I’ve briefly touched the subject of ketotic brain metabolism in some of my past posts. I’d say there’s much more to this subject than what I wrote before. Here I will discuss additional research findings along with a few personal experiences (anecdotes). My focus is on GABA and glutamate mediated effects.
I’ll begin with some personal reports:
Ever since I started experimenting with ketosis back in 2013 I noticed a dramatic shift in my mental condition. Prior to ketosis I was following a normal diet (glycolitic). I remember experiencing post-meal energy crashes that would last for a few hours and would render me mildly mentally incapacitated (exaggerating claim). If I were to engage in cognitive tasks of any kind, it would not have been easy to get through.
With ketosis that was not the case. Stable morning-to-evening energy levels, sharp-focus all the way, mental clarity – my new norms.
What’s even more important is that once engaged in a task I would be deep into it until deciding to switch. Switching between tasks with immediate regain of focus on the new task was another pleasant and surprising finding.
The combination of these effects made me stick to ketosis ever since. My approach to ketosis, however, has been altered almost continuously since 2013. In the beginning I was following a conventional high fat ketogenic diet – 80%+ of calories from fat. Gradually, I shifted towards ketosis without having to consume exaggerated amounts of fat – thus allowing the body to burn more fat from endogenous sources – provided that carbohydrate intake did not impair the process.
I’ve discovered through personal experience that I can remain ketotic if I choose my carbohydrates appropriately. Intermittent fasting provides additional support to this.
Besides mental clarity, steady state energy levels, and enhanced focus, I also noticed I become less mentally unstable, anxious, and panicky. It feels like being more mentally resilient. I consider myself better prepared to deal with stress than I was when my brain was predominantly glycolitic.
The desire to learn more about the mechanisms of the ketotic brain brought me to a few interesting papers that discuss brain metabolism in ketosis compared to the glycolitic state (which is characteristics of most people).
The Ketotic Brain
“During consumption of the ketogenic diet, marked alterations in brain energy metabolism occur, with ketone bodies partly replacing glucose as fuel.
Energy is derived largely from fatty acid oxidation in mitochondria. During high rates of fatty acid oxidation, large amounts of acetyl-CoA are generated, leading to the synthesis, primarily in the liver, of the three ketone bodies β-hydroxybutyrate, acetoacetate, and acetone (Fig. 1).” 
According to Hartman and colleagues (2007)  “ketone bodies may be a more efficient source of energy per unit oxygen than glucose. In addition, the ketogenic diet causes a coordinated upregulation of mitochondrial genes and genes involved in energy metabolism, and appear to stimulate the biogenesis of mitochondria as assessed by electron microscopy.”
They hypothesize that the higher energy availability particular to ketosis would increase the capacity of neurons to stand up against greater metabolic challenges and that it may also provide protection against neurodegeneration.
George Cahill, leading researcher in obesity and fasting, conducted insightful experiments on this ever since the 1960s, showing how during fasting-derived ketosis more than 60% of brain fuel is derived from ketones.
Recent research shows no advantage (in terms of energy expenditure) to ketosis compared to the glycolitic state.
Yet, there are other advantages to the ketotic state (in my opinion) if it is approached appropriately, contextually, and in a personalized manner. Some may use it for the management of disease conditions, others for athletic performance, others for weight loss, and so on. And each strategy should be designed accordingly.
Personally, I do not (currently) eat too much fat to be in ketosis. I just limit my intake of carbohydrates from simple (fast absorbing) sugars and nutritiously poor foods (high-sugar-high-fat). I consume a lot of plant foods and fibrous vegetables in an attempt to optimize for micronutrient and phytochemical intake and to attain a more diverse microbiota. As said, intermittent fasting may support my ketosis approach, especially if my fasting window stretches beyond 20 hours.
Others may reach ketosis by eating a lot of fat and protein and by focusing on drastically reducing carbohydrates, without particular emphasis on micronutrients. Whether this is healthy or not remains debatable.
For disease management purposes, “it has been known since the time of Hippocrates that fasting is an effective treatment for seizures, and the ketogenic diet was designed to mimic the fasting state”. 
According to Vamecq and colleagues (2005) :
“The antiepileptic activity associated with ketogenic diets (KD) have been known for some time. First reports date back to the Middle Ages and even Biblical times where KD was achieved by fasting (i.e. ‘‘water diet’’). In the early 20th century, changes in the design of the KD were introduced, shifting the so-called ‘‘water diet’’ to a high-fat diet.” 
Moreover, when designing a dietary strategy for seizure management, researchers explain :
“The protocol, as applied at the Johns Hopkins Hospital, consists of fat in a 4:1 ratio with respect to protein and carbohydrate combined. In the 1950s, a medium-chain triglyceride diet was introduced, which was thought to be more palatable.”
Interestingly, many patients experience a prolonged decrease in seizure frequency even after they stopped doing the ketogenic diet. However, not all subjects suffering from seizures respond favorably to the ketogenic diet, suggesting the existence of other factors to affect this condition.
“Moreover, exogenously administered β-hydroxybutyrate is not anticonvulsant in animal models such as the Frings audiogenic seizure-susceptible mouse. In contrast, acetoacetate and acetone do have anticonvulsant properties in animal models.” 
The majority of anticonvulsant medication targets the GABA system (Gamma Amino Butyric Acid – inhibitory neurotransmitter). GABA is made from glutamate in GABAergic neurons.
Hartman et al (2007)  propose that there is no compelling evidence for the ketogenic diet to globally affect GABA levels, but that the possibility of brain regional changes occurring in GABA levels are good avenues for further research. I would assume that ketosis may influence GABA in an indirect manner.
Along those lines, a study on rats on a low calorie diet for 7 days showed association between the ketogenic diet and GABA driven synaptic inhibition:
“However, the fact that inhibition was also enhanced with calorie restriction alone suggests that it may be the calorie restriction in the ketogenic diet, and not ketosis per se, that is the critical factor in the effect on inhibitory synaptic function. This conclusion is compatible with the studies, already noted, in which ketone bodies did not influence GABA receptor responses.” 
When talking about GABA, glutamate should also come into discussion. Glutamate, the major excitatory neurotransmitter, is created in the brain and upon its action it has to be rapidly removed (buffered) from the synaptic space for two reasons:
“(a) maintaining low levels of glutamate in the synapse maximizes the signal-to-noise ratio upon release of this transmitter from nerve endings;
(b) a chronic elevation of glutamate in the synaptic space can excessively excite post-dendritic glutamate receptors (“excitotoxicity”) and injure susceptible neurons, a factor that may figure in phenomena such as hypoxic-ischemic brain injury, hypoglycemia, epilepsy, certain inborn errors of metabolism and other neurologic disorders.” 
Lower glutamate levels may be one of the reasons for the anticonvulsant properties of ketosis. 
“A recent study of cerebrospinal fluid amino acids in 26 children (ages 1.3 to 15.8 years) on the ketogenic diet provides partial confirmation that the diet induces alterations in the metabolism of excitatory amino acids, with greater effects on aspartate than on glutamate. In these children, there were nonsignificant trends toward reduced aspartate (72% of baseline) and glutamate (75% of baseline) levels in cerebrospinal fluid samples obtained during the diet, compared with a prediet baseline value.” 
In my opinion, the lower glutamate and aspartate levels in CSF may enhance the brain’s electrical stability. Others think that increased astrocyte metabolism of the ketotic brain enhances glutamate to glutamine conversion resulting in:
“(a) more efficient removal of glutamate, the most important excitatory neurotransmitter;
(b) more efficient conversion of glutamine to GABA, the major inhibitory neurotransmitter.” 
The intensified mitochondrial metabolism and the enhanced formation of glutamine within astrocytes allows for intensified buffering of glutamate and higher production of GABA precursors; and, again, this can contribute to the anticonvulsant properties of ketosis. 
In brief, Yudkoff et al (2008)  describe brain metabolic changes specific to ketosis:
1. Higher astrocyte glutamine synthesis => higher synaptic glutamate buffering.
2. Higher availability of glutamine to GABAergic neurons => more GABA synthesis (GABA is the major inhibitory neurotransmitter)
3. Similarly to 2, “in ketosis, less glutamate is metabolized and more becomes available to the glutamate decarboxylase reaction for the purpose of GABA synthesis.” 
These mechanisms seem to point out to a reduced excitatory/more inhibitory environment within the brain through Glutamate-Glutamine-GABA related effects. It could potentially explain my personal experiences with constant ketosis and prolonged fasting, especially when it comes to mood stability, steady-state energy levels, and increased focus.
- Hartman, A. L., Gasior, M., Vining, E. P., & Rogawski, M. A. (2007). The neuropharmacology of the ketogenic diet. Pediatric neurology, 36(5), 281-292.
- Yudkoff, M., Daikhin, Y., Horyn, O., Nissim, I., & Nissim, I. (2008). Ketosis and brain handling of glutamate, glutamine, and GABA. Epilepsia, 49(s8), 73-75.
- Vamecq, J., Vallée, L., Lesage, F., Gressens, P., & Stables, J. P. (2005). Antiepileptic popular ketogenic diet: emerging twists in an ancient story. Progress in neurobiology, 75(1), 1-28.
- Gano, L. B., Patel, M., & Rho, J. M. (2014). Ketogenic diets, mitochondria, and neurological diseases. Journal of lipid research, 55(11), 2211-2228.
Images: here and here