Mixed Results in Five Small Trials Temper Creatine Claims for Depression

The review examined creatine monohydrate doses ranging from 5 g to 20 g daily for 4 to 12 weeks, either alone or combined with antidepressants or psychotherapy. Two trials reported statistically significant Hamilton Depression Rating Scale reductions of 5–7 points versus placebo; the remaining three detected no difference. All studies were underpowered, used heterogeneous entry criteria, and lacked standardized brain creatine imaging to confirm target engagement.

Brain energy metabolism offers a plausible mechanism. Creatine buffers ATP in prefrontal neurons; observational data link lower frontal creatine to major depression and bipolar disorder. Yet population studies showing lower depression rates among high dietary creatine consumers remain confounded by overall protein intake and socioeconomic factors, limiting causal inference.

Larger, adequately powered trials with pre-specified primary endpoints, 12-week minimum duration, and MRS imaging are required before creatine can be positioned as an adjunct. Current evidence does not support routine clinical recommendation outside research settings.

Regulatory bodies have issued no guidance; ongoing phase-2 studies will clarify dose-response by late 2026.