The investigators will evaluate the safety and efficacy of metformin for preventive treatment of migraine in a randomized, double-blind, placebo-controlled, crossover trial.

This will be a single-center, double-blind, randomized, placebo-controlled, crossover study. The investigators will enroll 40 subjects. Subjects will be recruited from the outpatient Mayo Headache Clinic, Mayo Women's Health Clinic, Mayo Community Internal Medicine, and the Mayo Clinic- Arizona State University Neurology Clinic. The Headache Clinic employs 6 headache specialists and 1 fellow which is sufficient staffing to support this study and recruitment of patients with migraine.

Before study enrollment, patients will undergo a 2-hour oral glucose tolerance test to confirm the absence of diabetes mellitus.

Subjects will then keep a headache diary for 4 weeks to establish baseline characteristics, including number of migraine days per month, number of moderate to severe headache days per month, and number of days per month of acute medication use. The 4-week baseline period will be followed by 2 treatment periods of 12 weeks each, separated by a washout period of 4 weeks (total study duration, 32 weeks). For the 12-week treatment periods, subjects will receive either metformin 500mg twice daily or matching placebo twice daily.

Subjects will have 7 study visits. Routine laboratory studies and a pregnancy test will be performed at enrollment and week 20. Abnormal kidney or liver function will exclude subjects. Pregnancy will exclude subjects. General and neurologic examinations will be performed during 3 of the 7 visits. At each visit, subjects will receive medication for the period until the next visit. A headache diary will be used for the trial. For every day that the subject has a headache of any type, she or he will record headache characteristics, associated features, and medications used.

Inclusion Criteria:

1. age 18-65 years
2. a diagnosis of migraine with or without aura for >1 year according to the International Classification of Headache Disorders-IIIb

Exclusion Criteria:

1. a diagnosis of diabetes mellitus or polycystic ovarian syndrome
2. overuse of acute migraine treatments
3. failure to respond to 3 or more classes of preventive drug treatments
4. change in dose of migraine-preventive medication within 2 months of beginning the baseline diary phase
5. significant somatic or psychiatric disease
6. known alcohol or other substance abuse
7. pregnant or breastfeeding.

Adverse Events were collected from a period of baseline to four weeks post last intervention for a total of approximately 32 weeks

Safety population included all participants who received at least one dose of intervention.