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Mf6.0
Methylfolate Research
Likely helps
46 peer-reviewed studies
What the evidence says
Likely helps
Methylfolate appears to help in 14 of 16 studies with measurable effects — the evidence leans clearly favourable.
Most evidence is from high-quality meta-analyses and randomised trials published 2005–2026 with a typical study size of 68 participants.
Based on 46 studies · 6 meta-analyses · 27 RCTs · 12,157 total participants
Confidence
High confidence
What the studies found
14helped1unclear1didn't help· 30 more without graded effect data
By outcome
Depression & moodImproved mood, especially if MTHFR variant present · 2-4 weeks
Likely helps38 studies
Therapeutic & clinical
Likely helps21 studies
Heart & blood pressure
Likely helps11 studies
Women's healthProvides essential nutrients for healthy pregnancy · Ongoing
Mostly mechanism / observational9 studies
Cognitive functionFolate supports homocysteine metabolism critical for cognitive health · 4-8 weeks
Mostly mechanism / observational5 studies
Folate deficiency & anemia
Mostly mechanism / observational3 studies
Safety profile
Mostly mechanism / observational3 studies
Neuroprotection & brain agingLowers homocysteine, a risk factor for cognitive decline · 8-12 weeks
Too few graded studies1 study
Fertility & reproductiveMay support reproductive health and fertility markers · 4-12 weeks
Too few graded studies1 study
Inflammation
Too few graded studies1 study
By the numbers
Pulled from 38 studies with measurable effects
Likely real effects
73%
across studies
People studied
12k
typical study: 68 people
Strongest designs
33
6 pooled, 27 randomised
Showed benefit
88%
14/16 studies
How long studies ran
1–4 weeks
1
1–3 months
3
3+ months
6
Populations Studied
Patients with peripheral arterial disease2
Patients with major depressive disorder2
Pregnant women2
Children of mothers supplemented during pregnancy2
Active research area
25 studies in the last 5 years · Latest meta-analysis: 2022
200520152026
1Systematic ReviewCited 44×n=2,256 · very large study2023
As for anxiety symptoms, the availability of results is limited to adjuvant vitamin D therapy.
Borges-Vieira JG et al. · Nutritional neuroscience (2023)
2Depression response (Hamilton Rating Scale for Depression-17)Meta-AnalysisCited 12×n=6,707 · very large study2022
Adjunctive L-methylfolate may have modest efficacy in antidepressant-treated adults with MDD.
Maruf AA et al. · Pharmacopsychiatry (2022)
Large harm
← WorseNo effectBetter →
Likely real
In the meta-analysis of categorical Hamilton Rating Scale for Depression-17 response, (three studies, N=483) adjunctive L-methylfolate was associated with a small effect versus antidepressant monotherapy (relative risk: 1.25, 95% confidence interval [CI]=1.08 to 1.46, p=0.004).
A meta-analysis of four studies (N=507) using a continuous measure of depressive symptoms showed a similar effect of adjunctive L-methylfolate (standardized mean difference=- 0.38, 95% CI=- 0.59 to-0.17, p=0.0003).
Adjunctive L-methylfolate may have modest efficacy in antidepressant-treated adults with MDD.
3Negative symptoms in schizophreniaMeta-AnalysisCited 22×n=925 · large study2018
Our findings suggest that pooled FA + AP treatment improves negative symptoms in schizophrenia patients.
Sakuma K et al. · Psychopharmacology (2018)
Noticeable benefit
← WorseNo effectBetter →
Likely real
Pooled FA + AP treatments were more effective than placebo + AP for negative symptoms (N = 5, n = 281; SMD = -0.25, 95% CI = -0.49, -0.01, p = 0.04, I2 = 0%).
Our findings suggest that pooled FA + AP treatment improves negative symptoms in schizophrenia patients.
5Treatment recommendations for nutraceuticals and phytoceuticals in psychiatric disordersMeta-AnalysisCited 117×2022
Based on the current data and clinician input, a range of nutraceuticals and phytoceuticals were given either a supportive recommendation or a provisional recommendation across a range of various psychiatric disorders.
Sarris J et al. · The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry (2022)
Based on the current data and clinician input, a range of nutraceuticals and phytoceuticals were given either a supportive recommendation or a provisional recommendation across a range of various psychiatric disorders.
However several had only a weak endorsement for potential use; for a few it was not possible to reach a clear recommendation direction, largely due to mixed study findings; while some other agents showed no obvious therapeutic benefit and were clearly not recommended for use.
It is the intention of these guidelines to inform psychiatric/medical, and health professional practice globally.
6Clinical outcomes for psychiatric diseasesSystematic ReviewCited 39×n=23 · very small study2022
Increasing evidence from clinical trials consistently demonstrate folate supplements, especially levomefolic acid or 5-methylfolate, may improve clinical outcomes for certain psychiatric diseases, especially as an adjunct pharmacotherapy with minimal side effects.
Increasing evidence from clinical trials consistently demonstrate folate supplements, especially levomefolic acid or 5-methylfolate, may improve clinical outcomes for certain psychiatric diseases, especially as an adjunct pharmacotherapy with minimal side effects.
8Folate bioavailability of different supplement formsSystematic ReviewCited 7×n=23 · very small study2019
This review has found a number of methodological limitations and conflicting results.
Bayes J et al. · Journal of alternative and complementary medicine (New York, N.Y.) (2019)
Only three studies found a statistically significant difference in folate bioavailability when evaluating different supplement forms.
This review has found a number of methodological limitations and conflicting results.
Quality absorption studies assessing the bioavailability of oral folate supplements are crucial if clinicians are to make effective evidence-based recommendations.
These evidence-based interventions aim to restore endothelial homeostasis, slow disease progression, and improve patient outcomes across a variety of disorders linked to poor vascular health.
Ayoub G. · Nutrients (2025)
Folate is noted for its central function in one-carbon metabolism and in converting homocysteine to methionine, thereby reducing vascular toxicity.
We cover natural dietary sources of folate, synthetic folic acid, and the biologically active forms 5-methyl-(6S)-tetrahydrofolate (L-5-MTHF, L-methylfolate) and 5-formyl-(6S)-tetrahydrofolate (levoleucovorin).
These evidence-based interventions aim to restore endothelial homeostasis, slow disease progression, and improve patient outcomes across a variety of disorders linked to poor vascular health.
12Cardiovascular disorders and depression preventionReview2024
With regard to the prevention of cardiovascular disorders, available evidence is not conclusive.
Rubini M, Di Minno G, Ferrazzi E. · European review for medical and pharmacological sciences (2024)
Otherwise, the role of 5-MTHF in the management of cardiovascular risk is still debated due to the multiple confounding factors that characterize this patient setting.
A link between folate deficiency in pregnancy and postpartum depression has been proposed, as well as between folate levels and the onset of depression.
In conclusion, evidence from the literature supports the additional role of 5-MTHF as a pleiotropic drug with a transversal effect in different therapeutic contexts.
Finally, relevant nutritional guidelines are presented with their conclusion for the role of each nutrient in the management of depression.
Tobin D, Vuckovic A, Sarris J. · Nutrients (2024)
This paper provides a narrative review of three nutrients which have significant scientific support for the management of depression.
A deficiency in each nutrient is associated with depression, and interventional studies indicate that the correction of the nutritional deficiency may provide clinical benefit.
We present epidemiological evidence, a mechanistic explanation and a review of interventional studies for these nutrients.
Our aim is to improve the identification of individuals at high risk of CAD and enhance their prognosis.
Pietruszyńska-Reszetarska A, Pietruszyński R, Irzmański R. · International journal of molecular sciences (2024)
This review explores the significance of the methylation pathway and folate metabolism in CAD pathogenesis, with a focus on endothelial dysfunction resulting from deficiency in the active form of folate (5-MTHF).
We discuss emerging areas of research into CAD biomarkers and factors influencing the methylation process.
By highlighting genetically determined methylation disorders, particularly the MTHFR polymorphism, we propose the potential use of the active form of folate (5-MTHF) as a novel CAD biomarker and personalized pharmaceutical for selected patient groups.
Conclusions : Despite the potential value of 5-MTHF as an alternative to FA, clinical studies would be urgently needed to support the efficacy, dosage, timing, and/or safety of its use as a supplement.
However, more studies are definitely still needed to establish 5-MTHF as a safe and effective therapeutic approach comparable with FA.
Moreover, there is a lack of clinical studies that evaluate the efficacy of 5-MTHF supplementation in the prevention of NTDs.
The present evidence-based narrative review discusses differences between FA and 5-MTHF in terms of structure, metabolism, bioavailability, clinical efficacy, and safety.
16Liver fat content (CAP)RCTCited 3×n=155 · medium study2024
These findings suggest that this supplementation regimen could be a beneficial adjunct therapy for improving liver health in adults with obesity-induced MASLD.
Perva IT et al. · Medicina (Kaunas, Lithuania) (2024)
Barely noticeable benefit
← WorseNo effectBetter →
Borderline
The treatment group exhibited a mean reduction in CAP of 4% (p < 0.05) and a mean reduction in TE of 7.8% (p < 0.05), indicative of a decline in liver fat content and fibrosis.
The administration of the nutritional supplement resulted in a notable reduction in both CAP and TE scores when compared to the placebo group.
Conclusions: The supplementation over a period of three months led to a significant amelioration of liver fibrosis and steatosis parameters in adults with metabolic syndrome and obesity.
17Subclinical depression symptomsRCTCited 1×n=140 · medium study2023
Conclusions: The received results confirm the available evidence for the properties of SAMe in depression and complement them with evidence of the ef-fectiveness of the Deprilium® complex that contains SAMe and L-methylfolate with methylcobalamin, which together produce pharmacological and clinical synergy to reduce the severity of subclinical depressive manifestations in patients with NCD.
Results: After 60 days a statistically significant difference was observed in all clinical indicators between the intervention group and the control group.
When comparing the indicators of the intervention group on the 1st and on the 60th day of the study, statistically significant changes (p <0.000) were observed in all three indicators.
Further studies of the effectiveness of the use of the Deprilium® complex in patients with NCD are required.
18Homocysteine levelsRCTCited 8×n=54 · small study2024
Methylfolate, P5P, and methylcobalamin supplementation tailored to genetic profiles effectively reduced homocysteine and LDL-C levels in patients with specific MTHFR, MTR, and MTRR polymorphisms, particularly with homozygous minor allele polymorphisms.
Pokushalov E et al. · Nutrients (2024)
Huge benefit
← WorseNo effectBetter →
Likely real
At the 6 months follow-up, the treatment group demonstrated a significant reduction in homocysteine levels by 30.0% (95% CI: -39.7% to -20.3%) and LDL-C by 7.5% (95% CI: -10.3% to -4.7%), compared to the placebo (p < 0.01 for all).
LDL-C levels decreased by 11.8% in homozygous carriers (95% CI: -15.8% to -7.8%, p < 0.01) and 4.8% in mixed allele carriers (95% CI: -6.8% to -2.8%, p < 0.01), with a significant between-group difference (7.0%, 95% CI: -13.0% to -1.0%, p < 0.01).
Methylfolate, P5P, and methylcobalamin supplementation tailored to genetic profiles effectively reduced homocysteine and LDL-C levels in patients with specific MTHFR, MTR, and MTRR polymorphisms, particularly with homozygous minor allele polymorphisms.
19Blood pressure and serum homocysteine levelsRCTn=51 · small study2026
A three-month supplementation with a combination of 800 mcg methylfolate and 1000 mcg methylcobalamin showed promise in lowering blood pressure and serum homocysteine levels in ESRD patients with resistant hypertension.
Salem MS et al. · BMC nephrology (2026)
Likely real
Between-group analysis found a statistically significant difference in the change in homocysteine levels among the two groups (p = 0.006).
Furthermore, the treatment group had statistically significant lower pre- and post-dialysis blood pressure readings.
A three-month supplementation with a combination of 800 mcg methylfolate and 1000 mcg methylcobalamin showed promise in lowering blood pressure and serum homocysteine levels in ESRD patients with resistant hypertension.
20Depression symptom improvementRCTCited 1×n=28 · very small study2025
Combination therapy of antidepressants with low-dose methylfolate may provide a safe and effective treatment strategy for patients with depressive disorder.
Siddique A et al. · BMC pharmacology & toxicology (2025)
Huge benefit
← WorseNo effectBetter →
Borderline
On day 28, patients on low dose methylfolate and antidepressant combination therapy showed a 40.33% improvement in depression symptoms, compared to 26.43% in patients on antidepressant monotherapy (p-value < 0.05).
This treatment strategy had no effect on the time-lag of outcomes on day 14 and the remission rate on day 28 was not found statistically significant.
Combination therapy of antidepressants with low-dose methylfolate may provide a safe and effective treatment strategy for patients with depressive disorder.