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.
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:-
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.
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.
Autonomic Nervous System (ANS)
The ANS is divided into three main sub-systems:
PSNS is often considered the
"rest and digest" or "feed and breed" 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
- 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.
Other
Target
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M3:[
increases secretion of both insulin and glucagon.[16][17]
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Nerve "Wiring Diagram"
The PSNS (parasympathetic nerve system) is wired together
via the Vagus Nerve
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.
