycle creatine)?

No. There is no scientific justification for cycling creatine. The downregulation of the SLC6A8 transporter under prolonged saturation is a natural and reversible phenomenon, with no demonstrated clinical consequence. The ISSN position stand and 30 years of safety data support continuous supplementation at 3–5 g/day with no scheduled breaks.

Is creatine recommended for teenagers?

Positions differ. The ISSN (2017) considers creatine acceptable in healthy adolescents, under medical supervision, if the diet is balanced and the goal is related to athletic performance. ANSES and EFSA advise against supplementation in people under 18 and in pregnant women, as a precaution and for lack of long-term data in these populations. In practice, the absolute priority remains optimizing diet, sleep, and training before considering any supplement in an adolescent.

To explore the topics covered in this article further:

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• Methylation, microbiome, and nutrition — the link between the methylation cycle (GAMT, SAM) and endogenous creatine
• All our biohacking articles — the full category

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