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📰Read the full 5-MTHF evidence review on GMJ News →Complete clinical article, references and updates on news.gmj.ge. This page is the structured safety summary.⚠ MTHFR C677T homozygotes: 70% reduced folic acid conversion — 5-MTHF essential [2]
⚠ Deplin 15 mg for SSRI-resistant depression (2 RCTs) [2]
⚠ Patient on methotrexate — L-methylfolate may reduce drug efficacy [2]
⚠ Crosses BBB — relevant for neuropsychiatric applications [2]
⚠ Avoids UMFA concern [1]
ℹ️ Not obtained from food. Not applicable — this is not obtained from food in meaningful amounts; supplementation is the practical route.
🔬 Lab interpreter
Recommended test
Serum folate
Serum folate
Reference range / target
>20 nmol/L
>20 nmol/L
5-MTHF raises serum folate effectively [1].
Full lab monitoring ↓⚕ For professionals — confirm ranges against your local laboratory.
Clinical verdict
5-MTHF is the active folate that bypasses MTHFR — essential for the 10–15% with C677T homozygosity (70% reduced folic acid conversion). Crosses BBB (folic acid does not). Deplin (Rx, 15 mg) improved SSRI-resistant depression in 2 RCTs. Avoids unmetabolized folic acid. A reasonable upgrade from folic acid for everyone; ESSENTIAL for MTHFR carriers [1] [2].
1 How much do I need?
👤 Adults: Specific dosage data under clinical review
👴 Elderly: Specific dosage data under clinical review
🤰 Pregnancy: Specific dosage data under clinical review
👦 Pediatric: See guidance
See Folate entry [1].
🏃 Athletes: Standard dose
⚖️ Obesity: Standard dose
Fat-soluble compounds may require dose adjustment in obesity.
🩺 Renal: Consult specialist
Dose adjustment may be needed in renal impairment.
🌱 Vegan: Standard dose
How to take
🍽 Timing: Any time [1].
💊 With food: With or without food [1].
🚫 Avoid: Methotrexate (without specialist guidance) [2].
2 Which form?
| Form | Bioavailability | Vegan | Cost |
|---|---|---|---|
| ['L-methylfolate (Quatrefolic, Metafolin)', 'preferred', 'Active isomer. Patented forms. Most supplements use these [1].'] | Standard | Check label | |
| ['Deplin (prescription)', '', 'L-methylfolate 7.5 or 15 mg. FDA medical food for depression. Prescription [2].'] | Standard | Check label | |
| ['Folic acid (for comparison)', '', 'Synthetic. Requires MTHFR. Cheap. Standard in fortified foods [1].'] | Standard | Check label |
3 Common questions
Do I need 5-MTHF if I have MTHFR? ▼
If you are homozygous C677T (TT genotype): yes, 5-MTHF is strongly preferred because your ability to convert folic acid to the active form is reduced by ~70%. Heterozygous (CT): 5-MTHF is preferred but folic acid still works partially [2].
Is folic acid dangerous? ▼
Not dangerous for most people. Theoretical concerns about unmetabolized folic acid (UMFA) accumulating in blood at high doses have been raised but NOT confirmed to cause harm. However, 5-MTHF avoids this entirely [1].
What is Deplin? ▼
Prescription L-methylfolate at 7.5 or 15 mg — classified as a 'medical food' for depression. Two RCTs showed it improved SSRI response in treatment-resistant depression. It provides the methylfolate needed for monoamine neurotransmitter synthesis [2].
4 Clinical evidence
Strong
5-MTHF is the biologically active folate — established biochemistry [1]. MTHFR C677T polymorphism reduces folic acid → 5-MTHF conversion by ~30% (heterozygous) to ~70% (homozygous) [2]. 5-MTHF raises blood folate comparably or better than folic acid [1]. HIGH
Moderate
MTHFR + depression: L-methylfolate (Deplin) 15 mg/day improved SSRI response in treatment-resistant depression in 2 RCTs [2]. Pregnancy: 5-MTHF effectively prevents NTDs (non-inferior to folic acid in trials) [1]. Hyperhomocysteinemia: 5-MTHF reduces homocysteine effectively, including in MTHFR C677T carriers [2]. Unmetabolized folic acid (UMFA) avoidance: 5-MTHF does not produce UMFA in blood (theoretical concern about folic acid) [1]. MODERATE
Insufficient
5 Safety, toxicity & adverse events
Relative
⚠ Can mask the hematologic signs of B12 deficiency while neuropathy progresses — check B12 status
⚠ Concurrent methotrexate, antiepileptics and other folate-affected drugs
⚠ Bipolar disorder — high-dose folate caution
🚩 Red flags
● Methotrexate patient — L-methylfolate may reduce drug efficacy [2]
● Overmethylation symptoms (insomnia, anxiety, irritability) at high doses — reduce dose [2]
● Patient assuming MTHFR mutation = serious disease — counsel that heterozygous C677T is extremely common and usually clinically benign [2]
6 Interactions
Drug interactions
Methotrexate Major
Mechanism: L-methylfolate provides the active folate that methotrexate aims to deplete. [2]
Effect: May reduce methotrexate anti-cancer or anti-inflammatory efficacy. [2]
Action: Use only under specialist guidance in MTX-treated patients [2].
Anticonvulsants (phenytoin) Moderate
Mechanism: Folate may increase phenytoin metabolism. [1]
Effect: Potentially reduced anticonvulsant levels. [1]
Action: Monitor anticonvulsant levels [1].
Supplement synergies
Vitamin B12 (methylcobalamin) · 500–1,000 µg methylcobalamin
B12 is required to recycle 5-MTHF in the methionine synthase reaction. Without B12, 5-MTHF becomes 'trapped' [1].
B12 is required to recycle 5-MTHF in the methionine synthase reaction. Without B12, 5-MTHF becomes 'trapped' [1].
Vitamin B6 (P5P) · 25–50 mg P5P
B6 supports the transsulfuration pathway (alternative homocysteine disposal). Complete one-carbon metabolism support [2].
B6 supports the transsulfuration pathway (alternative homocysteine disposal). Complete one-carbon metabolism support [2].
7 Regulatory
United States (FDA): Dietary supplement (Quatrefolic, Metafolin). Deplin: medical food for depression (prescription) [2].
European Union: Available as food supplement [1].
8 Cite this page
Vancouver: Pkhakadze G. 5-MTHF — safety profile [Internet]. Tbilisi: PHIG; 2026 [cited 2026 Aug 15]. Available from: https://supplement.ge/ingredients/5-mthf/
APA 7th: Pkhakadze, G. (2026). 5-MTHF — Safety profile. Public Health Institute of Georgia. https://supplement.ge/ingredients/5-mthf/
📋 Editorial information
Author: Prof. G. Pkhakadze, MD, MPH, PhD
Institution: Public Health Institute of Georgia (PHIG)
Affiliation: David Tvildiani Medical University (DTMU)
First published: January 2026
Last reviewed: 2026-05-29
Next review: February 2027
References: 2 cited sources
COI: SupplementIndex receives no funding from supplement manufacturers. All content independently authored by PHIG.
Process: Systematic literature review
📄 License & reuse
Published under Creative Commons Attribution 4.0 International (CC BY 4.0). You may share and adapt for any purpose with attribution.
Pkhakadze G. "5-MTHF — Safety Profile." SupplementIndex, PHIG, 2026. https://supplement.ge/ingredients/5-mthf/ CC BY 4.0.
GP
Prof. G. Pkhakadze, MD, MPH, PhD
Professor of Public Health · Head of Department, DTMU
Editor-in-Chief, Georgian Medical Journal (ISSN 3088-4322)
Chair, Public Health Institute of Georgia · UEMS Public Health Section
Educational and public health purposes. CC BY 4.0. Consult your healthcare provider before starting any supplement. Corrections: info@accreditation.ge. Publisher: PHIG