Methylfolate (5-MTHF) vs Vitamin K2 (MK-7)

Mechanism

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.

Standard Dosing

400-800 mcg daily (general health); 5-15mg for depression/MTHFR homozygous

Timing

Morning with B-complex. Start low and titrate up, especially in COMT slow metabolizers.

Cycle Duration

ongoing

Side Effects

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

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

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Mechanism

Vitamin K2 (menaquinone-7) activates vitamin K-dependent proteins via gamma-carboxylation of glutamic acid residues. Key targets: osteocalcin (directs calcium into bone matrix), matrix Gla protein (MGP, inhibits arterial calcification), Gas6 (cell signaling, neuroprotection), and protein S (anticoagulant). MK-7 has a long half-life (~72 hours vs 1-2 hours for K1) enabling consistent carboxylation activity with once-daily dosing. It works synergistically with Vitamin D3 to regulate calcium metabolism — D3 increases calcium absorption while K2 directs its deposition.

Standard Dosing

100-200 mcg MK-7 daily

Timing

With fat-containing meal alongside Vitamin D3.

Cycle Duration

ongoing (mandatory co-supplement with Vitamin D3)

Side Effects

• Generally very well tolerated
• Rare: mild GI discomfort
• Theoretical thrombotic risk in deficiency-rebound scenario (unproven)

Contraindications

• Warfarin/coumarin anticoagulant therapy (unless specifically directed by physician with INR monitoring)

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