UA-45667900-1

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.

  
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


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

Heart

Target
β1, (β2): increases
M2: decreases

Other

Target
α2: aggregates
---
β2: inhibits

Endocrine system


Target
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.



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.






20 comments:

  1. Transcutaneous auricular vagal nerve stimulation (basically TENS on the ear lobe) is supposed to improve vagal nerve tone and autonomic function. I am planning on trying it, but before I do I want to monitor my heart rate variability (a good marker for autonomic function) for a while to get a baseline and then see if it actually improves HRV.
    https://forums.phoenixrising.me/index.php?threads/make-your-own-vagus-nerve-stimulator.59129/

    ReplyDelete
    Replies
    1. Hi Rhyothemis

      Did you try TENS device? Pls share feedback in case you did.

      Thanks,
      Rahul

      Delete
  2. Hi Peter I got my hands on some verapamil of 80 mg. I want to try a trial starting Thursday because my daughter is free from school for 4 days. My daughter is 8 y, with severe autism, around 25 kg so I plan to start with 20 mg (to cut the pill somewhat in 4 parts) one dose in the morning and one in the early afternoon. My daughter dose not takes any medicine at the moment beside lactulose for constipation she takes also melatonine 3 mg at night and some vitamins (B complex, D, B12, folinic acid, etc minerals (mag, zn) and amino acids (serine, threonine, glutamine and arginine) and some herb tincture for SIBO. Do you think I cand give her verapamil in the same time with her routine supplement cocktail? After how long do I will know that she is a responder? Thank you for any thought!

    ReplyDelete
    Replies
    1. prada, Verapamil's effect on anxiety/aggression is within an hour of the very first dose. Give it to her at a time you will be able to observe her behavior for next couple of hours.

      I would start with just a single 20mg dose. In Monty's case a single dose was enough to see the benefit, he went from anxious/stressed/aggressive to calm. I would make the trial at a time of day you are not giving the supplements.

      Verapamil's effect on GI issues will take a little longer, but if this is going to happen, it will develop over then next days.

      Delete
  3. I have access to the calcium channel blocker called amlodipine. Is it comparable to verapamil?
    Thank you!

    ReplyDelete
    Replies
    1. Linda, calcium channel blockers are all slightly different. The effects of Verapamil will overlap with the effects of Amlodipine, but there will be differences.

      Some people using Verapamil for autism are actually benefiting from its effect not on L-type channels, but on Q channels like Cav2.1.

      I looked at the research and then picked Verapamil. It worked so I never tried anything else.

      If Amlodipine is beneficial, do let us know.

      Delete
  4. Hi Peter,

    I had a question when reading your post. Since, verapamil activates the Nf-KB transcription factor and increases expression of the IL-6 gene, wouldn't this mean verapamil has pro-inflammatory effects as well?

    In the paper on the IL-6 gene you linked, the researchers wrote that "the increase of IL-6 ... was independent of a concomitant increase of IL-1a, IL-1b, or TNF-a."

    Perhaps the tiny pro-inflammatory effects verapamil has is outweighed by the tremendous benefits it has for allergies?

    Thanks again for sharing your expertise on such an important topic.

    ReplyDelete
    Replies
    1. Nothing is simple. Here is another extract from a different paper:

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788213/

      "Calcium channel blockers (CCBs) such as verapamil exert their cardiovascular effects by blocking voltage-dependent L-type calcium channels. Increased calcium influx through type L calcium channels causes the activation of various signaling cascades, such as reactive oxygen and nitrogen species and activation of proinflammatory cytokines. According to previous studies, verapamil can inhibit the production of inflammatory cytokines such as TNF-α, IL-1 and IL-6 and increase plasma levels of inflammatory cytokines such as IL-10."

      This would appear to contradict the previous paper.

      We also have to remember that even IL-6 can be both a pro-inflammatory and an anti-inflammatory cytokine. In chronic inflammation it is pro-inflammatory.

      Delete
    2. Thank you so much!

      I just read over the paper. It appears that calcium ions are also used in the production of inflammatory mediators, which just adds to the benefits of using verapamil.

      I also found this paper by Dr. Theoharides interesting. He created a novel flavone, methlut, which he found to be a stronger mast cell inhibitor than luteolin. He wrote that "the mechanism of action for methlut might be due to its ability to inhibit intracellular calcium level increases."

      Since you have been using verapamil for so long, I am sure this is not news to you.

      The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells
      https://www.sciencedirect.com/science/article/abs/pii/S0091674914015747

      Delete
  5. Hi Peter
    Do you know any alternative to verapamil for my son (10 y.o) - he has low blood pressure and gets dizzy from verapamil. I am wondering if there are any other mast stabilizing agents as an alternative? He has allergies and are treated for that. I am sure there is an inmunological component in his autism - both because of the allergies but also because of his tendency to easily get really high fevers.

    I started seing autistic traits in him from age 2,5-3. He seemed to regress on several parameters after some infections: regression was socially, he was more and more withdrawed, he developed echolalia and he started loosing blander control for a period of time, after having had full control.
    Our psychiatrist says that regressive autism is quite rare, but I'm sure there was (and is) signs of regression, even though it is not severe enough to be called regressive autism.

    Best regards

    ReplyDelete
    Replies
    1. Cromolyn sodium is a good mast cell stabilizer. Ketotifen is another option. It all depends where you live and so what options you have. Not all antihistamines are equal and you can try several and see what works best. I like Cetirizine and Azalastine, but people respond differently.
      Many people with mast cell issues take more than one antihistamine. Quercetin is also worth a try.

      Delete
    2. Thanks - again - for sharing your profound insight. I have ordered quercetin. Will write here after we have trialed it.

      As for the allergy medications, we are switching between levocetirizine and fexofenadine, as these should be the least sedative and he is struggling with fatigue. Fexofenadine has a longer half life, but he needs the adult dose to get enough effectiveness. I will look into your recommendations 👍
      Have just "ordered" genetic testing (whole genome sequencing) and perhaps it can (also) tell us if something is up with how he metabolizes meds, since he needs higher doses of antihistamines.

      Best regards

      Delete
  6. Hi Peter thanks for your work. Bought your book and have been reading your blog for 3-4 years. Recently tried verapamil for my 14 year old son with rage episodes, etc and it was remarkable for that at 20mg 2- 3 times a day. Good mood, etc. Then at day 4-5 a very noticeable increase in OCD which has been a key issue of his as well, but triggered in the past with brain inflammation (pans pandas diagnosed in 2022 treated with Ivig). Would you have any perspective into why his ocd would increase 4-5 days into the trial and not dissipate over the course of this trial? No other side effects. He is on low dose risperidone (.65 mg) and I’ve wondered if that complicates things but I’m doubtful on that. Could it be binding affinity of verapamil to serotonin or melatonin? Could it be something with cerebral calcium from ER stress and adding verapamil just is too much and interrupts the neurotransmitter signaling. Pretty encouraging but discouraged at the same time. My feeling is it still points to mast cell relief as we’ve seen similar relief from Claritin for example. But maybe a different calcium blocker? What are your thoughts on this phenomenon we are experiencing with verapamil? Thanks again

    ReplyDelete
    Replies
    1. If it was me I would try Verapamil without the Risperidone.

      You could try a different calcium channel blocker. In our case Amlodopine also works well. It is similar but not the same as Verapamil.

      All these drugs have multiple effects and odd reactions can be expected.

      Delete
    2. Hey thank you so much for the reply. I brought amlodipine up to doctor today and they are open to it. Was curious on dosage for this purpose of preventing mast cell degranulation. He’s 93 lbs 14 years old. She mentioned taking the 2.5 mg tablet and quartering it and starting one a quarter a day of that tablet and see. That would be .63 mg/day. What was your son’s experience in dosage if you don’t mind sharing. Thanks a million

      Delete
    3. The dose I use adjusted for your son's weight is 1.6 mg once a day.

      Delete
    4. Many thanks. I’ll be sure to update this entry with what we see with Amlodipine.

      Last questions for now: with verapamil, we could see results in 30-45 minutes. What about Amlodipine?

      When we give it, does it work that way (that quickly) in the calcium signaling in the brain, or take longer to see an effect for our purposes of mast cells, rage, anxiety.

      Have you seen it provide a “anti-degranulization” effect to mast cells for the hours in between the next daily dose.

      Lastly, curious why you tried Amlodipine.

      Delete
    5. Also, we were instructed not o give once daily (first thing in morning), which I assume is common with this drug.

      Let me know if this is the way you’ve given it in your situation. Thanks!

      Delete
    6. Verapamil blocks several ion channels but its greatest effect is on Cav1.2 whereas Amlodipine has greatest effect on Cav1.3.

      So the effects of the 2 drugs should be somewhat different. I do not see any cognitive or speech benefit from Verapamil. One reader saw a cognitive/speech benefit from Amlodipine, so I tried it.

      Verapamil needs to be taken 3 times a day, whereas Amlodipine is long lasting and so you can take it once a day. I give it before breakfast with all the other pills. This makes things very simple.

      I would go back to Verapamil for summertime raging if needed. I now add Pioglitazone during spring and summer and have not needed to switch back from Amlodipine to Verapamil.

      Pioglitazone is a diabetes drug that has actually been trialed in autism. It has some specific anti-inflammatory properties that fit our summertime raging.

      Delete

Post a comment