The antidepressant properties of S-adenosylmethionine, an endogenous methyl donor, were studied in inpatients who met the DSM-III criteria for major depression. Nine patients given intravenous S-adenosylmethionine and nine given low oral doses of imipramine were compared in a double-blind design for 14 days. The S-adenosylmethionine produced superior results by the end of the first week of treatment. By the end of the second week, 66% of the S-adenosylmethionine patients had a clinically significant improvement in depressive symptoms, compared to 22% of the imipramine patients. Side effects appeared to be fewer with S-adenosylmethionine than with imipramine during the last 5 days of the study.