Published on April 18, 2011 by Emily Deans, M.D. in Evolutionary Psychiatry

Full Story:  http://www.psychologytoday.com/blog/evolutionary-psychiatry/201104/your-brain-ketones

The modern prescription of high carbohydrate, low fat diets and eating snacks between meals has coincided with an increase in obesity, diabetes, and and increase in the incidence of many mental health disorders, including depression, anxiety, and eating disorders. In addition, many of these disorders are striking the population at younger ages. While most people would agree that diet has a lot to do with the development of obesity and diabetes, many would disagree that what we eat has much to do with our mental health and outlook. I believe that what we eat has a lot to do with the health of our brains, though of course mental illness (like physical illness) has multifactorial causes, and by no means should we diminish the importance of addressing all the causes in each individual. But let’s examine the opposite of the modern high carbohydrate, low fat, constant snacking lifestyle and how that might affect the brain.

The opposite of a low fat, snacking lifestyle would be the lifestyle our ancestors lived for tens of thousands of generations, the lifestyle for which our brains are primarily evolved. It seems reasonable that we would have had extended periods without food, either because there was none available, or we were busy doing something else. Then we would follow that period with a filling meal of gathered plant and animal products, preferentially selecting the fat. During the day we might have eaten a piece of fruit, or greens, or a grub we dug up, but anything filling or high in calories (such as a starchy tuber) would have to be killed, butchered, and/or carefully prepared before eating. Fortunately, we have a terrific system of fuel for periods of fasting or low carbohydrate eating – our body (and brain) can readily shift from burning glucose to burning what are called ketone bodies.

It is true that some parts of some brain cells can only burn glucose, but fortunately our bodies can turn protein into glucose through a process known as gluconeogenesis. This fact means that while there are essential requirements for both fat or protein (meaning we would die without eating at least some fat and at least some protein), we can live quite happily while consuming no carbohydrate at all. That’s not saying there aren’t some disadvantages or side effects to a so-called “zero carb” diet, but it won’t cause the massive health problems and death that consuming zero fat or zero protein would.

All of us who are metabolically healthy will shift into some amount of ketosis, typically overnight while we are sleeping. If your breath is a little funky when you wake up, and your urine smells a bit strong, you may well be in ketosis, which, unless you are a poorly controlled diabetic (a different kind of pathologic ketosis occurs in uncontrolled diabetes), being in ketosis in the morning is a good sign of a healthy metabolism. What does ketosis mean to the brain, and why would it be more healthy, perhaps, than our regular old carbohydrate burning metabolism? And does the high carbohydrate, low fat diet of constant snacking have a cost to our brains by robbing us of more regular and deeper bouts of ketosis?

Ketogenic diets, which are very high in fat and low in carbohydrate and protein, have been prescribed for seizures for a long time. The actual research diets used in the past were pretty dismal and seemed to involve drinking a lot of cream and eating a lot of mayonnaise (premade ketogenic formulas are nightmarish combination of omega 6 seed oils and corn solids).  At Johns Hopkins, pediatric patients were admitted to the hospital for a 48 hour fast and then given eggnog (minus the rum and sugar, I’m guessing) until ketosis was achieved (usually took about 4 days). In addition, ketogenic diets were calorie restricted to just 75-90% of what would be considered a child’s usual calorie intake, and often they were fluid-restricted too (1)! If we’re talking soybean oil mayonnaise, you could see how someone could get into trouble with mineral deficiencies and liver problems pretty quickly.

To understand “dismal,” some of the latest research showed that a “modified Atkins protocol” was just as good as the classic ketogenic diet, and so much more liberating, as the patients were allowed up to 10 grams of carbohydrates daily, and they didn’t begin with the fast, and they weren’t calorie restricted (2)(3). While the classic ketogenic diet was 4:1:1 fat to carbs to protein. If you use medium chain triglyceride (MCT) oil for 50% of your calories (have to add it in slowly though to prevent vomiting, diarrhea, and cramping!), you could increase the carbohydrates and proteins to a 1.2:1:1 fat:carb:protein and still get the same numbers of magical ketones circulating. And while “MCT oil” sounds nice and yummy when it is gorgeous coconut milk, this MCT Oil 100% Pure 32 fl.oz doesn’t look quite as appetizing, especially when that is going the be half of what you eat for the foreseeable future (4). You can see why researchers consider ketogenic diets (especially the original versions) to be extremely difficult and unappetizing (they were), whereas seasoned low-carbers (who have a bit of a different idea what a ketogenic diet is) will find that attitude ridiculous, especially when you compare a ketogenic diet to the side effects of some anti-epileptic medications.

So it looks like modified Atkins (very very low carb, but not zero carb) and a preponderance of MCT is the same, ketone-wise, for the brain as the classic ketogenic diet. And what does it mean to have a ketogenic brain? Let’s examine neurotransmitters and brain energy more closely. Specifically, glutamate and GABA (5).

GABA is the major inhibitory neurotransmitter in the mammalian nervous system. Turns out, GABA is made from glutamate, which just happens to be the major excitatory neurotransmitter. You need them both, but we seem to get into trouble when have too much glutamate. Too much excitement in the brain means neurotoxicity, the extreme manifestation of which is seizures. But neurological diseases as varied as depression, bipolar disorder, migraines, ALS, and dementia have all been linked in some way to neurotoxicity.

Glutamate has several fates, rather like our old buddy tryptophan. It can become GABA (inhibitory), or aspartate (excitatory and, in excess, neurotoxic). Ketogenic diets seem to favor glutamate becoming GABA rather than aspartate. No one knows exactly why, but part of the reason has to do with how ketones are metabolized, and how ketosis favors using acetate (acetoacetate is one of the ketone bodies, after all) for fuel. Acetate becomes glutamine, an essential precursor for GABA.

What can be confusing is that there are a variety of theoretic advantages in the brain to a ketogenic diet, and we’re not sure which ones are more important. A classic ketogenic diet had three major components which were thought to contribute to the anti-seizure effect. One, it was calorie restricted. Just calorie restricting epileptic monkeys (no matter what the macronutrient ratios) reduces seizure frequency (and increases longevity). Secondly, it was acidic, and the extra protons themselves could block proton-sensitive ion channels, or the ketone bodies or fats themselves could affect the neuron membranes, making them harder to excite. (For the biochem geeks out there, ketones or fats seem to affect ATP sensitive K+ ion channels, making hyperpolarization easier to maintain). Thirdly, it lowered glucose levels. And lower glucose is associated with a higher seizure threshold (that’s good – one doesn’t want to easily have a seizure!) and less neuronal excitability. Gads. Doesn’t sound to me like glucose really is the preferred fuel for the brain after all.

And now let’s really get down to the mitochondrial level. Mitochondria are the power plants of our cells, where all the energy is produced (as ATP). Now, when I was taught about biochemical fuel-burning, I was taught that glucose was “clean” and ketones were “smokey.” That glucose was clearly the preferred fuel for our muscles for exercise and definitely the key fuel for the brain. Except here’s the dirty little secret about glucose – when you look at the amount of garbage leftover in the mitochondria, it is actually less efficient to make ATP from glucose than it is to make ATP from ketone bodies! A more efficient energy supply makes it easier to restore membranes in the brain to their normal states after a depolarizing electrical energy spike occurs, and means that energy is produced with fewer destructive free radicals leftover.

What does it all mean? Well, in the brain, energy is everything. The brain needs a great deal of energy to keep all those membrane potentials maintained – to keep pushing sodium out of the cells and pulling potassium into the cells. In fact, the brain, which is only 2% of our body weight, uses 20% of our oxygen and 10% of our glucose stores just to keep running. (Some cells in our brain are actually too small (or have tendrils that are too small) to accommodate mitochondria (the power plants). In those places, we must use glucose itself (via glycolysis) to create ATP.) When we change the main fuel of the brain from glucose to ketones, we change amino acid handling. And that means we change the ratios of glutamate and GABA. The best responders to a ketogenic diet for epilepsy end up with the highest amount of GABA in the central nervous system.

One of the things the brain has to keep a tight rein on is the amount of glutamate hanging out in the synapse. Lots of glutamate in the synapse means brain injury, or seizures, or low level ongoing damaging excitotoxicity as you might see in depression. The brain is humming along, using energy like a madman. Even a little bit more efficient use of the energy makes it easier for the brain to pull the glutamate back into the cells. And that, my friends, is a good thing.

Let me put it this way. Breast milk is very high in fat. Newborns spend time in ketosis, and are therefore to some extent ketoadapted. Breast milk is also high in sugar, but babies’ brains are so big they can handle a lot more sugar than us full-grown folks. Being ketoadapted means that babies can more easily turn ketone bodies into acetyl-coA and into myelin. Ketosis helps babies construct and grow their brains. (For those interested in nitty gritty details – babies are in mild ketosis, but very young babies seem to utilize lactate as a fuel in lieu of glucose also – and the utilization of lactate also promotes the same use of acetyl-CoA and gives the neonates some of the advantages of ketoadaptation without being in heavy ketosis.)

We know (more or less) what all this means for epilepsy (and babies!). We don’t precisely know what it means for everyone else, at least brain-wise. Ketosis occurs with carbohydrate and protein restriction, MCT oil use, or fasting. Some people believe that being ketoadapted is the ideal – others will suggest that we can be more relaxed, and eat a mostly low sugar diet with a bit of intermittent fasting thrown in to give us periods of ketosis. (A caveat – I don’t recommend intermittent fasting for anyone with an eating disorder without some extra support and consideration). Ketosis for the body means fat-burning (hip hip hooray!). For the brain, it means a lower seizure risk and a better environment for neuronal recovery and repair.