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Showing posts with label Clemastine. Show all posts
Showing posts with label Clemastine. Show all posts

Wednesday, 30 October 2019

More Research to support a Trial of Clemastine in Autism and particularly in Pitt Hopkins




                                                

Clemastine is an old antihistamine drug that we saw in earlier posts can stimulate oligodendrocytes to work harder and produce more myelin.

Myelin is needed to learn new skills and to control your body. It only starts to form in the third trimester, as the brain begins to grow rapidly. Myelination continues after birth but the rate appears to be controlled by social/emotional exposure.  The more isolated the baby is, the less myelin is produced.





                          









Interruption of the myelination process is known to cause long term problems.

Loss of myelin and lack of remyelination underlies Multiple Sclerosis.

It appears that loss of myelin may underlie cognitive loss in regressive autism, childhood disintegrative disorder and adult hypoxia.  First the myelin layer is lost and, depending on the underlying dysfunction, the neuron may die.  If it is just a case of lost myelin this can potentially be repaired.

Girls with Rett syndrome regress and lose previously acquired skills at about 18 months.  Is the loss of skills also a manifestation of a loss of myelin?  If so, can this loss of skills be controlled to minimize its effect?

In a previous post we have looked at the repurposing of Clemastine to improve remyelination.  At high doses this is an emerging therapy for Multiple Sclerosis (MS).  MS is a progressive disease where myelin is repeatedly lost.  Myelin is not permanent and constantly needs to be “remyelinated”.

As Ling has noted, the Pitt Hopkins syndrome researchers have published their results looking at mouse models of both Pitt Hopkins and broader autism and they have found that the same oligodendrocyte genes are indeed dysregulated in all these cases.
We already knew that myelin in idiopathic autism is thinner than it should be, which was why I was originally looking at ways to enhance myelination.

The new research gives further support for remyelination as a target for improving learning, cognitive function and motor skills in autism.  The new data shows that this likely particularly applies to those with Pitt Hopkins syndrome.  This syndrome is caused by a lack of Transcription Factor 4 (TCF4) when one of the two copies of its gene is not functional.  A more modest lack of TC4 is likely to be much more common that Pitt Hopkins itself.



Autism Spectrum Disorder (ASD) is genetically heterogeneous in nature with convergent symptomatology, suggesting dysregulation of common molecular pathways. We analyzed transcriptional changes in the brains of five independent mouse models of Pitt-Hopkins Syndrome (PTHS), a syndromic ASD caused by autosomal dominant mutation in TCF4, and identified considerable overlap in differentially expressed genes (DEGs). Gene and cell-type enrichment analyses of these DEGs highlighted oligodendrocyte dysregulation and we confirmed the myelin-associated transcriptional signature in two additional mouse models of syndromic ASD (Ptenm3m4/m3m4, Mecp2tm1.1Bird). We subsequently validated oligodendrocyte deficits in our Tcf4 mouse model which showed inefficient oligodendrocyte maturation in both an isolated oligodendrocyte in vitro cell culture system and ex vivo at day 24 (P24) and day 42 (P42). Furthermore, we used transmission electron microscopy (TEM) to visualize myelination in the corpus callosum (CC) of Tcf4+/tr and Tcf4+/+ littermates, observing a significant decrease in the proportion of myelinated axons in the CC of Tcf4+/tr mice compared to Tcf4+/+ littermates. Similar to our ex vivo IHC results, we observed a significant reduction in the number of CNP-positive oligodendrocytes in primary cultures derived from Tcf4+/tr mice compared to Tcf4+/+ littermates. When comparing compound action potentials (CAP) using electrophysiology, we show the ratio of N1/N2 is significantly reduced in the Tcf4+/tr mice compared to Tcf4+/+ littermates, indicative of a greater proportion of CAP traveling down unmyelinated axons. Moreover, we integrated syndromic PTHS mouse model DEGs with human ASD genes (SFARI) and human idiopathic ASD postmortem brain RNA-seq, and found significant enrichment of overlapping DEGs and common biological pathways associated with myelination. Remarkably, we show that DEGs from syndromic ASD mouse models can be used to identify human idiopathic ASD cases from controls. These results from seven independent mouse models of ASD are validated in human brain, implicating disruptions in oligodendrocyte biology as shared mechanisms in ASD pathology.


Here is more on the same paper:-



Genes involved in the formation of myelin, a fatty substance that sheathes neurons, are altered in brain tissue from autistic people and in several mouse models. The mice also have unusually few myelinated nerve fibers.
Researchers presented the unpublished findings yesterday at the 2019 Society for Neuroscience annual meeting in Chicago, Illinois.
“In general, across the whole spectrum, there’s a defect in myelination,” says Brady Maher, lead investigator at the Lieber Institute for Brain Development in Baltimore, Maryland.
Myelination is the process by which neuronal fibers are coated in myelin. Myelin is made by brain cells called oligodendrocytes, and it enables fast neuronal signaling.
Maher and his colleagues saw hints that myelination is disrupted in Pitt-Hopkins syndrome, an autism-related condition caused by mutations in a gene called TCF4. Children with this rare syndrome are slow to learn to walk, and most are minimally verbal; some have autism.
The researchers analyzed gene expression patterns in five mouse models of this syndrome, each with a different mutation in TCF4. They found that in all of the mice, genes involved in myelination are among those with altered expression.

The researchers then compared gene expression patterns of the mutant mice with those of two other autism mouse models: mice with mutations in MECP2 or PTEN. All three mouse models show alterations in the expression of a shared set of 34 genes, most of which are involved in myelination.
The same genes show atypical expression in two independent gene-expression datasets from autistic people, the researchers found.
Maher says his team is investigating why the TCF4 mutant mice have too few oligodendrocytes. They are also testing whether drugs that enhance myelination reverse the mice’s problems.

Clemastine in Autism

Several readers of this blog have reported a positive effect from Clemastine, you can find their comments in earlier posts.

Monty, aged 16 with ASD, has been using it for many months and it will be added to my Polypill at the next update.

In the US Clemastine is no longer available in the OTC form.  It is available as a generic with a prescription


In the rest of the world it is called Tavegil, or Tavegyl and being a common hay fever drug is usually OTC (no prescription).

In the Baltic states 20 tablets cost Eur 5 (USD 5.50). In the United Kingdom 60 tablets costs GBP 10 (USD 13).  You may have to ask the pharmacy to order it for you, it is not widely stocked, or order it online.

A 1 mg tablet of Clemastine contains 1.34 mg of Clemastine hydrogen fumarate.  This can be confusing because one product is marked 1mg and the identical tablet is elsewhere marked 1.34mg.

The US product by Teva is Clemastine 2mg containing 2.7 mg of Clemastine hydrogen fumarate

The experimental dose in Multiple Sclerosis is so high it causes drowsiness.  Clemastine affects histamine H1 receptors in the brain and so makes you sleepy.

My “autism dose” is less than the hay fever dose and is 1mg Clemastine (containing 1.34 mg of Clemastine hydrogen fumarate) taken in the evening.

Some readers are giving a morning dose and an evening dose, as you would for hay fever.  I would expect this to have a greater effect on oligodendrocytes, but will come at the cost of a degree of drowsiness, which may or may not be important.

I think people should be given clemastine immediately after a regression into autism and also anyone suffering as result of hypoxia. We saw the MRI of a man treated with clemastine after hypoxia in an earlier post and we saw the myelin damage and its repair.

Given 18 months of age is the typical age for the first regression in autism, perhaps pediatricians should take note? Perhaps the Johns Hopkins doctors should try using it on their patients with mitochondrial disorders?

I would also think those with what was called CDD (childhood disintegrative disorder) would be likely beneficiaries.

Comments so far suggest that clemastine benefits some people more than others, but this is exactly what you would expect.  In the case of the man with hypoxia, clemastine really was a silver bullet, it was given very promptly and loss of myelin was his only problem.  Most people with severe autism have more problems than just patchy myelin.


Treatment Window

In some single gene autism there does appear to be a treatment window and this has been confirmed in animal models. One example is the very expensive use of the drug Rapamycin in TSC (tuberous sclerosis complex).

Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain


Many interventions however do seem to be beneficial regardless of age.

This can be summed up as “it's never too late, but the sooner you start the better the result will be”.

Will a toddler with Pitt Hopkins learn to walk much earlier if taking Clemastine?  The logic is there to support this.

Will a girl with Rett Syndrome regress less far if taking Clemastine, during the regression?


Conclusion

Most parents naturally hesitate to give drugs to treat children with autism. They do not hesitate to give numerous drugs to their elderly relatives, who are the ones who are most likely to get side effects and have much less time to benefit from them.

Some drugs are much safer than others and the irony is that the drugs commonly used to treat autism by psychiatrists are the ones with known problems.

It appears that many very safe existing drugs can be used to treat features of autism.

Do you wait a decade, or likely more, to see if a safe old hay fever drug might improve cognition and/or motor skills in your case of autism or Pitt Hopkins? Or just buy these hay fever pills and see for yourself?

7 Previous posts on/including Clemastine:- 








Thursday, 28 March 2019

Improving Myelination through Social Interaction and more on Clemastine


Since anecdotal evidence is beginning to support this blog’s suggestion that pro-myelinating therapy might be beneficial in autism, particularly improving human adaptive behaviour, I will continue to highlight further supporting research.



Improving Jerry’s Brain Myelination - Hard without Tom


Today’s main paper shows how social intervention can also be used as a pro-myelinating therapy (in mice, like Jerry). I found the research interesting, but I think most parents would opt for a pill as a short cut.

The study looked at the effect of rearing an autistic mouse with social mice.  The autistic mouse shares the myelin defects of autistic humans. The research interestingly shows that it is the social interaction only after weening that has an impact on myelination. So in the human equivalent of this research, it is not interactions with Mum/Mom that matter most, it is interactions with toddler peers. So make sure your toddler with autism hangs out with bubbly neuro-typical toddlers, or has bubbly neuro-typical assistants/ therapists/kindergarten teachers.


Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, poor communication skills, and repetitive/restrictive behaviours. Recent studies have indicated that early rehabilitative intervention can alleviate the symptoms of individuals with ASD. However, it remains unknown whether rehabilitative intervention can restore brain structures such as myelin, which generally shows abnormalities in individuals with ASD. Therefore, in the present study, we used a mouse model of ASD (BTBR mice) that demonstrated asocial behaviours and hypomyelination in the medial prefrontal cortex (mPFC) to investigate whether interaction with social peers (C57BL/6J mice) has an effect on myelination. We found that housing with C57BL/6J mice after weaning through adulthood increased the myelin thickness in mPFC, but not in the motor cortex, of BTBR mice. There was no effect of cross-rearing with C57BL/6J mice on axon diameter in mPFC of BTBR mice. This finding suggests that early rehabilitative intervention may alleviate myelin abnormalities in mPFC as well as clinical symptoms in individuals with ASD.
In the present study, we found that interaction with social peers, which has been shown to improve sociability (Yang et al., 2011), considerably influences myelination in the BTBR mouse model of ASD. This finding supports the theory that rehabilitative interventions can affect brain structures as well as brain functions in individuals with ASD.
Individuals with ASD who have received intensive early intervention demonstrate improved long-term outcomes, and the effectiveness depends on the age at intervention. Earlier interventions such as ABA lead to more substantial resolution of ASD symptoms (Harris and Handleman, 2000). Although the biological mechanisms underlying the effects of early intervention remain unclear, recent findings propose that myelination in the relevant brain regions is a potential factor.

First, we found that BTBR mice exhibit thinner myelin in mPFC, but not in the motor cortex, compared with C57BL/6J mice (Fig. 1a). This finding was similar to those in postmortem brain studies of individuals with ASD (Zikopoulos and Barbas, 2010). Because BTBR mice are generally considered genetic models of ASD (McFarlane et al., 2008), hypomyelination in mPFC could occur due to genetic mechanisms. The elevated expression of proinflammatory cytokines such as interleukin-6 in the brains of BTBR mice (Wei et al., 2016) may cause hypomyelination, as shown in our previous study (Makinodan et al., 2016). If so, myelin in the motor cortex of BTBR mice should also be thinner than that in the motor cortex of C57BL/6J mice.

Second, we found that social interaction with C57BL6/J mice increased the myelin thickness in mPFC of BTBR mice. Given an increase in the social interaction of BTBR mice after cross-rearing with C57BL6/J mice (Yang et al., 2011), the restoration of myelination could be attributed to mPFC neuronal activities in relation to social interaction (Yamamuro et al., 2017), on the basis of findings that myelination is axonal activity-dependent (Wake et al., 2011). On the other hand, the alteration of social experience in the present study did not change myelination in the motor cortex, indicating that myelination in the motor cortex is independent of social experience. Interestingly, cross-fostering of BTBR mice with C57BL/6J mice during the neonatal period produced no significant effects on ASD-like behaviors such as altered ultrasonic vocalization and repetitive behaviors (Yang et al., 2007), implying that social interaction with peers influences the symptoms of ASD more than the mother’s care. These findings are consistent with the denial of the “refrigerator mother” theory and higher contribution of nonshared environmental factors compared with that of shared environmental factors with regard to the development of ASD





 (d) The cumulative probability curve of g-ratio; At P65, the mPFC myelin is thinner in the BTBR-only group than in the B6-only group (P  0.05). After housing with C57BL/6J mice from P21 through P65, the mPFC myelin thickness has increased in the BTBR-mixed group compared with that in the BTBR-only group (P  0.05). After housing with BTBR mice from P21 through P65, there is no change in mPFC myelination in the B6-only group (P > 0.05).



I should remind readers of the Bucharest Early Intervention Project (BEIP); it was highlighted in the post below.  It was a long running study that included measurable brain damage/difference cause by childhood neglect.


The study showed that orphans placed in high quality foster care not only do better than peers left in the State orphanage, but you can actually measure difference using MRI imaging.

The study showed that poor treatment in the orphanage could produce autistic children.  This would not have surprised Kanner. It highlights a little publicized risk in adopting children from orphanages in poor countries.


Early Intervention for young children with severe autism

There are numerous different models proposed as therapy for kids with autism. One of the outliers is the Son Rise program. I remember going on a course in London 12 years ago to learn PECS (Picture Exchange Communication System) and the trainer clearly thought Son Rise was completely mad. I did employ a very broad interpretation of ABA in Monty’s early therapy, we also included a large element of getting down on the floor (à la Floortime method) and be as “crazy” as him, which is really what Son Rise is all about; “enter his world” and draw him out of it. I still do this and if Monty has some new script he keeps repeating, I join in and soon he is asking me to stop scripting. I am not reinforcing his script, I am hijacking it and then he no longer uses it.

Doing the unexpected I found very beneficial as a means to diminish aggressive behaviour. I find the idea of social rehabilitation leading to biological rehabilitation very appealing.  It is also quite therapeutic for the adult. I think many parents just do not know what to do when faced with aggressive behaviours from their small offspring; one way or another, best to figure it out before he is bigger and stronger than you.

What dose of Clemastine?

There is research that you can use to get an idea of how much clemastine you might need to promote myelination. I was forwarded some calculations based on the paper below.

Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis



I did skip to this chart below in the supplemental data to the paper, which shows what you want to know. One you get to 10nM concentration of clemastine things really start happening. Increasing the concentration by a factor of 100 only doubles the effect.  

Recall that  MBP = Myelin Basic Protein  (more is good)

Then you have to convert 10nM into a human dosage in your blood.

From high school chemistry nM means nanomolar.






In practical terms, 1 to 2 mg once a day in the evening seems a pretty sensible dosage and well within the standard allergy dose.

“Cross rearing with social peers” from today’s first study does have implications. I always thought it was a bit odd to combine multiple kids with severe autism in play activity, or social gatherings. I know lots of families with special needs kids hang out together. This might be better for the parents than the kids.

Hanging out with typical kids who are not in the slightest interested in a special needs kid does not work.

In kindergarten and primary school there usually is a constant supply of nice little girls who genuinely want to get involved with kids with severe autism. It repeats all around the world. It gets rarer after puberty, but even at 13 years old some girls are genuinely interested in social interactions with special people. Teenage boys really are not interested in including people with disabilities, unless they themselves are outsiders, like the gay ones (yes, I know that will upset somebody).  Girls are a safer bet.

The best way to “cross rear with social peers” is to have fun assistants at school. This works directly in the child being exposed to a fun bubbly person, but it also makes it much more likely that typical kids will want to join in.

In theory being a 1:1 assistant might be a good job for an Aspie, but having tried that for a year I can strongly suggest a lively enthusiastic young-at-heart NT assistant is the ideal. He/she also needs to be good at maths and science.
   
Happy myelinating!






Thursday, 7 March 2019

A Case Study Treating Adult Hypoxia with Clemastine - a potential treatment to promote myelin recovery in premature infants


I did think we had finished with Clemastine for a while, but a researcher reader of this blog sent me a very interesting recent case study about a man with brain damage caused by hypoxia (lack of oxygen) and we have the MRI brain scans showing how that damage was reversed by this OTC antihistamine. Hypoxia is often caused by carbon monoxide poisoning or in childbirth, if things get tangled up.


The researchers go on to suggest Clemastine treatment to promote myelin recovery in premature infants. In this case the graphics in the paper relate to mice, not humans, but are really impressive.
This means that what is called Ataxic Cerebral Palsy, which is caused by a lack of oxygen during birth might now have a treatment.
Some children with autism, including some discussed in the comments in this blog, appear to have suffered hypoxia during birth. This caused damage which resulted in symptoms of autism.  You would expect that damage to show up on the “right sort of MRI” in the same way as the adult male, below. Some of these children are reported by parents to respond to hyperbaric oxygen, even though it is carried out years after the hypoxia.

Findings in human DPHL case treated with clemastine. Axial FLAIR (fluid attenuated inversion recovery) at 1 (A), 2 (B), 6 (C), and 12 (D) months after injury in a human case of DPHL, showing MRI white matter abnormalities on FLAIR and diffusion weighted images, subtle at 1 month and striking at 2 months, parallel to patient’s worsening clinical course; white matter signal changes showed a periventricular/ deep white matter distribution with involvement of the corpus callosum (particularly splenium), with sparing of U-fibres. The patient was started on clemastine treatment at 2 months. At 6 months, MRI abnormalities in the white matter were partially normalized, showing fuzzy signal changes, unchanged at 12 months follow-up.

What I found interesting was the time delay, it was two months after the hypoxia that the man’s symptoms became really severe, but rather than being game over, the white patches in the month 2 MRI gradually fade away, after clemastine treatment started.
In my posts on autism and myelin, I pointed out that the problem appears to be re-myelination, which is the repair and maintenance of existing myelin. In autism you could consider it as “Friday afternoon myelination”, when the oligodendrocytes are thinking more about the weekend than your axons. In the man in the case study he already had plenty of myelin prior to his hypoxia, but the hypoxia affected his capacity to re-myelinate his axons.
The progressive cognitive decline with profound short-term memory loss, impaired executive function, and paucity of speech, psychomotor retardation, urinary incontinence and gait impairment was reversed.  The patient was seen in follow-up 5 months after his hypoxic event. His cognitive function had markedly improved and he was able to return to work.  All thanks to OTC clemastine and I think he should thank someone for reading the Multiple Sclerosis research on clemastine.
The researchers then looked in detail at a mouse model of hypoxia and among other things, Myelin Basic Protein (MBP).


suggesting a rescue of MBP expression defects by clemastine during chronic hypoxia
Daily treatment with oral clemastine during hypoxia leads to significant (3-fold) increases in MBP in the cerebellar foliae compared to untreated hypoxic littermates
We found that oral administration of clemastine in murine neonatal hypoxia leads to significant increases in the numbers of differentiating OPCs expressing the markers proteolipid protein (Plp) and myelin associated glycoprotein (Mag) mRNA in corpus callosum and striatum compared to untreated hypoxic littermates




Clemastine promotes myelin protein expression in neonatal hypoxia.(A) MBP protein expression in the (A) forebrain, (C) striatum white matter of postnatal Day 10 (P10) normoxic mice (‘Normoxia’), versus those exposed to neonatal hypoxia (‘Hypoxia’), versus hypoxic littermates treated with clemastine (‘Hypoxia + Clemastine’) 

Hypoxia can injure brain white matter tracts, comprised of axons and myelinating oligodendrocytes, leading to cerebral palsy in neonates and delayed post-hypoxic leukoencephalopathy (DPHL) in adults. In these conditions, white matter injury can be followed by myelin regeneration, but myelination often fails and is a significant contributor to fixed demyelinated lesions, with ensuing permanent neurological injury. Non-myelinating oligodendrocyte precursor cells are often found in lesions in plentiful numbers, but fail to mature, suggesting oligodendrocyte precursor cell differentiation arrest as a critical contributor to failed myelination in hypoxia. We report a case of an adult patient who developed the rare condition DPHL and made a nearly complete recovery in the setting of treatment with clemastine, a widely available antihistamine that in preclinical models promotes oligodendrocyte precursor cell differentiation. This suggested possible therapeutic benefit in the more clinically prevalent hypoxic injury of newborns, and we demonstrate in murine neonatal hypoxic injury that clemastine dramatically promotes oligodendrocyte precursor cell differentiation, myelination, and improves functional recovery. We show that its effect in hypoxia is oligodendroglial specific via an effect on the M1 muscarinic receptor on oligodendrocyte precursor cells. We propose clemastine as a potential therapy for hypoxic brain injuries associated with white matter injury and oligodendrocyte precursor cell maturation arrest. 


Conclusion

The days of cheap clemastine in North America are probably numbered.



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.