# Association Between Homocysteine, Vitamin B12, Folate and Migraine: An Updated Systematic Review and Meta-Analysis

## TL;DR

People with migraines have higher homocysteine and lower vitamin B12 and folate levels, suggesting a possible metabolic link to migraine risk and severity.

## Contribution

An updated systematic review and meta-analysis clarifying the association between homocysteine, vitamin B12, folate, and migraine in adults and children.

## Key findings

- Migraine patients have significantly higher homocysteine levels than non-migraine controls.
- Vitamin B12 and folate levels are significantly lower in individuals with migraines.
- The observed differences are consistent across geographic regions and laboratory methods.

## Abstract

What are the main findings?
Adults and children with migraines were found to have higher levels of homocysteine in their blood and lower levels of vitamin B12 and folate than people without migraines.These biochemical differences persist across geographic regions and laboratory methods, supporting a potential metabolic link between migraine and one-carbon metabolism.

Adults and children with migraines were found to have higher levels of homocysteine in their blood and lower levels of vitamin B12 and folate than people without migraines.

These biochemical differences persist across geographic regions and laboratory methods, supporting a potential metabolic link between migraine and one-carbon metabolism.

What are the implications of the main findings?
Clinicians may consider evaluating homocysteine, vitamin B12, and folate levels in migraine patients, as these factors may influence migraine risk and severity.Implementing routine assessment and targeted correction of these markers could provide a practical adjunct to migraine prevention and management.

Clinicians may consider evaluating homocysteine, vitamin B12, and folate levels in migraine patients, as these factors may influence migraine risk and severity.

Implementing routine assessment and targeted correction of these markers could provide a practical adjunct to migraine prevention and management.

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; I2 = 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; I2 = 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; I2 = 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; I2 = 92.1%] and folate [10 studies included with 793 cases vs. 1011 controls, SMD = −0.25 [−0.47; −0.04], p = 0.02; I2 = 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.