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Mf9.0
Methylfolate Research
Likely helpsHigh safety
34 peer-reviewed studies
What the evidence says
Likely helps
Methylfolate appears to help in 13 of 15 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 34 studies · 6 meta-analyses · 24 RCTs · 12,117 total participants
Confidence
High
What the studies found
13helped1unclear1didn't help· 19 more without graded effect data
By outcome
Depression & moodImproved mood, especially if MTHFR variant present · 2-4 weeks
Likely helps29 studies
Therapeutic & clinical
Likely helps17 studies
Heart & blood pressure
Likely helps9 studies
Cognitive functionFolate supports homocysteine metabolism critical for cognitive health · 4-8 weeks
Mostly mechanism / observational4 studies
Women's healthProvides essential nutrients for healthy pregnancy · Ongoing
Mostly mechanism / observational3 studies
Fertility & reproductiveMay support reproductive health and fertility markers · 4-12 weeks
Too few graded studies1 study
Folate deficiency & anemia
Too few graded studies1 study
Inflammation
Too few graded studies1 study
Safety profile
Too few graded studies1 study
By the numbers
Pulled from 33 studies with measurable effects
Likely real effects
73%
across studies
People studied
12k
typical study: 68 people
Strongest designs
30
6 pooled, 24 randomised
Showed benefit
87%
13/15 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
Children of mothers supplemented during pregnancy2
Adults with major depressive disorder1
Active research area
13 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.
11Liver 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.
12Subclinical 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.
13Homocysteine 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.
14Blood 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.
15Depression 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.
Despite concerns about the impact that SAMe therapy may have on homocysteine levels and risk of adverse cardiovascular effects, the lack of significant increase in tHCY levels after treatment suggests that no toxic effects from SAMe should be expected.
Mischoulon D et al. · The Journal of clinical psychiatry (2012)
Despite concerns about the impact that SAMe therapy may have on homocysteine levels and risk of adverse cardiovascular effects, the lack of significant increase in tHCY levels after treatment suggests that no toxic effects from SAMe should be expected.
Our findings, however, have some significant limitations and should be interpreted with caution.
17Homocysteine level reductionRCTCited 7×n=117 · medium study2015
In the 246 enrolled subjects, a significant reduction of tHcy levels occurred after the first cycle of treatment (from 31.6 ± 13.6 to 14.4 ± 5.77 μmol/L, P < .001) and during the whole 2-year follo...
Ambrosino P et al. · Nutrition research (New York, N.Y.) (2015)
Noticeable benefit
← WorseNo effectBetter →
Likely real
In the 246 enrolled subjects, a significant reduction of tHcy levels occurred after the first cycle of treatment (from 31.6 ± 13.6 to 14.4 ± 5.77 μmol/L, P < .001) and during the whole 2-year follow-up (from 31.6 ± 13.6 to 12.18 ± 3.03 μmol/L, P < .001).
The values of tHcy returned to reference range in 117 subjects (51.3%) after the first cycle and in 198 (86.8%) during the follow-up.
This study clearly shows that a cyclic schedule (1 month of therapy followed by 2 months of withdrawal) of 5-MTHF supplementation is able to significantly reduce tHcy levels in patients with mild/moderate HHcy.
18Serum folate concentrationsRCTCited 2×n=172 · medium study2024
Supplementation of multimicronutrients with 800 µg folate mix for 8 weeks causes higher serum (6S)-5-MTHF concentrations, but not a higher prevalence of detectable FA compares to 400 µg folate.
Obeid R et al. · Molecular nutrition & food research (2024)
The prevalence of FA concentrations ≥0.20 nmol L-1 increases between baseline and week 8 in both groups, but is not different between the groups (p = 0.116).
The mean percentage of (6S)-5-MTHF of total serum folate increases in both intervention groups, but is not different between the groups at 8 weeks (95.5 (4.1)% versus 94.4 (5.7)%, p = 0.309).
Supplementation of multimicronutrients with 800 µg folate mix for 8 weeks causes higher serum (6S)-5-MTHF concentrations, but not a higher prevalence of detectable FA compares to 400 µg folate.
In patients with cirrhosis and portal hypertension, 5-MTHF administration significantly enhanced the HVPG reduction achieved with propranolol.
Vukotic R et al. · Journal of hepatology (2023)
Large benefit
← WorseNo effectBetter →
Likely real
HVPG decreased in both groups, but the magnitude of the change was significantly greater in the group treated with 5-MTHF+propranolol compared to placebo+propranolol (percentage decrease, 20 [29-9] vs. 12.5 [22-0], p = 0.028), without differences in hepatic blood flow.
In patients with cirrhosis and portal hypertension, 5-MTHF administration significantly enhanced the HVPG reduction achieved with propranolol.
This effect appears to be mediated by improved nitric oxide bioavailability in the hepatic microcirculation.
20ADHD symptom measures and methylphenidate efficacyRCTCited 4×n=44 · small study2019
L-Methylfolate was associated with no change in efficacy on measures relevant to neuropsychiatric function in adults with ADHD, other than suggestion of reduced efficacy of methylphenidate.
Surman C et al. · Journal of clinical psychopharmacology (2019)
Likely real
L-Methylfolate was well tolerated, with no significant effect over placebo except improvement from abnormal measures on the mean adaptive dimension of the ASR scale (χ = 4.36, P = 0.04).
Methylphenidate dosing was significantly higher in individuals on L-methylfolate over time (χ = 7.35, P = 0.007).
L-Methylfolate was associated with no change in efficacy on measures relevant to neuropsychiatric function in adults with ADHD, other than suggestion of reduced efficacy of methylphenidate.