UA-45667900-1
Showing posts with label Caprylic acid. Show all posts
Showing posts with label Caprylic acid. Show all posts

Thursday, 11 April 2019

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:


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.


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

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

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.



Thursday, 28 February 2019

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:-

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.






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


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.


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).
  • 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.




Tuesday, 8 January 2019

BHB + C8 in Autism, a Work-in-Progress



The potential benefit of the ketone BHB in autism was covered extensively in earlier posts.  It looks like different people may benefit for entirely different reasons and some may not benefit at all. 

Some MCT oils, taken as precursors to BHB, can actually make people worse.


Measuring ketones and glucose in blood


Click for a summary of the previous posts.

I know that some readers of this blog have found that BHB/C8 does indeed provide a benefit in their specific type of autism.  The benefit seems to vary, but given all the biological modes of action of the ketone BHB that is not surprising.  Increased speech is a frequently noted benefit.
My initial combination of Ketoforce plus C8 continues to be effective.
Substituting a cheaper MCT oil containing both C8 and C10 (Bulletproof XCT oil), was less effective and after a matter of weeks produced a negative effect. It appears that C10, after a while, can produce mild anxiety and agitation in some people. In our case this goes away when stopping the C8+C10 MCT oil and then reappears restarting it.
When it comes to C8, it appears that not all food grade 98% C8 products are actually what they claim to be. This is a recurring theme with all supplements, they lack the quality control you get with pharmaceuticals.
Our reader Yi did at one point raise the issue of BHB causing diuresis. We also experienced this and much more so with the “mixed” C8+C10 MCT oil, rather than the “pure” C8.
The combination of increased diuresis and all the sodium, magnesium, potassium in the BHB salts may very well create an issue with electrolyte levels. Potassium does seem to be the most critical one to monitor.
Different BHB products contain very different amounts of sodium, magnesium, potassium and so it is unwise to simply substitute one for another.
Our reader Agnieszka did experiment with different BHB products and found that, based on urine testing, Ketoforce was the most effective. I also think this is likely the best choice.  Ideally you would measure BHB in blood and devices are available (see above photo).
For people living in Europe, BHB products have fallen foul of EU legislation that requires new supplements to be approved before they can be sold in the European Union. As BHB is a recently introduced supplement, it cannot legally be sold in the EU until someone pays for it to be approved. This means that in EU countries that strictly apply the rules, like the UK, you cannot buy BHB, but in other EU countries you still can.
The same legal status regarding BHB in the EU also applies to Agmatine.
Another oddity is that Melatonin is banned as a supplement in the UK, but not other EU countries; it is a very popular supplement in North America.




Wednesday, 3 October 2018

Ketones and Autism Part 6 - Capric Acid (C10) for Mitochondrial Disease, in Particular Complex 1, plus more on Metformin



Capric Acid (C10) is so named because it smells like a goat (Goat in Latin = Caper)
Photographer: Armin Kübelbeck, CC-BY-SA, Wikimedia Commons

Rather than Goaty acid, C10 is called Capric acid, or indeed Decanoic acid (after its 10 carbon atoms). Today’s post is indirectly again about ketones, because if you eat a Ketogenic Diet (KD) you are likely to consume a fair amount of Capric acid (C10).
I have written a lot in this blog about mitochondria, even though I do not think my son has mitochondrial dysfunction. Clearly many people with autism do have a lack of one or more of the critical mitochondrial enzyme complexes that allow glucose to be converted to ATP (usable energy), by the clever process OXPHOS (Oxidative phosphorylation).

The “rate limiting” enzyme is usually Complex 1, meaning that is the one it is most important not to be short of.
Another favourite, but obscure, subject of this blog is PPAR gamma.

Peroxisome proliferator-activated receptors (PPARs) are a group of proteins that function as transcription factors regulating the expression of certain genes. Transcription factors are particularly important because they trigger numerous effects.
PPAR gamma plays a key role in fat storage and glucose metabolism, but has other functions. 

Activation of PPAR-gamma by Capric acid (C10) has been shown to increase the number of mitochondria, increase the mitochondrial enzyme citrate synthase, increase complex I activity in mitochondria, and increase activity of the antioxidant enzyme catalase. 
So, if you have autism and impaired mitochondrial function, C10 may well give a benefit because it can increase the peak power available to your brain.


The Ketogenic diet (KD) is an effective treatment with regards to treating pharmaco-resistant epilepsy. However, there are difficulties around compliance and tolerability. Consequently, there is a need for refined/simpler formulations that could replicate the efficacy of the KD. One of the proposed hypotheses is that the KD increases cellular mitochondrial content which results in elevation of the seizure threshold. Here, we have focussed on the medium-chain triglyceride form of the diet and the observation that plasma octanoic acid (C8) and decanoic acid (C10) levels are elevated in patients on the medium-chain triglyceride KD. Using a neuronal cell line (SH-SY5Y), we demonstrated that 250-μM C10, but not C8, caused, over a 6-day period, a marked increase in the mitochondrial enzyme, citrate synthase along with complex I activity and catalase activity. Increased mitochondrial number was also indicated by electron microscopy. C10 is a reported peroxisome proliferator activator receptor γ agonist, and the use of a peroxisome proliferator activator receptor γ antagonist was shown to prevent the C10-mediated increase in mitochondrial content and catalase. C10 may mimic the mitochondrial proliferation associated with the KD and raises the possibility that formulations based on this fatty acid could replace a more complex diet. We propose that decanoic acid (C10) results in increased mitochondrial number. Our data suggest that this may occur via the activation of the PPARγ receptor and its target genes involved in mitochondrial biogenesis. This finding could be of significant benefit to epilepsy patients who are currently on a strict ketogenic diet. Evidence that C10 on its own can modulate mitochondrial number raises the possibility that a simplified and less stringent C10-based diet could be developed.

Capric Acid (C10) as a PPARγ agonist

As shown in the above study the mechanism by which C10 benefits the mitochondria is via PPARγ agonism.

Here is another study confirming that C10 is indeed a PPARγ agonist.


Background: Mechanism of action of medium chain fatty acid remains unknown.

Results: Our results show that decanoic acid (C10) binds and activates PPARγ.

Conclusion: Decanoic acid acts as a modulator of PPARγ and reduces blood glucose levels with no weight gain.

Significance: This study could lead to design of better type 2 diabetes drugs.


Other PPARγ agonists
PPARγ agonists have been covered previously in this blog and we know that glitazones, a class of drugs for diabetes, do improve some types of autism. Glitazones are PPARγ agonists.

Metformin, a very widely used drug for type 2 diabetes, works differently to Glitazones, but I did suggest a while back it should help some types of autism. Last year it was indeed found to be beneficial in Fragile X.


 "Basically, it's something like a wonder drug," Sonenberg said.
The study suggests that metformin might also be used to treat other autism spectrum disorders, said Ilse Gantois, a research associate in Sonenberg's lab at McGill.
"We mostly looked at the autistic form of behaviour in the Fragile X mouse model," explained Gantois, who is co-lead author with McGill researchers Arkady Khoutorsky and Jelena Popic. "We want to start testing other mouse models to see if the drug could also have benefits for other types of autism."

Metformin is very cheap and has been used in humans for 60 years. It is another example of re-purposing a drug from Grandpa’s medicine cabinet to treat Grandson’s autism. 

Metformin has been trialled to combat obesity in idiopathic autism caused by antipsychotics. It did help with weight gain, but no comments were made about behavioural improvements, but then those studied were on antipsychotic drugs, which might mask such effects. 
Glitazone-type drugs appear more problematic than Metformin.

There are natural PPAR gamma agonists and they are often used to lower cholesterol, lower blood sugar and improve insulin sensitivity.
Sytrinol, a product containing flavanols tangeretin and nobiletin does indeed have a positive effect on some people’s autism, but for most people (but not all) the effect is lost after a few days.

Our doctor reader Maja, did suggest combining it with a PPARα agonist to see if the effect might be maintained.
This combination has indeed been researched for type 2 diabetes.               

The effect of dual PPAR alpha/gamma stimulation with combination of rosiglitazone and fenofibrate on metabolic parameters in type 2 diabetic patients.


There actually is another natural substance that is an agonist of both PPARγ and PPARα, Berberine, the alkaloid long used in Chinese medicine.
In the research it is suggested that BRB localizes in mitochondria, inhibits respiratory electron chain and activates AMPK”, which is not what you would want. But this may not be correct.

People who like supplements might want to follow up on Berberine.
Berberine is used by many people with diabetes and a few with autism, for all kinds of reasons, from mercury to GI problems.

Berberine is a potent agonist of peroxisome proliferator activated receptor alpha.


Although berberine has hypolipidemic effects with a high affinity to nuclear proteins, the underlying molecular mechanism for this effect remains unclear. Here, we determine whether berberine is an agonist of peroxisome proliferator-activated receptor alpha (PPARalpha), with a lipid-lowering effect. The cell-based reporter gene analysis showed that berberine selectively activates PPARalpha (EC50 =0.58 mM, Emax =102.4). The radioligand binding assay shows that berberine binds directly to the ligand-binding domain of PPARalpha (Ki=0.73 mM) with similar affinity to fenofibrate. The mRNA and protein levels of CPT-Ialpha gene from HepG2 cells and hyperlipidemic rat liver are remarkably up-regulated by berberine, and this effect can be blocked by MK886, a non-competitive antagonist of PPARalpha. A comparison assay in which berberine and fenofibrate were used to treat hyperlipidaemic rats for three months shows that these drugs produce similar lipid-lowering effects, except that berberine increases high-density lipoprotein cholesterol more effectively than fenofibrate. These findings provide the first evidence that berberine is a potent agonist of PPARalpha and seems to be superior to fenofibrate for treating hyperlipidemia.


                                                                                                                                     

Sources of Capric Acid (C10)
Goat milk is a good source of capric acid.
Capric acid is 8-10% of coconut oil and 4% of palm kernel oil

Capric acid is a large component (about 40%) of the less expensive MCT oil supplements.


1.2. Fatty acid composition in goat milk fat Average goat milk fat differs in contents of its fatty acids significantly from average cow milk fat, being much higher in butyric (C4:0), caproic (C6:0), caprylic (C8:0), capric (C10:0), lauric (C12:0), myristic (C14:0), palmitic (C16:0), linoleic (C18:2), but lower in stearic (C18:0), and oleic acid (C18:1) (Table 1). Three of the medium chain fatty acids (caproic, caprylic, and capric) have actually been named after goats, due to their predominance in goat milk. They contribute to 15% of the total fatty acid content in goat milk in comparison to 5% in cow milk (Haenlein, 1993). The presence of relatively high levels of medium chain fatty acids (C6:0 to C10:0) in goat milk fat could be responsible for its inferior flavour (Skjevdal, 1979). 

             
Conclusion
If someone responds well to coconut oil or cheaper MCT oil the reason may have more to do with PPAR gamma and improved mitochondrial function than anything to do with ketones and what they do.
Cheaper MCT oils are mainly a mixture of C8 and C10. To maximize the production of the ketone BHB you really want just C8, but if what you really need is a PPAR gamma agonist, to perk up your mitochondria, it is the C10 you need.
You may indeed benefit from both ketones and agonizing PPAR gamma, in which case you either follow the Ketogenic Diet, or supplement BHB, C8 and C10.
I think this explains why some people with autism reportedly respond well to teaspoon-sized doses of cheaper MCT oil or small amounts of coconut oil.
If you have Complex 1 mitochondrial dysfunction then a dose of Capric acid (C10) is likely to help.
Berberine may, or may not be, as effective as C10. I doubt we will ever know. I think C10 is the better option. 
I wonder when the Canadian researchers will publish their results showing whether Metformin is beneficial beyond Fragile X syndrome. They do not really know why it helps, but that is a repeating theme in medicine.  It is a cheap safe drug, so it would be a pity to waste time finding out if it could be repurposed for some autism.