Folic acid, for heart health and an ally for athletes

IN BRIEF

• Folic acid (vitamin B9) is essential for DNA synthesis and red blood cell formation; it is particularly important in the periconceptional period to reduce the risk of neural tube defects.
• Evidence on the effect of folate supplementation on cardiovascular diseases is mixed: some analyses show a reduction in stroke risk in selected contexts, while others show no net benefit in patients with pre-existing vascular disease.
• In female athletes with amenorrhea related to low energy availability, high-dose supplementation has shown improvements in vascular function in one controlled study [2].
• The natural form is represented by folates in food; folic acid is the synthetic form used in supplements and fortification. Alternative forms (e.g., 5-MTHF) are under study to reduce the accumulation of unmetabolized folic acid.
• Folate deficiency manifests with hematological and neurological symptoms; certain conditions and medications can increase the risk (malabsorption, dialysis, chronic therapy with certain drugs) and require clinical evaluation.

Abstract: What does science say?

Vitamin B9 (folates or folic acid) is a micronutrient with key roles in DNA synthesis, cell replication, and homocysteine metabolism. The strongest evidence concerns the prevention of neural tube defects with periconceptional supplementation. For cardiovascular health, the results are heterogeneous: observational studies indicate associations between elevated homocysteine and vascular risk, but randomized trials and meta-analyses show variable effects of supplementation; some contexts—populations not exposed to fortification or with low baseline folate levels—have shown reductions in stroke. For athletes, laboratory data and small-scale trials suggest that supplementation can improve endothelial function in amenorrheic female athletes. The chemical form (folic acid vs. dietary folates or 5-MTHF), dose, and context (nutritional status, food fortification, comorbidities) influence the observable effects. In summary: strong recommendations for the prevention of neural defects; more nuanced indications for heart and athletic performance that require contextualization and further research.

Role in pregnancy and prevention of congenital malformations

The most established evidence regarding folic acid concerns the prevention of neural tube defects (anencephaly, spina bifida) when intake is adequate in the periods immediately preceding conception and in the first weeks of gestation. A large multicenter randomized trial showed a marked reduction in the risk of recurrence of neural tube defects with folate supplementation around conception [1]. On this basis, many health authorities recommend a sustained intake of folate in women of childbearing potential. It is important to emphasize that prevention is dependent on timing (periconceptional) and dose: the critical window is in the first weeks of embryonic development, often before pregnancy is recognized.

Folic Acid and Athletic Performance: What Studies Indicate

In athletes, the role of folate is not limited to red blood cell production: it supports metabolic processes that influence the availability of oxygen and nutrients to tissues. In particular, in female athletes with amenorrhea related to low energy availability, alterations in endothelial function have been observed, which can limit vasodilation and blood flow. A clinical study conducted on amenorrheic female athletes reported an improvement in flow-mediated dilation after four weeks of folic acid supplementation, suggesting an effect on vascular function that may have implications for health and, potentially, for performance [2]. However, these results are derived from a limited-size study and require broader confirmation and evaluations of optimal doses and duration.

Cardiovascular Health: Evidence, Uncertainties, and Context

The relationship between folate, homocysteine, and cardiovascular risk has been the subject of numerous observational studies and clinical trials. Meta-analyses of randomized trials show heterogeneous results: while some global analyses do not document a clear effect of supplementation on the overall reduction of cardiovascular events, there are signs of stroke risk reduction in some populations and in subgroups with low baseline folate levels or in contexts without food fortification [3].

For example, large trials in patients with established vascular disease have not shown a net benefit of folate and other B vitamin therapy on secondary prevention [4]. Conversely, in a randomized study on a hypertensive population in China, the addition of folate to antihypertensive treatment reduced the incidence of first stroke in individuals with relatively low serum folate levels, indicating that nutritional and genetic context can modulate the effect [5].

In practice, the strength of the evidence depends heavily on the study design (observational vs. RCT), the nutritional status of the population, the presence of food fortification of bread/cereals, and the clinical objective (primary vs. secondary prevention). Therefore, recommendations must be contextualized and not generalized.

Physiology: why vitamin B9 is important

Folates participate in essential biochemical reactions for DNA synthesis, methylation, and nucleotide production; they are therefore fundamental for cell replication and the differentiation of rapidly turning over tissues, such as bone marrow and the developing embryo. Deficiency alters erythrocyte maturation, leading to megaloblastosis with anemia, and can increase plasma homocysteine levels, a marker that in observational studies has been associated with vascular risk. However, the simple reduction of homocysteine through supplementation has not always translated into consistent reductions in clinical events in populations with established vascular disease [6].

Chemical forms, foods, and practical considerations

Vitamin B9 is found in foods as folates (natural forms) and, in supplements or fortified foods, as folic acid (synthetic form). The metabolism of folic acid can lead to the appearance of unmetabolized folic acid in circulation; for this reason, comparisons are ongoing between folic acid and the biologically active form 5-methyltetrahydrofolate (5-MTHF). A randomized study in pregnant women showed that supplementation with 5-MTHF maintains maternal folate status with lower amounts of unmetabolized folate compared to folic acid, suggesting possible advantages of biochemical tolerability in specific contexts [7].

Dietary sources rich in folate include green leafy vegetables, legumes, some fruits, and whole grains. Prolonged cooking reduces folate content, so the contribution of raw or lightly cooked foods is significant. Public health recommendations on food fortification and periconceptional supplementation are based on balancing benefits and potential risks, as assessed by the scientific community.

Deficiency and clinical signs

Folate deficiency frequently manifests as macrocytic (megaloblastic) anemia, asthenia, pallor, and in some cases, neurological or neuropsychiatric symptoms. Clinical and laboratory data guiding diagnosis include hemoglobin, mean corpuscular volume (MCV), serum folate levels, and sometimes homocysteine; distinguishing it from vitamin B12 deficiency is clinically important because treatments differ. A recent clinical review describes the typical hematological pictures of megaloblastosis and common causes of deficiency (malnutrition, malabsorption, drugs) [6].

Drug interactions and at-risk populations

Certain drugs and conditions can reduce folate status: antifolate antimetabolite drugs (e.g., methotrexate), medications that interfere with intestinal absorption or increase excretion, conditions of intestinal malabsorption, and dialysis therapy. Furthermore, chronic metformin therapy is associated with an increased risk of vitamin alterations (especially vitamin B12), with implications for homocysteine and hematological parameters; randomized trials and observational analyses have highlighted this association, suggesting the need for targeted monitoring in at-risk individuals [8].

Folate and neurological functions: what is the evidence?

There is data linking folate deficiency to neurological problems and mood disorders. However, evidence on the effectiveness of supplementation to prevent or slow cognitive decline in subjects with neurodegenerative disease is conflicting. A randomized trial in Alzheimer's patients showed that the use of high doses of B vitamins reduced homocysteine but did not slow global cognitive decline in the studied population; subsequent studies explored subgroups and interactions with other factors (e.g., omega-3) showing heterogeneous results [9]. In summary, the evidence does not currently support the generalized use of high doses of B-vitamins for dementia outside of cases with documented deficiency.

Limitations of Evidence

To interpret research on folic acid, it is essential to distinguish between observational associations and causal evidence from randomized trials. Observational studies have identified correlations between folate/homocysteine levels and clinical outcomes, but these results can be influenced by confounding factors (nutritional status, health behaviors, socioeconomic factors). Randomized trials provide more direct evidence of causality, but have produced variable results: some large RCTs have not documented clinical benefits in secondary prevention, while trials in unfortified populations or those with low baseline folate status have shown reductions in stroke [3][4][5].

Other common limitations include variability in the doses used, in the forms of folate (folic acid vs 5-MTHF), in the duration of the intervention, and in the composition of participants (age, comorbidities, exposure to food fortification). These factors make it difficult to extend results from one context to another without caution.

Key points to remember

• Prevention of neural tube defects through periconceptional folate Intake is one of the most established recommendations.
• For cardiovascular health, evidence is heterogeneous: benefits appear to depend on the nutritional context and baseline folate status.
• In athletes, some evidence suggests beneficial effects on vascular function in amenorrheic female athletes, but data are limited and not generalizable without further research.
• Chemical form and dose matter: 5-MTHF is studied as an alternative to folic acid with detectable biochemical differences.
• At-risk populations (malabsorption, dialysis, chronic use of certain medications) require clinical and laboratory evaluation before drawing conclusions.

Editorial Conclusion

Folic acid is an essential nutrient with well-defined biological roles: the prevention of neural tube defects represents its best-documented benefit. For cardiovascular health and athletic performance, the evidence is more nuanced and depends on the context: the nutritional status of the population, the presence or absence of food fortification, the chemical form of folate, and the specificity of the endpoints studied. Decisions regarding supplementation and monitoring should be contextualized, based on clinical evaluation and, when appropriate, laboratory tests. Research continues to explore different forms of folate and subgroups that may benefit more; meanwhile, public health policies promoting periconceptional intake remain a proven preventive measure.

Editorial Note

This article has been updated to reflect current scientific literature and to clarify the limitations and contexts of the evidence. The information provided is for informational purposes only and does not constitute medical advice. For personal or therapeutic decisions, consult your doctor.

SCIENTIFIC RESEARCH

1. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991;338:131–137. https://doi.org/10.1016/0140-6736(91)90133-A
2. Hoch AZ, Lynch SL, Jurva JW, Schimke JE, Gutterman DD. Folic acid supplementation improves vascular function in amenorrheic runners. Clin J Sport Med. 2010 May;20(3):205–210. https://doi.org/10.1097/JSM.0b013e3181df59f4
3. Zhou YH, Tang JY, Wu MJ, et al. Effect of folic acid supplementation on cardiovascular outcomes: a systematic review and meta-analysis. PLoS One. 2011;6(9):e25142. https://doi.org/10.1371/journal.pone.0025142
4. HOPE-2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354:1567–1577. https://doi.org/10.1056/NEJMoa060900
5. Huo Y, Li J, Qin X, et al.; CSPPT Investigators. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA. 2015;313(13):1325–1335. https://doi.org/10.1001/jama.2015.2274
6. Socha DS, DeSouza SI, Flagg A, Sekeres M, Rogers HJ. Severe megaloblastic anemia: vitamin deficiency and other causes. Cleveland Clin J Med. 2020;87(3):153–164. https://doi.org/10.3949/ccjm.87a.19072
7. Supplementation with (6S)-5‑methyltetrahydrofolic acid appears as effective as folic acid in maintaining maternal folate status while reducing unmetabolised folic acid in maternal plasma: a randomised trial of pregnant women in Canada. Br J Nutr. 2024. https://doi.org/10.1017/S0007114523001733
8. DeJager J, Kooy A, Lehert P, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B‑12 deficiency: randomised placebo controlled trial. BMJ. 2010;340:c2181. https://doi.org/10.1136/bmj.c2181
9. Aisen PS, Schneider LS, Sano M, et al. High‑dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008;300(15):1774–1783. https://doi.org/10.1001/jama.300.15.1774