Supplement evidence
Creatine
The depression syntheses, and why a raised creatinine reading is not kidney damage.
What Its Legal Status Actually Means
Read this before anything below it. Legal to sell is not the same fact as reviewed, verified, or approved.
Creatine monohydrate is sold in the US as a dietary supplement under DSHEA, marketed overwhelmingly for exercise performance and muscle mass. It has no FDA approval for depression or any other psychiatric or medical condition, no FDA review of safety or effectiveness precedes it going on sale, and there is no prescription creatine product. Creatine is one of the better-characterised supplement ingredients — it is a single well-defined molecule, third-party purity testing is common, and the sports-nutrition safety literature is unusually large — but purity and long-term physical safety are entirely separate questions from whether it treats depression, and nothing about its regulatory status implies psychiatric benefit.
Quoted whole from the 2026-08-18 study harvest. Not summarized, not shortened.
What the Research Shows
5 records from the 2026-08-18 harvest, each checked against PubMed and Europe PMC on that date. How a study was designed, how many people were in it, and who paid for it are printed above what it found, because those three facts decide how much the finding is worth.
Study 1 · 2012
- Randomized trial
- 52 participants
- Top-tier journal
- Independently funded
- Preregistered
- Declared conflicts of interest
strong77/100Well-supported by good-quality research.
Read this first: The disclosure statement records that the senior author, Dr Renshaw, "is also an inventor on related patent applications assigned to McLean Hospital and the University of Utah" — an intellectual-property interest in the intervention being tested, which is why independence is marked false here even though the funding is public. The trial was women-only, single-country, and n=52; a later trial in female adolescents found no difference from placebo.
52 South Korean women with major depression all received escitalopram and were randomised to add creatine 5 g/day (n=25) or placebo (n=27) for eight weeks. The creatine group improved significantly more on the Hamilton Depression Rating Scale from week 2 onward, with the advantage maintained at weeks 4 and 8; dropout (32.0% versus 18.5%) and total adverse events (36 versus 45) did not differ. This is the trial the whole creatine-for-depression case is built on, and it enrolled 52 women at one site and has never been directly replicated.
How this record was checked
PubMed record 22864465 fetched via NCBI efetch 2026-08-18; title, all eight authors, journal (Am J Psychiatry 2012;169(9):937-945), year, DOI, N=52 (25 creatine, 27 placebo), the 5 g/day dose, and the 8-week design confirmed from the abstract. PMC full text PMC4624319 read 2026-08-18: funded by a NARSAD independent investigator award, Korean government programmes (2011K000273, KRF-2008-220-E00021), the VA MIRECC, and NIH grants DA-015116, DA-031247, DA-024070 and MH-058681, with "The sponsors of the study had no role" — hence INDEPENDENT; the same page carries the author disclosure quoted above (hence conflicts true, independent false) and a ClinicalTrials.gov registration (hence preregistered true).
Study 2 · 2025
- Randomized trial
- 100 participants
- Reputable journal
- Independently funded
- Declared conflicts of interest
strong80/100Well-supported by good-quality research.
Read this first: A 5-point PHQ-9 difference is large for a supplement, which is itself a reason for caution in a 100-person pilot that was explicitly powered for feasibility rather than efficacy and was conducted at a single site in a setting where access to other care is limited. No trial registration appears in the PubMed record, so the primary outcome cannot be checked against a pre-specified protocol. It has not been replicated.
100 adults with depression in an under-resourced region of India (mean age 30.4, mean baseline PHQ-9 17.6, half women) were randomised to creatine plus cognitive behavioural therapy or placebo plus CBT for eight weeks. Both arms improved; the creatine arm improved more, by a mean difference of 5.12 points on the PHQ-9. Dropouts and adverse events were comparable between arms. The authors describe it as a pilot, feasibility and hypothesis-generating trial and call for longer and larger studies — their own published follow-up correspondence is titled "Preliminary evidence should be treated as such."
How this record was checked
PubMed record 39488067 fetched via NCBI efetch 2026-08-18; title, all six authors, journal (Eur Neuropsychopharmacol 2025;90:28-35), year, DOI, N=100 (50 per arm), mean age 30.4, mean baseline PHQ-9 17.6, and the -5.12 mean difference confirmed from the abstract, which also carries "The authors declare none" (hence conflicts true). Europe PMC core record fetched 2026-08-18 lists a single funder, the Universal Human Rights and Social Development Association (UHRSDA), a non-commercial NGO and not a creatine manufacturer, hence funding INDEPENDENT. No registration identifier appears in the record, so preregistered is false.
Study 3 · 2025
- Meta-analysis of randomized trials
- 1,093 participants
- Reputable journal
- Funding not established
strong73/100Well-supported by good-quality research.
Read this first: The remission odds ratio of 3.6 looks dramatic but rests on three trials and is contradicted by the response outcome from two trials pointing the other way — a pattern that usually means too few events, not a real dissociation. The reviewers' own bias analyses point the same direction. No funding or competing-interests statement could be read (the Cambridge Core page returned only the abstract), so both are recorded conservatively.
Pooling eleven randomised trials and 1,093 participants, creatine's effect on depressive symptoms was SMD -0.34 (95% CI -0.68 to -0.00) — about 2.2 points on the 17-item Hamilton scale, below the 3.0-point minimal important difference, with a confidence interval touching zero, substantial heterogeneity (I-squared 71.3%), and a GRADE rating of very low certainty. Remission favoured creatine across three trials (OR 3.60, 95% CI 1.76 to 7.56) but treatment response across two did not (OR 0.72, 95% CI 0.28 to 1.88). Trim-and-fill and subgroup analyses indicated substantial bias favouring creatine, and the authors conclude the true effect may be trivial or null.
How this record was checked
PubMed record 41189312 fetched via NCBI efetch 2026-08-18; title, all three authors, journal (Br J Nutr 2025;134(11):947-959), year, DOI, 11 trials, N=1,093 participants, SMD -0.34 (95% CI -0.68 to -0.00), I-squared 71.3%, the remission and response odds ratios, and the GRADE very-low rating confirmed from the abstract. Europe PMC core record checked 2026-08-18: no PMC full text, no grant list, no funding statement. The Cambridge Core article page was fetched 2026-08-18 and returned abstract and references only — no financial-support, competing-interests, or PROSPERO line was readable — so funding is UNKNOWN, conflicts false, and preregistered false rather than guessed.
Study 4 · 2020
- Cross-sectional study
- 22,692 participants
- Reputable journal
- Independently funded
- Declared conflicts of interest
moderate58/100Reasonable evidence with real limitations.
Read this first: Cross-sectional design: this cannot establish that creatine intake reduces depression risk, and reverse causation is at least as plausible as the causal reading. The paper states the authors have no conflict of interest, but co-author Dr Renshaw is disclosed elsewhere in this literature (in the 2012 AJP creatine trial above) as an inventor on related patent applications, which is why independence is marked false here.
Among 22,692 adults in the 2005-2012 NHANES surveys, depression prevalence was 10.23 per 100 people in the lowest quartile of dietary creatine intake versus 5.98 per 100 in the highest (P<0.001), with an adjusted odds ratio of 0.68 (95% CI 0.52 to 0.88) after controlling for income, race, sex, age, education, BMI, healthcare access, smoking, physical activity, and psychiatric medication use. This is a snapshot of diet and mood measured at the same moment: dietary creatine comes overwhelmingly from meat and fish, so the association is inseparable from overall diet, income, and the well-documented fact that depression itself changes what people eat.
How this record was checked
PubMed record 32066709 fetched via NCBI efetch 2026-08-18; title, all five authors, journal (Transl Psychiatry 2020;10(1):52), year, DOI, N=22,692 NHANES participants aged 20 and over, the 2005-2012 survey window, the 10.23 versus 5.98 per 100 prevalence figures, and the adjusted OR 0.68 (95% CI 0.52-0.88) confirmed from the abstract, which also carries "The authors declare that they have no conflict of interest" (hence conflicts true). Europe PMC core record fetched 2026-08-18 lists NIMH grant R33 MH096858, hence funding INDEPENDENT.
Study 5 · 2026
- Systematic review of randomized trials
- 238 participants
- Reputable journal
- No funding reported
- Declared conflicts of interest
strong74/100Well-supported by good-quality research.
Read this first: The declaration of conflicting interests records that co-author Dr Candow "serves on the Scientific Advisory Board for Alzchem and Create (companies that manufacture creatine)" and has received industry creatine research funding and product donations, and that Dr Ostojic "is the co-founder of KRE-ALL, a company which develops food products enriched with creatine" — commercial ties to the intervention being reviewed, which is why independence is marked false despite the review itself being unfunded and its conclusions being cautious. No PROSPERO registration was found on the published page.
Searching to September 2025, the reviewers found only five randomised trials of creatine in people with a diagnosed mental disorder — 126 on creatine and 112 on placebo, 238 people in total across the entire literature, and 26% male. Four concerned major depression and one bipolar depression; two were low risk of bias and three had some concerns. Creatine combined with escitalopram outperformed SSRI plus placebo in one trial and creatine plus CBT outperformed CBT plus placebo in another, but it showed no difference from placebo in female adolescents or in bipolar depression. Two of 17 participants in one trial developed hypomania or mania. No psychiatric condition other than depression has been studied at all.
How this record was checked
PubMed record 41558805 fetched via NCBI efetch 2026-08-18; title, all ten authors, journal (Can J Psychiatry 2026, online ahead of print 20 January 2026), DOI, the five-RCT/six-article count, N=126 creatine and 112 placebo, mean age 36, 26% male, the per-condition results, and the 2-of-17 hypomania/mania figure confirmed from the abstract. PMC full text PMC12823350 read 2026-08-18: "Funding: The authors received no financial support for the research, authorship, and/or publication of this article" (hence funding NONE) and a full "Declaration of Conflicting Interest" section (hence conflicts true) containing the Alzchem, Create, and KRE-ALL disclosures quoted above.
The Risks
Nobody checks this purchase the way a prescription is checked. No prescriber reviews it against the rest of what you take, no pharmacist screens the interaction, and no regulator confirms the dose in the capsule before it is sold. That is why this section sits here at full length rather than as a footnote.
What the paragraph below covers:
- Psychosis and mania
- Weight gain
- Stomach and gut
At the doses used in the depression trials (roughly 2-10 g/day) creatine is among the better-tolerated supplements. The common effects are water retention with a few pounds of weight gain, bloating, and gastrointestinal upset, and randomised trials have not shown meaningfully more dropout on creatine than placebo. The practical caution is kidney disease: creatine raises serum creatinine, which can look like worsening kidney function on a routine blood test even when nothing is wrong, so anyone with reduced kidney function, or who is having kidney labs monitored for any reason, should tell their clinician they are taking it before the result is misread. In psychiatric use specifically, the 2026 systematic review of creatine RCTs in mental disorders recorded 2 of 17 participants in one trial experiencing hypomania or mania, so bipolar disorder is a reason to involve a psychiatrist before starting. The larger honest caveat is not safety but evidence: the trials are small, several were conducted only in women, and the pooled effect on depressive symptoms falls below the threshold for a clinically important change.
What Is Not Known
The boundaries of the section above, in the harvest’s own words. What it excluded, why, and where it looked and found nothing. An absence of evidence is not evidence of absence, and it is not evidence of benefit either.
What Was Left Out, and Why
Quoted from the harvest, where these notes sat above the study list rather than after it. Where a note says “below” it means the studies in the section above.
- The 2025 correspondence exchange in European Neuropsychopharmacology about creatine and exercise for depression (Fabiano & Stubbs, PMID 40056509; Sherpa & De Giorgi, PMID 40220579; De Giorgi et al., PMID 39879837) was fetched and verified but excluded as study records: these are letters, not studies. The authors' own warning in one of them — "Preliminary evidence should be treated as such" — is reflected in the notes below.
- Animal and rodent creatine-antidepressant work is out of scope.
- Individual creatine RCTs other than the two listed are excluded; they are pooled inside the two 2025-2026 evidence syntheses included here, which between them cover every randomised trial of creatine in a psychiatric population.
The Retraction Check
PubMed efetch records for all five PMIDs inspected 2026-08-18 for "Retraction in" flags; none present, and no errata or expressions of concern.
Questions for a Prescriber or Pharmacist
This page does not tell anyone to take Creatine or to avoid it. It is not able to: it does not know what else you take, what you have tried, or what you are treating. These are the questions each study above raises, written to be asked out loud.
- The main creatine trial studied 52 women adding it to an SSRI — if I'm already on an antidepressant that's only partly working, how does creatine compare to the augmentation strategies you'd normally use?
- The newest creatine trial added it to therapy rather than to medication — if I'm in therapy, is that a combination worth trying, and how would we tell whether it helped?
- Pooled across every trial, creatine moves depression scores about 2 points on a scale where 3 points is the smallest change that matters — is that worth taking a daily supplement for?
- People who eat more meat and fish report less depression in survey data — is there any reason to think a creatine capsule does the same thing a different diet does?
- Every randomised trial of creatine in psychiatry put together comes to 238 people — is that enough evidence to build a treatment plan on, or is it enough to justify an experiment we monitor?
And the one to ask at the counter, whatever the answers above turn out to be: given everything I am already taking, what would you want to know about Creatine before I put it in the same body?
Where This Page Comes From
Transcribed from the study-harvest-2026-08-18 record for creatine, built into this page by scripts/supplement-ingest.mjs on 2026-09-07. Nothing here is fetched at page load, and nothing here was written by a model without a citation behind it.
| Source file | study-harvest/2026-08-18/creatine.yaml |
|---|---|
| Source repo | REPTechnologies/avalo-backend |
| SHA-256 | a8109a69940a27ad25074b0874338fcf69941640977997d70d5d87b4fa30d512 |
| Also searched as | creatine monohydrate, CrM, Creapure, creatine HCl, creatine ethyl ester |
The Other Substances
- 5-HTP
- Ashwagandha
- Cannabidiol (CBD)
- Cannabis and THC
- Kratom
- L-Theanine
- Magnesium
- Melatonin
- Methylene Blue
- Microdosing
- N-Acetylcysteine (NAC)
- Omega-3
- Phenibut
- SAMe
- St John’s Wort
- Valerian
Do any supplements actually work? asks the question across all of them. The full library has the medication records, the funding investigations, and the glossary.