| Magnesium Glycinate | 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 reduced attack frequency in one meta-analysis, while a later review judged the evidence insufficient14. Level B evidence from AAN. | 400 to 600 mg elemental magnesium/day (as glycinate) | With dinner; or split morning and evening | No routine test reflects total body magnesium well. Glycinate is usually better tolerated than citrate or oxide14, though high doses can still loosen stools. Avoid citrate form if loose stools are present. This whole range is above the 350 mg/day upper intake level for supplemental magnesium; above that, diarrhea is common. With kidney disease, take it only on your clinician's advice. |
| 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. In pooled trials, riboflavin at 400 mg/day for three months reduced migraine days, frequency and pain8. | 400 mg/day | With breakfast | 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 Complexes I and II and Complex III, essential for neuronal ATP production. A 2005 randomized trial reported benefit at 300 mg/day; a later meta-analysis found no significant reduction in frequency8. | 300 mg/day (ubiquinol form) | With a fat-containing meal, essential for absorption | Ubiquinol is the reduced form of CoQ10. CoQ10 may interact with some blood thinners and with insulin, so check with your prescriber first if you take either21. |
| 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 randomized trial of 245 people found 75 mg 2x/day cut migraine attack frequency by 48% over 4 months, against 26% on placebo16. The American Academy of Neurology recommended butterbur in 2012 but stopped recommending it in 2015 because of serious safety concerns15. | 75 mg 2x/day (PA-free certified extract) | With meals | Must be certified PA-free (pyrrolizidine alkaloid-free). PAs in non-certified butterbur cause serious liver damage, and rare liver injury has been reported even with PA-free products15. |
| Feverfew (Tanacetum parthenium) | Parthenolide, the active compound, inhibits platelet serotonin release, blocks prostaglandin synthesis and reduces NF-ΞΊB-mediated neuroinflammation in trigeminal neurons. A Cochrane review of six trials found mixed, low-quality evidence; the largest trial reported 0.6 fewer attacks a month than placebo, with no difference in attack intensity17. Most effective for prevention when taken continuously, not for acute treatment. | 50 to 150 mg/day (standardized to 0.2 to 0.6% parthenolide) | With food | Do not stop abruptly after prolonged use: this can cause "post-feverfew syndrome" (rebound headaches, nervousness, insomnia). Taper gradually. Avoid in pregnancy. It may slow blood clotting, so stop it at least 2 weeks before planned surgery, and check with your prescriber if you take other medicines, including migraine medicines22. |
| 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 and restores sleep architecture. A 2016 randomized trial found melatonin effective for migraine prevention, better tolerated than a prescription preventive and without weight gain, though this is a single trial against one prescription drug18. | 3 to 5 mg at bedtime | 30 to 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. Melatonin is commonly sold at doses well above what is needed, and more is not better. The trial used 3 mg; start there rather than higher. Discuss it with your prescriber if you take sedatives, anticoagulants or immunosuppressants. |
| 5-HTP (5-Hydroxytryptophan) | The direct precursor to serotonin, bypassing the rate-limiting tryptophan hydroxylase step. Older small trials of 400 to 600 mg/day reported fewer attacks; the evidence has not been updated with modern trials. The range given here is lower than the trial doses and has not been tested for migraine. Proposed to help sleep and mood, both of which influence migraine threshold. | 100 to 200 mg/day (starting low) | Before bed (serotonin β melatonin pathway supports sleep) | Do not combine with SSRIs, SNRIs, triptans or MAOIs: risk of serotonin syndrome. Do not use it if you take any serotonergic medication. |
| 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 small randomized trial reported fewer attacks at 600 mg/day. Combination benefits have not been established. | 600 mg/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. |
