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Sources: FDA MedWatch, EMA EudraVigilance, WHO VigiBase, WADA Prohibited List · 2026-05-29
Updated: 2026-05-29 · v2.0 · Prof. G. Pkhakadze, MD, MPH, PhD📎 Cite 📄 PDF
1 Identity

5-MTHF

L-Methylfolate (active folate)
Generally SafeEvidence: StrongWater-Soluble Vitamins
5-Methyltetrahydrofolate (5-MTHF, L-methylfolate) is the biologically active form of folate — the form that circulates in blood, crosses the blood-brain barrier, and directly participates in one-carbon metabolism (homocysteine remethylation, DNA synthesis, neurotransmitter production) [1]. Unlike folic acid (synthetic), 5-MTHF does NOT require reduction by MTHFR enzyme, making it the preferred form for individuals with MTHFR polymorphisms (C677T — present in 10–15% of the population homozygously, up to 50% heterozygously) [2]. Prescription L-methylfolate (Deplin) is FDA-approved as a medical food for depression [2].
1
5-MTHF
L-Methylfolate (active folate)
Generally SafeEvidence: StrongWater-Soluble Vitamins
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].
RDA
Equivalent to 400 mcg DFE
Target range
>20 nmol/L
Upper limit
No UL
Evidence
Strong
Population dosing — click to filter
🔗 Best with: Vitamin B12, Vitamin B6, Betaine (TMG)✅ USP Verified, NSF Contents Certified, ConsumerLab Approved
2 Risk self-assessment
Not applicable — not an essential nutrient [1]
Select factors above to see your risk level
Clinical pearl for practitioners
SupplementIndex
5-MTHF
L-Methylfolate (active folate) · Generally Safe · Evidence: Strong
RDA
Equivalent to 400 mcg DFE
Upper limit
No UL
Evidence
Strong
Clinical bottom line
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].
Do not miss
⚠ 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]
Pregnancy
Effectively prevents NTDs. Preferred for MTHFR C677T carriers. 400–800 µg/day [1].
4 Dietary sources
µg DFE
See main Folate (B9) entry. Natural food folate is primarily 5-MTHF and other reduced forms. Folic acid (synthetic) is in fortified foods [1].
5 Lab interpreter

Serum folate

<12 Deficient
12–20 Insufficient
20–50 Optimal
50–100 Excess
>150 Toxic
Your level:
Enter a value above
⚕ For healthcare professionals. Does not replace clinical judgment.
6 Quick facts
CategoryWater-Soluble Vitamins
Safety levelGenerally Safe
EvidenceStrong
RDAEquivalent to 400 mcg DFE
Upper limit (UL)No UL
Scientific nameL-Methylfolate (active folate)
Chemical classActive folate (5-methyltetrahydrofolic acid) [1]
vs Folic acidFolic acid = synthetic, requires MTHFR reduction. 5-MTHF = active, bypasses MTHFR [1]
MTHFR polymorphismC677T: 10–15% homozygous. Up to 50% heterozygous. Impaired folic acid → 5-MTHF conversion [2]
BBB penetration5-MTHF crosses BBB (folic acid does not significantly) [2]
DeplinPrescription L-methylfolate for depression (medical food) [2]
Typical dose400–1,000 µg/day (supplement); 7.5–15 mg/day (Deplin for depression) [2]
7 Dosage by population

Adults Moderate

See product label

Elderly Moderate

See product label
Consider reduced renal/hepatic clearance. Start at lower end of range.

Pregnancy Moderate

NTD prevention. Equivalent to folic acid [1].

Pediatric Moderate

See guidance
See Folate entry [1].

Athletes Limited

Standard dose

Obesity Limited

Standard dose
Fat-soluble compounds may require dose adjustment in obesity.

Renal Limited

Consult specialist
Dose adjustment may be needed in renal impairment.

Vegan Moderate

Standard dose
General: 400–1,000 µg/day 5-MTHF. Pregnancy: 400–800 µg/day. Depression (Deplin): 7.5–15 mg/day (prescription). MTHFR C677T homozygotes: 5-MTHF strongly preferred over folic acid [2].
8 Form comparison
FormBioavailabilityVeganCost/day
['L-methylfolate (Quatrefolic, Metafolin)', 'preferred', 'Active isomer. Patented forms. Most supplements use these [1].']StandardCheck label
['Deplin (prescription)', '', 'L-methylfolate 7.5 or 15 mg. FDA medical food for depression. Prescription [2].']StandardCheck label
['Folic acid (for comparison)', '', 'Synthetic. Requires MTHFR. Cheap. Standard in fortified foods [1].']StandardCheck label
9 Clinical evidence

Strong evidence

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 evidence

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 evidence

Cardiovascular event reduction via homocysteine lowering [2]. Cancer risk: the relationship between folate form and cancer is complex and unresolved [1]. Autism prevention [1]. Cognitive decline prevention [1]. LOW
10 Safety

🚩 Red flags — when to stop and refer

● 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]

Pregnancy

5-MTHF effectively prevents NTDs. Recommended by some guidelines for women with MTHFR C677T. Standard prenatal doses (400–800 µg) apply [1].

Pediatric

See Folate entry [1].
11 Toxicity and overdose

12 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].
13 Supplement interactions

Best combined with

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].
Vitamin B6 (P5P) · 25–50 mg P5P
B6 supports the transsulfuration pathway (alternative homocysteine disposal). Complete one-carbon metabolism support [2].
14 Laboratory monitoring
Serum folate Primary
Target: >20 nmol/L · If monitoring supplementation [1].
5-MTHF raises serum folate effectively [1].
Plasma homocysteine Secondary
Target: <15 µmol/L · If hyperhomocysteinemia indication [2].
MTHFR genotype Secondary
Target: C677T status · Once (genetic) [2].
15 Deficiency and prevalence
0%
[1]

Risk factors

• Not applicable — not an essential nutrient [1]
16 Frequently asked 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].
Should everyone switch to 5-MTHF? ▼
Reasonable but not mandatory. 5-MTHF is the active form, avoids MTHFR concerns, and doesn't produce UMFA. The main barrier is cost (5-MTHF > folic acid). For MTHFR C677T carriers: strongly recommended. For everyone else: a reasonable upgrade [1] [2].
17 Regulatory status
United States (FDA): Dietary supplement (Quatrefolic, Metafolin). Deplin: medical food for depression (prescription) [2].
European Union: Available as food supplement [1].
18 References
[1]National Institutes of Health, ODS. Folate — Fact sheet for health professionals. Updated 2024. ods.od.nih.gov REVIEW
[2]Papakostas GI, et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry. 2012;169(12):1267-1274. doi:10.1176/appi.ajp.2012.11071114 RCT
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20 Cite this page
Vancouver
Pkhakadze G. 5-MTHF — safety profile [Internet]. Tbilisi: Public Health Institute of Georgia; 2026 [cited 2026 May 30]. 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/
CC BY 4.0
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Reviewed by Prof. G. Pkhakadze, MD, MPH, PhD
Editor-in-Chief, Georgian Medical Journal · Chair, PHIG
Last reviewed: May 2026 · Next: November 2026
This entry is provided for educational and public health purposes under CC BY 4.0. Consult your healthcare provider before starting any supplement. For corrections: info@accreditation.ge.
Publisher: PHIG · Editor-in-Chief: Prof. Giorgi Pkhakadze, MD, MPH, PhD