Creatine is best known as a workout supplement, but researchers are also studying whether it may have a role in brain health. A new review suggests it may hold some promise for depression, but the evidence is still far from settled.
The review, published in Brain Medicine, looked at five randomized controlled trials testing creatine monohydrate for mood disorders. Two trials found signs of benefit when creatine was added to standard depression treatment, while three did not. The review did not show that creatine can treat depression on its own, and it should not be used as a replacement for therapy, medication or other mental health care.
Creatine helps cells replenish adenosine triphosphate, or ATP, a molecule the body uses for energy. Most people associate that energy support with muscles, but the brain also has high energy demands. That has led researchers to ask whether creatine could help in conditions where brain energy metabolism may be disrupted.
The review included six published reports describing five randomized controlled trials from South Korea, the United States, Brazil, Israel and India. Together, the trials included 238 participants at baseline. Four trials involved major depressive disorder, while one involved people with bipolar disorder who were experiencing a depressive episode.
Because the trials varied widely, the authors did not combine them into one overall estimate. Instead, they summarized the studies individually.
Two reports from the same trial found that 5 grams per day of creatine, when added to the antidepressant escitalopram, helped reduce depressive symptoms in women with major depressive disorder after eight weeks. Another trial found that creatine added to cognitive behavioral therapy was linked with a greater drop in depressive symptoms than therapy plus placebo.
But the other studies did not find a benefit. One trial found no significant treatment or dose effect in people who had not responded adequately to medication. Another found no significant difference between creatine and placebo in adolescent girls with major depressive disorder. A trial in people with bipolar disorder found no significant treatment effect during a depressive episode.
That bipolar disorder finding also raised an important safety note. Two participants with bipolar disorder who were taking creatine developed hypomania or mania, which the review authors said should be considered in future studies.
“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.”
Creatine was generally well tolerated in the reviewed trials, with reported side effects limited mainly to mild gastrointestinal discomfort. But “generally well tolerated” does not mean risk-free for everyone, especially in the context of mental health conditions, medications or bipolar-spectrum symptoms.
Nicholas Fabiano, corresponding author and a psychiatry resident at the University of Ottawa, said the findings should be viewed 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.”
The review also found important gaps in the evidence. The trials were small, most participants were women and two studies enrolled only women. Study quality varied, with two trials judged at low risk of bias and three raising some concerns, mostly related to randomization and missing outcome data.
The authors called for larger, longer and more representative trials. They also noted that future studies should examine creatine alongside first-line treatments, possible sex differences, different doses and whether combining creatine with exercise changes outcomes.
For now, creatine is best understood as a research lead, not a proven depression treatment. People who are interested in creatine for mood should talk with a health care professional, especially if they take medication, have kidney disease, have bipolar disorder or have ever experienced mania or hypomania.
No funding source was identified in the published article or news release.