Folate (Vitamin B9)
L-5-Methyltetrahydrofolate
TL;DR
Folate is essential for DNA synthesis and methylation. 400 mcg daily prevents neural tube defects; methylfolate suits those who prefer the active form.
Ideal For
- Women planning pregnancy or in early pregnancy
- People with megaloblastic anaemia
- Those on methotrexate, who need folate replacement
- People with malabsorption, coeliac disease or high alcohol intake
- Those with an MTHFR variant preferring methylfolate
Avoid If
- You have untreated or unassessed B12 deficiency
- You are on methotrexate for cancer, where timing is prescribed
Frequently Asked Questions
Do I need methylfolate instead of folic acid?
When should I start before pregnancy?
Why does B12 need checking first?
Can I get enough from food?
Overview
Folate, vitamin B9, is required for one-carbon metabolism: synthesising purines and thymidylate for DNA, and regenerating methionine from homocysteine so that S-adenosylmethionine can supply methyl groups for hundreds of reactions. Deficiency shows up first in rapidly dividing tissue, producing megaloblastic anaemia, and in the developing neural tube.
Folic acid — the synthetic, fully oxidised form — is what fortification programmes and most trials use, and the public health result has been unambiguous: mandatory fortification reduced neural tube defect rates by 25-50% in the countries that adopted it. Because the neural tube closes by around day 28, before many pregnancies are recognised, all women who could become pregnant are advised to take 400 mcg daily, rising to 4-5 mg where there is a previous affected pregnancy, diabetes, obesity or antiepileptic use.
The MTHFR discussion needs proportion. The C677T variant reduces enzyme activity, and homozygotes have modestly higher homocysteine and lower red cell folate. Methylfolate (5-MTHF) bypasses that step and is a perfectly reasonable choice, but folic acid still works for the great majority of homozygotes at standard doses, and MTHFR testing is not routinely recommended. The one genuine hazard is that folate corrects the anaemia of B12 deficiency while the neurological damage continues silently, so B12 must be checked alongside.
How It Works
- Supplies one-carbon units for purine and thymidylate synthesis in DNA replication
- Regenerates methionine from homocysteine via methionine synthase, which requires B12
- Feeds S-adenosylmethionine production for DNA, protein and neurotransmitter methylation
- Required for neural tube closure in the first 28 days of pregnancy
- Methylfolate bypasses the MTHFR conversion step directly
Quick Facts
- Essential for DNA synthesis and repair
- Critical for fetal neural tube development
- Supports mental health and mood
- Important for heart health
- Up to 40% have genetic variations affecting folate use
Benefits & Outcomes
Sperm Quality
Folate is important for DNA integrity but supplementation has not delivered live birth benefit.
Homocysteine Reduction
Folate reliably lowers homocysteine, typically by 20-25 percent, and is the single most effective nutrient for this marker.
Pregnancy Support
Periconceptional folic acid is one of the best-proven interventions in all of preventive medicine.
DNA Repair Enhancement
Folate is genuinely required for DNA synthesis and repair, and correcting deficiency reduces measurable chromosome damage.
Fertility Support Female
Non-negotiable preconception supplement with definitive evidence.
Cellular Health
Folate is essential for DNA synthesis and repair, and adequate status is important for normal cell division.
Mood Stabilization
L-methylfolate has some support as an add-on to antidepressants, particularly in people with low folate status.
Cognitive Function
Folate lowers homocysteine and may slow cognitive decline in people with high homocysteine, but general cognitive benefit is unproven.
Reproductive Health
Periconceptional folic acid is one of the best-established supplement interventions in medicine for preventing neural tube defects.
Health Concerns Addressed
Alcohol Use Disorder
Standard supportive nutrition in alcohol use disorder. Always assess B12 before supplementing folate to avoid masking a neurological deficiency.
MTHFR Mutation
Several RCTs show folic acid corrects the folate and homocysteine effects of MTHFR C677T, but carrier-specific clinical benefits and any advantage for methylfolate are unproven.
Colorectal Cancer
A dual effect that makes timing decisive — and unknowable in an individual.
Ischemic Stroke
Folic acid lowers homocysteine and produced a modest stroke reduction in folate-unfortified populations, with little effect where fortification exists.
Female Infertility
Essential preconception supplement for fetal development; cohort support for ovulatory benefit. Start before trying.
Hearing Changes
One good trial in a folate-deplete population slowed hearing decline. Unlikely to help where dietary folate is already adequate.
Supporting Research36 studies
MTHFR 677C->T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation
Crider KS, Zhu JH, Hao L +4 more
MTHFR TT was associated with lower folate concentrations
MTHFR C677T and MTR A2756G polymorphisms and the homocysteine lowering efficacy of different doses of folic acid in hypertensive Chinese adults
Qin X, Li J, Cui Y +4 more
CC 10.8% vs. TT: 22.0%, P = 0.005
The impact of MTHFR 677 C/T genotypes on folate status markers: a meta-analysis of folic acid intervention studies
Colson NJ, Naug HL, Nikbakht E +2 more
there were no significant differences in plasma homocysteine levels
Homocysteine and Stroke Risk: Modifying Effect of Methylenetetrahydrofolate Reductase C677T Polymorphism and Folic Acid Intervention
Zhao M, Wang X, He M +4 more
folic acid intervention significantly reduced stroke risk in participants with CC/CT genotypes
Response of serum and red blood cell folate concentrations to folic acid supplementation depends on methylenetetrahydrofolate reductase C677T genotype: results from a crossover trial
Anderson CA, Beresford SA, McLerran D +4 more
this is true for each MTHFR C677T genotype
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
Cochrane KM, Elango R, Devlin AM +3 more
erythrocyte and serum folate did not differ by treatment group
Effect of Methylfolate, Pyridoxal-5'-Phosphate, and Methylcobalamin (SolowaysTM) Supplementation on Homocysteine and Low-Density Lipoprotein Cholesterol Levels in Patients with Methylenetetrahydrofolate Reductase, Methionine Synthase, and Methionine Synthase Reductase Polymorphisms: A Randomized Controlled Trial
Pokushalov E, Ponomarenko A, Bayramova S +4 more
Homozygous Minor Allele Carriers showed a more significant reduction in homocysteine levels
Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies
Tsang BL, Devine OJ, Cordero AM +4 more
a clear pattern of CC > CT > TT
Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age
Lamers Y, Prinz-Langenohl R, Brämswig S +1 more
[6S]-5-MTHF might be an efficient and safe alternative to folic acid
Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials
Holmes MV, Newcombe P, Hubacek JA +4 more
an absence of benefit from lowering of homocysteine for prevention of stroke
5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women
Fohr IP, Prinz-Langenohl R, Brönstrup A +4 more
FA is more effective than MTHF in lowering plasma tHcy
[6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C-->T polymorphism of methylenetetrahydrofolate reductase
Prinz-Langenohl R, Brämswig S, Tobolski O +4 more
[6S]-5-MTHF increases plasma folate more effectively than FA irrespective of the 677C-->T mutation
Effect of vitamin B2, vitamin C, vitamin D, vitamin E and folic acid in adults with essential hypertension: a systematic review and network meta-analysis
Qi S, Luo X, Liu S +3 more
Among the five vitamins, only vitamin E was significantly more effective at reducing SBP
The effects of folinic acid and l-methylfolate supplementation on serum total homocysteine levels in healthy adults
Mazokopakis EE, Papadomanolaki MG, Papadakis JA
no difference in the reduction of serum tHcy levels
Antioxidant Treatment and the Chance to Conceive in Men Seeking Fertility Care: The SUMMER Randomized Clinical Trial
de Ligny WR, de Bruin JP, Smits RM +1 more
The antioxidant supplement (Impryl) ... contained betaine (200 mg), L-cystine (200 mg), niacin (16 mg), zinc (10 mg), vitamin B6 (1.4 mg), vitamin B2 (1.4 mg), folic acid (400 µg), and vitamin B12 (2.5 µg)
Effects and safety of periconceptional oral folate supplementation for preventing birth defects
De-Regil LM, Pena-Rosas JP, Fernandez-Gaxiola AC +1 more
Folic acid supplementation had a protective effect against neural tube defects (RR 0.31).
Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment: A Randomized Clinical Trial
Schisterman EF, Sjaarda LA, Clemons T +8 more
Folic acid and zinc supplementation did not improve live birth rates or semen quality
Dietary supplements for preventing postnatal depression
Miller BJ, Murray L, Beckmann MM +1 more
To assess the benefits of dietary supplements for preventing postnatal depression either in the antenatal period, postnatal period, or both.
Aspirin and folic acid for the prevention of recurrent colorectal adenomas
Logan RF, Grainge MJ, Shepherd VC +2 more
A multicenter, randomized, double-blind trial of aspirin (300 mg/day) and folate supplements (0.5 mg/day) to prevent colorectal adenoma recurrence
L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials
Papakostas GI, et al
Adjunctive L-methylfolate at 15 mg/day may constitute an effective, safe, and relatively well tolerated treatment strategy for patients with major depressive disorder who have a partial response or no response to SSRIs.
B vitamins and prevention of cognitive decline and incident dementia: a systematic review and meta-analysis
Wang Z, et al.
Higher intake of dietary folate, but not B12 or B6, is associated with a reduced risk of incident dementia.
Premature graying of hair: Risk factors, co-morbid conditions, pharmacotherapy and reversal - A systematic review and meta-analysis
Mahendiratta S
Vitamin deficiency (B12, folic acid, and B7) is found to be associated with PGH.
Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial
Smith AD, et al.
The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins.
Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals
Clarke R
Homocysteine lowering by using B vitamins had no significant effect on individual cognitive domains or global cognitive function or on cognitive aging.
Dietary Intervention Modifies DNA Methylation Age Assessed by the Epigenetic Clock
Sae-Lee C, Corsi S, Barrow TM
After supplementation with folic acid + vitamin B12, epigenetic age, estimated by the Horvath "epigenetic clock" model, is reduced in women with the MTHFR 677CC genotype.
Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial
Frye RE, Slattery J, Delhey L +2 more
Improvement in verbal communication was significantly greater in participants receiving folinic acid as compared with those receiving placebo.
The Effect of Vitamin B12 and Folic Acid Supplementation on Serum Homocysteine, Anemia Status and Quality of Life of Patients with Multiple Sclerosis
Nozari E, et al
Serum homocysteine level decrease and anemia status improvement with vitamin B12 and folic acid supplementation reveal the potential role of these two vitamins in improving the life quality of MS patients.
Riboflavin lowers blood pressure in cardiovascular disease patients homozygous for the 677C-->T polymorphism in MTHFR
Horigan G
Riboflavin is effective in reducing blood pressure specifically in patients with the MTHFR 677 TT genotype.
Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials
Li Y, Huang T, Zheng Y +3 more
Folic acid supplementation reduced the risk of stroke by 10% and overall cardiovascular disease by 4%.
Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment: A Randomized Clinical Trial
Schisterman EF, Sjaarda LA, Clemons T +4 more
The use of folic acid and zinc supplementation by male partners, compared with placebo, did not significantly improve semen quality or couples live birth rates.
Effect of B-vitamins on stroke risk among individuals with vascular disease who are not on antiplatelets: A meta-analysis
Park JH, Saposnik G, Ovbiagele B +1 more
randomized controlled trials of homocysteine-lowering therapy with B-vitamins
Impact of folic acid supplementation on the epigenetic profile in healthy unfortified individuals - a randomized intervention trial
Michels KB, Binder AM
We conducted a randomized intervention trial to test the influence of folic acid supplementation on DNA methylation in an unfortified population in Germany.
Effects of folic acid supplementation on hearing in older adults: a randomized, controlled trial
Durga J, Verhoef P, Anteunis LJ +2 more
After 3 years, thresholds of the low frequencies increased by 1.0 dB in the folic acid group and by 1.7 dB in the placebo group (difference, -0.7 dB; P = 0.020). Folic acid supplementation did not affect the decline in hearing high frequencies.
Efficacy of Folic Acid Therapy in Primary Prevention of Stroke Among Adults With Hypertension in China (CSPPT)
Huo Y, Li J, Qin X +3 more
First stroke occurred in 2.7% of participants receiving enalapril plus folic acid versus 3.4% receiving enalapril alone.
Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals
Vollset SE, Clarke R, Lewington S +3 more
Folic acid supplementation did not substantially increase or decrease incidence of site-specific or overall cancer.
Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people
Malouf R, Grimley Evans J
There was no consistent evidence that folic acid, with or without vitamin B12, improved cognitive function in healthy or cognitively impaired older people.
Safety Information
Potential Side Effects
Very well tolerated. High supplemental doses can cause unmetabolised folic acid in circulation, the long-term significance of which is debated. Masking of B12 deficiency is the clinically important risk, not direct toxicity.
Contraindications
Never supplement folate without checking B12 status. Folate corrects the megaloblastic anaemia of B12 deficiency while allowing irreversible neurological damage to progress unnoticed.
Drug Interactions
- Methotrexate — a folate antagonist; folate is co-prescribed in rheumatology but timing matters in oncology
- Antiepileptics including phenytoin, carbamazepine and valproate — deplete folate and folate can lower drug levels
- Sulfasalazine and trimethoprim — inhibit folate absorption or metabolism
- Alcohol — impairs folate absorption and increases excretion
Pregnancy & Breastfeeding
Pregnancy: Considered safe
Breastfeeding: Considered safe
Dosage Guidelines
Dosage Used in Studies
400-800 mcg
Best Time to Take
Morning, consistently, so it is not missed
Best Form
Folic acid for straightforward prevention; L-methylfolate for those who prefer the active form or have an MTHFR variant
Bioavailability
Methylfolate (5-MTHF) bypasses MTHFR enzyme, better for those with genetic variants. Folic acid requires conversion. Essential for DNA synthesis and cell division.
Dosing by Goal
| Goal | Dose | Notes |
|---|---|---|
| RDA | 400 mcg dietary folate equivalents per day for adults | |
| Deficiency | 1-5 mg/day until corrected | |
| High-risk pregnancy | 4-5 mg/day where there is a previous neural tube defect, diabetes, obesity or antiepileptic use | |
| Preconception and pregnancy | 400-800 mcg/day, starting at least one month before conception | |
| Upper limit | 1000 mcg/day of supplemental folic acid for adults |
Forms Compared
Folic acid
Synthetic, stable, used in fortification and virtually all clinical trials
L-methylfolate (5-MTHF)
The active circulating form; bypasses MTHFR conversion
Folinic acid
Used in medicine to rescue methotrexate toxicity; also a supplemental form
Food folate
Leafy greens, legumes, liver and citrus; less stable and less bioavailable than folic acid
Food & Timing
With or without food
Medical Disclaimer
The information provided on this website is for educational and informational purposes only and is not intended as a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition or before starting any supplement regimen.
Individual results may vary. The statements on this website have not been evaluated by the Food and Drug Administration. Products and information are not intended to diagnose, treat, cure, or prevent any disease.