In the Papakostas study (1), side effects were no more common with l-methylfolate than with placebo. The study is small, however, and limited for assessment of safety. One concern is that folate administration may mask B12 deficiency (3). A possible association with an increased risk of cancer has been suggested, but this remains controversial (4). Increased mortality was observed in the Iowa Women’s Health Study in women taking multivitamins, vitamin B6, folic acid, iron, magnesium, or copper (10). The authors examined mortality rates in 38,772 older women who were taking or not taking various vitamin and mineral supplements between 1986 and 2004. During that period, supplement use increased from 62.7% to 85.1%. Folic acid supplementation was associated with an increase of 5.9% in mortality risk. If supplementation is used to treat a disorder for which efficacy is established, the benefit will likely outweigh the harm, but the data suggest that these compounds are not harmless. Although the FDA asks the manufacturers of dietary supplements and medical foods to attest to their safety, these agents are not systematically studied in the manner that pharmaceutical agents are.