AccScience Publishing / GTM / Online First / DOI: 10.36922/gtm.2509

Folic acid supplementation for stroke prevention: The devil is in the details

Kate C. Chiang1 Teja Kankanala2 Priya Kankanala2 Prisha Desai2 Ajay Gupta2,3,4*
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1 School of Medicine, University College Dublin, Dublin, Ireland
2 Charak Foundation, California, United States of America
3 Division of Nephrology, Hypertension and Kidney Transplantation, University of California Irvine, Orange, California, United States of America
4 Department of Medical Education, School of Medicine, California University of Science and Medicine, Colton, California, United States of America
Global Translational Medicine 2024, 3(2), 2509
Submitted: 22 December 2023 | Accepted: 18 March 2024 | Published: 19 June 2024
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( )

Cerebrovascular disease (CVD) is the second leading cause of death worldwide. In addition to the traditional risk factors such as hypertension, diabetes, and hyperlipidemia, nutritional folate deficiency may be an important risk factor for CVD, especially in low-income countries. Folic acid supplementation has been considered for stroke prevention, but trial results have been variable. Therefore, in general, stroke patients do not receive folic acid supplementation routinely, partly due to the lack of consensus regarding such necessity. To be metabolically active, the synthetic folic acid, which is often taken as a supplement, needs to be enzymatically converted to 5-methyltetrahydrofolate (5-MTHF) by the endogenous enzyme methylenetetrahydrofolate reductase (MTHFR). 5-MTHF promotes homocysteine catabolism while improving endothelial function and reducing superoxide generation. It has been shown that supplementation with synthetic folic acid reduced the incidence of ischemic strokes in individuals with hypertension, but the efficacy of folic acid supplementation in primary prevention of ischemic strokes was markedly reduced in the subset of hypertensive patients with mutations in the MTHFR gene. Furthermore, supplementation with synthetic folic acid may promote accumulation of unmetabolized free folic acid which may increase risk of cancer, immune suppression, and cognitive impairment, especially in patients with mutations in MTHFR. Since MTHFR genotyping is neither feasible nor cost-effective in the vast population of patients at risk of ischemic stroke, supplementation with low-dose 5-MTHF merits examination in large well-designed clinical trials.

Folic acid
Methylenetetrahydrofolate reductase
Cerebrovascular disease
Cardiovascular disease
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Conflict of interest
The authors declare that they have no competing interests.
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