High dose Betaine/TMG, Low Dose Ponstan, Galavit, Humira, HMB (β-hydroxy-β-methylbutyrate) and Cetirizine for Palilalia/Scripting

 

Our reader in Canada, AJ, did highlight a case series from Norway that showed that high dose Betaine/TMG was effective in improving functioning in people with autism due to creatine transporter deficiency.  The use of Betaine/TMG was really just stumbled upon and the authors considered what the beneficial possible mode of action could be. 

Betaine (TMG) and Gene Therapy as potential alternatives to Bumetanide Treatment in Autism? 

The effect was only present at high dose (7-10 g a day) not the much lower dose used by some DAN/MAPS doctors, who do prescribe TMG and the closely related DMG.

The paper suggested that one possible effect might have been lowering chloride levels within neurons.  This is also the effect of Bumetanide.

AJ suggested that Betaine/TMG might be an alternative to Bumetanide and one that does not need a prescription.

Our reader Nancy reported a benefit in her adult son.

The question is not whether or not high dose TMG is a useful therapy, we already know that it is, in some cases. The question is whether it is a bumetanide alternative.

My conclusion is that high dose TMG does not seem to be a bumetanide alternative.  If it was an effective alternative then I would be suggesting everyone using bumetanide should go and buy some.

I did try TMG for s couple of weeks and did not see any additional effect over the continued therapy of 2mg of bumetanide.  In our case there is a benefit from additional bumetanide/Azosemide. If TMG shared the same mode of action as Bumetanide then 7g TMG + 2mg Bumetanide should show some improvement over 2mg Bumetanide.  It did not.

There is a long list of other modes of action to explain why Nancy’s son and the two Norwegians improved.

 

Low dose Ponstan for sound sensitivity

Low dose Ponstan (Mefenamic Acid) was proposed as a treatment for sound sensitivity.  Within Europe it seems that Greece is the place to buy Ponstan; it is sold OTC and cheap.  One pack (15 x 500mg) costs less than 2 USD/EUR.

In some people the effect of 250mg lasts all day, while for others it lasts for a few hours.

Ponstan is also widely used as a syrup to reduce fever in young children (antipyretic).

In the US the common brand name is Ponstel, but the price is dramatically higher.

Galavit + Cromolyn Sodium

The combination of the common mast cell stabilizer Cromolyn Sodium, used by many readers, with a Russian drug called Galavit is used by at least two readers. Dragos recently told us that the combination has put an end to his adult son’s aggressive behaviors.

Galavit has multiple anti-inflammatory modes of action.  It is not a mast cell stabilizer like Cromolyn Sodium.

Galavit is not expensive, but may hard to get hold of.

It does look like there is an overlap between responders to Verapamil and responders to Galavit.  So, if you respond well to Verapamil but get one of the rare side effects, like Maja’s daughter, it might be worth investigating further. 

Humira 

Humira is a TNF alpha inhibitor normally used to treat auto-immune conditions like rheumatoid arthritis, Cohn's disease, ulcerative colitis, psoriasis and juvenile arthritis.

I was recently contacted by an Aspie lady with auto-immune conditions, who found Humira not only controlled those conditions but moderated her autism symptoms, notably sound sensitivity.  One injection produced a benefit that lasted 7 weeks.

Kanner’s subject #1 went on to develop juvenile arthritis and this made his autism much worse.  There was no Humira back in his day, but his arthritis did respond to treatment.

Apparently, many children with autism and GI problems are taking Humira. 

IVIG seems to be the “go-to” therapy for immunomodulation in autism.  It is now quite commonly used in the US, but much less so elsewhere due to the cost.

I wonder if Humira might be an alternative for some?

 

HMB (β-hydroxy-β-methylbutyrate)

Our reader Natasa did mention the sports supplement HMB to me.

It has many interesting modes of action and it is a precursor to the ketone BHB, which has been covered in great depth in this blog.

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

In Europe ketone supplements like BHB fell foul of the rules on supplements and have been banned. In the US they are widely sold.

If you want to try BHB, by cannot buy it in Europe, you might want to look into HMB (β-hydroxy-β-methylbutyrate).

 

Cetirizine for Palilalia/Scripting 

I am a big fan of the OTC antihistamine Cetirizine/Zyrtec and I was interested to read the recent comment below about its effect on one 12-year-old boy.

“I realize this is 5 years old, but as a result of this blog, I tested cetirizine on my 12 yo yesterday. He has a nonstop palilalia (obsessive speaking that is nonsense or only makes sense to him). It's his "chief feature" and inhibits social development. For 4 glorious hours, it went away. Today, I gave him 5 mg of Zyrtec again. Yet again, the palilalia went away, AND he had strong focus on school (he has serious attention issues).”

 

Many people’s autism gets worse when auto-immune conditions flare up.  In some cases, the auto-immune condition is very mild, but the consequences are not.  For one person the result is aggressive behavior, while in another it is talking nonsense.

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. 

Metabolism of Exogenous D-Beta-Hydroxybutyrate, an Energy Substrate Avidly Consumed by the Heart and Kidney

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, 11–14). 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, CMR_AcAc and K_AcAc 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 CMR_AcAc and K_AcAc 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 C_max 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 C_max 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 T_max 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. 

Autism Polypill Version 5

Agnieszka's KetoForce and C8 are new additions, last time it was Tyler's Agmatine as additions to the Full Polypill

I recently updated my autism Polypill. It is now the fifth version, so it is becoming ever more personalized to one specific case of autism.  I added caprylic acid C8 and KetoForce Beta Hydroxybutyrate.

The full Polypill version 5 is here:

   https://epiphanyasd.blogspot.com/p/polypill-for-autism.html

I do feel that I am getting near the final version. I already am pretty sure what is going to be added in the sixth version. There are one or two potentially clever ideas in this blog that I have not yet developed.

After my first year of autism research my doctor mother thought the result was good enough to stop, but I persevered and some further improvement did come. She was supportive of the concept but rather surprised it was possible. I think I have now achieved most of what is possible, which took an additional five years.

Having recently been reviewing the expected prognosis in longitudinal autism studies, including the one up to 22 years of age by Catherine Lord in the US, I think the result speaks for itself. In long term studies the remarkable improvement that rarely does occur, takes place by the age of eight. Verbal skills at the age of two is the best predictor of outcome at 19 years old.  I only started with my Polypill at the age of nine, when we were five years into trying to teach prepositions and maths was at the level of struggling with single digit addition and subtraction. Today at 15 years old, maths is at the same level as neurotypical 13-year-old classmates; so, we can say his maths age is 13.

I did suggest years ago to the French Bumetanide researchers that they measure IQ to show the impact of their therapy.

I think that in severe autism, and also Down Syndrome, huge strides forward are possible just by raising IQ.  We saw from the 15-year French study that the entire lower group, representing 80% of the total, had an IQ far less than 70 when they age out of school. An IQ of 70 is the threshold for MR/ID and affects 2.3% of the population.  Many of those French had IQs less than 40. 

Many parents do not like the term Mental Retardation (MR), so they made a nicer term Intellectual Disability (ID), which to me sounds like you might struggle playing chess, rather than dressing yourself and tying shoelaces.

Much MR/ID clearly is treatable.  That makes what is left of autism much easier to deal with. It makes the impact of any expensive 1:1 therapy much more substantial and therefore cost effective.

Recall we also have 81 other types of MR/ID that have been identified and are treatable.

        http://www.treatable-id.org/

As part of another project, I recently updated an old chart from this blog that shows the change in my autism index over time, including 6 years of the Polypill. I started treatment with Bumetanide on 17 December 2012. That was the sharp drop in the black line, followed rapidly by NAC and Atorvastatin. 

The big spike in the black line is the effect of the summertime allergy “stopping” the cognitive effect of bumetanide and producing the self-injurious behaviour of the same kind as the first big spike in the orange line.

The orange line after December 2012 is my forecast of what would happen, including a spike in bad behaviors likely to be triggered by puberty.

The spike in the black line at 13.5 years was a PANS-like episode that only lasted a couple of weeks, and was immediately treated using prednisone.

Heading towards 16 years old, Monty is still above the blue area, which we could call the “nerd cloud”. This is where you will find all those very mildly autistic, fully verbal people that now receive a medical or educational diagnosis of autism. Back in 1970s, 80s and 90s these were the nerdy kids at your school, who generally got by without any medical diagnosis/label. A small percentage will subsequently have attempted suicide.

On my chart typical development is not zero on the autism scale.

What is “normal” changes, typical kids develop their sense of “cool” group behavior before puberty and this continue until they become parents or just busy and fully employed. Then cool gradually fades and by 30 years old a socially awkward Aspie type really is not so different from a Dad who is juggling his job, commuting and his family obligations. There is no time to be cool.

I think around 18 is the peak difference between an NT young person and an Aspie.  Once the Aspie gets to College/University and meets more fellow Aspies life should get much better.  Find a job in a University or NASA and you will do just fine.

My therapy goal is just to keep heading towards zero on my scale. Entering the nerd cloud would be a great success; all that effort to reach the point many people with today's "autism" start from!

The IQ difference is already overcome. If you can do algebra, your IQ is way above 70.

Optimizing adaptive behaviour is the remaining goal. As the French longitudinal study and Catherine Lord from Cornell University highlighted in their studies, being fully verbal is a big part of enhancing adaptive behavior.  If you can be chatty, many aspects of life and functioning automatically get much easier.

So, in Monty’s case the emphasis has to be on expressive verbal communication, which is his weak point.

Fortunately, the additions in version 5 of the Polypill (Caprylic acid C8 and KetoForce BHB) and the expected additions in Version 6 will target this area. 

I did also write about critical periods and sensitive periods in the treatment of autism. It is clear that while it is never too late to start therapy, the sooner you start the bigger the effect will be. This is another reason why I doubt I will ever get to Version 10 - the clock is ticking.

Time is indeed a great healer, so even just Version 5 for another five years should continue to help Monty close the gap with typical people.

At another visit to the dentist last week when Monty had anaesthetic in his rear lower jaw, which apparently is the most difficult for a dentist treating a person with autism, the dentist was visibly relieved “it was exactly as you said it would be … he was better than my typical patients”.  That is the result of Polypills version 1 to 4 from 2012 to 2119; it is not down to parenting as the dentist believes. We did practise with a syringe and a drill at home, but it really was not needed. Monty understands why the process is necessary and what the steps involved are and so he is happy to sit back and open wide. Ten years ago this was not the case.

According to Catherine Lord at Cornell, based on her longitudinal studies from diagnosis up to adulthood, verbal skills at the age of 2 are the best predictor of outcome at 19 years old. Monty's verbal skills at the age of 2 were zero.

Unfortunately over 60% of the children she followed from 2 years old end up with a very poor outcome in adulthood - severe MR/ID, the adaptive skills of a four year old  and drugged up on psychotropic meds.  As in the 15 year long French longitudinal study of autism we looked at, the measured IQ falls over time. Anyone still think severe autism should not be treated? Perhaps they need their heads examining?

The optimal group of 10% do well, with an IQ shooting up to 111 (average IQ for typical people is 100) and OK with an adaptive functional age of 101 months (8.5 years old). Of them, 63% had a job and the great majority were not on psychotropic meds.  

It appears that in Lovaas' flawed ABA research he selected the kids that completed his trial from this Optimal 10% group. So yes, 50% did great, but they were already on track to do pretty well.  We learned from Dr Siegel that he weeded out the less able kids who did not respond to his therapy during the trial itself. You might think that all his research should now be rescinded.

LA ASD = less able ASD  (62% of the group) have IQ less than 70<70 div="">

MA ASD = more able ASD (38% of the group) with a subset called Optimal = the top 10%

Source: Catherine Lord's Presentation at UC Davis

https://www.youtube.com/watch?v=C-XczxdYM4E&t=14m36s

I always wondered why American Psychiatrists decided to keep relaxing the boundaries of autism. There was no rational reason to do it, because it makes all the data incompatible and so comparisons meaningless. One good reason would be to hide the appalling outcomes of severe autism (DSM3 autism, Strictly Defined Autism etc), by adding more and more much milder autism the overall outcome looks quite acceptable.

Dr Lord is a psychologist and she comments in her presentation that today the prognosis results would look much better, as if that is a good thing. Being of logical engineer origin, I would counter that this is a nonsense. The results today would be exactly the same for those kind of kids; just that a sample in 2019 of 200 kids with newly diagnosed autism would include 100 who would not have been given a diagnosis 25 years ago when Dr Lord started her study. Nobody would have even sent those fully verbal quirky two year olds for evaluation.

For the final word on prognosis, we might recall from this earlier post

          Autism Biology, Comorbidity, Mortality and Better use of Existing Research 

that 

"Autistic adults with a learning disability were found to die more than 30 years before non-autistic people."

Time to customize your personalized medical therapy for autism?  If your child was fully verbal at two years old, then you might not need to bother.

Conclusion

My conclusion is that after 480 posts, this blog is now giving a fairly complete picture of autism. The features provided by Blogger/Google make it hard to navigate this blog and the very useful index by label is no longer available. Only a few people have read the entire blog.

It could be reorganized as follows.

• Prevalence of the many Autisms
• Prognosis
• Evidence from clinical trials and case studies that shows improvement is genuinely possible and so it is worth your while to commit serious time to the process
• Lots of science blah blah 
• Precision medicine leading to a personalized therapy 

Unfortunately the science blah blah does get very detailed and does lose many people.  Biology is not complicated like math, there is just an awful lot of it and it remains only partially understood, so it changes.  Most people can follow the science, if they are willing to spend enough time, but you need to know that genuine improvement is indeed possible.  Some people are lucky and find their type of autism is similar to someone else's who has already found an effective therapy.

At some point I will get someone to write the java script to make a better index to the blog, so at least I can find things. 

Hopefully Version 6 of the Polpill will include two steps forward.

Who lives in Libya? And Raising the level of BHB in your blood.

Today’s post is mainly about some “home-research” that was sent to me by a company that sold me C8 oil (caprylic acid MCT oil).

It is not peer-reviewed research, but it is a well thought out home experiment measuring the level of the ketone BHB in the blood of two healthy young adults testing a range of commercially available products. It is important to note that BHB was measured in blood and not urine, which is a big plus for the experiment.

Dr D’Agostino’s starting dose

First, a recap of where we started a few months ago in this blog.

One of the leading ketone researchers is Dr D’Agostino and his suggested starting dose on ketone supplements is 10 ml of Ketoforce and 10ml of C8/caprylic acid.

We saw in earlier posts that the amount of BHB produced by taking C8 is highly dependent on whether it is taken with food. Taken on an empty stomach resulted in more BHB in the bloodstream.

10 ml of KetoForce contains 4g of BHB along with 500mg of sodium and 500mg of potassium.

BHB salts and BHB esters

Until recently BHB supplements were all salts, so the BHB was combined with sodium, potassium, calcium or magnesium.

Taking large amounts of sodium, calcium, potassium or magnesium will likely disturb the electrolytes in your body and may cause you problems.

Ketone esters are composed of a ketone molecule like BHB bound to a ketone precursor using an ester bond (butanediol or glycerol).

Ketone esters are commercially available, but very expensive.  They are currently used by athletes and the US military.

The first commercial product was developed based on the work of researchers at Oxford University in the UK, but the resulting product cannot legally be sold in the UK. HVMN, a company in the US, are currently selling it as a supplement for athletes. I wonder if it has been declared a banned substance by sports doping agencies.

Some of the research:-

Novel ketone diet enhances physical and cognitive performance.

Ketone bodies are the most energy-efficient fuel and yield more ATP per mole of substrate than pyruvate and increase the free energy released from ATP hydrolysis. Elevation of circulating ketones via high-fat, low-carbohydrate diets has been used for the treatment of drug-refractory epilepsy and for neurodegenerative diseases, such as Parkinson’s disease. Ketones may also be beneficial for muscle and brain in times of stress, such as endurance exercise. The challenge has been to raise circulating ketone levels by using a palatable diet without altering lipid levels. We found that blood ketone levels can be increased and cholesterol and triglycerides decreased by feeding rats a novel ketone ester diet: chow that is supplemented with (R)-3-hydroxybutyl (R)-3-hydroxybutyrate as 30% of calories. For 5 d, rats on the ketone diet ran 32% further on a treadmill than did control rats that ate an isocaloric diet that was supplemented with either corn starch or palm oil (P < 0.05). Ketone-fed rats completed an 8-arm radial maze test 38% faster than did those on the other diets, making more correct decisions before making a mistake (P < 0.05). Isolated, perfused hearts from rats that were fed the ketone diet had greater free energy available from ATP hydrolysis during increased work than did hearts from rats on the other diets as shown by using [³¹P]-NMR spectroscopy. The novel ketone diet, therefore, improved physical performance and cognitive function in rats, and its energy-sparing properties suggest that it may help to treat a range of human conditions with metabolic abnormalities.

https://hvmn.com/blog/exogenous-ketones/beta-hydroxybutyrate-or-bhb-all-you-need-to-know#Murray2016

The Military as Early Adopters

For centuries military forces have sought to gain a competitive advantage using drugs, so it is not surprising that the current US military are interested in ways to increase physical endurance.

Survival rations for downed airmen, or just reducing the weight of food rations for Special Forces, would be obvious applications for BHB esters.

In modern times it was the Germans who made the greatest military use of drugs with their Pervitin tablets that enabled their soldiers and airmen to fight for days without sleep. Pervitin turned out to be Methamphetamine. Such drugs are used today by irregular forces.

Extensive use was made of drugs to counter altitude sickness in Afghanistan, first by the Russians and later by the Americans. Diamox/Acetazolamide is the Western drug and this same drug has application in some channelopathies and some types of autism.

Drugs that improve exercise endurance, and so are likely banned for use in sport, are potentially interesting for people with mitochondrial disease, vascular abnormalities and even glucose transporter dysfunctions. In short if you have restricted ATP production in your brain, anything that can overcome whatever the route problem is, should improve brain function. Alzheimer’s disease is a good example where apparently quite different reasons result in reduced power output within the brain. 

I thought it was encouraging to see that military funding is being used to develop medical therapies for PTSD and suicide prevention. The latter was the application for the hormone TRH, which I suggested as a possible autism treatment, since it affects a chain reaction of important hormones affecting mood.

The n=2 home trials of BHB-raising supplements

You can read the full report by clicking the link below

https://ketosource.co/keto-experiment-exogenous-ketones/?utm_source=drip&utm_medium=email&utm_campaign=Keto+Update%3A+Results+from%C2%A0Ketone+Supplement+Experiments+AND+Metabolic+Health+Summit+Interviews#disqus_thread

I have extracted some interesting highlights.

·      HVMN and KE4 are very expensive ketone esters (red and green lines)

·      C8 MCT oil is the product that I currently use (20ml a day) (purple line)

·      Keto Max and KETOCANA are ketone salts (blue and orange lines)

 Recall an earlier graphic of "the ketone zone" so you can put BHB levels into context.

Summary: The Takeaways

·       We confirmed that ketone supplements increase ketones: All of the ketone supplements tested resulted in an increase in ketones for a temporary time period.

·       Rapid 3-Hour Windows: Ketone esters and ketone salts rapidly increase ketones within 30 minutes. The effects last for a ~3 hour period.

·       Slow 5-Hour Window: C8 MCT oil increases ketones more slowly. However, the ketone increase lasts for a more prolonged period of ~5 hours (see C8 MCT Oil research review covering this).

·       What Does this Say About When to Use Which Supplement? This is a complex question that requires further investigation into the different applications. However, we have three hypotheses to start with based on these results.

1.     For higher ketone boosting needs: If you are looking to boost ketones into the therapeutic range of 2-4mmol, it is more cost effective to take KetoCaNa (Ketone Salts). But a more gut tolerable option would be a Ketone Ester – at a greater price. Both are able to boost ketones enough to meet this target.

2.     For lower ketone boosting needs: If you are looking for less than a 1 mmol boost in ketones, the most cost effective and convenient (longer duration) approach is via C8 MCT oil. This may be most relevant to A) People not on ketogenic diets who want some of the ‘satiation benefits’ of ketosis, and B) People on ketogenic diets who already have raised ketones and only want a small additional boost (e.g. you’re at 1 or 2 mmol, and want to increase to 2 or 3 mmol respectively).

3.     For the highest ketone boosting needs: Should you want a greater increase in ketones for any reason Ketone Esters are the best option (this article explores where and why this may be interesting)

My conclusions

The effect of C8 is slightly different to Ketone salts like Ketoforce and I think D’Agostino’s advice to combine them is wise.

A dose of 20ml of C8 appears a good upper limit, since its effect at producing BHB gradually fades. Better to make sure it is taken without food to maximize the effect. Even though it is the cheapest supplement there appears to be no point taking larger doses like 50ml.
Ketone salts are definitely limited by their composition of sodium, potassium, calcium or magnesium. I think high doses are extremely unwise. D’Agostino’s 10 ml of Ketoforce seems safe.

Ketone esters are very expensive, but do actually provide a genuine energy-boosting level of BHB, which will also trigger all the other suggested effects of BHB (summarized in the old post below), quite possible at increased levels.

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

So I suppose the ideal autism research study would be to use KetoneAid KE4 or the HVMN BHB Ester, as used by the US military.

I expect the BHB Ester would have a big effect on someone with Alzheimer’s disease. They have a problem with the glucose transporter at the blood brain barrier and with reduced insulin sensitivity. The large amount of BHB from the ester supplement would provide an alternative fuel for the mitochondria, which are not producing enough ATP from glucose to power the brain.

We saw that Nestle is investing in MCT as a nutraceutical for Alzheimer’s. Today’s home research suggests that high doses of MCT are not going to be effective at raising BHB levels in the blood to a very significant level. BHB esters look much more promising.

This would be an expensive Alzheimer’s therapy, but still much cheaper than relocating to a care home. 

I did check and there actually is a case history; it is a physician wife treating her own husband who has early onset Alzheimer's. She read the research and translated it into a novel therapy for him. Nice work! This would of course be frowned upon in most countries as treating hubby like a guinea pig and doctors are not meant to treat family members, but to me it looks like the most caring thing she could do.  The good thing is that she published the result. Mainstream doctors treating their own children with autism, or even sometimes others, rarely seek to publish/share their results, so helping to maintain the convenient false perception that all autism treatments are just quackery (some are, while some clearly are not).

A new way to produce hyperketonemia: use of ketone ester in a case of Alzheimer’s

• After six to eight weeks of taking 28.7g of the KME thrice daily, he began to exhibit improvement in memory retrieval, spontaneously discussing events that occurred up to a week earlier. He was again able to perform more complex tasks, such as vacuuming, washing dishes by hand, and yard work.

• Plasma βHB levels were measured occasionally to assess KME-plasma βHB dose-response relationships (Fig. 2). Noticeable improvements in performance (conversation, interaction) were observed at higher, post-dose βHB levels, compared to pre-dose values.

• In treatment of TP’s long-standing AD dementia, KME-produced repeated diurnal elevations of circulating βHB levels were clearly effective, during the 20-month study, in improving behavior, and cognitive and daily-activity performance. The physician-caregiver noted that performance seemed to track plasma ketone concentrations, with conversation and interaction declining as levels fell toward baseline. From requiring almost constant supervision, TP became much more self-sufficient on KME

The question in autism is what level of BHB do you need to maximize the effect and how long does this spike in blood BHB produce its beneficial effect. Do you need a constant level for 24 hours (I think not)? Do you need one BHB elevation/spike a day? Does a second daily dose have any benefit?
The BHB ester would be a good research tool, since it should not disturb electrolyte levels.

Who does live in Libya?

Anecdotal evidence has always got to be taken with a large pinch of salt, but if all you are doing is an N=1 trial that is often all you have got.

From more than half a year of experimenting with the combination BHB salts and C8 oil, the effect is clear. It causes an increase in relevant speech, directly related to current activities. You could call this unprompted commenting.

Monty will now answer the phone at home, rather than just hanging up to stop the annoying ringing noise, or having an ultra-trivial conversation. He will have a functional conversation in either of his two languages. This was particularly noted by his Grandmother as an improvement.

The good thing is the increased conversation fades when BHB/C8 is paused and returns when re-started.

Along the way we have discovered that not all BHB salts are equal. The Ketoforce liquid is the best, because it has most effect and does not disturb electrolytes, as Primaforce BHB powder appeared to, not by much, but enough to have an impact.

Using a mixture of C8 + C10 oil, produced a negative effect (aggression) after a few weeks. So while C10 may have a unique effect on mitochondria, beneficial to some, it was not tolerated.

10ml of Ketoforce and 20ml of C8 a day means one bottle of Ketoforce and one litre of C8 lasts 50 days.

The beneficial effect is not on the magnitude of bumetanide. The Ketoforce/C8 therapy costs 15 times more than bumetanide, but I think that really just means that generic bumetanide is extremely cheap.

Adding the small 0.5mg dose of Clemastine in the evening does seem to have an incremental effect after a few weeks.

It does appear to manifest itself again in improved speech. Now the comments are not related to current activities, but also past events and making connections.

“Colin has a moustache, like Poirot”

Colin is a friend of mine who Monty last saw a few months ago. He does have a moustache and so does Hercule Poirot.

The strangest recent “conversation” started with:-

“Who lives in Libya?  …  Do Indians live in Libya?” asked Monty

“No, Indians do not live in Libya, Arabs live in Libya”, I replied.

“Indians live in London” he countered

            “Yes, some Indians do live in London, but a lot more live in India”

“Who lives in Israel?” he asked    (We did recently visit Jerusalem)

            “Jewish people and Arabs live in Israel”, I replied

            “Who lives in France?” I asked

“Leopoldine” (a former classmate from school) he answered

            “Who lives in Italy?” and so it continued.

This is not the sort of “conversation” you normally have with Monty. This was the longest ever "conversation".

You would not expect him to recall that London has a large population of Asian descent. He lives far away.

Is this the cumulative effect of BHB/C8, or an emerging benefit of a quarter dose of an OTC hay fever drug?

Clemastine, taken in the evening, has had no negative side effects and is not expensive. $10 buys 60 pills that will last 4 months. Daniel Kerlinsky, the enlightened US psychiatrist we encountered in a post a while back, was keen to point out that it takes months for low dose Clemastine to show its effect (myelin, microglia or both).

In our case BHB/C8 looks like it is heading towards being included in the PolyPill. The only side effect is feeling thirsty, which is manageable. I am surprised to be considering adding what is a Californian diet therapy to my son’s autism therapy. Incidentally he has not lost any weight, he continues to gain it.

The jury is still out on Clemastine. Due to the onset of its potential benefit being very slow, it is not so easy to make a withdrawal trial (stopping a therapy, seeing if the believed effect is lost and then restarting to see if that effect returns). I will wait to see the feedback of other readers of this blog.