Rethinking folic acid fortification: A call for nuanced strategies and broader investigations

This comment letter responds to Edward H. Reynolds' comprehensive review on folate, vitamin B12, one‑carbon metabolism, and nervous system health. While commending the review's insights into the potential neurological harms of excess folic acid, especially with vitamin B12 deficiency, we expand on several critical areas. We emphasize distinguishing synthetic folic acid's neurotoxicity from natural folates, urging further comparative studies. We highlight the underexplored long-term consequences of supraphysiological folic acid exposure in children and adolescents during critical neurodevelopment. The profound implications of transgenerational epigenetic effects from ancestral folate status are stressed, demanding urgent investigation in human cohorts. Crucially, we address the practical challenges of revising global fortification policies, noting the significant logistical, economic, and regulatory hurdles in shifting from folic acid to natural folate forms combined with vitamin B12. We conclude by advocating for a nuanced, multi-pronged approach to fortification, urging reconsideration of the folic acid UL, enhanced population surveillance, and continued research to balance benefits of neural tube defect prevention with potential harms of excess folate.