Creatine shows early promise in depression

Clinical takeaway: Creatine is well-tolerated and cheap, but the evidence is too mixed to recommend it for depression.

Antidepressants often leave patients with only partial relief, so the search for effective treatment add-ons continues. Creatine, a commonly used muscle-building supplement, has drawn interest as one candidate since the brain runs on much the same energy chemistry that the muscles do. Its benefits for muscle strength and high-intensity exercise are well established; its potential effects on the brain are far less known. But the randomized evidence remains thin and divided. A new review found creatine eased depressive symptoms in two of five trials, but did nothing in the other three.

The clearest benefit came from a trial of women with major depression, where adding five grams of creatine daily to escitalopram cut depression scores to 5.4 versus a placebo-arm at 9.8 after eight weeks on the Hamilton Depression Rating Scale. The effect was large by the usual statistical measures, and more women reached remission. A separate trial paired creatine with cognitive behavioral therapy and found a steeper symptom drop than therapy plus placebo.

The remaining trials found no benefit. Creatine made no difference in patients who had already failed medication, across several doses in adolescent girls, or in bipolar patients during a depressive episode. In that bipolar trial, two patients on creatine developed hypomania or mania, a reminder that the same compound can behave differently by diagnosis.

The review covered five randomized trials enrolling 238 participants, conducted in South Korea, the United States, Brazil, Israel, and India. Four studied major depressive disorder and one studied bipolar disorder during a depressive episode. The average age was 36, about three-quarters of participants were women, and two trials enrolled women only. Because the trials varied too much in design and dosing to combine, the authors summarized them narratively rather than pooling the numbers.

Why the trials disagreed is an interesting question, and sex may be part of the answer. The trials that found benefit skewed heavily female. The authors are clear that the findings are not generalizable and that the link between brain creatine and mood remains correlational.

"The signal is interesting, but it is not a verdict. 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," said Bassam Fares, first author and a medical student at the University of Ottawa.

Source: Jeryous Fares B, et al. (2026 Jun 30) Brain Medicine. Creatine as a treatment for depression