Abstract
Background: Migraine is a neurovascular disease; its pathogenesis has been linked to higher levels of homocysteine (Hcy) and/or deficiencies in vitamins (vitamin B12 and folate). However, previously published studies remained inconclusive. Therefore, the aim of this study is to review the literature to update the current evidence and clarify the association between Hcy, vitamin B12, folate and migraine in adult and pediatric patients. Methods: We searched the databases PubMed, ScienceDirect, Google Scholar, and the Cochrane Library for articles that investigated levels of Hcy, B12, and folate in association with migraine headaches, since inception through December 2025. The package "meta" in R software was used to calculate the standardized mean difference (SMD) of Hcy, B12 and folate in cases of migraine and compared with non-migraine controls. Results: A total of 17 studies (15 case-control and 2 cross-sectional) investigated the levels of Hcy, encompassing 1549 cases of migraine and 1824 non-migraine controls. The random effect model showed a significantly higher SMD for Hcy in migraine cases compared with non-migraine controls [SMD = 0.48, 95% CI (0.12; 0.83); p < 0.01; I(2) = 91.0%]. Stratification analysis showed the same trends in a group of studies that was conducted in European countries [SMD = 0.29; 95% CI (0.04; 0.54); p = 0.02; I(2) = 87.0%] and group of studies that used analytical methods other than immunoassays [SMD = 0.28; 95% CI (0.08; 0.49); p < 0.001; I(2) = 84.0%]. Meta-regression results showed that only the year of publication had a significant positive effect [estimation coefficient = 0.087; p = 0.017]. Serum levels of vitamin B12 [16 studies included 1330 cases vs. 1533 controls, SMD = -0.36, 95% CI (-0.62; -0.10); p < 0.01; I(2) = 92.1%] and folate [10 studies included with 793 cases vs. 1011 controls, SMD = -0.25 [-0.47; -0.04], p = 0.02; I(2) = 77.3%] were found to be significantly lower in migraine cases compared with non-migraine controls, respectively. Conclusions: Adult and pediatric patients with migraine had elevated Hcy levels and lower vitamin B12 and folate levels. Clinicians may check and correct for Hcy, vitamin B12, and folate levels as prophylactic and therapeutic interventions for migraine. Further studies with a longitudinal design are needed to establish a causal relationship.