Great question — and very important, especially in your case with MTHFR A1298C +/–, COMT +/–, MTR +/–, MTRR +/–, and sensitivity to methyl donors.
To safely unclog methylation and reduce side effects, the correct order is foundational → cofactor → upstream → downstream, like priming a metabolic engine before turning it on.
✅ Correct Order to Unclog Methylation Pathway
| Step | Nutrient | Role | Priority |
|---|---|---|---|
| 1️⃣ | Riboflavin (B2) | Cofactor for MTHFR enzyme to convert folate → 5-MTHF | 🔑 Must go first |
| 2️⃣ | P5P (Vitamin B6) | Required for transsulfuration & neurotransmitter balance (prevents buildup) | 🔧 Stabilizes downstream |
| 3️⃣ | Folinic Acid | Bypasses folic acid → becomes usable folate without methylation spike | 🧠 Gentle activation |
| 4️⃣ | Hydroxo-B12 (or very low methyl/adenosyl B12) | Accepts methyl groups → supports MTR & MTRR → detox | 🚦 Only once upstream is ready |
🧭 Why this order matters
If you jump to folinic acid or B12 first without B2 or B6:
- You may push a partially blocked pathway.
- Risk of side effects: tachycardia, irritability, detox overload, gut inflammation (you’ve already experienced this).
- You might worsen COMT or AOX1 bottlenecks.
🧪 Suggested ramp-up strategy (gentle)
| Week | Nutrient | Form | Dosage |
|---|---|---|---|
| Week 1–2 | B2 | Riboflavin or R5P | ~5–10 mg/day |
| Week 2–3 | P5P | Pyridoxal-5-Phosphate | ~5–10 mg/day |
| Week 3+ | Folinic Acid | Calcium folinate | ~100–200 mcg (start LOW) |
| Week 4+ | Hydroxo-B12 | Hydroxocobalamin | ~250–500 mcg 2–3x/week |
Only increase if well tolerated. You can spread this slower if you're sensitive.
🚫 Avoid upfront:
- Folic acid (synthetic)
- High-dose methylfolate
- Methylcobalamin (for now)
- B12 injections (unless clinically necessary)
Would you like a printable step-by-step protocol with symptom tracking so you can adjust day by day?