Creatine as an Add-On Therapy for Depression: Systematic Review Reveals Mixed Evidence, Calls for Larger Trials
Key Insights
A systematic review of five randomized controlled trials found that creatine as an add-on therapy showed benefit in two trials involving women with major depressive disorder (search) but no effect in three other trials.
In one positive trial, 5 grams of daily creatine added to escitalopram produced a large effect size (Cohen's d of 1.13) on the Hamilton Depression Rating Scale over eight weeks.
Two participants with bipolar disorder (search) who received creatine developed hypomania or mania, signaling potential risks depending on underlying diagnosis.
A new systematic review published in Brain Medicine examines whether creatine, a supplement widely known for muscle building, could serve as an add-on treatment for depression. The findings offer a split verdict: two trials showed meaningful benefit, three did not, and the authors conclude that the question deserves further exploration but does not yet support changes in clinical practice.
The review, led by Bassam Jeryous Fares of the University of Ottawa, screened the existing literature and identified six published reports covering five randomized controlled trials conducted across South Korea, the United States, Brazil, Israel, and India. Together, the trials enrolled 238 participants at baseline—126 receiving creatine and 112 receiving placebo—with an average age of 36 years. Most participants were women, and two trials enrolled women exclusively. Four trials studied major depressive disorder (search), while one examined people with bipolar disorder (search) experiencing a depressive episode. Because the studies differed substantially in design, the authors did not pool the data into a single meta-analysis, opting instead for a narrative synthesis.
Evidence of Benefit in Two Trials
Two of the five trials, both drawn from the same study of women with major depressive disorder (search), found that creatine provided additional benefit. When five grams of creatine per day was added to the antidepressant escitalopram, depressive symptoms fell further than they did on placebo after eight weeks. The effect was large by conventional statistical standards, with a Cohen's d of 1.13 on the Hamilton Depression Rating Scale, and more women in the creatine group reached remission.
A separate trial paired creatine with cognitive behavioral therapy and observed a steeper drop in symptoms on a standard questionnaire compared with therapy plus placebo.
Three Trials Show No Benefit, Safety Signal in Bipolar Disorder (search)
The remaining three trials found no meaningful effect. One study reported that neither five nor ten grams of creatine per day improved symptoms in people whose depression had not responded to medication. Another, testing several doses in adolescent girls, found no difference from placebo. A third trial involving people with bipolar disorder (search) in a depressive episode also showed no treatment benefit.
Notably, two participants with bipolar disorder (search) who received creatine developed hypomania or mania—a finding the authors describe as a sober reminder that the same compound can behave very differently depending on the diagnosis.
Biological Rationale
The brain is an energy-intensive organ, and creatine helps cells regenerate adenosine triphosphate (ATP), the molecule that powers cellular work. Previous research has identified altered creatine metabolism in the brains of people with mood disorders, and impaired energy production has been proposed as one contributor to depression. Creatine may also influence dopamine and serotonin pathways, the neurotransmitter systems targeted by most antidepressants. The authors caution, however, that the link between brain creatine and mood remains correlational rather than proven cause and effect.
Expert Perspectives
"The signal is interesting, but it is not a verdict," said Bassam Jeryous Fares, first author of the review and a student in the Faculty of Medicine at the University of Ottawa. "Two trials pointed one way and three 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."
Nicholas Fabiano, corresponding author and a psychiatry resident at the University of Ottawa, framed the work as a starting point. "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."
Limitations and Future Directions
The authors flag several limitations. The trials were small, the sexes were unbalanced, and study quality varied—two trials were judged at low risk of bias, while three carried some concern, primarily related to participant assignment and handling of missing data. The findings, the authors stress, are not yet generalizable.
The review calls for larger and longer trials extending beyond eight weeks, studies testing creatine alongside exercise, and investigations of higher doses. Animal research offers an additional clue: creatine altered depression-like behavior differently in male and female rodents, which may help explain why the human trials with more women showed more promise.
The peer-reviewed article, "Creatine as a treatment for depression," was published in Brain Medicine and is available through Open Access as of June 30, 2026.