Folate (Vitamin B9)
vitamin · also known as folate, folic acid, methylfolate, L-methylfolate, 5-MTHF, L-5-MTHF, levomefolic acid, Metafolin, Quatrefolic, folinic acid, vitamin B-9, B9
This is general information, not medical advice. Supplements can interact with medicines and health conditions. Always check with your doctor or pharmacist before starting or changing supplements.
What it is
Folate is the water-soluble B vitamin required for DNA synthesis and cell division, and for converting homocysteine to methionine. "Folate" is the natural family found in leafy greens, legumes and liver; "folic acid" is the synthetic form used in supplements and in fortified staple foods, and it is the form behind almost all of the trial evidence. Folate carries the single strongest claim on this site: taken around the time of conception, folic acid prevents a large proportion of neural tube defects, a finding from randomised trials so clear it reshaped food policy in dozens of countries. Outside pregnancy the picture is more mixed and more interesting. Folic acid reliably lowers homocysteine and modestly reduces stroke risk, but does not reduce heart attacks or overall mortality. And it carries two genuine cautions that most labels do not mention: it can mask the anaemia of vitamin B12 deficiency while nerve damage continues underneath, and prolonged high-dose use has been associated in trials with more advanced colorectal lesions and, in one secondary analysis, more prostate cancer.
Which form to choose
Grades here rate how well the evidence supports choosing a form, which is not the same as how much that form has been studied: a well-studied form can be graded low precisely because the studies argue against it. This is a different scale from the claim grades below — see our editorial policy.
The synthetic form, and the one used in essentially every trial cited below, including both neural tube defect trials and the stroke trial. It is more stable and more efficiently absorbed than natural food folate — roughly 1.7 times so, which is why reference intakes are expressed in dietary folate equivalents. It is not itself active: the body must reduce it enzymatically, and above roughly 200-280 mcg absorbed at once that capacity is exceeded and unmetabolised folic acid appears in the bloodstream. That this happens is well established. What it does to you, if anything, is not: no trial has linked circulating unmetabolised folic acid to a clinical outcome, and treating it as a known harm overstates what is known.
Graded on trial use, which for folate is the decisive consideration. Every clinical outcome this monograph reports rests on folic acid: both randomised neural tube defect prevention trials used it, as did the homocysteine meta-analysis and the stroke prevention trial. No other folate form has an outcome trial behind it. The known drawback is real but narrower than it is usually made to sound: above roughly 200 to 280 mcg absorbed at once, unmetabolised folic acid appears in blood, and no trial has linked that to a clinical outcome.
The predominant form circulating naturally in blood, sold as Metafolin or Quatrefolic among others. It needs no enzymatic reduction, and in a crossover pharmacokinetic trial an equimolar dose produced roughly 2.25 times the area under the curve and 3.3 times the peak concentration of active plasma folate compared with folic acid, with no transient unmetabolised folic acid. A pharmacokinetic review nonetheless concludes the two have comparable physiological activity for raising folate status and lowering homocysteine at equimolar doses. Two theoretical advantages are often cited — less potential to mask B12 deficiency, and less interaction with drugs that inhibit dihydrofolate reductase such as methotrexate — and both remain mechanistic arguments rather than demonstrated clinical outcomes. The MTHFR marketing claim is discussed in the dosage notes below; it is weaker than it sounds.
Graded on comparative absorption, not on trial use, and the gap between those is the whole point. It reaches active plasma folate more efficiently than folic acid at equimolar doses and avoids the unmetabolised folic acid that follows a large folic acid dose, and a pharmacokinetic review judges the two comparable for raising folate status and lowering homocysteine. No outcome trial has used it: the neural tube and stroke evidence is folic acid's. So it is well supported as a way to raise folate status and unproven as a way to prevent anything, which is a real distinction where a reader is choosing between them.
Pharmacologically well established — it is used clinically as leucovorin to rescue patients from methotrexate toxicity — but much less common as a consumer supplement. In a three-month randomised trial in 272 healthy adults it raised serum folate more than L-methylfolate did, while lowering homocysteine to a similar degree overall. The genotype result from that trial is the interesting part, and it cuts against the usual marketing: people carrying one copy of the MTHFR C677T variant did significantly better on folinic acid than on L-methylfolate.
Graded on comparative absorption, with no trial use behind it. A systematic review of oral folate forms finds folinic acid raises folate status effectively, and it is pharmacologically well established in clinical use as leucovorin. What is missing is any outcome trial in general supplementation: nothing here shows it prevents anything. It sits below folic acid for that reason and below L-methylfolate on availability and study volume, while the MTHFR C677T result noted above is a genuine point in its favour that deserves more study than it has had.
Evidence-based benefits
Folic acid taken around the time of conception substantially reduces the risk of neural tube defects, both in women who have had a previously affected pregnancy and in women having a first pregnancy.
The MRC Vitamin Study randomised 1,817 women at high risk because of a previous affected pregnancy across 33 centres in seven countries. Among 1,195 completed pregnancies with a known outcome there were 27 neural tube defects: 6 in the folic acid groups against 21 in the groups without it, a 72% protective effect (relative risk 0.28, 95% CI 0.12-0.71). A mixture of seven other vitamins showed no significant protection, isolating folic acid as the active component. For first occurrence rather than recurrence, a Hungarian randomised trial of 4,753 women planning a pregnancy, given 0.8 mg/day folic acid in a multivitamin from at least a month before conception, found zero neural tube defects among 2,104 supplemented pregnancies against 6 among 2,052 given trace elements only (p=0.029), with total congenital malformations also lower (13.3 against 22.9 per 1,000, p=0.02). This is the best-evidenced claim on this site, and the reason folic acid is added to flour in many countries, South Africa among them.
- Grade A· Strong evidence[1]
Folic acid supplementation reliably lowers blood homocysteine, by roughly a quarter at typical Western baseline levels.
A meta-analysis of individual participant data from 12 randomised controlled trials (1,114 people) found folic acid reduced blood homocysteine by about 25% once standardised to typical Western pre-treatment levels, with a broadly similar effect across the whole 0.5-5 mg/day range tested — meaning there is little to gain from the top of that range. Adding vitamin B12 at around 0.5 mg/day gave a further 7% reduction; vitamin B6 added nothing significant. Reductions were larger in people who started with higher homocysteine or lower folate, which is the general pattern for this vitamin: the further from adequate you start, the more supplementing does. Whether this biochemical change is worth anything to you is the subject of the next claim.
Folic acid supplementation modestly reduces the risk of stroke, but does not reduce heart attacks or overall mortality — the cardiovascular benefit is specific to stroke rather than general.
A meta-analysis of 8 randomised trials found folic acid reduced stroke risk by 18% (relative risk 0.82, 95% CI 0.68-1.00), with larger effects in trials running beyond 36 months (RR 0.71, 0.57-0.87) or achieving more than a 20% reduction in homocysteine (RR 0.77, 0.63-0.94). The China Stroke Primary Prevention Trial then tested this directly in 20,702 adults with hypertension given enalapril with or without 0.8 mg folic acid over a median 4.5 years, and found first stroke in 2.7% against 3.4% (hazard ratio 0.79, 95% CI 0.68-0.93). Against that, a Cochrane review of 15 trials (71,422 participants) found homocysteine-lowering had no effect on myocardial infarction (RR 1.02, 95% CI 0.95-1.10) or all-cause death (RR 1.01, 0.96-1.06), while still finding reduced stroke (RR 0.90, 0.82-0.99). The stroke signal is consistent and real; the broader inference that lowering homocysteine prevents heart disease is not supported. Note also that the largest supporting trial was conducted in a population without mandatory folic acid fortification, so the benefit may be smaller where diets are already fortified.
- Grade B· Limited evidence[1]
In older adults with raised homocysteine and normal B12, three years of folic acid improved memory and information-processing speed; this comes from a single trial in a deliberately selected group and does not show that folic acid improves cognition generally.
The FACIT trial randomised 818 adults aged 50-70 with raised plasma homocysteine and normal B12 to 800 mcg/day folic acid or placebo for three years. Serum folate rose 576% and homocysteine fell 26%. Against placebo, folic acid produced significantly better three-year outcomes for memory (Z-score difference 0.132, 95% CI 0.032-0.233) and information-processing speed (0.087, 95% CI 0.016-0.158), with a borderline effect on sensorimotor speed. The selection criteria are the whole story here: participants were chosen for having raised homocysteine and adequate B12, which is precisely the group most likely to respond. Nothing in this trial supports taking folic acid for cognition if your homocysteine is normal, and we found no large confirmatory trial in an unselected population. Read alongside the Cochrane finding of no cognitive benefit from B vitamins in generally healthy people, cited on our B12 page.
Risks & contraindications
In people with undiagnosed vitamin B12 deficiency, a high folate intake is associated with worse anaemia and cognitive impairment, consistent with the long-standing concern that folic acid corrects the blood signs of B12 deficiency while neurological damage continues unnoticed.
In an analysis of 1,459 older Americans from NHANES, conducted after folic acid fortification began, people with low B12 status who also had high serum folate (above 59 nmol/L, the 80th percentile) had markedly raised odds of anaemia (odds ratio 3.1, 95% CI 1.5-6.6) and of cognitive impairment (OR 2.6, 95% CI 1.1-6.1) compared with those with low serum folate. Among people whose B12 was normal, high folate was if anything protective against cognitive impairment (OR 0.4, 95% CI 0.2-0.9) — the harm is specific to the combination, not to folate itself. A 2024 review concludes the evidence that excess folic acid worsens B12 deficiency is largely correlative or drawn from uncontrolled clinical observation and the mechanism remains untested, while judging it compelling enough to warrant vigilance. It is worth saying plainly that this is contested: a competing review argues the masking concern is overstated and the existing 1 mg/day limit is adequately protective. The practical consequence is unaffected by who is right — if you are supplementing folate and could plausibly be low in B12, have the B12 measured rather than inferred.
Folic acid at 1 mg/day does not prevent recurrence of colorectal adenomas, and with longer exposure has been associated with more advanced lesions; one secondary analysis of the same trial also found increased prostate cancer.
A randomised trial of 1,021 people with previous colorectal adenomas found 1 mg/day folic acid produced no reduction in recurrence (44.1% against 42.4%) and, at a second follow-up beyond six years, a higher risk of advanced lesions (11.6% against 6.9%, relative risk 1.67, 95% CI 1.00-2.80) along with more people having three or more adenomas. A meta-analysis found no increased risk at three years or less (odds ratio 1.09, 95% CI 0.93-1.28) but an increased risk beyond three years (OR 1.35, 95% CI 1.06-1.70), rising to 1.50 (1.06-2.10) for advanced lesions — a duration effect rather than a blanket one. A pooled analysis of three large trials found a null overall effect, so this is genuinely inconsistent rather than settled. Separately, a secondary analysis of 643 men in that first trial found a 10-year prostate cancer probability of 9.7% on folic acid against 3.3% on placebo (age-adjusted hazard ratio 2.63, 95% CI 1.23-5.65) — striking, but a secondary and not pre-specified outcome in a small subgroup, and not confirmed elsewhere. Neither "proven safe long-term at high dose" nor "causes cancer" is a fair reading. What the evidence does support is that taking 1 mg/day for years, without a reason to, has a plausible downside and no demonstrated benefit.
Dosage & how to take it
- Folic acid: 400–1000 mcg/day, any time of day, with or without food. 400 mcg/day is the standard periconceptional dose in public health guidance and the low end of what the prevention trials used; the Hungarian first-occurrence trial used 800 mcg/day. Women who have already had a pregnancy affected by a neural tube defect are a separate case — the MRC trial used 4 mg/day in that group, roughly ten times the general dose, and that is a prescribing decision for a doctor, not a shelf purchase. The upper figure of 1,000 mcg/day is the established tolerable upper intake level for folic acid from supplements and fortified food, and the reason it exists is the B12 masking risk above rather than any direct toxicity. Two things worth holding together: the homocysteine meta-analysis found little added benefit above roughly 0.5-1 mg/day, and the colorectal evidence suggests the downside of prolonged high-dose use grows past three years. There is therefore little reason to sit near the ceiling indefinitely. No duration limit is set because none can be cited precisely, but the honest summary is that this is a vitamin with a clear short-term indication and a weaker case as a permanent daily habit.
- L-5-methyltetrahydrofolate (L-methylfolate): 400–1000 mcg/day, any time of day, with or without food. Dosed on the same scale as folic acid, since pharmacokinetic work finds comparable activity at equimolar doses for raising folate status and lowering homocysteine. No tolerable upper intake level has been set for L-methylfolate, on the reasoning that it bypasses enzymatic reduction and is not thought to mask B12 deficiency — but that position rests on a narrower and more industry-adjacent evidence base than the folic acid limit does, so we have kept the same ceiling rather than treating the absence of a limit as permission. On MTHFR: people carrying the C677T variant do have reduced enzyme activity, and bypassing that step with L-methylfolate is a reasonable mechanistic argument. It is not more than that. No trial has randomised people by MTHFR genotype to folic acid against L-methylfolate and measured a real clinical outcome. The largest trial to stratify by that genotype used ordinary folic acid and still found a stroke benefit, and the one head-to-head comparison by genotype found people with one copy of the variant did better on folinic acid than on L-methylfolate. If you are being sold methylfolate specifically because of an MTHFR result, that recommendation is running ahead of the evidence. Importantly, the neural tube defect trials used folic acid, so folic acid remains the form with proven outcomes in pregnancy.
- Folinic acid (5-formyltetrahydrofolate): 400–800 mcg/day, any time of day, with or without food. The range reflects the dosing used in the three-month randomised comparison against L-methylfolate in healthy adults, which is the main consumer-relevant dosing evidence available; there is not enough dedicated dose-ranging work to justify going higher with any confidence. Folinic acid is uncommon as a general supplement and its main clinical use is quite different — rescuing patients from methotrexate toxicity — so if you are taking methotrexate for any reason, folate supplementation of any form is a conversation with your prescriber rather than a self-directed choice.
Interactions
These two work on the same pathway, and taking folate without knowing your B12 status is the one combination worth thinking about carefully. Folate and B12 both feed the conversion of homocysteine to methionine, and a shortage of either produces the same macrocytic anaemia. Folic acid can correct that anaemia on its own — which sounds like a good thing, and is the problem. The anaemia is the visible warning sign of B12 deficiency; the damage that matters is neurological, and it continues underneath while the blood count looks normal. In an analysis of 1,459 older Americans after folic acid fortification began, people with low B12 who also had high serum folate had roughly three times the odds of anaemia and 2.6 times the odds of cognitive impairment compared with those with low folate, while in people whose B12 was normal high folate was, if anything, protective. The harm is specific to the pairing of high folate with low B12, not to folate itself. Taking the two together is therefore the sensible arrangement rather than a risky one, which is why this is marked supportive: adequate B12 removes the thing that makes high folate a problem. Two caveats worth carrying. A supplement is not a test — if you have a reason to suspect low B12, such as a vegan diet, being over 60, or long-term metformin or acid-suppressing medication, ask for it to be measured rather than assuming a combined tablet has covered it. And the evidence is genuinely contested: a 2024 review judges the masking concern compelling enough to warrant vigilance while noting it rests largely on correlational data, and other authors argue it is overstated. The practical advice is the same either way.
Our medication coverage is not exhaustive. Absence of a warning here is not evidence of safety. Always confirm with your pharmacist.
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