Over-the-counter compounds

St John's wort is available over-the-counter as a herbal remedy in some parts of the world; however, the evidence of its effectiveness for the treatment of major depression is varying and confusing. Its safety can be compromised by inconsistency in pharmaceutical quality and in the amounts of active ingredient in different preparations Further, it interacts with numerous prescribed medicines including antidepressants, and it can reduce the effectiveness of hormonal contraception.

The issue of efficacy of omega-3 fatty acids for major depression is controversial, with controlled studies and meta-analyses supporting both positive and negative conclusions. Reviews of short-term clinical trials of S-adenosylmethionine (SAMe) indicate that it may be effective in treating major depression in adults. A 2002 review reported that tryptophan and 5-hydroxytryptophan appear to be better than placebo, but it did not recommend their widespread use owing to lack of conclusive evidence on efficacy and safety, and generally preferred the use of safer antidepressants instead.