Monday, August 30, 2010

Your Brain on Ketones

Ketogenic diets 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.  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 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 cream-heavy ketogenic diet.  And what does it mean to have a ketogenic brain?  Before, we talked about protons, but now I'm going to examine neurotransmitters and brain energy more closely.  Specifically, glutamate and GABA (5).

If you recall, 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. 

Here's the confusing part.  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 - once 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.

Umph.  What does it all mean?  Well, in the brain, energy is everything.  The brain needs a crapload 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.  Breastmilk is high in fat.  Newborns (should) spend a lot of time in ketosis, and are therefore ketoadapted.  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. (Update - looked more into this specifically and it seems that babies are in mild ketosis, but very young babies seem to utilize lactate as a fuel in lieu of glucose also - some of these were rat studies, though - 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 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 (though in general I don't recommend intermittent fasting for anyone with an eating disorder).  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.

51 comments:

  1. Cool.

    We always got the 'fat burns in a carbohydrate flame' speech in biochem/ex phys/nutrition. Without carbs, the TCA grinds to a halt and fat & protein derived ketones cannot be burned. What they forgot is that you don't need 5-10g CHO/kg of bodyweight to keep the TCA going... oh and they forgot about gluconeogenesis...

    I've read about a few of the ketogenic diets used in research and they are foul... just because one knows about the biochemistry, it doesn't mean one should cook the food!

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  2. Nice overview. I read somewhere recently (I'm having source amnesia) about an elderly woman who was able to reverse her Alzheimer's disease dementia through a ketogenic diet. Medical science may think they produce miracles every day (and they do usually at great cost), but nutritional science has a lot going for it, too!

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  3. I'm surprised that you say breastmilk would keep babies in ketosis. The composition seems to be 7:1.1:4.2 (cho:pro:fat) i.e. roughly 40%:6%:54% by calories. I'd be extremely surprised, despite their heightened energy needs, if newborns were in ketosis on a 40% carbohydrate diet.

    I always found it the cause of a small amount of cognitive dissonance than humans started off their life outside of ketosis. I assumed however that this was contingent upon the fact that the early years were a time of extraordinary growth (far more so than the most extreme bodybuilder) and so the large amount of carbohydrate would be necessary, or at least, not harmful. I would be sure, prima facie, that ketosis would be the best state for the growth and development of a newborn's brain either. While I grant that calorie restriction and fat-burning is associated with repair, typically carbohydrate, 'plenty' (and even high insulin) seems to be associated more with growth. I wouldn't even be (but you're the expert) that heightened levels of GABA would be ideal for a newborn. Perhaps if you're epileptic or bipolar, but I'd have thought that newborns' notoriously active brains might well be "humming along" in a highly excited sense. In general, a lot of paleo/evolutionary thinkers seem to think of ketosis as mimicking starvation, which, if you believe, probably sits at odds with it being the mode of choice for newborns.

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    1. One thing about breast milk is it is also raw milk, the blood sugar response from raw milk is greatly reduced, and so is the insulin response, thus even with the lactose you could likely be producing ketones (even newborns do not reach that nutritonal ketosis standard Phinney and Volek prescribe).

      Super starch is another example of a starch that does not jack insulin and barely affects ketogenesis.

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  4. DM - I agree, but the montster review paper I was looking at last night is not the first time (in a research paper) I've seen the babies in ketosis spiel - they seem to be pretty confident about it. I'm going to look more closely, because here is what I was thinking last night - just as you do, that breast milk is more like melted ice cream than plain old cream (lactose!), also, that pregnancy is a state where you crave carbs like gangbusters. "Ketosis" mimicking starvation is why the original ketogenic diets were calorie restricted too for epilepsy, but it seems from later research you don't need to do that to get the benefits, and for newborns, even though they consume loads of fat, they eat every 2-4 hours (or more often, obviously) for quite some time. Despite the urban fat loss myths, you can gain weight on a ketogenic diet (as babies do). One more possibly unrelated tidbit food for thought - average age of onset of the seizures in several of the reviews and studies I read was a bit over one year of age, which happens to be when breast milk (or formula) tends to be wholly replaced with SAD.

    I certainly don't have all the answers!

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  5. Aaron - there are case reports of ketogenic diets being used for autism and dementia and traumatic brain injury. Again, anti seizure meds are often used for those conditions for various reasons. Interesting stuff!

    Jamie - glucose is necessary for the astrocytes but ketones do just fine elsewhere, as we know! Imagine how surprised to doctors were when Steffanson didn't drop dead or get scurvy on his all meat diet!

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  6. DM -one last thought - part of the advantage for a ketogenic diet in the brain is with nitrogen balance and amino acid transport changes compared to a wholly glucose fueled brain - it would have required a bunch more explaining and I thought I had tortured the readers enough with the biochem in this post - but that advantage and the more efficient use of acetyl-CoA is what seems to be happening in babies.

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  7. I just had a nerdgasm. Great blog! I'll be reading this!

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  8. Thanks for the reply Emily. My university doesn't have access to the review article's journal, so I can't comment on that specifically. It's certainly possible that babies' growth is simply so extreme that they suck up all the carbohydrate from breast milk and need to generate some ketones in addition, though it's certainly striking if so. That would be like me eating 250g of carbs and still being in ketosis! One paper I did find (http://www.ncbi.nlm.nih.gov/pubmed/11482735) screened 21,342 babies and found 47 in ketosis. Ketosis was also associated with reduced growth. It does, however, note that most of those who were in ketosis were on breastmilk (28/47).

    Incidentally I agree that you don't need to restrict calories or eat infrequently to enter ketosis; by mimicking starvation, I meant that being in ketosis (which, in an evolutionary context, might result from extended starvation), seems to be associated with many of the benefits/harms of starvation and calorie restriction. It might therefore be very good if you're an adult who want to extend one's life, reduce risk of cancer etc, while being suboptimal for a neonate.

    Ned Kock shows a good table here (http://healthcorrelator.blogspot.com/2010/04/ketones-and-ketosis-physiological-and.html) which shows neonates are typically in slight ketosis, but around a third the extent of an adult fed a "high fat diet."



    I quite agree that you don't need starvation to enter ketosis, jus

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  9. Hi DM - thanks for looking into that because that was my next step :) - I'm *very* curious about how good ketosis is. For a certain condition, epilepsy, it is likely very good for most (it is highly beneficial for 50% of people with refractory seizures - which is a great number, as we are talking about those who haven't responded to two or more med trials and combinations.) But is it a requirement for "optimal" functioning for a healthier brain? I'd rather not have to worry about being in ketosis all the time, frankly, and have some fruit! And we have those pesky high-carb Kitavans who have no dementia (though eat a lot of coconut, and may be on the anxious side though I am speculating A LOT with that). And are we dealing with an on-off switch - either we are fat burning or we are sugar-burning, or is the mixture natural, healthy, and optimal? I'd like to believe the second.

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    1. Ketosis is terrific for my brain. I've never had a seizure, but I've been anxious for as long as I can remember. Now that I eat a LCHF diet, the anxiety is gone. If I slip and eat a few too many carbs I wake up with bad dreams and anxiety. I really wish someone had told me (or my mother) about a ketogenic diet when I was an anxious, overweight, school hating 7 year old. Or a 200lb first time Mom with anxiety and anger issues. Maybe not everyone needs to be in ketosis to be happy, but it may be a non-pharmaceutical lifesaver for some.

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    2. Hey K,

      Ive always suffered from anxiety as well. How long did it take for your anxiety to disappear? Do you continue feeling good in the long run?

      Personnally, ketosis makes me calm and energetic for a couple of days in the beginning, but then the feeling disappears. I dont get it! I'm still going to continue though.

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  10. wow, great read, ad cannot wait for more on the topic!! interestig about MCT, when i was in need of gaining weight i found it incredibly hard when i consumed cconut oil, coconut milk etc... but my carbs and overall fat & protein were high?

    how would ketosis be beneficial to a weight restored ED person? i know i personally FEEL better, sleepwise, moodwise, cognition wise while in a fat burning environment. however, i am also hounded abot carbohydrate and a glucose metabolism being good for fertility, cortisol/adrenals, serotonin.... any input?

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  11. Have you seen the "Cooling Inflammation" Blog? I think you may like that blog as well.

    Thank you so much! This information comes too late for my epileptic, diabetic, heart-damaged uncle, but I am so grateful that you and others are blogging about low-carb nutrition and helping others. Thanks.

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  12. Hi malpaz - that's a big question! I think it is harder to gain weight in ketosis. But I'm a paleo carbs fan, to be honest, so I may too biased to answer your question honestly. :) There was guest post at heart scan blog from a reproductive endocrinologist who had excellent results with low carb diets and fertility - but since a lot of infertility is caused by insulin resistance and PCOS nowadays maybe he was successfully treating that. High fat dairy and ice cream improved fertility in that study... Can't remember the reference now but it was huge news and I'm sure very googleable.

    Hi Marie - yes, I've read a bit of cooling inflammation but probably not enough (need to check out the archives on Ned Kock's site too...)

    Mark - hope your nerdgasm was in a private place!

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  13. have read that post actually! i do eat a rather very high fat diet, paleo but lots of dairy. i dont know what my problem is or WHY i havent menstruated yet. i have wacky blood sugar readings but i always attribute them to my body trying to 'normalize'. who knows i read a lot for good results with low carb.
    anwyays, thanks for he reply

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  14. I have just found your site. Im really looking forward to reading more. I study animal behaviour and so often wonder about the evolution of behaviour and how this is reflected in humans. I have added you to my links.

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  15. Hi Emily,
    I agree that it's a mixed bag. My practical response to the ambiguity is to aim to eat only just enough carbs to stay just on the edge of shallow ketosis (as per Jan Kwasniewski's Optimal Diet which I came across at the Hyperlipid blog). In practise I seem to end up eating rather lower carb, but I think that I'm somewhat more active when I have had some carbs.

    I do think there's something in the picture that we're fat burning or sugar-burning (at any one time)- e.g. the standard Taubes picture that fairly minimal carbohydrate can suppress fat metabolism. In my normal 'edge of ketosis' state however, then my muscles etc should be running on fat (without ketones) and my brain should be mostly running on my limited carbs, with ketones making up the shortfall. We should probably remember that for our current purposes we're not looking at sugar-burning versus fat-burning, but (significant) ketone burning versus non-ketone burning. You could be running most of your metabolism on free fatty acids without generating significant ketones. It looks like even slight, infrequent consumption of carbohydrates makes a significant dent in ketone production from the table above. Hopefully high fat eating, plus the odd 12-24 fast, plus heavy exercise will produce periods of ample ketosis even while eating as many vegetables as one likes.

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  16. Wikipedia says that by adapting to a ketogenic diet glucose requirements can go from 120g to 40g. When you say "Some cells in our brain are actually too small to accommodate mitochondria", is it those cells that need these 40 grams? Do you agree 40g is a correct number?

    http://en.wikipedia.org/wiki/Ketone_bodies

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  17. Hi Tim - yes, the parts of the cells that use glycolysis for energy absolutely require glucose, which is 30% of the energy but I would have to look up the grams. 40 sounds about right. You can make that via gluconeogenesis so there is no dietary requirement for carbohydrate. Carbohydrates are gustatory extravagances.

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  18. If the brain needs 40g glucose and the red blood cells also need some (I think?), why is zero carb used for epilepsy? If one eats 50g carbs I guess at least 40g would go straight to the brain and would not affect ketone metabolizing at all? Or maybe it's not that simple. But perhaps this is why the research you write about indicates that one doesn't have to go zero carbs?

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  19. Hi Tim - the ketosis part is the important part for epilepsy, and the fewer carbs you eat, the more likely you are to be in heavy ketone burning mode. And what is even preferred is being "ketoadapted" where you metabolic machinery has shifted to being more efficient at using ketones. When you are ketoadapted, your muscles, for example, will be fairly insulin resistant so that your glucose is really shuttled straight off to the brain as you describe. On 40g glucose daily, I think many people would be in only mild ketosis, even over a long time, if at all. It all depends on the fat, obviously, as MCT oil can induce a more reliable state of ketosis at higher carb intake. I've also seen ketogenic diets based on corn oil (shudder) and olive oil. Kurt Harris has a lot of info on this process over at PaNu, and then the advanced course is available free of charge over at Hyperlipid.

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  20. I've had epilepsy since I was 16, and I've been on Depakote for about 30 years. Fortunatly, I've been able to escape the side effects.
    I've been siezure free since the age of 27 (I'm 50 now) and am considering trying to go off the med. I eat a carb restricted diet and am in ketosis most of the time, and have been for the last 2 years or so.
    But... a seizure at the wrong time can really screw up your life. It's a difficult decision...

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  21. just one quibble--IF helped my eating disorder tremendously--not 24 hr fasts--that made it worse--but 16 hr fasts from 7pm to 11am the next day has totally eradicated any desire to binge--along with low carb of course--so something is happening there--

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  22. Ouizoid - I can see how a healthy approach to IFing while on a higher fat diet would be helpful for an eating disorder. Partly because you don't have to spend Every Second Thinking About Food. I wouldn't want anyone to try it without a lot of discussion and support, though, and it certainly wouldn't be step one getting started with healing, which is why I put "as a general rule."

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  23. Hi Emily
    love the blog.
    re: glucose requirements: Doesn't your body need a minimal amount of glucose to make glycoproteins, and for immune system respiratory bursts? or is this glucose available from Gluconeogenesis?

    Speaking of which, my understanding is that your body releases extra cortisol to break down protein when it needs glucose. Would this have a serious impact on one's mood?

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  24. Dancin' Pete - my personal opinion is that living in a constant state of ketosis is too constrictive unless you have to. Though there are some people who seem to really thrive on near carniverous diets, so to each his own. We can certainly make whatever glucose we need for survival via gluconeogenesis. Some people are vulnerable to dry eyes and whatnot, suggesting they might do better on more carbs. I like carbs, personally. I like squash and sweet potatoes and have a serving or so nearly every day. Rice once a week or so too. I dip Into ketosis several times a week via IFing or a few very low carb days. Don't know about the cortisol/gluconeogenesis connection.

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  25. I've been learning in my classes about hyperpolarization and ion channels and the like, so this was a great connection :)

    There is a paper I've looked into recently on the role carnitines have in transporting fats to brain mitochondria, during ketosis, once again showing the brain burns fat. You might make connections with that if you haven't seen it.
    PMID: 19720082

    Cheers

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  26. This was a great article! I'm no biochemist, but I've been living ketogenically for a little over a year and some of the cognitive difference I've seen are quite substantial.

    I have ABI from a motor vehicle incident in 1996. I did 500$ damage to some guys car with my head and was then thrown about 40 ft. I had to learn to construct sentences, remember where my keys were (with, still, varying amounts of success) etc. I lost my sense of direction. To the point where I would have detailed instructions how to get somewhere (the KFC should be on your right, the hand with the blue ring).

    My sense of direction is fine. Not stellar - I'll never be a hiking guide or a sailor. But fine. My memory is good. Not excellent, I have to write stuff down.

    I was also put on antidepressants at 14 and spent the next 15 years or so on them. After about 3 months of cutting all carbs I went off my antidepressants. I've never felt so good. Calm, serene, energetic, interested & curious, engaged. I am simply not depressed. I don't get teary over everything, I don't go through long stretches where it feels like I have to fight just to pull it together. This is not even touching the physical changes.

    I have come to believe through my own experience, and anecdotally from others that carbohydrates are 'exciting' or 'irritating' to brains. Can we survive on them? sure. We've been doing it since the age of agriculture. But I don't think we thrive on them.

    So y'all can talk about mitochondria and ATP production... I just know what I see.

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    1. Were the effects on your mood gradual? I've also been anxious and depressed my whole life. I experience some sort of calm euphoria when I go on ketosis for 3 days. The euphoria and energy lasts a couple days, and then disappears progressively. I do not understand how it works. If only I could feel energetic and anxiety-free in the long run!

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  27. Just from memory, but Steffanson and Anderson were not in ketosis after adapting to the all meat diet. This, coupled with my own "difficulty" staying in ketosis while eschewing carbs, leads me to believe that the liver is easily capable of ramping up gluconeogenesis to cover CHO reqs. This also explains the strict protein restriction of the classic epileptic ketogenic diet.

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  28. Hi Robert - there's no question that the liver can make the glucose we need - I think the only question is whether that is an optimal long term strategy, to rely entirely on gluconeogenesis.

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  29. Dr.Deans, there's an interested and related blog entry to yours on nephropal. It quickly goes over some of Thomas Seyfried and Purna Mukherjee's review of the effects of a ketogenic diet on brain tumours in rats.

    "1) more energy is produced (meaning more Acetyl-CoA and thus more ATP - a major source of cellular energy)

    2) more oxygen efficiency

    3) reduced free radicals by enhancing the capacity of glutathione (one of the body's main natural antioxidants)"

    http://nephropal.blogspot.com/search/label/Ketogenic%20Diet

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  30. I love your blog! This diet is one which we followed for my father's brain cancer and it worked on the cancer and the seizures. It was based on an NIH diet study for children with brai tumors and seizures. What they found is that not only did it help with the epilepsy, but their brain cancers growth slowed as well. But whenever I tell this to the neurologists treating my dad in the hospital, they think I am crazy.

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  31. BTW, I have had many exchanges with Dr. Seyfried and he directed me to the NIH study. Linda Nebeling from the NIH sent us the menus they used. I wish I could find them for you but we moved and they got lost. We followed a low carb, high good fat plan. Interestingly, when his diet changed to vegetable oil and higher carbs (because the lady we hired did not think it was a big deal) he got sick again and a new cancer developed. And vegetable oils are bad but once they are cooked (as she prepared them) they turn into a toxic trans fat. Again, I am getting loads of resistance here in the hospital saying that the diet is "controversial." :( So frustrating.

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  32. BTW, another great resource for this way of eating is the Rosedale diet. He also talks about Leptin and heart health. He warns about gluconeogenesis. He says you can become too efficient in that and that could lead to long-term issues so he recommends not getting too much protein because the protein turns to sugar, not the fat. My recommendation is eat the fat first. It will keep your blood sugar low and steady throughout the meal and after. Lots of coconut oil, EVOO, Fish oil, Flax oil...

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  33. I would think the mother's diet would have a huge impact on the composition of the breast milk, or is that not the case?

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  34. Dr.Deans, you mentioned that certain brain cells lack mitochondria and are glycolytic. Could you elaborate on which parts of the brain are glucose-dependent and which can use both fuel sources? Using evolutionary logic, I would assume the brain stem and limbic system would be glucose-dependent, while the newer neocortex would have been evolved during a time of abundant fat availability.

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  35. A paper reporting a protective effect from ketones:
    http://www.ncbi.nlm.nih.gov/pubmed/17240074

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  36. I like this post a lot Emily. You do a great job explaining the biochem and physiology. I have been thinking a lot about the argument of ketones versus glucose (carbs) for brain metabolism and what is ideal. To me, it just seems like the wrong question (either-or), or at least the wrong way to look at it. The way I see it is the brain is the hallmark organ for humans. It allows us to actually reduce our energy requirements in the big picture because we don't have to be fast, furry, have sharp claws, and teeth. It has allowed us to become a super-super predators that can adapt easily, rather than superpredators which it seems live in a more precarious state and can go extinct with changes in their environment. By developing language, hunting and organizing collectively, we have used the environment around us instead of our own body an energy to survive ie the use of fire, build shelter, and store food (salting, fermenting). So, my point is if I were the ruler of human evolution, and I wanted a brain, and the cost of it was a high energy requirement, of course I would want the easiest form to use, like sugar. But since sugar is not readily always readily available to me in my environment, the way I would hedge against the lack of free glucose like fruits and honey etc. is to have multiple pathways that use both proteins and fats. I would have to make those pathways just as efficient if I want to survive and thrive. So to me, it's a process of diversification that is occurring because it seems to me and glucose and ketones both work really well for the brain. Which is better? It depends, though my personal feeling is that each pesents significant advantages and disadvantages situationally, it seems. It does require us to take a systems view to figure this out rather than either-or. For example, I did mention super-predators and that they have tenuous existences because they are so specifically adapted. There is a super-predator that has also been around for 300 million years, and perhaps is the reason there is life on land in the first place. The shark. Why have they been around for so long? People aren't sure, but it may be because of their skin, which is highly-antibacterial and does this through its nano-technology sructure. Perhaps the debate is not all about ketones and sugar. It may be bacteria. That is one of thing we miss as low-carbers. It may be other things, it seems. I personally like Paul Jaminet a lot because he makes mention of this as perhaps a cause of obesity, which seems to get glossed over in the debate over which carbs to eat. You have mentioned bugs working in concert with diet as well too in the development of mental disease. Taking that wide view is great, and it is important so we don't fall into the trap of either-or, eat this-not that, theory of everything. To paraphrase Micheal Pollan, I am not willing to declare my allegiance to any one thing, and I am not willing re-reconsider my viewpoint if necessary. I'd rather have a discussion and dialogue. Just some thoughts and ramblings based on your very good post. Keep up the excellent work.

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  37. Could the use of Adderall prevent you from entering Ketosis....Does it increase your glucose levels? My back story (please try to answer my question regardless of the story) is I unknowingly entered ketosis this summer. Fat just fell off me, I felt high on life, I was more attentive and picked up every detail, was a better worker, and way more organized (prior my organizational skills were terrible) and driven. I wasn't even overweight prior to it, I was just very lean and muscular when in it, no more chubby cheeks, no longer went to the gym (used to be a serious lifter) yet I felt surprising strong and very efficiently built. When I laid down at night I slept and when 8 am rolled around I was wide awake. Since the end of the summer and the return to my more normal diet, I went back to the old me which puzzled me because I thought my body had just matured...this wasn't the case. After a lot of research I realized I was in Ketosis and my diet was similar to a Paleo/caveman diet. The reason why I ask about Aderall is that once off Ketosis and back to the old me I felt stupid. I was literally smarter on Ketosis to the point that I shocked people. "Where did this super smart "Gumby" come from?" close friends would ask. I felt so relatively dumb again that I got prescribed Adderal to compensate because now I knew how much attention I could have and no longer had it (excluding this summer I really did have heavy symptoms of ADD)....I've came across a story or 2 on random forum comments about people claiming that while on Ketosis their ADD was non-existant. Although Adderall has helped, it was nothing like being in Ketosis and it felt much more natural....I'm having a tough time finding anything concrete on the internet, so I was wondering what sort of relationships can be found between Adderall, glucose levels, and Ketosis??? Based off my loose research, I feel that now that I take Adderall, I will not be able to enter Ketosis again, even if I follow my summer regiment. Any advice would be appreciated.

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  38. There are far more studies since 2004 that have shown a lot of beneficial effects of going low-carb, and some that show impacts going purely ketogenic. I looked through these comments and some people are still quoting 'facts' that stemmed from fallacious studies from decades prior.

    If you want to get involved with spreading the word about ketogenic/low-carb lifestyles, join my facebook page (website soon to come!) and join in the conversation!

    http://www.facebook.com/KetoLiving

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  39. A friend just sent me the link to this article because I have been talking to him about the wide spectrum of benefits of nutritional ketosis for the last 5 years. I enjoyed reading your article very much, and it is heart-warming to find others "of like minds". Thanks so much for trying to help. Much too few of us do. I've been writing articles on my blog for about 1 year and can claim to have had some success in helping people change their diet and regain health, but it is rather limited to a friends and colleagues and a few others around the world. I wish I (we) could reach more people that desperately need it, simply dying from eating carbs and processed junk.

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  40. JimT.
    Everyone assumes that the Paleo diet was a bunch of cavemen who ate meat with a stove and grill to cook on. They ate mostly if not totally raw meat. Raw meat is actually alkaline, after an hour or two it starts to turn acidic as it deteriorates. Cooked meat destroys over 50% of the protein studies have shown and unless it is prime steak, meat does not have a full set of amino acids, it is deficient! The correct way to eat the Paleo diet is to kill and eat the meat raw within an hour after killing it!
    Sounds terrible but these were cavemen not Americans!

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  41. This is purely anecdotal, but I have a condition called Trichotillomania (compulsive hair pulling, traditionally categorized as an OCD disorder) and I find my urges are practically non-existent on a ketogenic diet. I found this out by accident a couple years ago when I went on the Atkins diet to lose weight. It was a happy accident.

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  42. This is such a fascinating topic, and one that seems so critical in the field of evolutionary psychiatry. We almost certainly evolved in a state of food insecurity, and thus had to endure involuntary fasts--and the resulting ketosis--on a regular basis. I suspect we didn't fall to pieces mentally as a result. So, I wonder if Dr. Deans has come across any further interesting information in the past few years with regard to this important topic . . . . (hint:)).

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  43. All of this has been a great read for me, I stumbled upon this / the paleo diet a couple of weeks ago due to me wondering if anyone had tried to mimick how we use to eat thousands of years ago.

    It makes sense how with the majority of the human era we have been in an ice age, with little vedge and only seasonal fruit once in a blue moon, protein was our main food source (obviously combined with animal fat); the benefits of this diet and the common sense it exudes by trying to match how we evolved in to eating and had to survive off is unquestionable.

    The main point I wanted to repeat really was it's disappointing to see people follow fads, supplements etc which have been created by the food and health industries, these make billions a year from people buying their products and being fat/ unwell. American hospitals make over 1+billion USD a year from Gastric bands alone, of course they don't want everyone to be slim and healthy, the medical industry, food industry, fitness industry would all lose billions so they will push people in the wrong direction to ensure they do the WRONG things. Study upon study by the government to try and prove animal fats are linked to coronary heart disease have been carried out and time and time again they fail to come to a conclusive result (in their favor obviously). Why so determined to sway people from eating this? Coronary heart disease wasn't discovered until around 1907, funnily enough trans fats were invented in 1902 and was later marketed increasingly in things like Crisco (which was brought out 1912).

    ~Finally, with England having the NHS where treatment is "free", our food / fast food market is wholly smaller than Americas, now obesity in England is increasing, talks of charging for weight related procedures is on the cards.

    America's health care charges everyone so they also benefit from people being fat and unhealthy, here their fast food markets and fitness industries are huge, they are making a fortune out of people following their misleading and unhealthy advice.

    Just my 2 cents on the matter!

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  44. This is incredibly interesting. I wrote an essay on glutamate and excitoxicity research in neuroscience in my biomedical sciences degree, and it was by far the most difficult essay I have ever researched!

    But so, while GABA is crucial in embryonic brain development, in adults, neuroplasticity via long-term potentiation is more associated with glutamate transmission. What do think might be the implications of a ketogenic diet for those wanting to grow their brains?

    I think it really helped me because I had some kind of glutamate excess in the depression and episodic aphasia I suffered from a few years ago, which a fatty acid dominant metabolism has completely corrected. But I am trying to acquire a lot of new and really challenging knowledge these days, so I don't want to limit the beneficial possibilities of glutamate mediate LTP now either....

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  45. I love your blog!! some of the best info on the net.. Around 2006 I discovered the hcg diet and the world of Ketosis..I stopped having migraines, my borderline personality symptoms dissipated and experienced less depression after changing to a ketogenic diet. I also was able to reverse metabolic syndrome and loose weight after a lifetime of being overweight. I notice a huge change in my behavior when I convert to "regular" carb intake. I used a multi-vit and 5htp because I feel that I have serotonin deficiencies and it becomes difficult to control my mood some days. Thanks for all your info!

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  46. I've been doing some reading about ketones and how it helps with my epilepsy, I too use a modified ketone diet that includes very small amounts of carbs and I also use medical cannabis. I have been reading and watching some material about how there is cannabinoid receptors in out brains. Hey Doc do you think there might be some connection between ketosis/ketones and cannabis and those cannabinoid receptors in our brains? What I'm getting at is that the ketone diet with the added cannabis has eliminated both my front left lobe attacks (petits and grands) and my myoclonic attacks, in fact I've only had 2 small episodes in over 18 months.

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