Verapamil still working after 3+ years, for SIB in Autism

There are numerous ideas about how to treat self injurious behavior (SIB) associated with autism. ARI (the former home of Defeat Autism Now) have just had their take on the subject published.

https://www.autism.com/sib_book

In this blog we have seen that Tyler has developed a BCAA (branch chained amino acid) therapy, based on the idea of Acute Tryptophan Depletion, to control his son’s type of self injury.

The silver bullet for my son’s summer time raging and self-injury continues to be the L-type calcium channel blocker Verapamil.

I think many people will be skeptical of both BCAAs and Verapamil, which is entirely understandable. Unlike other aspects of autism, which are hard to measure, self-injury is really easy to measure and so you know when you have cracked the problem; what other people think tends not to matter.  

Now that Monty, aged 14 with ASD, has moved to secondary/high school the routine has changed a little and his assistant forgets to give him his midday dose of verapamil.

On the days she forgets, between 4.00pm and 4.30pm Monty starts to punch himself. On all other days and during the entire summer there has been no sign of self injury.

So when asked is it really necessary Monty keeps taking his pills, my answer remains yes.  In the case of verapamil I now have further evidence that after more than three years of use, his pollen allergy driven self injury continues to be entirely controllable using this therapy.

I do not know what ARI have put forward in their book. If your child has SIB that does not respond to whatever therapies you have tried, it might well be a helpful read. 

Other readers have noted GI and behavioral improvement from Verapamil and our doctor reader Agnieszka did try and collect case reports, but it seems parents are more interested in reading reports than writing them.
           

 Verapamil use in Autism – Request for Case Reports from Parents

Electro Convulsive Therapy (ECT) and Cannabidiol (CBD) in Autism

Today’s post is another one to fill in some of the gaps in this blog.

Psychiatrists have long been using electric shocks, of one kind or the other, to treat their patients. There is even a special school in the US (the Judge Rotenberg Center) where they used electric shocks as aversive therapy, until very recently.  

FDA Proposes Ban On Electric Shock Devices Used On Autistic Children 

Cannabis, in the form of Cannabidiol (CBD), is currently the subject of an autism trial in Israel, home to some very innovative people.

Electroconvulsive therapy (ECT)

Electroconvulsive therapy (ECT), formerly known as electroshock therapy, and often referred to as shock treatment, is a psychiatric treatment in which seizures are electrically induced in patients to provide relief from mental disorders. The ECT procedure was first conducted in 1938 is often used as a last line of intervention for major depressive disorder, mania, and catatonia.

As of 2001, it was estimated that about one million people received ECT annually.

Several hundred people with autism have been treated with ECT in the US. 

Transcranial Magnetic Stimulation (TMS)

Do not confuse ECT with Transcranial Magnetic Stimulation (TMS).

Transcranial magnetic stimulation (TMS) is a magnetic method used to stimulate small regions of the brain. During a TMS procedure, a magnetic field generator is placed near the head of the person receiving the treatment. The coil produces small electric currents in the region of the brain just under the coil via electromagnetic induction. This is rather similar to the way the base station of a rechargeable electric toothbrush works.

A big fan of TMS is Manuel Casanova, a neurologist and Autism blogger. 

A while back I watched a BBC documentary following an autistic girl adopted from a Serbian orphanage by a US family. All was going well until she later developed a serious problem with aggression and self-injury that was being treated by monthly visits to the hospital for electroconvulsive therapy.  The shocks did indeed seem to do the trick and suppress her aggressive tendencies. She is an example of what I call double tap autism, where an autistic person later suffers a profound setback for some reason. 

Video:- 

My Child, ECT (electric shock) and Me (click the picture below)

Long article from Spectrum News:- 

How ‘shock therapy’ is saving some children with autism 

What I found interesting was that you could see that when you took away the SIB, the girl was pretty high functioning. She could read, write and do math.

This made me recall a previous idea of mine that you might grade people’s autism in terms of both their good days and their bad days.  So on a scale of 100, this girl might have been 30/100.  On a bad day she was a major danger to herself and those around her and so she scored 100, but on a good day she was able to be part of the family and be educated.  She clearly had autism but not such a severe kind, so she might score a 30.

The point missed by the BBC was that in this example, electric shock therapy was not an autism therapy, it was an SIB therapy and it appears to have been a pretty effective one.

Many people with autism do not have flare-ups, they do not have SIB; they are pretty constant in their behavior, so they might be a constant 30/30.  

Cannabis 

Much is written on the internet about the use of cannabis for all kinds of conditions, the ones relevant to this blog are autism and epilepsy.  There is a study currently underway in Israel where they are using CBD oil, the non psychoactive part of cannabis, as an autism therapy.

As you might expect they had no difficulty recruiting people to participate in the study, which is still ongoing. 

Israeli Doctors to Use Cannabis to Treat Autism in First-of-its-kind Study

 In pioneering study, Israeli researchers target autism with cannabis 

Israeli Study Shows Medical Cannabis Can Treat Autism In Children

Dr. Aran is the Director of the Neuro-pediatric unit in Shaare Zedek Medical Center and his latest research involves treating the symptoms of autism using medical marijuana. “So far,” Aran tells NoCamels, “our impression is that it’s working.”

The clinical study began in January 2017 in Jerusalem at the Shaare Zedek Medical Center. There are 120 participants, including children and young adults, diagnosed with various degrees of ASD ranging from mild to severe. Dr. Aran hopes to have final results by December 2017.

According to Dr. Aran, “there are theories” for why medical cannabis can alleviate symptoms of autism, “but we don’t know exactly how. There are theories and models but we don’t know. It can’t be explained.”

This is worrisome given that cannabis is being given to children with little knowledge of why or how it may help. Of course, “We are worried with children because of the long-term impact. But it is considered mostly safe and we have already tested it with epilepsy.” Other studies, like the one published in Seizure: European Journal of Epilepsy 2016, conducted in Israel, successfully demonstrated that cannabis reduced the number of seizures of children with epilepsy. Nonetheless, Aran admits that “There are always worries that something will happen that we don’t know about.”

It is key to note that the participants are receiving cannabidiol (CBD), a non-psychoactive compound, as opposed to the more commonly known tetrahyrdrocannabinol (THC), which creates the “high” feeling. Therefore, the benefits they seem gain from the treatment “help the children cooperate more,” reduce behavioral problems, and “improve their functioning.”

While the study offers much hope for the children and families affected by ASD, Aran warns that “It won’t cure the symptoms, that’s for sure. It will never cure autism. But it certainly can help the quality of life of the families.” 

The lead researcher recently made some revealing comments, he suggested that the results so far are very positive and that it seems that the quality of life has been improved but it does not cure the symptoms. That made be draw the connection to the adopted child in the US; the therapy does indeed seem to be helpful because it is treating the “100” in the 30/100. So it may not improve cognition or reduce stereotypy, but it makes life better, just like the girl receiving the electric shocks.  Hopefully when they publish the results Dr Aran will be much more precise as to the effect of his therapy, since perhaps I am inferring too much from his comments. 

Why does any of this matter?

Well if you want to solve a problem, you have to define it and the more precisely you can define it, the more likely you are to find a solution.

If you have a girl who is a stable 30/30 with no SIB and no epilepsy, it might well be shown that neither electric shocks nor CBD oil will help here.

If you have a girl who is 30/100 with SIB and epilepsy it might well be the case that both electric shocks and CBD oil might help here; but it appears that neither will improve her core autism (which is the 30).

Mode of Action

Neither the doctors using electric shocks nor CBD oil claim to fully understand the mode of action. There are of course various plausible theories.

In the case of CBD it is an antagonist of GPR55, a G protein-coupled receptor and putative cannabinoid receptor that is expressed in the caudate nucleus and putamen in the brain. It has also been shown to act as a 5-HT_1A receptor partial agonist, and this action may be involved in the antidepressant, anxiolytic, and neuroprotective effects of cannabidiol. It is an allosteric modulator of the μ- and δ-opioid receptors as well.  Cannabidiol's pharmacological effects have additionally been attributed to PPARγ agonism and intracellular calcium release.

Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders

  

Do the therapies “work”?

What we have seen in this blog to date is that there are very many things that do seem to help specific people.  It is sometimes hard to figure out for sure the mode of action; but if high doses of biotin, or vitamin B6, or anything else consistently improve someone’s condition over years of use you have to take note.

The electric shocks did indeed seem to successfully control SIB for 3-4 weeks.  Maybe someone clever might figure out the biological cause triggering her SIB and so provide an alternative  drug therapy, but for now it seems she will go once a month for more shocks.

There are people who think long term use of CBD oil will have negative effects and I guess monthly electric shocks may also have some unforeseen consequences.

The Israeli researchers seem pretty keen on pursuing CBD oil and so they may well end up with a large enough clinical trial to make people take notice.

I do not see hundreds of parents signing up to a clinical trial of electric shock therapy, so it looks likely to be a niche therapy used by one or two clinicians.

CBD oil is the sort of therapy that will appeal to many parents and it is being trialed on so many different people we will soon know if there are harmful long term effects.

  

My Take

It looks to me that electroconvulsive therapy is rather crude and while it does evidently help some people, it might not be without serious risk. If the person has uncontrollable SIB, it looks a risk worth taking.

Short term use of CBD oil looks a safer bet, but if the effect required is just calming/sedating there may be other ways to achieve this.  Many parents are already using CBD oil as a home autism therapy.

There are hundreds of clinical trials completed, or in progress, using CBD to treat everything from ulcerative colitis to anxiety. It is being trialed in schizophrenia and even Dravet Syndrome and other kinds of epilepsy.  There is even a trial of a CBD chewing gum to treat Irritable Bowel Syndrome. CBD actually now has designated orphan drug status with the FDA for Dravet Syndrome.

I have no plans to use either therapy; I seem to have addressed the variable nature of my case of autism.  I am more interested in treating the core autism symptoms, the “30” in the 30/100; it is clear that much more remains possible.  

Tackling the “30”

An interesting recent finding came from a study on Oxytocin at Stanford. This time researchers had the good sense to actually measure the level of the oxytocin hormone in the blood of the trial participants before and after they started having oxytocin squirted up their noses. 

Oxytocin improves social abilities in some kids with autism, Stanford study finds 

Not surprisingly it was people with low natural levels of oxytocin who were the favorable responders and interestingly those in the placebo group who also responded actually increased their natural level of oxytocin production.

As we know there are other ways to increase you level of oxytocin, one of which is via certain L. reuteri probiotic bacteria.

Oxytocin would fit in the tackling the “30” category, for those with naturally lower levels of this hormone.

The Stanford researcher is again Dr Hardan, from that interesting phase 2 trial of the antioxidant NAC.  He is now planning a larger oxytocin trial. Has he forgotten about making a phase 3 trial of NAC?   

Self Injurious Behavior (SIB)

You do wonder why some clinician does not compile a list of all the known causes and therapies for self-injurious behavior (SIB) in autism.  There is even a study planned at Emory University to test the efficacy of NAC to treat SIB, but with only 14 participants, I do not really see the point.

We do know that a small number of people with SIB respond well to NAC. If just 10% are responders, you would need a really large trial prove anything at all. With 14 participants you should have just one, but as luck might have it, it could be none.

With a more scientific/engineering approach you might identify five sometimes effective SIB therapies, and then go systematically through testing each therapy on each person with SIB. Then you would have some useful data.    

As I mentioned in a recent comment, the late Bernie Rimland from ARI, was a big believer in high dose vitamin B6 to treat SIB.  For some people it is a nicotine patch, for my son in summer it is an L-type calcium channel blocker.

The reality is that numerous complex dysfunctions can lead to SIB, but so do some simple things like untreated pain and inflammation, which could be from IBS/IBD or even tooth eruption/shedding or just tooth decay.

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.

A single species of gut bacteria can reverse autism-related social behavior 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.

Cytokines from the Eruption of Permanent Teeth causing Flare-ups in Autism

A recent post looked again at inflammation in autism and some possible therapies to try.  Over Christmas and New Year, Monty, aged 11 with ASD, had occasional outbursts, more typical of his summertime raging, which was later solved using allergy /mast cell therapies.

At least it did let me establish whether Verapamil was a universal “cure” for SIB.  It is not.  It works great for allergy-driven aggressive behaviors, but had no effect on these ones.

Christmas is often a stressful period for many people with, or without, autism; but Monty likes presents and he loves food.

Having pulled out a wobbly tooth on Boxing Day and noticed an apparent behavior change, I thought that perhaps the loss of milk teeth and development of permanent teeth might cause an effect similar to that of his mild pollen allergy.  Monty, in common with many people with autism, has a high pain threshold.  While teething causes well known problems in babies, most children have minimal problems when their milk teeth are replaced by their permanent ones.

I just wondered if perhaps the underlying biological mechanism might provide an inflammatory insult to the highly inflammation-sensitive autistic brain.

Just as histamine provokes a release of inflammatory cytokines like IL-6, perhaps losing your milk teeth does something similar.

Ibuprofen experiment

I decided that I would buy some Ibuprofen, the least problematic NSAID.   A day or two later, Monty declared that another tooth was wobbly and needed to be pulled out.  This tooth was, and remains, well and truly attached.

So I decided that in advance of another, potentially stressful, Christmas event, I would give 10 ml of Ibuprofen.  I did not give it in response to any comment about pain.

It did indeed seem to work.

Skiing

A few days later we were in the Alps for skiing.

Monty can ski, but we always give him a 1:1 instructor.  On the first day, without Ibuprofen, he got agitated during the queuing at the bottom of the beginners’ ski lift.  The instructor thought it was the loud booming music.  It was clear that by the end of the lesson, it was no fun at all.

The following days, I gave 10 ml of Ibuprofen, 20 minutes before the lesson started.  He had a great time, going up by cable car to the top of the mountain and skiing along the blue/red slopes and coming down in a neighboring resort a couple of hours later.  Even a change of instructor on one day, passed without issue.

It might not be scientific proof of the effectiveness of Ibuprofen, but it was enough for me.

The Science

Since this is a scientific blog, arriving home I did some checking on the biology of what happens when you lose your milk teeth.

There is more written about “teething” when you first get your milk teeth, but there is information about “root resorption” of milk teeth and “eruption” of the permanent teeth.  The process is indeed modulated by inflammatory cytokines and transcription factors.

These cytokines will then circulate around the body and cross the blood brain barrier.

Cytokine levels in gingival crevicular fluid of erupting primary teeth correlated with systemic disturbances accompanying teething.

Abstract

PURPOSE:

The aim of this study was to investigate whether there are increased levels of the inflammatory cytokines IL-1beta, IL-8, and TNF alpha in the gingival crevicular fluid (GCF) of erupting primary teeth. This increase could explain such clinical manifestations as fever, diarrhea, increased crying, and sleeping and eating disturbances that occur at this time.

METHODS:

Sixteen healthy children aged 5 to 14 months (mean=9.8 months) were examined twice a week over 5 months. Gingival crevicular fluid samples were taken from erupting teeth. As a control, GCF was collected from the same teeth 1 month later. Cytokine production was measured by ELISA. Signs and clinical symptoms were listed. Pearson correlation coefficients were used in the comparisons described below. A paired t test was used to analyze the same variable at different times.

RESULTS:

Fifty teeth of the 16 children were studied. GCF samples were collected from 21 of these teeth. Statistically significant differences (P<.05) were found with regard to the occurrence of fever, behavioral problems, and coughing during the teething period and the control period. During the control period, 72% of the children did not exhibit any clinical manifestations, whereas during the teething period only 22% of the children did not exhibit any clinical manifestations. The study revealed high levels of inflammatory cytokines during the teething period, with a statistically significant difference in TNF alpha levels (P<.05) between the teething period and the control period. Correlations were found between cytokine levels and some of the clinical symptoms of teething: IL-1beta and TNF alpha were correlated with fever and sleep disturbances; IL-beta and IL-8 were correlated with gastrointestinal disturbances; IL-1beta was correlated with appetite disturbances.

CONCLUSIONS:

Cytokines appear in the GCF of erupting primary teeth. The cytokine levels are correlated to some symptoms of teething.

Mechanism of Human Tooth Eruption: Review Article Including a New Theory for Future Studies on the Eruption Process

Physiologic root resorption in primary teeth: molecular and histological events

Root resorption is a physiologic event for the primary teeth. It is still unclear whether odontoclasts, the cells which resorb the dental hard tissue, are different from the osteoclasts, the cells that resorb bone. Root resorption seems to be initiated and regulated by the stellate reticulum and the dental follicle of the underlying permanent tooth via the secretion of stimulatory molecules, i.e. cytokines and transcription factors. The primary root resorption process is regulated in a manner similar to bone remodeling, involving the same receptor ligand system known as RANK/RANKL (receptor activator of nuclear factor-kappa B/ RANK Ligand). Primary teeth without a permanent successor eventually exfoliate as well, but our current understanding on the underlying mechanism is slim. The literature is also vague on how resorption of the pulp and periodontal ligament of the primary teeth occurs. Knowledge on the mechanisms involved in the physiologic root resorption process may enable us to delay or even inhibit exfoliation of primary teeth in those cases that the permanent successor teeth are not present and thus preservation of the primary teeth is desirable. (J. Oral Sci. 49, 1-12, 2007)

Nonsteroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen, work by inhibiting the enzyme COX which converts arachidonic acid to prostaglandin H₂ (PGH₂). PGH₂, in turn, is converted by other enzymes to several other prostaglandins ,which are mediators of pain, inflammation, and fever.

Prostaglandin E synthase

Prostaglandin E₂ (PGE₂) is generated from the action of prostaglandin E synthases on prostaglandin H₂ (PGH₂).

PGE₂ has various known effects, but one known effect is to increase the pro-inflammatory cytokine IL-6.  The same one that is increased by histamine released from mast cells during allergic reactions.

Elevated interleukin 6 is induced by prostaglandin E2 in a murine model of inflammation: possible role of cyclooxygenase-2.

Abstract

Injection of mineral oils such as pristane into the peritoneal cavities of BALB/c mice results in a chronic peritonitis associated with high tissue levels of interleukin 6 (IL-6). Here we show that increased prostaglandin E2 (PGE2) synthesis causes induction of IL-6 and that expression of an inducible cyclooxygenase, Cox-2, may mediate this process. Levels of both PGE2 and IL-6 are elevated in inflammatory exudates from pristane-treated mice compared with lavage samples from untreated mice. The Cox-2 gene is induced in the peritoneal macrophage fraction isolated from the mice. A cause and effect relationship between increased macrophage PGE2 and IL-6 production is shown in vitro. When peritoneal macrophages are activated with an inflammatory stimulus (polymerized albumin), the Cox-2 gene is induced and secretion of PGE2 and IL-6 increases, with elevated PGE2 appearing before IL-6. Cotreatment with 1 microM indomethacin inhibits PGE2 production by the cells and reduces the induction of IL-6 mRNA but has no effect on Cox-2 mRNA, consistent with the fact that the drug inhibits catalytic activity of the cyclooxygenase but does not affect expression of the gene. Addition of exogenous PGE2 to macrophages induces IL-6 protein and mRNA synthesis, indicating that the eicosanoid stimulates IL-6 production at the level of gene expression. PGE2-stimulated IL-6 production is unaffected by addition of indomethacin. Taken together with the earlier finding that indomethacin diminishes the elevation of IL-6 in pristane-treated mice, the results show that PGE2 can induce IL-6 production in vivo and implicate expression of the Cox-2 gene in the regulation of this cytokine

Indomethacin is another NSAID, like Ibuprofen.

Implications

If, as seems likely, many incidents of anxiety, aggression, explosive behavior, or "meltdowns" are made possible by elevated levels of the pro-inflammatory cytokine IL-6, then the occasional use of drugs known to inhibit IL-6 makes a lot of sense.

Ibuprofen is an NSAID and it is known that some people respond much better to certain NSAIDs and suffer side effects from others.   NSAID drugs work by affecting both COX-1 and COX-2.  It appears that desired effect of NSAIDs comes from their effect on COX-2, while the side effects come from changes made to COX-1.  So it is logical that some NSAIDs are better tolerated than others and for some people a different NSAID may be more appropriate.

Other common drugs also lower IL-6;  leukotriene receptor antagonists like Montelukast (Singulair)  being an example.  This drug is used in autism, but a known side-effect in typical people is to worsen behavior, sometimes severely.  There are plenty of reports of Singulair in autism, some good and some bad.  Since almost all drugs have multiple effects, this is not surprising.

Interestingly, one of the drugs in my Polypill, NAC, is also known to reduce IL-6; but it also reduces the “good” anti-inflammatory cytokines like IL-10.  Perhaps this is why NAC is not beneficial to some people with autism?

Occasional use of Ibuprofen at times anticipated to be stressful makes a lot of sense. 

Conclusion

While it is well known that Ibuprofen relieves pain from teething, low level pain is often completely ignored by people with ASD.  The cytokine release associated with the resorption of the milk teeth and the eruption of the permanent tooth appears to be much more problematic.

Ibuprofen, available OTC, limits the production of pain mediators, called prostaglandins, which in turn stimulate production of the inflammatory cytokine IL-6.

Ibuprofen will reduce both pain and the level of cytokines like IL-6.

In earlier extensive posts on mast cell degranulation in autism, I concluded that the resulting elevated levels of IL-6 likely produced behaviors ranging from anxiety, through aggression, all the way to self-injury.

Channelopathies in Autism - treating Cav1.2 with Verapamil

 

In December 2013 I wrote about a leading Italian researcher and clinician called Professor Antonio Persico and gave a link to an excellent presentation he gave in the US, about his views on the underlying biological process behind autism.

Excess Calcium and Calcium Signaling in the Autistic Brain

  

He had a nice graphic in which he depicted the puzzle that is autism.

  

One of his findings was that in the autistic brain there is an excess of both physical calcium and calcium signaling (via ion channels). He did not draw any therapeutic conclusions, which as I said was a pity.

In fact, Persico is far from the first scientist to point the finger at calcium channelopathies.

A few months before this, I had decided I would apply myself to see if there were any safe, practical therapies that could be applied, based on all the scientific research about calcium ion channels; incomplete as it might be.

After a few hours, or so, of reading about the biology of calcium channels, the available drugs and the existing research in their use in conditions other than autism, I came to the conclusion that Verapamil looked a very likely candidate.

Verapamil is a so-called L-type calcium channel blocker (L representing long-lasting length of activation); it particularly affects a type of voltage-gated calcium channel called Cav1.2.  For various reasons, I had deduced that these Cav1.2 channels were possible open more often than they should be in the brain of Monty, aged 10 with ASD.  I proposed that over activation of these channels resulted in extreme agitation that leads to aggression and self-injurious behavior in autism.

Back in September 2013, Monty was still having behavioral problems, apparently brought about by summertime pollen allergies.  I did write extensively about this and how I had narrowed the problem down to mast cell degranulation and histamine.  Treating the allergy did a lot of good, but was never a complete solution, since the standard allergy drugs worked for only a couple of hours, rather than the 24 hours they claimed.

So I had Monty in a state of near explosion by mid-afternoon most days, with a red face and letting us all know he was not feeling good.  He would say things including “be nice”, “I want to be nice”, “to hit your head” or even, on a good day, “to hit your head and see birdies”.  By then, he was also having Rupatadine, a mast cell stabilizer, which did seem to help.  The eruptions were far less often and less severe than in July, but it was clear that more could be done.

One afternoon, I decided to give a very small dose (20mg) of Verapamil, and before my eyes, the anger and agitation began to fade and was replaced by calm.  It was the most amazing experiment that I have witnessed and within 20 minutes there was complete calm.

In the following weeks, I would still hear Monty say “be nice”, but this was no longer followed by any aggressive behaviour.  The trigger was still there to energize these channels, but they had blocked by Verapamil.  It was like firing a gun, but with no ammunition; there was a “click”, but no “bang”.

This is the reason that Verapamil is in the PolyPill, in case anyone has wondered.

Before you start googling, there is absolutely no published research to support the use of Verapamil in autism.  This is part of the reason I did not to write about it at the time.

Verapamil is also a blocker of certain voltage-gated potassium channels and has the effect of raising potassium levels in the blood.  We have seen in earlier posts that potassium channel dysfunction is also present in autism and that raising potassium levels helps reduce sensory overload.  One effect of bumetanide is that it lowers levels of potassium, so bumetanide and verapamil are in that way very complementary.

Subsequently, I have read that mutation of the CACNA1C gene is associated with schizophrenia, which is like adult-onset autism.  The calcium channel produced from the CACNA1C gene is Cav1.2.  So this might be a case of what helps in autism might help in schizophrenia.

The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia.

 If you are interested in why I decided to test Verapamil, read on.

 

Observations

Anger & SIB

Anger, leading to violence against others and to yourself are behaviours that arise in many people with autism.  There are undoubtedly many causes, and many are behavioral.  If a non-verbal person cannot express what he wants, or a partially verbal child has some pain (e.g. toothache) and does not understand it, things are likely to get out of control.

But there are other times, when for no apparent reason, nasty behaviour can occur, so I presumed that there might be a biological explanation.  If there was one, then I would think about a biological intervention.

My wife always asked Monty if his head was hurting when these kinds of behaviors popped up.  He would usually say “yes”, but it could well have been to avoid any other questions.  But why not consider it as possible that there is a pain prior to SIB.

Fever Effect

Then we have the recurring observation about autistic behaviours changing when the person has a high temperature; the fever effect.  This has now been studied by literally warming people up in hot water and then carrying out behavioural test.

Hyperthermia and the Amelioration of AutismSymptoms

As usual in autism, this effect applies much more to some people than to others.  Monty is moderately affected, but some people are dramatically improved.

Headaches

Headaches are very common, but some people do seem to get far more than their fair share.  Migraines are particular nasty and so is another type, the cluster headache.

Cluster headaches are severe headaches that are clustered together.

Cluster headaches are occasionally referred to as "alarm clock headaches" because of the regularity of their timing and they may awaken individuals from sleep. Both individual attacks and the cluster grouping can have a metronomic regularity; attacks striking at a precise time of day each morning or night is typical. This has prompted researchers to speculate involvement, or dysfunction of the brain's hypothalamus, which controls the body's "biological clock" and circadian rhythm.

Now I have noted that in some literature it is claimed that parents of children with autism often have a history of headaches (and I do not mean caused by dealing with their child’s autism).  

Note that most younger people with autism have a “faulty” biological clock, so they have trouble sleeping through the night.

 

Febrile seizures

Seizures and autism are closely related.  Febrile seizures occur in some children when they have a temperature greater than 38 °C (100.4 °F).  They are twice as common in Japanese children than they are in Western children, occurring in up to 9% of children and mainly in boys.

It is not agreed exactly what causes febrile seizures, Japanese research points to voltage-gated sodium channels, which does not really support my theory.  However, rather than delete this part of the post, I did a little more digging and found a paper in the Journal of Neuroscience that does neatly fit by theory.

Temperature-sensitive Cav1.2 calcium channels support intrinsic firing of pyramidal neurons andprovide a target for the treatment of febrile seizures.

Comorbidities

It is well documented that poor cardiac health is associated with autism.  I have commented before that it is not entirely by coincidence that some drugs that help autism were actually developed as drugs for heart problems.  By treating the autism, a side benefit is that you may also be treating (and perhaps avoiding) the heart disease that would otherwise likely to develop at quite a young age.

So, while giving statins and calcium channel blockers to a healthy young person would be irresponsible, the same may not true for people with autism.  In the same way that people with type 1 diabetes have been recognized as being at high risk of heart disease and are put on preventative drugs at a much younger age than the wider public. Patients with type 1 diabetes are 10 times more at risk from heart disease than other healthy patients.  They are recommended statins, aspirin therapy and an ACE inhibitor.  An ACE inhibitor reduces blood pressure in a different way to how Verapamil also lowers blood pressure.

Due to the severity of neurological/behavioral problems of autism, medical practitioners are not really worrying about cardiac health.

Too Much Calcium

There are opposing views about the role of vitamin D in autism; in other words, too much or too little.  There have been some interesting thoughts about milk and autism, and not about whether or not it is fortified with extra vitamin D; the point was the role played by calcium.

Then there is the mother who found that supplementing her autistic child with calcium had some frightening consequences, producing profound regression.

Basic Biology

If you want to read about the basic biology of calcium channels, here are links to Wikipedia;-

Calcium Channels

L-type Calcium Channels

Calcium Channel Blockers

Connections with the biology

One of the things that drew my attention was the fact that the behaviour of some calcium channels is temperature dependent.  There are other ion channels that are also temperature dependent.  The Cav1.2 channels are known to behave differently according to their temperature.

Connections within the literature

Timothy syndrome

I have covered Timothy syndrome previously in this blog.

This is a, thankfully, extremely rare condition in which the most people do not survive to childhood; those few that do are likely to have autistic-like symptoms.

The syndrome is caused by severe mutations of the CACNA1C gene.  As a result it is also associated with severe heart problems, since this gene expresses the Cav1.2 channel that is found in the heart and the brain.

The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels

In the following article, Dr Ricardo Dolmetsch used an experimental L-type calcium channel blocker, called Roscovitine, to “successfully” treat his model of Timothy Syndrome.

Scientists identify defect in brain cell channel that may cause autism-like syndrome 

Dolmetsch is now Head of Neuroscience at the Novartis Institute for Biomedical Research.  I did write to him once, when he was still at Stanford, to ask if he was interested in discussing some of my ideas – no answer, I guess he was busy curing autism.

Headaches

It has been known for many years that some L-type calcium channel blockers are effective in treating both migraine headaches and cluster headaches.

Individualizing treatment with verapamil for cluster headache patients

 

CONCLUSIONS:

Providing the dosage for each individual is adequate, preventing CH with verapamil is highly effective, taken three (occasionally with higher doses, four) times a day. In the majority (94%) with episodic CH steady dose increase under supervision, totally suppressed attacks. However in the chronic variety only 55% were completely relieved, 69% men, but only 20% women. In both groups, for those with partial attack suppression, additional prophylactic drugs or acute treatment was necessary.

This study found that some people required 5 times higher dose than others and doses were up to 960mg per day.

Verapamil in prophylactic therapy of migraine

We conducted a double-blind, placebo-controlled crossover study of verapamil HCI in the prophylaxis of chronic migraine headaches. Verapamil significantly reduced both headache frequency and duration with few side effects. The drug may be useful for a segment of the migraine population refractory to other prophylactic agents or for those who cannot tolerate the side effects of other drugs

Mice and SIB (Self Injurious Behaviour)

Lots of people do not like the idea of being compared to mice, or even worse rats.  Nonetheless, this following paper is indeed very relevant, it showed that it you active the L type calcium channels in mice they will engage in self injurious behaviour.

Calcium channel activation and self-biting in mice

The L type calcium channel agonist Bay K 8644 has been reported to cause characteristic motor abnormalities in adult mice. The current study shows that administration of this drug can also cause the unusual phenomenon of self-injurious biting, particularly when given to young mice.

The self-biting provoked by Bay K 8644 can be inhibited by pretreating the mice with dihydropyridine L type calcium channel antagonists such as nifedipine, nimodipine, or nitrendipine.

However, self-biting is not inhibited by nondihydropyridine antagonists including diltiazem, flunarizine, or verapamil.

If Monty was a mouse, verapamil would therefore likely not work and I would probably have had to use nimodipine.

Genes

I do not claim to be an expert in Genetics, but I can uses genes to support my case.

In 2013 a paper was published in the Lancet that looked for genetic links between a range of neurological disorders.

Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis

In this paper you can find out many things, including:-

•  Gain-of-function mutations in CACNA1C causes Timothy syndrome

•  CACNA1C is a susceptibility gene for bipolar disorder, schizophrenia, and major depressive disorder

• neuroimaging studies have documented effects of CACNA1C variants on a range of structural and functional brain phenotypes, including circuitry involved in emotion processing, executive function, attention, and memory

• Mutation in the CACNB2 gene are associated with Brugada syndrome, autism, attention deficit-hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, and schizophrenia

• CACNB2 encodes an auxiliary voltage-gated calcium-channel subunit that interacts with L-type calcium-channel subunits (including CACNA1C, CACNA1D, and CACNA1S) to promote their trafficking to the plasma membrane, increase their function, and regulate their modulation by other signaling proteins and molecules

Now “my” Calcium channel, also known as Cav1.2, is encoded by the very same CACNA1C gene.

In a similar paper, autism also gets a mention 

“Genetic variation in CACNA1C have also been associated with depression, schizophrenia, autism spectrum disorders”

CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease

So all in all the genetic analysis also point to Cav1.2 as a good candidate for some intervention.

Epilepsy

Verapamil is being investigated to treat various forms of epilepsy and seizure.  This is interesting, since seizures are highly comorbid with autism.

Seizures tend to develop in early puberty in many cases of autism.  It appears possible (maybe not probable) that if you can avoid the onset of epilepsy during this time of hormonal change, you may be free of it for life.  The science has shown that the first seizure makes a biological change occur;  the same is indeed true with asthma.  If you can identify the at risk group (i.e. people with autism for epilepsy and atopic dermatitis for asthma) you may indeed be able to avoid it.

I was not aware of this until after Monty, aged 10 with ASD, had developed asthma, but I am well aware of it now.  I am actively taking steps to avoid epilepsy.

The other useful aspect of this research is that they are all clinical trials of Verapamil in children.  This is important from the safety perspective.

Study suggests Verapamil could be used to fight refractory epilepsies

Verapamil as Therapy for Children and Young Adults With Dravet Syndrome

Addition of verapamil in the treatment of severe myoclonic epilepsy in infancy

Calcium channel blocker Verapamil Administration in Prolonged and Refractory Status Epilepticus

Choice of Channel Blocker

In medicine, calcium channel blockers were developed to treat heart conditions.  A common problem in treating autism is the need for drugs to freely cross the blood barrier (BBB); most do not.

Other issues include the half-life of the drug and most importantly the safety of the drug.

Given these considerations, and the fact that I know precisely which calcium channel I want to block, this led to me to Verapamil.

It is very widely used, and is available very cheaply as a generic in sizes down to 40mg.  Adult and indeed child dosages go all the way up to 400+mg a day.

Since the idea is to subtly affect the brain and not dilate blood vessels in the heart, which increases the supply of blood and oxygen; a small dose was envisaged, 20 mg.

On paper, Nimodipine, also looks a very interesting candidate, but it is rarely used in children.  It would be useful to trial it on adults with autism.  It works better than verapamil in mice with SIB.

Conclusion

I must admit that some of my “evidence” was gathered after I had proved my theory was valid, like the mice with SIB after their L-type channels were activated.

Given all of the “evidence” it does amaze me that it did not occur to anyone to try a drug like Verapamil in children with autism.

Clearly all drugs carry a risk, but so does violence and self-injury.

P.S.  Note that magnesium is also a calcium channel blocker