Interest in nonpharmaceutical supplements for treating major depressive disorder 
(MDD) has increased signiﬁcantly, both among patients and among clinicians 
during the past decades. Despite the large array of antidepressants (ADs) 
available, many patients continue to experience relatively modest response and 
remission rates, in addition to a burden of side effects that can hinder 
treatment compliance and acceptability. In this article, we review the 
literature on folates and S-adenosylmethionine (SAMe), 2 natural compounds 
linked in the 1-carbon cycle metabolic pathway, for which substantial evidence 
supports their involvement in mood disorders. Background information, efﬁcacy 
data, proposed mechanisms of action, and side effects are reviewed. Based on 
existing data, supplementation with SAMe, as well as with various formulations 
of folates, appears to be efficacious and well tolerated in reducing depressive 
symptoms. Compared with other forms of folates, 5-methyltetrahydrofolate 
(L-methylfolate or 5-MTHF) may represent a preferable treatment option for MDD 
given its greater bioavailability in patients with a genetic polymorphism, and 
the lower risk of specific side effects associated with folic acid. Although 
further randomized controlled trials in this area appear warranted, SAMe and 
L-methylfolate may represent a useful addition to the AD armamentarium.