Sodium benzoate (Cinnamon) trialed for Schizophrenia (Adult-onset Autism)

Regular readers will have noticed that behavioral diagnosese like autism, ADHD, schizophrenia or even intermittent explosive disorder (IED) do not impress me.  I think that patients deserve a biological diagnosis from a neurologist.

To me, Schizophrenia might as well be called adult-onset autism and ADHD be called autism-lite.

We have already seen an overlap in the genetics/channelopathies of these three conditions.

Schizophrenia affects adults that developed “normally” as children and so they do not have the physical brain damage that has been shown to occur in many cases of autism.  According to Courchesne, the physical abnormalities he finds in autistic brains have occurred before most children even get diagnosed (before 3-5 years of age).  The young brain does remain plastic and this appears to explain why some children make excellent progress.  The various dysfunctions in utero and thereafter have caused some structural abnormalities in the brain.  In schizophrenia, the dysfunctions occur well after the brain has matured; so the result is different.  There are nonetheless very many similarities both in the underlying genetics and also in the observed behaviors.

So I term Schizophrenia, adult-onset autism.  (Many years ago, autism was called child onset Schizophrenia).  Any therapies that show promise in adults with schizophrenia should be trialed in children and adults with autism.

Just as there are many different dysfunctions that can lead to autism, there will be many that lead to schizophrenia.  I believe that there will be a wide overlap between those two groups of dysfunctions.

Back to Sodium Benzoate, Cinnamon and Schizophrenia

In my last post I started to look at Parkinson’s and COPD (severe asthma) and I suggested that the same anti-oxidant gene DJ-1 might also be relevant to autism.

I proposed that sodium benzoate, taken in the form of cinnamon, might be a useful therapy.

Having received a comment that some people with autism do not find sodium benzoate agreeable (it is found in carbonated drinks and is a common food additive), I did some more checking.

Firstly, if you are histamine intolerant, you should avoid cocoa, sodium benzoate and cinnamon.

For anyone unaffected, I found that a trial has already been carried out using Sodium Benzoate in Schizophrenia, with very promising results.

Add-on Treatment of (Sodium) Benzoate for Schizophrenia

DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, placebo-controlled trial in 2 major medical centers in Taiwan composed of 52 patients with chronic schizophrenia who had been stabilized with antipsychotic medications for 3 months or longer.

INTERVENTIONS Six weeks of add-on treatment of 1 g/d of sodium benzoate or placebo.

MAIN OUTCOMES AND MEASURES The primary outcome measure was the Positive and Negative Syndrome Scale (PANSS) total score. Clinical efficacy and adverse effects were assessed biweekly. Cognitive functions were measured before and after the add-on treatment.

RESULTS Benzoate produced a 21% improvement in PANSS total score and large effect sizes (range, 1.16-1.69) in the PANSS total and subscales, Scales for the Assessment of Negative Symptoms–20 items, Global Assessment of Function, Quality of Life Scale and Clinical Global Impression and improvement in the neurocognition subtests as recommended by the National Institute of Mental Health’s Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative, including the domains of processing speed and visual learning. Benzoate was well tolerated without significant adverse effects.

CONCLUSIONS AND RELEVANCE Benzoate adjunctive therapy significantly improved a variety of symptom domains and neurocognition in patients with chronic schizophrenia. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for new drug development for schizophrenia.

As to be expected, the proposed method of action is nothing to do with DJ-1 and oxidative stress.  They believe it is all about enhancing NMDAR-mediated neurotransmission.

Quite frankly, I do not mind why they think it works, or who is right.

For me what matters is that in adult-onset autism 1 g/day of sodium benzoate produced a 21% improvement in PANSS total score and in other rating scales. 

If you are wondering what is a PANSS score, according to Wikipedia:-

The PANSS or the Positive and Negative Syndrome Scale

To assess a patient using PANSS, an approximately 45-minute clinical interview is conducted. The patient is rated from 1 to 7 on 30 different symptoms based on the interview as well as reports of family members or primary care hospital workers.

Positive scale

7 Items, (minimum score = 7, maximum score = 49)

·         Delusions

·         Conceptual disorganization

·         Hallucinations

·         Hyperactivity

·         Grandiosity

·         Suspiciousness/persecution

·         Hostility

Negative scale

7 Items, (minimum score = 7, maximum score = 49)

·         Blunted affect

·         Emotional withdrawal

·         Poor rapport

·         Passive/apathetic social withdrawal

·         Difficulty in abstract thinking

·         Lack of spontaneity and flow of conversation

·         Stereotyped thinking

General Psychopathology scale

16 Items, (minimum score = 16, maximum score = 112)

·         Somatic concern

·         Anxiety

·         Guilt feelings

·         Tension

·         Mannerisms and posturing

·         Depression

·         Motor retardation

·         Uncooperativeness

·         Unusual thought content

·         Disorientation

·         Poor attention

·         Lack of judgment and insight

·         Disturbance of volition

·         Poor impulse control

·         Preoccupation

·         Active social avoidance

PANSS Total score minimum = 30, maximum = 210

Note regarding Histamine

Some people have a deficiency of diamine oxidase, this means that their body cannot break down histamine in their food, or produced by their food.  They are histamine intolerant.

Histamine and histamine intolerance

There are also mast cell disorders:- Mast Cell Activation Syndrome (MCAS) and Mastocytosis that can affect some people with autism.

This area is not well understood and is subjective to diagnose and therefore treat.  Much will depend on which country you happen to live in.

Some people may have pollen allergies, but be histamine tolerant when it comes to food.  This just means that they produce enough diamine oxidase.

Some people have debilitating problems associated with mast cell disorders combined with histamine intolerance.

Histamine Intolerance

Many people with autism have allergies.  Some people have food intolerance.

In an allergic response, an allergen stimulates the release of antibodies, which attach themselves to mast cells. When histamine is released from the mast cells it may cause one or more of the following symptoms

· Eyes to itch, burn, or become watery

· Nose to itch, sneeze, and produce more mucus

· Skin to itch, develop rashes

· Sinuses to become congested and cause headaches

· Lungs to wheeze or have spasms

· Stomach to experience cramps and diarrhea

The release of histamine can be caused by almost any allergen. Examples include inhalant allergens (ragweed pollen, dust mite, etc.), drugs (penicillin, aspirin), stinging insect venoms, and foods (egg, wheat, milk, fish, etc.).

Histamine in Foods

There are many foods that contain histamine or cause the body to release histamine when eaten. These types of reactions are food intolerances, and are different from food allergy, in that the immune system is not involved in the reaction. The symptoms, however, can be the same as a food allergy.

An enzyme called diamine oxidase should break down any histamine that is absorbed from a histamine-containing food. So when you eat a food which contains histamine it should not affect you. However, some people have a low level of this enzyme. When they eat too many histamine-rich foods they may suffer ‘allergy-like’ symptoms such as headaches, rashes, itching, diarrhea, and vomiting or abdominal pain. This is called histamine intolerance.

Fermented foods may cause allergy symptoms because they are either rich in histamine or because yeast or mold is involved in the fermentation process.

Histamine-Rich Foods (including fermented foods):

· Alcoholic beverages, especially beer and wine.

· Anchovies, Mackerel

· Cheeses, especially aged or fermented cheese, such as parmesan

· Dried fruits such as apricots, dates, prunes, figs and raisins

· Fermented foods, such as pickled or smoked meats, sauerkraut

· Mushrooms, spinach, tomatoes, avocados

· Processed meats - sausage, hot dogs, salami, etc.

· Sardines, Smoked fish - herring, sardines, etc.

· Sour cream, sour milk, buttermilk, yogurt

· Soured breads, such as pumpernickel, coffee cakes and other foods made with large amounts of yeast.

· Vinegar or vinegar-containing foods, such as mayonnaise, salad dressing, ketchup, chili sauce, pickles, pickled beets, relishes, olives.

Histamine-Releasing Foods:

· Alcohol

· Bananas

· Chocolate

· Eggs

· Fish/Shellfish

· Milk

· Papayas

· Pineapple

· Strawberries

· Tomatoes

Allergies, Autism and Cognitive Impairment

Previous posts showed how pollen allergies can lead to summertime flare-ups in autism; most noticeable are violent/aggressive behaviours, but there is actually much more going on.

I established that Verapamil, the calcium channel blocker, and surprisingly also a mast cell stabilizer, can very effectively extinguish the aggression, but without really solving the usual allergy symptoms like itchy eyes.  As a result, you need to use a convention anti-allergy treatment as well.

Asthma/Pollen Hot Spots

Any asthma suffer will be able to tell you about the places that make them feel worse and the places that places that reduce their symptoms.  It seems that pine forests high in the mountains and on certain coastlines are best.

Forested areas around cities are not good for asthma, Berlin being an example. So you can easily check if you live in an asthma hot spot, or in a better place.

Cognitive Impairment

We just spent two weeks under the olive trees beside the sea in Greece, which I would classify as a low pollen location.  Having returned home to a big city and a house directly opposite a forest, we could see the effect of an asthma/pollen hot spot.

Monty, aged 11 with ASD, mild pollen allergy and mild asthma, did change his behaviour almost immediately.

The Verapamil does continue to block aggressive behaviour, but what changed was an immediate return of mild atopic dermatitis (red patches behind knees) and what Monty’s brother Ted, aged 14, described as Monty became “more stupid”.  It is not a nice way to describe it, but when you look closely, it is there.  The allergy has effectively lowered his cognitive function.  It is very easy to check, just ask some simple maths questions or memory questions (what did you have for breakfast?).  It is as if he is very mildly intoxicated (drunk), he is not staggering around, but he is not as sharp as he was in Greece, or at home in the spring.

Faced with an aggressive child, the last thing you would bother about is how good he is at mental maths, and so you would probably never notice it.  But having solved the aggression we are left with the observation that the allergy causes some temporary cognitive impairment.  I say temporary, because if you take away the allergens, everything improves and returns to where it was.

What is going on?

We know that allergens cause mast cell degranulation, which releases histamine, IL-6, and other pro-inflammatory substances in a chain reaction.  We know that these cross the BBB (blood brain barrier) where there are several types of histamine receptor.  The body has at least 4 types: - H1, H2, H3 and H4, and maybe more not yet identified.

Typical anti-histamines only block H1, and the newer ones are specifically designed not to cross the BBB, so as not to make you drowsy.  We later discovered that most H1 anti-histamines have moderate mast cell stabilizing properties, meaning they do reduce the release of histamine itself.

Calcium channel signaling is known to be disturbed in autism and there is excess physical calcium found in the autistic brain.  This did suggest that modifying calcium channel behaviour might be of benefit.  A known genetic variation in autism does affect the L-type calcium channels.  This suggested that blocking the L-channels might be helpful.  This was shown to be true in Timothy syndrome and I showed it to be true in Monty.

Other research has shown that Verapamil is an effective mast cell stabilizer, which did come as a surprise.

Now we come back to the effect of the allergy.  If untreated, it will “dumb down” the child and also lead to extreme behaviours like aggression, but also even odd physical tics, like moving the head forwards and backwards like a pigeon.

Perhaps there is a two stage process going on, which ultimately leads to the aberrant signaling of the L-type calcium channels and aggression.  Or is it just a progression from mild to severe?

Is it a coincidence that a calcium channel blocker can stabilize mast cells?  I think it unlikely.

Autism as an Allergy of the Brain

The idea put forward by Professor Theoharides, that autism is, at least in part, an allergy of the brain, looks more and more valid.  It was the subject of an earlier post.

Is a Subtype of Autism an Allergy of the Brain?

I do wonder how much mental retardation (MR) / cognitive impairment is also caused by the same mechanism.  Depending on how you define “autism” and whose figures you use, between 20% and 50% of people with autism have MR.  MR is defined as an IQ of 70 or less.

·        Mild retardation: Mild retardation: IQ level 50-55 to approximately 70 (85% of people with mental retardation are in this category)
·        Moderate retardation: IQ level 35-40 to 50-55 (10% of people with mental retardation)
·        Severe retardation: IQ level 20-25 to 35-40 (3 - 4% of people with mental retardation)
·        Profound retardation: IQ level below 20 or 25 (1 - 2% of people with mental retardation)

I would suggest that many people with autism might be “cognitively impaired” by allergies, be they caused by pollen, cats, dust, food, detergents, pollution or anything else.  Maybe they just dropped from a potential IQ of 120 to 110, or maybe they dropped from 80 to 35 and are now known as severely retarded.

Verapamil treats more than aggression and SIB

Based on my sample of one, it would be conceivable that Verapamil merely treats aggression and self-injurious behaviour (SIB), and that allergies are a side issue.  But thanks to the feedback on this blog, it is clear that Verapamil is treating the allergy.  One reader gave very extensive feedback showing how Verapamil greatly reduced her child’s GI problems (caused by food intolerance/allergies) and improved behaviour.  So based on a sample of two, Verapamil’s effect does seem to be related to mast cell degranulation and allergies.

Conclusion

I am very happy to have discovered the benefits of Verapamil, but I will continue to look into how further to reduce the “brain allergy effect”.  Perhaps the allergy is somehow affecting the excitatory/inhibitory balance of the Neurotransmitter GABA, I say this because Monty’s behaviour somehow resembles life without Bumetanide.  

Bumetanide’s role in autism is to lower brain Cl^- concentration and to switch GABA to be inhibitory.  A recent comment on one of my Bumetanide posts was from somebody highlighting a paper that questioned whether enough Bumetanide crosses into the brain to switch GABA to be inhibitory.  

Note that a recently published comprehensive review on the use of bumetanide in the treatment of neonatal seizures indicates that theres is no evidence to support the use of this drug in the treatment of central nervous system disorders via the NKCC1-dependent mechanism described above, as at the very low doses that are given to infants and children bumetanide does not reach sufficient levels in the brain.

direct link to the original review:
http://onlinelibrary.wiley.com/doi/10.1111/epi.12620/pdf

It is conceivable that allergies affect the blood brain barrier (BBB), although you might expect allergies to weaken the BBB, rather than strengthen it; but the body does plenty of strange things.  So a second daily dose of Bumetanide just might help.  In France, the autism researchers working with Bumetanide do give it twice a day.

The simplest method to reduce the “brain allergy effect” would be to just avoid the allergen(s).  In the case of Monty, this would be to go and live in a low pollen environment, and perhaps even avoid cats.

Since 30+% of people with autism apparently suffer from asthma, then 30% of people with autism might also find behavioral relief by avoiding pollen.  Those suffering from aggression and SIB would very likely benefit dramatically from Verapamil.

This might also suggest that residential facilities for people with severe autism should be in low pollen areas.

Incidentally, our local special needs school used to be surrounded by a rampant overgrowth of ragweed/ambrosia.  This is one of the most notorious plants for causing allergies in humans.  The current number 1 in the ATP world tennis rankings then gave them some money to tidy up the grounds.  Coincidentally, like many of the “inmates”, he also favors a gluten free diet.

“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.

Mast cell tryptase potentiates histamine-induced

contraction in human sensitized bronchus

  

Discussion

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.

Abstract

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.

COMPARATIVE STUDY OF AZELASTINE AND VERAPAMIL IN THE MODIFICATION OF OVALBUMIN SENSITIZED LUNGPARENCHYMAL TISSUES OF GUINEA PIGS 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

Calcium Channel Blockers Activate the Interleukin-6 Gene

Via the Transcription Factors NF-IL6 and NF-kB in

Primary Human Vascular Smooth Muscle Cells

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:

Verapamil as Therapy for Children and Young Adults With Dravet Syndrome

and their sources were:-

Lefrandt JD, Heitmann J, Sevre K, Castellano M, Hausberg M, Fallon M, Fluckiger L, Urbigkeit A, Rostrup M, Agabiti-Rosei E, Rahn KH, Murphy M, Zannad F, de Kam PJ, van Roon AM, Smit AJ. The effects of dihydropyridine and phenylalkylamine calcium antagonist classes on autonomic function in hypertension: the VAMPHYRE study. Am J Hypertens. 2001 Nov;14(11 Pt 1):1083-9.

Petretta M, Canonico V, Madrid A, Mickiewicz M, Spinelli L, Marciano F, Vetrano A, Signorini A, Bonaduce D. Comparison of verapamil versus felodipine on heart rate variability in hypertensive patients. J Hypertens. 1999 May;17(5):707-13.

Forslund L, Björkander I, Ericson M, Held C, Kahan T, Rehnqvist N, Hjemdahl P. Prognostic implications of autonomic function assessed by analyses of catecholamines and heart rate variability in stable angina pectoris. Heart. 2002 May;87(5):415-22.

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.

  

The vagus: A mediator of behavioural and visceral features associated with autism 

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.

Investigating the Autonomic Nervous System Response to Anxiety in Children with Autism Spectrum Disorders

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:

1. parasympathetic nervous system (PSNS)

PSNS is often considered the "rest and digest" or "feed and breed" system

2. sympathetic nervous system (SNS),

SNS is often considered the "fight or flight" system

 3.enteric nervous system (ENS).

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

Heart

Target	Sympathetic (adrenergic)	Parasympathetic (muscarinic)
cardiac output	β1, (β2): increases	M2: decreases

Other

Target	Sympathetic (adrenergic)	Parasympathetic (muscarinic)
platelets	α2: aggregates	---
mast cells - histamine	β2: inhibits

Endocrine system

Target	Sympathetic (adrenergic)	Parasympathetic (muscarinic)
pancreas (islets)	α2: decreases insulin secretion from beta cells, increases glucagon secretion from alpha cells	M3:[ increases secretion of both insulin and glucagon.[16][17]
adrenal medulla	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.

Conclusion

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.