Research & Education

Is There a Role for Ketones in Traumatic Brain Injury?

“Cerebral metabolism of glucose has been shown to be altered after head injury and increasing cerebral metabolism of alternative substrates (ketones) has been shown to be neuroprotective in several models of traumatic brain injury. This altered dietary approach may have tremendous therapeutic potential for both the pediatric and adult head injured populations.” (Prins, 2008)

Owing to publicity surrounding the underreported incidence of multiple concussions and other head trauma among professional athletes, public attention is increasingly focused on the long-term consequences of traumatic brain injury (TBI). Injuries sustained by members of the armed forces during prolonged military operations has also led to renewed focus in this area. However, concussion, TBI and other head trauma are not limited to pro football players and military personnel. No one is immune to everyday accidents and injuries. In the U.S. alone, TBI affects 1.5 million people every year, about half of whom are children and young adults.

Aside from pain relievers, physical therapy, and medication to deal with downstream effects of TBI (such as anxiety and depression), the medical profession has little to offer people recovering from and living with TBI. The ketogenic diet and exogenous ketones, growing in popularity due to their potential benefits for neurological disorders, metabolic syndrome, and more, may offer a new therapeutic avenue.

The biochemical and physiological changes induced by TBI have significant overlap with those observed in Alzheimer’s disease and other neurodegenerative conditions. This suggests there could be a beneficial role for the ketogenic diet among the TBI patient population. There is a critical lack of good data exploring this in human subjects. The majority of research in this area has been done in animals, but the results are promising and worth looking at.

TBI resembles Alzheimer’s disease (AD) in that it results in reduced capacity of the brain to harness energy from glucose. Another similarity between TBI and AD is the increased deposition of beta-amyloid proteins. Contrary to long-held belief, increasing evidence suggests amyloid is actually a protective factor, secreted in response to neuronal injury. Single, moderate-to-severe TBIs result in increased amyloid deposition, and repetitive mild TBIs, such as may occur during youth or adult sports—result in still greater amounts of amyloid.

Upon cranial impact and immediately afterward, brain fuel metabolism is altered: ionic equilibrium across neuronal membranes is disrupted, with injury severity having a direct relationship with increases in extracellular potassium and glutamate, and intracellular calcium accumulation. Cellular energy is required to reestablish homeostasis, which is reflected by an initial increase in cerebral glucose uptake. However, this increase is only temporary. Over the long term, glucose metabolism is decreased (as it is in Alzheimer’s), and the magnitude and duration of this decrease increases with injury severity and age. (Not surprisingly, younger TBI victims tend to be more resilient and typically experience more effective recoveries than older individuals.)

Owing to reduced cerebral glucose uptake and metabolism in TBI, there may be an important role for ketogenic diets and/or exogenous ketones for these patients: 

“Under these post-brain injury conditions of impaired glycolytic metabolism, glucose becomes a less favorable energy substrate. Ketone bodies are the only known natural alternative substrate to glucose for cerebral energy metabolism. While it has been demonstrated that other fuels (pyruvate, lactate, and acetyl-L-carnitine) can be metabolized by the brain, ketones are the only endogenous fuel that can contribute significantly to cerebral metabolism.” (Prins, Matsumoto, 2014)


But ketone metabolism does more than just provide damaged neurons with an energy alternative to glucose. Ketones are a more efficient substrate than glucose. Their oxidation produces more ATP than that of glucose or fatty acids, while also generating fewer reactive oxygen species (ROS). Increased ATP synthesis together with fewer ROS is a kind of “one-two-punch” for a brain that has suffered a physical trauma and is experiencing the ravages of uncontrolled oxidative stress.  

The metabolic and biochemical changes in a brain affected by TBI have important implications for how injured individuals are treated in hospitals, including military medical outposts. The initial increase in brain glucose metabolism after TBI is believed to be protective, but over the long term, chronic hyperglycemia ultimately exacerbates damage and leads to worse outcomes in TBI patients. Being that intravenous fluids typically contain glucose or dextrose, perhaps a ketogenic formula may be a better alternative. This would also be an excellent circumstance in which to use intravenous βOHB infusion to immediately elevate ketone levels. Not only would this provide a readily usable fuel, but ketones and ketogenic diets protect against apoptosis and may increase brain-derived neurotrophic factor (BDNF), so there are multiple avenues by which ketones or a ketogenic diet could potentially salvage and protect struggling neurons.

It is interesting to note that expression of the monocarboxylate transporters that bring ketones into the brain is upregulated following head trauma—almost as if the brain has an expectation of ketone delivery. This may be a protective mechanism: the decline in glucose metabolism in the brain may be because instead of being used as a fuel substrate, glucose is shunted toward the pentose phosphate pathway to generate protective and reparative compounds. As a result, the brain may be priming itself to take up an alternative fuel. If ketones are present, this is an elegant rescue mechanism, but if ketones are not present, such as would typically be the case in a patient following a standard high-carb diet or being provided with glucose/dextrose-based intravenous nutrition, these damaged neurons will continue to suffer.  

In animal studies looking at the ketogenic diet (KD) for TBI, the KD has been shown to decrease neuronal death, increase ATP, decrease edema, reduce seizures, and increase cell survival in the face of ischemia and hypoxia.


Change Induced by TBI

Role for Ketones and/or Ketogenic Diet

Decreased ATP production

Increased ATP production

Decreased glucose uptake and utilization as fuel; glucose shunted away from energy generation and toward pathways for repair and regeneration

Alternative fuel source to glucose; provides more energy

Increased oxidative damage to structural proteins and lipids

Decreased ROS; increased antioxidant capacity

Increased glutamate excitotoxicity

Reduced glutamate synthesis

Increased apoptosis/loss of neurons

Reduced apoptosis; increased BDNF

Possibility for seizures

Anti-seizure effects


It may be worthwhile to consider implementing a KD, possibly in conjunction with exogenous ketones, for individuals who suffer TBI. The multiple ways by which the KD modulates brain fuel metabolism, antioxidant status, neuronal membrane potential, and neuroplasticity make it a candidate for frontline intervention in these cases.