Creatine Shows a Mixed Signal for Depression, Systematic Review Finds

Creatine is among the most commercially established ingredients in the sports nutrition category, carried in virtually every supplement aisle and backed by decades of muscle performance research.

A newly published systematic review in Brain Medicine¹ now asks whether the same compound, long associated with physical energy metabolism, might have a role to play in treating depression, and arrives at a carefully qualified answer.

For nutraceutical manufacturers operating in or adjacent to the mood and cognitive health categories, the review represents an early but substantive signal worth tracking as the evidence base develops.

"The signal is interesting, but it is not a verdict," said Bassam Jeryous Fares, first author of the review and a researcher at the University of Ottawa Faculty of Medicine noted in a release.² "Two trials pointed one way and 3 pointed another. That is not the kind of evidence on which you change clinical practice. It is the kind that tells you the question is worth further exploration."

What Did the Systematic Review Find?

The research team screened the published literature and identified 6 reports describing 5 randomized controlled trials, conducted across 5 countries and enrolling 238 participants in total, with 126 receiving creatine and 112 receiving placebo.¹ The average participant age was 36 years, and most were women. Because the trials differed substantially in design, the authors chose a narrative rather than pooled statistical summary, letting each study's results stand on their own terms.

The findings divided along a clear line. Two of the 5 trials, both drawn from research involving women with major depressive disorder, found meaningful benefit when 5 g of creatine daily was added to the antidepressant escitalopram. Depressive symptom scores fell further than placebo after 8 weeks, with a Cohen's d of 1.13 on the Hamilton Depression Rating Scale, and more participants reached remission. A separate trial pairing creatine with cognitive behavioral therapy also showed a steeper reduction in symptom scores than therapy plus placebo.¹

The remaining 3 trials produced null results. Creatine at 5 or 10 g daily showed no benefit in patients who had already failed to respond to antidepressant medication, no difference from placebo in a trial of adolescent girls, and no effect in adults with bipolar disorder in a depressive episode. In that bipolar trial, 2 participants taking creatine developed hypomania or mania, an outcome the review's authors flag explicitly as a meaningful safety consideration for that diagnostic population.

Why Is the Brain a Plausible Target for Creatine Supplementation?

The neurobiological rationale behind the trials is grounded in energy metabolism. The brain consumes a disproportionate share of the body's total energy output, and prior research has found altered creatine concentrations and phosphocreatine metabolism in individuals with mood disorders, with lower prefrontal creatine levels associated with greater depressive symptom severity.³

Creatine's role in regenerating adenosine triphosphate positions it as a candidate for addressing those bioenergetic deficits, and preclinical research has also suggested possible interactions with dopamine and serotonin pathways, though those mechanisms have not been confirmed in the clinical trials reviewed here.¹

How Should Formulators Interpret These Findings?

Nicholas Fabiano, corresponding author and a psychiatry resident at the University of Ottawa, was careful to frame the evidence accordingly.² "Creatine appears to be a safe intervention. The adverse events we found were limited to mild gastrointestinal discomfort. We cannot yet reliably say that creatine helps with depressive symptoms or if the findings are generalizable to everyone."

For manufacturers, the review identifies a biologically coherent rationale and a preliminary human signal, but not a basis for strong efficacy claims in a mood or mental health context. The trials where benefit appeared most clearly were adjunctive designs, pairing creatine with existing treatments rather than testing it alone, and were conducted primarily in women.

What Are the Review's Limitations and What Comes Next?

The trials included in the review were small, and 2 of the 5 were judged at some concern for risk of bias based on assignment methodology and handling of missing data. The disproportionate representation of women across the studies limits the generalizability of the findings, and trial durations were short, with none extending meaningfully beyond 8 weeks.¹

The authors call for larger, longer, and more diverse trials, and note an intriguing signal from animal research suggesting creatine may affect mood-related behavior differently in male and female subjects, which could help explain the pattern of results observed so far.

References

1. Fares BJ, Zhou C, Fabiano N, Wong S. Creatine as a treatment for depression. Brain Med. 2026. doi:10.61373/bm026l.0039

2. Genomic Press. Scientists say creatine may help fight depression. ScienceDaily. June 30, 2026. Accessed July 1, 2026. https://www.sciencedaily.com/releases/2026/06/260630020231.htm

3. Kious BM, Kondo DG, Renshaw PF. Creatine for the treatment of depression. Biomolecules. 2019;9(9):406. doi:10.3390/biom9090406