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Friday 24 April 2020

The Ketone D-BHB as a Medical Food for Heart, Kidney and Brain Disease (Alzheimer’s, some Autism …)



 Nestle’s research centre in Lausanne, Switzerland
I did write extensively about the potential to treat some autism using the ketone BHB (beta hydroxybutyrate). This can be achieved either by following a strict ketogenic diet or just by eating medical foods that contain/produce BHB.
Some readers are now big consumers of BHB supplements and anyone taking BHB should be interested in today’s paper, that I assume was paid for by Nestlé.
Nestlé make everything from baby milk formula to George Clooney’s Nespresso.  You may not be aware that they also have a business selling medical food; they have been looking at ketones to treat Alzheimer’s for some time.  This is quite similar to Mars developing Cocoa flavanols to improve heart and brain health.
Most ketone supplements are sold to help you lose weight or boost athletic performance.  The military also uses ketones in survival rations. 
We saw that you can increase the level of ketones in your body by supplementing: -
·        MCT oil (medium chain triglyceride oil, which usually contains about 60% caprylic C8 acid and 40% capric C10 acid).  This is a product already sold by Nestlé
·        Neat caprylic acid, C8
·        BHB salts (potassium, sodium, calcium etc)
·        BHB esters (also called ketone esters KE)
These products range from expensive to very expensive.
People requiring ketones as an alternative fuel to glucose, like those with Alzheimer’s need quite large amounts of the supplements.  In Alzheimer’s a glucose transporter at the blood brain barrier is restricting the flow of glucose in blood and so the brain is starved of “fuel”.  Mitochondria in the brain can be powered by both ketones and glucose, so if not enough glucose cannot get through, you have the option to increase the amount of ketones.
Babies fed with mother’s milk are on a high ketone diet.  You can safely combine both glucose and ketones as a fuel for your body.
The news from today’s paper has already been translated to a usable therapy. 
There is growing interest in the metabolism of ketones owing to their reported benefits in neurological and more recently in cardiovascular and renal diseases. As an alternative to a very high fat ketogenic diet, ketones precursors for oral intake are being developed to achieve ketosis without the need for dietary carbohydrate restriction. Here we report that an oral D-beta-hydroxybutyrate (D-BHB) supplement is rapidly absorbed and metabolized in humans and increases blood ketones to millimolar levels. At the same dose, D-BHB is significantly more ketogenic and provides fewer calories than a racemic mixture of BHB or medium chain triglyceride. In a whole body ketone positron emission tomography pilot study, we observed that after D-BHB consumption, the ketone tracer 11C-acetoacetate is rapidly metabolized, mostly by the heart and the kidneys. Beyond brain energy rescue, this opens additional opportunities for therapeutic exploration of D-BHB supplements as a “super fuel” in cardiac and chronic kidney diseases.
One of the main benefits of ketones is their ability to act as an alternative energy source to glucose or fatty acids for production of ATP by mitochondria. Caloric restriction and intermittent fasting also produce transient mild-moderate ketosis (6, 7).
While a high dose of MCT can provide a moderate increase in blood ketones (+0.5–1.0 mM), gastrointestinal intolerance and high caloric load limit their use. Second, ketone esters (KE) made of a BHB ester linked to butanediol provide one molecule of D-BHB after digestion, with the butanediol being further metabolized by the liver to D-BHB (9). KE increase blood ketones above 1 mM but are also limited at high dose by their gastric tolerability and severe bitterness (10).
Third, perhaps the most physiologic way to raise blood ketones is via the oral intake of D-BHB itself. Exogenous D-BHB is directly absorbed into the circulation, with some of it being converted to AcAc by the liver, and both ketones being distributed throughout the body. Until recently, only racemic mixtures of dextro (D) and levo (L) BHB (D+L-BHB) were available and oral human studies with them have been reported (9, 1114). As L-BHB is not metabolized significantly into energy intermediates and is slowly excreted in the urine (9, 15), D+L-BHB would be anticipated to be less ketogenic than pure D-BHB. 
Levo, Dextro and Racemic
When certain chemicals are manufactured, they usually contain an equal mixture of the left-handed and right-handed version, this is called a racemic mixture. These versions are called enantiomers.
One enantiomer is an optical stereoisomer of another enantiomer. The two molecules are mirror images of each other, which are not superimposable - much like your left and right hand.
In the case of the chemical BHB, only the right-handed version has an effect on your body.  If you take the salt potassium BHB, half of the product has no effect other than raise your level of potassium.
Zyrtec is an antihistamine made of Cetirizine, but it is a racemic mixture.  If you want pure L-Cetirizine, you would buy Xyzal not Zyrtec.
Arbaclofen/ R-baclofen is the right-handed version of baclofen
Rezular/R-verapamil is the right-handed version of verapamil.
Back to the study:
The study compared three therapies: -

D-BHB

14.1 g of pure salts of the D enantiomer of D-BHB were used. The D-BHB supplement tested was formulated as a mixture of three salts: sodium D-beta-hydroxybutyrate, magnesium (D-beta-hydroxybutyrate and calcium (D-beta-hydroxybutyrate). Each oral serving provided 12 g D-beta-hydroxybutyric acid, 0.78 g sodium, 0.42 g magnesium, and 0.88 g calcium, citrus flavouring and sweetener (Stevia), dissolved in 150 mL of drinking water.

D+L-BHB

14.5 g of an equimolar mixture of commercial D and L beta-hydroxybutyrate salt was used (KetoCaNa, KetoSports, USA). Each serving provided a mixture of 12 g D+L-Beta-hydroxybutyric acid, 1.3 g sodium, 1.2 g calcium, orange flavoring and stevia, dissolved in 150 mL of drinking water.

MCT oil

Fifteen grams of medium chain triglyceride (MCT) (60% caprylic C8 acid and 40% capric C10 acid) emulsified in 70 mL of a 5% aqueous milk protein solution.


This chart shows the concentration of ketones in your blood plasma after taking either of the three therapies.

This chart shows the concentration of just the ketone D-BHB in your blood plasma after taking either of the three therapies.
 This chart shows the concentration of the ketone ACAc in your blood plasma after taking either of the three therapies.
  

This chart shows where the ketones are going; the chart shows the distribution of the ketone “tracer” acetoacetate (AcAc) by organ after D-BHB oral intake.  The effect is greatest on the heart and kidney, but some does reach the brain.

From the dynamic brain scan, CMRAcAc and KAcAc could be determined for all main regions of the brain and compared to baseline values previously determined in healthy young adults. Overall and compared to baseline, each region demonstrated an increase in CMRAcAc and KAcAc of ~4.7 and 2.3-fold, respectively, about 1 h after taking D-BHB. This indicated that AcAc is effectively taken by the brain and by other organs particularly the heart and the kidney.
Ketone production from an exogenous dietary source has been traditionally achieved by MCT. This requires a bolus intake to saturate the liver with MCFA, producing excess acetyl-CoA which is then transformed to AcAc and BHB, which are released into systemic circulation. The Cmax achieved with MCT is usually between 300 and 600 μM, with higher values being difficult to reach due to GI side effects and liver saturation. Here we show that D-BHB, a natural and biologically active ketone isomer, raises blood ketone Cmax above 1 mM without noticeable side effects. In comparison, an equivalent dose of D+L-BHB or MCT only achieved half this ketone level, with similar Tmax at 1 h. Thus, compared to D+L-BHB, D-BHB significantly reduces the salt intake needed to achieve the same plasma ketone response.
Results from a previous study (9) comparing KE to D+L-BHB showed that at the same dose of D-BHB equivalent, the increase blood ketone iAUC had the same magnitude, suggesting that exogenous D-BHB and KE produce similar ketosis.
Note that KE means Ketone Ester and the study (9) is this one: -

On the Metabolism of Exogenous Ketones in Humans

Ketone esters are available, but horribly expensive and taste really bad.

Conclusion
In previous posts the numerous possible beneficial modes of action of BHB were outlined. The summary post is here: -

Ketone Therapy in Autism (Summary of Parts 1-6)

In practise some people with autism seem to benefit a lot, some moderately and some not at all.
Monty, aged 16 with ASD, fits in the “moderately benefits” category.  The combination of about 20ml of caprylic acid (C8) plus a scoop of Potassium BHB powder does produce more speech.
It is not a cheap or very convenient therapy, compared the others I use.
I would agree with Nestlé that the limiting factor with BHB salts is the “salt”.  As they comment in their paper 
“compared to D+L-BHB, D-BHB significantly reduces the salt intake needed to achieve the same plasma ketone response”
Giving someone with heart disease "sodium anything" is not a good idea. A potassium salt would be safer, but even then, your heart is the limiting factor on potassium use.  Calcium salts are unwise in people with autism, because it appears to be able to upset calcium ion signalling, which would also be a potential risk in heart disease.
As I mentioned to one parent who is a big time user of BHB salts, if you switch to D-BHB you can either produce twice the ketones of regular potassium BHB, with the existing potassium load, or reduce your dosage by half and keep the same effect and save some money.
I think potassium D-BHB is good choice.  If you are taking bumetanide you may no longer need a potassium supplement (K-BHB becomes your potassium supplement).
I think people with autism and genuine mitochondrial disease are highly likely to benefit from D-BHB.  These are people who show symptoms in their entire body, i.e. lack of exercise endurance. For these people, eating (or producing via diet) large amounts of ketones will increase the production of ATP in their brains and so improve cognitive function.  D-BHB undergoes a different process to glucose, as it “converted” to ATP by the process called OXPHOS
(Oxidative phosphorylation). Some people with autism lack the enzyme complexes needed to complete OXPHOS, these people who should try D-BHB.
BHB has other beneficial effects, some relating to inflammation that seem to explain its benefit in other types of autism.  The effects were investigated here.
In the brains of people with Alzheimer’s there is decreased expression of glucose transporter 1 (GLUT 1) at the blood brain barrier. This starves the brain of glucose, which is fuel for the brain. D-BHB is an alternative fuel for mitochondria that is not dependent on GLUT 1.  People with early onset Alzheimer's would seem the best ones for this therapy, that would include many people with Down Syndrome. 


24 comments:

  1. Yes, yes! Just the post I needed!
    Thank you Peter, it is lovely.
    :-)

    /Ling

    ReplyDelete
  2. https://www.sciencedaily.com/releases/2020/04/200421094257.htm?fbclid=IwAR1ndrVsJ10CfUzhX-PVeWeCN8f0e8V4gRotgTuAGFjqi2Ru9e-Xz3_69_g

    great news, immune therapy for OCD on the way. whatever paves the way towards understanding that there are no ‘mental’ problems considering that the human body does not have a ‘mental’ body part...

    ReplyDelete
  3. https://prototypenutrition.com/products/ketone-ester Peter, do you think this ketone product can resolve the problem with salts? I am looking into giving her ketones but bc of bumetanide really trying to avoid complications with salts.

    ReplyDelete
  4. HVMN and KE4 seem to be the more well known ketone ester products. I think you have to be careful who is making these products.

    Ketone Esters do have advantages as discussed here:

    https://epiphanyasd.blogspot.com/2019/02/who-lives-in-libya-and-raising-level-of.html

    ReplyDelete
  5. Was not aware of the racemic differences in Ketone esters. Is the BHB powder you use with Monty the racemic version?

    ReplyDelete
    Replies
    1. I used the racemic version, first the liquid form of K-BHB (KetoForce) and finally a powder version of K-BHB (from iHerb). IHerb still sell the racemic version, but I think it is now replaced by the producer with K D-BHB, which is currently sold on Amazon in the US. I guess iHerb are selling off their old stock.

      I tried a powder BHB made with a mixture of salts (K, Na, Ca), this did not work well. I think K or Mg are best salts to avoid other issues. Na has never caused a problem, but is not healthy. I think the problem is Ca.

      One doctor reader uses K-BHB at high doses of K, with no problems at all. He did look into the safety issue of K. I think the safety issue of K is likely exaggerated, particularly in the US. Nonetheless, I think halving the K input is a big advantage of D-BHB.

      BHB products are not available in many countries outside the US.

      Delete
  6. I just read what you linked to, and in it you mentioned TRH and I went back to your old article on it. Its a description of exactly what happens to my daughter. Rollercoasters and long beach walks on windy beaches are almost a cure. We spent 2 months in Ibiza this winter, taking a walk on their Salinas beach which is long and windy almost every day, and her general attitude improved by about 80 percent. When you say you use Broccoli for the effect, do you mean it has the same effect or works on the same issues in the body? We used Prostaphane last spring and then stopped. I will try it again if its still good after sitting in the fridge for a year, waiting to hear from the makers.

    ReplyDelete
    Replies
    1. I think if you could put "exhilaration" in a pill you would have an effective autism therapy. I put this in my "hormonal dysfunction" category of what causes the problem in much autism. The effect is near instant and does last a while after the "exhilaration". TRH was my idea for re-creating it. Broccoli is increasing serotonin and makes some people euphoric, but not exhilarated, it is not the same effect.

      It is not a post-exercise high, it is a sensory high. That is why I ended up looking at the study of people about to jump out of a plane with a parachute.

      Delete
  7. Also, since you asked about readers experience with Tavegyl - been on it about 4 weeks, so far nothing noticeable. she is anyway full of allergies so why not, but no effect visible as such.

    ReplyDelete
  8. I could not agree more on exhiliration. If you recall fron my comments its the reason I wanted to try and SSRI, perhaps even at the Goldstein dose of 10mg. I will get broccoli back and see about the THR therapy. Maybe they can be stacked. Why did you discontinue it?

    ReplyDelete
    Replies
    1. TRH is not easy to get. It is also very expensive in its standard form from Japan, as Ceredist. I think you just need a microdose, but it does not have a long shelf life, so you keep needing more.

      The easy way to buy it is actually in Germany, from an international pharmacy, who import it for you with a prescription from any doctor. I got mine from a helpful doctor in Japan.

      It did have an effect, but not so big. All in all, I decided is not practical as a therapy.

      Some people clearly do benefit from a lose dose SSRI, but for others it does nothing.

      Delete
  9. For the life of me I can’t remember or find what the dose of Sulforaphane should be. Prostaphane seems to be 10mg in one pill. I can’t remember what we gave :-/.

    ReplyDelete
  10. Thanks Peter,
    I plan on trying the C8 + ketosports, luckily I think I fit in very similarly to the pathways that has affected your son. I don't think I have quite the abilities to interpret all this information without your help... thanks!
    I am actually very curious about this idea of negative effects of calcium. Do you plan your diet around reducing calcium or anything like that? Like cheese is extremely high in calcium... and very delicious... :(

    ReplyDelete
    Replies
    1. The negative effect is from calcium supplements, not from calcium in food. Supplements containing calcium or potassium, for example, are rapidly absorbed, unlike food, and can produce negative effects. This is a risk with electrolytes like calcium, which have multiple functions in your body.

      Calcium in diet is essential, most calcium is in your bones, only a tiny amount is in your blood. It is generally always much better to get nutrients in the form of food, where possible.

      Delete
  11. Today we gave the third dose of Prostaphane - sulforaphane, restarting it after we stopped last spring, wrongly deducing that it wasnt helping. At the time we were dealing with non asd medical issues which by chance were using the same therapies some autism uses, like antibiotics and antifungals, and I wrongly deduced that the amazing spring we had was because of them (though they for sure played a role as well). Afted 48h now I can tell that if this trend of communication improvement we have seen were to last for 5 months like this, she would be fully conversationally verbal by then. We also had a very moving moment today. My daughter uses her hands to wave them in front of her face, escaping in a dreamworld where the hands are George (she is Peppa). Five times today she gave me her hand, looked me in the eyes, laughed and said “Not George”. she knows it upsets me and decided to stop it. I am blown away.

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    Replies
    1. That is great. What dose of Prostaphane are you using?

      Delete
  12. I just winged it on dosage and am giving her half a pill of Prostaphane crushed in Nutella. I cover them in nutella the second I crush them and she swallows it in 5 seconds so the crushing shouldn’t affect the sulforaphane.

    ReplyDelete
  13. Hi Peter and all. I was in the hospital a couple weeks ago for colitis and I definitely noticed the the metronidazole and ceftriaxone definitely help my mood for 5 to 7 days and then didn't really feel like much difference once I was done with them, I was on them for a week. However, during my hospital stay my inpatient doctor saw in my file I had never tried immediate release verapmil and she offered to switch me to it and I excitedly accepted.

    There is no question the immediate release verapmil is more helpful than the extended release. It makes my urge to bang my head when j can't sleep or have a headache go away

    ReplyDelete
  14. Hi Peter,
    I have question bit off topic, anyway I thing it would be interesting to hear you opinion for others too.
    I got quite good experiences with Bumetanide for our 8,5yo son with atypical autism. But for now I'm bit confused with dosage.
    I used to give him 1mg/day which is calming him down and setting more focused, but I wonder if from farmaco-kinetic view is it better to split this dose into 2 halves or even 4 quarters served in 4 hour intervals or just one dose in the evenig or morning?

    ReplyDelete
    Replies
    1. los_palos, the "autism effect" of bumetanide is the effect of what you took over the last 2+ weeks, that has gradually lowered chloride inside neurons. Today's dose does not produce much of today's effect.

      The exact details of bumetanide action is disputed, since only a tiny amount can cross the blood brain barrier and some questions do remain unanswered.

      In my opinion, a single big dose has more benefit than splitting it into 2 or indeed 4 doses. I now give 2mg of bumetanide all at once. I found 1mg once a day effective, but 0.5mg twice a day was not. 2mg once a day is more effective than 1mg once a day. The limiting factor is the diuresis; I have no doubt that 3mg will be more effective than 2mg.

      Bumetanide is a partially effective therapy, but the best available today.

      Delete
  15. Hi Peter, this is very interesting. Is any D-BHB salt available on sale now?

    In my limited experience I couldn't see any benefits of the ketone ester over the BHB salts (racemic mixture I assume), but it would be good to compare D-BHB potassium salt as well.

    ReplyDelete
    Replies
    1. Yes, it is sold in the US, but not yet by iHerb, who are selling the old version.

      The new version of potassium D-BHB:

      https://julianbakery.com/product/instaketones-d-max/

      I expect when iHerb run out of the old version, they will start selling the new version.

      Delete
  16. guy, did you see this paper
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5044872/
    acetaminophen maybe cause autism . btw i want ask you about my kid, he maybe have problem with his endocannabinoid system, he said something when he fever, so with your knowledge, what drug you recommend except PEA? PEA maybe does not cross BBB and CBD very illegal and not exist at my country, what else maybe help?

    ReplyDelete
    Replies
    1. The fever effect is well documented in autism, but it applies to a minority of people. Nobody has figured it out 100%.

      Best to ask what worked for kids who improve when they have a fever. My son gets more autistic when sick.

      I think it is a sign of a specific subgroup of immune abnormality in autism.

      Delete

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