Ketogenic diets may lower migraine frequency and medication use

By reframing migraine as an energy deficit disorder, this review spotlights ketogenic therapy as a targeted metabolic intervention that could lower attack frequency and drug reliance, pending high-quality trials and structured monitoring.

Review: The Hypometabolic State of the Migraine Brain: Is a Ketogenic Diet the Answer? Image Credit: Lightspring / Shutterstock

In a recent Brain and Behavior review paper, researchers in Australia examined evidence linking metabolic dysfunctions to chronic migraines. They also explored ketogenic diets (KDs) as a possible therapy.

They found that KDs may reduce migraine frequency and pain intensity. KDs may also help migraine patients use less medication. However, large, rigorous randomized trials are still needed to confirm these findings.

Background

The link between metabolic dysfunction and migraine has been recognized for nearly a century. In 1935, researchers observed that hypoglycemia could trigger migraine attacks and that correcting low blood sugar relieved symptoms.

In 1982, elevated lactate levels in blood and cerebrospinal fluid during migraines suggested that the brain’s oxygen supply was low. These early findings highlighted metabolic abnormalities as key to migraine pathophysiology.

Current evidence suggests that migraines result from a combination of interrelated metabolic disturbances. These include mitochondrial dysfunction, imbalances in the gut microbiome, neuroinflammation coupled with oxidative stress, weight regulation problems, and impaired glucose metabolism. Such disruptions may collectively drive the hypometabolic state frequently seen in migraine patients.

Following a KD alters energy metabolism by shifting the brain’s fuel source from glucose to ketones, and has been proposed as a way to correct these abnormalities. Historical and recent studies suggest that KDs may reduce migraine burden by improving cerebral metabolism.

Migraines are linked to metabolic changes

Migraine progression involves multiple phases tied closely to energy imbalance. Early prodromal symptoms, such as yawning, cravings, and fatigue, may represent the body’s attempts to conserve or restore energy.

During aura, cortical spreading depression (CSD) consumes large amounts of glucose, worsening the brain’s metabolic deficit.

This wave triggers the trigeminovascular system, releasing inflammatory neuropeptides like CGRP and substance P, which amplify pain and sensitivity. Recovery from CSD further heightens oxygen and energy demands, creating hypoxia and mitochondrial stress.

Role of mitochondrial dysfunction

Mitochondria, which are responsible for producing adenosine triphosphate (ATP), are impaired in migraine, leaving the brain in a chronic state of energy deficiency. Excess reactive oxygen species (ROS) overwhelm antioxidant defenses, contributing to inflammation and the release of calcitonin gene-related peptide (CGRP).

Imaging studies show reduced ATP levels (up to 16% lower) and impaired mitochondrial enzyme function in migraine patients, correlating with attack severity. This dysfunction may explain the overlap between migraine and mitochondrial disorders.

Disrupted glucose metabolism also plays a role. Migraine sufferers often exhibit insulin resistance, limiting glucose entry into the brain during periods of high demand. Fasting and hypoglycemia are known triggers. Scans confirm that migraine brains frequently exceed their glucose supply during stimulation, leaving them vulnerable to attacks.

Other key mechanisms

The gut-brain axis is influenced by altered microbiota compositions, with migraine patients exhibiting higher levels of pathogenic bacteria and lower levels of beneficial strains.

While gastrointestinal symptoms suggest a role for gut health, the efficacy of probiotic therapies remains inconclusive. Neuroinflammation is another key mechanism, with elevated pro-inflammatory peptides sustaining headaches.

Finally, obesity increases migraine risk and severity, possibly through adipose-driven inflammation and higher CGRP levels. Weight loss, whether via bariatric surgery or lifestyle changes, consistently improves migraine frequency and intensity.

KD and ketosis

Ketosis can be achieved through either a KD or caloric restriction. The KD is a low-carbohydrate, high-fat, moderate-protein diet designed to mimic fasting while providing a steady source of energy.

When glucose is depleted, the body metabolizes fatty acids into ketone bodies such as beta-hydroxybutyrate (BHB), acetoacetate, and acetone. BHB can supply up to 75% of the brain’s energy, offering a more efficient fuel source than glucose.

Several KD variations exist, the most restrictive being the ‘classical’ 4:1 fat-to-carbohydrate plus protein ratio, in which 90% of calories come from fat.

However, less strict forms, such as modified Atkins diets, are more tolerable and widely used, aiming to achieve physiological ketosis within a range of 0.5–5 mmol/L of serum BHB.

The review paper emphasizes that the diet should be initiated under the guidance of a dietitian and a medical professional to minimize the risk of complications. Without expert supervision, individuals may experience side effects like “keto flu” (nausea and dizziness), renal stones, vitamin deficiencies, and hypotension. The paper also notes that some animal studies raise concerns about potential long-term risks, such as accelerated atherosclerosis associated with a high-fat diet, although long-term human data are lacking.

Evidence from Migraine Studies

Research on KD for chronic migraine dates back to the late 1920s. Early case series reported that approximately half of patients experienced reduced headache frequency or resolution, although the methods used were inconsistent.

More recent randomized controlled trials and observational studies, predominantly from Italy, consistently show reductions in monthly migraine days, headache duration, and medication use among KD groups compared to standard or low-calorie diets.

Some studies have found correlations between ketone levels and symptom improvement. However, ketone measurement methods varied widely, with significant differences in macronutrient ratios, inconsistent (or absent) ketone monitoring, and varying patient populations, including one notable study on patients with both chronic migraine and medication-overuse headache.

Despite differences in macronutrient composition, study design, and compliance, the findings suggest that KD may be an effective non-drug therapy for chronic migraines, warranting larger, standardized trials.

What About Ketogenic Supplements?

The review also examined ketogenic supplements, such as medium-chain triglycerides (MCTs) and oral exogenous ketones, as a less restrictive alternative to the full diet. However, the authors found that the evidence for these supplements is currently limited and inconclusive. One study on beta-hydroxybutyrate salt suggested that supplementation did not provide the same benefits as intensive KD therapy, indicating that the diet’s effects may go beyond ketosis alone.

Conclusions

The KD shows promise as a preventive strategy for chronic migraine, likely by addressing cerebral hypometabolism, a key factor in migraine pathophysiology.

However, robust prospective trials are needed to assess its safety, tolerability, effectiveness, and mechanisms. Future studies should clearly report macronutrient ratios, transition timing, and methods of ketone measurement.

Standardized reporting would enable meaningful comparisons across studies and help establish evidence-based clinical guidelines for incorporating KD into the management of chronic migraines.