Based on our pre-specified criteria, five randomized controlled trials (n = 2 placebo controlled trials, n = 3 antidepressant controlled trials) were included in our review. A large effect size was found for saffron supplementation vs. placebo control in treating depressive symptoms (M ES = 1.62, p < 0.001), revealing that saffron supplementation significantly reduced depression symptoms compared to the placebo control condition.