Showing posts with label azelastine. Show all posts
Showing posts with label azelastine. Show all posts

Sunday, 14 June 2020

Summertime Autism Raging and Dumber in the Summer

By far the most read post in this blog is one about histamine and allergies, which means many people are searching on Google for “histamine, allergy and autism”.

Our reader Kei recently commented that his daughter, without allergy, was again showing signs of summertime raging and that his neurologist confirmed that summertime raging does indeed happen and nobody knows why.

I did figure out how to deal with our version of “summertime raging” and the post-bumetanide “dumber in the summer” phenomena.  There were several posts on this subject.  The lasting solution was to treat the raging as if it was caused by inflammation driven by pollen allergy and to note that inflammation will further worsen the KCC2/NKCC1 imbalance in Bumetanide-responsive autism, making those people appear “dumber in the summer”.  This also accounts for the “Bumetanide has stopped working” phenomenon, reported by some parents.  You need to minimize inflammation from allergy and increase Bumetanide (or add Azosemide).  My discovery was that Verapamil was actually more effective than anti-histamines and actual mast cell stabilizers. Mast cells degranulate via a process dependent of the L-type calcium channels that Verapamil blocks. Mast cells release histamine and inflammatory cytokines like IL-6.

This spring when Monty’s brother asked why Monty was acting dumber, it was time to implement the “dumber in the summer” therapies.  Add a morning tablet of cetirizine (Zyrtec) and a nasal spray of Dymista (Azelastine + Fluticasone).

Dymista is inexpensive and OTC where we live, but I see in the US it is quite an expensive prescription drug.  It is a favourite of Monty’s pediatrician and his ENT doctor. 

Summertime Regression in the Research Literature

I recently came across two very relevant papers on this subject by a proactive American immunologist called Dr Marvin Boris.  If you live in New York, he looks like a useful person to know.

In his first study he investigated whether the onset of the allergy season caused a deterioration in behavior of children with autism or ADHD; in more than half of the trial subjects, it did.

In his second study he went on to make a double‐blind crossover study with nasal inhalation of a pollen extract or placebo on alternate weeks during the winter.  This was his way to recreate the pollen season during winter.

Sixteen of 29 (55%) children with ASD and 12 of 18 (67%) children with ADHD or a total of 28 of 47 (60%) children regressed significantly from their baseline. Nasal pollen challenge produced significant neurobehavioral regression in these children. This regression occurred in both allergic and non‐allergic children and was not associated with respiratory symptoms.

In other words, half of children with autism regress when exposed to pollen, even though they may not show any symptoms of allergy, or test positive for allergy.  This should be of interest to Kei and his neurologist.

Purpose: To determine whether children with autistic spectrum disorders (ASD) or attention deficit hyperactive disorder (ADHD) exhibit neurobehavioral regressive changes during pollen seasons.
Design: A behavioral questionnaire‐based survey, with results matched to pollen counts; an uncontrolled, open non‐intervention study.
Materials and Methods: Twenty‐nine children identified with ASD and 18 children with ADHD comprised the study population. The parents of the study children completed the Allergic Symptom Screen for 2 weeks during the winter prior to the pollen allergy season under investigation. The parents of the ASD children also completed the Aberrant Behavior Checklist and the parents of the ADHD children completed Conners' Revised Parent Short Form for the same periods. The parents completed the respective forms weekly from 1 March to 31 October 2002. Pollen counts from the geographical area of study were recorded on a daily basis during this period.
Results: During natural pollen exposure, 15 of 29 (52%) children with ASD and 10 of 18 (56%) children with ADHD demonstrated neurobehavioral regression. There was no correlation with the child's allergic status (IgE, skin tests and RAST) or allergy symptoms.
Conclusions: Pollen exposure can produce neurobehavioral regression in the majority of children with ASD or ADHD on a non‐IgE‐mediated mechanism. Psychological dysfunction can be potentiated by environmental exposures. 

Pollen Exposure as a Cause for the Deterioration of Neurobehavioral Function in Children with Autism and Attention Deficit Hyperactive Disorder: Nasal Pollen Challenge 

Purpose: In a previous study it was established that children with attention deficit hyperactive disorder (ADHD) and autistic spectrum disorders (ASD) had regressed during pollen seasons. The purpose of this study was to determine if these children regressed on direct nasal pollen challenge. 

Design: A double‐blind crossover placebo‐controlled nasal challenge study. Materials and Methods: Twenty‐nine children with ASD and 18 with ADHD comprised the population. The study was a double‐blind crossover with nasal instillation of a pollen extract or placebo on alternate weeks during the winter. The pollens used were oak tree, timothy grass and ragweed. The dose insufflated into each nostril was 25 mg (±15%) of each pollen. 

Results: Sixteen of 29 (55%) children with ASD and 12 of 18 (67%) children with ADHD or a total of 28 of 47 (60%) children regressed significantly from their baseline. 

Nasal pollen challenge produced significant neurobehavioral regression in these children. This regression occurred in both allergic and non‐allergic children and was not associated with respiratory symptoms. There was no correlation to the child's IgE level, positive RAST pollen tests, or skin tests.


When I was figuring out Monty’s summertime raging and cognitive decline, several years ago, there were no significant signs of allergy present.  Nowadays there are far more visible signs of allergy.

Dr Boris does not suggest any therapy for summertime raging, but he did show that it can be driven by pollen in half of those with autism, even children who have no signs of having any allergy.

His studies were published more than a decade ago and seem to have been forgotten.  This seems a pity, but it says a lot.

I only stumbled upon his papers because I was reading another of his decade old papers.  That paper is based on his early use of Pioglitazone in autism, which resulted in several hundred children being successfully prescribed this drug.  Pioglitazone selectively stimulates the peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α.

There was a bladder cancer scare, lots of hungry lawyers and I suppose people stopped prescribing Pioglitazone for autism a decade ago.  The numerous subsequent safety studies and meta-analysis show either a small increased risk, or no increased risk, very much dependent on who financed the research.  Pioglitazone is given to people with type 2 diabetes, and they are already at an increased risk of bladder cancer.  In those people, that risk increases between 0 and about 20%, depending on the study.  We are talking about 0.07% to 0.1% of people with T2 diabetes taking Pioglitazone later developing bladder cancer.

A decade later and Pioglitazone is again back in fashion with trials in humans with autism and studies in mouse models of autism. The current autism research does not see cancer risk as reason not to use Pioglitazone.  I agree with them. 

It looks like a minority of people taking Pioglitazone are more likely to suffer upper respiratory tract infections.  That is the risk that I consider relevant.  I also note that in trials even the placebo can appear to cause upper respiratory tract infections.

Pioglitazone was covered in earlier posts, 

but there will soon be a new post.  For most people I think histamine, allergy and summertime raging will continue to be of more interest.

Tuesday, 26 July 2016

Autism, Allergies and Summertime Raging in 2016

This time of year many parents in the northern hemisphere are looking up “autism and allergy” on Google and more than 20,000 have ended up at my post from 2013 on this subject.

Not just for Stomach Health

It is clear that many people have noticed that allergy makes autism worse, even if your family doctor might think you are imagining it.

This year, thanks to our reader Alli from Switzerland, there is a new innovation in my therapy for Monty, now aged 13 with ASD.  Now we are firm believers in a specific probiotic bacteria to dampen the immune system (more IL-10, less IL-6 and likely more regulatory T cells) and minimize the development of pollen allergy and all its consequences.

There is a wide range of H1 antihistamines, mast cell stabilizers and inhaled steroids available and many readers of this blog are using a combination of some or all of these to control allergy and mast cell activation.

By using the Bio Gaia probiotic bacteria the magnitude of the allergic response to allergens is substantially reduced, so whatever problems allergy worsens in your specific subtype of autism, these should become much milder.

In our case the allergy will trigger summertime raging and loss of cognitive function.

The use of the calcium channel blocker Verapamil very effectively halts/prevents the raging, but it does not reduce the other effects of the allergy or the loss of cognitive function.

The use of the Bio Gaia probiotic reduces the problem at source; it greatly reduces the allergy itself.  Less allergy equals less summertime raging and equals less loss of cognitive function.

So for anyone filling up on antihistamines, steroids and mast cell stabilizers it could be well worth reading up on the studies on probiotics and allergy, or just make a two day trial with Bio Gaia.

Prior to Bio Gaia, we used Allergodil (Azelastine mast cell stabilizer and antihistamine) nasal spray or the more potent Dymista (Azelastine plus Fluticasone) nasal spray, plus oral H1 antihistamine (Claritin or Xyzal) and sometimes quercetin.  Verapamil was introduced to halt the raging/SIB caused by the allergy, which it does within minutes or can be given preventatively.

Each year the pollen allergy got worse than the previous year, starting five years ago at almost imperceptible and ending up with blood red sides of his nose.  With Bio Gaia there is just a faint pinkness at the side of his nose.

There are additional positive effects of Bio Gaia beyond the allergy reduction, but they do seem to vary from person to person.  In our case there is an increase in hugging and singing.  The research on this bacteria does show it increases the hormone oxytocin in mice.

In some people without obvious allergy, Bio Gaia’s effect on the immune system can also be quite dramatic.  In some people the standard dose is effective, but in others a much higher dose is needed.  The good thing is that the effect is visible very quickly and does seem to be maintained.  The main post on Bio Gaia is here.  

Bio Gaia is based on serious science but is available over the counter.

Tuesday, 12 May 2015

Minimizing Summertime Autism Flare-ups in 2015

When I first connected histamine to autism, I did not realize that this might be a common problem.  The most frequently viewed post on this blog is one on histamine and autism; so at least 10,000 people out there have googled “autism and histamine”.

Two years later, the therapy is still evolving and it should be said that, what works best for one person may not help in another person.  The main point is that in some people with autism, they face a summertime regression due to the effect of allergy.  So bad behaviours and aggression increase and good behaviours and indeed cognitive function decrease.  This appears to be the result of histamine and a pro-inflammatory cytokine called IL-6.

For the 2015 pollen season, which started early where we live, this is what we are using:-

Azelastine nasal spray, this is an H1 antihistamine that is also inhibits mast cells from “degranulating” and emptying their load of pro-inflammatory substances.  Once a day.

Quercetin is a cheap flavonoid that has numerous actions including on histamine H1 receptors, mast cells, and inflammation. 125mg two or three times a day.

Verapamil is an L-type calcium channel blocker and also a mast cell stabilizer. 40mg three times a day

Fluticasone propionate 50 µg (micrograms) – see below.  It is a steroid that has recently been shown to have some unexpected effects on mast cells.  

I have found that oral antihistamines were effective for only a couple of hours, but their effect varies widely from person to person.

In theory, Rupatadine should be the most effective anti-histamine, since it is also a potent mast cell stabilizer.  The old first generation antihistamines (that make you drowsy) could in theory be better than the new ones like Claritin, Zyrtec, since they can also cross the blood brain barrier (BBB).

Ketotifen and cromolyn sodium should also be useful, but if the allergy is pollen related, you really need the nasal spray (nasalcrom etc) to get the most effect.  In some countries they sell eye drops and not the nasal spray.  Usually the eye drops are more diluted than the nasal spray.  For example, the Azelastine eye drops contain 50% less Azelastine than the nasal spray, but are otherwise the same.  Where we live they have run out of the nasal spray but not the eye drops, so you could refill the spray with eye drops and double the number of sprays to get the same dose.

Drugs like Claritin and Zyrtec are H1 antihistamines and also partial mast cell stabilizers; they have a positive behavioral effect in some people with ASD, who are apparently allergy free.

New for 2015

I expect that two recent anti-inflammatory therapies, the Tangeretin flavonoid and the Miyairi 588 bacteria/probiotic may have a beneficial, indirect, effect on our usual summertime regression.

A more convention approach is to add fluticasone propionate to reduce the inflammation caused by allergy.  This drug is a steroid and widely used either as an inhaler to control asthma and COPD, or as a nasal spray to treat allergies.

As Flixotide inhaler, Monty, aged 11 with ASD and asthma, has already been taking fluticasone propionate for a few years.  We now use a tiny dose (50 µg), since his autism therapies have greatly reduced any asthma tendencies.

Fluticasone propionate nasal spray (Flixonase, Flonase etc) is widely sold as a treatment for hay fever and rhinitis and was recently combined with Azelastine (see above) as a treatment for moderate to severe allergies in a product call Dymista.

The combination of H1 antihistamine, mast cell stabilizer and anti-inflammatory all in one spray does seem a good idea.  The steroid dose using Dymista is actually lower than the usual dose of steroid when using Fluticasone propionate nasal spray alone.  You want to minimize the amount of steroid absorbed in the blood. When used as a spray/inhaler the amount is tiny, but still should be considered.

Dymista (Azelastine + Fluticasone propionate) does indeed work better than Azelastine alone.  There is no sign of allergy at all (no red eyes, sneezing, itchy nose), with Azelastine you still have an itchy nose.

In our case, the allergy symptoms, even minors ones, do correlate with the change in behaviour and cognitive function; so the target is no allergy symptoms at all.

If anyone has other therapies for summertime flare ups, feel free to share them.

Tuesday, 13 May 2014

“Spray Fire in my Head” and how putting it out with Verapamil links Histamine, IL6, Mast cells, Calcium Channel Cav1.2, and even the Vagus Nerve

After 18 months of researching autism, things are falling nicely into place.  For regular readers of this blog, it may seem that we have uncovered a bewildering number of issues/dysfunctions that need to be addressed by the science.  In fact, when you look closer still, you will see that many of these issues are interrelated and you do not need to treat each one.  Also, it is clear that many different methods can be used to treat the same dysfunction.  The best methods though would be the simplest, safest, cheapest and the ones that address multiple issues at once.

One such little gem is Verapamil, an extremely cheap calcium channel blocker that has been widely used for 30 years for other conditions. 

Spray Fire in my Head

Monty, aged 10 with ASD, suffers from allergies like many children.  I noticed that his pollen allergy provoked a dramatic increase in his autistic behaviors.  Last year I spent time developing a treatment for these summertime autism flare-ups, to avoid summertime misery for all of us.

My final secret weapon was not a commonly known allergy drug; in fact almost nobody would even consider it for this purpose, except those who read the old research.

Where we live, last the weekend the air was full of tree pollen and it was 280 C/ 820 F; so I was expecting a response from Monty.

He soon had red eyes, briefly rolled about on the floor and declared “spray fire in my head”.

In anticipation of the pollen season, for the last few weeks I have been giving him some mast cell stabilizing treatments, but clearly they were not sufficient; so I mixed up some extra verapamil, and as expected, a few minutes later peace was fully restored.

I have told you about channelopathies in previous posts.  Verapamil blocks the calcium channel called Cav1.2, but I did not tell you that in addition to this Cav1.2 channel affecting behavior and heart disease, it also appears to directly affect allergies and even the vagus nerve.

It would seem that one cheap little pill can address all of these issues.

The take-home points from the literature are these:-

Verapamil is very widely prescribed calcium channel blocker, used to lower blood pressure; but in the literature it is shown that:-
  • Verapamil inhibits mast cells and is shown to successfully treat asthma
  • Verapamil is more potent than the allergy drug Azelastine (the best mast cell stabilizing anti-histamine drug available)
  • Verapamil will reduce histamine release and therefore inflammatory cytokine Interleukin-6 (IL6), already elevated in autism
  • Verapamil activates the Gene for IL6
  • Verapamil alters the balance between parts of the autonomic nervous system's function, with a shift toward decreased sympathetic tone and increased parasympathetic (vagus nerve) tone
  • Autism is associated with an atypical autonomic response to anxiety that is most consistent with sympathetic over-arousal and parasympathetic under-arousal.  So increasing the parasympathetic (vagus nerve) tone is desirable.
Verapamil, Allergies and Asthma

Pollen allergies are a common trigger for asthma, and since every year many people die from asthma, the underlying science is well researched/understood.

This study has demonstrated, for the first time, that mast cell tryptase potentiates the contractile response to histamine in human isolated airways. Moreover, this potentiation occurs only in tissues derived from patients whose bronchi exhibit a contractile response to antigen, i.e. which are sensitized. The potentiation was not observed in nonsensitized tissue. The mechanism underlying the tryptase-induced potentiation is related to Ca2+ flux through voltage-dependent channels, since it was inhibited by verapamil.

Inhibition of rat mast cell degranulation by verapamil.

Calcium antagonists, e.g. verapamil, prevent exercise-induced asthma. This protective effect may proceed from inhibition of contraction of bronchial smooth muscle, release of mediators by primary effector cells, e.g. mast cells, or both. Therefore, we studied the inhibitory effect of increasing concentrations of verapamil on both in vitro antigen-induced degranulation and ionophore A23187-induced release of labelled serotonin by rat peritoneal mast cells. There was a dose-dependent inhibition by verapamil of both ovalbumin-induced degranulation of mast cells passively sensitized by incubation with mice IgE-rich serum and ionophore-induced release of tritiated serotonin by mast cells previously incubated with (3H)-5HT; the 50% inhibiting concentration was 1.4 X 10(-4) mol I-1 and 5.2 X 10(-5) mol I-1, respectively. An attractive explanation of our results is that verapamil inhibits the antigen-induced release of mediators by mast cells through its calcium antagonist effect. Our results also suggest that the preventing effect of calcium antagonists on asthma may be multi-factorial since other authors have clearly shown that these drugs inhibit contraction of guinea-pig tracheal smooth muscle in vitro.


The inhibition of mediator released by Azelastine may help to explain their protective action in anaphylaxis. Our observations are in agreement that Azelastine exerts inhibitory effect on synthesis and release of chemical mediators from mast cell (Chand et al., 1983), including the leukotrienes (Hamasaki et al., 1996).

 Azelastine is a second-generation antihistamine approved for treatment ofallergic conditions. This randomized, double-blind, placebo- and active-controlled, parallel group clinical trial evaluated the efficacy and safety of Azelastine in patients with moderate to-severe seasonal allergic conditions (Shah et al., 2009).  Reussi et al. (1980) have demonstrated the inhibition of release of chemical mediators from mast cells by Ca++ channel blocker in animals in vivo and demonstrate the inhibition of antigen-induced brocho-constriction by Verapamil in sheep, allergic to ascaris sum antigen but Verapamil failed to block in the same non-sensitized animal. It is speculated that calcium channel blocker protect against the allergic broncho-constriction predominantly by preventing the release of chemical mediators from the mast cells.

Fig. 2. Graph shows dose dependent inhibitory effect of Azelastine and Verapamil with the treatment of EC50 ovalbumin. Line in the box indicates the ovalbumin EC50 induced contraction (Control). Each point represent mean of six observationsSyed Saud Hasan et al. 49  On the other hand Henderson et al. (1983) found significant inhibition of allergic response with Nifedipine and Lee at al. (1983) also supported the finding, which observed inhibition of mediator release from human lung in vitro by Verapamil.

   Verapamil in concentration 10-10 g/ml did not exhibit any inhibition but as the concentration increases to 10-9 g/ml showed marked inhibition in contractile effect of ovalbumin EC50 (0.3x10-6). Further increases in concentration of Verapamil i.e. 10-8 g/ml completely antagonized the ovalbumin induced contraction. Azelastine in concentration of 10-9 g/ml (1ng/ml) did not exhibit any inhibition as the concentration increase to 10-8 g/ml showed mark inhibition i.e. 20% contraction to EC50 (0.3x10-6) ovalbumin, when compared before treatment with Azelastine and the concentration 10-7 g/ml antagonized the effect of EC50 (Table and Figure 2).

CONCLUSION It can be inferred from the observations that response produced by antigen can be controlled better with Verapamil than Azelastine and emerging with similar activity regardless of exact mechanism involved.

Verapamil and the IL-6 Gene

Conclusions—The results demonstrate that CCB of all 3 subclasses are capable of activating NF-IL6 and NF-kB. CCB may thus directly regulate cellular functions by affecting the activity of transcription factors independent of changes of intracellular calcium concentrations, an observation that is of interest considering the biological effects induced by CCB.

A major result of our investigations is the discovery of the activation of  transcription factors resulting from CCB treatment. In general, CCB are postulated to exert their biological effects by decreasing the intracellular concentration of calcium ions.1–4 Experimentally, this effect is usually achieved at micromolar concentrations of the drugs. However, accumulating evidence suggests that CCB, used at therapeutically effective doses (ie, at the nanomolar range), activate calcium in dependent signal transduction pathway(s) altering gene expression.14–17 Here, we show that CCB directly activate the transcription factors NF-IL6 and NF-kB in human VSMC, independent of intracellular calcium levels. This is supported by the existence of multiple regulatory regions within the intracellular part of the L-type calcium channel. It remains to be investigated, however, along which signal transduction pathway this action of CCB occurs.

Verapamil and the Vagus Nerve

Two of the most popular subjects on this blog are “autism and allergies” and “autism and the vagus nerve”.

The vagus nerve connects many parts of the body and seems to be a conduit for inflammatory signaling within the body.  It is deeply involved the process leading to arthritis and epilepsy; by stimulating this nerve with electrical signals, both epilepsy and arthritis can be reduced markedly in certain people.  It is often suggested that the GI problems in many autistic people and linked to aberrant behaviors via the vagus nerve, what some call the “gut brain connection”.

To understand what is going on and why is does affect autism we need to introduce something new, the autonomic nervous system.  For those who already know about this, the interesting finding is that:-

Verapamil alters the balance between parts of the autonomic nervous system's function  with a shift toward decreased sympathetic tone and increased parasympathetic (vagus nerve) tone.

The source of this statement is:

and their sources were:-

We learned in an earlier post about autism and the Vagus Nerve that it seems to link many strange things in autism.

We learned from Professor Porges that, for example, the neural mechanism for making eye contact is shared with those needed to listen to the human voice; people with autism struggle with both.  Anything that can “wake up” the vagus nerve system could be interesting.

In the complicated science we will see that the vagus nerve is also called the parasympathetic nervous system.  The paper below shows how this parasympathetic (Vagus) system is out of balance with the opposing sympathetic nervous system, this then leads to anxiety commonly found in autism.

Assessment of anxiety symptoms in autism spectrum disorders (ASD) is a challenging task due to the symptom overlap between the two conditions as well as the difficulties in communication and awareness of emotions in ASD. This motivates the development of a physiological marker of anxiety in ASD that is independent of language and does not require observation of overt behaviour. In this study, we investigated the feasibility of using indicators of autonomic nervous system (ANS) activity for this purpose. Specially, the objectives of the study were to 1) examine whether or not anxiety causes significant measurable changes in indicators of ANS in an ASD population, and 2) characterize the pattern of these changes in ASD. We measured three physiological indicators of the autonomic nervous system response (heart rate, electrodermal activity, and skin temperature) during a baseline (movie watching) and anxiety condition (Stroop task) in a sample of typically developing children (n = 17) and children with ASD (n = 12). The anxiety condition caused significant changes in heart rate and electrodermal activity in both groups, however, a differential pattern of response was found between the two groups. In particular, the ASD group showed elevated heart rate during both baseline and anxiety conditions. Elevated and blunted phasic electrodermal activity were found in the ASD group during baseline and anxiety conditions, respectively. Finally, the ASD group did not show the typical decrease in skin temperature in response to anxiety. These results suggest that 1) signals of the autonomic nervous system may be used as indicators of anxiety in children with ASD, and 2) ASD may be associated with an atypical autonomic response to anxiety that is most consistent with sympathetic over-arousal and parasympathetic under-arousal.

The following explanation of the Autonomic Nervous System is edited from Wikipedia.

Autonomic Nervous System (ANS)

The autonomic nervous system (ANS) is the part of the peripheral nervous system that acts as a control system that functions largely below the level of consciousness to control functions,] including heart rate, digestion, respiratory rate, salivation, perspiration, pupillary dilation, micturition (urination), sexual arousal, breathing and swallowing. Most autonomous functions are involuntary but they can often work in conjunction with the somatic nervous system which provides voluntary control.

The ANS is divided into three main sub-systems:

PSNS is often considered the "rest and digest" or "feed and breed" system
SNS is often considered the "fight or flight" system
ENS consists of a mesh-like system of neurons that governs the function of the gastrointestinal system

Depending on the circumstances, these sub-systems may operate independently of each other or interact co-operatively.

In many cases, PSNS and SNS have "opposite" actions where one system activates a physiological response and the other inhibits it. The modern characterization is that the sympathetic nervous system is a quick response mobilizing system and the parasympathetic is a more slowly activated dampening system.

In general, ANS functions can be divided into sensory (afferent) and motor (efferent) subsystems. Within both, there are inhibitory and excitatory synapses between neurons. Relatively recently, a third subsystem of neurons that have been named 'non-adrenergic and non-cholinergic' neurons (because they use nitric oxide as a neurotransmitter) have been described and found to be integral in autonomic function, in particular in the gut and the lungs

Neurotransmitters and pharmacology

At the effector organs, sympathetic ganglionic neurons release noradrenaline (norepinephrine), along with other cotransmitters such as ATP, to act on adrenergic receptors, with the exception of the sweat glands and the adrenal medulla:
  • Acetylcholine is the preganglionic neurotransmitter for both divisions of the ANS, as well as the postganglionic neurotransmitter of parasympathetic neurons.
  • Nerves that release acetylcholine are said to be cholinergic. In the parasympathetic system, ganglionic neurons use acetylcholine as a neurotransmitter to stimulate muscarinic receptors.
  • At the adrenal medulla, there is no postsynaptic neuron. Instead the presynaptic neuron releases acetylcholine to act on nicotinic receptors. Stimulation of the adrenal medulla releases adrenaline (epinephrine) into the bloodstream, which acts on adrenoceptors, producing a widespread increase in sympathetic activity.

 Circulatory system


β1, (β2): increases
M2: decreases


α2: aggregates
β2: inhibits

Endocrine system

α2: decreases insulin secretion from beta cells, increases glucagon secretion from alpha cells
M3:[ increases secretion of both insulin and glucagon.[16][17]
N (nicotinic ACh receptor): secretes epinephrine and norepinephrine

Nerve "Wiring Diagram"

The PSNS (parasympathetic nerve system) is wired together via the Vagus Nerve
The SNS (sympathetic nerve system) is wired together via the splanchnic nerves.

Autonomic nervous system, showing splanchnic nerves in middle, and the vagus nerve as "X" in blue. The heart and organs below in list to right are regarded as viscera.
The viscera are mainly innervated parasympathetically by the vagus nerve and sympathetically by the splanchnic nerves.


For those of you that made it this far, here are my conclusions.

People who have autism and any kind of allergy, be it pollen, food intolerance, asthma or anything similar, might consider asking their doctor to let them trial a very low dose of Verapamil for a couple of days.  The effect is almost instant and so there is no point trialing it for weeks.  Verapamil will lower your blood pressure, in a dose dependent fashion.  The effective autism dose for a severe allergy case is about 1mg/kg.  The half-life varies person to person, so you might need two doses a day, or you might need three.

If you know an adult with severe asthma, look hard and you may see some very mild signs of autism (need for order, anxiety, lack of flexibility etc).

It appears that in all these cases, the gene CACNA1C is misbehaving to varying degrees in different parts of the body.  This gene produces the calcium channel Cav1.2.

You could check if you have the mutated gene, but I do not see the point.  It would only tell you what might happen.  To know what actually has happened, you would need to use proteomics

This emerging science will ultimately be able to provide biomarkers for neurological conditions like autism, depression, bipolar etc, so that the neurologist will know, with certainly, what specific dysfunctions each individual person has.  At that point, behavioral assessments and psychiatry will finally be consigned to history and people will get “smart drugs”, to treat precisely diagnosed neurological dysfunctions.