Medical foods are neither drugs nor supplements – they are specially formulated and processed products for dietary management of diseases with a metabolic component. They are taken orally and aimed for sufferers with limited or impaired capacity to ingest, digest, absorb or metabolize ordinary foodstuff or certain nutrients and a resulting special nutrient or metabolic requirements. These requirements cannot be achieved by a modification of a normal diet alone. They were defined in the Orphan Drug Act (21 USC 360ee(b)(3)) and are regulated by the 21 CFR 101.9(j)(8) and have to be used under medical supervision.
In contrast to supplements which are aimed for healthy individuals. medical foods are the only food products which can be marketed to sufferers with medical conditions that have special & unique dietary needs. In contrast to drugs, medical foods do not require FDA approval and consist only of ingredients which are generally recognised as safe (GRAS).
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 tables linked below:
Table 1 |Human peripheral blood studies showing metabolic abnormalities in migraine.
Table 2 |Neuroimaging studies that demonstrate metabolic alterations in migraine.
As discussed in detail above, one of the most consistently reported changes in migraine is abnormal energy metabolism. Therefore, migraineurs seem to have distinct metabolic and nutrient requirements for an additional and more efficient energy source and/or improved energy production overall.
KETONE BODIES
Ketone bodies are the ideal candidates for such an energy source, as they are known to be metabolized by the brain (Baxter et al., 1989; Nehlig, 2004; Sokoloff, 1973) and are energy efficient, with a high heat of combustion (calorific value) i.e. amount of energy available for ATP synthesis per oxygen molecule (Puchalska & Crawford, 2017; Veech, 2004). They are water-soluble fatty molecules produced by human liver in times of increased fatty acid metabolism, such as during fasting or ketogenic diet (trace amounts can be produced all the time). They can also be supplemented exogenously to provide an additional, more efficient energy source. While there are 3 types of ketone bodies, BHB (beta-hydroxybutyrate) is the most abundant and stable one. D-BHB is the only isomer which our body can use and L-BHB can actually compete with it for uptake (Achanta et al., 2017). Moreover, while on today’s carbohydrate-rich diet the brain is sourcing its energy almost exclusively from glucose, it has been originally engineered to burn ketones whenever available – it prefers them over glucose and babies are born in ketosis (Gross et al., 2019).
The majority of ketone bodies which are used by the brain are crossing the blood-brain barrier (BBB) through monocarboxylate transporters, mostly MCT2 (on neurons) and MCT4 (on astrocytes), as well as sodium-dependent MCT (SMCT) (Pierre & Pellerin, 2005). This uptake is availability-dependent, meaning that if more ketone bodies are present in the bloodstream, more will be absorbed by the brain and immediately metabolized. This rapid utilization was shown in two studies with non- fasted (only overnight) individuals (Blomqvist et al., 1995; Pan et al., 2002). Additionally, a positive correlation was found between blood concentration and cerebral utilization of ketone bodies (Blomqvist et al., 1995). The varying mechanisms of uptake between ketone bodies and glucose form one of the reasons as to how ketone bodies could help in cases of impaired glucose metabolism. This is further evidenced by the role ketogenic diet can play in GLUT1 deficiency syndrome which impairs glucose’s entry into the brain (Mergenthaler et al., 2013).
Furthermore, studies showed that acute administration of BHB (through IV infusions) led to a 14% decrease in cerebral glucose consumption and 30% increase in cerebral blood flow. The oxygen use was constant which implies that ketone bodies were being used as alternative fuel, even in the presence of glucose (Svart et al., 2018).
Apart from varying entry routes into the brain, another important difference between the two substrates is that glucose has to first go through the process of glycolysis in the cytosol, resulting in creation of pyruvate which then needs to enter the mitochondria and be further metabolized there. Only after this step acetyl-CoA is created which enters the citric acid cycle. With BHB, on the other hand, everything occurs directly in the mitochondria (Hertz et al., 2015). Therefore, the process itself is more direct and in contrast to glycolysis, does not require ATP (Jensen et al., 2020). Additionally, omitting glycolysis might also help to counteract the loss of glucose metabolism in cases where enzymes involved in the process are impaired, e.g. pyruvate dehydrogenase complex (LaManna et al., 2009).
Moreover, the changes occurring before the oxidative phosphorylation step can still influence it, as they change the balance of substrates present which can affect the rate of the redox reactions. For example, metabolism of ketone bodies results in excess succinate which is necessary for later stages of ETC, further increasing the ATP yield by allowing to skip complex I and go directly to complex II, which has general positive effects on energy production (Achanta et al., 2017).
BHB on its own was also found to increase ATP production in mitochondria isolated from the brain (Suzuki et al., 2001) and the ketogenic diet might have an enhancing effect on mitochondrial genetic expression (Bough et al., 2007; Noh et al., 2004).
MAGNESIUM
Magnesium is another molecule crucial for healthy metabolism (Bohra et al., 2022) and its disequilibrium can contribute to hyperexcitability (Boska et al., 2002). A significant reduction of free magnesium levels has been identified in migraineurs using 31P-MRS (magnetic resonance spectroscopy; Lodi et al., 2001) and decreased magnesium levels have been reported in migraine sufferers for decades (Welch & Ramadan, 1995). Magnesium is known to be tightly connected in enzymatic reactions to ATP as it is a key cofactor in oxidative phosphorylation – the process of producing ATP via the electron transport chain and chemiosmosis (Younis et al., 2017). Two analyses of a dataset from a national examination from 1999/2001-2004 suggest that lower amounts of dietary magnesium seem to correlate with migraine in ages 20-50 (Meng Shu-Han et al., 2021; Slavin et al., 2021). It is now recognized, together with riboflavin, as a Level B migraine medication (Holland et al., 2012).
RIBOFLAVIN (VIT. B2)
Riboflavin is crucial for mitochondrial energy production (specifically the ETC step) and has been studied in migraine (Yamanaka et al., 2021). It is now classified as a Level B medication for migraine by the American Academy of Neurology, together with magnesium (Holland et al., 2012).
SUMMARY
Overall, migraineurs seems to not only have requirements for additional energy sources but also require additional key cofactors and enzymes which support the energy production process, such as magnesium, riboflavin or coenzyme Q10 (Gross et al., 2019).
The specific nutritional and metabolic requirements of migraineurs cannot be met with simple adaptations of a normal diet.
Firstly, the levels of many key ingredients of MigraKet® 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 and sufferers that have overconsumed analgesics for decades can struggle with liver function – the primary place of ketone bodies’ A ketogenic diet is based on very limited carbohydrate and moderate protein intake with a simultaneous increase in fat consumption, which imitates some aspects of fasting and resets the body to lipid-based metabolism, i.e. obtaining ketone bodies through FAO (fatty acid oxidation) in the liver. A strict ketogenic diet usually results in values around 2 mmol/l – with nutritional ketosis beginning at 0.5mM (Poff et al., 2020). However, there may be side effects and some risks it entails long-term (Kossoff et al., 2018), as it requires a drastic reduction of foods such as fruits and colorful vegetables, which are generally considerd as healthy. These include gastrointestinal problems, increase in blood cholesterol, deficiencies in minerals and other nutrients, and – on a psychological level – social constraints. Constant fasting and/or strict ketogenic diet (to the extent of reaching therapeutic levels of ketosis meaning under 20g of carbs per day) is extremely hard to sustain long-term and adherence is one of the main problems (Maalouf et al., 2009) and it can hardly be considered an adaptation of normal diet. Moreover, if not monitored properly it can result in other complications such as kidney stones (Sampath et al., 2007) or increase in blood cholesterol (Gross et al., 2019).
Therefore, bioidentical exogenous ketone bodies, in the form of D-beta-hydroxybutyrate (D-BHB) mineral salts, in addition to various micronutrients and antioxidants that have been shown to be beneficial in migraine, could provide a feasible alternative with improved compliance due to no demanding lifestyle changes and lack of other potential complications described above. Exogenous ketone bodies are those which are not produced by your body, but produced in the lab and delivered in a form of e.g. a powder, as in MigraKet®. They have the same chemical structure as the one produced by the liver and are known to be absorbed by the body and – depending on the type – metabolized in the liver or directly enter the blood circulation (Plecko et al., 2002). They can include only the active, D-BHB isomer, which makes them even more tolerable and effective than the racemic versions (Soto-Mota et al., 2020; Stubbs et al., 2017). This is the form of BHB used in MigraKet®. Studies have shown that exogenous supplementation can cause a rapid and sustained elevation of BHB (Kesl et al., 2016).
As described above, migraine can be considered a metabolic disorder and as a consequence, migraineurs have specific metabolic and nutritional requirements, which include a need for an additional and more efficient energy source, and support alongside the energy production process.
MigraKet® is specifically formulated so that it meets exactly those needs. It is designed to boost brain’s metabolism and therefore manage migraine via a nutrition 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 co-factors and enzymes key in energy production, such as magnesium, riboflavin, L-carnitine and coenzyme Q10 (explained in question above). Many of its ingredients have also been studied in migraine clinical trials (see reference list in question below).
The increase in energy production caused by the ketone bodies together with other ingredients of MigraKet® can counterbalance the dysfunctional metabolism which might be the root cause of migraine attacks and provides a way to dietary manage the disease.
Many ingredients of MigraKet® 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, 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).
Kӧseoglu, 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)
For a references list please click here