Magnesium (Mg), the second most abundant intracellular divalent cation, is a cofactor of many enzymes and is involved in a plethora of cellular functions. Magnesium is a natural mineral that helps keep blood pressure stable, promotes heart health, regulates nerve and muscle function, and builds bone, DNA, and protein. A lack of magnesium may also contribute to headaches and migraines. Low serum, cerebrospinal fluid and cerebral tissue levels of magnesium have been found to be low in patients with migraine. Various hypotheses abound as to the reason behind the hypomagnesemia observed in migraineurs. Some suggest that during a migraine headache, excessive amounts of magnesium are excreted due to stress. Others propose that stress triggers excretion of magnesium, with secondary hypomagnesemia causing a migraine. Magnesium is believed to be involved in a number of the aspects of migraine patho-physiology, and deficiency has been linked to cortical spreading depression, platelet aggregation, release of substance P, neurotransmitter release and vasoconstriction.  Intravenous magnesium may be used in patients who are unable to tolerate or absorb oral. It may also be used for the treatment of acute migraines, or as a monthly prophylactic infusion, often administered premenstrually.

Vitamin B2, or riboflavin, is a member of naturally occurring compounds known as flavins. Flavins have a critical role in numerous biochemical reactions, primarily those that are classified as oxidation-reduction reactions, otherwise referred to as redox reactions. Riboflavin is an essential component of coenzymes involved in multiple cellular metabolic pathways, including the energy-producing respiratory pathways. This includes a reaction in the tricarboxylic acid (TCA) cycle and beta-oxidation of fatty acids for energy. Flavoproteins are catalysts in a number of mitochondrial oxidative and reductive reactions and function as electron transporters. In adults, Riboflavin reduces migraine frequency by more than 50% and is similar in efficacy to sodium valproate with significantly fewer side effects.

One of the major genetic disorders that has been linked to migraine headaches is dysfunctional mitochondria. A study proved a link between migraine headaches and cyclic vomiting with variations in gene sequence of mitochondrial DNA (mtDNA). Mitochondria, also known as the “power house” of the cell, and the nucleus are the only two human cell organelles that possess a distinct DNA called mtDNA and nuclear DNA, respectively. As most of the cellular oxygen is utilized by mitochondria (almost 90%), dysfunctional mitochondria can result in the generation of reactive oxygen species which results in oxidative stress to the organelle. The production of free radicals in the mitochondria increases the probability of mtDNA mutation, which can lead to cell death.

Another study has investigated the relationship between the therapeutic responses of patients with migraine headache to riboflavin with its association with specific mtDNA haplogroups. It is known, for example, that non-H haplotype mtDNA is less metabolically active than H haplotype mtDNA. The authors postulated that riboflavin might be more effective in non-H haplotype mtDNA migraine headache sufferers than those with H haplotype mtDNA. Their results found that patients with non-H mtDNA haplotypes responded significantly better to riboflavin treatment (77%) than with H mtDNA haplotypes (44.8%) (P<.01). In addition, they found a significant reduction in mean monthly attack frequency between baseline and the fourth month of riboflavin monotherapy in the total population of patients treated (P<.001).