Migraine is a common neurological disorder characterized by recurrent headaches, sensory disturbances, and a significant reduction in quality of life. It is recognized as a complex disease involving neurovascular, genetic, and metabolic mechanisms. Historical findings linking increased lactate and hypoglycemia with migraine show that cerebral energy imbalance is a main factor. Evidence further indicates that oxidative stress, mitochondrial dysfunction, altered gut health, neuroinflammation, and metabolic dysregulation contribute to the onset and progression of the disease. These findings have stimulated interest in metabolic therapies, particularly the ketogenic diet (KD), which may correct cerebral hypometabolism and restore energy balance.
This study aimed to review current evidence on the role of KD in the prevention of migraine, specifically chronic migraine, and to assess the hypothesized mechanisms. It investigates the metabolic basis of migraine, explains how ketosis may counteract the pathogenic process, and evaluates both emerging and classical clinical research on dietary intervention.
A comprehensive literature review was conducted, including historical accounts, case series, randomized controlled trials, and observational studies over a century. It focuses on reports from the past two decades, which provide more methodological rigor and mechanistic insight. The review also included studies that investigated related strategies like caloric restriction, medium-chain triglyceride supplements, and exogenous ketones. Key outcomes were changes in monthly migraine days, headache intensity and duration, acute analgesic use, metabolic markers like ketone levels, and patient tolerability of the treatments.
The results of this review highlight that KD exerts a positive effect on migraine by multiple mechanisms. Ketone bodies provide more efficient cerebral energy than glucose, with beta-hydroxybutyrate (BHB) and acetoacetate producing more adenosine triphosphate (ATP) per substrate unit. KD promotes mitochondrial biogenesis, enhances oxidative phosphorylation, and reduces reactive oxygen species, thereby addressing the fundamental energy deficits. Inflammatory pathways commonly activated during migraine attacks are mitigated by BHB, which inhibits inflammasome activation, reduces cytokine release, and enhances anti-inflammatory gene expression. Ketone bodies also modulate neurotransmission by increasing gamma-aminobutyric acid (GABA) and decreasing glutamate, thereby reducing cortical hyperexcitability and susceptibility to cortical spreading depression. KD’s secondary effects, like weight loss and improved insulin sensitivity, may further contribute to overall migraine reduction in the predisposed individuals.
Clinical research supporting migraine remission with KD remains limited by inconsistent macronutrient reporting and varied compliance. Recent studies have shown that people who follow the KD diet for weight loss often experience spontaneous migraine improvement. A 2025 randomized controlled trial showed that low-calorie diets resulted in faster reduction in headache days and painkiller usage. Further studies show that there is a reduction in migraine frequencies, severity, and medication usage in individuals on the KD diet.
Alternative ketogenic methods have also been investigated. MCT supplementation can increase ketone levels more quickly than strict KD. It has shown mixed outcomes: one small trial reported a 53% reduction in monthly migraine frequency, while another showed no change compared with placebo and was complicated by gastrointestinal adverse effects. Exogenous ketone salts and esters increase circulating ketones but do not mimic the broader therapeutic effects of KD. This suggests that diet-induced metabolic reprogramming, rather than ketosis alone, is necessary for clinical benefit.
Overall, KD represents a promising non-pharmacological option for chronic migraine prevention, targeting cerebral hypometabolism, neurotransmission, and neuroinflammation. However, existing clinical studies are limited by small sample sizes, inaccurate ketone monitoring, and short follow-up periods. Large and long-term randomized controlled trials are required to define the ideal composition of macronutrients, efficacy, and safety. Despite potential side effects and challenges with tolerability, KD may offer a valuable alternative or adjunct to standard migraine therapies.
References: Gunasekera L, Ray JC, Butzkueven H, et al. The hypometabolic state of the migraine brain: Is a ketogenic diet the answer?. Brain Behav. 2025;15(9):e70860. doi:10.1002/brb3.70860
