Serum Vitamin B12 and Methylmalonic Acid Status in Migraineurs: A Case-Control Study

Headache. 2019 Oct;59(9):1492-1503. doi: 10.1111/head.13618. Epub 2019 Aug 31.


Background: Although the exact pathophysiological mechanistic pathways that result in the initiation of migraine attacks remain unclear, there are some proposed mechanisms including neurogenic inflammation, trigeminovascular system activation, vascular dysfunction, and augmented release of nitric oxide (NO) and homocysteine (Hcy). Vitamin B12 is thought to be involved in important pathways that seem to be related to the pathogenesis of migraine including scavenging against NO and prevention of hyperhomocysteinemia. Therefore, the aim of the current study was to evaluate the serum vitamin B12 and methylmalonic acid (MMA) status in a group of migraine patients compared to healthy controls.

Methods: After the recruitment of cases and controls, demographic data and migraine characteristics (including the number of headache days, severity of headaches, and duration of each attack in hours) were recorded. Serum vitamin B12 and MMA levels were measured using the enzyme-linked immunosorbent assay technique.

Results: Seventy migraine patients and 70 healthy subjects were enrolled in this case control study. The serum levels of B12 were found to be significantly lower in migraine patients than in healthy subjects (512 ± 300 vs 667 ± 351 pg/mL, P = .007); whereas migraineurs had higher levels of MMA than controls (1.39 [0.59,4.01] vs 1.01 [0.49,1.45] µg/dL, P = .027). In the fully adjusted multiple regression model, those in the highest vs the lowest serum B12 quartile had 80% decrease in the odds of having migraine ([OR = 0.20, 95% CI = 0.05-0.73], [P for trend = .008]); while, patients in the highest quartile of MMA had more than 5 times increased risk of having migraine ([OR = 5.44, 95% CI = 1.49-19.87] [P for trend = .002]). There was no association between serum B12 and MMA levels and headache characteristics.

Conclusion: Taken together, these findings suggest that participants with lower vitamin B12 and higher MMA levels that considered as lower functional activity of B12 had higher odds of migraine.

Keywords: hyperhomocysteinemia; methylmalonic acid; migraine; vitamin B12.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Anthropometry
  • Case-Control Studies
  • Cost of Illness
  • Disease Progression
  • Female
  • Homocysteine / blood
  • Humans
  • Male
  • Methylmalonic Acid / blood*
  • Middle Aged
  • Migraine Disorders / blood*
  • Nutritional Status
  • Pain Measurement
  • Social Class
  • Vitamin B 12 / blood*
  • Young Adult


  • Homocysteine
  • Methylmalonic Acid
  • Vitamin B 12