Folate
Folate, also known as vitamin B9, is a water-soluble vitamin commonly supplemented as folic acid or its bioactive form, 5-methyltetrahydrofolate (5-MTHF), essential for DNA synthesis, cell division, and red blood cell formation. It supports the prevention of neural tube defects in early pregnancy, making it critical for prenatal health. Folate aids in homocysteine metabolism, reducing levels that are linked to cardiovascular disease and cognitive decline. It also supports mood regulation by contributing to neurotransmitter synthesis, potentially alleviating symptoms of depression. Supplements typically provide 400–800 mcg/day, with higher doses (up to 5 mg) used for deficiency or pregnancy. Excessive intake (>1000 mcg/day of folic acid) may mask vitamin B12 deficiency or cause side effects like digestive upset or, rarely, neurological issues. Consult a healthcare provider for appropriate dosing, especially if on medications like methotrexate or with conditions affecting folate metabolism.
Benefits
May Improve Mental Health
Folate plays a role in neurotransmitter production, and low levels are linked to depression and cognitive decline. Some studies suggest folate supplements may support mood and cognitive function, particularly in those with deficiency.
Potential Cancer Risk Reduction
Adequate folate may lower the risk of certain cancers (e.g., colorectal) by supporting DNA repair. However, excessive folic acid intake might promote tumor growth in some cases, so moderation is key.
Aids in Fertility
Folate supports reproductive health in both men and women by improving sperm quality and ovulation, potentially enhancing fertility outcomes.
Supports DNA Synthesis and Cell Division
Folate is critical for DNA and RNA production, making it essential for cell growth and repair. This is especially important during periods of rapid growth, such as pregnancy or infancy.
Prevents Neural Tube Defects in Pregnancy
Folate supplementation (often as folic acid) is widely recommended for pregnant women or those planning pregnancy. It significantly reduces the risk of neural tube defects like spina bifida in developing fetuses. The recommended dose is typically 400–800 mcg daily for women of childbearing age.
Reduces Risk of Anemia
Folate aids in red blood cell production. Deficiency can lead to megaloblastic anemia, characterized by large, immature red blood cells. Supplementation helps correct this, improving energy and oxygen transport.
Supports Heart Health
Folate helps lower homocysteine levels, an amino acid linked to heart disease when elevated. By reducing homocysteine, folate may decrease the risk of cardiovascular issues, though evidence on direct heart disease prevention is mixed.
Mechanism of Action
DNA and RNA Synthesis
Folate, as THF, donates one-carbon units in the synthesis of purines and pyrimidines, the building blocks of DNA and RNA. Specifically, it supports the conversion of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (TMP), a key step in DNA synthesis, catalyzed by the enzyme thymidylate synthase. This is crucial for cell division and growth, particularly in rapidly dividing cells like those in bone marrow, skin, or the developing fetus.
Methylation Reactions
Folate is integral to the methionine cycle, where 5-methyltetrahydrofolate (5-MTHF) donates a methyl group to homocysteine, converting it to methionine via the enzyme methionine synthase, with vitamin B12 as a cofactor. Methionine is then converted to S-adenosylmethionine (SAM), the primary methyl donor for DNA, RNA, proteins, and lipid methylation, influencing gene expression and epigenetic regulation.
Homocysteine Metabolism
By facilitating the conversion of homocysteine to methionine, folate helps prevent the accumulation of homocysteine, high levels of which are associated with cardiovascular disease and neurological issues.
Red Blood Cell Formation
Folate supports erythropoiesis (red blood cell production) by enabling DNA synthesis in developing red blood cells. Deficiency can lead to megaloblastic anemia, characterized by large, immature red blood cells.
Antioxidant and Cellular Protection
Folate indirectly supports cellular health by maintaining proper methylation and reducing oxidative stress, which can protect against DNA damage and related diseases.
Clinical Trials
Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial
Study: The Folic Acid and Carotid Intima-media Thickness (FACIT) trial was a randomized, double-blind, placebo-controlled study conducted in the Netherlands. It involved 818 older adults (aged 50–70 years) with elevated homocysteine levels, randomized to receive 800 mcg/day of folic acid or placebo for 3 years. The study assessed cognitive function using neuropsychological tests.
Findings: Folic acid supplementation significantly improved cognitive performance, particularly in memory and information processing speed, compared to placebo. Homocysteine levels decreased by 26% in the folic acid group. No significant effect was observed on global DNA methylation.
Link: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)60109-3/fulltext
Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial
Study: The Folic Acid Clinical Trial (FACT) was a randomized, double-blind, placebo-controlled, phase III trial conducted across 70 obstetrical centers in Argentina, Australia, Canada, Jamaica, and the UK. It included 2,464 pregnant women with at least one risk factor for pre-eclampsia (e.g., pre-existing hypertension, diabetes, twin pregnancy, prior pre-eclampsia, or BMI ≥35). Participants were randomized to receive 4.0 mg/day folic acid or placebo from 8–16 weeks of gestation until delivery.
Findings: High-dose folic acid (4.0 mg/day) did not significantly reduce the incidence of pre-eclampsia compared to placebo. However, maternal serum folate levels increased significantly, with no evidence of altered 1-carbon metabolism. Higher unmetabolized folic acid (UMFA) concentrations were noted in the high-dose group, suggesting supraphysiologic dosing.
Link: https://www.bmj.com/content/362/bmj.k3478
Folate Augmentation of Treatment – Evaluation for Depression (FolATED): randomised trial and economic evaluation
Study: The FolATED trial was a double-blind, placebo-controlled, randomized trial conducted in three centers in Wales. It included 453 participants with depression, aiming to assess whether 5 mg/day folic acid augmented antidepressant medication. The primary outcome was the Beck Depression Inventory version 2 (BDI-II) score, with a target of 358 participants for 80% power to detect a small effect.
Findings: Folic acid (5 mg/day) showed no clinical or cost-effectiveness in augmenting antidepressant treatment. The study suggested methylfolate might be a better candidate for depression treatment, challenging guidelines advocating folic acid.
Link: https://www.ncbi.nlm.nih.gov/books/NBK262347
Folic acid supplementation improves cognitive function by reducing the levels of peripheral inflammatory cytokines in elderly Chinese subjects with MCI
Study: This randomized controlled trial (RCT) in Tianjin, China, involved 152 elderly participants with mild cognitive impairment (MCI). Participants were assigned to receive 400 mcg/day folic acid or conventional treatment for 12 months. Neuropsychological tests and biomarkers (folate, homocysteine, vitamin B12, IL-6, TNF-α, Aβ-42, Aβ-40) were measured at baseline, 6, and 12 months.
Findings: The folic acid group showed significant improvements in cognitive performance (Full Scale IQ), folate levels, and reductions in homocysteine, IL-6, TNF-α, and Aβ-42 compared to the conventional treatment group. The study suggests folic acid may improve cognition by reducing inflammatory cytokines.
Link: https://www.nature.com/articles/srep37486
A pilot trial examining the absorption of oral forms of folate supplementation in a healthy population: A randomized control trial
Study: This single-blind pilot RCT in Australia involved 30 healthy individuals to compare the absorption of three folate forms: folic acid, folinic acid, and 5-methyltetrahydrofolate (5-MTHF). Participants received one of these supplements or a control for 4 weeks, with serum folate levels measured at baseline, week 2, and week 4.
Findings: Folinic acid showed the highest increase in serum folate levels, followed by 5-MTHF, compared to controls (p=0.0005 at week 2, p=0.0003 at week 4). No significant changes occurred in the control group. Further research is needed to confirm tissue utilization of folinic acid.
Link: https://www.sciencedirect.com/science/article/pii/S2405844022019636
Secondary prevention with folic acid: effects on clinical outcomes
Study: This RCT, published in the Journal of the American College of Cardiology, investigated folic acid supplementation (0.5 mg/day) in 593 patients with coronary artery disease (CAD) post-angioplasty, without stent placement. The study measured restenosis rates and clinical outcomes over 12 months.
Findings: Folic acid reduced homocysteine levels by 18% and significantly lowered the rate of restenosis after coronary angioplasty (without stents). However, no significant reduction in vascular events was observed (16.3% in folic acid group vs. 19.1% in controls).
Link: https://www.jacc.org/doi/10.1016/S0735-1097%2803%2900485-5
Folate therapy and in-stent restenosis after coronary stenting
Study: This double-blind, multicenter RCT by Lange et al. enrolled 636 patients undergoing coronary stenting, randomized to receive folate (1 mg/day) or placebo. Homocysteine levels and coronary angiograms were assessed before and 6 months after stenting.
Findings: Folate reduced homocysteine levels (9.0 μmol/L, p<0.001), but increased the risk of in-stent restenosis by 8% (p=0.05). Coronary luminal diameter decreased (1.59 mm vs. 1.74 mm, p=0.008), suggesting an adverse effect of folate in stented patients.
Link: https://www.nejm.org/doi/full/10.1056/NEJMoa032758
Norwegian Vitamin Trial (NORVIT)
Study: The NORVIT trial, referenced in The Lancet, was the largest RCT to test folate supplementation (0.8 mg/day) for cardiovascular disease (CVD) prevention in patients with a history of myocardial infarction. It included over 3,000 participants, assessing cardiovascular events over several years.
Findings: Folate supplementation reduced homocysteine levels but showed no benefit in reducing the risk of cardiovascular events (e.g., coronary heart disease or stroke). A potential increase in adverse events was noted, disappointing expectations from observational studies.
Link: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)67737-0/fulltext
Potential Side Effects
Gastrointestinal Issues
Nausea, bloating, or upset stomach. Loss of appetite or flatulence in some individuals.
Masking Vitamin B12 Deficiency
High doses of folic acid can correct anemia caused by B12 deficiency but mask neurological damage, potentially leading to irreversible nerve damage if B12 deficiency is untreated.
Allergic Reactions (Rare)
Rash, itching, or breathing difficulties in sensitive individuals.
Sleep Disturbances
Some people report insomnia or restlessness, particularly with high doses.
Mood or Behavioral Changes
Rare cases of irritability, excitability, or depression, especially in those with pre-existing mental health conditions.
Potential Cancer Risk
Excessive folic acid intake (e.g., >1,000 mcg/day) may increase the risk of certain cancers (e.g., colorectal or prostate) in some studies, though evidence is conflicting.
Kidney or Liver Strain
Very high doses may stress kidneys or liver, particularly in those with pre-existing conditions.