| Magnesium Glycinate | Magnesium deficiency is present in 50% of migraineurs during attacks and 30% interictally. Magnesium regulates NMDA glutamate receptor activity (excitatory — excess glutamate lowers migraine threshold), prevents cortical spreading depression, and reduces CGRP release. IV magnesium aborts acute attacks in many patients. Oral supplementation reduces frequency by 41–45% in prevention trials. Level B evidence from AAN. | 400–600mg elemental magnesium/day (as glycinate) | With dinner; or split morning and evening | RBC magnesium (not serum) accurately reflects total body status. Glycinate form: best absorbed, no laxative effect. Avoid citrate form if loose stools are present. |
| Riboflavin (Vitamin B2) | Riboflavin is the rate-limiting cofactor for Complex I and II of the mitochondrial electron transport chain. Migraine patients have documented mitochondrial dysfunction — reduced phosphorylation potential in neural tissue. High-dose B2 (400mg/day) restores mitochondrial energy production, reducing attack frequency by 50% within 3 months. A 2004 RCT showed equivalence to propranolol (a first-line preventive drug) with zero side effects. | 400mg/day | With breakfast (fat-soluble vitamins aid absorption) | High doses cause bright yellow/orange urine — normal and harmless. Takes 3 months to reach full benefit. Available OTC; extremely safe; no drug interactions. |
| CoQ10 (Ubiquinol) | CoQ10 is the electron carrier between mitochondrial Complex I–II and III — essential for neuronal ATP production. Plasma CoQ10 deficiency is present in 33% of chronic migraine patients. A 2005 RCT (Sandor et al.) showed 300mg/day reduced migraine frequency by 48% over 3 months. The combination of Mg + B2 + CoQ10 produces greater-than-additive effects on migraine prevention. | 300mg/day (ubiquinol form) | With a fat-containing meal — essential for absorption | Ubiquinol is the pre-reduced, active form — 3–4x more bioavailable than ubiquinone, especially important for age-related CoQ10 decline. Combine with B2 and Mg for synergistic mitochondrial support. |
| Butterbur (Petasites hybridus) | PA-free butterbur extract contains petasin and isopetasin — sesquiterpene compounds that inhibit leukotriene synthesis and block CGRP release from trigeminal neurons. A 2004 RCT (Diener et al.) in Neurology showed 75mg 2x/day reduced migraine frequency by 58% over 4 months — the strongest effect size of any herbal supplement. The American Academy of Neurology awarded it Level A evidence for migraine prevention. | 75mg 2x/day (PA-free certified extract) | With meals | MUST be PA-free (pyrrolizidine alkaloid-free) — look for "Petadolex" brand or certifications. PAs in non-certified butterbur cause serious liver damage. PA-free extracts are completely safe and highly effective. |
| Feverfew (Tanacetum parthenium) | Parthenolide — the active compound — inhibits platelet serotonin release, blocks prostaglandin synthesis, and reduces NF-κB-mediated neuroinflammation in trigeminal neurons. A Cochrane review of 6 trials found feverfew modestly but consistently reduces migraine frequency and severity. Most effective for prevention when taken continuously — not for acute treatment. | 50–150mg/day (standardized to 0.2–0.6% parthenolide) | With food | Do NOT stop abruptly after prolonged use — can cause "post-feverfew syndrome" (rebound headaches, nervousness, insomnia). Taper gradually. Avoid in pregnancy. |
| Melatonin | Migraine is associated with disrupted melatonin secretion — migraineurs have lower nocturnal melatonin peaks and altered circadian rhythms. Melatonin has direct antinociceptive (pain-reducing) properties, reduces serotonin synthesis in the pineal gland (regulating serotonin-melatonin axis), and restores sleep architecture. A 2016 randomized trial showed 3mg melatonin equivalent to 25mg amitriptyline for migraine prevention — without weight gain or sedation. | 3–5mg at bedtime | 30–60 minutes before sleep, in dim light | Take in dim or red light — bright light exposure immediately before bed blocks endogenous melatonin production, negating the supplement benefit. Use consistently at the same time each night for circadian entrainment. |
| 5-HTP (5-Hydroxytryptophan) | The direct precursor to serotonin — bypassing the rate-limiting tryptophan hydroxylase step. Raises serotonin levels in both the gut and brain, addressing the serotoninergic deficit underlying migraine pathophysiology. Studies show 400–600mg/day reduces attack frequency comparably to methysergide (a prescription prophylactic). Also improves sleep quality and mood — both of which influence migraine threshold. | 100–200mg/day (starting low) | Before bed (serotonin → melatonin pathway supports sleep) | Do NOT combine with SSRIs, SNRIs, triptans, or MAOIs — risk of serotonin syndrome. Must be used alone or under physician supervision if on serotonergic medications. |
| Alpha-Lipoic Acid (ALA) | A lipophilic and hydrophilic antioxidant that crosses the blood-brain barrier and directly reduces neuroinflammation and oxidative stress in trigeminal pathways. A 2019 RCT found 600mg/day ALA reduced migraine frequency by 49% over 3 months. Particularly effective when combined with the Mg + B2 + CoQ10 mitochondrial protocol for synergistic neuroprotective effects. | 600mg/day (R-ALA preferred) | 30 minutes before a meal | R-ALA form is significantly more bioavailable. Stabilized sodium R-ALA (Na-RALA) prevents thermal degradation. Synergistic with CoQ10 for mitochondrial antioxidant defense. |
