Methylfolate (5-MTHF) vs Vitamin B6 (P5P)

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

Pyridoxal-5-phosphate (P5P) is the active coenzyme form of vitamin B6, required by over 150 enzymes. Key roles: transamination and decarboxylation of amino acids, serving as a cofactor for aromatic L-amino acid decarboxylase (converting 5-HTP to serotonin and L-DOPA to dopamine), glutamic acid decarboxylase (producing GABA), cystathionine beta-synthase (homocysteine transsulfuration to cysteine), serine hydroxymethyltransferase (one-carbon folate metabolism), glycogen phosphorylase (glycogenolysis), and aminolevulinic acid synthase (heme synthesis).

Standard Dosing

25-50mg P5P daily

Timing

Morning with food. Often included in B-complex.

Cycle Duration

ongoing

Side Effects

• Peripheral neuropathy at chronic doses >200mg/day (numbness, tingling)
• Photosensitivity
• Nausea
• Vivid dreams

Contraindications

• Levodopa monotherapy
• Doses >200mg/day chronically (peripheral neuropathy risk)

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