Showing posts with label PPARγ. Show all posts
Showing posts with label PPARγ. Show all posts

Monday, 16 August 2021

Pioglitazone for Autism and Specifically Summertime Raging and Verapamil-responsive Autism?


Adult-sized people with autism can cause property damage and much worse.

I am told that summertime raging is a common problem encountered by neurologists, but it remains poorly understood and usually remains untreated.

The most common worry for parents of toddlers diagnosed with severe autism is their lack of speech.

By the time these children reach adulthood, the biggest worry for parents is often aggression and self-injury. Often it is the mother who faces the worst episodes of aggression, which is a really cruel turn of events.

Aggression is usually not present in young children with autism, in some people it never develops, but in others it later becomes established as a learned behavior and then you are stuck with how to deal with it.

One of my own therapy targets has long been to improve cognitive function; this can indeed be achieved and then you can improve important daily living skills (adaptive function). Some steps that you can take to improve cognition, and indeed speech, have a downside in that they increase anxiety, which may lead to aggression. Calcium Folinate (Leucovorin) does cause aggression in a significant minority of people.  I think that low dose Roflumilast (60mcg) is cognitive enhancing, as proposed by the researchers at 100mcg, but it does seem to increase edginess/anxiety. DMF (Dimethyl fumarate) increases alertness, which is a good thing, but too much alertness will make you anxious.

When dealing with a full sized adult, which is more important, increased cognition/speech or avoiding explosive aggression?

Clearly there is a need for a compromise.

In adults with severe autism, living at home, entirely extinguishing aggressive behavior looks like the number one treatment goal.

For children in mainstream school, following the regular curriculum, cognitive function has to be a top priority.  Fortunately, this is our case, but only after starting Bumetanide therapy in 2012.

It looks like you can potentially have the best of both worlds - increased IQ and adaptive function, but without aggressive behavior. That is my own experience, but it was not simple.

Pioglitazone has been covered quite extensively in this blog and it is again featuring in the research. Pioglitazone is an interesting old drug used to treat people with type 2 diabetes; the phase 2 trial for autism has been completed.  I doubt there will be a phase 3 trial due to the high costs. Pioglitazone is broadly anti-inflammatory; it reduces the pro-inflammatory cytokine IL-6 and increases the anti-inflammatory cytokine IL-10.

We have seen in early posts how important is IL-6 and that it plays a key role in both allergy and even how milk teeth roots “dissolve” and then permanent teeth erupt. This transition to permanent teeth is another common cause of raging in autism, in our case it was mostly wintertime raging. 

IL-6, either directly or indirectly, seems to negatively affect behavior.


PPAR gamma

In earlier posts there was a lot about the various PPARs. These are used in medicine as targets to treat conditions like high cholesterol and type 2 diabetes.

Resveratrol and Pterostilbene are the OTC supplements that some readers are using. Sytrinol is another such supplement, but its cognitive benefit unfortunately just lasts a few days.

Here is a relatively recent paper on the subject, for those seeking the details. 


Nuclear Peroxisome Proliferator-Activated Receptors (PPARs) as Therapeutic Targets of Resveratrol for Autism Spectrum Disorder


Or just look up the old posts in this blog:-

PPARs are rather complicated, but do seem to be very relevant.  For example, the master regulator of mitochondrial biogenesis, something called PGC-1 alpha, is activated by PPAR gamma. If you have mitochondrial dysfunction that included a reduced number of mitochondria, you might want to make more mitochondria. A PPAR gamma agonist might be beneficial.

Dysregulation of PGC-1 alpha is associated with neurodegenerative and metabolic disorders including Parkinson's, Alzheimer's and Huntington's.

Outside this blog, there is some interest in PGC-1 alpha and autism, particularly in connection with oxidative stress and mitochondrial dysfunction.


“In conclusion, we demonstrated mitochondrial oxidative stress may affect a significant subgroup of ASD children and that the SIRT1/PGC-1α signaling pathway may be a promising medical treatment for ASD.”

Source: Role of SIRT1/PGC-1α in mitochondrial oxidative stress in autistic spectrum disorder

It does look like PPARs can be targeted and provide a benefit for at least some types of autism. My choice is Pioglitazone.


Dumber in the Summer

In parallel with summertime raging comes the phenomenon I called “Dumber in the Summer”, where cognitive function regresses.

Monty’s assistant told me recently there is no “Dumber in the Summer” this year, and I opened my medicine cupboard and explained why this is indeed the case.

At least in our case, when you resolve summertime raging, you also protect against cognitive regression. That therapy involves Verapamil, Pioglitazone and allergy therapies, Dymista spray (azelastine + fluticasone) plus Ceterizine and Clemastine. Clemastine also has the pro-myelination effect and stabilizes microglia.


Pioglitazone Side effects

In the stage 2 trials for autism doses of 0.25 mg/kg, 0.5 mg/kg and 0.75 mg/kg were all found to be safe and well tolerated.

As a summertime add-on therapy it appears very well tolerated.

In adults with type 2 diabetes, who will tend to be overweight and not so healthy, there are common side effects.  At one point, it was thought that there was an association between this drug and bladder cancer. Now this is thought not to be the case.

For adults with severe untreated autism, who are aggressive and self-injure, these behaviors very much limit where they can live and what they can do during the day. Life expectancy is also severely reduced. If Pioglitazone can help control these behaviors, some side effects are likely a price worth paying. 



Pioglitazone, by the standards of autism drugs, has plenty of evidence in the literature, regarding both mouse models and humans, to support an n=1 trial.  It addresses neuro-inflammation, one key feature of autism and it has beneficial effects on mitochondria.

Pioglitazone abolishes autistic-like behaviors via the IL-6 pathway

In a small cohort of autistic children, daily treatment with pioglitazone eased some autistic behaviors, such as irritability, lethargy, stereotypy, and hyperactivity, without significant side effects

 pioglitazone treatment inhibits the secretion of proinflammatory factors, such as nitric oxide and IL-6, and enhances the levels of the secretion of anti-inflammatory factors IL-4 and IL-10. Therefore, considering the results of Qiu and Li and our present findings, pioglitazone acted to benefit autistic-like behaviors possibly via the inhibition of IL-6 secretion in astrocytes stimulated by LPS, which inhibited the neuroinflammatory response.


I think for people whose child with autism has a behavioural or cognitive regression in summer, there is good reason to expect a benefit.  They very likely have allergies or other autoimmune conditions.

For people who deal with aggression and self-injury in a person who responds partially, but not 100%, to Verapamil, they may find that Pioglitazone helps to complete their anti-aggression therapy.

Our doctor reader Agnieszka did her best to collect case studies of people with autism responsive to Verapamil, but not enough parents wanted to participate.

Based on the comments section in this blog, it would look like our reader George in Romania has a son whose son’s aggression is reduced by Verapamil.  If some aggression persists in summer, I think there is a very good chance that Pioglitazone will help reduce it.  George did recently share with us the the anti-inflammatory Probiotic Lactobacillus Plantarum 299v, from the previous post and widely used for irritable bowel syndrome (IBS), improved his son's speech.  

Note that the research clearly shows that most autism has an "inflammatory" element, but the exact nature varies (for details read the work of Paul Ashwood at the MIND Institute).  There are very many different anti-inflammatory therapies that are reported to benefit specific people, but there are no unifying therapies that work for all. Some will inevitably make non-responders worse and potentially dramatically so, like L.reuteri ATCC PTA 6475, found in Biogaia Gastrus. Trial and error seems unavoidable if you want to find an effective therapy.

The research proposes Pioglitazone as a year round therapy for idiopathic autism.  In the phase 2 trial almost half of the children were deemed to be responders to the treatment; not a bad result. I think it also has potential as just a summertime add-on therapy. We used it last summer and now again this summer.

People with a diagnosis of mitochondrial disease, who also present with lethargy, might be another target group because of PGC-1 alpha.

Wednesday, 10 October 2018

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

Open the above file via Google Drive, so it is big enough to read. Click the link below. You can also take links from it to the relevant blog post.

In the mini series of posts on ketones and autism we have come across a long list of effects that will benefit certain groups of people.

1.     Change in gut Bacteria

2.     Ketones as a brain fuel    

3.     Niacin Receptor HCA2/ GPR109A

4.     NAD sparing

5.     CtBP Activation by reducing NADH/NAD+ ratio

6.     NLRP3 Inflammasome inhibition

7.     Class 1 HDAC inhibition

8.     Increase BDNF

9.     Ramification of Microglia

10.PKA activation

11.PPAR gamma activation
It was interesting that the beneficial effect of the Ketogenic Diet in epilepsy is driven by changes the high fat diet makes to the bacteria in your gut and seems to have nothing really to do with ketones. Well it took a hundred years to figure that one out.
In the case of Alzheimer’s, you can see that more than one effect is potentially beneficial. People with Alzheimer’s do have low glucose uptake to the brain, but they also have elevated inflammatory cytokine IL-1B.
In Huntington’s it is the HDAC inhibition effect that seems to be what helps.  This brings us back to HDAC inhibition as a potentially transformative therapy with long lasting effects. It appears that the small number of people who achieve long lasting benefit from short term use of sulforaphane or EGCG may have experienced HDAC inhibition changing the expression of up to 200 genes.  In the case of sulforaphane from broccoli, some people have gut bacteria that produces large amounts of the enzyme myrosinase, which means they convert very much more of the glucoraphanin in broccoli to sulforaphane (an HDAC inhibitor).
It does look like a low dose of a potent HDAC inhibiting cancer drug is what is needed by certain single gene autisms and perhaps some idiopathic autism. This was covered in a dedicated post where we saw the long-lasting benefit of short-term use of Romidepsin. Vorinostat, a very similar drug, but which is taken orally, should be trialled in Shank 3, Pitt Hopkins and Kabuki, to see if the same transformative long-lasting effect can be reproduced.
In Multiple Sclerosis (MS) the effect on Niacin receptor HCA2/GPR109A should help a lot, but so should PKA activation.
In mitochondrial disease it was suggested that increased ketosis will help conserve NAD, which may be deficient. Also, using ketones as an alternative brain fuel may bypass problems that occur when glucose is supposed to be the fuel and thereby boost brain function. The most important effect is likely to be activation of PPAR gamma by C10, which increases the number of mitochondria and boosts the enzyme complex 1.
Many of the people with autism and an overactive immune system stand to benefit from activating CtBP, inhibiting the NLRP3 inflammasome, or activating HCA2/GPR109A.
I think there should be clinical trials using a potent HCA2 activator in autism comorbid with immune over-activation. 
We can see that some people who respond to BHB, experience an immune rebound on cessation, so this helps narrow down the likely beneficial mode of action.  In this immune sub-group, the idea to using other activators of HCA2/GPR109A would seem worthwhile. 

PPAR gamma activation should help those with mitochondrial dysfunction, but this effect is produced only by C10, not BHB or C8. For C10 you eat a ketogenic diet or add it as a supplement (e.g. cheaper MCT oil, or coconut oil).

As recently highlighted by our reader Agnieszka, perhaps the fever effect in autism can be explained by short-term ketosis. Fever is known to sometimes raise the level of ketones, particularly in children (it is called non-diabetic ketosis).  So if your child's autism improves during, or just after fever, test the level of ketones in their urine.


We may have shown the benefits of a high fat ketogenic diet, but there are very many different fats and they do not all produce the same effects.

There are many saturated fatty acids, they are numbered based on how many Carbon atoms they have.

So, C8, known as Caprylic acid has the formula  C8H16O2

Eating C8 looks to be a great way to increase the level of ketones in your blood.

Eating C10 should be good for people with mitochondrial dysfunction and people with diabetes.

Your food contains many other saturated fatty acids and your gut bacteria produce even more.

Common Name Systematic Name Structural Formula Lipid Numbers
Propionic acid Propanoic acid CH3CH2COOH C3:0
Butyric acid Butanoic acid CH3(CH2)2COOH C4:0
Valeric acid Pentanoic acid CH3(CH2)3COOH C5:0
Caproic acid Hexanoic acid CH3(CH2)4COOH C6:0
Enanthic acid Heptanoic acid CH3(CH2)5COOH C7:0
Caprylic acid Octanoic acid CH3(CH2)6COOH C8:0
Pelargonic acid Nonanoic acid CH3(CH2)7COOH C9:0
Capric acid Decanoic acid CH3(CH2)8COOH C10:0
Undecylic acid Undecanoic acid CH3(CH2)9COOH C11:0
Lauric acid Dodecanoic acid CH3(CH2)10COOH C12:0
Tridecylic acid Tridecanoic acid CH3(CH2)11COOH C13:0
Myristic acid Tetradecanoic acid CH3(CH2)12COOH C14:0
Pentadecylic acid Pentadecanoic acid CH3(CH2)13COOH C15:0
Palmitic acid Hexadecanoic acid CH3(CH2)14COOH C16:0
Margaric acid Heptadecanoic acid CH3(CH2)15COOH C17:0
Stearic acid Octadecanoic acid CH3(CH2)16COOH C18:0
Nonadecylic acid Nonadecanoic acid CH3(CH2)17COOH C19:0
Arachidic acid Eicosanoic acid CH3(CH2)18COOH C20:0

C4, familiar as Butyric acid, helps maintain the integrity of the intestinal barrier and the blood brain barrier.  Butyric acid, or butyrate, is also an HDAC inhibitor and it seems that in animal models, and some humans, a small amount can be beneficial but large amounts can have a negative effect. A small amount in humans seems to be about 500 mg a day.  There are earlier posts is this blog on butyrate.

C3, familiar as Propionic acid, is bad for you and too much propionic acid will by itself cause autistic behaviours. NAC counters the effect of propionic acid in mouse models.

All those people eating coconut oil are consuming a 99% mixture of fatty acids with 1% phytosterols.

Phytosterols like β-SitosterolStigmasterolAvenasterol and Campesterol likely explain why coconut oil actually reduces "bad" cholesterol, rather than increasing it, as predicted by the American Heart Association and others. This counters the negative effect of the Palmitic acid (C16).

Lauric acid (C12) is thought to increase HDL ("good") cholesterol and may have a beneficial effect on acne.

Myristic acid (C14) is also thought to increase HDL ("good") cholesterol.

Palmitic acid (C16) raises LDL ("bad") cholesterol and large amounts have other negative effects.

Oleic acid is also found in olive oil and is seen as a fat with beneficial effects.

Fatty acid content of coconut oil
Type of fatty acid pct
Caprylic saturated C8
Decanoic saturated C10
Lauric saturated C12
Myristic saturated C14
Palmitic saturated C16
Oleic monounsaturated C18:1
black: Saturated; grey: Monounsaturated; blue: Polyunsaturated

So the only "bad" part of coconut oil is the Palmitic acid (C16).

As for MCT oil, what is in that?

In pharmaceutical MCT oil, like the one sold by Nestle, the contents are:-

Shorter than C8      1%
C8 (Octanoic)      54%
C10 (Decanoic)   41%
Longer than C10    4%

What is the effect of those fatty acids with more than 10 carbon atoms?  Nobody likely knows.

Cooking with MCT Oil? 

This is what Nestle has in mind for dinner.

Mct Spaghetti With Meat Sauce

4 Tbsp. MCT Oil® (Medium Chain Triglycerides)
1 lb. very lean ground veal or beef
1 tsp. salt
1/2 tsp. pepper
1/4 cup chopped onion
3 Tbsp. chopped green pepper
1 cup MCT Tomato Sauce (see recipe on site)
2 cups cooked spaghetti

Heat MCT Oil; add veal, salt and pepper.
Cook until meat is brown.
Add onion, green pepper, and tomato sauce. Cook for 30 minutes over low heat.
Add cooked spaghetti, stir and serve.