The antidepressant activity of oral S-adenosyl-L-methionine (SAMe) was evaluated in a randomized, double-blind, imipramine-controlled trial in 30 patients with major depression. The results suggest that oral SAMe is a safe, effective antidepressant with negligible side effects and a rapid onset of action. Only one patient became hypomanic but did not drop out of the study. SAMe may be useful for patients who cannot tolerate other antidepressant agents or for patients with other risk factors. These findings suggest a role for methylation in the pathophysiology of depression.