Energy for the Brain
Condition: Migraine; Episodic Migraine
MeSH terms: Migraine Disorders
Study type: Interventional

Summary: 
      Approx. one billion people are suffering from migraine worldwide and yet, therapeutic options
      are still very limited. Research suggests that changes in energy metabolism could be part of
      migraine pathophysiology. Ketone bodies (KB) are endogenous alternative energy substrates.
      Our clinical trial assesses the efficacy and safety of KB supplements in 60-90 adult
      migraineurs (5-14 migraine days / months) at the University Hospital Basel. The total
      duration of the trial is approx. 6 months, consisting of 4 weeks baseline, 12 weeks
      intervention with KB powder or matched placebo and 8 weeks follow-up. The primary endpoint is
      the change in migraine days at the end of intervention compared to baseline. Additionally,
      changes in gene expression, fat-, and glucose metabolism, inflammatory markers and quality of
      life will be examined.
    

Detailed description: 
      Migraine is a complex, common and debilitating neurological disorder. It affects
      approximately 17% of women and 8% of men in Europe and yet, its primary pathogenic mechanisms
      are still largely unknown. Various lines of research suggest that brain energy metabolism
      abnormalities are likely to be part of migraine pathophysiology. Specifically, there is some
      evidence for reversible abnormalities in mitochondrial functioning in migraine. For example,
      treatment with riboflavin and coenzyme Q10 has been shown to have migraine protective
      effects, probably via a positive effect on energy metabolism. Lactic and pyruvic acid,
      markers of mitochondrial (mt) disease, have been found to be increased in migraineurs;
      31P-magnetic resonance spectroscopy (MRS) patterns seen in migraine are consistent with what
      is seen in mitochondrial disorders; cytochrome oxidase (COX)-negative fibres typical of mt
      diseases have also been seen in some patients with migraine. A break-down of the resting
      membrane potential due to lack of adenosine triphosphate (ATP) could explain cortical
      abnormalities in excitability, which have been reported in migraine. Despite causing a huge
      amount of suffering and a substantial amount of costs for society current migraine treatment
      options are limited. None of the prophylactic agents licensed to date are migraine-specific
      and most are associated with significant- sometimes intolerable- side-effects. Furthermore,
      their migraine-preventive properties are moderate at most. Hence, there is a need for
      developing alternative anti-migraine therapies. Several case studies and a first proof of
      concept study have demonstrated a reduction in migraine attack frequency, severity and use of
      acute anti-migraine medication during ketosis - with effects sizes ranging from total absence
      of attacks to a reduction to 1/5th of the run-in period. In addition, preliminary evidence
      suggests that the migraine-protective effect may outlast the duration of ketosis. This might
      be a result of longer-lasting gene-expression changes. However, a strict ketogenic diet (KD)
      is unlikely to provide a feasible long-term solution for episodic migraine patients, because
      it is difficult to implement in an ambulatory setting and patient adherence may be limited.
      An alternative means to induce a state of mild to medium nutritional ketosis (0.4-1 mmol/l),
      irrespective of blood glucose levels, is the dietary supplementation with ketogenic
      substances, such as beta-hydroxybutyrate (bHB) salts (and unpublished observations). This
      approach could be easily implemented with intake of a ketogenic powder dissolved in water
      (consisting of a calcium-magnesium-bHB salt) three times a day (with or after a meal). This
      nutritional intervention seems much more feasible than a KD in larger patient populations and
      avoids the complications of a very restricted high-fat diet.
    

Intervention name(s): Beta-hydroxybutyrate calcium and magnesium salt; placebo powder
Intervention type(s): Dietary Supplement; Other
Intervention description(s): Exogenous ketone body in mineral salt form.; matched placebo powder to the IMP.
Intervention MeSH terms: Calcium
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Migraine; Prevention; Prophylaxis; Ketone bodies; Beta-hydroxybutyrate; Double-blind; Randomised; Placebo controlled; Mitochondrial functioning; Energy metabolism; Intervention; Dietary Supplement