The current study is the first placebo-controlled trial of SAMe for adjunctive use. There is a modest literature exploring the efficacy of SAMe as monotherapy in depression. A systematic review commissioned by the Agency for Healthcare Research and Quality found 11 placebo-controlled trials of SAMe that reported change on a standard scale (3). The trials ranged in size from 15 to 75. The effect size of the difference between SAMe and placebo in these trials was 0.65, a moderate and meaningful effect. The analysis found significant heterogeneity that might reflect differences in route of administration, dose, or other unidentified factors, and an asymmetry test for publication bias was near significant (p=0.07). Six of these trials reported response rates and were examined in another meta-analysis that found a significant advantage for SAMe with an effect size of 0.38 (4). Only four of these placebo-controlled trials employed an oral form of SAMe. Three of these trials found an advantage for SAMe relative to placebo, but two of these studies were small (i.e., less than 20 patients). The two largest oral administration trials differed. Fava et al. (5) selected 55 patients with major depression and found no difference in response to drug and placebo: 67% versus 65%. Salmaggi et al. (6) studied 60 postmenopausal women between the ages of 45 and 55 with major depression or dysthymia and a HAMD ≥17. In these selected patients, SAMe was much more effective than placebo, with CGI response rates of 67% versus 3%, respectively. I have emphasized the oral administration trials, since that route will be the preferred.