Iron Bisglycinate vs Methylfolate (5-MTHF)

Mechanism

Iron is essential for hemoglobin (oxygen transport), myoglobin (muscle oxygen storage), cytochrome enzymes (electron transport chain — Complexes I, II, III, IV), cytochrome P450 enzymes (drug/hormone metabolism), catalase (H2O2 decomposition), ribonucleotide reductase (DNA synthesis), and aconitase (Krebs cycle). Iron bisglycinate (Ferrochel) uses amino acid chelation to bypass the normal DMT1/ferroportin pathway, instead being absorbed intact via PepT1 transporter. This mechanism avoids the GI side effects of ionic iron (free Fe2+ generates hydroxyl radicals via Fenton reaction in the gut lumen) and is not inhibited by phytates, tannins, or calcium.

Standard Dosing

25-36mg elemental iron (as bisglycinate) daily for deficiency correction

Timing

On empty stomach or with vitamin C for absorption. Alternate day dosing (every other day) may be superior due to hepcidin cycling. Separate from calcium, zinc, tea, coffee by 2+ hours.

Cycle Duration

Until ferritin >50 ng/mL, then reassess (typically 3-6 months). Not for ongoing supplementation unless chronic blood loss.

Side Effects

• GI distress (significantly less than ferrous sulfate)
• Constipation (less common with bisglycinate)
• Dark stools
• Nausea
• Iron overload if supplemented unnecessarily

Contraindications

• Hemochromatosis
• Iron overload conditions
• Thalassemia (without documented deficiency)
• Hemolytic anemias (unless also iron deficient)
• Chronic transfusion therapy

Best Stacking Partners

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

Best Stacking Partners