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 1^st generation and other people say 2^nd 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 -

Compared pharmacological characteristics in humans of racemic cetirizine and levocetirizine, two histamine H1-receptorantagonists

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).

Antihistaminic, Anti-Inflammatory, and Antiallergic  Properties of the Nonsedating Second-Generation Antihistamine Desloratadine: A Review ofthe Evidence

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.

 

 

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.

The histaminergic system in brain: neurophysiology

Other good ones, not available free include:

The physiology of brainhistamine

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.

Niaprazine in the Treatment of Autistic Disorder  (H1 antagonist)

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).

 Famotidine treatment of children with autistic spectrum disorders: pilot research using single subject research design.  H2 receptor antagonists

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 2^nd and 3^rd 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

Controlling Anger In Autism with H1 antagonist, Claritin

Today’s post is about a little experiment I carried out.

If you have been following my blog, you will know that I have been looking into certain related diseases to autism (comorbidities).  One of the subjects that come up in asthma research is the role of a special kind of cell, called the mast cell.  One autism researcher in particular, Dr Theoharides, is also of the opinion that the mast cell plays a key role in autism.

For today, I am not going to give you the full detail on mast cells, just to tell you that play a key role in inflammatory responses and that they can get over-activated and cause problems in various parts of your body.

It is well established that you can calm down your overactive mast cells with histamine antagonists.  There are H1 antagonists like Claritin/Loratadine and H2 antagonists like Tagamet.  H1 antagonists are commonly used to control allergies, and H2 antagonists are commonly used for stomach ulcers and GERD.

Claritin is off patent, cheap and available over the counter in many countries.

I was reading about mast cells and various associated disorders; I came across a site written by a lady whose life had been taken over by over-activation of her mast cells.  It had taken many years to get an accurate diagnosis.  One of her symptoms was an unpleasant tingling sensation in her arms and legs.

 

This began to ring some bells in my mind.  Sometimes, you read of autistic people talking about a horrible sensation like something is crawling up their arms and legs.  This then provokes a big tantrum.

Monty, aged 10 and with ASD, is newly communicative about his feelings.  On occasion, when things are not going swimmingly, he now says “Ï want to be nice”, as he struggles to maintain self-control, and then something like “to hit your leg”  or “I feel angry” and then, if no intervention is made, he might actually hit his leg.  We fortunately no longer have classic autism tantrums, but it is still clear that something is not quite right.

This is a relatively recent development and so I felt the need to address it promptly.  So today when the pattern developed again, I was ready with a spoonful of Claritin.  Sure enough, within half an hour, everything was calm again and has remained so.

 

Monty did have mild signs of allergy, but not enough to have raised any concerns.

The immune system is intimately connected to the HPA-axis (hypothalamic-pituitary-adrenal axis), which controls and releases a whole range of hormones into your body.  So something going astray in your immune system can produce a whole cascade of effects which may appear to have nothing to do with the immune system.

Conclusion

If your child with ASD exhibits anger, tantrums or violence, try a dose of an anti-histamine drug like Claritin.  If everything resolves itself within half an hour, you would be well advised to read up on mast cells.

The self-proclaimed master of the mast cell is a Dr Theoharides, who has published many papers and has developed various supplements.  He has a very thorough website linking to his papers and some videos.

Related posts:-

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

More on anti-histamines in Autism and introducing H4

Scooter Therapy

One of the most read posts on this blog is the one about Lego Therapy.  We have lots of small Lego sets and they are indeed great as both tools and toys.  They are not exactly cheap, once you buy many of them.

Monty, now aged 10 and with autism, is also a big fan of music therapy, which regularly shows up as a favourite therapy among parents, although it is hard to prove its value scientifically.  In fact the other day Monty went to his first grown up ballet.  He went to see Sleeping Beauty and sat transfixed throughout the performance and behaved impeccably during the interval, surrounded by all the grown-ups in the audience.  It is clear that music has a power of its own, particularly over certain children.

Scooter therapy is my invention.  All you need is one of those new type of three wheeled scooters, which can be bought very cheaply.

Now, in any ABA programme you will have to work on both fine motor and gross motor skills, so that means finely controlling your hands to write neatly, or cut shapes with scissors and gross motor skills like kicking a football or throwing a basketball.  When you apply these skills to riding a bicycle, it may, or may not work.  Typical kids start with a small bike with stabilisers and then you soon take of the stabilisers and away they go.  You take for granted that the kids have situational awareness.  So if there is a wall straight ahead, they will apply the brakes, or swerve to avoid it.  If there is a nice row of flowers on one side, the kid may glance at them, but will soon focus again on where the bike is going.  With autistic kids the world can be very different, they may have no problem pedalling, but balance, using the brakes and situational awareness can be problems.

So I decided several months ago to take a step backwards and buy a little scooter and forget about bicycles.  The new type of three wheel scooters are great, they are more stable than the old type of two wheel scooter, but you still have to lean to turn left or right.  You can scoot on one leg, lean forwards to go fast and brake using your spare foot, or stand on the rear wheel.  All this fun and you are only a few centimetres off the ground, so it is hardly dangerous.

Well, after a few months, Monty has mastered his scooter and learnt about paying attention to obstacles, like oncoming bikes and pedestrians.  When something interesting comes into sight, he dismounts to investigate.  He can even safely scoot downhill on the pavement, while holding his ice cream and remember to stop at road junctions. 

This may not sound like much, but it is quite a transformation.  Sometimes to take two steps forward,  you have to first take one step backwards.

Scooting is also fun and you can go quite a long way.  A couple of months ago we managed to go 6km around a lake, which would have been a struggle on foot.

So, if you do not already have one, invest in a scooter.  They even have them for adults.

Endothelial Dysfunction - Oxidative Stress, Inflammation and BH4

This post is rather out of sequence, but it draws together several different topics that I have been investigating and introduces another chemical often mentioned in autism research, BH4.  The factor that links them all together is something called Endothelial Dysfunction.

This blog has already established that oxidative stress and neuroinflammation are the key drivers behind autism.  It has not been clear whether the oxidative stress causes the inflammation, vice versa, or perhaps they are self perpetuating.

In my ongoing investigation into the autism comorbidities of asthma and high cholesterol (proxy for cardiovascular disease), I have come across some tantalising fact, such as:-

• Asthma research shows that cigarette smoking gives you oxidative stress and this continues even after stopping smoking.  The oxidative stress reduces the effectiveness of asthma drugs.
• Oxidative stress is a key factor in cardiovascular disease.

• BH4 also known as Tetrahydrobiopterin, THB, trade name Kuvan or sapropterin is an enzymatic cofactor that is the subject of lots of research in cardiovascular disease and even in autism research.  As a drug, BH4 is so expensive that many national health services and insurers will not pay for it.  A pack of 30 pills of 100 mg cost $900.  The typical dose is 10-20mg per kg per day.  The cost per patient was reported to be over $100,000 per year.

The BH4 drug, Kuvan, is used to treat an extremely rare, but debilitating condition called Phenylketonuria, when the body cannot produce its own BH4.  In the UK, the National Health Service will not pay for Kuvan for the very small number of people who suffer Phenylketonuria.


A very interesting chart from the American Heart Association

The following chart was meant for cardiologists, but is extremely relevant if you want to understand autism.  I highlighted the parts in yellow.

In autism, people suffer from oxidative stress and typically exhibit hypercholesterolemia (high cholesterol).  They also suffer from neuroinflammation in the brain.  In my therapy, I use NAC to reduce oxidative stress and the behavioral impact is very marked.  In some autism trials they have given BH4 and the result have been visible, but not dramatic.  From the graphic above it would seem that BH4 is an extremely expensive way to reduce oxidative stress.

The latest BH4 autism trial was funded by the drug producer with 20 mg/kg/day.
 

Tetrahydrobiopterin as a Treatment for Autism Spectrum  Disorders: A Double-Blind, Placebo-Controlled Trial

More interesting for me is to now look into Endothelial Dysfunction and see if that is occurring in autism.

Long Term Mood Improvement using NAC in Autism

A more recent post on this subject is here:

http://epiphanyasd.blogspot.com/2014/08/nac-for-long-term-use-in-autism.html

NAC (N-Acetyl Cysteine) is an anti-oxidant that is part of the autism therapy I have implemented.  I have now received feedback from other parents who are also surprised by the positive effect it has on their child with autism.  So far, it has had a positive impact in 100% of cases.

In the literature, there are several schools of thought as to why NAC is effective. 

1. As a free radical scavenger in its own right
2. As a precursor to Glutathione (GSH)
3. As a glutamate antagonist
4. Reducing homocysteine

Glutamate is one of the brain's two most important neurotransmitters, the other being GABA.  Glutamate is excitatory and so too much of it would cause you a problem.  NAC can act as an antagonist to glumate.  This is all very nicely explained by Emily Deans, a psychiatrist in Massachusetts who has a very interesting blog of her own.

• Glutathione: We Loves It (NAC and Autism)

In my research into the autism comorbidity asthma, I also came across plenty of talk about oxidative stress and anti-oxidants.  NAC is used, but it seems like they are looking for something stronger.

The main impact is as a precursor to Glutathione (GSH)

I recently learnt that in autism (or at least the one my son is affected by) the reason is without doubt number two.  The other roles (scavenger/antagonist) are irrelevant.

The reason I know this, is that after a few months NAC effectively stopped working.  This coincided with an asthma flare-up.  Now, I initially thought that the asthma attacks had released inflammatory cytokines and that these had stimulated the ever-present neuro-inflammation in the brain.

This is highly plausible and indeed I have literature showing which cytokines are released by asthma attacks.  So I thought that by firmly dealing with the asthma, I would at the same time subdue the autism.  This did not happen.

So after a few days I came up with "plan B", which did prove to be successful.  I hypothesised that the NAC had stopped working because I was not giving enough vitamin B12, which is part of the chemical process in which GSH is synthesised from NAC.  I have no means of knowing how much is needed exactly. In related processes both vitamin B6 and B9 are also involved.

I increased the B vitamins and within hours things began to revert towards the previous behavioural equilibrium.

So it was most likely the failure of NAC to produce GSH, and thus reduce oxidative stress, that had sparked the asthma flare-up. (this is will be covered on my later post of asthma as a comorbidity in autism)

But how much B12 is needed to synthesise GSH?

In your diet you have vitamins B6, B9 and B12, but it is unclear how much is needed to synthesise GSH.  A further complication is that B vitamins are not well absorbed in the gut, and some people absorb them better than others.  Older people are known to absorb B12 poorly.  There are expensive sub lingual B vitamin supplements, but there is no evidence that they actually work better.

There are at least two NAC products targeted at older people to protect them from memory loss and Alzheimer's disease:-

• Betrinac   
• Cerefolin NAC

 Both products combine NAC with vitamins B6, B9 and B12,

                                             Over the counter NAC        Cerefolin NAC        Betrinac


N-acetylcysteine (NAC)              600mg                            600mg                     600mg
Vitamin B9 (folate)                                                          1,000 mcg               800 mcg
Vitamin B6                                                                           25mg                       20mg
Vitamin B12                                                                    1,000mcg                1,000mcg



 Both products are for preventing memory loss, rather than just increasing GSH.


For a comprehensive look into B vitamins including their role in the brain, and how they are (or are not) absorbed, take a look at this link from the US Office of Dietary Supplements.


Reducing homocysteine

Homocysteine is linked with strokes, and particularly in the US there are doctors who use NAC for the purpose of lowering homocysteine.

Dr. Baum, medical director of the Mind/Body Medical Institute, a Harvard affiliate, recommends 1,000 micrograms (mcg) of folate, plus 25 milligrams (mg) of vitamin B6, 1,000 mcg of B12, and 1,800 mg of the amino acid N-acetyl-cysteine (NAC). "With folate, B6, B12, and NAC supplements, almost everyone will have normal homocysteine levels," says Dr. Baum.

There is even a discussion about the role of homocysteine in autism.  A very recent paper from Poland is: A focus on homocysteine in autism

I think think that high homocysteine, just like low GSH, is a marker of oxidative stress.  In some of the literature it is stated that homocysteine cause oxidative stress.

Here is another paper: Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism

 

And yet another one:-

Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders

 

If you read all the papers you will come across various graphics showing biological cycles within the body, like the one below.  This is how I know that the various B vitamins are needed.

Vitamin B12 Therapy

I really just need to know how much B12 is needed and how to give it.  In the end the best resource turned out to be a  bulletin from a US medical insurer, and here it is:-

Clinical Policy Bulletin:  Vitamin B-12 Therapy

The document is very thorough; here are some key parts:-


Background

Vitamin B-12 belongs to the family of cobalamins. It is available in all animal-derived foods, and is absorbed at a rate of 5 mcg per day. After being ingested, vitamin B-12 becomes bound to intrinsic factor, a protein secreted by gastric parietal cells. The vitamin B-12/intrinsic factor complex is absorbed in the terminal ileum by cells with specific receptors for the complex. The absorbed complex is then transported via plasma and stored in the liver. Since the liver stores 2,000 to 5,000 mcg vitamin B-12 (adequate for up to 5 years), dietary deficiency of cobalamin (Cbl) is rare. In most cases, vitamin B-12 deficiency is due to an inability of the intestine to absorb the vitamin, which may result from an autoimmune disease that reduces the production or blocks the action of intrinsic factor, or from other diseases that result in intestinal malabsorption. The most frequent underlying cause of vitamin B-12 deficiency is pernicious anemia, which is associated with decreased production of intrinsic factor.


In a systematic review of randomized trials on vitamin B-6, B-12, and folic acid supplementation and cognitive function, Balk and colleagues (2007) stated that despite their important role in cognitive function, the value of B vitamin supplementation is unknown. A total of 14 trials met selection criteria; most were of low quality and limited applicability. Approximately 50 different cognitive function tests were assessed. Three trials of vitamin B-6 and 6 of vitamin B-12 found no effect overall in a variety of doses, routes of administration, and populations. One of 3 trials of folic acid found a benefit in cognitive function in people with cognitive impairment and low baseline serum folate levels. Six trials of combinations of the B vitamins all concluded that the interventions had no effect on cognitive function. Among 3 trials, those in the placebo arm had greater improvements in a small number of cognitive tests than participants receiving either folic acid or combination B-vitamin supplements. The evidence was limited by a sparsity of studies, small sample size, heterogeneity in outcomes, and a lack of studies that evaluated symptoms or clinical outcomes. The authors concluded that there is insufficient evidence of an effect of vitamin B-6, B-12, or folic acid supplementation, alone or in combination, on cognitive function testing in people with either normal or impaired cognitive function. This is in agreement with Clarke et al (2007) who stated that randomized trials are needed to ascertain the relevance of vitamin B-12 supplementation for the prevention of dementia.

Vitamin B-12 therapy can be administered orally or by injection. Vitamin B12 tablets of up to 5,000 mcg may be obtained over the counter without a prescription.

In a review on vitamin B-12 deficiency, Oh and Brown (2003) noted that, because most clinicians are generally unaware that oral vitamin B-12 therapy is effective, the traditional treatment for B-12 deficiency has been intramuscular injections. The authors cited evidence that demonstrates, however, that oral vitamin B-12 has been shown to have an efficacy equal to that of injections in the treatment of pernicious anemia and other B-12 deficiency states (Elia, 1998; Lederle, 1998; Kuzminski et al, 1998; Lederle, 1991). The authors explained that, although the majority of dietary vitamin B-12 is absorbed in the terminal ileum through a complex with intrinsic factor, there is mounting evidence that approximately 1 % of a large dose of oral vitamin B-12 is absorbed by simple diffusion which is independent of intrinsic factor or even an intact terminal ileum.
Kuzminzki et al (1998) reported on the outcome of 33 patients with vitamin B-12 deficiency who were randomized to receive oral or parenteral vitamin B-12 therapy. Patients in the parenteral therapy group received 1,000 mcg of vitamin B-12 intramuscularly on days 1, 3, 7, 10, 14, 21, 30, 60, and 90, while those in the oral treatment group received 2,000 mcg daily for 120 days. At the end of 120 days, patients who received oral therapy had significantly higher serum vitamin B-12 levels and lower methylmalonic acid levels than those in the parenteral therapy group.

 On treating B12 deficiency :-

Although the daily requirement of vitamin B-12 is approximately 2 mcg, the initial oral replacement dosage consists of a single daily dose of 1,000 to 2,000 mcg (Lederle, 1991; Oh and Brown, 2003). This high dose is required because of the variable absorption of oral vitamin B-12 in doses of 500 mcg or less. This regimen has been shown to be safe, cost-effective, and well tolerated by patients.


CONCLUSION


Long term high dose NAC will require careful supplementation with B vitamins.   If NAC is using up vitamin B12 faster than your child is absorbing it from food and supplements, B12 will be used up from the liver and other vitamin stores in the body.  These stores will eventually be depleted and vitamin B12 deficiency will result, if you continue to give NAC.  This is best avoided.

If money is of no concern, best to buy Cerefolin NAC or Betrinac.  If on a budget, then use the cheap NAC available on-line or in your pharmacy; but be careful to supplement far higher amounts of B6, B9 and B12 than the RDA (recommended daily amount).

Cerefolin NAC and  Betrinac have 400 times the RDA of B12, 4 times the RDA of B9 and 15 times of B6.  But each of these tablets only has 600mg of NAC.  In the autism trials the dose of NAC is 4 times higher.

It is evident that B12 is the key vitamin that acts as a precursor with NAC to form GSH (Glutathione), so this is the one to keep a close eye on should your child's NAC appear "to stop working".

It looks like 1,000 mcg of B12, of which 1% may be absorbed, is a fair place to start.  Such supplements are relatively inexpensive, and widely available.