Ketosis: anti-brain fog. Neurotransmitters, dietary protein, and the gut microbiome.

Treatment for dietary protein-induced brain fog: dark chocolate with 3% GOS and 10% MCTs.  Who’s in?

#IntermediaryMetabolism (bear with me here)
Ketosis from liver’s perspective:  increased fatty acid influx & [partial] oxidation causes acetyl-CoA levels to rise dramatically.  Concomitantly, gluconeogenesis redirects oxaloacetate (OAA) away from combining with acetyl-CoA via TCA cycle citrate synthesis and toward gluconeogenesis.  Since the acetyl-CoA doesn’t have much OAA with which to couple, it does itself to make acetoacetate.  Ergo, ketosis, and fortunately liver lacks ketolytic apparatus.

ketosis

 

Brain is singing a different tune.  Ketones provide ample acetyl-CoA and are efficiently metabolized in the TCA cycle.  Ketolysis is not ketogenesis in reverse, else liver would consume ketones.keto metabolism

Teleologically speaking (and I don’t really know what that word means), ketones are meant to spare glucose for the brain by replacing glucose as a fuel for peripheral tissues like skeletal muscle and displacing some brain glucose utilization.  The former is vital as one of the few sources of “new” glucose is skeletal muscle amino acids, and they would be exhausted in a short amount of time if skeletal muscle kept burning glucose –> incompatible with survival.  Getting some of that fuel from fatty acids, ie, ketones, is just way better.  Thus, the “glucose sparing effect of fat-derived fuel.”  And by “glucose,” I mean “muscle;” and by “fat-derived fuel,” I mean “ketones.”  There are numerous intracellular signaling events and biochemical pathways pwned, but that’s the gist of it.

Running brain on ketones considerably impacts amino acid metabolism, or more specifically neurotransmitters.  Ketogenic diets –> neuroprotective and improve cognitive functionimprove behavior in epileptic children, and even efficacious in bipolar disorder.  Many of these effects could be attributable to alterations in glutamate and gaba signaling.  Excitotoxicity.  brain fog.

Glutamate and gaba are two of the most quantitatively important neurotransmitters.  Glutamate can come from a transamination reaction or glutamine via phosphate-activated glutaminase.  It’s an expensive enzyme; one in which a few miscalculations in the lab can literally waste thousands of  a few of your tax bucks (ie, the kind of stuff that could’ve theoretically happened here) (sorry).  As it goes, glutamine is deaminated to glutamate, which is transaminated to alpha-ketoglutarate (aKG) or decarboxylated to gaba.  Glutamine is a precursor for glutamate and consequentially, gaba.  Glutamatergic neurons convert glutamine into glutamate, and gabaergic neurons convert glutamine to glutamate then via GAD to gaba (both of which can be recycled back to glutamine in astrocytes).Glutamine gaba

In liver, OAA is siphoned off for gluconeogenesis making it unavailable to facilitate fatty acid oxidation which leads to ketogenesis.  In brain, OAA effectively combines with ketone-derived acetyl-CoA, making it unavailable for transamination with aspartate (OAA + glutamate –> aspartate + aKG).

This could lead to elevated levels of glutamate (bad; excitotoxicity), but during ketosis, brain glutamate metabolism is apparently biased toward glutamine synthetase and GAD instead (both good).

Glutamine synthetase (GS)  mops up excess ammonia, which is thought to be a cause of brain fog at moderate levels and encephalopathy at high levels.  GS also detoxifies excitotoxic glutamate.  And GAD produces the calming neurotransmitter gaba.brain fog

Why no stellar data showing dramatic changes in vivo?  Speculation: said changes would be small and restricted to specific brain regions.  Total levels of glutamate & gaba might not even be altered, just flux and secretion patterns which would be difficult to detect.  However, this hasn’t stopped some review articles from saying these changes occur unequivocally (eg, Ruskin 2012), so maybe I’m wrong.  I’m still not going to bother trying to find studies where they dunk poor unsuspecting mouse into liquid nitrogen to prevent stress or anesthesia-induced alterations in extracellular neurotransmitters.   They probably exist, but I’m basing these assumptions on #IntermediaryMetabolism.

I suspect ammonia & glutamate are rather important in the etiology of brain fog due to the high sensitivity of Jane Plain’s brain to ketosis and dietary protein.

Glutamate and gaba are two ways ketosis may impact brain fog, but dietary protein might do so by a different mechanism: ammonia.

Ketogenic diets don’t include many bifidogenic foods.  Subtle alterations like this can lead to big changes in the way food is metabolized – some bugs love protein but hate nitrogen, or at least get rid of it via urease which creates ammonia.  Too much of this  = brain fog.  Forgetfulness, confusion, irritability.  Insomnia.  Ketogenic diet-induced increase in brain glutamine synthetase could likely take care of some, but may not be enough if dietary protein is too high.  And it isn’t frank encephalopathy, but rather some form of “clouding of consciousness.”   Although perhaps not so coincidentally, one way of managing hepatic encephalopathy is the bifidogenic laxative lactulose.

What about brain fog, treatment?  Ketogenic low protein diet, just like Mrs. Spratt (certainly not her husband)… although we suspect her problems were caused by an inherited disorder in the urea cycle.  Galactooligosaccharides (GOS) would work here because they have a strong potential to reduce urease-producing microbes.  And in at least one study (Malaguarnera 2007), bifidobacteria plus inulin worked for brain fog, which they called “minimal hepatic encephalopathy” probably because “clouding of consciousness” sounds ridiculous

[to journal editors who don't understand medical conditions at which you can't throw a statin or PPI (the latter being far worse in this case)].

Given that finding, I’m confident GOS would work better for two reasons: 1) supplementing live bifidobacteria requires financially restrictive doses to have an impact; and 2) GOS is far more bifidogenic than both inulin and actual bifidobacteria-based probiotics.

–> “Psychobiotics: a novel class of psychotropic” <–

HT Purposelessness –> “Melancholic microbes: a link between gut microbiota and depression?” <–

In sufferers of brain fog, the tolerable level of dietary protein might just be dependent on architecture of the gut microbiome and degree of ketonemia.  Zhang and colleagues showed a linear relationship between brain ketone usage and blood ketone levels, and higher ketone usage could enhance clearance of glutamate and ammonia (2013).  

To this end, MCTs or coconut oil may even facilitate the tolerance of brain fog to more dietary protein.  Throw in some galactooligosaccharides and we just might be on to something… I’m thinking a dark chocolate product supplemented with 3% GOS & 10% MCTs.  

Dark chocolate is an optimal vessel for prebiotics <– FACT, and some companies are already keen to this.  

Those percentages are negotiable, but 100 grams would provide a dose of GOS that is well-tolerated and remarkably bifidogenic.  MCTs at 10% should be OK, but if you love too much of this delicious chocolate, then too much more could cause digestive problems. 

Who’s in?

brain fog II

calories proper

Be Sociable, Share!
Share
  • Fred

    New coffee drink. Mix inulin-since it’s easy to buy- cocoa powder and coconut oil into a paste. Mix with coffee and butter/hwc. You read it here first! Rocket fuel.

  • George

    Very interesting.
    From another perspective, that of the transcriptome, ketogenesis looks like this:
    http://en.wikipedia.org/wiki/File:Human_hepatocyte_PPARalpha_transcriptome.png
    The really nice thing about PPAR-alpha, for us amateurs of genomics, is that its activity is simple and unambiguous. It really is a fat-burning gene, to put it very crudely. You don’t get that kind of clarity when you look at other transcription factors, like, say, NFkappa-beta, which is all over the place and majorly contingent. PPAR-alpha is contingent on nothing. If it’s there at all, it’s there to do this very specific thing. Teleologically speaking.

    PPAR-alpha is a transcription factor and a major regulator of lipid metabolism in the liver. PPAR-alpha is activated under conditions of energy deprivation and is necessary for the process of ketogenesis, a key adaptive response to prolonged fasting.[3] Activation of PPAR-alpha promotes uptake, utilization, and catabolism of fatty acids by upregulation of genes involved in fatty acid transport, fatty binding and activation, and peroxisomal and mitochondrial fatty acid ?-oxidation.[4] PPAR-alpha is primarily activated through ligand binding. Synthetic ligands include the fibrate drugs, which are used to treat hyperlipidemia, and a diverse set of insecticides, herbicides, plasticizers, and organic solvents collectively referred to as peroxisome proliferators. Endogenous ligands include fatty acids and various fatty acid-derived compounds.

    • http://www.caloriesproper.com/ William Lagakos

      Ha! I’ve done the calculations a million times for my own experiments and it’s always done to assume very low “free” fatty acids… that’s how it is in the blood. Albumin binds to just about anything remotely hydrophobic, it seems.

      With regard to disease states – I don’t know. Each fatty acid has a different affinity for albumin, so that might be involved… interesting idea. Actual “free” fatty acids don’t seem like they’d be friendly to things like membranes, etc. Detergent-like effects.

      • George

        Albumin drops as a result of liver disease; so if you had NAFLD and diabetic levels of NEFAs you might well see some of this toxicity?

  • Thomas Hemming Larsen

    Hi Bill,

    Good read even though some of the technical part went a little over my head. A few questions that I came to think of.

    Wouldn’t the effect of decreasing protein intake be greater than ‘supplementing’ with coconut oil and dark chocolate?
    Is raw cocoa mass superior to any chocolate <100% cocoa (as you hint at http://caloriesproper.com/?p=1583)? What about cocoa butter, does that have some of the beneficial bacteria?
    I'm thinking if it would make sense to mix dark chocolate and cocoa butter (I haven't been able to find the amount of MCT in it)?
    Would cocoa nibs and cocoa beans have some of the same beneficial effects?
    Br,
    Thomas

    • http://www.caloriesproper.com/ William Lagakos

      Hi Thomas, thanks.

      Protein vs. MCTs: gram for gram? I don’t know, but I suspect it’s a big “ymmv.”

      The bifidogenic effects of dark choc are likely attributable to something that in the cocoa nibs, beans, and cocoa powder (maybe the fiber, or some polyphenolic, etc.).

      Cocoa butter has a lot of stearate and probably no MCTs whereas coconut oil is somewhere around 70% MCTs.

      Stearate effects on the microbiota – that’d be interesting! It seems as though it’s the lack of specific carbs as opposed to the presence of fat that affects the microbiota… also because most dietary fat is absorbed prior to the distal intestine, unlike fibers and some complex carbs.

      • Thomas Hemming Larsen

        Thanks Bill.
        Yeah, I was just thinking that reducing protein would have a greater effect than trying to ‘out-supplement’ it with MCT.
        Interesting about the stearate. I was not aware that the sheer lack of carbs could affect the microbiota. Is this part of transistion the gut makes to adapt to a higher fat diet for instance? Anecdotally, previously I could get acid reflux from eating even small amounts of pure tallow whereas I now can eat it in any amount I like without any issues.

        • http://ashsimmonds.com/ Ash Simmonds

          It’s been pretty well covered that high fat/ketogenic diets modify the gut bacteria pretty extensively – most of the articles about such a thing though paint it in a negative light along the lines of “once you start eating shit again your body will be even worse”. I for one can’t see myself abandoning a mostly high fat carnivorous lifestyle, so it’s kinda a non-issue.

          • Thomas Hemming Larsen

            Thanks Ash.
            I have heard other mention that too and that it will be a problem eating shit again (but why would anyone?). I guess it makes sense that the gut modifies it bacteria to any kind of diet.

          • http://ashsimmonds.com/ Ash Simmonds

            Anecdotally – it’s DEFINITELY true.

            Here’s the last time I ate a meal without meat: http://aussieexotics.com/forum/off-topic/food-glorious-food-1346.msg180962.html#msg180962

            “I just went to a vegan restaurant with a “healthy” friend, only option that wasn’t some tofu lentil shit was a “curry”, basically a bowl of steamed potatoes in a watery goop with vague coconut flavour.
            That was 20 mins ago, currently sitting on the bogger with the runs and abdominal pains.”

          • Thomas Hemming Larsen

            Haha, good one :)

          • http://www.caloriesproper.com/ William Lagakos

            I imagine if you go back on carbs there will be a period of extensive bloating & gas while the new regime of microbes take over.

            that will be unpleasant
            +
            I rather like my current diet
            = it’s a non-issue for me, too.

          • Thomas Hemming Larsen

            Do you go all out ketogenic or just try to limit your carb intake?

          • http://www.caloriesproper.com/ William Lagakos

            Off the top of my head: my carbs come from dark chocolate, leafy greens, nuts, ‘kraut… so mainly fibrous. Ketostix are sometimes moderate, never purple probably due to protein.

        • http://www.caloriesproper.com/ William Lagakos

          “…transition…”
          Yes, I guess you could say that. The microbes that depended on carbs & fiber die. Some of them are replaced by others who can better tolerate the new environment.

      • John Lushefski

        Almond fat seems to be bifidogenic–that’s even on this site. That would then seem to imply that the PUFA isn’t an issue in that case.

        • http://www.caloriesproper.com/ William Lagakos

          Thanks, and that’s one of my favorite posts! (http://caloriesproper.com/?p=1676)

          …but I think you might have to say “almonds” instead of “almond fat,” because almond fat alone would be absorbed in the proximal small intestine. Eating actual almonds helps to deliver some of that almond fat to the distal intestine.

          • George

            It maybe that bacteria can digest phospholipids but not triglycerides.

  • http://ashsimmonds.com/ Ash Simmonds
  • Woodwose

    What is your opinion on resistant starch? I have been using it for at least half a year and it’s very stabilising for the gut.

    • http://www.caloriesproper.com/ William Lagakos

      Sounds like a pretty good “n=1″ to me!

      From a scientific aspect, they’re interesting. From a nutritional aspect, foods high in resistant starch are usually high in total carbs, so it depends on what kind of diet you’re trying to follow. Richard Nikolay has been writing about some resistant starch-based supplements that are supposedly keto-friendly (http://freetheanimal.com/2013/10/resistant-ingestion-blunting.html).

  • Risa

    What I heard:
    yada yada yada dark chocolate is good yada yada yada.

    I will devote the next 6 months to understanding this, if for no other reason than to better defend my consumption of dark chocolate.

    • http://www.caloriesproper.com/ William Lagakos

      no need to defend your consumption of dark chocolate here at The poor, misunderstood calorie ;-)

  • http://itsthewooo.blogspot.com/ Jane Plain (Woo)

    ” Ketogenic diet-induced increase in brain glutamine synthetase could likely take care of some, but may not be enough if dietary protein is too high. ”

    This is precisely what I think, Bill; evidence that is specifically related to amino acids is the fact I can tolerate very well and even thrive consuming protein sources that are high in glycine like collagen / connective tissues / skin, which is GABA-like and does not have the same liabilities of “meat” and typical amino acids blends found in meat.

    My symptoms when I consume too much protein for too long are not really brain fog, it’s more like mental agitation , dysphoria, mental disorganization. Extreme, disorganizing overstimulation of mind with no external triggers to prompt it. I’ve compared it to “feeling as if my brain is on fire”. It is always worse the further from sleep I am, and if I can go to sleep sometimes I will wake up and it is gone…but it may prevent sleep and it will worsen progressively.

    There are no normal human emotions to describe the way it feels, it’s much more comparable to taking a psychoactive substance that produces “bad trip” Or some other heinous abnormal mental state, than it would be the normal range of human emotions (happy, sad, bored, excited, angry). I am fairly sure it is pathological and represents my baseline neurological abnormalities that make me vulnerable to mood disorder and mental illness (fact is fact: I have a ton of genetic risk markers for mental illness as confirmed by 23andme, and have a family history rife with it) pretty sure whatever happens in my mind is not normal and does not apply to people without these risk factors.

    But considering the relationships between glutamine-glutamate-gaba-glycine, this condition makes sense when understood from the perspective that I only feel normal in ketosis, as a high amino acid intake would / could theoretically overwhelm ketosis’ ability to modulate glutamine into gaba and result in excesses of glutamate , or perhaps ammonia too. The primary way ketosis controls seizures and bipolar disorder is related to partitioning glutamine into gaba and away from glutamate as well as affecting sodium channels to reduce excitatory tone.

    I have used glycine rich foods to “rescue” myself from excessive protein excitatory overload and it works better than most anything else I have tried, nothing works as well. If consuming too many amino acids is overwhelming the ability of ketosis to modulate glutamate, it stands to reason directly consuming glycine will help the symptoms and decrease glutamate bias. Ordinarily, in a proper fasting ketosis, my glutamate / gaba levels are favorable but if I do something stupid like eat meat all day, they won’t be, even if I’m in ketosis, and then I can benefit from direct supplementation with either glutamine or glycine to calm my mind. I suspect the insulinogenic nature of protein is the main reason amino acids in large quantities carry these liabilities, as when I take isolated glutamine, it appears to be all dumped into GABA as long as I am in ketosis.

    http://www.ncbi.nlm.nih.gov/books/NBK11084/

    I no longer feel I require probiotics but when I was using them before vitamin D3 and zinc definitely did help my emotional state.

    I’ve also discovered, even though I find coconut oil to make me hungry , it can have a relatively rapid acute calming effect if I am suffering from symptoms of decreased ketosis, with enhanced mental clarity adn emotional stability… reminiscent of the way being in a proper ketosis in semi-fasted condition.

    • http://www.caloriesproper.com/ William Lagakos

      “There are no normal human emotions to describe the way it feels”
      this is confirmed by wikipedia’s definition of “clouding of consciousness” … it’s really all over the board, and I suspect that’s because it’s how brain fog is expressed irl.

  • George

    Classical herbal inulin supplements are chicory, dandelion, burdock roots, included in many herbal formulas despite having little drug activity except for dandelion.

  • Sylvie

    Hi, Bill. Great read. If I might ask a simple, unrelated question –have you found any scientific evidence for my low carb dairy (ie cheese) might cause weight stalls or prevent weight loss in some individuals? Kinda growing weary of the CICO explanations.

    • la Frite

      Hi, cheese has lots of dairy proteins, including whey. Whey promotes growth and is highly insulinogenic. That is why baby mamals need it :)

      • Sylvie

        But the insulin response is matched by a glucagon response.

        • La Frite

          Yes, probably, but that does not matter. Once insulin is elevated, free fatty acids are not exactly as available as without insulin. I am not sure whether it is that simple, because whey is really promoting growth. You actually could try some experiment: have whey shakes for 2 weeks, and then switch to casein shakes for the same amount of time. Casein takes much much longer to digest, probably for babies not to scream for milk ALL the time :)

        • La Frite

          Forgot to mention: you can try drained yogurt where most of the whey is removed. That’s what the Greek yogurt is about, isn’t it ?

      • http://www.caloriesproper.com/ William Lagakos

        Whey might not be all that bad!
        Biochemical a& metabolic mechanisms by which dietary whey protein may combat obesity and Type 2 diabetes.
        http://www.ncbi.nlm.nih.gov/pubmed/22995389

        (…but I’m still sticking with “ymmv”)

        • La Frite

          I forgot a word: I meant “promote muscle growth”. It is a darling of body builders. Weight loss stall might simply mean you are developing lean mass as well.

    • http://www.caloriesproper.com/ William Lagakos

      Hi Sylvie, thanks!

      In brief: no. There isn’t a great body of evidence showing dairy blunts weight loss in humans = ymmv.

  • Wenchypoo

    Common housewife with her sciency bone broken, so here goes:

    “glutamine is deaminated to glutamate, which is transaminated to alpha-ketoglutarate (aKG) or decarboxylated to gaba. Glutamine is a precursor for glutamate and consequentially, gaba. Glutamatergic neurons convert glutamine into glutamate, and gabaergic neurons convert glutamine to glutamate then via GAD to gaba (both of which can be recycled back to glutamine in astrocytes).”

    Does this mean glutamine may be a cure for hot flashes? I’ve been doing the Brain Trust Program protocol for months now, and the hot flashes went away for awhile, and are now back, in spite of seemingly-deadly doses of coconut oil, fish oil, and vitamin E, as well as maintaining a ketotic state.

    I also read just yesterday (in the Warrior Diet book) that l-glutamine on an empty stomach can pass through the blood-brain barrier without an estrogen wrapper–PERFECT for those in menopause!

    I ordered some and am going to conduct an N=1 study through November to see if this works. I’ll continue the rest of my above-state regimen as well, and tapering it off to normal human levels as I feel able to do so.

    This article was pure serendipity for me.

    • http://www.caloriesproper.com/ William Lagakos

      Glutamine supplementation may or may not work for this… or by that mechanism (ketosis-induced increased glutamine synthesis is probably the better route). Most of the glutamine ingested [on an empty stomach] will be metabolized by the intestinal epithelia. There might be some downstream effects; eg, gut-brain signaling? but unlikely that supplemented glutamine makes it to brain.

      That said, please please please post the results of your “n=1″ experiment!!! I don’t really have anything against HRT, but if a cocktail of glutamine & coconut oil worked… FTW.

      • Wenchypoo

        November’s not over yet, but I can say that glutamine alone makes the hot flashes hotter and more frequent (naturally–all the sugar)–even at night with an empty stomach. I had to add coconut oil, and eventually fish oil, back in to get all-night relief…now it’s just fine-tuning the doses of each.

        • http://www.caloriesproper.com/ William Lagakos

          thanks for posting the update. very interesting… i don’t know why that’s happening, but glad to hear it’s relatively under control.

        • Wenchypoo

          I have also found that I get into deeper ketosis (no meter–just going by breath here) and stay in ketosis longer through the night.

  • Pingback: Day 144 | Ketosis | November 16, 2013

  • Pingback: Ketosis, Protein, Increased Fasting Blood Sugars & Gut Microbiome (Nov 19, 2013)

  • Pingback: Ketosis: n=1 Protein Experiment, Protein Clarity or Protein Coma? Day 152 (11/24/13)

  • EmergentEcon

    This seems to be a recent problem for me.

    I currently have a strenuous exercise regime, mostly HIT (sprint cycling/running and weight-training) 2x a week.

    As such, I am maintaining a protein intake of 120g per day (1.5g/kg lean body mass): 60g in the ‘morning’ and 60g at ‘night’. I have a 18hr fasting/6hr eating window.

    While I have amazing clarity and super focus when I wake up in the morning, I notice though that within 30min of consuming 60g of protein, the most incredible brain fog sets in. This seems to dissipate within 2hrs of eating. The fog is so intense, that I can barely focus on a single sentence I am trying to read at the time.

    I am waiting for a new delivery of MCT oil – hoping that a tablespoon with breakfast will ameliorate the fog somewhat.

    Any other advice or maybe suggestions?

    Thanks!

    • http://www.caloriesproper.com/ William Lagakos

      The MCTs might help… I’m not sure what other n=1’s you’ve tested, but I can think of two more possibilities: 1) maybe 120 g/d is above your personal protein threshold… perhaps you could decrease on non-training days (?). And 2) maybe 2 meals a day isn’t working, or 60 grams all at once isn’t working. 3 meals a day, or maybe 3 meals on training days when protein intake is high. Just thoughts.

  • Thomas Hemming Larsen

    Can you buy pure GOS powder (the equivalent of inulin), what is the name of the compound and do you recommend a particular brand? Does it taste sweet like inulin/FOS?

    • http://www.caloriesproper.com/ William Lagakos

      surprisingly enough, there’s only one commercially available GOS product (to my knowledge). It’s by a company called “Bimuno” http://www.bimuno.com/ …they’re not paying me for advertising their product, but they should be!

      • Thomas Hemming Larsen

        Thanks Bill. I was also surprised to see how easy it was to find inulin but not GOS. I’ll try the inulin first and see if it helps. I basically just wanted a sweetener which had some other positive effects too.