Methylfolate (5-MTHF) vs Vitamin D3

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 D3 (cholecalciferol) is hydroxylated in the liver to 25(OH)D (calcidiol), then in the kidneys to 1,25(OH)2D (calcitriol), the active hormone. Calcitriol binds the nuclear vitamin D receptor (VDR), forming a heterodimer with RXR that regulates >1000 genes. Key actions: upregulation of intestinal calcium/phosphorus absorption (TRPV6, calbindin), modulation of innate immunity (cathelicidin LL-37 antimicrobial peptide production), suppression of adaptive immune overactivation (Th1/Th17 to Treg shift), regulation of PTH and osteocalcin for bone mineralization, and modulation of insulin secretion from beta cells.

Standard Dosing

5000 IU daily (125 mcg)

Timing

With largest fat-containing meal of the day (fat-soluble). Morning preferred.

Cycle Duration

ongoing (lifelong for most people in northern latitudes)

Side Effects

• Hypercalcemia at excessive doses (>10,000 IU/day long-term without monitoring)
• Nausea/vomiting (toxicity)
• Kidney stones (with excessive calcium)
• Metallic taste (toxicity sign)

Contraindications

• Hypercalcemia
• Granulomatous diseases (sarcoidosis, some lymphomas — unregulated 1-alpha hydroxylase conversion)
• Primary hyperparathyroidism (without monitoring)
• Williams syndrome

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