BackgroundMigraine is a severe neurological disorder that is recognized as one of the most common debilitating diseases worldwide. Although the exact cause of migraine is not known, research suggests that inflammation, oxidative stress, mitochondrial dysfunction, and insufficient nutrients may contribute to its development. Studies indicate that nutrition-based approaches are safer and more cost-effective strategies for managing migraine symptoms compared to medication. In this regard, the impact of nutrition, as a complementary medicine, is largely attributed to that of certain nutrients on inflammation and mitochondrial function. It is hypothesized that alpha-linolenic acid and L-carnitine, which possess anti-inflammatory and antioxidant properties, may be synergically beneficial for migraine patients. Therefore, this study will be conducted to assess the efficacy of alpha-linolenic acid and L-carnitine co-supplementation in patients with migraine.MethodsThis is a parallel, randomized, triple-blind, placebo-controlled clinical trial, in which 80 women aged 20 to 50 years with migraine will be assigned to receive either intervention group (n = 40) receiving both 1000 mg/day flaxseed oil and 500 mg/day L-carnitine simultaneously for 12 weeks, or control group (n = 40) receiving both 1000 mg/day paraffin oil and 500 mg/day maltodextrin as the placebos for the same duration. The primary outcomes include changes in clinical symptoms of migraine, including frequency, severity, and duration of attacks, serum levels of C–reactive protein (CRP), total antioxidant capacity (TAC), nitric oxide (NO), malondialdehyde (MDA), and superoxide dismutase (SOD). Secondary outcomes include mental health, sleep quality, and quality of life (QOL).DiscussionIn this study, we aim to investigate the potential benefits of combining alpha-linolenic acid and L-carnitine as a treatment option for migraine sufferers. Migraine, characterized by recurrent severe headaches, affects a significant portion of the population and can significantly impact an individual's quality of life. By studying alternative therapies such as alpha-linolenic acid and L-carnitine, researchers hope to expand the range of treatment options available and potentially provide relief to migraine sufferers.Trial registrationIranian Registry of Clinical Trials (www.irct.ir) (ID: IRCT20121216011763N57). Registration date: 29 March 2023.Trial statusThe protocol is version 1.0 dated December 30, 2023. Recruitment began on July 10, 2023, and is expected to be completed by January 22, 2024.