What happens if you significantly increase dietary folic acid intake? (2025)

A recent survey highlighted that increased dietary intake of folic acid causes adverse health effects by promoting angiogenesis, inflammation, and neurotoxicity.

Study:How Increased Dietary Folic Acid Intake Impacts Health Outcomes Through Changes in Inflammation, Angiogenesis, and Neurotoxicity. Image Credit:Danijela Maksimovic/Shutterstock.com

Scientists have recently reviewed the existing literature to understand the effect of increased dietary intake of folic acid on human health.

This review, published in Nutrients, also summarizes the proposed mechanisms through which dietary folic acid interacts with hypoxia to influence health outcomes.

The role of folic acids in humans

Folates are B vitamins that play a critical role in cellular growth and development. During pregnancy, women are advised to consume adequate amounts of folic acid to help reduce the risk of neural tube defects (NTDs) in the developing fetus. While the protective effect of folic acid against NTDs is well-established, the exact biological mechanism behind it remains unclear.

Folic acid is a key player in one-carbon (1C) metabolism, which supports vital processes such as DNA repair, nucleotide synthesis, and lipid metabolism. It also contributes to the generation of methyl groups, which are essential for the remethylation of homocysteine—a process important for maintaining cellular health and function.

Increased and reduced intake of folic acid in adults

Studies in mouse models have shown that high daily intake of folic acid in adults can lead to adverse health effects. These negative outcomes may stem from disruptions in the one-carbon (1C) metabolic pathway, including impaired folic acid receptor function and altered enzyme expression. However, more comprehensive research is needed to fully understand how elevated folic acid levels affect human health.

On the other hand, insufficient folic acid intake can result in elevated homocysteine levels, as the body lacks enough methyl groups to convert homocysteine back to methionine. High homocysteine levels are associated with an increased risk of cardiovascular diseases, including ischemic stroke.

Some studies have indicated that higher folic acid levels may enhance endothelial cell function—a key marker of cardiovascular health. Experimental research suggests that folates support endothelial function by boosting antioxidant activity and facilitating direct interactions with endothelial nitric oxide synthase (NOS).

Still, further investigation is necessary to clarify the precise mechanisms through which folic acid influences endothelial cells.

Key mechanisms

The current review obtained all relevant articles from PubMed, Web of Science, and Google Scholar databases and summarized the current proposed mechanisms concerning dietary folic acid’s impact on health outcomes by interacting with hypoxia. The key mechanisms are discussed below:

Inflammation and angiogenesis

Previous studies have highlighted that hypoxia triggers inflammatory responses in vascular diseases. Mechanistically, hypoxia initiates inflammation through the hypoxia-inducible factor-1 (HIF-1) pathway-mediated expression of interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α).

TNF-α includes and maintains inflammation in conditions of hypoxia by recruiting proteins and cells that aid inflammation (e.g., endothelial adhesion molecules and cytokines).

Interleukin-1beta (IL-1β) is a pro-inflammatory cytokine that triggers pro-inflammatory gene expression and pro-inflammatory protein production after the initiation of hypoxia-associated inflammation via HIF-1α.

Although optimal folic acid intake has exhibited an anti-inflammatory effect through downregulation of IL-1β and TNF-α protein levels, the intake of more than 40 µg/mL causes inhibition of 1L-10 in cultured human monocytic cells (THP-1).

Notch signaling

Folic acid controls neurogenesis and gliogenesis by triggering theNotch1 signaling pathway in embryonic neuronal stem cells (NSCs). Multiple studies have shown that the Notch signaling pathway is crucial for NSC proliferation and differentiation.

Notch gene expression promotes cell proliferation via growth factor-mediated pathways and inhibits apoptosis.

Increased folic acid levels facilitate NSC proliferation via the notch signaling pathway and are directly associated with increasingNotch1 andhairy and enhancer of split 5 (Hes5)mRNA and protein levels.

Neurotoxicity of folic acid

Experimental studies have shown that excessive folic acid intake triggers neurotoxicity. This effect is analogous to high levels of kainic acid (KA), which is a powerful equivalent of the neurotransmitter glutamate that causes neurotoxic glutamatergic postsynaptic receptor excitation.

Mice models indicated that methyl-tetrahydrofolate (MTHF), which is a derivative of folic acid, competes with KA for binding sites on cerebellar membranes.

Unmetabolized folic acid

Rodent studies have shown that very high levels of folic acid, i.e., approximately 20 folds higher than the required levels, cause growth retardation in newborn rodents.

In humans, a higher prevalence of increased intake of folic acid leads to similar levels of unmetabolized folic acid (UMFA).

Experimental studies have shown that UMFA may reduce immune function. More research is required to elucidate the precise effect of high UMFA levels on health outcomes and the mechanisms underlying the impact.

Vitamin B12 and folic acid actions

Vitamin B12 is involved with the recycling and regulation of 1C metabolism. This vitamin is necessary for various metabolic functions including red blood cell synthesis, macrocytic anemia, and reduction of the risk of neural tube defects.

Vitamin B12 deficiency can trap folic acid metabolites (e.g., 5-MTHF) and cause inhibition in the re-methylation of homocysteine.

A decrease in homocysteine remethylation may lead to neuropathy, megaloblastic anemia, and neuropsychiatric disorders. Individuals with normal B12 levels and high folic acid levels could be at a high risk of cognitive impairment through the accumulation of homocysteine.

Genetic deficiencies in 1c metabolism

Metabolites from folic acid 1C metabolism, particularly tetrahydrofolate (THF), are associated with methionine synthesis, DNA synthesis, polyglutamate deposition, and transulfuration.

Genetic deficiencies that disturb folic acid metabolism lead to an increase in the risk of ischemic stroke. Previous studies have shown that individuals with MTHFR 677TT genetic polymorphism have elevated levels of plasma homocysteine.

Sleep apnea and folic acid metabolism

Obstructive sleep apnea (OSA) is a breathing disorder that may lead to cognitive deficits and cardiovascular diseases via hypoxia. Folic acid is associated with antioxidant pathways that help prevent cognitive decline and cardiovascular diseases linked to OSA.

Previous studies have indicated that increased folic acid intake triggers OSA development due to A methylation discrepancies associated with improper responses to hypoxia.

Conclusions

The current study underscores the importance of optimal folic acid levels for improved health outcomes. It also documents the potential mechanism through which elevated folic acid levels adversely impact health.

This review highlights the necessity of assessing an individual's folic acid requirement prior to recommending additional supplements.