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