Headache disorders, particularly migraine, represent a significant global health concern. Migraine is a neurovascular disease that tends to run in families and likely has a genetic basis. It is the third biggest cause of disability across the world, impacting a substantial portion of the population, including children and adolescents. Its prevalence peaks between 35 and 39 years, affecting 7.7-9.1% of children, with girls being the most impacted. Migraine negatively impacts a child's quality of life, in particular on school performance, sports, and social activities. Current prophylactic therapies for migraine often suffer from a lack of specificity, poor tolerability, potential side effects, and limited efficacy, leading to unsatisfactory results in a large proportion of patients. Nutrition is a widely discussed environmental factor that may affect the course of migraine.
In recent years, the ketogenic diet (KD), a high-fat, low-carbohydrate dietary approach, has emerged as a potential therapeutic intervention for migraine. The International Ketogenic Diet Study Group cites migraine as one of the neurological diseases that can potentially benefit from ketogenic dietary treatment (KDT). This article delves into the current understanding of the ketogenic diet, its potential mechanisms of action in migraine prevention, and the available evidence supporting its efficacy.
Understanding Migraine and Its Impact
Headache is one of the most common disorders in the general population, and it is frequently diagnosed in childhood (1), with a prevalence of 54.4-58.4% in children and adolescents (2). In 2019 it was ranked 14th overall for global causes of disability-adjusted life years, rising to 10th place for females and ranked 2nd and 5th among individuals aged 10-24 and 25-49, respectively (4). According to the International Classification of Headache Disorders 3rd edition (ICHD-3) (5), headache is classified into primary headache, with no underlying organic causes, and secondary headache (6). Primary headache onset often occurs in childhood or adolescence and its prevalence grows with age. Tension-type headache (prevalence of 20-25%) is the most common cause of primary headache, followed by migraine (7).
Types of Migraine
According to the ICHD-3, the three main categories of migraine are migraine without aura, migraine with aura, and chronic migraine. Aura consists of reversible focal neurologic symptoms (visual scintillations, scotoma, and, less often, spreading hemisensory symptoms or speech dysfunction) that develop gradually over a period of 5-60 min (or less) followed by a subsequent headache, typically unilateral, pulsatile, and aggravated by physical activity.
The Etiopathogenesis of Migraine
The most widely accepted etiopathogenetic theory is Moskowitz's trigeminovascular hypothesis (10, 11). According to this theory, patients are predisposed to migraine attacks due to an over-sensitization of the trigeminal and trigemino-cervical neurons, which is associated with a lowered threshold of activation of nociceptive terminals by vasoactive peptides, the most important of which is CGRP (12). In addition, there is strong evidence to suggest that migraine is a brain energy deficit syndrome: several magnetic resonance spectroscopy studies have highlighted that the brains of migraine sufferers experience an energy deficit during attacks, likely in response to hypometabolism and increased oxidative stress in the brain (13).
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Dietary Triggers and Migraine
Nutrition is a widely discussed environmental factor that may affect the course of migraine (16). While there is a debate over how certain foods can act as favorable or protective factors in relation to migraine attacks and the pro-inflammatory state, it is accepted that migraine is sensitive to diet, including food amount and meal timing, and that some dietary ingredients can trigger migraine attacks (16). A long list of foods involved in the mechanism of migraine has been identified, such as chocolate, citrus fruits, nuts, ice cream, tomatoes, onions, dairy products, alcoholic beverages, coffee, caffeine, monosodium glutamate, histamine, tyramine, phenylethylamine, nitrites, aspartame, sucralose, and gluten. Some foods or ingredients can trigger headaches only in subgroups of patients (e.g., celiac groups), while others can cause migraines in case of abstinence (such as caffeine) (17). Even when these elements are correctly identified, the use of diets with certain food restrictions remains controversial (17). Low-fat or weight-loss dietary interventions for migraine have so far been inconclusive. The mechanisms through which nutrition could impact migraine could be related to decreasing inflammation, such as with high omega-3/low omega-6 diets, which can bring beneficial effects.
The Ketogenic Diet: An Overview
The ketogenic diet is a high-fat, moderate-protein, and very low-carbohydrate diet. By restricting carbohydrates (such as grains, legumes, fruits, and starchy vegetables), or through fasting, the body enters a state called ketosis. Normally, the body uses glucose from carbohydrate foods as its preferred fuel source, but in ketosis, it switches to burning ketones for energy. Ketones, or ketone bodies, are organic compounds that are released from fat cells in the body. Eating high-fat foods has the same effect, as the fat from the food is the source of the ketones.
History of the Ketogenic Diet
The ketogenic diet was designed in the 1920s to help control seizures in children with epilepsy. Traditionally, epilepsy was treated with fasting (i.e., going for an extended period without eating), but researchers hoped to find a way to treat seizures without starvation. It was found that a ketogenic diet had the same effect on seizures as fasting did. Since then, the diet has regained popularity as a solution for many modern health problems.
Types of Ketogenic Diets
Several ketogenic diets are proposed for the treatment of migraine, and they have in common the restriction of carbohydrates and an adequate protein intake, differentiating according to the variation of the lipid-to-carbohydrate and protein ratio. These include the low-glycemic-index diet (LGID) [16], the low-calorie-ketogenic-diet (LCKD) [17], the very-low-calorie-ketogenic-diet (VLCKD) [11, 12, 17, 18], the Modified Atkins Diet (MAD) [18,19,20,21], and the Classic KD [17, 19].
- Very Low-Calorie Ketogenic Diet (VLCKD): Patients were instructed to avoid rice, grains, cereals and derivatives (bread, pasta, crackers, cookies, etc.), legumes, starchy vegetables (potatoes, corn, and green peas), fruits, and dairy products other than cheese, cream, or butter. The diet plans of the studies included Italian dietary products developed by industries. Owing to dietary restrictions, nutraceutical integrators were prescribed. Salads were allowed ad libitum, dressed with a spoonful of olive oil. After the VLCKD period, patients progressively reintroduced carbohydrates from breakfast to dinner to wean themselves from ketogenesis. At the end of the transition period or for the control group, patients received a standard diet (SD) or low glycemic index diet (LGID). In these cases, the SD was considered a low-calorie diet (1,200-1,500 kcal) subdivided into five daily meals with the following profile: 46% of total energy from carbohydrates, 24% as protein, and 30% as total fat (< 8% saturated fat).
- Modified Atkins Diet (MAD): The approach consisted of a low-carbohydrate (~15 g/day), normal/low-protein (about 0.7-1.2 g/kg/day), and high-fat (approximately little more than the weight of carbohydrates and proteins together) diet prepared from common foods. Most articles allowed no more than 10 g of carbohydrates per day in the first month (after that, up to 20-30 g/day) subdivided into three regular-size meals a day or four to five smaller meals. Each meal consisted of a liberal combination of fat and protein in the form of fish, shellfish, poultry, red meat, eggs, or low-carbohydrate and high-fat cheese, dressed with butter, heavy whipping cream, mayonnaise, olive oil, and other vegetable oils. Almonds, nuts, and oilseeds were suitable as snacks. Salad vegetables were suggested twice per day, dressed with oil, mayonnaise or sour cream, vinegar (without added sugars, no balsamic), and salt. Leafy vegetables, up to 200 g per portion, were permitted, while other vegetables were limited.
- Classical Ketogenic Diet Therapy (cKDT): This ketogenic therapy was presented in individualized meal plans, calculated by a dietitian according to ratios of grams of total fat to carbohydrate plus protein (3:1, 2:1, and 1:1). Haslam et al. (35) provided meal plans for a rotating 7-day 1,600 (females) or 1,800 (males) kcal/day, presented as three meals per day. Participants had the option to snack on additional items from an approved list with a 3:1 ratio of total fat to combined carbohydrates plus protein (e.g., 30 g of nuts) or choose extra meals ad libitum from the meal plan to manage hunger and/or fatigue as needed. Participants were advised that they could flavor the meals with herbs, spices, salt, and pepper, as desired, but should avoid using pre-packaged sauces to moderate total carbohydrate intake. They were instructed to abstain from alcohol and not deviate from the meal plans. Black tea, coffee, and artificially sweetened beverages, such as diet soft/soda drinks, were recommended ad libitum.
- Low-Glycemic-Index Diet (LGID): LGID is characterized by a high daily intake of fats (60%), a low intake of carbohydrates (40-60 g) with a glycemic index < 50 (low tendency to increase to elevate blood glucose), and an intake of proteins of about 30%; the LGID has proven to be effective in epileptic patients that are unable to undergo KD due to scarce tolerability or palatability. LGID exerts its actions through the induction of the production of ketone bodies, although less pronounced than classic KD, and the prevention of dramatic fluctuations in blood glucose. There is limited data regarding the use of LGID in the migraine setting in the literature. Still, its application is encouraged in migraineurs that present scarce tolerability to classical KD.
Potential Mechanisms of Action for Migraine Prevention
Ketogenic diet therapies may affect migraine in several ways: (i) by replacing brain fuel from glucose to ketone bodies (KBs); (ii) through the positive influence of systemic ketosis on pathways of migraine pathophysiology; (iii) as signaling molecules, KBs could increase mitochondrial functioning, reduce oxidative stress, alter cerebral excitability, change cortical spreading depression, reduce systemic inflammation, and change the gut microbiome (22). It has been suggested that these ketones have protective effects against migraine (3).
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Brain Chemistry and Energy Metabolism
Ketone bodies provide the body and brain with more energy than glucose, meaning the muscles and brain work more efficiently. This is especially important for people with migraine, as there is often an energy shortage in their brain cells. The brain in migraine patients tends to present an energy deficit compared to healthy subjects. KD, providing an alternative and efficient source of fuel, may restore this metabolic imbalance. This is possible since the same weight of beta-hydroxybutyrate or acetoacetate can provide more ATP in respect to glucose [10], increasing the phosphocreatine/creatine ratio into the brain, as shown in an experiment on rats [30].
Anti-Inflammatory Effects
Ketones are also said to be anti-inflammatory, and inflammation is at the core of migraine. Adopting a ketogenic diet has been shown to reduce inflammation in the body. KD has anti-inflammatory properties that go beyond the effect of fat mass reduction and involve beta-hydroxybutyrate agonism on hydroxy-carboxylic acid receptor 2 (HCA2) and inhibition of the inflammasome [10,28]. Sterile meningeal inflammation is considered to be one of the pathogenetic mechanisms of migraine, which is probably initiated by the release of peptides from trigeminocervical nerve fibers that consequently activates the local immune system. The persistence of this inflammatory reaction is thought to contribute to the sensitization of meningeal nociceptors and central pain pathways, which are at the basis of migraine pathogenesis [27].
Weight Loss and Adiposity
Research suggests the ketogenic diet is effective for weight loss, which is significant as being overweight or obese is associated with chronic migraine. KD, although developed in a neurological setting [11], is currently used also for weight loss [20] and can effectively reduce fat mass [21,22]. Low-grade inflammation and hormonal changes may be the major actors of this relationship [19]. Consequently, weight loss proved to be effective in migraine reduction [7].
Neurotransmitter Balance
KD may also compensate the imbalance between excitatory and inhibitory neurotransmission in migraine [26]. This effect may be due to the KD facilitation of glutamate conversion to glutamine, allowing efficient glutamate removal and glutamine conversion to GABA [26]. The modulation of adenosine triphosphate-sensitive potassium channels that are opened by KD metabolites, consequently reducing firing in central neurons, may have a role as well [10].
Cortical Excitability
KD effect on central nervous system excitability was well described in a study on migraine patients who were characterized by a baseline increase in visual and somatosensory evoked potentials amplitude responses during repetitive stimulation (deficit of habituation) and in which dietetic intervention was followed by a significant evoked potential amplitude decrement (habituation) in parallel with clinical improvement [31]. Similarly, it has been reported that one month of KD can normalize at the cortical level the typical interictal deficit of habituation of migraineurs as measured by pain-related evoked potentials, although it does not modify such a habituation deficit in the brainstem as measured by nociceptive blink reflex [32].
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Evidence Supporting the Ketogenic Diet for Migraine
When evaluating a treatment, various levels of evidence need to be considered. Here are some preliminary observations suggesting that the ketogenic diet may have benefits for migraine:
Early Studies and Anecdotal Reports
Anecdotal reports about the ketogenic diets can be found online and on social media. In 1930, Barborka, a pioneer in popularizing the ketogenic diet among adults, reported significant improvements in migraine following the initiation of the ketogenic diet in a study of 50 patients. The first report dates back to 1928, when medical literature reported that 39% of people experienced some improvement in migraine frequency and severity with the keto diet (9). A later study in 1930 demonstrated that 28% of people with migraine who followed a keto diet experienced no migraine attacks for up to 3 months after entering ketosis, with another 25% reporting less severe or less frequent migraine attacks (10).
Stabilization of Brain Activity
The ketogenic diet stabilized the electrical activity of the brain in a study on 18 migraine patients using a technique with evoked potentials.
Comparative Trials
A rigorous comparative trial is the only way to demonstrate that a treatment works.
Di Lorenzo Study (2019)
One such study was published by Di Lorenzo in the Nutrients Journal in 2019. In this study, an Italian team compared two low-calorie diets in a group of 35 people with obesity and migraine. The participants followed a low-calorie non-ketogenic diet (LC) for one month, no diet for one month, and a ketogenic diet (KD) for one month, in a specific sequence. Key aspects of the study include:
- The participants did NOT have chronic migraine, averaging 7 headache days per month.
- All participants were obese, and 6 could not complete the study.
- The KD month led to a greater decrease in headache days (-3) compared to the LC month.
- 75% of participants had a 50% response during the KD month compared to 8% during the LC month.
- Both diets resulted in weight loss, but researchers suggest that the effects of the ketogenic diet were more related to ketones than weight loss.
This study, though small, was well-conducted in obese individuals with episodic migraine. However, it cannot predict outcomes in non-obese individuals with chronic migraine.
Retrospective Observational Study
We conducted a retrospective observational study on 23 migraine patients who received a KD and were evaluated at the baseline and then after 3 months both from a neurological and a nutritional point of view, including body mass composition analysis. We observed a reduction in monthly headache days (12.5 ± 9.5 vs. 6.7 ± 8.6; p < 0.001) and in days of acute medication intake (11.06 ± 9.37 vs. 4.93 ± 7.99; p = 0.008). We also observed a reduction in patients’ weight (73.8 ± 15.2 vs. 68.4 ± 14.6; p < 0.001) and BMI (26.9 ± 6.2 vs. 23.7 ± 8.1; p < 0.001) with a decrement of the fat mass (28.6 ± 12.5 vs. 20.6 ± 9.8; p < 0.001). Patients who responded to KD and those who did not had no differences with respect to weight or fat mass loss.
Udine Study
The present study aims to retrospectively investigate the efficacy and impact on the quality of life of two different diet protocols (LGID and 2:1 KD) in patients with high-frequency episodic and chronic migraine, assessed with validated migraine-specific questionnaires such as Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT-6); moreover. Moreover, we evaluated the adverse events and the effect on anthropometric features of the two diets.
In our study, LGID and 2:1 KD improved migraine intensity and frequency in high-frequency episodic and chronic migraineurs; both MIDAS and HIT-6 scales significantly improved. Efficacy data for KD and LGID are comparable with the literature.
Both groups presented a statistically significant reduction in migraine days/month and intensity; MIDAS and HIT-6 scales also improved significantly. Both chronic and high-frequency episodic migraineurs in each group had significant improvement in these variables.
After three months of therapy, the LGID and 2:1 ketogenic diet group had significantly reduced BMI, weight, and Fat Mass. The Fat-Free Mass was preserved regardless of the ketogenic ratio. Both chronic and high-frequency episodic migraineurs in each group presented the same results.
Considering responders (≥ 50% reduction of migraine days) and not responders (< 50% reduction of migraine days) in both groups, the response rate was identical: 26/39 (66.67%) and 14/21 (66.67%) responders in the LGID group 2:1 KD group respectively.
Recent Study in Nutrients Journal
A recent study published in the journal Nutrients explored the link between three ketogenic diets (KD) and migraine symptoms. Preliminary results suggested that all the three diets are associated with reductions in the frequency and intensity of migraines.
In this pilot study, researchers found promising evidence that KD therapies can effectively prevent migraine frequency and intensity while also reducing fatigue and improving quality of life. However, the team noted that further studies with larger sample sizes are required to validate these findings. They also acknowledged that the study was not a double-blinded study; they could, therefore, not exclude the possibility that their results were due to the placebo effect.
Tolerability and Safety
In general, all studies showed good tolerability of ketosis with some common related side effects, including constipation (32, 35, 36), fatigue, nausea (35, 36), bloating (33, 35), difficulty sleeping, dizziness, irritability, flatulence (35). The LGID group reported constipation (12.82%), diarrhea (2.56%), abdominal pain (23.08%), and nausea (2.56%) as adverse events of the diet, while the 2:1 KD group reported constipation (23.81%) and abdominal pain (23.81%); there were no significant differences between the two groups.
Interestingly, a study is underway to determine whether ketone supplements prevent migraine (14). Exogenous ketone supplements are produced synthetically but have been shown to increase blood ketone levels, mimicking what happens when you follow a keto diet (15, 16). That said, ketone supplements may be an alternative to following a keto diet for managing migraine attacks. Still, additional studies are needed to confirm the keto diet’s ability to manage migraine.
Limitations and Future Directions
The current evidence suggests that a keto diet can help reduce migraine frequency, duration, or severity. However, there’s still much to be learned about the keto diet before it can be routinely recommended as a primary or supplementary treatment option for people with migraine. For example, it’s unknown whether a state of ketosis must be maintained continuously or only some of the time to experience its protective effects against migraine.
Moreover, all of the studies showing the beneficial effects of the keto diet on migraine were performed in adults who had overweight or obesity based on their body mass index (BMI). Therefore, it’s unknown whether adults with a BMI in the “normal” range would experience the same benefits.
Most of the studies were also performed by the same group of researchers in the same geographical location and setting, which could bias the results and limit the findings to certain populations. Aside from these study weaknesses, the keto diet can be difficult to follow long term and cause changes to bowel habits. Plus, it may be contraindicated in people with certain liver conditions, such as pancreatitis, liver failure, and fat-metabolism-related disorders (2, 13).