A common dietary supplement, creatine monohydrate, may offer benefits as an adjunctive treatment for major depressive disorder, according to a systematic review published in Brain Medicine. The findings, however, are considered preliminary and require further investigation.
Researchers from Canada analyzed data from five randomized controlled trials, focusing on creatine monohydrate's impact on mental health. Four of these trials specifically examined major depressive disorder, while one evaluated bipolar disorder with a current depressive episode. One trial involving women with depression showed greater improvement after eight weeks when 5 grams of creatine daily were added to the antidepressant escitalopram. Another study indicated a benefit when creatine was incorporated alongside cognitive behavioral therapy.
Conversely, other studies yielded no positive results. One trial involving adolescent girls found no benefit from various creatine dosages after an eight-week period. Similarly, a study on bipolar depression reported no significant improvements when 6 grams of creatine were added to medication over six weeks.
Previous research suggests that individuals with mood disorders may process creatine differently in the brain. As creatine plays a role in energy production, disruptions in this process are hypothesized to contribute to depression. Creatine has also been linked to increased levels of dopamine and serotonin, neurotransmitters targeted by many antidepressants, although the precise connection between brain creatine and mood remains correlational.
Lead study author Bassam Jeryous Fares stated that the observed signal is "interesting, but not a verdict." He noted that with "two trials pointed one way, and three pointed another," the evidence is insufficient to change clinical practice but warrants further exploration.
Nicholas Fabiano, a co-author of the review, indicated that creatine appears to be a safe intervention, with reported side effects limited to mild stomach pain. However, he cautioned, "We cannot yet reliably say that creatine helps with depressive symptoms or if the findings are generalizable to everyone."
Dr. Thea Gallagher, director of wellness programs at NYU Langone, who was not involved in the study, explained that creatine supports brain energy production and utilization. "Researchers believe that some people with depression may have alterations in brain energy metabolism, and creatine could help support these energy-producing pathways," she said. Emerging evidence also suggests potential influence on neurotransmitters and a reduction in oxidative stress and inflammation, though these mechanisms are still under investigation.
Gallagher emphasized that the research suggests creatine might be most helpful when combined with established depression treatments, not as a replacement. She described the findings as encouraging, adding to evidence that supporting brain energy metabolism could be another avenue for improving depressive symptoms. "It’s exciting whenever we identify another potential tool that could complement existing treatments, particularly one that is relatively inexpensive and widely available."
The study authors acknowledged that their review of prior research, rather than a new clinical trial, is a limitation, and "larger, well-controlled trials are still needed."
Gallagher advised that creatine should be considered a potentially promising addition to treatment, not a substitute for psychotherapy, antidepressant medication, exercise, or adequate sleep. She also highlighted that while creatine generally has a strong safety profile for healthy adults, consulting a healthcare provider before starting any supplement is crucial, especially for individuals with kidney disease, pregnant women, or those with other medical conditions.
For individuals experiencing symptoms of depression, Gallagher recommends seeking evidence-based mental healthcare. She described depression as a "highly heterogeneous condition," meaning the specific patients most likely to benefit and the optimal treatment approach remain unclear.
Gallagher also cautioned that supplements can sometimes generate "early enthusiasm" that may diminish as larger studies reveal "more modest effects." She concluded, "Right now, I’d describe creatine as promising but not definitive. It’s an area that deserves continued research, but it’s not something people should view as a standalone treatment for depression."