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L-Methylfolate (5-MTHF)
Bioactive folate that bypasses MTHFR conversion — critical for the 30-40% of people with gene variants affecting mood and methylation.
What the evidence says
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
HighWhat the studies found
By outcome
See full supplement plans that include Methylfolate.
Methylfolate has an evidence score of 9/10 — very strong evidence based on 34 indexed studies, including 6 meta-analyses. Bioactive folate that bypasses MTHFR conversion — critical for the 30-40% of people with gene variants affecting mood and methylation.
The commonly studied dose of Methylfolate is 400-800mcg daily. Research points to an estimated optimal dose around 7500mcg, with a minimum effective dose near 2500mcg. Individual response varies — start low and adjust.
The best time to take Methylfolate is in the morning. Taking it with food is preferred. L-methylfolate (5-MTHF) is the biologically active form of folate, ready for use in one-carbon metabolism, DNA synthesis, and neurotransmitter production.
Vitamin B12
Likely helpsDrives nerve myelination, red blood cell formation, and DNA synthesis — deficiency is common in vegans, vegetarians, and older adults.
Acetyl-L-Carnitine
Likely helpsAcetylated carnitine that crosses the blood-brain barrier to fuel mitochondrial energy and donate acetyl groups for acetylcholine synthesis.
Last reviewed May 2026 · evidence from 40 studies · how we score
This information is for educational purposes only. It is not a substitute for professional medical advice. Always consult a qualified healthcare provider before starting, stopping, or changing any supplement or medication.
L-Methylfolate (5-MTHF) is the active, bioavailable form of vitamin B9 (folate). Unlike folic acid, it doesn't require conversion by the MTHFR enzyme, making it essential for the 30-40% of people with MTHFR gene variants who cannot efficiently convert folic acid. It plays crucial roles in neurotransmitter synthesis, DNA repair, and the methylation cycle that affects energy, mood, and detoxification.
Donates methyl groups for hundreds of biochemical reactions
Required for producing serotonin, dopamine, and norepinephrine
Essential for cell division and genetic repair
How Methylfolate works — from molecular targets to health outcomes. Click an edge to see supporting research.This visualization is in beta — pathways are being refined and expanded.
400-800mcg daily
Loading: Start low (400mcg) and increase gradually; some need higher doses (1-15mg) for depression
Can be taken without food
| Form | Type |
|---|---|
| 💊L-Methylfolate (5-MTHF) | Recommended |
| 💊Folinic acid (for those sensitive to methylfolate) | Alternative |
| 💊Quatrefolic (branded 5-MTHF) | Alternative |
Avoid folic acid if you have MTHFR variants. Look for 'L-methylfolate' or '5-MTHF' on the label.
Minimum: 4 weeks
Optimal: 12 weeks
Cycling: Not required
Note: Best taken in the morning as it can be energizing. Pair with methylcobalamin (B12) for optimal methylation support.
You can get methylfolate from these foods and drinks. Doses are typical per-serving estimates — actual content varies by brand, brew, cooking, etc.
358 mcg per cup
1 cup cooked. Iron is non-heme — pair with vitamin C to boost absorption ~3×. Folate is food-folate form; MTHFR-variant carriers convert less efficiently.
268 mcg per cup
1 cup cooked.
Based on meta-analysis showing small effect size for adjunctive L-methylfolate. RCT showed efficacy at high doses but effectiveness appears modest. Risk increases with higher doses due to overmethylation symptoms.
Better emotional balance, especially in those with low folate
Less fatigue, more mental clarity
Reduced cardiovascular risk marker
Anxiety, irritability if dose too high (especially with COMT variants)
Essential; 400-800mcg recommended for neural tube defect prevention
Especially beneficial; may need higher doses
May reduce effectiveness of methotrexate for certain conditions
May affect seizure threshold at high doses
Tip: Reduce dose; may indicate overmethylation
Tip: Take in morning; reduce dose
Tip: Start with lower dose
B vitamins work together in methylation
Optimal methylation cycle support with all B vitamins
Recycles homocysteine back to methionine
Healthy methylation cycle
Often combined for fertility support
Enhanced reproductive health and egg quality
Both work together in methylation
Optimal methylation and homocysteine metabolism
Methylfolate is generally well-tolerated and considered safe for most healthy adults at recommended doses. The most commonly reported side effects are anxiety/irritability, insomnia, headache. Use caution if any of these apply to you: History of bipolar disorder (may trigger mania - start very low); Seizure disorders (high doses).
Omega-3
Probably helpsEssential fatty acids critical for brain health, mood regulation, and reducing inflammation throughout the body.
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