Investigating the Role of Vitamin B12 and Folate Deficiency in the Association of Smoking and Migraine Severity

Background: Migraine is a common neurological condition characterized by recurrent, disabling headaches and is a leading cause of disability worldwide. Multiple factors contribute to migraine development, including oxidative stress, endothelial dysfunction, neuroinflammation, and impaired one-carbon metabolism. Individuals with migraines were found to have higher homocysteine levels and lower vitamin B12 (cobalamin) and folate (B9) levels than patients without migraines. National data shows a significant link between smoking status and severe headaches or migraines. Cigarette smoking has been independently associated with disrupted B12 and B9 status through impaired intestinal absorption, increased oxidative stress, and altered renal function. The objective of this study is to investigate whether smoking-related abnormalities in the vitamin B9 and B12 pathway correlate with migraine severity.

Methods: A retrospective chart review of patients with an ICD-10 G43 migraine diagnosis was conducted in the Hawaii Pacific Neuroscience (HPN) database between 2016 and 2026. Baseline demographics, smoking history, and laboratory values were collected from the electronic medical record. Migraine history, including migraine attack frequency, Migraine Disability Assessment (MIDAS), and Headache Impact Test (HIT-6), medications (including vitamin B12 and B9 supplementation), and comorbidities were collected. Biomarkers of interest included vitamin B12, B9, homocysteine, methylmalonic acid (MMA), mean corpuscular volume (MCV), which is an indirect indicator of vitamin B12 or B9 deficiency, and estimated glomerular filtration rate (eGFR) to account for renal function as a relevant confounder of vitamin B12-related biomarkers. We evaluated how these biomarkers relate to migraine severity outcomes and smoking history.

Results: Among 110 patients (mean age 54; 78% female), 18.9% were white, 12.6% Asian, 5.4% Native Hawaiian, 4.5% Pacific Islander, 4.5% Hispanic, 5.4% other, and 58% did not specify. Smoking history included 7 current smokers, 19 former smokers, 84 patients with no smoking history, and 1 patient with unknown status. Twelve patients were taking B12 supplements, while two patients were taking B9 supplements. There were no statistically significant differences in vitamin B12, folate, MCV, and eGFR levels across smoking groups of current smokers, former smokers, and patients without a smoking history. B12 and B9 levels also did not correlate significantly with migraine attack frequency. Homocysteine was documented in one patient with no methylmalonic acid (MMA) levels documented, which restricted the evaluation of the vitamin B12/folate metabolic pathway. Migraine severity using the MIDAS/HIT-6 scores was inconclusive based on limited documentation.

Conclusion: Consistent with national statistics, patients suffering from migraines were disproportionately female, and 23.4% had a current or past smoking history. There was no significant difference noted between smoking history and vitamin B12 and folate levels, which were within normal limits. However, the functional laboratory markers and validated severity instruments required to test the one-carbon metabolism hypothesis were rarely obtained as part of routine neurology care, substantially limiting the statistical power. This points to an actionable gap in standard migraine work-up and supports prospective data collection of MMA, homocysteine, and MIDAS/HIT-6 scores in future work to more rigorously study this pathway.