Methylfolate (5-MTHF)

Mechanism of Action

5-methyltetrahydrofolate (5-MTHF) is the biologically active form of folate and the primary methyl donor for remethylation of homocysteine to methionine via methionine synthase (requires B12). This reaction generates SAMe (S-adenosylmethionine), the universal methyl donor for >200 methyltransferase reactions including DNA methylation (gene expression), histone methylation (epigenetics), neurotransmitter synthesis (serotonin, melatonin, norepinephrine), creatine synthesis, and phospholipid methylation (phosphatidylcholine). 5-MTHF crosses the blood-brain barrier via folate receptors.

Dosing Protocol

Notes

MTHFR C677T homozygous individuals have ~70% reduced enzyme activity and REQUIRE methylfolate (not folic acid). The methylfolate-depression link is well-established — Deplin (prescription 15mg 5-MTHF) is FDA-approved as adjunctive treatment. Start low (400mcg) and titrate — overmethylation symptoms indicate dose reduction or need for niacin (methyl buffer). ALWAYS co-supplement with B12 to prevent 'methyl trap.' Genetic testing should precede high-dose methylfolate protocols.

Stacking

• Methylcobalamin (B12)
• P5P (B6)
• TMG (Betaine)
• Riboflavin (B2)
• SAMe

Interactions

• Methotrexate [HIGH] — Folate antagonist — supplementation may reduce anti-cancer/anti-inflammatory efficacy
• Phenytoin [MEDIUM] — Mutual interaction: phenytoin depletes folate; folate may increase phenytoin metabolism
• Sulfasalazine [MEDIUM] — Inhibits folate absorption

Contraindications

• Active methotrexate cancer therapy (discuss with oncologist — leucovorin rescue is different)
• Untreated B12 deficiency (folate can mask B12 deficiency, allowing neurological damage to progress)
• Some COMT slow metabolizers may not tolerate high doses

Side Effects

• Anxiety/irritability (overmethylation, especially COMT slow)
• Insomnia
• Headache
• Joint pain
• Nausea
• Depression paradoxical worsening (overmethylation)

Key Papers

• 10.1176/appi.ajp.2012.11071114
• 10.1016/j.jad.2017.07.032
• 10.3390/nu7085245

Source Quality

Quatrefolic (6S-5-MTHF glucosamine salt) is the 4th generation, most stable and bioavailable form. Metafolin (calcium-L-5-MTHF, Merck) is also well-studied. NEVER use folic acid — it requires 4 enzymatic steps (including DHFR, which is saturable, and MTHFR, which is polymorphic) to become 5-MTHF. Unmetabolized folic acid may block folate receptors. Brands: Thorne 5-MTHF, Jarrow Methyl Folate (Quatrefolic), Pure Encapsulations.

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