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Doctors have traditionally considered supplementation with these nutrients only when vitamin B6, vitamin B12, and folate supplementation fail to reduce homocysteine to optimal levels, but they can be key methyl donors in the presence of MTHFR mutations which impair methylation ability.52 Despite the beneficial health effects of supplementation with B vitamins, it is important to note that there are possible dual effects on atherosclerosis, with the intrinsic beneficial effects of homocysteine-lowering being offset by detrimental effects of unmetabolized synthetic folic acid and/or stimulation of inflammation (and possibly proliferation) in existing atherosclerotic lesions by B vitamins.15,36 These factors may partly explain why clinical trials on homocysteine lowering failed to report improvement in CV risk and clinical outcome, and are currently under intense investigation