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Folate (5-MTHF)

In reviews, folic acid reduced neural tube defects and stroke risk; folic acid and 5-methyltetrahydrofolate lower homocysteine levels, but the picture for cognition is mixed.

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We evaluated 290 human studies on Folate (5-MTHF), including 190 randomised controlled trials and 36 meta-analyses or systematic reviews; the controlled studies include 94,925 participants in total. As of 4 October 2026.

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1. What Is Folate (5-MTHF)? Occurrence, Origin and Forms

Folate is a group of water-soluble B vitamins that includes 5-methyltetrahydrofolate (5-MTHF), the form circulating in blood. Folate occurs naturally in green leafy vegetables, legumes and citrus fruit, while the oxidised, synthetically produced form is called folic acid. Common uses are a folate-rich diet, fortification of staple foods and folate supplements around pregnancy.

Folate occurs in green leafy vegetables, legumes, citrus fruit and liver, and 5-MTHF is the predominant form in blood. Fortified flours and cereal products can be an additional source.

Folic acid is produced synthetically and added in this stable form to supplements and fortified foods. Studies mainly examine folic acid, 5-MTHF as a salt and folinic acid, each given as a tablet, capsule or fortified food.

Forms and Preparations Studied

  • Folic acid (synthetic, oxidised form)
  • 5-MTHF (5-methyltetrahydrofolate)
  • Folinic acid (5-formyltetrahydrofolate)
  • Dietary folates as polyglutamates
  • Fortified foods and flours

Not covered on this page:

  • Vitamin B12 (cobalamin) – often studied together, but a substance of its own.
  • Methotrexate and other folate antagonists – drugs that interfere with folate metabolism.
  • Homocysteine – a metabolic intermediate and measured marker, not folate itself.
  • Folate deficiency – a deficiency state, not the substance.

2. What Does Folate (5-MTHF) Do? Results by Area

AreaResult in controlled studiesStrength of evidenceStudiesParticipants
Homocysteine metabolismmostly improvedhigh3 meta-analyses · 47 controlled · 12 other10,552
Heart and circulationmixedmoderate3 meta-analyses · 25 controlled · 9 other25,691
Cognition and memorymixedmoderate0 meta-analyses · 8 controlled · 9 other3,018
Pregnancy and neural tube developmentmostly improvedmoderate3 meta-analyses · 1 controlled · 12 other0
Blood formation and anaemiamostly no differencelow3 meta-analyses · 6 controlled · 1 other1,348
Fertilitymostly no differenceunclear0 meta-analyses · 2 controlled · 4 other70
Other investigationsmixedhigh8 meta-analyses · 97 controlled · 41 other27,084

How to read the table: counted are human studies whose results concern the area. “High” means at least one meta-analysis and two controlled studies showing improvement, or at least three controlled studies of which three quarters show improvement, with at least 300 participants in total. “Moderate” means at least two controlled studies showing improvement, as a majority, or one meta-analysis alongside controlled studies. “Low” means one controlled study showing improvement. Where an area has no controlled study, the strength of evidence is at most “low” (result “reviews only” or “observational data only”). Everything else is “unclear”. A study counts as showing improvement when at least half of its outcomes in this area improved. Reviews of combination products do not count as meta-analyses; results that only describe side effects or shares of users do not count as an effect. The same study is counted only once.

3. What the Studies Show in Detail

Folate (5-MTHF) and Homocysteine Metabolism: Human Studies

In adults with chronic kidney disease, folate-based supplementation lowered homocysteine levels; this was shown by a meta-analysis 8. In adults with type-2 diabetes, a meta-analysis also found a lowering of homocysteine levels 15. A network meta-analysis on healthy aging and mild cognitive impairment found lower homocysteine levels with folic acid, vitamin B12 and vitamin B6, individually or combined 18. In coronary heart disease, oral folic acid lowered homocysteine levels and raised plasma folate levels 106; in non-alcoholic fatty liver disease, the difference from placebo was narrowly not confirmed 94. In direct comparison, 5-methyltetrahydrofolate and folic acid lowered homocysteine equally strongly 80108. No difference in homocysteine was found by a higher versus a lower folic acid dose in pregnancy 146 and folic acid versus placebo in children with sickle cell anemia 122. The findings predominantly concern laboratory values; whether a clinical benefit follows from this is open.

StudyDesign · participantsPreparation · dose · duration · comparisonResult
7 Lassi et al. 2013systematic review · 17,771 participantsoral folic acid, alone or with other micronutrients; vs. no folic acid (placebo or same micronutrients without folic acid)mean pre-delivery serum folate levels: no difference (SMD 2.03, 95% CI 0.80 to 3.27)
8 Chan et al. 2026meta-analysis · 8,625 participantsFolate-based supplementation (folic acid or alternative folate forms); not reported; subgroup analysis by higher folate dosage; not reported; subgroup analysis by shorter treatment duration; vs. placebo, no intervention, or alternative folate formulationsplasma homocysteine: improved (MD, -8.09 µmol/L; 95% CI, -11.54 to -4.63)
15 Mokgalaboni et al. 2024meta-analysis · 426 participantsFolic acid supplementation; vs. PlaceboHomocysteine levels: improved (SMD = -1.53, 95%CI (-2.14,-0.93), p < 0.05)
18 Liu et al. 2026meta-analysisfolic acid alone or with DHA, vitamin B12, vitamin B6; vs. other nutritional supplements or controlblood homocysteine levels: improved
22 Yin et al. 2025meta-analysisFolic acid plus vitamin B12 (26 studies), plus B6 (1), plus B12+B6 (2); vs. Control groups of included RCTsSerum homocysteine: improved (SMD = -2.77, 95% CI [-3.23, -2.30], P < 0.0001)
24 Benvidi et al. 2025meta-analysisB-vitamin supplementation, including folic acid; vs. Diabetic controls without nephropathy or placebo/controlHomocysteine levels: improved (-3.35 µmol/L with folic acid)
25 Lee et al. 2024meta-analysisVitamin B12 and folic acid; 6 months; vs. Placeboblood homocysteine level: improved
34 Wang et al. 2009randomised controlled · 3,411 participantsAged garlic and steam-distilled garlic oil; vitamin C, vitamin E, selenium; Not reported; 7.3 years; vs. Placebo, 2(3) and 2(2) factorial designSerum homocysteine: no difference

Further studies in this area: 41 49 51 54 63 66 69 71 73 74 76 78 80 84 87 94 95 99 100 101 102 103 105 106 108 109 111 113 115 117 118 121 122 123 124 125 128 139 142 143 146 147 151 152 164 166 170 180 189 190 191 195 201 215

Folate (5-MTHF), Heart and Circulation: Human Studies

Two meta-analyses found a lower stroke risk with folic acid 13, especially in areas without grain fortification and in people without previous stroke or heart attack 3. In a large randomized controlled trial, enalapril plus folic acid reduced the risk of a first stroke more than enalapril alone 32. Folic acid improved flow-mediated dilation in coronary heart disease 106, but not in healthy adults 117136. In postmenopausal women, nighttime blood pressure fell with 5-methyltetrahydrofolate, but not with placebo 124. For cardiovascular events and mortality with folate administration in chronic kidney disease, no difference was found 8. The lipid profile also did not improve with folic acid in non-alcoholic fatty liver disease 94. In a randomized controlled trial with folic acid plus methylcobalamin in type-2 diabetes, there was likewise no difference in the serum lipid profile 87. A meta-analysis on folic acid plus vitamin B6 and vitamin B12 in people at high stroke risk found a reduction in total stroke risk 2. A randomized controlled trial with 5-methyltetrahydrofolate plus vitamin B6 and vitamin B12 as well as n-3 fatty acids in factorial arms showed no difference in blood pressure 37. A randomized controlled trial with a mixed preparation of garlic extract, vitamin B12, folic acid, vitamin B6 and L-arginine reported a lower progression of coronary calcium 95. The robustness is moderate; it remains open whether the stroke benefits also exist with grain fortification and in people who are already ill.

StudyDesign · participantsPreparation · dose · duration · comparisonResult
1 An et al. 2022meta-analysis · 883,627 participantsfolic acid as part of micronutrient supplementation; vs. control group without folic acid supplementationstroke risk: improved (RR: 0.84; 95% CI: 0.72-0.97)
2 Nguyen et al. 2026meta-analysis · 673,624 participantsVitamin B6 + B12 + folic acid (combination); vs. Control group and other non-pharmacological interventionsTotal stroke risk: improved (RR = 0.86; 95% CI: 0.77-0.95); Hemorrhagic stroke and transient ischemic attack risk: improved
3 Zhang et al. 2024meta-analysis · 115,559 participantsFolic acid supplementation, alone or in combination; not reported; not reported; vs. Placebo or controlrisk of stroke: improved (RR 0.90, 95%CI 0.83 to 0.98); stroke risk in areas without grain fortification: improved (RR = 0.83, 95% CI 0.75 to 0.93); stroke risk in areas with grain fortification: no difference (RR = 1.04)
8 Chan et al. 2026meta-analysis · 8,625 participantsFolate-based supplementation (folic acid or alternative folate forms); not reported; subgroup analysis by higher folate dosage; not reported; subgroup analysis by shorter treatment duration; vs. placebo, no intervention, or alternative folate formulationscardiovascular events: no difference (RR, 0.88; 95% CI, 0.68-1.13); cardiovascular mortality: no difference (RR, 0.99; 95% CI, 0.75-1.29)
9 De-Regil et al. 2015systematic review · 7,391 participantsFolic acid alone or with other vitamins and minerals; 400 µg (0.4 mg) or higher daily; periconceptional; vs. no intervention, placebo or micronutrients without folateCongenital cardiovascular defects: no difference (RR 0.57, 95% CI 0.24 to 1.33)
15 Mokgalaboni et al. 2024meta-analysis · 426 participantsFolic acid supplementation; vs. PlaceboC-reactive protein: improved (SMD = -0.68, 95%CI (-1.34, -0.01), p = 0.05); Tumor necrosis factor-α: no difference (SMD = -0.86, 95%CI (-2.65, 0.93), p = 0.34); Interleukin-6: no difference (SMD = -0.04, 95%CI (-1.08, 1.01), p = 0.95)
32 Zhao et al. 2017randomised controlled · 20,702 participantsEnalapril plus folic acid vs. enalapril alone; median 4.5 years; vs. enalapril alonerisk of first stroke: improved (reduced the risk of first stroke by 21%(HR, 0.79; 95%CI: 0.68–0.93))
37 Szabo et al. 2012randomised controlled · 2,501 participants5-methyl-THF 560 µg plus vitamin B6 3 mg and vitamin B12 20 µg; 560 µg 5-MTHF daily, two capsules daily; median 4·7 years (assessment up to 5 years); vs. placebo capsules for B-vitamins and n-3 fatty acidsblood pressure: no difference

Further studies in this area: 51 63 65 69 87 94 95 99 101 105 106 108 111 112 114 115 117 118 121 124 125 136 152 177 190 210 213 215 216

Folate (5-MTHF), Cognition and Memory: Human Studies

For cognition and memory, the controlled studies show a mixed picture. In a randomized controlled trial, folic acid improved total IQ, digit span and block design compared with the control in older people with mild cognitive impairment 71. A meta-analysis on folic acid plus vitamin B12 in Alzheimer's disease found a better MMSE score, but no difference in ADAS-Cog and everyday function 25. Folic acid plus methylcobalamin in mild cognitive impairment 66 and folic acid plus vitamin B12 in schizophrenia 103 remained without a confirmed difference. A re-analysis of a placebo-controlled study found a benefit of folic acid for cognition only with low omega-3 fatty acid status 160. The robustness is moderate. Several studies tested folic acid together with vitamin B12, vitamin B6, vitamin D3 or omega-3 fatty acids, so the effect cannot be reliably attributed to folate alone 396066116. It remains open whether the improvements in individual test scores under folic acid are confirmed in larger studies and are clinically meaningful.

StudyDesign · participantsPreparation · dose · duration · comparisonResult
5 Zhang et al. 2024meta-analysis · 42,768 participantsfolate-based B vitamin supplements, folic acid alone or in combination; vs. placebo or countries with versus without mandatory folic acid fortificationcognitive function (SMD): improved (Z = 3.84; p = 0.0001; SMD, 0.18; 95% CI, 0.09, 0.28); cognitive function in countries without fortification policy (SMD): improved (Z = 3.75; p = 0.0002; SMD, 0.27; 95% CI, 0.13, 0.40); cognitive function under mandatory fortification (SMD): no difference (Z = 0.75; p = 0.45; SMD, 0.03; 95% CI, -0.06, 0.13)
18 Liu et al. 2026meta-analysisfolic acid alone or with DHA, vitamin B12, vitamin B6; vs. other nutritional supplements or controlmemory: improved
25 Lee et al. 2024meta-analysisVitamin B12 and folic acid; 6 months; vs. PlaceboMMSE score: improved (SMD = 0.21, 95% CI = 0.01 to 0.32, p = 0.04); ADAS-Cog score: no difference (SMD = 0.06, 95% CI = -0.22 to 0.33, p = 0.68)
39 Andreeva et al. 2011randomised controlled · 1,748 participants5-methyltetrahydrofolate plus vitamins B6 and B12, partly with omega-3 fatty acids; folate 0.56 mg, B6 3 mg, B12 0.02 mg, EPA/DHA 600 mg (2:1); 4 years; vs. placebo in 2x2 factorial randomizationCognitive function (modified Telephone Interview for Cognitive Status): no difference; Decreased temporal orientation score in prior stroke subgroup (B vitamins plus omega-3 vs. placebo): improved (odds ratio: 0.43; 95% CI: 0.21, 0.86)
60 Liu et al. 2024randomised controlled · 402 participantsFolic acid alone or folic acid plus 1600 IU vitamin D3; Folic acid dose not reported; vitamin D3 1600 IU; 24 weeks; vs. Placebo and folic acid aloneChange in MoCA score (intention-to-treat): no difference (0.456 (95% CI -0.198 to 1.11; p=0.171)); Change in MoCA score (per-protocol): improved (0.659 (95% CI 0.005 to 1.313; p=0.048))
66 Gong et al. 2022randomised controlled · 279 participants500 µg methylcobalamin plus 400 µg folic acid or placebo; 400 µg folic acid + 500 µg methylcobalamin daily; 24 months; vs. placeboCDR_SOB (cognitive function): no difference (no significant effect on CDR_SOB); CDR_SOB with above median left frontal atrophy: improved (lower CDR_SOB scores)
69 Xie et al. 2026randomised controlled · 215 participantsoral thiamin 90 mg/day plus folic acid 30 mg/day; folic acid 30 mg/day, thiamin 90 mg/day; 96 weeks; vs. placeboADAS-Cog score: improved (from 21.25 ± 9.2 to 15.07 ± 8.38, p < 0.001)
71 Ma et al. 2016randomised controlled · 180 participantsOral folic acid; 400 µg/day; 6 months; vs. Conventional treatment (control group)Full Scale IQ: improved (p = .031; effect size d = 0.168); Digit Span: improved (p = .009; d = 0.176); Block Design: improved (p = .036; effect size d = 0.146)

Further studies in this area: 82 103 116 160 195 198 201 203 205

Folate (5-MTHF), Pregnancy and Neural Tube Development: Human Studies

A systematic review found that with folic acid, alone or with other vitamins and minerals, there were overall fewer neural tube defects, including recurrence after an affected pregnancy 9. The earlier version of this review reached the same conclusion; for first occurrence, only one study without a confirmed difference was available 10. Mainly folic acid was tested, sometimes in combination products with other vitamins and minerals 910. It remains open whether 5-methyltetrahydrofolate is equivalent to folic acid in protecting against neural tube defects, because the reviews are based on studies with folic acid.

StudyDesign · participantsPreparation · dose · duration · comparisonResult
7 Lassi et al. 2013systematic review · 17,771 participantsoral folic acid, alone or with other micronutrients; vs. no folic acid (placebo or same micronutrients without folic acid)preterm birth: no difference (RR 1.01, 95% CI 0.73 to 1.38); stillbirths/neonatal deaths: no difference (RR 1.33, 95% CI 0.96 to 1.85); mean birthweight: improved (MD 135.75, 95% CI 47.85 to 223.68)
9 De-Regil et al. 2015systematic review · 7,391 participantsFolic acid alone or with other vitamins and minerals; 400 µg (0.4 mg) or higher daily; periconceptional; vs. no intervention, placebo or micronutrients without folateNeural tube defects (all births): improved (RR 0.31, 95% CI 0.17 to 0.58); Neural tube defects (incidence): no difference (RR 0.07, 95% CI 0.00 to 1.32); Neural tube defects (recurrence): improved (RR 0.34, 95% CI 0.18 to 0.64)
10 De-Regil et al. 2010systematic review · 6,105 participantsFolic acid alone or with other vitamins and minerals; periconceptional (before and during early pregnancy); vs. no intervention/placebo or vitamins and minerals without folic acidNeural tube defects (recurrence): improved (RR 0.32, 95% CI 0.17 to 0.60); Neural tube defects (incidence): no difference (RR 0.08, 95% CI 0.00 to 1.33)
21 Xu et al. 2025meta-analysisserum folate levels (no folate supplement given); vs. RLS patients vs. non-RLS patientsserum folate levels in pregnant RLS patients: worsened (P = 0.007)
138 Tessema et al. 2026randomised controlledMMS with folic acid and iron vs. iron-folic acid (IFA); Jan 2023 to Dec 2024; vs. MMS versus IFA in routine antenatal careMean birthweight: improved (mean increase of 38 g (95% CI 20-55)); Mean birthweight among women taking at least 90 tablets: improved (58 g (38-79)); Stillbirth risk: no difference (7·5 per 1000 births in the IFA arm and 6·9 per 1000 births in the MMS arm)
180 Schwinger et al. 2021cross-sectional study · 561 participantsno intervention; measurement of plasma folate, cobalamin, tHcy, MMA; vs. no comparison; association with socio-economic status and dietprevalence of folate deficiency (1 %)
181 van et al. 2020study · 511 participantsFolic acid supplementation within a lifestyle program; 24 weeks; vs. Before-and-after comparison without control groupProbability of folic acid supplementation among women: improved (0.97 to 1)
183 John et al. 2023cross-sectional study · 420 participantsSerum folate measurement; no folate administration studied; vs. women with vs. without iron/folic acid supplementationprevalence of folate deficiency (24.0%); odds of folate deficiency without supplementation: worsened (Adjusted OR = 1.53 (95%CI 1.21-1.93))

Further studies in this area: 187 197 200 201 203 206 212 214

Folate (5-MTHF), Blood Formation and Anaemia: Human Studies

A randomized controlled trial with synthetic folic acid found an increase in red blood cell folate compared with placebo 151. In contrast, a randomized controlled trial with 5-MTHF glucosamine salt compared with folic acid found no difference in red blood cell folate 80, and the hematological measurements also did not differ from placebo under folic acid 122. For hemoglobin, two systematic reviews on folic acid showed no difference 1626. The evidence is low; synthetic folic acid, 5-MTHF and a multiple-fortified table salt with folic acid, iron, zinc, vitamin B12 and iodine were tested 49. It remains open whether this results in advantages in anemia.

StudyDesign · participantsPreparation · dose · duration · comparisonResult
7 Lassi et al. 2013systematic review · 17,771 participantsoral folic acid, alone or with other micronutrients; vs. no folic acid (placebo or same micronutrients without folic acid)pre-delivery anaemia: no difference (RR 0.62, 95% CI 0.35 to 1.10); mean pre-delivery haemoglobin level: no difference (MD -0.03, 95% CI -0.25 to 0.19); megaloblastic anaemia: improved (RR 0.21, 95% CI 0.11 to 0.38)
16 Dixit et al. 2018systematic review · 117 participantsFolic acid tablets vs. placebo (calcium lactate); 1 mg folic acid orally daily; one year; vs. placebo (calcium lactate)total haemoglobin concentrations: no difference
26 Arrey et al. 2024systematic reviewFolic acid supplements; vs. no comparator; review of studies from the last 10 yearshemoglobin levels: no difference (no discernible impact)
49 Goh et al. 2025randomised controlled · 998 participantsQuintuply-fortified salt (QFS) with folic acid, iron, zinc, vitamin B12, iodine; Salt disappearance 6.0 g/adult female equivalent/day; 12 months (assessments at 6 and 12 months); vs. Iodized saltIron deficiency: improved (OR: 0.64; 95% CI: 0.42, 0.98; P = 0.08); Anemia: no difference
74 Zappacosta et al. 2013randomised controlled · 149 participantsfolate-rich diet, 5-MTHF or folic acid vs. placebo; daily 200 µg folate from diet, 200 µg 5-MTHF or 200 µg folic acid; 13 weeks; vs. placebo, open randomized, double blindincrease in RBC folate concentration vs. placebo: improved
80 Ernawati et al. 2026randomised controlled · 110 participants5-MTHF glucosamine salt vs. folic acid; 1100 µg 5-MTHF vs. 600 µg folic acid, equimolar; 12 weeks; vs. folic acid 600 µgchange in RBC folate: no difference (p = 0.714)
122 Williams et al. 2025randomised controlled · 31 participantsfolic acid 1 mg/d versus placebo; 1 mg/d; 12 ± 1 wk, then 12 ± 1 wk washout, cross-over; vs. placebo, double-blind randomized, noninferiorityhematological measures: no difference
151 Duthie et al. 2010randomised controlledSynthetic folic acid; 1.2 mg folic acid daily; 12 weeks; vs. PlaceboRed cell folate: improved (doubled (P = 0.013))

Further studies in this area: 165 184

Folate (5-MTHF) and Fertility: Human Studies

In men with unexplained infertility, a randomized controlled trial found no differences in semen parameters compared with placebo under folic acid with selenium and vitamin E 92. A randomized controlled trial with folic acid plus zinc also found no differences in sperm DNA methylation and epigenetic age of sperm 144. Both controlled trials tested folic acid only in combination with other substances, so an effect cannot be attributed to folate alone. A meta-analysis on folic acid plus zinc in men with infertility reports promising semen parameters, but leaves the pregnancy rate open 31. The evidence is overall unclear; folic acid was studied as a tablet in mixed preparations.

StudyDesign · participantsPreparation · dose · duration · comparisonResult
31 Buhling et al. 2019meta-analysisFolic acid plus zinc, oral supplementation; folic acid 5 mg/day, zinc 66 mg/day; vs. placebo (randomized, double-blind)semen parameters (promising data): improved; pregnancy rate: unclear
92 Bahmyari et al. 2021randomised controlled · 70 participantsFolic acid tablet plus selenium tablet and vitamin E capsule; folic acid 5 mg/day oral; 3 months; vs. placebosperm motility index (SMI): improved (P=0.007); functional sperm concentration (FSC): improved (P=0.001); semen volume: no difference (P=0.610)
144 Jenkins et al. 2022randomised controlledFolic acid 5 mg plus elemental zinc 30 mg daily; 5 mg folic acid, 30 mg zinc daily; 6 months; vs. Placebosperm DNA methylation: no difference (No significant differences were identified between the treatment and placebo groups); epigenetic age: no difference
173 Regidor et al. 2018study · 3,602 participantsmyo-inositol + folic acid; 2 × 2000 mg myo-inositol + 2 × 200 µg folic acid/day; 2–3 months, mean use 10.2 weeks; vs. open, prospective, non-blinded, non-comparative; IVF part randomized vs placeborestored ovulation: improved; pregnancy rate: improved (15.1%); follicle/retrieved oocyte ratio: improved
204 Ramgir-Naidu et al. 2026reviewFolate among other micronutrientssperm concentration, motility, morphology, DNA integrity: unclear
217 Yao et al. 2016reviewCombination of zinc and folate; vs. Placebo or other therapies (not specified)Positive effects on male fertility: improved

Folate (5-MTHF): Further Outcomes in Studies

Under "Further investigations" are studies on very different questions; the results are mixed. Folic acid lowered the first occurrence of colorectal adenomas in a randomized controlled trial in older adults without prior findings 148. In children with autism, high-dose folinic acid improved social reciprocity compared with the control 86. In Rett syndrome, 5-MTHF in the cerebrospinal fluid increased under folinic acid, but an objective clinical improvement did not occur 133. Folic acid, 5-MTHF, folinic acid and dietary folates as polyglutamate were studied. It remains open which form and dose are most suitable for which population group and whether the observed laboratory changes also bring clinical advantages in the long term.

StudyDesign · participantsPreparation · dose · duration · comparisonResult
6 Luo et al. 2024meta-analysis · 34,700 participantsB vitamins (folate, B6, B12); vs. Placebo or controlfracture incidence: no difference (RR, 1.06; 95% CI, 0.95 - 1.18; p = 0.33); bone mineral density lumbar spine and femur neck: no difference; bone specific alkaline phosphatase: no difference
8 Chan et al. 2026meta-analysis · 8,625 participantsFolate-based supplementation (folic acid or alternative folate forms); not reported; subgroup analysis by higher folate dosage; not reported; subgroup analysis by shorter treatment duration; vs. placebo, no intervention, or alternative folate formulationsall-cause mortality: no difference (RR, 1.02; 95% CI, 0.92-1.13); serum creatinine (kidney function): no difference (MD, -0.27 mg/dL; 95% CI, -1.29 to 0.74)
9 De-Regil et al. 2015systematic review · 7,391 participantsFolic acid alone or with other vitamins and minerals; 400 µg (0.4 mg) or higher daily; periconceptional; vs. no intervention, placebo or micronutrients without folateCleft palate: no difference (RR 0.73, 95% CI 0.05 to 10.89); Cleft lip: no difference (RR 0.79, 95% CI 0.14 to 4.36)
10 De-Regil et al. 2010systematic review · 6,105 participantsFolic acid alone or with other vitamins and minerals; periconceptional (before and during early pregnancy); vs. no intervention/placebo or vitamins and minerals without folic acidCleft palate, cleft lip, congenital cardiovascular defects, miscarriages: no difference
12 Qi et al. 2026systematic review · 3,486 participantsFolic acid alone or with iron/vitamins/minerals; mostly >1.0 mg/day; one trial 400 µg/day; vs. Placebo or no folic acid, both with antimalarialsMalaria parasitaemia in pregnant women: no difference (RR 1.21; 95% CI 0.56 to 2.62; P = 0.63); Parasite clearance at day 3: worsened (RR 0.89; 95% CI 0.84 to 0.95)
13 Sakuma et al. 2018meta-analysis · 925 participantsFolic acid, methylfolate, or folinic acid added to antipsychotics; vs. Placebo plus antipsychoticsTotal symptoms: no difference (SMD = -0.20, 95% CI = -0.41, 0.02, p = 0.08); Negative symptoms: improved (SMD = -0.25, 95% CI = -0.49, -0.01, p = 0.04); Positive symptoms: no difference
14 Bae et al. 2021systematic review · 822 participantsfolic acid supplements, partly with creatine; 400 µg/d or 800 µg/d; 12 or 24 weeks; vs. placebo, creatine alone, or no interventionblood arsenic: improved (FA800 -17.8%, 95% CI -25.0 to -9.8; placebo -9.5%, 95% CI -16.5 to -1.8); total blood arsenic: improved (FA400 M -13.62%, SE ± 2.87; placebo M -2.49%, SE ± 3.25); monomethylarsonic acid (MMA): improved (FA400 M -22.24%, SE ± 2.86; placebo M -1.24%, SE ± 3.59)
16 Dixit et al. 2018systematic review · 117 participantsFolic acid tablets vs. placebo (calcium lactate); 1 mg folic acid orally daily; one year; vs. placebo (calcium lactate)serum folate above 18 µg/L: improved (33 of 41 (81%) compared to six of 39 (15%)); serum folate below 5 µg/L: improved (15 of 39 (39%) participants had levels below this threshold); minor infections: no difference (RR 0.99 (95% CI 0.85 to 1.15))

Further studies in this area: 17 18 20 21 22 23 24 25 26 27 28 29 30 34 36 38 41 42 47 48 49 50 52 53 54 55 56 57 59 61 62 63 64 65 67 68 69 70 71 72 73 75 76 77 78 79 80 81 82 83 85 86 87 88 89 90 91 93 94 96 97 98 102 103 104 106 107 110 111 112 116 119 120 122 123 124 126 127 129 130 131 132 133 134 135 137 139 140 141 145 146 148 149 150 151 152 153 154 155 156 157 158 159 161 162 163 164 165 167 168 169 171 172 173 174 175 176 178 179 182 185 186 188 189 190 191 192 193 194 196 198 199 201 202 207 208 209 211

4. How Is Folate (5-MTHF) Dosed? Preparation, Dose and Duration in Studies

The studies predominantly used oral folic acid and 5-methyltetrahydrofolate, and partly also folinic acid as well as dietary folates as polyglutamate within a green-Mediterranean diet. Some of the investigations tested folic acid or 5-methyltetrahydrofolate in mixed preparations with vitamin B12, vitamin B6, omega-3 fatty acids or other micronutrients. The exact doses and intake durations are shown in the table.

Preparation or formDoseDurationStudy
Enalapril plus folic acid vs. enalapril alone—median 4.5 years32
Multiple micronutrient supplement (MMS) vs. iron-folic acid (IFA)—Supplementation during pregnancy33
Aged garlic and steam-distilled garlic oil; vitamin C, vitamin E, seleniumNot reported7.3 years34
routine iron folic acid (IFA) vs. MMN vs. MQ-LNSIFA: 60 mg iron + folic acid; MMN: 20 micronutrients + 30 mg iron; MQ-LNS: 30 mg iron + 237 kcal—35
5-MTHF plus vitamin B6 and B12, some also omega-3 fatty acids5-MTHF 0.56 mg, B6 3 mg, B12 0.02 mg daily5 years36
5-methyl-THF 560 µg plus vitamin B6 3 mg and vitamin B12 20 µg560 µg 5-MTHF daily, two capsules dailymedian 4·7 years (assessment up to 5 years)37
5-methyltetrahydrofolate plus vitamins B6 and B120.56 mg 5-MTHF, 3 mg B6, 0.02 mg B12median 4.7 years38
5-methyltetrahydrofolate plus vitamins B6 and B12, partly with omega-3 fatty acidsfolate 0.56 mg, B6 3 mg, B12 0.02 mg, EPA/DHA 600 mg (2:1)4 years39
Standard supplement (folic acid, iron, calcium, iodine, β-carotene) vs. added myo-inositol, probiotics, micronutrients—up to 12 months40
Folic acid supplementation—6 months41
Folic acid0 mg to 2.4 mg once daily8 weeks42
Weekly folic acid alone, iron+folic acid, or multiple micronutrients before conception; daily iron+folic acid during pregnancy—Preconception until conception, then daily during pregnancy43
IFA (iron and folic acid) vs. MMS (multiple micronutrient supplements)—IFA 90 days; MMS 180 days44
IFA (iron + folic acid) vs. MMN (18 vitamins/minerals incl. iodine) vs. SQ-LNS60 mg/d Fe + 400 µg/d folic acid; MMN 250 µg/d iodine; LNS 20 g/duntil childbirth45
LNS, MMN or iron plus folic acid (IFA); LNS group additionally 6-18 months—Pregnancy to 6 months postpartum; child LNS 6-18 months46

5. Is Folate (5-MTHF) Safe? Side Effects in Studies

In a study with high-dose folinic acid in children with autism, no significant side effects occurred 86. A systematic review reports no evidence of short-term side effects 10. In a randomized controlled trial, prostate cancer was diagnosed more frequently with folic acid than with placebo 52. Details are shown in the table.

StudyReported side effects
3 Zhang et al. 2024not reported
4 Finkelstein et al. 2024Adverse effects: RR 1.29, 95% CI 0.83 to 2.02; very low-certainty evidence
8 Chan et al. 2026adverse events comparable to controls
9 De-Regil et al. 2015no evidence of negative effects reported
10 De-Regil et al. 2010no evidence of short-term side effects
11 Zhou et al. 2024Safety ranked by SUCRA; folic acid not among top 3
13 Sakuma et al. 2018Lower incidence of serious adverse events; no differences in other safety outcomes
16 Dixit et al. 2018no significant differences in infections reported
19 Dhiman et al. 2026Intermittent regimens had fewer gastrointestinal adverse effects
22 Yin et al. 2025Overall incidence and specific types of diabetes-related complications as safety outcomes
34 Wang et al. 2009Not reported
58 Huda et al. 2019Abdominal pain, indigestion, diarrhea and black stool significantly higher with ferrous sulfate

6. What Remains Open: Limits of the Evidence

  • Most findings concern laboratory values such as homocysteine or folate levels; whether a clinical benefit follows from this is open.
  • Many studies tested folic acid only in mixed preparations, so the effect cannot be reliably attributed to folate alone.
  • The stroke benefits have been observed mainly in areas without grain fortification; whether they also exist in people who are already ill remains open.
  • For cognition, blood formation and fertility, there are only a few controlled studies with folic acid alone.
  • Which form and dose is most suitable for which population group has not been clarified.

7. Bottom Line: What Is Established About Folate (5-MTHF)

According to systematic reviews, folic acid reduced neural tube defects, alone or with other vitamins and minerals 910. In meta-analyses and controlled trials, folic acid and 5-methyltetrahydrofolate lowered homocysteine levels, for example in chronic kidney disease, type 2 diabetes and coronary heart disease 815106. In direct comparison, 5-methyltetrahydrofolate and folic acid lowered homocysteine to a similar extent 80108; a higher dose during pregnancy 146 and folic acid in children with sickle cell anemia 122 did not change homocysteine. For the heart and circulation, two meta-analyses found a lower stroke risk with folic acid 13; the results on vascular function and blood pressure are mixed 106117124.

For cognition, the evidence is moderate; for blood formation and fertility, it is low to unclear; several studies tested folic acid only together with other substances 3992144. It remains open whether the observed laboratory changes bring clinical benefits in the long term and which form and dose are most suitable for which population group.

Frequently Asked Questions

How well has Folate (5-MTHF) been studied in humans?

We evaluated 290 human studies on Folate (5-MTHF), including 190 randomised controlled trials and 36 meta-analyses or systematic reviews; the controlled studies include 94,925 participants in total. As of 4 October 2026.

Does Folate (5-MTHF) help with homocysteine metabolism? What the studies show

We evaluated 3 meta-analyses or systematic reviews, 47 controlled studies and 12 further studies; the controlled studies include 10,552 participants in total. Result of the controlled studies: mostly improved. Strength of evidence under our published rules: high. Sources: 781518

Does Folate (5-MTHF) help with heart and circulation? What the studies show

We evaluated 3 meta-analyses or systematic reviews, 25 controlled studies and 9 further studies; the controlled studies include 25,691 participants in total. Result of the controlled studies: mixed. Strength of evidence under our published rules: moderate. Sources: 1238

Does Folate (5-MTHF) help with cognition and memory? What the studies show

We evaluated 8 controlled studies and 9 further studies; the controlled studies include 3,018 participants in total. Result of the controlled studies: mixed. Strength of evidence under our published rules: moderate. Sources: 5182539

Does Folate (5-MTHF) help with pregnancy and neural tube development? What the studies show

We evaluated 3 meta-analyses or systematic reviews, one controlled study and 12 further studies. Result of the controlled studies: mostly improved. Strength of evidence under our published rules: moderate. Sources: 791021

Does Folate (5-MTHF) help with blood formation and anaemia? What the studies show

We evaluated 3 meta-analyses or systematic reviews, 6 controlled studies and one further study; the controlled studies include 1,348 participants in total. Result of the controlled studies: mostly no difference. Strength of evidence under our published rules: low. Sources: 7162649

Does Folate (5-MTHF) help with fertility? What the studies show

We evaluated 2 controlled studies and 4 further studies; the controlled studies include 70 participants in total. Result of the controlled studies: mostly no difference. Strength of evidence under our published rules: unclear. Sources: 3192144173

Does folic acid lower homocysteine levels?

In adults with chronic kidney disease and in type-2 diabetes, folate-based administration lowered homocysteine levels 815. In coronary heart disease, oral folic acid lowered homocysteine levels and raised plasma folate levels 106; in non-alcoholic fatty liver disease, the difference from placebo was narrowly not confirmed 94.

Does folic acid affect stroke risk?

In a large randomized controlled trial, enalapril plus folic acid reduced the risk of a first stroke more than enalapril alone 32. Whether this benefit also exists with grain fortification and in people who are already ill remains open.

Does folic acid affect cognition and memory?

For cognition and memory, the controlled studies show a mixed picture. In a randomized controlled trial, folic acid improved total IQ, digit span and block design compared with the control in older people with mild cognitive impairment 71. A meta-analysis on folic acid plus vitamin B12 in Alzheimer's disease found a better MMSE score, but no difference in ADAS-Cog and everyday function 25. Folic acid plus methylcobalamin in mild cognitive impairment 66 and folic acid plus vitamin B12 in schizophrenia 103 remained without a confirmed difference. A secondary analysis of a placebo-controlled study found a benefit of folic acid for cognition only with low omega-3 fatty acid status 160. Several studies investigated mixed preparations, so the effect cannot be reliably attributed to folate alone.

Which forms of folate were used in the studies?

The studies predominantly used oral folic acid and 5-methyltetrahydrofolate, and partly also folinic acid as well as dietary folates as polyglutamate within a green-Mediterranean diet. Some of the investigations tested folic acid or 5-methyltetrahydrofolate in mixed preparations with vitamin B12, vitamin B6, omega-3 fatty acids or other micronutrients. The exact doses and intake durations are shown in the table.

How well tolerated is folic acid?

A systematic review reports no evidence of short-term side effects 10. In a randomized controlled trial, prostate cancer was diagnosed more frequently with folic acid than with placebo 52.

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Every statement on this page carries its evidence tier — proven, plausible or hypothesis — and leads to the original work. The decision in the individual case rests with the practitioner; we provide the connections.

International Health Research · https://ih-research.com/en/knowledge/folate/ · Last updated: 2026-10-15