Homocysteine and migraine. A narrative review

Recent evidence suggests that migraine is associated with an increased risk of cardiovascular disorders, so that it is increasingly hypothesized that this primary form of headache may be linked to thrombotic diseases by some biological pathways and risk factors. Homocysteine, a sulfur-containing molecule, is now recognized as an independent risk factor for a variety of thrombotic disorders, especially ischemic heart disease and stroke. This article is hence aimed to provide an overview of epidemiological evidence about the association between homocysteine and migraine published in cross-sectional, prospective or interventional studies. Overall, the evidence gathered from cross-sectional studies that measured plasma homocysteine levels suggests that the epidemiological link between the plasma concentration of this biomarker and migraine is very weak, at best. Contradictory evidence emerged from interventional studies, in which treatment of hyperhomocysteinemia with folic acid or vitamin B supplementation was effective to lower plasma homocysteine and decrease frequency and/or severity of migraine. The association remains largely speculative, however, since it could not be clearly demonstrated that these two biological effects were directly linked. The only study that has assessed homocysteine in cerebrospinal fluid reported that the concentration of this biomarker in migraine patients was significantly increased compared to controls. Although this evidence must be obviously confirmed in larger trials, some putative mechanisms may support a causal link between increased generation of homocysteine in the brain environment and migraine.