L-Methylfolate (5-MTHF)
Bioactive folate that bypasses MTHFR conversion — critical for the 30-40% of people with gene variants affecting mood and methylation.
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.
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
Top studies from 40+ peer-reviewed papers
Borges-Vieira JG et al. • Nutritional neuroscience (2023)
“As for anxiety symptoms, the availability of results is limited to adjuvant vitamin D therapy.”
Maruf AA et al. • Pharmacopsychiatry (2022)
“Adjunctive L-methylfolate may have modest efficacy in antidepressant-treated adults with MDD.”
Sakuma K et al. • Psychopharmacology (2018)
“Our findings suggest that pooled FA + AP treatment improves negative symptoms in schizophrenia patients.”
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.”
Papakostas GI et al. • American Journal of Psychiatry (2012)
“L-methylfolate at 15mg/day significantly improved outcomes in patients with SSRI-resistant depression.”
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