Cocoa Flavanols for Migraine: A Pilot Study - Project Summary Migraine, a chronic intermittent headache disorder, ranks in the top five causes for years lived with disability. Approximately 15% of the US population experiences migraine, with women afflicted approximately twice as often as men. Although pharmacologic medications are often used as first-line treatments for migraine, these treatments may have difficult side effects and may increase the risk for migraine chronification. As a result, individuals with migraine often turn to other treatment modalities, including the use of natural products and dietary supplements, for long-term migraine management. Preliminary evidence from the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) suggests a cocoa extract supplement may have beneficial effects on migraine. COSMOS was a randomized, double-blind, placebo-controlled trial testing a cocoa extract supplement containing 500 mg cocoa flavanols/d (including 80 mg (-)-epicatechin, plus 15 mg caffeine and 50 mg theobromine) for the prevention of cancer and cardiovascular disease in 21,442 older adults. Every six months, participants were asked about the occurrence of adverse events, including migraine. Individuals randomized to the cocoa extract supplement were significantly less likely to report migraine (hazard ratio (HR)=0.85; 95% confidence interval (CI): 0.78, 0.93) than those assigned to placebo. However, several important gaps in knowledge remain. First, COSMOS enrolled only older adults but the prevalence and disability burden of migraine is highest at younger ages (i.e. 15-49 years) and it is unknown if cocoa extract is effective in a younger population. Second, COSMOS did not collect detailed information on changes in migraine frequency, as recommended by current guidelines for trials of migraine treatments. Finally, an animal study suggested a potential dose-response relationship between cocoa consumption and migraine pathophysiology, highlighting the importance of considering higher amounts of cocoa extract and bioactive content in future human studies. Our long-term goal is to conduct a fully powered trial evaluating the effectiveness of a cocoa extract supplement on reducing the frequency of migraine attacks. As a first step, we propose to conduct a three-arm pilot study. We will recruit and randomize (1:1:1 allocation ratio) 114 adults with episodic migraine to receive one of the following treatments for 12 weeks: 1) 1000 mg of cocoa extract (including 160 mg/d (-)-epicatechin, 100 mg theobromine, and 30 mg caffeine); 2) 500 mg of cocoa extract (including 80 mg/d (-)-epicatechin, 50 mg theobromine, and 15 mg caffeine); or 3) placebo. Our proposed pilot study will allow us to address the following aims: 1) to assess the feasibility of recruitment, retention, and adherence; 2) to determine the acceptability of higher doses of cocoa extract supplement to this patient population; 3) to optimize data collection and data management and establish the infrastructure needed for a large-scale trial.
