Vitamin B9 (folic acid): benefits, dosage, contraindications
Other name(s)
Folic acid, folate
Scientific name(s)
5'-methyltetrahydrofolate
Family or group:
Vitamins
Indications
Scoring methodology
EFSA approval.
Vitamin B9 deficiency ✪✪✪✪✪
The mismatch between dietary intake and needs is the leading cause of deficiency worldwide, particularly when requirements increase (pregnancy, breastfeeding, chronic hemolysis) or when digestive absorption is impaired in chronic diarrhea and inflammatory digestive diseases (Crohn's disease, tropical sprue, celiac disease). Chronic alcoholism also causes deficiencies related to inadequate intake, malabsorption, impaired hepatic uptake, and increased renal excretion. Renal failure requiring dialysis is also associated with folate deficiency, as are certain "antimetabolite" treatments that impair the use of folates, such as antiepileptic drugs. The most typical consequence of these deficiencies is hematopoietic, a direct reflection of decreased DNA synthesis. This explains the mucosal disorders associated with these deficiencies, notably glossitis, and above all the classic megaloblastic anemia. Vitamin B9 deficiency is also accompanied by various neurological disorders, due to shortages of ATP and GTP (coenzymes that transfer phosphate groups) and of the phospholipids that form myelin sheaths. In cases of anemia, doses of about 5 to 15 mg per day are usually prescribed.
Posologie
Oral
0.33 - 15 mg
Pregnancy ✪✪✪✪✪
Epidemiological studies have shown an association between mothers' folic acid status and the frequency of miscarriages, the rate of prematurity, and neural tube defects. rnrnWomen's folate needs increase by 50% during pregnancy, during which, in the first trimester, an intake of at least 600 micrograms/day (600 mcg/day) of folate is recommended. Before conception, supplementation with 400 mcg of folate is recommended for 1 to 3 months. rnrnWomen with a history of congenital neural tube defects generally take a higher dose of folic acid corresponding to 4 mg per day, starting one month before and continuing up to 3 months after conception.rnrn
Posologie
Orally
0.4 - 4 mg
Synergies
Folic acid supplementation for the prevention of neural tube defects: US preventive services task force recommendation statement
Folic acid supplementation for the prevention of neural tube defects: US preventive services task force recommendation statement.
The effect of folic acid, protein energy and multiple micronutrient supplements in pregnancy on stillbirths.
Folic acid, methylation and neural tube closure in humans.
Folate status during pregnancy in women is improved by long-term high vegetable intake compared with the average western diet.
Scientific Opinion on the substantiation of health claims related to folate and blood formation (ID 79), homocysteine metabolism (ID 80), energy-yielding metabolism (ID 90), function of the immune system (ID 91), function of blood vessels (ID 94, 175, 192), cell division (ID 193), and maternal tissue growth during pregnancy (ID 2882)
Guidelines for Perinatal Care. 7th ed. Washington, DC: The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists;
Letter regarding dietary supplement health claim for folic acid with respect to neural tube defects.
Effect of folic acid supplementation during pregnancy on gestational hypertension/preeclampsia: A systematic review and meta-analysis.
Maternal folic acid supplementation for the prevention of preeclampsia: A systematic review and meta-analysis.
Folic acid to reduce neonatal mortality from neural tube disorders.
Fatigue ✪✪✪✪✪
Vitamin B9 (folate) plays a role in reducing fatigue by supporting cellular energy production and regulating oxygen in the body. Folate is involved in several one-carbon transfer reactions essential for amino acid metabolism and the synthesis of nucleic acids. rnrnFolate deficiency can lead to megaloblastic anemia, reducing the blood's oxygen-carrying capacity and increasing fatigue. Supplementation with folate and B vitamins can be an effective strategy to support cognitive function and reduce fatigue. rnrnThe European health authorities (EFSA, the European Food Safety Authority, and the European Commission) have concluded that dietary supplements containing vitamin B9 can claim to contribute to the reduction of fatigue and to normal cognitive function.
Posologie
Oral
0.4 - 15 mg
Synergies
Scientific Opinion on the substantiation of health claims related to folate and contribution to normal psychological functions (ID 81, 85, 86, 88), maintenance of normal vision (ID 83, 87), reduction of tiredness and fatigue (ID 84), cell division (ID 195, 2881) and contribution to normal amino acid synthesis (ID 195, 2881)
Fetal development ✪✪✪✪✪
Folic acid, essential before and during pregnancy, plays a key role in fetal development. Low folic acid levels increase the risk of congenital malformations such as neural tube defects. Supplementation with folic acid before conception and during the first months of pregnancy is associated with a significant reduction in these risks. rnrnA Cochrane review showed that folic acid supplementation improves mean birth weight and reduces the incidence of megaloblastic anemia, with no significant impact on pregnancy outcomes such as preterm birth or preeclampsia.rnrnClinical guidelines recommend that anyone who may become pregnant take 400 mcg of folic acid daily through fortified foods or supplements to prevent neural tube defects in infants. During pregnancy, 600 mcg of folic acid per day is advised. rnrn
Posologie
Oral
0.33 - 15 mg
Synergies
Folic Acid Supplementation for the Prevention of Neural Tube Defects: US Preventive Services Task Force Recommendation Statement
Folic acid supplementation during pregnancy for maternal health and pregnancy outcomes
Depression ✪✪✪✪✪
Studies suggest that depression is linked to low folate levels, particularly in women. Oral folic acid taken in combination with conventional antidepressants appears to improve treatment response in patients with major depressive disorder. However, taking folic acid alone does not appear to be effective.rnrnFolic acid has been used at a dose of 200 mcg to 15 mg per day for 6 months, in combination with antidepressants.rnrn
Posologie
Oral
0.2 - 15 mg
6 - months
Oral 5'-methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study.
Enhancement of the antidepressant action of fluoxetine by folic acid: a randomized, placebo-controlled trial.
Is low folate a risk factor for depression? A meta-analysis and exploration of heterogeneity.
Folate for depressive disorders.
Relationship of homocysteine, folic acid and vitamin B12 with depression in a middle-aged community sample.
Plasma folate concentrations are associated with depressive symptoms in elderly Latina women despite folic acid fortification.
Hyperhomocysteinemia ✪✪✪✪✪
Oral folic acid intake lowers fasting homocysteine levels by 20% to 30% in people with normal to moderately elevated homocysteine levels. The higher the homocysteine level and the lower the folate level before treatment, the greater the effect of folic acid supplementation.rnrnOther evidence suggests that the higher the initial homocysteine levels, the lower the dose of folic acid required to achieve the maximal reduction in homocysteine levels. rnrnThe effects of folic acid supplementation on homocysteine concentrations appear to be greater in women than in men.rnrnMoreover, the combination of 50 to 250 mg of pyridoxine and folic acid appears to further reduce postprandial hyperhomocysteinemia. This combination is generally recommended. In addition, adding 500 mcg of vitamin B12 daily to folic acid results in an additional average reduction in homocysteine levels of about 7%, but this effect is likely present only in people who are vitamin B12 deficient.rnrnA dose of 200 mcg to 15 mg per day of folic acid for 4 weeks to 3.5 years has been used, with or without vitamin B12 and/or pyridoxine.rnrn
Posologie
Oral
0.2 - 15 mg
Potential clinical and economic effects of homocyst(e)ine lowering.
Vitamin supplementation reduces blood homocysteine levels: a controlled trial in patients with venous thrombosis and healthy volunteers.
Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials.
Folate status of elderly women following moderate folate depletion responds only to a higher folate intake.
Secondary prevention with folic acid: effects on clinical outcomes.
Diagnosis and treatment of hyperhomocysteinemia.
The effect of different treatment regimens in reducing fasting and postmethionine-load homocysteine concentrations.
Folic acid and reduction of plasma homocysteine concentrations in older adults: a dose-response study.
Multivitamin supplements are effective and inexpensive agents to lower homocysteine levels.
Combination of low-dose folic acid and pyridoxine for treatment of hyperhomocysteinemia in patients with premature arterial disease and their relatives.
Randomized trial of folic acid supplementation and serum homocysteine levels.
Lowering blood homocysteine with folic acid-based supplements: meta-analysis of randomized trials. Homocysteine Lowering Trialists' Collaboration.
Renal insufficiency ✪✪✪✪✪
More than 85% of people with end-stage renal disease (ESRD) have hyperhomocysteinemia, due to reduced renal clearance and metabolism of homocysteine in severe renal failure; additionally, hemodialysis can contribute to vitamin deficiencies. Oral folic acid intake reduces homocysteine levels in patients with ESRD. Daily doses of 800 mcg to 15 mg are generally used. In many studies, folic acid has been combined with vitamin B12 and pyridoxine.
Posologie
Oral administration
0.8 - 15 mg
Hyperhomocysteinemia in hemodialysis patients: effects of 12-month supplementation with hydrosoluble vitamins.
Treatment of hyperhomocysteinemia in hemodialysis patients and renal transplant recipients.
Does folic acid decrease plasma homocysteine and improve endothelial function in patients with predialysis renal failure?
Enhanced reduction of fasting total homocysteine levels with supraphysiological versus standard multivitamin dose folic acid supplementation in renal transplant recipients.
Treatment of mild hyperhomocysteinemia in renal transplant recipients versus hemodialysis patients.
Effect of high dose folic acid therapy on hyperhomocysteinemia in hemodialysis patients: results of the Vienna multicenter study.
Oral vitamin B(12) and high-dose folic acid in hemodialysis patients with hyper-homocyst(e)inemia.
Homocysteine lowering effect of different multivitamin preparations in patients with end-stage renal disease.
Controlled comparison of L-5-methyltetrahydrofolate versus folic acid for the treatment of hyperhomocysteinemia in hemodialysis patients.
High blood pressure ✪✪✪✪✪
Clinical research shows that daily intake of 5 to 10 mg of folic acid for at least 6 weeks reduces systolic blood pressure by 2.03 mmHg and improves vascular dilation in people with hypertension.rnrnFurthermore, some studies have shown that taking folic acid in combination with enalapril (an antihypertensive medication) does not improve blood pressure compared to enalapril alone.rnrn
Posologie
Oral
5 - 10 mg
6 - weeks
Folic acid therapy reduces the risk of mortality associated with heavy proteinuria among hypertensive patients.
High-dose folic acid supplementation effects on endothelial function and blood pressure in hypertensive patients: a meta-analysis of randomized controlled clinical trials.
Stroke ✪✪✪✪✪
Epidemiological studies have shown that people with higher dietary folate intake have a reduced risk of hemorrhagic stroke but not ischemic stroke. Several studies conducted in regions lacking policies to fortify foods with folic acid have found that folic acid supplementation, with or without other B vitamins, reduces the risk of stroke by 10% to 25%. The effect appears to be greater when folic acid is taken at low doses (generally 0.8 mg per day or less), in patients with higher baseline cholesterol, in patients whose homocysteine level decreased by at least 20%, and in patients with the lowest baseline folate levels.
Posologie
Oral
0.8 mg
Folic Acid Supplementation for Stroke Prevention in Patients With Cardiovascular Disease.
Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials.
Meta-analysis of folic acid efficacy trials in stroke prevention: Insight into effect modifiers.
Efficacy of folic acid supplementation in cardiovascular disease prevention: an updated meta-analysis of randomized controlled trials.
Efficacy of folic acid supplementation in stroke prevention: new insight from a meta-analysis.
Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial.
Efficacy of folic acid supplementation in stroke prevention: a meta-analysis.
Folate, vitamin B12, and risk of ischemic and hemorrhagic stroke: a prospective, nested case-referent study of plasma concentrations and dietary intake.
AMD ✪✪✪✪✪
A large-scale clinical study shows that taking 50 mg of pyridoxine per day in combination with 1 mg of cyanocobalamin and 2.5 mg of folic acid, for an average of 7.3 years, significantly reduces the risk of developing AMD (age-related macular degeneration) in women aged 40 with a history of cardiovascular disease or who have cardiovascular risk factors, compared with placebo.
Posologie
Oral
2.5 mg
Cognitive decline ✪✪✪✪✪
Research indicates that folic acid may play a role in preventing cognitive decline, particularly in older people with elevated homocysteine levels, a factor associated with increased risks of neurodegenerative diseases. One study administered 800 mcg/day of folic acid for 3 years to participants with high homocysteine levels, observing a notable improvement in several cognitive domains. Other studies have explored the impact of folic acid on cognitive decline, showing positive results. A clinical trial in patients over 65 with mild cognitive impairment found that daily supplementation with 400 mcg of folic acid for two years improved IQ scores. Other research has reported improvements in cognitive function with higher doses. Combining folic acid with other B vitamins or DHA has also shown benefits.
Posologie
Oral
0.4 - 15 mg
Synergies
Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial
Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomized, double-blind, controlled trial
Influences of Folate Supplementation on Homocysteine and Cognition in Patients with Folate Deficiency and Cognitive Impairment
Scientific Opinion on the substantiation of health claims related to folate and contribution to normal psychological functions (ID 81, 85, 86, 88), maintenance of normal vision (ID 83, 87), reduction of tiredness and fatigue (ID 84), cell division (ID 195, 2881) and contribution to normal amino acid synthesis (ID 195, 2881)
Effect of folic acid combined with docosahexaenoic acid intervention on mild cognitive impairment in elderly: a randomized double-blind, placebo-controlled trial
Alzheimer's disease ✪✪✪✪✪
Clinical evidence suggests that older adults who have a dietary intake of folate or folic acid supplementation higher than the recommended nutritional intake have a reduced risk of developing Alzheimer's disease compared with those with lower intake.rnrnClinical research suggests that taking 1 mg of folic acid per day for 6 months appears to improve the response of patients with Alzheimer's disease to cholinesterase inhibitors compared with placebo.rnrn
Posologie
Oral
1 - 1 mg
6 - months
Reduced risk of Alzheimer's disease with high folate intake: the Baltimore Longitudinal Study of Aging.
Effects of folic acid supplementation on cognitive function and Aβ-related biomarkers in mild cognitive impairment: a randomized controlled trial
Properties
Essential
Vitamin B9 acts as a coenzyme in intracellular metabolism and is essential for the proper functioning of cells. Indeed, in the body, folates are involved as cofactors in one-carbon unit transfer reactions that are essential to cellular metabolism, since they participate in nucleotide synthesis, the synthesis of certain amino acids and, indirectly, in the transfer of methyl groups. Vitamin B9 also plays a role in maintaining pregnancy and in preventing fetal development problems (cleft lip, neural tube closure defects). Vitamin B9 deficiency is accompanied by various neurological disorders, due to deficiencies in ATP and GTP (coenzymes for phosphate group transfer) and in the phospholipids that form the myelin sheaths. Furthermore, in the bone marrow, a deficiency of vitamin B9 leads to abnormal cell maturation and division, producing abnormal red blood cell precursors called megaloblasts. Megaloblasts are unable to complete maturation into red blood cells and many of them are phagocytosed by macrophages in the bone marrow, resulting in anemia called megaloblastic anemia.
Usages associés
Cardiovascular
Folic acid can improve endothelial dysfunction in people with atherosclerosis and at high risk of developing coronary artery disease. There is also evidence that folic acid can decrease levels of von Willebrand factor (a factor necessary for platelet adhesion and the transport of factor VIII in blood coagulation). Folic acid can also decrease fibrinogen concentrations (a coagulation factor). On the other hand, the remethylation of homocysteine to methionine requires folate and vitamin B12 as cofactors. So a folic acid deficiency is associated with increased homocysteine levels, which are known to be a risk factor for cardiovascular disease. The higher the homocysteine level, the better the response to folic acid treatment. Moreover, folic acid has little effect on normal homocysteine levels.
Usages associés
Cognitive function
Evidence suggests that low folate concentration may be linked to atrophy of the cerebral cortex. In addition, in older adults, functional and mental deterioration is sometimes associated with low folate levels. In patients with Alzheimer's disease, folic acid may improve the response to cholinesterase inhibitors by reducing homocysteine levels.
Usages associés
Antidepressant
Folic acid deficiency is common in people with depression. Low folate levels have been linked to poor response to antidepressant treatment. rnrnIn the general population, people with low folic acid levels or low dietary folate intake have a higher risk of developing depression. Additionally, low folate levels have been linked to poor response to antidepressant treatment. The exact role of folic acid in depression is not yet known, but it is necessary for the remethylation of homocysteine to methionine and for the formation of S-adenosylmethionine (SAMe). The remethylation of homocysteine to methionine is important because it prevents the accumulation of homocysteine, a risk factor for cardiovascular disease and potentially for depression. Methionine is then converted into S-adenosylmethionine (SAMe), a molecule involved in the synthesis of neurotransmitters such as serotonin and dopamine, which are essential for mood. rnrnFolic acid also participates in the methylation of tetrahydrobiopterin, an essential cofactor for hydroxylase enzymes involved in the production of neurotransmitters such as serotonin.
Usages associés
Anticancer
Some cancers, such as malignant hematologic disorders or colorectal cancers, have been statistically associated with reduced folate levels. Potentially harmful effects of folic acid supplementation on tumor progression have been suggested but remain debated. rnrn
Safe dosage
Infant up to 12 months: 80 µg
Child 1 to 3 years: 120 µg - 200 µg
Adult 18 years and older: 330 µg - 1000 µg
Child 4 to 6 years: 140 µg - 300 µg
Child 7 to 10 years: 200 µg - 400 µg
Child 11 to 14 years: 270 µg - 600 µg
Child 15 to 17 years: 330 µg - 800 µg
Pregnant women 18 years and older: 600 µg - 1000 µg
Breastfeeding women 18 years and older: 500 µg - 1000 µg
Interactions
Médicaments
Anticonvulsants: moderate interaction
Folic acid may be a cofactor in the metabolism of phenytoin. At doses of 1 mg per day or more, folic acid may reduce serum phenytoin levels in some patients. In addition, phenytoin also reduces serum folate levels.rnrnFolic acid may have a direct convulsant activity in some people, which may impair seizure control by phenobarbital. Phenytoin may also reduce serum folate levels.rnrnOn the other hand, carbamazepine may reduce serum folic acid levels. Possible mechanisms include reduced absorption of folic acid and increased metabolism by hepatic enzymes.
5-fluorouracil: moderate interaction
Theoretically, high doses of folic acid could increase the toxicity of 5-fluorouracil. An increase in gastrointestinal side effects with 5-fluorouracil, such as stomatitis and diarrhea, has been reported.
Methotrexate: moderate interaction
Methotrexate exerts cytotoxic effects by preventing the conversion of folic acid to the active form required by cells. There is evidence that folic acid supplements reduce the effectiveness of methotrexate in the treatment of acute lymphoblastic leukemia and, theoretically, they may reduce its effectiveness in the treatment of other cancers. In addition, methotrexate can reduce serum folate levels.
Estrogens: moderate interaction
Reduced serum folate levels may occur in some women taking conjugated estrogens or oral contraceptives, but this effect is unlikely in women with an adequate dietary intake of folate. Possible mechanisms by which estrogens contribute to folate deficiency include reduced absorption of dietary folate, increased excretion, induction of hepatic enzymes, and increased binding of folate to serum proteins.
