A team of Swiss researchers at The 18th Congress of the International Headache Society (IHC) in September 2017 recently presented their research on a novel therapeutic approach for migraine reduction: ketone supplementation.1 

One in seven American adults suffer from migraine headaches, but effective therapies are lacking.2 Females, especially during reproductive years, are disproportionately affected by migraines, with a migraine prevalence of approximately 20% in females vs. 9% in males.2 Migraines are a leading cause of outpatient and emergency room visits.2 The personal disability and public health burdens from migraines are obvious, but solutions for migraine prevention and treatment are more elusive.

Exogenous ketone supplementation is being explored as a potential solution. A ketogenic diet is characterized by high-fat, low-carbohydrate intake. Ketone bodies (KB), D-3-β-hydroxybutyrate (bHB), acetoacetate and acetone, are produced by the liver to compensate for reduced glucose availability.3 Historically, the ketogenic diet has been utilized primarily for seizure management in childhood refractory epilepsy, and also for weight loss.4 Over the past five years, however, a new and promising area of research is exploring the neuroprotective effects of ketogenesis in neurological conditions, including migraines.1,3,5-6

Although strict ketogenic diets and approved drugs can benefit migraineurs, long-term diet adherence is difficult, and intolerable side effects to drugs do occur.1 To avoid these limitations, the researchers opted to explore the isolated effects of adding bHB, the major circulating ketone during nutritional ketosis, on migraines to see if migraine improvements observed from ketogenic diets can be replicated with exogenous KB. Migraines may involve an energy deficit disorder; supplying ketones, a more efficient fuel than glucose, may help mitigate this energy metabolism problem.

The open-label ketone supplement pilot study included 5 migraine patients (25-61 years old; 1 male) and explored pharmacokinetics and efficacy:1 

Pharmacokinetics:

Changes in bHB blood levels were measured at baseline, 30 minutes and 60 minutes after ingestion of a one-time dose of 10 grams of bHB salts. The peak bHB level (0.62 mmol/L) occurred after 1 hour, with modest reduction in glucose levels and no serious side effects observed. However, one patient dropped out of the study after experiencing gastrointestinal upset and diarrhea.

Efficacy: four weeks of daily supplementation with 20 grams of bHB (sodium and calcium bHB salts in liquid formulation split across two doses) cut average migraine days in half (51% reduction).1

The preliminary case series observations are promising and congruent with previously published research demonstrating the ability of ketogenic diets to attenuate migraines.5-6 The migraine reduction effect of exogenous ketone bHB is not only statistically significant, but also clinically important: study patients suffered 6-24 migraine days per month (average of 16.25 days each month) before bHB intervention vs. an average of 8 migraine days per month with bHB. Interestingly, this benefit appeared to coincide with a drop in average peak bHB (from 0.62 mmol/L to 0.3 mmol/L) after 1-2 weeks on the regimen; authors attribute this bHB drop to metabolic adaptation, namely improved uptake and usage of bHB preferentially over glucose.1,8

Although exact mechanisms mediating the effects of ketones on migraine improvement remain to be discovered, possible neuroprotective mechanisms have been described, including: enhanced mitochondrial energy metabolism, reduced neural inflammation, and increased activity of neurotrophic factors.4,7 Furthermore, lead researcher Elena Gross points out that ketone bodies are not only fuel, but also act as anti-inflammatory reactive oxygen specific inhibitors and signaling molecules with the ability to reduce brain excitability.1

To further explore the mechanisms and effects of exogenous ketone bodies on migraines, Gross and her colleagues have begun enrollment for a randomized, double-blind, placebo-controlled bHB supplementation trial, which will boast a cross-over design spanning three months in 90 patients.8

Why is this Clinically Relevant?

  • Migraines and other neurological conditions affect 1 out of every 7 US adults annually; this prevalence has remained stable over the past decade2
  • Effective evidence-based treatments that minimize barriers to compliance and adverse effects are needed to reduce the personal disability and economic burden of neurological disorders
  • Exogenous ketones may prove to be a novel neuroprotective regimen for migraine patients, with potential benefits for other neurological conditions
  • Rigorously designed efficacy and safety studies targeting the ketogenic effects on neurological disorder prevention and treatment are warranted to validate and optimize observations to date for clinical adoption

Reference

Medscape article link

Citations

  1. Gross EC, Sandor P, Fischer D. Preliminary data on exogenous ketone bodies in migraine prevention. Cephalalgia. International Headache Society. 2017;37(1S):96-97.
  2. Burch RC, Loder S. The prevalence and burden of migraine and severe headache in the United States: updated statistics from government health surveillance studies. Headache. 2015;55(1):21-34.
  3. McPherson PA, McEneny J. The biochemistry of ketogenesis and its role in weight management, neurological disease and oxidative stress. J Physiol Biochem. 2012;68(1):141-151.
  4. McNally MA, Hartman AL. Ketone bodies in epilepsy. J Neurochem. 2012;121(1):28-35.
  5. Di Lorenzo C, Curra A, Sirianni G, et al. Diet transiently improves migraine in two twin sisters: possible role of ketogenesis? Funct Neurol. 2013;28(4):305-308.
  6. Di Lorenzo C, Coppola G, Sirianni G, et al. Migraine improvement during short lasting ketogenesis: a proof-of-concept study. Eur J Neurol. 2015;22(1):170-177.
  7. Maalouf M, Rho JM. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Reb. 2009;59(2):293-315.
  8. Keller DM. Dietary supplement with ketones may mitigate migraine attacks. Medscape Web site. http://www.medscape.com/viewarticle/886000. Accessed October 11, 2017.

 

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