Creatine for depression has become a topic of growing interest in nutritional psychiatry, and a new systematic review of randomized controlled trials found mixed results for creatine monohydrate as an adjunct treatment for depression. Two trials in women with major depressive disorder (MDD) reported benefits when creatine was added to standard antidepressant medication or cognitive behavioral therapy, while three other trials found no meaningful advantage over placebo.
Researchers examined whether creatine supplementation could address disruptions in brain energy metabolism that have been observed in some people with mood disorders. Creatine plays a key role in regenerating adenosine triphosphate (ATP), the primary energy currency of cells, including neurons. Prior observational and preclinical work had linked lower brain creatine levels or altered creatine metabolism to depressive symptoms, and animal studies suggested potential antidepressant-like effects, sometimes varying by sex.
Before this review, evidence came mainly from small individual trials and non-systematic summaries. Some earlier studies, particularly in women, had shown promise for creatine as an add-on therapy, but results were not synthesized using systematic methods limited to randomized controlled trials (RCTs).
The review, led by researchers at the University of Ottawa, searched the literature and included six reports from five RCTs. These trials involved 238 participants at baseline (126 assigned to creatine monohydrate [CrM], 112 to placebo). Participants had a mean age of about 36 years, and most were women; two studies included only women. Four trials examined MDD and one examined bipolar depression during a depressive episode. Doses ranged from 2 to 10 grams per day, given for 4–8 weeks as an adjunct to other treatments. The researchers assessed risk of bias and evaluated studies individually rather than pooling data due to differences in design.
Results varied across the trials. In one MDD trial, women receiving 5 g/day of creatine plus escitalopram showed greater symptom reduction after eight weeks than those receiving escitalopram plus placebo (Cohen’s d = 1.13 on the Hamilton Depression Rating Scale; larger improvements also seen on other scales). Another trial found that creatine added to cognitive behavioral therapy produced greater reductions in depressive symptoms than therapy plus placebo. The other three trials—testing creatine as pharmacotherapy augmentation in treatment-resistant adults, in adolescent girls, and in bipolar depression—reported no significant benefit over placebo.
Two trials that included brain imaging found correlations between increases in brain N-acetylaspartate and phosphocreatine levels with creatine use and larger improvements in symptoms. Creatine was generally well tolerated, with mild gastrointestinal issues as the main side effect. However, two participants with bipolar disorder who received creatine developed hypomania or mania.
The authors concluded that creatine monohydrate shows promise as a combination treatment with selective serotonin reuptake inhibitors (SSRIs) or for augmenting psychotherapy in adults with MDD, but larger studies are needed. “The signal is interesting, but it is not a verdict,” said Bassam Jeryous Fares, HBSc, first author and a student in the Faculty of Medicine at the University of Ottawa. Nicholas Fabiano, corresponding author and a psychiatry resident at the University of Ottawa, noted that while creatine appears safe in the reviewed trials, “We cannot yet reliably say that creatine helps with depressive symptoms or if the findings are generalizable to everyone.”
Limitations are substantial. The trials were small, short in duration, included mostly women, and varied in quality (two judged low risk of bias, three with some concerns, especially regarding randomization and missing data). Findings cannot be generalized broadly, particularly to men or other populations. No meta-analysis was performed due to heterogeneity, and the review did not identify benefits in bipolar depression or treatment-resistant cases in the included studies. The researchers call for larger, longer double-blind RCTs.
This work sits within the broader field of nutritional psychiatry and research on brain bioenergetics in mood disorders. It does not claim creatine is a standalone treatment, that benefits apply equally across sexes or conditions, or that mechanisms are proven causal in humans. It also does not assert that current evidence supports changing clinical practice.
Reference:
The Effect of Creatine Monohydrate on Mental Disorders: A Systematic Review of Randomized Controlled Trials, Bassam Jeryous Fares, Carl Zhou, Nicholas Fabiano, Stanley Wong, Brendon Stubbs, Risa Shorr, David Puder, Darren G. Candow, Sergej M. Ostojic, Marco Solmi. Canadian Journal of Psychiatry, 2026.
(Note: The provided press materials referenced Brain Medicine; the peer-reviewed publication appeared in the Canadian Journal of Psychiatry.)
