For nearly a century, ketogenic diets have been used by the medical community and health-seeking consumers (Paoli et al. 2013). The ketogenic diet is a very low carbohydrate (< 50 g/day) regimen that promotes the metabolism of fats rather than carbohydrates. Conventional wisdom has it that the carbohydrates in food are converted into glucose, which is in turn transported throughout every organ system in the body, including the brain. However, if there is a deficiency of carbohydrate either because of dietary manipulation, malnutrition, disease, or surgery or if the body is unable to utilize glucose (as in diabetes), a healthy liver will metabolize free fatty acids and produce ketone bodies as alternative energy sources (Fukao et al. 2004).

Ketone bodies, namely acetoacetate, beta-hydroxybutyrate, and acetone, are produced by the mitochondria within liver cells when carbohydrate availability is limited as during fasting or its utilization is impaired as in diabetes and obesity. In these cases, cellular energy must be obtained from fatty acid metabolism preferentially over glucose metabolism.

The progressive elevation of blood concentration of these ketones leads to a state of ketonemia (ketones in the blood). Extra-cellular and intracellular body buffers, such as proteins, can limit ketonemia to levels compatible with physiologic equilibrium. At this point, dramatic beneficial effects in central nervous system disturbances such as childhood seizures have been well documented (Neal et al. 2009). In the context of the central nervous system, the ketone bodies pass into the brain and in effect replace glucose as the primary energy source (Kim and Rho 2008).

However, it must be noted that if the accumulated ketones exceed the body’s capacity to extract and process them, they overflow into urine, a presentation known as ketonuria. If this situation is not treated in timely fashion, a greater accumulation of organic acids typically leads to metabolic acidosis (e.g., ketoacidosis), which is associated with a significant drop in pH and bicarbonate serum levels (Mrozik and Yung 2009).

The classic therapeutic ketogenic diet was developed for the treatment of pediatric epilepsy in the 1920s and was widely used into the next decade, but its popularity waned with the introduction of effective anticonvulsant drugs. Renewed interest came about in the mid-1990s because of celebrity media attention and then with the subsequent recognition that a significant portion of patients who were unresponsive to pharmacologic treatment of epilepsy did in fact respond favorably to a ketogenic diet (Kossoff et al. 2008).

A major report out of Johns Hopkins University also set the stage for a resurgence in popularity and mainstream trials (Freeman et al. 1998). The Johns Hopkins protocol included screening for contraindications and standardized procedures for safe initiation in light of the array of hazards and risks associated with ketosis and ketogenic diets (Kim and Rho 2008).

Ketogenic diets are valuable, even absolute, indications for children with select inborn errors of metabolism such as glycogen storage diseases that interfere with the capacity to utilize carbohydrates as fuel. There is anecdotal evidence and mounting evidence from uncontrolled clinical trials and animal studies suggesting that ketogenic diets may also have a role as adjunctive treatment in a stunning variety of pathologies, including autism, depressive illness, migraine syndromes, brain tumors, Alzheimer’s disease, Parkinson’s disease, stroke, multiple sclerosis, and traumatic brain injury. Ongoing research is certainly indicated.

The classic ketogenic diet contains a 4:1 ratio by weight of fat to combined protein and carbohydrate (90% of calories from fat, 8% from protein, and 2% from carbohydrates). This is achieved with the exclusion of starchy fruits and vegetables, bread, pasta, grains, and added sugar, while increasing the consumption of foods high in fat, such as nuts, cream, and butter. A modified Atkins diet contains 64% of calories from fat, 30% from protein, and 6% from carbohydrates. In a typical (nonketogenic) diet, about half the calories are from carbohydrates, 35% from fat, and 15% from protein. It is interesting to note that recent work presented at the 31st International Epilepsy Conference reported a seizure reduction of 50% in adults (p=.04) who had been placed on a modified Atkins diet (Zare et al. 2015). Seizure reduction among those with seizure disorders such as epilepsy following administration of ketogenic diets may be, in many cases, as high as 85% after four months and possibly more effective than the administration of anti-seizure medications, especially among children whose condition is drug-resistant (Klein et al. 2014, Li et al. 2013, Martin et al. 2016).

Most dietary fat is constituted of long-chain triglycerides (LCTs). However, medium-chain triglycerides (MCTs)—made from fatty acids with shorter carbon chains than LCTs—are more ketogenic. A variant of the classic diet known as the MCT ketogenic diet uses a form of coconut oil, which is rich in MCTs, to provide about half the calories. As less fat is needed in this variant of the diet, a greater proportion of calories from carbohydrate and protein can be consumed, allowing a greater variety of food choices (Liu 2008, Zupec-Kania et al. 2008). It should also be noted that some MCTs can cross the blood brain barrier and may be neuroprotective (Ebert et al. 2003, Marin-Valencia et al. 2013).

Apart from elucidating the mechanisms of neuroprotection that may be operating in seizure disorders, there has been some promising experimental work in traumatic brain injury patients. These individuals often present a hyperglycolysis that results in a sustained and pathologic depression of glucose metabolism. Importantly, with ketogenic intervention, reduction of contusion volume and improvement in neuropsychological performance were demonstrated in comparison to control subjects (Prins et al. 2005, Appelberg et al. 2009).

As for the spectrum of cancer, there is speculation that ketogenic diets may be effective in specific types of metastatic cancers. In this case, it appears that elevated ketones may improve mitochondrial functions while decreasing the availability of glucose as primary cellular fuel. The downside of this approach among cancer patients is that these diets may contribute to weight gain, insulin insensitivity, and even dyslipidemia as suggested in a mouse model (Meidenbauer et al. 2014).

There are multiple reports about ketogenic diets and malignancies affecting the central nervous system. Glioblastoma multiforme, the most dreaded form of brain cancer, has invited laboratory studies, again via animal model systems, with respect to response to dietary ketone exposure as a possible adjunct to primary therapeutic interventions. Several studies suggest mechanisms of action involving modulation of glucose availability, reduction of the lactic acid–inflammatory microenvironment, and inhibition of the malignancy-specific signaling pathways (Abdelwahab et al. 2012, Klement and Cham 2014, Poff et al. 2014, Maroon et al. 2013).

Ketone supplementation to halt or slow the progression of dementing illness in Alzheimer’s disease or in normal cognitive decline with age may be ushering in an intriguing, even promising area for investigation. Despite the well-described neuropathological features (including the development of amyloid plaques, neurofibrillary tangles, the progressive loss of cholinergic transmission, increased oxidative stress, and defects in mitochondrial function and cellular energy metabolism), a cure for Alzheimer’s disease is elusive (Lovestone 2009).

Clinical evidence and experience suggest that ketone bodies are an effective alternative energy substrate for the brain. Elevation of plasma ketone body levels through an oral dose of MCTs may improve cognitive functioning in older adults with memory disorders (Reger et al. 2004). Recent research in this area has certainly escalated, but human trials are largely observational and the experimental work has utilized mouse models.

Any intervention, no matter how benign it appears empirically, must be embraced with caution. Even with dietary modulation, medical contraindications such as allergy, intolerance, endocrine/metabolic disorders, and cardiac disease must be identified to the extent possible in prospective patients or research subjects. Dehydration, gastrointestinal disturbances, pancreatitis, persistent acidosis, and osteopenia have been reported with ketogenic dietary treatment (Kang et al. 2004)

In summary, the subject of ketogenic diets must be taken seriously, not only as an intervention for rare inborn errors of human metabolism, but as adjunctive yet serious treatment for pediatric seizure disorders, dementia, and possibly for some similar syndromes observed among adults. Moreover, imaginative investigational work teases us with the prospect of other indications and applications that have already raised intriguing hypotheses about management of diseases that may have ketone bodies as one link in chains that could not be more dissimilar. The overarching research challenge is to determine which ketone(s) may be the most bioactive or relevant for each type of neurodegenerative condition or, in fact, whether it is the ketogenic food matrix itself that may be internally synergistic in exerting a health-promoting or disease-modifying effect. The implications for the food industry are implicit; a nutritional approach to modifying the trajectory of any disease may be seen as innovative, safe, and cost-effective, with ease of administration and social acceptability. At least as an adjunct to established or emerging drug therapies, evidence-based nutritional intervention with well-defined approaches to patient selection and character and timing of intervention may yield genuine progress in management of some of our most vexing illnesses.


Roger ClemensRoger Clemens, DrPH, CFS, Contributing Editor
Adjunct Professor, Univ. of Southern California School of Pharmacy, Los Angeles, Calif.
[email protected]

In This Article

  1. Food, Health and Nutrition