The World Health Organization (WHO) reports that migraine headache is the third most common disease worldwide. One in seven adults in the US are affected by migraines; approximately 20% of women and 7% of men. Migraine can truly limit one’s quality of life and leads to extreme suffering, loss of work productivity, and can incur steep medical costs. Understanding the underlying cause is essential before addressing effective treatments.
What is Migraine?
A migraine attack is not simply a “bad headache”. On the contrary, apart from severe pain, a migraine often includes intense sensitivity to light, sound, and/or smell, nausea and vomiting, and in one third of sufferers, an aura that can range from blindness in parts of the visual field to paralysis of the body (hemiplegic paralysis).
The cause of migraine is still not fully understood, and because of this, current therapies are limited, relatively ineffective, and/or accompanied by undesirable side effects. Temporary relief can be achieved with medications that treat the symptoms of individual attacks, but do not address the root cause. Beyond this issue, it is not recommended that they be taken on frequent occasions due to the risk of “overuse headaches”, addiction, and side effects.
Migraine and Brain Energy Metabolism
Without getting too far into the weeds, there is increasing evidence to suggest that the cause of migraine is in part due to reduced brain glucose metabolism leading to mitochondrial dysfunction. This is similar to other neurological disorders such as epilepsy, Alzheimer’s disease and Parkinson’s disease, among others. Mitochondria are called the “powerhouse of the cell” where our energy (called ATP) is produced. Thus, when mitochondria are functioning poorly, our cells are not generating adequate amounts of energy. In essence, it is likely that migraines are due to the brain not receiving enough glucose and/or mitochondria are not functioning as they should. Similar to an old-fashioned car that is almost out of gas and is struggling to function, the brain is suffering an energy deficit, ultimately promoting symptoms of migraine.
What Triggers Migraine?
Various factors have been identified as common migraine triggers and in all cases can be linked to reduced brain energy metabolism and oxidative stress.
- Fasting/skipping meals
- Changes in sleep (too much or too little)
- Female hormonal changes (e.g. menstruation and oral contraceptives)
- Changes in weather (wind, high and low altitudes)
- Diet triggers; caffeine, nitrates, sulfates, sugar or high-glycemic index foods
- Strong scents, i.e. the often toxic chemicals included in them (e.g. perfumes and cigarette smoke)
- Intense light (e.g. bright and blue light)
- Loud noises
Potential Targets of Ketosis for Migraine Protection
Interestingly, there are various features shared between migraine and epilepsy, so it is not too surprising that therapeutic ketosis can be applied here.
Features of migraine where ketones may be protective:
- Reduced glucose metabolism and transport
- Reduced mitochondrial function
- Oxidative stress
- Increased neuronal firing (cerebral excitability)
- Increased inflammation
Ketones are an alternative energy source to glucose
The inability to properly transport glucose into the brain, and/or utilize glucose as fuel efficiently can cause an energy deficit in the brain and contribute to migraine. Hypoglycemia (low blood glucose) itself is a known trigger of migraine, and in this scenario the brain isn’t receiving enough fuel.
On a typical carbohydrate-rich diet, the main source of energy is glucose which enters the trillions of mitochondria in the brain and makes loads of ATP. However, we know that the brain can use up to 70% of its energy needs from ketones. Ketones are small fat-derived compounds produced by the liver during times of fasting and can serve as an alternative fuel when glucose availability is limited. One of the greatest benefits of a ketogenic diet, a diet that mimics fasting and hence the production of ketone bodies, is more stable blood glucose levels . Ketones and glucose use separate transporters to enter into the brain; imagine two separate doors. The advantage of ketosis, i.e. the presence of ketones, is if the glucose “door” is closed, the ketone “door” is open. Ketones generate energy through a different pathway than glucose, so if any of the steps of glucose metabolism are impaired, ketones can bypass this. In addition, the amount of energy ATP that is produced from ketones is greater than ATP from glucose. You can think of it a bit like petrol gas (glucose) versus diesel (ketone) engines (brain) in cars. If you feed a diesel engine with petrol gas, it will never reach its full speed and will at some point break down. The same is true for the brain.
Ketosis is a strategy to overcome hypoglycemia and/or impaired glucose transport and metabolism, restoring the flow of energy to the brain and preventing the energy crisis that could be contributing to a migraine attack.
Ketones can enhance mitochondrial function
Poor mitochondrial health has been associated with migraine. In fact, the prevalence of migraine in individuals with mitochondrial disorders is more than twice as high.
Ketones support the health of our mitochondria on in several ways. First, ketones have been shown to increase mitochondrial biogenesis, a fancy way of saying an increase in mitochondria power. For the sake of generating energy, the more mitochondria, the better. Again, ketones can generate more energy (ATP) than glucose when it comes down to the nitty gritty of energy metabolism.
The mitochondria are also the major source of a process called oxidative stress. Oxidative stress occurs when we burn fuel to make ATP resulting in byproducts called reactive oxygen species (ROS). We often hear of the benefits of anti-oxidants, well ROS are the pro-oxidants that anti-oxidants are trying to get rid of. Burning ketones produce less ROS then burning glucose. Ketones are not only more efficient, but also a cleaner fuel source, a bit like renewable energy versus coal which emits pollutants. Migraine is associated with an increase in oxidative stress, therefore strategies that lower this stress can be very beneficial. Ketones can protect our cells from oxidative stress further by supporting our anti-oxidant pathways. By enhancing mitochondrial function while simultaneously reducing oxidative stress, ketones may offer protection against this aspect of migraine.
Ketones can stabilize the brain
Excessive neuronal firing can “over-excite” the brain, this is referred to as neuronal hyperexcitability and is a characteristic feature of migraine.
By simply offering an alternative source of fuel, improving mitochondrial function, and reducing oxidative stress, ketones can aid in reducing neuronal excitability. In fact, frequent blood glucose fluctuations, which are mitigated by a ketogenic diet, can promote a hyperexcited brain. Another mechanism to highlight is ketone’s ability to increase brain levels of a compound called GABA and also reduce glutamate. GABA (short for Gamma-Aminobutyric Acid)
and glutamate are neurotransmitters that work in opposition, controlling and maintaining stability of the brain’s overall electrical impulses. GABA acts like a yoga class, calming the brain acting as an inhibitory neurotransmitter, whereas glutamate is like a trampoline, the brain’s excitatory neurotransmitter. An imbalance of these two highly in favor of glutamate promotes this hyperexcitability that contributes to migraine. Glutamate in excess can even damage neurons, a toxic effect. Ketones have been shown to lower glutamate and increase GABA, shifting this ratio in favor of GABA, reducing the potential excitability contributing to migraine.
Ketones may reduce inflammation in the brain
Inflammation in the brain, otherwise known as neuroinflammation, is an underlying feature of migraine. Ketones may act as potent anti-inflammatory agents, targeting inflammation in more than one way. For one, oxidative stress can trigger an inflammatory response, and as mentioned, ketones can lower oxidative stress. Improving the energy function can aid in lowering inflammation, as metabolic stress can also promote inflammation. In addition, ketones have been shown experimentally to block inflammatory pathways preventing the release of angry inflammatory molecules. Through these various mechanisms, ketones may protect against the neuroinflammation contributing to migraine.
Things to consider
A pilot study conducted by Dr. C. Di Lorenzo in 2014 of 96 overweight women diagnosed with chronic migraine headaches found improvement in those who followed a professionally supervised low calorie (800) and low-carbohydrate (30gm/day) diet over those on a standard diet. He concluded that “the underlying mechanisms of KD efficacy could be related to its ability to enhance mitochondrial energy metabolism and counteract neural inflammation.”
Exogenous ketones or ketogenic agents such as MCTs could be very useful along with a low-carbohydrate diet to assist with ketone production. Ketone salts (also known as racemic ketone salt) are another option, for inducing immediate but short sustained ketosis. Taking such substances can prevent the major symptoms of temporary hypoglycemia as your body switches from a glucose dominant metabolism to a fat-based metabolism. The transition can be uncomfortable for even healthy individuals, but for migraine sufferers, could trigger an attack and should therefore be carefully considered along with a health professional. A more powerful ketone supplement containing the human identical ketone body, D-beta-hydroxybutyrate, might be preferable. It does not lower blood glucose as much as a racemic ketone salts and can be longer lasting. Products with as little additives and sweeteners as possible are advised.
Carbohydrate restriction is often accompanied by an increase in electrolyte , risking imbalances or deficiencies that can contribute to migraine. Electrolyte and mineral supplements, notably sodium, potassium, and magnesium, are recommended to prevent any potential issues. Ketone body salts with a balanced mineral mix can also be helpful as they help both with the energy deficit and the minerals being excreted.
Potential keto-friendly triggers
There are certain foods and products that may be ketogenic, such as caffeine, dairy, artificial sweeteners, alcohol and vegetable oils, but may be problematic for migraine. If migraines persist with a ketogenic diet and you are consuming these foods, it may be worth keeping a diary to see if any of these foods are triggering migraine.
If migraine is in fact rooted in the intricacies of energy use in the brain, ketosis is very likely to offer an effective, safe, and sustainable treatment. Ketosis and the actions of ketones themselves have the ability to target the root causes of migraine and prevent or relieve the symptoms that occur. This includes restoring brain energy metabolism, improving mitochondrial function, reducing oxidative stress, calming the brain, and preventing and lowering inflammation.
Migraine improvement during short lasting ketogenesis: a proof-of- concept study. European Journal of Neurology 2015, 22: 170–177.