What causes migraine?

Riboflavin (vitamin B₂) is a water-soluble vitamin that the body cannot produce on its own. It serves as a precursor to two key coenzymes — flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) — which act as electron carriers in the mitochondrial electron transport chain, enabling cells to convert carbohydrates, fats, and proteins into usable energy (ATP). Beyond energy metabolism, riboflavin supports antioxidant defence (by regenerating glutathione), maintains healthy skin, eyes, and the nervous system, and is required for the metabolism of other B vitamins (niacin, B₆, folate). Dietary sources include dairy products, eggs, lean meats, green leafy vegetables, legumes, nuts, and fortified cereals. The recommended daily allowance is roughly 1.1–1.3 mg for adults.

it's worth noting that high-dose riboflavin (400 mg/day) — far above the dietary RDA (307 times the RDA) — is recommended by the NICE guidelines and the Canadian Headache Society as a preventive treatment for migraine. It is thought to work by improving mitochondrial energy production in brain cells and reducing oxidative stress and neuroinflammation, both of which are implicated in migraine pathophysiology. Benefits typically take 2–3 months of consistent use to appear, and it is well tolerated with few side effects.

Methylcobalamin — it's a necessary cofactor without which both the one-carbon pathway (homocysteine clearance) and the TCA cycle (mitochondrial energy) are impaired. Migraineurs are more likely to be functionally deficient (OR ~2.9), and correcting that deficiency is a prerequisite for the methylfolate to work. It's the missing link between the two other pieces of the puzzle:

• Riboflavin → fixes ETC (Complexes I, II)
• Methylfolate → fixes one-carbon / methylation
• Methylcobalamin → enables methylfolate AND independently supports TCA cycle flux Without it, you're fixing two of three bottlenecks and leaving the third (and the gatekeeper for the second) in place.

Practical protocol

Weeks 1-4 Start with magnesium 400–600 mg elemental magnesium as magnesium glycinate (split AM/PM) — fastest onset, best evidence, cheapest, safest
Weeks 8–12: Assess improvement. If not perfect, add Riboflavin 400 mg/day (as 200mg in morning and 200mg in evening) + methylfolate 100 µg + methylcobalamin 25 µg + P-5-P 25 mg. Monitor for overstimulation (anxiety, insomnia, palpitations).
Week 9+: If tolerated, increase methylfolate to 400 µg. If still well-tolerated at week 8–12, consider 800 µg.
Month 3: Reassess migraine frequency/severity. If no improvement, the bottleneck may be elsewhere ( CoQ10, CGRP pathway).
Ongoing: Continue indefinitely if effective. No need to cycle.

If mitochondria malfunction is suspected, there are numerous mitochondria affecting supplements, like methylene blue (effects within 1 hour), urolithin-a, coq10, mito-q, DHM Dihydromyricetin, zinc, L-Carnetine, Creatine, Glycine, Taurine

There are lots of anti-inflamatory supplements that will calm inappropriate inflamation. The evidence (migraine-specific)
Melatonin — strongest mechanistic story:
2025 Frontiers in Immunology review: "Within the trigeminal nucleus caudalis, melatonin polarises resident microglia away from an iNOS-high M1 phenotype toward an Arg-1-expressing M2 state, diminishing IL-1β and TNF-α release and dampening central sensitisation" Via MT2 receptors on dural vessels: "suppresses CGRP release, stabilises mast-cell degranulation, and curtails neurogenic plasma extravasation" RCT (Gonçalves et al.): melatonin 3 mg vs. amitriptyline 25 mg vs. placebo — melatonin was non-inferior to amitriptyline Dose: 3 mg at bedtime (endogenous peak is nocturnal; timing matters)
Alpha-lipoic acid — most direct CGRP data:
2023 adolescent RCT (add-on to flunarizine): 600 mg/day × 12 weeks → CGRP −122.4 pg/mL, attack frequency significantly reduced (P = .001) 2021 RCT (women with episodic migraine): 600 mg/day × 3 months → significant reduction in CRP, MDA (lipid peroxidation), and CGRP 2007 Magis RCT: 600 mg/day × 3 months → significant reduction in frequency, severity, and headache days Dose: 600 mg/day (300 mg BID)
NAC — pilot data, larger trial pending:
2020 pilot RCT (NEC = NAC 600 mg + Vit E 250 IU + Vit C 500 mg, BID × 3 months): migraine days −3.1 vs. sham, P = .018 MIGRANT trial (NCT02629536, n = 90) was the confirmatory study Dose: 600 mg BID (1.2 g/day) Mechanism is primarily GSH regeneration → reduces the oxidative stress that sensitises trigeminal neurons and drives NF-κB → TNF-α
Glycine — weakest direct evidence, most mechanistic uncertainty:
No migraine-specific RCT
The NMDA glycine co-agonist site means glycine could theoretically increase NMDA activity (excitatory), while GlyR activation is inhibitory. The net effect at 3–5 g/day is likely GlyR-dominant (inhibitory) Nrf2 activation at high doses (≥3 g) provides an anti-inflammatory pathway independent of the NMDA question Dose if used: 3 g/day (split), more for the antioxidant/Nrf2 effect than for the NMDA question