The Ketogenic Diet: “Best Hits” of Early 2019

by Milene Brownlow, PhD; Sara Gottfried, MD; Nikky Contractor, PhD

Here at Metagenics Institute, our goal is to keep you abreast of the latest scientific literature in health, nutrition, and personalized lifestyle medicine. As the ketogenic diet continues to grow in popularity in mainstream and clinical settings, we want to know what’s new and what patient populations or individuals may be uniquely positioned to benefit from a ketogenic dietary approach.

In the past 10 years, citations for the ketogenic diet have tripled on PubMed. While not all of those publications are of the highest scientific rigor, in this blog, we will highlight some of the “best hits” of 2019—science and clinical research that may impact or even shift your clinical paradigm for specific clinical conditions, such as migraine, Alzheimer’s disease, schizophrenia, epilepsy, as well as in healthy, normal-weight adults.

Healthy, normal-weight adults¹

Iacovides S et al.¹ reported that 11 healthy, normal-weight adults who followed a ketogenic diet for three weeks showed no differences in sleep quality, morning vigilance, mood, nor cognitive performance when compared to a high-carbohydrate, low-fat diet. The goal of this randomized, controlled crossover study was to dissociate diet’s effects from disease conditions, and the authors acknowledge study limitations such as small sample size and short study duration. It’s important to highlight that the authors were investigating whether following a ketogenic diet could improve or augment health outcomes, and according to their results, being healthy or metabolically flexible at the outset likely blunted any further improvements. In any case, bear in mind that not all outcome studies are positive, but studies like this one help set the stage for further investigation into long-term outcomes with a ketogenic diet.

Alzheimer’s disease^2-4

It is estimated that 5.7 million Americans are living with Alzheimer’s disease (AD).² Two case reports add to the existing body of literature investigating the effects of ketogenic diets in patients with mild AD.^3-4 Both patients tested positive for a heterozygous ApoEƐ4 variation, which is a genetic polymorphism associated with increased metabolic risk for late-onset AD and pronounced brain degeneration. A lifestyle intervention that included a clinically monitored ketogenic diet, time-restricted feeding window, and moderate-intensity exercise three days per week resulted in improved cognitive function and metabolic syndrome biomarkers. These studies highlight that the lifestyle intervention-induced benefits were associated with increased cerebral metabolic rate even on the most treatment-resistant conditions, including carriers of the ApoEƐ4 variant who were obese.

Curious about the neuroprotective effects of the ketogenic diet? Dr. Brownlow wrote a three-part series on the topic, starting with a historical perspective in Part 1. Part 2 covers mechanisms and evidence, and Part 3 describes specific conditions, including traumatic brain injury, stroke, brain tumors, neuromuscular diseases, autism, cluster headaches, migraines, cognitive augmentation, and, of course, Alzheimer’s disease. If you’d like to read more about medium-chain triglycerides and how they may help with brain energy metabolism, click here. 

Migraine (and exogenous ketone salts)^5-9

Chronic migraines are debilitating and affect approximately 2 percent of the global population,⁵ and women experience migraine at triple the rate of men.⁶ In January 2019, Gross et al.⁷ published the protocol for a crossover study designed to investigate the effects of β-hydroxybutyrate (βHB) mineral salts on migraine treatment and prevention. This is the first publication of a study protocol describing a randomized, placebo-controlled chronic (meaning the exogenous ketone salts will be taken for 12 weeks) trial using βHB salts in humans. Most studies so far have focused on acute models (in other words, typically only one dose) of exogenous supplement-induced ketosis or used preclinical models. This work builds on Gross’ preliminary work on exogenous ketone salts for migraine.⁸

In April, Gross et al.⁹ reviewed the biological pathways relevant for both migraine pathology and ketosis. Among key migraine pathophysiological mechanisms are brain hypometabolism, decreased cerebral glucose transport, reduced mitochondrial efficiency, increased cerebral excitability, increased cortical spreading depression incidence, increased oxidative stress, increased inflammation, gut microbiome abnormalities, and reduced digestive health. βHB (regardless of the context of nutritional ketosis or exogenous supplementation) has been shown to positively influence each of these mechanisms.

Schizophrenia¹⁰

Expanding the list of conditions that may benefit from a ketogenic approach, Palmer et al.¹⁰  described how bioenergetic abnormalities might be associated with psychotic symptoms. They described two cases of patients with a diagnosis of schizophrenia (in one case for over 65 years) who achieved complete remission of psychotic symptoms following the start of a ketogenic diet. Both patients were able to remove antipsychotic medications, suggesting that in some cases a ketogenic diet may be an effective treatment for schizophrenia, restoring function and quality of life.

Epilepsy^11-13

While we are not experts at veterinary medicine, many of us own and love our pets. Epilepsy is the most common neurologic disorder in dogs,¹¹ and, similar to humans, a significant amount (i.e., 33 percent in canines) do not respond consistently to medication(s) or have severe and unacceptable side effects.¹² Describing two case reports of dogs with epilepsy, Masino et al.¹³ showed that homemade, nonproprietary diets based on whole foods and avoidance of carbohydrates resulted in fewer seizures and side effects compared to antiepileptic drugs, including complete cessation of seizures for extended periods. Like in humans suffering from epilepsy, these canine findings underscore the need for strict dietary compliance, as well as the ongoing risk of losing seizure control due to stress, illness, and disruption in routine.

One of us, Dr. Brownlow, has an epileptic dog at home, Weston. When Weston was 6 years old, Dr. Brownlow decided to wean him off his phenobarbital because he had become lethargic and overweight. At the same time, she introduced long daily walks and changed his diet from a grain-based to a simpler one focused on vegetables and protein. She also supplemented Weston’s diet with coconut oil, omega-3 fatty acids from fish oil, and fiber (usually from canned green beans). Weston went from having multiple seizures per week to maybe two per year. He is now at the ripe age of 16, and while he slowed down a bit, Weston is still his usual, adorable self who loves belly rubs and long car rides—and a modified ketogenic diet has been the right match for him. Like us, dogs can benefit from personalized treatment approaches that leverage lifestyle and nutritional strategies, too!

Last word

While the ketogenic diet is not a panacea, and no diet is right for all, there are certain clinical conditions—including those covered in this update like migraine headaches, epilepsy, and possibly Alzheimer’s disease and schizophrenia—that may prove to be the right match for a personalized ketogenic diet. The scientific literature basis is also growing for the utility of a keto approach in cardiometabolic disease management and sports applications.

As the body of scientific literature continues to grow for diverse aspects of “keto” and its clinical applications, Metagenics Institute will keep asking important questions, which future research will no doubt help elucidate, such as: Who are the best candidates for the ketogenic diet? What are the most important nutrigenomic levers? What are the absolute and relative contraindications? What are the gene/environment interactions that we need to be aware of to support patients on the ketogenic diet? How might we stabilize or improve the microbiome on the ketogenic diet? Are women less likely to be successful on a ketogenic diet, and if so, why? How might we help them reap the benefits of the ketogenic diet? The ketogenic diet affects insulin and glucose signaling—but, do individuals with resistance to ketogenic benefits have specific signaling abnormalities preventing them from achieving clinical benefits, and how can we bypass this? Should we all be adding medium-chain triglycerides to our coffee? While the neurological relevance for ketogenic diets goes way back, keto is now all the rage for a multitude of conditions, so we remain healthy skeptics and await robust proof for specific applications.

References

1. Iacovides S et al. Three consecutive weeks of nutritional ketosis has no effect on cognitive function, sleep, and mood compared with a high-carbohydrate, low-fat diet in healthy individuals: a randomized, crossover, controlled trial.Am J Clin Nutr. 2019:nqz073. [Epub ahead of print].
2. CDC. https://www.cdc.gov/chronicdisease/resources/publications/aag/alzheimers.htm. Accessed July 2, 2019.
3. Stoykovich S et al. APOE Ɛ4, the door to insulin-resistant dyslipidemia and brain fog? A case study.Alzheimers Dement (Amst). 2019;11:264-269.
4. Morrill SJ et al. Ketogenic diet rescues cognition in ApoE4þ patient with mild Alzheimer’s disease: A case study.Diabetes Metab Syndr: Clin Res Rev. 2019;13(2):1187-1191.
5. Natoli JL et al. Global prevalence of chronic migraine: a systematic review. Cephalalgia. 2010;30(5):599-609.
6. Migraine Research Foundation. https://migraineresearchfoundation.org/about-migraine/migraine-in-women/. Accessed July 2, 2019.
7. Gross E et al. Efficacy and safety of exogenous ketone bodies for preventive treatment of migraine: A study protocol for a single-centered, randomized, placebo-controlled, double-blind crossover trial.Trials. 2019;20(1):61.
8. Gross EC et al. Preliminary data on exogenous ketone bodies in migraine prevention. Cephalalgia. 2017;37(1S):96-97.
9. Gross EC et al. Potential protective mechanisms of ketone bodies in migraine prevention. Nutrients. 2019;11(4):E811.
10. Palmer CM et al. The ketogenic diet and remission of psychotic symptoms in schizophrenia: two case studies.Schizophr Res. 2019;208:439-440.
11. American Kennel Club Canine Health Foundation, Inc. http://www.akcchf.org/canine-health/top-health-concerns/epilepsy/understanding-canine-epilepsy.html. Accessed July 2, 2019.
12. Muñana KR. Management of refractory epilepsy. Top Companion Anim Med. 2013;28(2):67-71.
13. Masino SA et al. Dietary intervention for canine epilepsy: Two case reports. Epilepsia Open. 2019;4(1):193-199.

Milene Brownlow, PhD is a Nutrition Scientist for the Cognitive Platform at Metagenics. She has earned her PhD from the University of South Florida, studying the role of diet-induced ketosis and calorie restriction on Alzheimer’s pathology. During her postdoctoral fellowship at the Air Force Research Laboratory she investigated nutritional approaches to optimizing brain health and cognitive performance. Dr. Brownlow has extensive experience in designing, managing and executing studies in behavioral neuroscience and has authored over 15 peer-reviewed publications. In her spare time, she enjoys spending time with her husband and their daughter, exploring the beautiful Pacific Northwest.

Sara Gottfried, MD is a board-certified gynecologist and physician scientist. She graduated from Harvard Medical School and the Massachusetts Institute of Technology and completed residency at the University of California at San Francisco. Over the past two decades, Dr. Gottfried has seen more than 25,000 patients and specializes in identifying the underlying cause of her patients’ conditions to achieve true and lasting health transformations, not just symptom management.

Dr. Gottfried is a global keynote speaker who practices evidence-based integrative, precision, and Functional Medicine. She recently published a new book, Brain Body Diet, and has also authored three New York Times bestselling books: The Hormone Cure, The Hormone Reset Diet, and Younger.

Nikky Contractor, PhD is Vice President of R&D and Regulatory at Metagenics. She earned her PhD in Immunology from the University of Pennsylvania where she studied the role of gut microbiota in models of inflammation, and the function of the intestinal immune system. She continued these research interests as a postdoctoral research fellow at the National Institutes of Health in Bethesda, MD. Dr. Contractor has led academic and industry research programs across preclinical to clinical research with over 10 years of experience in the development of nutritional products to meet the health goals of individuals. In her spare time she enjoys playing ultimate frisbee and hanging out with her husband and twin daughters.