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Wednesday 28 August 2013

Potassium may play an important role in Autistic Behaviours

This is not the kind of post that I expected to be writing.  How can the effect of something so simple as a mineral, not have been noticed by others and researched in depth?

Potassium (K+),  is one of several electrolytes that occur in humans, the others being sodium(Na+), calcium (Ca2+), magnesium (Mg2+), chloride (Cl), hydrogen phosphate (HPO42−), and hydrogen carbonate (HCO3)

Electrolyte balance or homeostasis is regulated by specific hormones.  These electrolytes are used to control many aspects of your body.  The concentration of each electrolyte varies across the boundary of each cell.  Electrolytes pass through the cell wall/membrane through so called ion channels.  These are like special valves that open and close based on particular pre-programmed circumstances.  When these ion channels malfunction, often due to a genetic fault, disease occurs.  Ion channel diseases have a special name - channelopathies.  This is still an emerging area of science.

In autism the brain has developed in an unusual way and although it is thankfully not a degenerative disease, the biological equilibrium it has evolved to is not the one originally intended.  There are both channelopathies and hormonal irregularities; indeed the two are interrelated.

Many hormones are interrelated and have multiple functions and therefore a change in one may have a cascading effect on others.  The same applies to the electrolytes, for example a deficiency in magnesium will trigger a deficiency in potassium.

Choride (Cl-)

I started my blog when I read about a successful clinical trial that set out to prove whether an imbalance in chloride between the extra/intra cellular fluid could cause one of the brain’s main neurotransmitters (GABA) to malfunction.  A clever Frenchman called Ben-Ari, had been researching neonatal seizures and proposed to trial the drug Bumetanide.    Bumetanide is known to block the NKCC1 cation-chloride co-transporter, and thus decreases internal chloride concentration in neurons. In turn, this concentration change makes the action of GABA more hyperpolarizing.  Do not be put off if this does not make sense to you.

The trial showed the positive effect on autistic behaviours of this long established and inexpensive drug.
 
A randomised controlled trial of bumetanide in the treatment of autism inchildren


Potassium (K+)

Not long after making a trial of bumetanide on Monty, then aged 9 years, I started this blog and my own research.  I soon came across a condition called Hypokalemic Sensory Overstimulation.  In this condition, the subject becomes overwhelmed by his senses of sound, light, smell etc.  After taking oral potassium, the symptoms disappear within 20 minutes.  It is claimed that this is also a characteristic of ADHD (attention deficit hyperactivity disorder).  Well sensory overload is pretty common in autism, and, as I have learnt, ADHD is really just a light case of autism.

There is almost no research into this condition, which is odd since it is linked to the very common ADHD condition.  The paper below  was only ever cited 3 times in other research, and only once in English.

I then did my own experiment using a small dose of K+  supplement (equivalent to one banana) to see if by any chance I could see a reduction in sensory overload.  I tested both my sons, and only in the ASD son did the potassium have any impact; and it was a marked impact.  I wrote this up in a blog post.

I kept potassium and channelopathy on my list of things to research and left it at that.

 
Ion Channels & Ion Channel Diseases (Channelopathies)

Ion channels are an emerging area of science all about how signals are sent throughout your body to control it.  It gets very complicated and is still far from fully understood.  So you may want to skip this part.

So far 300 types of ion channel have been identified.  The main types are:-

·         Chloride (Cl-) channels

·         Potassium channels

·         Sodium channels

·         Calcium channels

·         Proton channels

·         Non-selective cation channels

 Then there are differing ways in which the channels open and close such as:-

·         Voltage gated

·         Ligand gated

And odd ones like
 
·         Light gated

·         Temperature gated

·         Calcium activated potassium channels

When the ion channel and/or its gating does not work properly then a disease called a channelopathy may result.  Examples of well know disease are cystic fibrosis, various types of epilepsy and ataxia.

 
Puberty and Epilepsy  

As a result of the changes in hormones triggered by puberty it is therefore not surprising that around this time other changes occur in the body.  In some children with asthma, their symptoms become more mild or even appear to disappear.  In autism the hormonal changes often trigger an improvement, but may be the trigger of the onset of epilepsy.  When you consider the importance of all these electrolyte levels, and the variation of each across one each cell boundary in the body and how this is intertwined with how the neurotransmitters function, it is not surprising that a shift in Homeostatis occurs.

That shift in Homeostatis could be reflected in a mellowing of autistic characteristics.  But if you can now make some small adjustments in these levels via diet and mild drugs, why not investigate it?  You will not be able to achieve perfection, but you might be able to shift from one stable equilibrium to another one, with milder autism and no troubling side effects.

This would also imply that those children developing epilepsy during puberty might be able to treat it using the diuretic bumetanide.  By blocking the NKCC1 transporter, the level of Cl- is blocked and GABA becomes more inhibitory and thus the risk of an epileptic attack might be reduced, or perhaps eliminated.  This is surely worth some research?

 
K+ ion channel disease – Epilepsy & Autism

There is existing research linking potassium ion channels to both epilepsy and autism





ADHD & Ritalin

I read some research about a stimulant drug used to calm children with ADHD.  It seemed odd to use a stimulant to produce calm.  Here again potassium (K+) and sodium (Na+) levels are at the centre of argument.
 
Then I noted a very recent article (July 2013) reporting a study of Ritalin on children with ASD and/or ADHD.

In the world of alternative medicine there is talk of Ritalin helping in ADHD due to it altering the level of potassium:-


This inverted ratio of Na/K may be helpful in explaining why a stimulant drug like Ritalin would have a calming effect on hyperactive children and adolescents. Ritalin does, indeed, have a stimulating effect on these children, but its stimulating mechanism is neuroendocrine and biochemical, not behavioural. More specifically, its stimulating effect is on the adrenal glands and the retention of sodium in the tissues relative to potassium. It is critical for normal cellular functioning that sodium and potassium (Na and K) be in balance for the optimal operation of the Na/K pump at the cellular level. It is also critical for efficient neurotransmissions that there be a proper balance between sodium and potassium (Na and K) for neuronal conductance.

 
Measuring electrolyte (Ka, Na, Mg, Cl etc.) levels

I would have expected that it was easy to check the level of electrolytes and indeed to check the levels in blood is very easy.  I have done this and all was normal.  When you read further in the literature, you will realize that the level of electrolytes at the extra/intra cellular level is not so easy to measure.  A whole business has been created by people analyzing hair samples for clues as to the balance or imbalance of various minerals in the body.

Hair analysis is used in forensic toxicology and  drug testing to detect the presence of various chemicals in the body.  The method has been adopted by the complementary and alternative medicine (CAM) community to try to predict food intolerance and dietary deficiency.  It is viewed by the scientific community that much of the CAM use of the technology is not valid and potentially fraudulent,

So there is no certain way of checking the cellular level of electrolytes.  You can only measure what you eat and you can measure what is in your blood.


Other suspected electrolyte imbalances in Autism

There have been several studies regarding Magnesium and autism, but the peer reviews of these studies are highly critical of the methodologies used and conclude that nothing has been proven.

Vitamin B6-magnesium treatment for autism: the current status of the research

Calcium has also been put forward as an intervention.  One mother spent a great deal of time collecting supporting information in her paper below.


 
DAN doctors and Spironolactone

Having come across a “bible” of therapies proposed by DAN (Defeat Autism Now) doctors I noted the use of a potassium-sparing diuretic called Spironolactone.  For a change, there is actually a published paper setting out their case for this drug.  The case made has nothing to do with potassium, even though the intended purpose of the drug is to raise potassium levels.

Bradstreet et al wrote a paper on this in 2006.  It has been cited only 7 times up until 2013 and two of these times by the authors themselves.  This tells you that other researchers were either skeptical or just disinterested.
 


Potassium Supplements
 
There are many hundreds of types of mineral and vitamin supplements; these days many contain far more than recommended daily amount (RDA).  This is not the case with potassium.  Even though the RDA for adults is 3,500 – 4,700 mg, in the US supplements by law may not contain more than 100 mg of potassium.  In Europe potassium supplements with 500mg are common.

A typical banana contains over 400mg of potassium, which would seem to make a 100mg supplement pretty pointless.

In the US it seems that there is a perceived fear of potassium poisoning.  It is indeed the home of the lethal injection.  Potassium chloride in a very high dose will stop your heart.

You will even find people debating whether you can poison yourself with bananasIt would seem that while you can reduce your high blood pressure with bananas, it does not kill you.  One person was even eating 30 bananas a day!!

The fear of potassium though remains and it is all over the American internet.
 
But, in the UK, the National Health Service advises:-

You should be able to get all the potassium you need by eating a varied and balanced diet. If you take potassium supplements, do not take too much because this could be harmful.

Taking 3,700mg or less of potassium supplements a day is unlikely to cause any harm.

That amount of potassium would require 37 American supplement tablets each and every day!

In reality, a concentrated dose of potassium may indeed upset your stomach and this is why it is better to get it from a healthy mix of fruit and vegetables.  The average American apparently consumes about 1,000mg of potassium per day.

Internet Chatter

If, like me, you use Google to see what other people are up to, you will come across talk of potassium and autism.  The discussions in forums never get far, because someone starts talking about lethal injections, and then fear prevails.

Sodium Potassium Pump  (Na+/K+-ATPase)

The sodium-potassium pump was discovered in the 1957 by a Danish Scientist, who later went on to win a Nobel prize for his discovery in 1997.  Its main application has been in the understanding and treatment of heart disease, but it is now thought to be directly involved in a critical part of the brain already known to be damaged in autism. 


As I have already mentioned in my blog, the comorbidities of autism (asthma, high cholesterol etc.) mean that much of the work has already been done by others.

Those many people with hypertension (high blood pressure) are suffering due the way the sodium potassium pump works.  They eat too much sodium and far too little potassium and the end result is high blood pressure.

An author and researcher, Dr Richard Moore, has a simple explanation on his website and a link to his book showing how diet can indeed control your blood pressure.  If you check the book on Amazon you will see many very favourable comments from people who have indeed lowered their blood pressure with bananas.

His book is called: The High Blood Pressure Solution: A Scientifically Proven Program for Preventing Strokes and Heart Disease.

 
Sodium Potassium Pump and Autism

I was looking for evidence (other than my own) that potassium levels affect the autistic brain.  Potassium plays a key role in how most ion channels function, but I was looking for something really tangible.  I think I have found it.

In my earlier posts I introduced readers to a part of the cerebellum called the Purkinje Cell Layer (PCL).  This is a critical part of the brain and unfortunately in autism, half of the cells are dead and this then manifests itself in altered brain functioning and hence behaviour.  

As recently as 2012, scientists in England showed that the neurons in the PCL are controlled by the Sodium Potassium Pump.


The paper’s summary concludes “We propose that Na+/K+ pump activity controls the intrinsic firing mode of cerebellar Purkinje cells”
 
Our new friend Dr Richard Moore puts it very simply:-

For the Na-K-pump to operate normally, the diet must have a ratio of potassium to sodium ratio (the K/Na ratio, or "K Factor") that is above a threshold that is somewhere between 2 and 4. Our ancestors ate a diet with a K/Na ratio ranging between 12 and 16. However, the average American white eats a diet with a K/Na ratio of less than 1 - about 0.6 - and the average American black eats a diet with an average K/Na ratio of about only 0.38! Obviously, the American diet generally has a very deficient K/Na ratio.

A low dietary K/Na ratio causes a low K/Na ratio in each and every cell in your body. This has been known since the end of World War II when whole body radio-active counters were used to determine the amount of potassium (a small part of which is naturally radioactive) in the human body. Almost universally, to their surprise, it was found that people with hypertension have a deficient amount of potassium in their body.

By 1983, several scientists including myself had worked out the vital role of the Na-K-pump in cell function to the point where our understanding predicted that other dysfunctions, or disease states, of the body's cells would occur. Not until the mid 1990's did anyone bother to look for these other conditions. Since then, it has become well established that in the U.S., our typical diet with its low K/Na ratio is the cause of:

About 95% of the cases of high blood pressure.
At least 90% of strokes whether or not high blood pressure is involved.
Much of the osteoporosis and kidney stones.
An increased likelihood of h-pylori infection with resulting stomach ulcer and stomach cancer.
An increase in the severity of asthma.
An increased likelihood of mental decline with aging.

In addition, there is some evidence that this low K/Na ratio in the American diet contributes to insulin resistance, to obesity, and to adult diabetes

  
So since in autism a critical part of the brain is already damaged and has been shown to be subject to oxidative attack and neuroinflammation, it is not surprising that it is particularly susceptible to further interference.  As a result whereas, in a typical childlike Ted, aged 13 with an aversion to fruit and vegetables, can function perfectly well and additional potassium made no measurable difference to his sensory behaviour, the same was not true of Monty, aged 10 with ASD, and with a diet full of fruits and vegetables.  The additional potassium actually changed his sensory behavoiur.  Now I have a plausible explanation

Electrolytes etc.

 If you really want to go into the biology and understand intercellular/extra cellular fluid, role of hormones vasopressin and aldosterone and all about sodium and potassium balance, then take 10 minutes to carefully read the following link:-
 

 
Autism and Heart Disease, Diabetes and Cancer

On this blog I have already shown that several strategies for cardiac health also help autism.  Since in autism there is proven high cholesterol and high neuroinflammation and most likely also hypertension, it would make great sense reduce these risks regardless of the fact that those steps may likely also reduce autistic behaviours and improve functioning.

I made a study into omega 3 and conclude “eat fish”, it is cheaper than omega 3 oil, and it definitely will help cardiac health, but probably will do little to nothing for the autism.


A high potassium diet, particularly if it is based on food rather than supplements, will protect your child from heart disease later in life.  He/she is already in an at risk group.

 So there are two very good reasons increase potassium and reduce sodium in his/her diet.  If you are not aware of the health issues surrounding autism, take a look at this:-


Without intervention, adults with autism spectrum disorder appear to be at significant risk for developing diabetes, coronary heart disease, and cancer by midlife.

For a general discussion on these and other health issues, there is a well-researched paper called:
 

  
Conclusion

In the case of Monty, aged 10 with ASD, incremental potassium in diet and via an over the counter potassium supplement (that also contains magnesium and B vitamins) has a positive effect on autistic behaviours.  The total daily potassium ingested (1g as supplement, plus banana, orange juice, potato etc.) is still probably below the adult RDA of 3.5g, but much higher than most 10 year olds with ASD.

There is a scientific logic to show why potassium might produce beneficial effects due to better functioning of the sodium-potassium pump, particularly in the Purkinje cell layer of the brain, which is a known to be damaged in ASD.

It may also be that the magnesium, that is also present in the potassium supplement, is having a beneficial effect.  This could easily be investigated by some further research, should anyone be so inclined.

In any case, a relatively high potassium diet is well established to be very healthy and, along with strategies to lower cholesterol, will promote a healthy heart.  The literature shows that autistic people have elevated cardiac risk and so already have a good reason to be following this kind of diet;  I have just added another good reason.

 

Thursday 22 August 2013

Autism - A Neurodevelopmental Journey from Genes to Behaviour

I am getting a little behind in writing up the findings of my research; I have several posts in preparation.  Here today is a link for those scientists among you:-

Autism - A Neurodevelopmental Journey from Genes to Behaviour


This is a free e-book with 24 scientific papers.  You can download the entire book or just individual chapters.  The book is from 2011, so it is quite up to date.

In the meantime I am looking at ion channels and transporters; and a new term to me "sensory gating".  This is all connected to an earlier observation I have noted about the effect of potassium (K+) on behaviour and a paper I found about the use of spironolactone (a potassium-sparing diuretic) as a therapy in autism.  The paper claims the benefits are do to a secondary anti-inflammatory effect of the drug; I am not so sure they got their science right.  This all goes back to the role of the neurotransmitter GABA, its role in how the brain develops as it grows and then how it functions thereafter; this is all affected by transporters NKCC1 and KCC2.


Asthma - Autism Hypothesis
 

Friday 16 August 2013

Autism flare ups and comorbidities



Anyone familiar with autism will know that it seems to go in waves of good and not so good.  Generally this gets accepted as just the way it has to be.

I chanced upon an unusual paper recently, it was all about comorbidities in autism.  As you may know, comorbidities are other diseases that seem to frequently occur alongside autism.  The main point of the paper and the charity behind it, is that comorbidities should be diagnosed and treated, rather than ignored, just because the person has ASD.

The paper was produced by Treating Autism, a UK charity that follows a biomedical approach similar to the American DAN organisation.  They have a link to a very comprehensive summary of what DAN actually recommends. The DAN paper is by a Dr Jepson.

The idea of treating the comorbidities as they crop up, seems entirely logical to me; but it seems to miss the bigger issue of what the comorbidity might help tell us about the autism itself.

Their list of comorbidities to keep a look at for:-

·         Allergic disorders in ASD: effects of allergies on behaviour, cognition and anxiety. Food and inhalant allergies, allergic rhinitis.
·         Autoimmunity in ASD. 
·         Autonomic nervous system dysfunction (dysautonomia) in ASD
·         Seizure disorders in ASD

Allergic rhinitis was of course the one that caught my eye.  This is the medical name for the itchy red eyes and runny nose caused by summertime pollen and pollution.  This reinforced by own observation that histamine can have a major negative impact on behaviour in ASD.  This was presented in my recent posts on histamine and antihistamine drugs.

Also of note to me was the observation that atopic dermatitis (itchy skin) and asthma are comorbidities.  Asthma was one of the comorbidities I choose to investigate myself.  An interesting observation I came across was that atopic dermatitis is actually a good predictor of developing asthma and, in fact, that by effectively treating it with a particular drug (ketotifen), you can actually halt the progression to asthma.  There is a study investigating exactly this issue; one half of the trial were itchy toddlers with a placebo and the other itchy toddlers had ketotifen.  A year later the group with ketotifen had a far lower percentage that had developed asthma than the placebo group.  I call that interesting but how many family doctors, let alone parents, are aware of that?



Also, another interesting paper all about childhood allergies is called The Allergic March.


Conclusion

Autism flare ups seem to be common and a little investigation may well lead to a better understanding of your child’s type of autism.  By recording data on bad behaviours, as in an ABA programme, or my preference, by just be keeping a watchful eye, you may well identify the cause and then find a remedy.  It might be a wobbly tooth, or it might be something more subtle like histamine.

I also believe that a detailed understanding of the comorbidities will ultimately lead to some effective therapies for autism itself.  Since it is clear that different people have different types of autism, knowing what triggers your child's flare ups may well help define what type of autism he/she has and therefore what therapies may or may not prove effective.


Saturday 27 July 2013

More on anti-histamines in Autism and introducing H4

In my previous posts on histamine, you would have read that I found that Claritin appeared to reduce autistic behaviours.  Once I had got to the bottom of what was going on, I found out that histamine has a long record of stimulating challenging behaviour in all children.  It also became clear that typical anti-histamines (H1 antagonists) are all slightly different and one may be effective in one person and ineffective in another.  Each one tends to have additional secondary effects.

It now appears that the secondary effect of certain H1 antagonists may actually be more important than the primary intended effect of reducing itchy eyes and runny noses.
There are three generations of H1 drugs.  The fastest working and most potent is still the first generation, the second generation are non-drowsy derivatives of the first generation.  The third generation are the active metabolite of the second generation.  As you will see in today’s central paper, the third generation probably does not warrant the tittle.  For many users they may be just expensive versions of the second generation drug.

The excellent paper  New anti histamines: a critical view is from Brazil, but it has an English version.  It is highly readable.  It tells of the specific secondary effects of certain second generation  H1 antagonists.   (She omits to mention the secondary effects of the first generation. Some people say Ketotifen is 1st generation and other people say 2nd generation, anyway it appears not to be sold in Brazil).  I suggest you read the paper, if you have a child with an ASD. The key section is this:

Antiallergic/anti-inflammatory effects

Originally, studies of the relative potencies of H1 antihistamines were based on the capacity of different compounds to competitively inhibit the H1 receptor binding of histamine, i.e. on their blocking effect on the receptor.8 Nevertheless, it has already been known for some time that, in addition to acting on H1 receptors, many H1 antihistamines, at appropriate doses, are capable of inhibiting not only the release of histamine by mast cells,9,10 but also mast cell activation itself.11 Some of them can even regulate the expression and/or release of cytokines, chemokines, adhesion molecules and inflammatory mediators.5,8

Therefore, the antiallergic properties of H1 antihistamines are generally a reflection of their capacity to affect mast cell and basophil activity, inhibiting the release of preformed mediators such as histamine, tryptase, leukotrienes and others.8 Several second-generation H1 antihistamines have demonstrated antiallergic properties, irrespective of their interaction with the H1 receptor.5,8

Chronic allergic inflammation resulting from the late-phase reaction, exhibits components that are similar to other forms of inflammation, including chemotaxis of inflammatory cells followed by activation and proliferation, with subsequent production and release of many chemical mediators. Among cells involved in allergic inflammation are: antigen-presenting cells (for example, macrophages), mast cells, basophils, T lymphocytes, epithelial/endothelial cells and eosinophils - major effectors of chronic inflammation. Cytokines, chemokines, inflammatory mediators and adhesion molecules also contribute to this process which ultimately leads to dysfunction of the affected organ.8

Many second-generation H1 antihistamines (particularly cetirizine) are capable of inhibiting the influx of eosinophils to the site of allergen challenge in sensitized individuals.5,8 Studies have demonstrated that some of them can also alter adhesion molecules expression on epithelium and eosinophils, and reduce in vitro survival of eosinophils. Finally, some second-generation H1 antihistamines are capable, in vitro and in vivo, of altering the production of inflammatory cytokines (for example, TNF-a, IL-1b and IL-6) and the Th1/Th2 balance regulation cytokines (for example, IL-4 and IL-13).5,8

Therefore, it is well established that, in addition to their effects on H1 receptors, many second-generation H1 antihistamines also manifest antiallergic and anti-inflammatory properties which differ depending upon their molecules and the experiments used for their evaluation.5

 
From my own experience, I have already replaced Claritine (Loratadine) with Cetirizine to see if it will remain active for longer.  Rather than working for 24 hours, Claritine is working for about 5 hours.
I thought Cetirizine might remain active for longer, but the main difference seems to be in how it works, rather than for how long it works.  With Cetirizine autistic behaviour has pretty much returned to where it was at the start of summer, before the allergy season.  With Claritine things improved greatly, but not all the way back to "normal".

Reading the paper and one of its references -
makes me think that the expensive new  version of Cetirizine, called Levocetirizine, might be even better.  It happens to be available locally, but it is seven times as expensive.

The Brazilian paper does rather contradict some of what Dr Theoharides says about stabilizing mast cells.  You can choose who you think has got it right.  The good thing is that both Dr Inês Cristina Camelo-Nunes and Dr Theoharides seem very serious, objective people, which cannot be said about all the people offering their advice on the internet.

In fact, I found an interesting paper on the anti-inflammatory effects of the new version of Claritin, called Aerius/Clarinex (Desloratadine).


It really seems to be the case of trying several antihistamines and selecting the one that works best for you.
 
The H4 Histamine Receptor and Inflammation
You may recall that there is a fourth histamine receptor, naturally called H4.

It was only recently discovered, as you might guess from the short entry in Wikipedia.  It seems that the H4 receptor plays a substantial role in the inflammatory response.  It is seen as playing a key role in conditions ranging from arthritis to asthma.
Here is a full text paper for those interested in the science:-

The role of histamine H4 receptor in immune and inflammatory disorders

 Here is a graphic from that paper:-

I wonder if that H4 is a ticking bomb in autism as well ?

Those more peaceful people among you will be less aware of what C4 is, and hence the sticks of H4 dynamite.





 



 

Wednesday 24 July 2013

Histamine, allergies and reducing challenging “autistic-like” behaviours

Having recently discovered that an anti-histamine drug like Claritin can markedly reduce autistic behaviours, I have been looking into exactly why this might be and to see if there could be any other related interventions.  Here are the results and they pull together all sorts of related comorbidities and in the end I seem to have found a better solution for managing summertime autism flare-ups.

Allergies have long been linked to aggressive behaviours
It seems to be well known among allergists, that children with allergies may exhibit challenging behaviours.  It goes beyond the simple fact that the child with an allergy will be irritable and therefore behave badly; the allergy itself is affecting the behaviour.  Allergies tend to worsen behaviour and the science can explain exactly why this happens.   This applied to pollen type allergies, food allergies and even asthma.

In the case of asthma, I found several studies, one is called:  Prevalence of Behavior Problems in US Children With Asthma

The study concluded with:
Clinicians caring for children with asthma and their families should be aware of the relationship between asthma and emotional and/or behavioural problems and anticipate that a substantial number of their patients may have mental health services needs.
One alternative health website, gives a list of symptoms they believe histamine allergies produce in kids with ASD.

Some different types of responses to histamine seen in ASD children: If histamines become too high, you can see hyperactivity, compulsive behaviors, depression, abnormal fears, intense mood swings, runny nose, itchy eyes, sneezing, perfectionism, strong wills, explosive anger, anxiety, hair pulling, lack of focus, scripting (repeating commercials or television programs, etc.), high libido, giggling (which can be a sign of yeasty behaviors), aggression, change in bowel movements, a craving for salt, frequent urination and rashes. Those who have seasonal allergies tend to see a worsening of these symptoms during spring time.

 What I recently noticed in Monty, aged 10 with ASD, were some of these behavioural problems, but  with only the slightest outward sign of an allergy.
Food allergies causing autism-like behaviours
I was surprised to find one allergy site listing the behavioural effects of food allergies, it reads like a long list of autistic behaviours.  This made me wonder if many of the milder cases of autism and the so-called autism epidemic may just be unresolved food allergies.  Many of the DAN interventions are about “healing the gut”, so maybe they are really more about treating food allergies.  Many cases of classic autism appear to have no problem with their digestive system at all.

Here is a list of behaviours from one site on food allergies:
 Poor coordination

Trouble communicating

Self-destructive behavior

Staring

Difficulty in group games or sports

Obsessions

Nonsense talk
Inability to read tones of voice and/or body language

The best studied/documented allergies
Asthma is the best researched allergic condition that I found, followed by food allergies and the rare condition of mastocystitis; this condition is rare but sufferers write extensively about it on the internet.  They also report on the effect of different drug combinations in managing their conditions.   Mastocystitis is also a comorbidity of autism that has been researched by Theoharides, who proposes his NeuroProtek supplement.

The result is that there has been a great deal of research and many established drug therapies exist.  The link between allergies and behaviour was investigated in the 1980s, but there has not been much written since, which is a pity.

Mastocystitis
The Mastocystitis Society of Canada have a good website.  It defines Mastocytosis as a myeloproliferative neoplastic (mpn) stem cell disorder, caused by an over-abundance of good immune system cells called mast cells and the release of mast cell mediators.

What that really means is that when the mast cells encounter an allergen they overreact and release too much histamine and also inflammatory messenger, such as cytokines.  These chemical disperse throughout the body.  The histamine activates the four types of histamine receptors around the body.  The pro inflammatory cytokines react in a different way, but promote an excessive inflammatory response.
To grossly simply the condition, mastocystitis is an extreme form of allergic response.

Mastocystitis is a comorbidity of autism and the mast cell response has been proposed to be a key part of autism.  It is interesting to look at how mastocystitis is treated.  Click the link here.
Note the use of both H1 and H2 histamine antagonists, many asthma drugs including the steroid Prednisone, and the mast cell stabilizer Ketotifen.

Histamine & Histamine Antagonists

 Histamine is a chemical in your body with three distinct functions:-

1.       Histamine triggers the inflammatory response
2.       Regulates physiological function in the gut
3.       Acts as a neurotransmitter


Most histamine in the body is generated in granules in mast cells or in white blood cells called basophils. Mast cells are especially numerous at sites of potential injury — the nose, mouth, and feet, internal body surfaces, and blood vessels.

Histamine functions in coordination in 4 types of receptors (H1, H2, H3 and H4).  In the central nervous system H1 and H3 receptors.  H1 is involved in allergies and asthma.  H2 is mainly involved invasodilation and gastric acid secretion.  H3 controls neurotransmitter release (histamine, acetylcholine, norepinephrine, serotonin).  H4 Plays a role in chemotaxis.

Histamine antagonists are drugs that inhibit the action of histamine by blocking specific receptors in specific parts of the body.  The most common drugs are H1 antagonists that block the H1 receptor in summertime allergies.  H2 antagonists reduce gastric acid secretion to heal peptic ulcers.
Histamine is the link between allergies and behavioural change
Histamine in the brain has been shown to directly influence behaviour (see later in this post for links).  There is also plenty of anecdotal evidence from allergists, as shown earlier in this post.

In addition histamine has been shown to weaken the blood brain barrier.   This would then let into the brain pro-inflammatory agents that might then cause a spike in neuroinflammation and oxidative stress.  This in turn leads to more challenging behaviours.   

The disruption to the BBB can be best reduced by the use of H2 antagonist. H1 antagonists have a much smaller effect.  See this study, which concludes:

 It is concluded that histamine causes an increase in blood-brain barrier permeability which is mediated via endothelial H2 receptors,

Ketotifen
Ketotifen is an H1 histamine antagonist.  It is a 40 year old antihistamine drug that is available over the counter in Europe.  Not only can it be used to treat  allergies (it is the active ingredient in many eye drops) and help control asthma, but it has some additional benefits.  It acts as a mast cell stabilizer, reducing the amount of histamine released by the mast cells when they encounter allergens.  It is the only  H1 histamine antagonist that does this.  In  addition it also blocks H1 receptors like the other widely used H1 histamine antagonists.
It is also used by body builders.  They are using another asthma drug called Clenbuterol.  This drug has the side effect of reducing your body mass index (BMI), so it makes you more muscular if you take enough of it for long enough.  Such use of Clenbuterol has side effects, the body builders are using Ketotifen to reduce these and allow them to use Clenbuterol for longer.  The misuse of Clenbuterol  affected beta-adrenergic receptor functions, for those who are curious.  Ketotifen blocks this from happening.

Celebrities, like a certain very well-known footballer’s wife, take Clenbuterol to stay thin.  Maybe they also take Ketotifen?
Ketotifen is extremely cheap and widely available in Europe and Canada.  In the US it is much more difficult to get hold of and so seems to have great rarity value.

In the US, some DAN doctors give Ketotifen to autistic children as a therapy for Gastrointestinal problems.  The well-known DAN doctor, with an audio lecture on this subject, states that Ketotifen is “mainly active in the gut”.  He obviously has not read the research, since the opposite is actually true.  Based on my limited research, it appears that some of these kids may just have autistic-like symptoms causes by the excess histamine in their brain. In other words they may just have a case of food intolerance / Irritable bowel syndrome rather than autism.  That would certainly be a relief to the parents concerned.
Other H1 Antagonists
You will know these drugs by their brand names :  Claritin, Zyrtec, Benadryl, Allegra, Phenergan etc.  There are several types of these drugs.  The early examples passed into the brain and so made people drowsy.  The second generation are the current big sellers, based on their non-drowsy effect.  When you dig deeper, you will see that they are all slightly different, and some work better than others in different people.  They also vary in which part of the body they have the most affect.
The older types are off patent and sold cheaply as generic over the counter drugs.

Mast cell stabilizers and irritable bowel syndrome
It has been long known that certain drugs reduce the allergic reaction in food intolerance.  Remarkably the same drugs are today also used to treat asthma.  The expensive drug I was prescribed as child called Intal (Cromoglicic acid) for food intolerance, is today called a mast cell stabilizer and  used in asthma therapy.

Mast cell stabilizers prevent the release of inflammatory chemicals like histamine from mast cells.
Another insight courtesy of the Mastocystitis Society of Canada:-

“Mast Cell Stabilizers - Ketotifen is preferred as most effective for entire body, Cromolyn mainly targets gastrointestinal system”
So it looks like the DAN doctors have chosen the wrong treatment for their GI problems, they should be using Intal not Ketotifen.

Modern second generation anti-histamines do not enter the CNS
First generation H1 antagonist crossed the blood brain barrier and had a sedative effect, making sufferers drowsy.  As a result there was a big search made of drugs that could relieve allergy symptoms but not make sufferers drowsy.  These second generation drugs are the current big sellers, although the first generation drugs are still widely available.
These modern drugs should therefore have less impact on histamine driven challenging behaviours than the old ones.
Most anti-histamines block the receptor rather reducing the amount of histamine
The popular H1 antagonist like Claritin do not reduce the amount of histamine produced in the body, they rather block the receptors used to detect it.  The amount of histamine flowing through your body remains the same.  That histamine weakens the blood brain barrier, allowing in things that might be better kept out.
It turns out that the H2 antagonists can reduce this degradation of the BBB, but H1 antagonists like Claritin have only a marginal effect.  This is all based on research in rats.

Sufferers of mastocystitis take copious amounts of H1 antagonists and H2 antagonists plus a whole host of other drugs.  H2 antagonists are old drugs like Tagamet, that were designed to reduce acidity in your stomach for treating ulcers and GERD.  It appears that also have unforeseen effects in your brain and elsewhere.
Histamine in the Brain
For those scientists among you, the areas to read up on are mast cells and how histamine functions in the brain.  Many of the papers on histamine in the brain are not available without payment.  Here is a short paper that is available.


Other good ones, not available free include:

and from way back in 1988:- 
Behavioral effects of histamine and its antagonists: a review

Research studies in to the use of H1 and H2 antagonist in autism
I was pleased to find that I was not the first to look into the use of histamine drugs in autism.  I did find two studies, and both were positive.  It is strange that in the 12 years since these studies were carried out, the research effort has not been followed up.
From my recently acquired insight, the H1 antagonist improved behaviour by blocking some of the unwanted response to histamine in the brain and the H2 antagonist help restore the blood brain barrier and keep out those unwanted pro-inflammatory agents like cytokines and perhaps even some histamine.


Abstract

Niaprazine is a histamine H1-receptor antagonist with marked sedative properties. It has been employed in subjects with behavior and sleep disorders. No data concerning the use of niaprazine in subjects with autistic disorder are reported in the literature. The authors performed an open study to assess niaprazine efficacy in a sample of 25 subjects with autistic disorder and associated behavior and sleep disorders. Niaprazine was administered at 1 mg/kg/day for 60 days. A positive effect was found in 52% of patients, particularly on hyperkinesia, unstable attention, resistance to change and frustration, mild anxiety signs, heteroaggressiveness, and sleep disorders. Statistical comparison between responders and nonresponders showed no influence on niaprazine effect by age over or under 12 years, presence of neurologic signs, epilepsy, or abnormalities seen on brain imaging. Niaprazine was more efficacious in subjects with a mild or moderate degree of mental retardation. No side effects were observed. Because of its sedative effects and good tolerability, niaprazine can be used as a first-choice drug to improve behavior and sleep disorders in patients with autistic disorder. (J Child Neurol 1999;14:547-550).


Abstract

Using single subject research design, we performed pilot research to evaluate the safety and efficacy of famotidine for the treatment of children with autistic spectrum disorders. We studied 9 Caucasian boys, 3.8-8.1 years old, with a DSM-IV diagnosis of a pervasive developmental disorder, living with their families, receiving no chronic medications, and without significant gastrointestinal symptoms. The dose of oral famotidine was 2 mg/kg/day (given in two divided doses); the maximum total daily dose was 100 mg. Using single-subject research analysis and medication given in a randomized, double-blind, placebo-controlled, cross-over design, 4 of 9 children randomized (44%) had evidence of behavioral improvement. Primary efficacy was based on data kept by primary caregivers, including a daily diary; daily visual analogue scales of affection, reciting, or aspects of social interaction; Aberrant Behavior Checklists (ABC, Aman); and Clinical Global Improvement scales. Children with marked stereotypy (meaningless, repetitive behaviors) did not respond. Our subjects did not have prominent gastrointestinal symptoms and endoscopy was not part of our protocol; thus, we cannot exclude the possibility that our subjects improved due to the effective treatment of asymptomatic esophagitis. The use of famotidine for the treatment of children with autistic spectrum disorders warrants further investigation.

Conclusion
Several important conclusions can be drawn based on a few hours of research on Google Scholar.
·         Your child may be subject to an allergic response that is outwardly hardly visible

·         The allergic response may be visible first as challenging autistic-like behaviour, rather than sneezing, runny nose, red eyes or wheezing

·         H1 antagonists can supress both the autistic-like behaviours and the typical allergic reactions

·         People do not all react the same way to H1 antagonist drugs.  A little experimentation is in order.  A drug that should work 24 hours can be effective for only 4 hours.

·         To avoid excessive use and possible side effects, allergists often combine different H1 antagonists, even though the information from the drug firm warns not to do this.

·         In some people the old H1 antagonists, that make you drowsy, work better than the new 2nd and 3rd generation drugs.

·         One old H1 antagonist called Ketotifen, seems to work wonders for some people.  It is both a mast cell stabilizer and a histamine receptor blocker.

I have ended up with a combination of Ketotifen and Claritin.  Claritin has an effect on behaviour within 20 minutes, Ketotifen had no apparent impact in the short term whatsoever.   You cannot keep giving Claritin every 4 hours.  It is supposed to be 10ml per day.
The day after taking Ketotifen things did change, and without having to overuse the Claritin.  The allergy is still mildly visible, but the challenging behaviours have gone.

I wish I had known about this last summer.  When Monty was aged 9, he went completely berserk on an aircraft and so as to restrain him, I was almost sitting on top of him, holding arms, legs and head; the flight attendant was asking if he would like a glass of water.  This year I will be well prepared with my Ketotifen/Claritin combo and anticipate no such problems.



Related Post:-

More on anti-histamines in Autism and introducing H4