Frequently asked questions

Brain Ritual® is a unique holistic medical food containing antioxidants and most micro- and macro-nutrients necessary for energy production, including bioactive, human-identical ketone bodies — the brain's preferred fuel source.

It is specifically formulated to meet the nutritional requirements of migraine sufferers and to compensate for the dysfunctional brain energy metabolism which can be a root of migraine attacks that cannot be addressed through diet modification alone.

Store in a dry place at room temperature away from heat, light, and moisture.

MigraKet® is now Brain Ritual®. We've rebranded in an effort to better convey the core focus of our mission, which is to promote long-term brain health through daily rituals that give our brains the fuel we need to thrive.

More and more research suggests that migraine is, at least partially, an energy deficiency syndrome, and a migraine attack may be a signal for low energy in the brain. On a carbohydrate-rich diet the brain's primary source of energy is glucose. However, we know that ketone bodies can serve as a cleaner and more efficient fuel for the brain.

Brain Ritual® is made with ketone bodies, in addition to vital nutrients and antioxidants that support the entire process of energy metabolism and, through that, manage migraine. This is difficult to achieve through dietary modifications alone.

Brain Ritual® is formulated with high-quality, bioactive ingredients including a mixture of exogenous ketone bodies, vitamins (fat- and water-soluble), minerals, trace minerals, ketogenic and other amino acids, functional sugars (ribose and allulose), and antioxidants such as CoQ10 — without artificial flavoring or synthetic coloring.

For current ingredient amounts and Supplement Facts, please see the Ingredients page and the product label.

The science behind Brain Ritual® originated in Switzerland, where we developed our product. It is manufactured in the US with globally sourced ingredients for the highest quality and efficacy.

Brain Ritual® is manufactured in a cGMP (current Good Manufacturing Practices) facility which is registered with the FDA and follows the required codes of CFR 110, 111 and 117. Additionally, we conduct strict quality controls of partner labs throughout the process.

Brain Ritual® is neither a supplement nor a drug — as a medical food, it is a product specifically formulated to meet the nutritional requirements of migraine patients.

Unlike most supplements, we use only bioactive ingredients which can be absorbed and used by your body without the need for activation or breakdown, and many of our ingredients have been clinically tested in migraine. Unlike drugs, Brain Ritual® contains only ingredients which are generally considered safe, without major side effects.

In case you want to make a more informed decision, you can read the science and research behind migraine and how Brain Ritual® addresses this issue on our Science page. You can also learn more by visiting our social media channels and the Migraine Journal, where the metabolism articles cover the energy research in depth.

The optimal dosage for best results is 2 servings per day (1 morning, 1 afternoon), which is 60 servings per month. However, we suggest gradually working up to the optimal 2 daily servings to ease your digestive system into the high nutrient load.

Your first 30-serving box will get you ready for the optimal dose by following our ramp-up guidelines, and will help you determine if Brain Ritual® is for you. Please note that responses can vary and it may take up to 3 months to determine whether you are a responder or not.

Days 1–11: start with half a serving per day.

Days 12–22: increase to 1 full serving per day (half in the morning, half in the afternoon).

Days 23–27: increase to 1.5 servings per day (split into morning and afternoon).

Days 28–30: increase to the optimal 2 servings per day (1 morning, 1 afternoon).

Everyone is different — please feel free to ramp up more slowly or more quickly, if your GI system needs more or less time to adapt.

Dissolve a stick pack in cold or room-temperature water, tea (not hot) or another beverage, and adjust to taste — we recommend around 16 to 20 oz. You can also add ice cubes, or use sparkling water, juice or other cold beverages.

Ideally take Brain Ritual® with or after food, or sip throughout the day, especially if you experience any gastrointestinal upset. This will help decrease the mineral load on an empty stomach. If gastrointestinal upset persists, please halve your dose. Do not take in addition to a general multivitamin unless advised by your medical professional. Recommended to be used under medical supervision.

Brain Ritual® primarily focuses on nourishing the brain with essential nutrients and supporting energy metabolism, which may help manage various migraine symptoms, including auras. The blend of vitamins, minerals, and other bioactive ingredients works synergistically to enhance overall brain performance.

However, it is essential to consult with a healthcare professional to determine the most suitable approach for managing your migraine, including auras.

Brain Ritual® addresses nutritional deficiencies linked to migraine through a blend of vitamins, minerals, and bioactive ingredients. This combination supports brain health and energy metabolism, targeting migraine symptoms like headache intensity and frequency.

Vitamins A, C, D, E, K and a comprehensive B-vitamin complex offer antioxidant protection and energy-production support. Essential minerals like magnesium, calcium, and zinc aid cellular hydration and enzyme function. Coenzyme Q10, L-carnitine, D-ribose, and D-beta-hydroxybutyrate enhance mitochondrial efficiency and energy production. This comprehensive approach is backed by Swiss science.

Brain Ritual® is designed to support your metabolism and address your nutritional needs, and can be taken long-term.

Metabolism can be a root cause of migraine, but not in all cases. It's an extremely heterogeneous disorder and there is no one-size-fits-all solution. Approximately half of migraine sufferers might have suboptimal metabolism contributing to migraine, but it is still early to give an exact percentage here.

Brain Ritual® is designed to nourish your brain's depleted nutrients, and this process takes time. Your body has probably been struggling with migraine for years, so it will require patience and consistency.

Every person is unique. Some customers report immediate improvements and others have experienced results months later. We encourage you to try Brain Ritual® for at least three months to give yourself a fair shot at experiencing results.

Yes. Brain Ritual® is designed to nourish the brain with essential nutrients that enhance energy metabolism and performance. Its comprehensive blend of bioactive vitamins, minerals, and other bioactive ingredients not only targets migraine but also promotes overall brain health.

Ingredients such as Coenzyme Q10, L-carnitine, D-ribose, and D-beta-hydroxybutyrate enhance mitochondrial efficiency and energy production, while antioxidants and electrolytes support brain function and hydration.

There are no major systemic side effects. Minor side effects may include gastrointestinal distress, due to the high mineral and nutrient load. We suggest gradually working up to the optimal 2 daily servings to ease your digestive system into the high nutrient load, following our 30-day ramp-up guidelines and adapting as needed.

Should you still experience GI distress, try taking Brain Ritual® after a meal or sip it throughout the day to reduce the mineral load on an empty stomach; if it persists, please reduce the dose by half. The B vitamins in Brain Ritual® may turn your urine yellow — this is harmless. Always check with your medical professional if you are experiencing any side effects.

Do not use Brain Ritual® if you suffer from type 1 diabetes, severe kidney disease, rare inborn disorders of fat metabolism, or any hypersensitivities or allergies to the ingredients contained in this product.

Consider recommended upper daily limits when taking additional supplements, or refrain from using a broad-spectrum multivitamin. Consult your physician on dosage for children under the age of 16, or when planning or being pregnant.

Many of the nutrients contained in Brain Ritual® are also part of a prenatal formulation, and ketone bodies are important for a baby's brain development. However, because Brain Ritual® is a medical food for migraine, some nutrients such as riboflavin come in very high doses and this has not been studied in pregnant women.

Please consult with your medical doctor before using Brain Ritual® during pregnancy or lactation.

For children under 16 years of age, please consult your physician to determine whether Brain Ritual® is appropriate and what dosage is best.

While our ingredients are generally regarded as safe and have been used by healthcare professionals with younger individuals, Brain Ritual® has not been specifically tested in children.

Brain Ritual® is a medical food. Medical foods, being neither drugs nor supplements, are defined in section 5(b) of the Orphan Drug Act (21 U.S.C. 360ee(b)(3)) and are regulated by the US Food and Drug Administration (FDA). They fall under the same strict requirements as food production and must consist of ingredients which are generally recognized as safe. Similar to supplements, there is no pre-market approval.

The main active ingredient of Brain Ritual® is patented for use in migraine under U.S. Patent No. 11,166,928.

Yes — Brain Ritual® is dairy-free and suitable for vegans. It's also gluten-free, with no artificial flavors or synthetic colorings, and is free from all nine major allergens.

Allergen warning: processed in a facility and/or manufacturing line that also processes milk, eggs, soybeans, wheat, shellfish, fish oil, tree nuts and peanut flavor.

Yes. Brain Ritual® is safe for those following a gluten-free diet and continues to meet the FDA's gluten-free labeling requirements. To maintain the highest quality and transparency, we independently test our product for gluten and other allergens. Brain Ritual® is free from all nine major allergens.

Allergen warning: processed in a facility and/or manufacturing line that also processes milk, eggs, soybeans, wheat, shellfish, fish oil, tree nuts and peanut flavor.

All ingredients are non-GMO. However, one of our non-GMO sweeteners is fermented with bacteria that is genetically modified, but completely removed from the final product.

Yes. Brain Ritual® contains D-beta-hydroxybutyrate (as R-3-hydroxybutyric acid calcium magnesium salts), which is the most abundant ketone body the body produces during a ketogenic diet.

The added functional sugars are sugars in the chemical sense of the word, but do not raise blood glucose, as they are metabolized differently — and in the case of ribose are used as building blocks.

Yes. Brain Ritual® is designed to address nutritional deficiencies linked to migraine and to support overall brain health, making it suitable for ongoing use. Unlike many migraine drugs, Brain Ritual® has no systemic side effects.

We recommend a low-carb or low-glycemic-index diet consisting of whole foods. This may further help in managing your migraine. However, dietary modification is not necessary when taking Brain Ritual®.

Brain Ritual® features a peach and passion fruit flavor, crafted with organic, natural flavors.

We recommend adjusting to taste by dissolving Brain Ritual® in your favorite cold beverages — we love mixing ours into tart juices, cold teas, and smoothies. Stay tuned for new flavors in the future.

Since Brain Ritual® is packed with multivitamins, we suggest not taking an additional general multivitamin unless advised by your medical professional.

With a high load of nutrients, including high doses of those key for migraine management such as B2, any combination with a supplement should be discussed with your doctor.

Brain Ritual® has no added sugar and contains only 7g of carbohydrates. It is naturally sweetened with two carefully selected functional sugars: allulose and D-ribose.

Allulose is a naturally derived sweetener, often better tolerated among migraineurs, that does not raise blood sugar (glucose) or insulin levels. D-ribose is a naturally occurring functional sugar that helps the brain make ATP — the body's main energy currency — supporting energy production and repair when demand is high.

Diarrhea and gastrointestinal upset may occur due to the high mineral and nutrient load in Brain Ritual®. To reduce digestive issues, try taking it after a meal or sip it throughout the day.

Please also start with a smaller dose, such as half or a third of a stick pack, and gradually increase it. If GI discomfort persists, reduce the dose by half. Always consult a medical professional if you experience any side effects.

Please consult your medical professional prior to adding Brain Ritual® to your daily regimen, as it has to be taken under medical supervision.

Please take it at least 30 minutes away from any thyroid medication. Please do not use Brain Ritual® with a general multivitamin formulation unless advised by your medical professional. Do not take it together with any medication that cannot be taken with the minerals, vitamins, amino acids, ketone bodies or other ingredients contained in Brain Ritual®.

You do not need a prescription, as Brain Ritual® only contains ingredients generally recognized as safe. However, as it is intended to be used by patients, Brain Ritual® is recommended to be used under medical supervision — there can be interactions between drugs and nutrients.

Brain Ritual® is not billed through or directly covered by traditional health insurance plans at this time. However, we've partnered with Truemed so that eligible customers can use HSA/FSA funds when a clinician determines their purchase is medically necessary.

At checkout (or via the Truemed link you'll receive after checkout), you'll complete a brief health intake that is reviewed by an independent licensed provider. If they approve your case, a Letter of Medical Necessity is issued, allowing you to pay with your HSA/FSA card or submit your receipt for reimbursement, depending on your plan's rules. If your purchase is not approved as medically necessary, you can still complete your order using a regular payment method.

Because HSA/FSA eligibility is individual and plan-dependent, we always recommend checking with your benefits administrator if you have questions about your specific coverage.

Yes — many customers are able to use their HSA or FSA funds when they qualify through Truemed. Truemed connects you with a licensed provider who determines whether Brain Ritual® qualifies for your individual needs.

Health savings accounts (HSA) and flexible spending accounts (FSA) are programs that allow you to set aside pre-tax dollars for eligible healthcare expenses. If you're unsure whether you have an HSA or FSA account, please check with your employer or insurance company.

HSA/FSA accounts allow eligible customers to use pre-tax money for qualified medical expenses. Because limits and eligibility rules can change annually and vary by plan, please confirm your options with your benefits administrator and current IRS guidance.

For 2026, IRS HSA contribution limits are $4,400 for self-only HDHP coverage and $8,750 for family HDHP coverage, with an additional $1,000 catch-up contribution for eligible individuals age 55+. The 2026 health FSA salary-reduction limit is $3,400.

Food, supplements, and other wellness purchases qualify as medical expenses if they treat or prevent an illness and a doctor substantiates the need. The items in your Truemed Letter of Medical Necessity are qualified medical expenses in the same way a visit to the doctor's office or a pharmaceutical product is.

Your Truemed Letter of Medical Necessity satisfies IRS requirements to make your eligible spend reimbursable.

Generally it takes 2–5 hours. In some cases, Truemed's provider team will require additional time based on the needs associated with an individual qualification survey. If you aren't seeing your letter in your inbox, check spam, then reach out to support@truemed.com for help.

If you have already received a Letter of Medical Necessity for purchasing specific products from a merchant, you do not need to complete Truemed's survey again, so long as your Letter of Medical Necessity remains valid. Letters of Medical Necessity are typically valid for 12 months after they are first issued.

You do still need to submit your receipts for reimbursement with your HSA/FSA administrator.

We do not recommend attempting to check out with your HSA/FSA card, for compliance purposes. We strongly encourage simply transacting with your normal credit or debit card and submitting for reimbursement, for the greatest likelihood of success.

For most FSA/HSA administrators, your expenses will be approved within days when you submit your claim for reimbursement along with your receipt and a Letter of Medical Necessity. The exact timing will vary based on your administrator.

While this depends on your specific HSA or FSA administrator's policies, we advise that you only submit expenses incurred on or after the date listed on your Letter of Medical Necessity.

You can still submit for partial reimbursement. For example: if you purchase an eligible item for $100 but only have $60 in your account, you can reimburse $60 of your purchase with your tax-free funds, with the remaining $40 paid for as normal.

The cost is included with your purchase, as long as you are shopping with a Truemed partner merchant.

You can use your HSA/FSA dollars all year long. However, FSA dollars often expire at the end of the year and unused money may not roll over into the next year. Some plans allow a limited carryover or grace period; check your plan rules.

We offer a 30-day money-back guarantee on your first box. If your first order contains multiple boxes, one opened box is covered without a physical return required, but all remaining boxes must be returned unused and unopened to receive a full refund. For all subsequent orders, you may return unused and unopened products within 30 days of the delivery date. Please contact Support for prior authorization before shipping. Customers are responsible for return shipping costs, and refunds are processed within 2 weeks of receiving the item at our warehouse. 

Orders typically ship within 1–2 weekdays, excluding weekends and holidays. Once your order has shipped, you will receive a confirmation email with tracking information.

You will be emailed tracking information upon shipment. If you have a Brain Ritual® account, you can also check for details there via your Shop account login.

Brain Ritual® does not ship internationally — we ship exclusively to the US and Canada. US orders receive free standard shipping, while Canada orders have shipping fees calculated and added at checkout based on location and order weight.

Yes. As long as the order has not yet been fulfilled, you have the option to cancel. Please contact us via the chat prompt at the bottom right of your browser and we will gladly assist you.

We are sorry to hear there was an issue with your order. Please contact our team at info@brainritual.com for any replacement requests and we would be happy to assist.

We accept all major credit cards, Shop Pay, Google Pay, Apple Pay and Meta Pay.

Medical foods are neither drugs nor supplements — they are specially formulated and processed products for the dietary management of diseases with a metabolic component. They are taken orally and aimed at sufferers with limited or impaired capacity to ingest, digest, absorb or metabolize ordinary foodstuffs or certain nutrients, and with resulting special nutrient or metabolic requirements. These requirements cannot be achieved by modification of a normal diet alone.

They were defined in the Orphan Drug Act (21 USC 360ee(b)(3)), are regulated under 21 CFR 101.9(j)(8), and have to be used under medical supervision.

In contrast to supplements, which are aimed at healthy individuals, medical foods are the only food products which can be marketed to sufferers with medical conditions that have special and unique dietary needs. In contrast to drugs, medical foods do not require FDA approval and consist only of ingredients which are generally recognized as safe (GRAS).

One of the most consistently reported changes in migraine is abnormal energy metabolism. Migraineurs therefore appear to have distinct metabolic and nutrient requirements for an additional and more efficient energy source, and for improved energy production overall.

The specific nutritional and metabolic requirements of migraineurs cannot be met with simple adaptations of a normal diet. The levels of many key ingredients of Brain Ritual®, such as magnesium and riboflavin, are specifically designed to meet the unique requirements of migraine sufferers and are not achievable through a normal diet.

Furthermore, while ketosis can be achieved via a ketogenic diet, it is hard to maintain in the long term.

Brain Ritual® is designed to boost the brain's metabolism and therefore manage migraine via a nutritional route, as it contains most micro- and macro-nutrients necessary for energy production. This includes the bioactive form of ketone bodies (D-BHB) — the brain's preferred fuel source — and other cofactors and enzymes key in energy production, such as magnesium, riboflavin, L-carnitine and coenzyme Q10.

The increase in energy production caused by the ketone bodies, together with the other ingredients of Brain Ritual®, can counterbalance the dysfunctional metabolism which might be the root cause of migraine attacks, and provides a way to dietarily manage the disease.

Many ingredients of Brain Ritual® have been evaluated in clinical migraine studies, and the key ingredient is patented by us for use in migraine. Please refer to the scientific literature below.

U.S. Patent No. 11,166,928, “Migraine Prevention and Treatment”.

Gross et al., Defining metabolic migraine with a distinct subgroup of sufferers with suboptimal inflammatory and metabolic markers (2023). Scientific Reports, 13(1), 3787.

Hajihashemi et al., The effects of concurrent coenzyme Q10 and L-carnitine supplementation in migraine prophylaxis: a randomized, placebo-controlled, double-blind trial. Cephalalgia (2019).

Ghorbani et al., Vitamin D3 might improve headache characteristics and protect against inflammation in migraine: a randomized clinical trial. Neurological Sciences (2020).

Schoenen et al., Effectiveness of high-dose riboflavin in migraine prophylaxis. American Academy of Neurology (1998).

Peikert et al., Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia (1996).

Köseoglu et al., The effects of magnesium prophylaxis in migraine without aura. Magnesium Research (2008).

Rozen et al., Open-label trial of coenzyme Q10 as a migraine preventive. Cephalalgia (2002).

Shoeibi et al., Effectiveness of coenzyme Q10 in prophylactic treatment of migraine headache: an open-label, add-on, controlled trial. Belgian Neurological Society (2016).

Karimi et al., The efficacy of magnesium oxide and sodium valproate in prevention of migraine headache: a randomized, controlled, double-blind, crossover study. Belgian Neurological Society (2019).

Boehnke et al., High-dose riboflavin treatment is efficacious in migraine prophylaxis: an open study in a tertiary care centre. European Journal of Neurology (2004).

Rahimdel et al., Effectiveness of vitamin B2 versus sodium valproate in migraine prophylaxis: a randomized clinical trial. Electronic Physician (2008).

We worked with one of the best regulatory agents in the US, and other experts have assembled a medical food dossier. All ingredients are generally regarded as safe.

Brain Ritual® is manufactured in a cGMP (current Good Manufacturing Practices) facility which is registered with the FDA and follows the required codes of CFR 110, 111 and 117. Additionally, we conduct strict quality controls of partner labs throughout the process.

Migraine is the most common neurological disease, with about 1 billion sufferers across the world, out of which there are twice as many women than men (Stovner et al., 2018). It’s also the 2nd biggest cause of disability in the world and 1st among young women (Steiner et al., 2020). While its pathophysiology is not clear, hypoglycemia has been associated with migraine for almost a century (Gray & Burtness, 1935) and its symptoms (such as dizziness, pale skin, nausea, low blood pressure, tiredness, sugar cravings, cognitive difficulties) bear striking resemblance to those associated with migraine, particularly in the premonitory phase (Binder & Bendtson, 1992). A large number of studies in migraine point towards a variety of different metabolic abnormalities, and in fact, one of the most consistently reported changes in migraine is energy metabolism, including mitochondrial dysfunction (S. Ashina et al., 2021) and higher fasting glucose levels (Cavestro et al., 2007; Gross, Lisicki, et al., 2019; Siva et al., 2018). Hypothalamus (controlling homeostasis) is known to be activated early on during migraine attacks (Denuelle et al., 2007; Maniyar et al., 2014; Schulte et al., 2016). Moreover, dysfunctional metabolic responses have been observed after GTT in several studies of sufferers with migraine (Shaw et al., 1997), as have been interictal impairments of glucose tolerance (Cavestro et al., 2007; Dexter et al., 1978). These various abnormalities in combination with unfavourable environmental factors can lead to a higher energy expenditure than supply and might determine disease severity.

Changes in energy availability are usually examined with 31P-MRS (magnetic resonance spectroscopy), which can measure the amount of ATP and ADP, i.e. free energy levels suggestive of the bioenergetic condition (Lodi et al., 2001). Using 31P-MRS, one study found significant reduction of free energy, but also of free magnesium levels which is key for oxidative phosphorylation (Lodi et al., 2001), and other studies using the same methodology have found similar impairments in mitochondrial oxidative phosphorylation during and between migraine attacks (Barbiroli et al., 1992; Kim et al., 2010; Lodi et al., 1997; Lodi et al., 2001; Montagna et al., 1994; Reyngoudt et al., 2012; Schulz et al., 2007; Welch et al., 1989). One hypothesis is that defective production of ATP by mitochondria decreases the cells’ ability to deal with metabolic stress (Lodi et al., 2001). There are also reports of increased ketone bodies during and before an attack which could be suggestive of the brain trying to counterbalance the lack of available energy (Del Moro et al., 2022; Hockaday et al., 1971). A recent systematic review has strengthened this conclusion, stating that the result of decreased neuronal energy in migraine, which suggests mitochondrial dysfunction, is consistent and reproducible (Younis et al., 2017).

Studies have shown that hypoglycemia can prolong CSD in contrast to hyperglycemia which was found to have a protective effect (Hoffmann et al., 2013). Interestingly, migraine with aura is very prevalent in populations living in high altitude which could also suggest an association with hypoxia (Arregui et al., 1991; Linde et al., 2017). Another metabolic feature is an increase in lactate levels which could suggest impairments in oxygenation (as it’s a signal of the brain turning to the alternative energy sources; Di Lorenzo et al., 2016; Okada et al., 1998; Sandor et al., 2005; Watanabe et al., 1996), although strong conclusions cannot be drawn due to variabilities in methodologies and sufferer selection criteria. Yet another interesting finding is that of increased ADP concentrations and decreased phosphocreatine, which normally regenerates ATP from ADP in times of rapidly changing energy demands (Barbiroli et al., 1992; Lodi, Kemp, et al., 1997; Schulz et al., 2007). Examining other markers of mitochondrial function and oxidative stress in high frequency migraineurs showed that many of them are abnormal, most significantly lowered ALA (alpha-lipoic acid) (Gross et al., 2021) which is important for the citric acid cycle (specifically pyruvate dehydrogenase, a step crucial for metabolizing glucose) and is a known antioxidant (Packer et al., 1995). While this was a study of sufferer population only and needs to be further validated in comparisons with a control group, alpha-lipoic acid also contains thiol-groups which were found to be decreased in migraineurs separately from ALA itself (Eren et al., 2015). Metabolic changes were also found to modulate the activity of the pain receptors in the trigeminal nerve in a rat model (Martins-Oliveira et al., 2017).

Other mitochondrial enzymes, such as succinate dehydrogenase, reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase, citrate synthetase, cyclooxygenase and monoamine oxidase have also been found to have reduced activity in the platelets of migraine sufferers, further suggesting a generalized metabolic dysfunction (Littlewood et al., 1984; Sangiorgi et al., 1994).

Neuronal hyperexcitability, which is one of the most consistent findings in migraineurs, is intrinsically related to Cortical Spreading Depression (CSD; the underlying pathophysiological mechanism behind aura), as it could increase its likelihood of occurrence by lowering the “trigger” threshold. In support of that, there are reports of increased excitatory activity in e.g. the occipital (visual) cortex which is also linked to a visually triggered migraine (Aurora et al., 1999). More generally, hyperexcitability in migraineurs was measured experimentally as lack of habituation to repetitive stimuli (Brighina et al., 2009), which was confirmed in a recent study (Di Lorenzo et al., 2016). This hyperexcitability feature of the migraineur’s brain means that the it needs huge amounts of additional energy as under normal conditions, most of the glucose is normally used on the action potentials and postsynaptic potentials (Mergenthaler et al., 2013). CSD also disturbs the metabolism in the brain as a lot of additional energy is needed to restore the ion homeostasis, which can result in temporary hypoxia (Takano et al., 2007). Further, using a PET scanner which allows for monitoring glucose with a radioactive tracer, the neuronal activation evoked by visual stimuli was found to exceed glucose uptake in migraine sufferers but not healthy controls (Lisicki et al., 2018).

Oxidative stress and inflammation are also characteristics of dysfunctional metabolic state, as it makes the body less capable of dealing with those factors. Interestingly, all common migraine triggers are likely to increase the levels of oxidative stress. One study in mice showed that if there is insufficient energy or O2 present, it can cause synaptic metabolic stress and lower the threshold or even prolong CSD (Kilic et al., 2018; Takano et al., 2007). The disturbances in energy and the subsequent oxidative stress could also potentially account for activation of nociceptive ion channels which are sensitive to oxidants (Fila et al., 2021). Many of the common triggers can be connected to dysfunctional metabolism and supplements of key co-factors of metabolic pathways such as riboflavin or CoQ10 have been shown to be helpful in migraine management. In cases of disturbed metabolism, the pain signaling would still originate from the trigeminovascular activation and CGRP release, potentially caused by activation of pannexin channels, opening when neurons are stressed and which could mediate the CSD-CGRP connection (Karatas et al., 2013). Interestingly, they also open in response to metabolic changes which could provide a link between the metabolic dysfunction and pain signaling of the trigeminal nerve (Kilic et al., 2018).

Finally, not everyone will be showing the same metabolic dysfunctions – in a recent review it was suggested that there might in fact be a metabolic subgroup of sufferers which has dysfunctional energy metabolism as the root cause of their migraine, but which would not be the case for everybody (Gross, Lisicki, et al., 2019). Further, this might be a result of an adaptive mechanism of a “hyperexcitable” brain which becomes overactive in reaction to any number of stimuli (migraine triggers), experiences CSD and as a consequence, the depletion of its energy resources. As a response, pain signaling is activated which forces energy-preserving mechanisms, such as rest, avoidance of intense stimuli, lack of movement etc. Several recent reviews have discussed extensively the possibility of mitochondrial dysfunction and impaired brain glucose metabolism as the underlying cause of migraine (Bohra et al., 2022; Del Moro et al., 2022; Islam & Nyholt, 2022).

In summary, migraine seems to be characterized by a mismatch between increased energy demand and decreased energy availability. For a comprehensive review of metabolic abnormalities in migraine, please refer to the table linked below:

Table 1 |Human peripheral blood studies showing metabolic abnormalities in migraine.