Methylfolate Research
42 peer-reviewed studies · Evidence score: 9/10
Efficacy of B-vitamins and vitamin D therapy in improving depressive and anxiety disorders: a systematic review of randomized controlled trials
Borges-Vieira JG et al. • Nutritional neuroscience (2023)
As for anxiety symptoms, the availability of results is limited to adjuvant vitamin D therapy.
- Systematic review examining Methylfolate efficacy
- Published in Nutritional neuroscience (2023)
- Further research warranted to confirm findings
Systematic Review and Meta-Analysis of L-Methylfolate Augmentation in Depressive Disorders
Maruf AA et al. • Pharmacopsychiatry (2022)
Adjunctive L-methylfolate may have modest efficacy in antidepressant-treated adults with MDD.
- 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.
Folic acid/methylfolate for the treatment of psychopathology in schizophrenia: a systematic review and meta-analysis
Sakuma K et al. • Psychopharmacology (2018)
Our findings suggest that pooled FA + AP treatment improves negative symptoms in schizophrenia patients.
- 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.
- Moreover, this treatment was well tolerated.
Homocysteine lowering interventions for peripheral arterial disease and bypass grafts
Andras A et al. • The Cochrane database of systematic reviews (2013)
Currently, no recommendation can be made regarding the value of treatment of hyperhomocysteinaemia in peripheral arterial disease.
- Currently, no recommendation can be made regarding the value of treatment of hyperhomocysteinaemia in peripheral arterial disease.
- Further, well constructed trials are urgently required.
- Further research warranted to confirm findings
Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce
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.
- 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.
The potential use of folate and its derivatives in treating psychiatric disorders: A systematic review
Lam NSK et al. • Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (2022)
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.
- Published in Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (2022)
- Further research warranted to confirm findings
Folate as adjunct therapy to SSRI/SNRI for major depressive disorder: Systematic review & meta-analysis
Altaf R et al. • Complementary therapies in medicine (2021)
Adjunct therapy with l-Methylfolate or folic acid improves depression scale scores, patient response, and remission rates.
- Adjunct therapy with l-Methylfolate or folic acid improves depression scale scores, patient response, and remission rates.
- Published in Complementary therapies in medicine (2021)
- Further research warranted to confirm findings
The Bioavailability of Various Oral Forms of Folate Supplementation in Healthy Populations and Animal Models: A Systematic Review
Bayes J et al. • Journal of alternative and complementary medicine (New York, N.Y.) (2019)
This review has found a number of methodological limitations and conflicting results.
- 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.
Caveat emptor: Folate in unipolar depressive illness, a systematic review and meta-analysis
Roberts E et al. • Journal of psychopharmacology (Oxford, England) (2018)
All evidence was graded as low or very low quality for each outcome.
- Meta-analysis examining Methylfolate efficacy
- Published in Journal of psychopharmacology (Oxford, England) (2018)
- Further research warranted to confirm findings
Cerebrospinal fluid monoamines, pterins, and folate in patients with mitochondrial diseases: systematic review and hospital experience
Batllori M et al. • Journal of inherited metabolic disease (2018)
High CSF HVA values, together with a severe cerebral folate deficiency, were observed in KSS patients and in other mtDNA mutation syndromes.
- A chi-square test showed a statistically significant association between high homovanillic acid (HVA) values and low CSF 5-MTHF values (chi-square = 10.916; p = 0.001).
- Seven out of the eight patients with high CSF HVA values showed cerebral folate deficiency.
- Five of them harbored mtDNA deletions associated with Kearns-Sayre syndrome (KSS), one had a mitochondrial point mutation at the mtDNA ATPase6 gene, and one had a POLG mutation.
Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses
Sarris J et al. • The American journal of psychiatry (2016)
Current evidence supports adjunctive use of SAMe, methylfolate, omega-3, and vitamin D with antidepressants to reduce depressive symptoms.
- Current evidence supports adjunctive use of SAMe, methylfolate, omega-3, and vitamin D with antidepressants to reduce depressive symptoms.
- Published in The American journal of psychiatry (2016)
- Further research warranted to confirm findings
MTHFR polymorphisms and disease
Liew SC, Gupta ED • BioMed Research International (2015)
MTHFR variants affect 30-40% of the population and impair folate metabolism.
- Common genetic variants affect folate processing
- Methylfolate bypasses the MTHFR enzyme
- Important for cardiovascular and mental health
Use of a Micronutrient Cocktail to Improve Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) in Adults with Obesity: A Randomized, Double-Blinded Pilot Clinical Trial
Perva IT et al. • Medicina (Kaunas, Lithuania) (2024)
These findings suggest that this supplementation regimen could be a beneficial adjunct therapy for improving liver health in adults with obesity-induced MASLD.
- 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.
Folate and depression: a neglected problem
Coppen A, Bolander-Gouaille C • Journal of Psychopharmacology (2005)
Low folate status is linked to poor antidepressant response and depression severity.
- Folate status affects depression outcomes
- Supplementation may enhance antidepressant response
- Methylfolate preferred for those with MTHFR variants
SAFETY AND EFFICACY OF THE COMPLEX DEPRILIUM® IN REDUCING SUBCLINICAL SYMPTOMS OF DEPRESSION IN PATIENTS WITH CHRONIC NON-COMMUNICABLE DISEASES: DOUBLE-BLIND RANDOMIZED CONTROLLED STUDY
Chaban ОS et al. • Wiadomosci lekarskie (Warsaw, Poland : 1960) (2023)
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.
Effect of Methylfolate, Pyridoxal-5'-Phosphate, and Methylcobalamin (Soloways(TM)) 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 et al. • Nutrients (2024)
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.
- 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.
Effect of combination therapy of methylfolate with antidepressants in patients with depressive disorder
Siddique A et al. • BMC pharmacology & toxicology (2025)
Combination therapy of antidepressants with low-dose methylfolate may provide a safe and effective treatment strategy for patients with depressive disorder.
- 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.
Bioavailability of S-adenosyl methionine and impact on response in a randomized, double-blind, placebo-controlled trial in major depressive disorder
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.
- 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.
- Further research warranted to confirm findings
Infant blood concentrations of folate markers and catabolites are modified by 5,10-methylenetetrahydrofolate reductase C677T genotype and dietary folate source
Obeid R et al. • The American journal of clinical nutrition (2023)
Folate intake from infant formula according to the present EU legislation increased RBC folate and plasma pABG concentrations in infants to a greater extent than breastfeeding, particularly in carriers of the TT genotype.
- CC) had lower mean (SD) concentrations (all in nmol/L) of red blood cell (RBC) folate [1194 (507) vs. 1440 (521), P = 0.033) and plasma pABG [5.7 (4.9) vs. 12.5 (8.1), P < 0.001] but higher plasma 5-MTHF [33.9 (16.8) vs. 24.0 (12.6), P < 0.001].
- Irrespective of the genotype, infant formula with 5-MTHF (vs. folic acid) caused a significant increase in RBC folate concentration [1278 (466) vs. 947 (552), P < 0.001].
- At 16 wk, plasma pABG concentrations remained ∼50% lower in carriers of the TT (vs. the CC) genotype among all feeding groups.
Cyclic supplementation of 5-MTHF is effective for the correction of hyperhomocysteinemia
Ambrosino P et al. • Nutrition research (New York, N.Y.) (2015)
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- 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.Copyright © 2015 Elsevier Inc.