Dietary Supplement With Ketones May Mitigate Migraine Attacks

Daniel M. Keller, PhD

September 21, 2017

VANCOUVER, Canada — Preliminary evidence indicates that a daily dietary supplement providing ketones can reduce the frequency of migraine headaches with no adverse effects.

Increasing evidence suggests an energy deficit disorder exists in migraine, the researchers note. By supplying ketones as an alternative fuel to glucose, several deleterious components of the deficit may be avoided.

During a poster session here at the 18th Congress of the International Headache Society (IHC) 2017, doctoral candidate Elena Gross, MSc, University of Basel Children's Hospital, Switzerland, told attendees that although a strict ketogenic diet is known to be beneficial in migraine, it is very difficult to follow long term.

"So the idea was what if a lot of the benefits you get from a ketogenic diet are actually due to the presence of ketone bodies vs the absence of glucose?" she asked. "This is where ketogenic substances came in, and we played around with this quite a lot." She said the predominant ketone body (KB) in a physiologic, endogenous state of nutritional ketosis is β-hydroxybutyrate (bHB).

She therefore designed a drink containing calcium and sodium salts of bHB to raise KB levels in the blood. On a typical Western diet, KB blood levels are 0.2 mmol/L or less. Nutritional ketosis can see levels of 0.5 mmol/L to 8 mmol/L, which is below the level of greater than 15 mmol/L at which ketoacidosis occurs.

To assess pharmacokinetics, 4 women and 1 man with migraine (age range, 25 to 61 years; 6 to 24 migraine days/month) received 10 g of the bHB salts twice a day by mouth in a liquid formulation for 4 weeks.

From a mean baseline of 0.162 mmol/L at time 0, blood levels of bHB peaked 1 hour after ingestion at 0.62 mmol/L, with a concomitant drop of 1 mmol/L (18 mg/dL) of blood glucose.

Participants consumed a mixed breakfast 1 hour after ingesting the bHB preparation but before the blood draw at 1 hour. Blood levels of bHB returned approximately to baseline at 3 hours. After 3 weeks of daily intake, the bHB blood levels nearly halved from 0.62 mmol/L to 0.33 mmol/L at 1 hour after ingestion.

Session moderator Stephen Silberstein, MD, Thomas Jefferson University, Philadelphia, Pennsylvannia, commented that this finding suggests that "after a while the ketone drops off." Gross suggested that the drop in blood ketone levels may indicate that the body has now developed more ketone transporters and enzymes and is more able to use the ketones for energy in preference to glucose.

"With a rise in ketone levels, we see a drop in glucose, and first I thought this was due to changes in insulin or glucose transport, but I think it's actually dampening gluconeogenesis," she said.

Dr Silberstein noted that patients may lose weight at this point, and Gross said other studies have shown some patients experience weight loss from appetite suppression by ketones.

She added that in pilot observations for efficacy, the drop in ketones was accompanied by a reduction in migraine frequency from a mean of 16 days/month to 8 days/month, "and that is within the first month of supplementation."

The participants reported no serious side effects, but one did drop out because of gastrointestinal upset and unpleasant taste of the solution.

Possible Mechanisms  

Gross gave a detailed explanation of the possible mechanisms underlying the beneficial effect of a supplement rich in KBs.

"We know that ketone bodies are not only metabolized, they're also signaling molecules. First of all, they're a more efficient fuel than glucose. Per molecule, they produce a lot more ATP [adenosine triphosphate] than a molecule of glucose," she said. "They also induce mitochondrial biogenesis, [and] they're very potent reactive oxygen species inhibitors.

Further, they produce less oxidative stress per molecule burned and reduce brain excitability, she added. "They shift the equilibrium between glutamate and GABA [γ-aminobutyric acid] in the direction of GABA, and they also have an influence on glutamate transport itself."

She went on to note that supplying more KBs increases ketone body transporter mechanisms, they are anti-inflammatory, and they reduce blood glucose levels. "So they have a variety of potential migraine-relevant mechanisms in addition to being a more effective fuel" than glucose.

She and her colleagues have started enrolling patients with migraine in a double-blind, randomized, placebo-controlled trial (NCT03132233) to test the bHB supplement in a crossover design over 3 months in a group of 90 participants.

The impetus for this work was the fact that Gross developed migraines in her mid-teens, and she said she wants something that will work for her and for many other patients with migraine. The side effects of currently approved prophylactic drugs are "intolerable for most patients," she said, and avoiding food and lifestyle triggers of migraines severely limits ones activities and life.

Tthere was no commercial funding of the study. Ms Gross has disclosed no relevant financial relationships. Dr Silberstein is a consultant to Alder, Allergan, Autonomic Technologies, Avanir, Curelater Inc, Depomed, Dr. Reddy's Laboratories, Ensured Inc, electroCore Medical LLC, eNeura Therapeutics, INSYS Therapeutics, Lilly USA LLC, Supernus Pharmaceuticals, Teva Pharmaceuticals, Theranica, and Trigemina Inc.

18th Congress of the International Headache Society (IHC) 2017. Abstract PO-01-069. Presented September 8, 2017.

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