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Creatine is among the most studied supplements in sports, with evidence that it can boost strength, improve high-intensity performance, and help muscles recover. Now researchers are asking a harder question: Could the same compound that fuels a workout also help treat depression?

A new review that appeared in Brain Medicine found the answer, for now, is unsettled: two clinical trials found benefits, three did not, and one study in bipolar depression raised a safety concern.

An Effective Supplement Meets a Difficult Mental Condition

Depression affects mood, sleep, concentration, appetite, and the ability to feel pleasure. Many people improve with medication or therapy, but many others get only partial relief. That gap has pushed researchers to test add-on treatments that might support the brain in different ways.

Creatine is an appealing candidate because the brain uses enormous amounts of energy. The compound helps cells replenish adenosine triphosphate (ATP), the molecule cells use as fuel. Researchers have also found changes in brain creatine metabolism in some people with mood disorders, though the link remains inconsistent and does not prove cause and effect.

Bassam Jeryous Fares of the University of Ottawa and colleagues reviewed six published reports describing five randomized controlled trials. The studies took place in South Korea, the United States, Brazil, India, and Israel. Together, they included 238 participants at the start: 126 received creatine and 112 received placebo. The average age was 36, and most participants were women.

Four trials focused on major depressive disorder. One studied people with bipolar disorder who were in a depressive episode. Because the trials used different designs, doses, and patient groups, the authors did not combine the results into one pooled estimate.

The Results Split Down the Middle

The strongest positive evidence came from women with major depressive disorder. In one trial, adding five grams of creatine a day to escitalopram, a common antidepressant, produced larger symptom reductions after eight weeks than escitalopram plus placebo. More participants also reached remission.

Another trial paired creatine with cognitive behavioral therapy. People who received creatine showed a larger drop in symptoms on a standard depression questionnaire than those who received therapy with placebo.

But three other trials failed to find a meaningful benefit. Creatine did not outperform placebo in people whose depression had not responded well to medication. It also showed no clear advantage in adolescent girls with major depressive disorder, even at different doses. In bipolar depression, six grams a day did not improve symptoms.

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That bipolar trial also raised a warning. Two participants taking creatine developed hypomania or mania, suggesting researchers need to study the risk of mood switching before testing the supplement more widely in bipolar disorder.

“The signal is interesting, but it is not a verdict,” Fares said in a statement. “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, a psychiatry resident at the University of Ottawa and corresponding author, struck a similar note. “Creatine appears to be a safe intervention. The adverse events we found were limited to mild gastrointestinal discomfort,” he said. “We cannot yet reliably say that creatine helps with depressive symptoms or if the findings are generalizable to everyone.”

Worth Exploring

The biological idea is straightforward. Depression may involve, among many factors, problems in how brain cells produce and manage energy. Creatine could help supply that energy buffer. It may also influence pathways involving dopamine and serotonin, two chemical messengers involved in mood.

Still, the review’s authors warn against overreading the evidence. The trials were small. Two enrolled only women. Only two were judged at low risk of bias, while three raised concerns involving randomization or missing data. The current findings also say little about men, older adults, or people with other mental health conditions.

“Genetics plays a role here as well,” Sarah Carolides, a functional medicine and nutrition expert not involved in the review, told Newsweek: “In a nutshell, I think what this review indicates is that for the right person, creatine monohydrate could be a very useful addition to a protocol for depression—but it is not a one size fits all remedy.”

The researchers call for larger, longer trials that run beyond eight weeks, include more representative groups and test creatine with established treatments, including exercise. Animal studies hint that sex may affect the response, which could help explain why the most promising human results came from studies with women.

For now, creatine is not a proven depression treatment. It is a low-cost, familiar compound with a new scientific question attached: whether supporting the brain’s energy system can help ease the weight of depression for some patients.