Autism and Non-Antibiotic Properties of Common Beta-lactam Antibiotics

If you are looking for personalized medicine, you or your doctor need to be a good detective. Not to mention you need some clues.

If you are treating a condition like autism and certain things cause a marked change in the severity of the condition, these are pretty good places to start.

In the case of our reader in Delhi, it is Beta-lactam antibiotics (penicillin, amoxicillin etc), that consistently seem to improve her son’s autism. Improvement during treatment with antibiotics is reported quite often in autism, but with all kinds of different antibiotic.  Nothing is simple.

For non-medical readers, there are several categories of antibiotics; common types including:-

·        Beta-lactams (e.g. Penicillins)

·        Macrolides (e.g. Erythromycin, Azithromycin)

·        Fluoroquinolones (e.g. Ciprofloxacin) 

·        Tetracyclines (e.g. Minocycline) 

Macrolides have already had a dedicated post about their immunomodulatory effects, which did also cover some history about Poland from Monty's homework.

Macrolide Antibiotics for Some Autism? Or better still, Azithromycin analogue CSY0073, or just Nystatin?

Beta Lactam Antibiotics

In earlier posts we came across something called glutamate transporter GLT1 (also known as EAAT2).

Glutamate is the major excitatory neurotransmitter, and is inactivated by uptake via GLT-1 (EAAT2) and GLAST (EAAT1) transporters.

Many people given the observational diagnosis of autism appear to have an underlying imbalance between excitatory and inhibitory neurotransmitters (E/I imbalance). By correcting the specific type of E/I imbalance, even profound symptoms of autism including MR/ID and epilepsy can be moderated. If you have autism and/or epilepsy tuning your E/I imbalance is likely the most important step you can take.

Some drugs increase the expression of GLT-1 and so reduce the amount of glutamate. Macrolide antibiotics are one of these drugs.

So if a person has too much glutamate and this causes/contributes to their E/I imbalance then improved behaviour while taking penicillin antibiotics, who have a simple explanation.

Since you would not want to take penicillin forever you would then look for a non antibiotic drug that also increases the uptake of Glutamate. Once such drug, Riluzole, does exist and has already been trialed on children with OCD. 

But beta-lactams have other effects, so it is not certain that GLT-1 accounts for the beneficial effect sometimes found in autism. Fortunately some researchers have assembled most previous research into a single review paper. This paper does not mention autism and does miss some things out.

Review of Antibiotic and Non-Antibiotic Properties of Beta-lactam Molecules.

There are seven categories:-

·        Antibiotic

·        Epileptogenic

·        Neuroprotective

·        Analgesic

·        Immunomodulatory

·        Anxiolytic

·        Antineoplastic

Antibiotic Effect

We all know something about bacteria. If you have a bacterial infection like an ear infection your doctor might prescribe you an antibiotic.

As well as inflaming your ear, the bacteria may well affect gene expression. We saw in a previous post that bacteria and viruses change the expression of many genes, but the study of this is in its infancy. In autism we know that many genes are miss-expressed, but this varies from person to person. So a bacteria or virus has the potential to make autism worse (e.g. PANS and PANDAS), but also better. Bacteria are not always bad.

A person whose autism responds to an antibiotic might have bacteria that are worsening his autism. This is simplest of explanation of all.

The question then is where is the bacteria? If it is an intestinal bacterium this could be proven by using an antibiotic that only works there, like Vancomycin.

Epileptogenic effects

In this review they concluded the effects relate to GABA and here we are talking about negative effects. 

penicillin is a potent epileptogenic agent = it is capable of causing an epileptic attack

“This could mean that penicillin is a competitive GABA specific antagonist, which would further explain its epileptogenic properties.”

The paper omits to point out that in some people beta-lactams protect from epileptic seizures. The effect on Glutamate is likely at least sometimes what stops seizures.

Beta-Lactam Antibiotics as A Possible Novel Therapy for Managing Epilepsy and Autism, A Case Report and Review of Literature

The really clever thing in the above case report is that appears that the effect on glutamate may be by an epigenetic mechanism (via GLT1), since the effect is long lasting. Read later in this post about the epigenetic effects of beta-lactams.

Neuroprotective properties

“These results suggest that the neuroprotective effect induced by beta-lactam antibiotics is due to their capacity to stimulate GLT1 expression and thus regulate the concentration of glutamate in the synaptic cleft. GLT1 is a glutamate transporter inducing its reuptake by astrocytes preventing excessive glutamate concentration in the synaptic cleft

It was subsequently shown that the neuroprotective effect of BLMs was due not only to glutamate down regulation, but also to a diminished glutamate-induced intracellular Ca2+ concentration and an increased uptake of glutamate

Another probable mechanism of neuroprotection induced by BLMs is down-regulation of oxidative stress and modulation of apoptotic pathways shown in rat spinal cord when CFX was administered for 7 days prior to induction of constrictive neuropathy. This effect was apparently mediated by both a reduction in proapoptotic proteins Bax, and an increment in the antiapoptotic protein Bcl2.

CFX (Ceftiaxone) may induce neuroprotection by other mechanisms besides GLT1 overexpression. Yamada and Jinno [51] reported that the antibiotic reversed axotomy-induced up regulation of GFAP, a neuronal damage marker, and increased neuronal survival; apparently not only through glutamatergic regulation, but also by direct reduction of glial hypereactivity. Supplementary to this is the finding of an attenuation of microglial activation induced IL-1 expression in an ischemic injury model when CFX was administered as a pre-treatment [52]. This result may indicate a direct action on glial cells since partial reduction of astrocytes and microglia was observed.”

Analgesic (pain killing) Properties

“Interestingly, despite the widespread clinical use of BLMs (beta-lactams), some of their known non-antibiotic effects have been either disregarded or misinterpreted as resulting from bacterial microbiome regulation. For example, Caperton, Heim-Duthoy [54] hypothesized that chronic inflammatory arthritis could have a bacterial component and that therefore the clinical course of a patient could be affected by administration of CFX (Ceftriaxone).

Both the anti-inflammatory and neuromodulating effects exerted by BLMs either peripherally or centrally may be related to their analgesic properties in some pathologies that are difficult to treat such as the complex regional pain syndrome [65] or to the analgesic effect of a single preoperative dose of CFX in a clinical protocol [66].

Immunomodulatory Properties 

Not many people seem to have read this paper. They did not flesh out immunomodulation, so I draw on a different paper. People who write about immunomodulation usually say that beta-lactams do not have this effect, but that appears to be incorrect. 

Beta-lactam antibiotics modulate T-cell functions and gene expression via covalent binding to cellular albumin

Recent work has suggested that beta-lactam antibiotics might directly affect eukaryotic cellular functions. Here, we studied the effects of commonly used beta-lactam antibiotics on rodent and human T cells in vitro and in vivo on T-cell–mediated experimental autoimmune diseases. We now report that experimental autoimmune encephalomyelitis and adjuvant arthritis were significantly more severe in rats treated with cefuroxime and other beta-lactams. T cells appeared to mediate the effect: an anti-myelin basic protein T-cell line treated with cefuroxime or penicillin was more encephalitogenic in adoptive transfer experiments. The beta-lactam ampicillin, in contrast to cefuroxime and penicillin, did not enhance encephalomyelitis, but did inhibit the autoimmune diabetes developing spontaneously in non-obese diabetic mice. Gene expression analysis of human peripheral blood T cells showed that numerous genes associated with T helper 2 (Th2) and T regulatory (Treg) differentiation were down-regulated in T cells stimulated in the presence of cefuroxime; these genes were up-regulated in the presence of ampicillin. The T-cell protein that covalently bound beta-lactam antibiotics was found to be albumin. Human and rodent T cells expressed albumin mRNA and protein, and penicillin-modified albumin was taken up by rat T cells, leading to enhanced encephalitogenicity. Thus, beta-lactam antibiotics in wide clinical use have marked effects on T-cell behavior; beta-lactam antibiotics can function as immunomodulators, apparently through covalent binding to albumin.

 Anxiolytic effects (reduce anxiety)

“CA (Clavulanic acid) has proven effective as an anxiolytic drug, since it was reported that this drug diminished anxiety-like conduct in both rodent and primate models”

Antineoplastic effects (preventing tumors)

“CFX (Ceftriaxone) elicit antitumor activity both in vitro and in vivo models”

Addiction

Addiction did not appear in the chart above, but it gets a mention in the text 

“When tested in an opiate dependence model, both CFX [72] and CA [73] inhibited both physical dependence and withdrawal symptoms. This could mean that the effect shown by CFX is not due to its particular molecular structure, but can be reproduced by other BLMs (several BLMs effects shown on Fig. 3)

Other effects

“CA (Clavulanic acid) has been shown to increase dopamine release”

Epigenetic Effects

These were not mentioned in the paper, but I do think epigenetics is a fundamental part of many diseases, including much autism.

The paper really explains why short term use of beta-lactams can stop a person with epilepsy having seizures for a long time.

Off-Target drug effects resulting in altered gene expression events with epigenetic and"Quasi-Epigenetic" origins.

This review synthesizes examples of pharmacological agents who have off-target effects of an epigenetic nature. We expand upon the paradigm of epigenetics to include "quasi-epigenetic" mechanisms. Quasi-epigenetics includes mechanisms of drugs acting upstream of epigenetic machinery or may themselves impact transcription factor regulation on a more global scale. We explore these avenues with four examples of conventional pharmaceuticals and their unintended, but not necessarily adverse, biological effects. The quasi-epigenetic drugs identified in this review include the use of beta-lactam antibiotics to alter glutamate receptor activity and the action of cyclosporine on multiple transcription factors. In addition, we report on more canonical epigenome changes associated with pharmacological agents such as lithium impacting autophagy of aberrant proteins, and opioid drugs whose chronic use increases the expression of genes associated with addictive phenotypes. By expanding our appreciation of transcriptomic regulation and the effects these drugs have on the epigenome, it is possible to enhance therapeutic applications by exploiting off-target effects and even repurposing established pharmaceuticals. That is, exploration of "pharmacoepigenetic" mechanisms can expand the breadth of the useful activity of a drug beyond the traditional drug targets such as receptors and enzymes.

DAO inhibition

As our reader Agnieszka pointed out in the comments section, one commonly prescribed beta-lactam antibiotic called Augmentin contains a second antibiotic, Clavulanic acid, to boost its effectiveness; by chance is also a very potent DAO inhibitor. Diamine oxidase (DAO), also known as histaminase, is an enzyme in your body that is used to inactivate histamine. Histamine is found in food that you eat as well as being produced in your body and released by your mast cells during an allergic reaction.

DAO neutralizes the histamine in food so it does not enter your bloodstream.

So this particular antibiotic should be avoided by those people who are histamine intolerant and so do not produce enough DAO. This is about 1% of the general population, but might be more common in those with autism although there is no data on this subject.

Some people believe that ADHD is associated with a reduced level of DAO.

Indeed there is a patent to treat ADHD with a combination of DAO and caffeine.

Diamine oxidase for use in the treatment or prevention of attention deficit hyperactivity disorder (ADHD)

[0087] DAO can also be mixed with caffeine, strengthening the role of prevention and treatment of attention deficit hyperactivity disorder. Thus, also disclosed herein compositions comprising DAO and caffeine. 

[0088] Caffeine, a xanthine alkaloid group having stimulating properties for the treatment of attention deficit hyperactivity disorder. 

[0089] DAO content of the present invention per unit dose 0 · l-50mg, preferably 2-20mg. 

[0090] The present invention is caffeine content per unit dose 1-lOOmg, preferably 5-50mg. 

[0091] for the prevention and treatment of attention deficit hyperactivity disorder DAO or compositions comprising DAO may be before a meal or postprandial meal administration.

[0092] The use of DAO of the invention or compositions comprising DAO directly affect blood histamine levels, thus affecting the symptoms of attention deficit cumulative histamine levels induced hyperactivity disorder.

You can actually buy DAO supplements and of course caffeine.

Perhaps people consuming DAO inhibitors long term, such as NAC and Verapamil, and have chronic allergies or mast cell disorders might benefit from extra DAO. 

Evaluation of the inhibitory effect of various drugs / active ingredients on the activity of human diamine oxidase in vitro

Most DAO is actually in your digestive tract, where the dietary histamine is.

You can measure DAO levels in your blood.

Serum diamine oxidase (DAO) activity as a diagnostic test for histamine intolerance  

We can conclude that determination of DAO activity in serum is a useful diagnostic tool, together with detailed history to differentiate between food allergy and histamine intolerance.

We found that DAO activity was significantly lower in patients than in healthy control subjects.

Conclusion

I think there is plenty of food for thought here for parents of children whose autism and/or epilepsy improves when taking a beta-lactam antibiotic.  Hopefully some people will figure out which effect is the beneficial one and find something else to replicate it.

There is a lot previously written in this blog about upregulating GLT1, other than by a beta-lactam. My favoured option was Riluzole, but Bromocriptine will also do this, among its other actions. Riluzole is a drug for ALS, that has been trialed in children with OCD, without side effects.    

People technically without histamine intolerance (normal levels of DAO) who incidentally take large amounts of DAO inhibitors, may end up exacerbating an existing mast cell related problem. One potential solution for that small group might be taking an OTC DAO supplement.

Verapamil or Rezular (R-verapamil) for Irritable Bowel Syndrome (IBS)?

A nasty condition that is equally nasty to spell - diarrhoea/diarrhea

Today’s post may help to explain why some people’s GI problems seem to vanish when they take Verapamil for their autism.

Verapamil is usually prescribed as an L-type calcium channel blocker, to lower blood pressure. This type of ion channel is widely expressed in the brain, the heart and the pancreas. The pancreas is where your body makes those digestive enzymes. Mast cells that release histamine also contain L-type calcium channels.

Verapamil blocks the L-type calcium channel Cav1.2, which in posts a few years ago I showed could be relevant for some types of autism. An extreme dysfunction of this ion channel leads to Timothy Syndrome, which is a single gene variant of autism with severe heart defects.  There is now some more recently published research which I have highlighted below.

L-type calcium channels as drug targets in CNS disorders

L-type calcium channels are present in most electrically excitable cells and are needed for proper brain, muscle, endocrine and sensory function. There is accumulating evidence for their involvement in brain diseases such as Parkinson disease, febrile seizures and neuropsychiatric disorders. Pharmacological inhibition of brain L-type channel isoforms, Cav1.2 and Cav1.3, may therefore be of therapeutic value. Organic calcium channels blockers are clinically used since decades for the treatment of hypertension, cardiac ischemia, and arrhythmias with a well-known and excellent safety profile. This pharmacological benefit is mainly mediated by the inhibition of Cav1.2 channels in the cardiovascular system. Despite their different biophysical properties and physiological functions, both brain channel isoforms are similarly inhibited by existing calcium channel blockers. In this review we will discuss evidence for altered L-type channel activity in human brain pathologies, new therapeutic implications of existing blockers and the rationale and current efforts to develop Cav1.3-selective compounds.

From Gene to Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric Symptoms.

The L-type calcium channels (LTCCs) Ca_v1.2 and Ca_v1.3, encoded by the CACNA1C and CACNA1D genes, respectively, are important regulators of calcium influx into cells and are critical for normal brain development and plasticity. In humans, CACNA1C has emerged as one of the most widely reproduced and prominent candidate risk genes for a range of neuropsychiatric disorders, including bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder, autism spectrum disorder, and attention deficit hyperactivity disorder. Separately, CACNA1D has been found to be associated with BD and autism spectrum disorder, as well as cocaine dependence, a comorbid feature associated with psychiatric disorders. Despite growing evidence of a significant link between CACNA1C and CACNA1D and psychiatric disorders, our understanding of the biological mechanisms by which these LTCCs mediate neuropsychiatric-associated endophenotypes, many of which are shared across the different disorders, remains rudimentary. Clinical studies with LTCC blockers testing their efficacy to alleviate symptoms associated with BD, SCZ, and drug dependence have provided mixed results, underscoring the importance of further exploring the neurobiological consequences of dysregulated Ca_v1.2 and Ca_v1.3. Here, we provide a review of clinical studies that have evaluated LTCC blockers for BD, SCZ, and drug dependence-associated symptoms, as well as rodent studies that have identified Ca_v1.2- and Ca_v1.3-specific molecular and cellular cascades that underlie mood (anxiety, depression), social behavior, cognition, and addiction.

I have crossed these ion channels off my “to do” list because I have found an effective therapy that works for my son and for the children of some other readers.  It does not work for everyone, but that should not come as a surprise. I think those with mast cell disorders and/or major GI problems are most likely to be responders. 

As well as halting the cascade of anxiety towards self-injury, reducing allergy, it was reported that Verapamil made long term GI symptoms vanish.

In your pancreas β-cells make insulin. These β-cells have Cav1.2 calcium channels. In people with type-1 diabetes their β-cells have died so their pancreas produces no insulin. In people with the increasingly common type-2 diabetes, they start out with enough insulin but their body has a reduced sensitivity to it; often as they age their β-cells begin to die, at which point they start having to inject insulin like a type-1 diabetic. We saw that by blocking Cav1.2 you can stop these β-cells from dying. This means that a person with type-2 diabetes should take Verapamil to maintain their pancreas producing insulin.

Without wanting to go further into how the pancreas functions, I assumed that perhaps there were other Cav1.2 calcium channels involved in producing enzymes in the pancreas that might result in digestive problems in some people, that in turn produce symptoms of IBS.

I already highlighted in a post that Verapamil also affects an interesting potassium channel called Kv1.3. This channel is involved in the inflammatory response and this is the channel that TSO parasites use to trick their host into not attacking and expelling them.

It appears that Kv1.3 is over expressed in auto-immune diseases including MS. So inhibitors of this ion channel are potential treatments for MS. Add TSO parasites to that list of novel MS therapies!

Some venoms are Kv1.3 inhibitors and may form the basis of new drugs.

Toxins Targeting the KV1.3Channel: Potential Immunomodulators for Autoimmune Diseases

Since autism is in-part an auto-immune disease a Kv1.3 inhibitor could be therapeutic.
Verapamil does inhibit Kv1.3, but I do not know if it is to a therapeutic extent.  Most drugs have numerous effects but only one dominant one.


Melatonin MT1 and Serotonin 5-HT2b receptors

Today we learn that two further receptors are affected by Verapamil, one Melatonin and one Serotonin.

Melatonin, at high doses, we saw in an old post has potent beneficial effects on some GI conditions and trials showed it to be as effective as prescription drugs for those conditions. Melatonin is very cheap, but cannot be patented, so will not be researched seriously.

The two isomers of Verapamil

When you think of a chemical you may think of its formula, but it can be more complex, as you might have learnt in high school chemistry.

The two compounds below are both thalidomide. R-thalidomide is effective against  insomnia and morning sickness, but the mirror image called L-thalidomide can cause birth defects.

This was discovered too late, for many people.

Many drugs are a mixture of Right and Left, confusingly they like to also call Left “S”. In Latin sinister is the adjective left and dexter is the adjective for right.

Recall Arbaclofen (R-Baclofen) ? I am sure Roche does, a $40 million bet that did not pay off.

Now we have R-Verapamil.

Pharmacology of R-Verapamil: A Novel Therapy in IBS

John Devane, Mary Martin, John Kelly

Racemic verapamil, primarily a cardiovascular agent, has been widely used off-label in patients with irritable bowel syndrome (IBS). Initial observations of its usefulness followed recognition of a high incidence of constipation with use in cardiovascular conditions. The enantiomers of verapamil are known to differ in cardiovascular potency, the S-isomer being much more potent than the R-isomer. In addition we found the S-isomer to be equiactive in relaxing vascular and colonic smooth muscle but the R-isomer to be 5-times more potent in relaxing colonic than vascular muscle. This selectivity led us to develop R-verapamil (Rezular) as a gut selective treatment in IBS and we have shown doses from 60mg/day to 240mg/day to greatly improve symptoms in non-constipation IBS patients. To better understand the mechanism by which R- verapamil improved the symptoms of IBS, we undertook an in-vitro screen of binding of R-verapamil to 147 receptors/receptor sub-types. Specific ligand binding was initially assessed using 10x-5 M verapamil and if there was greater than 50% inhibition of control specific binding, then binding at 8 different concentrations was tested andIC50 values (concentrationfor half-maximalinhibition of controlspecific binding (x10 -7M)) calculated. The therapeutic plasma concentration range of free R-verapamil was conservatively set at 0.1-3x10-7 M. Within this range R-verapamil showed affinity for 3 receptors: melatonin (MT1)(IC50 0.6), 5-HT2b (IC50 1.1) and L-type calcium channel (IC50 2.4). In addition compared with S-verapamil, R-verapamil showed stereoselectivity x40)for MT1 binding, whereas S-verapamil showed stereo selectivity (x3) for L-type calcium channel binding. R-Verapamil was selective for 5-HT2b relative to other 5-HT receptor sub types and affinity was low for 5-HT3(IC 50 3,400) or 5-HT4(>100) receptors.It was also highly selective for MT1(IC50 0.6) versus MT2 (IC50 >100) receptors. We conclude that R verapamil most likely exerts its therapeutic effects in IBS via a previously unrecognized mechanism involving combined effects at melatonin receptors, serotonin receptors and L type calcium channels

  

https://www.drugdevelopment-technology.com/projects/rezular/

"In May 2009, Rezular (arverapamil) failed in Phase III development, where it underwent extensive evaluation in the ARDIS clinical trial programme in patients with IBS-D.

Phase III trials were taken up with patients already receiving treatment in the ARDIS-1 trial. In this randomised, double-blind, placebo-controlled, parallel group the efficacy and safety of Rezular (arverapamil) was assessed in about 1,200 patients.

Three doses of Rezular (arverapamil) were compared with placebo over a 12-week treatment period.

In September 2009, AGI announced that it plans to consider alternative uses of Rezular. The company believes that Rezular can prove effective in treating diarrhoea and non-diarrhoea related problems.

IBS is a common, but until recently poorly understood, disorder of the gastrointestinal (GI) tract. It is described as a functional disorder of the GI tract, in which there is no obvious underlying pathology.

IBS has proved notoriously difficult to diagnose and treat effectively. Until recently no drugs were specifically indicated for the treatment of IBS. Instead, patients would often seek over-the-counter (OTC) remedies to treat constipation, diarrhoea, abdominal pain and bloating associated with IBS.

AGI Therapeutics, Rezular (arverapamil) is a single enantiomer moiety of racemic verapamil, a cardiovascular drug that has been in clinical use for 35 years.

However, in contrast to currently available commercial forms of racemic verapamil (a mixture of two enantiomers), arverapamil shows preferential activity in treating the symptoms of IBS-D without the traditional cardiovascular actions of the racemic drug. It combines affinity at L-type calcium channels with 5-HT_2b and melatonin (MT1) receptor binding.

Gut function is controlled by both the enteric (intestinal) nervous system (ENS) and CNS, in which the neurotransmitter serotonin (5-HT) plays a fundamental role. Serotonin is present in large amounts in the ENS where it is involved in sensory, motor and secretory processes within the gut. It modulates gut motility and the perception of pain and also mediates intestinal secretion. Minor disturbances in serotonergic function can lead to symptoms of IBS described above."

Irritable bowel syndrome (IBS) is a common comorbidity of autism.

According to the Mayo Clinic:-

https://www.mayoclinic.org/diseases-conditions/irritable-bowe

l-syndrome/symptoms-causes/syc-20360016

IBS is a chronic condition that you'll need to manage long term.

Only a small number of people with IBS have severe signs and symptoms. Some people can control their symptoms by managing diet, lifestyle and stress. More-severe symptoms can be treated with medication”

The precise cause of IBS isn't known. Factors that appear to play a role include:

·       Muscle contractions in the intestine. The walls of the intestines are lined with layers of muscle that contract as they move food through your digestive tract. Contractions that are stronger and last longer than normal can cause gas, bloating and diarrhea. Weak intestinal contractions can slow food passage and lead to hard, dry stools.

• Nervous system. Abnormalities in the nerves in your digestive system may cause you to experience greater than normal discomfort when your abdomen stretches from gas or stool. Poorly coordinated signals between the brain and the intestines can cause your body to overreact to changes that normally occur in the digestive process, resulting in pain, diarrhea or constipation.
• Inflammation in the intestines. Some people with IBS have an increased number of immune-system cells in their intestines. This immune-system response is associated with pain and diarrhea.
• Severe infection. IBS can develop after a severe bout of diarrhea (gastroenteritis) caused by bacteria or a virus. IBS might also be associated with a surplus of bacteria in the intestines (bacterial overgrowth).
• Changes in bacteria in the gut (microflora). Microflora are the "good" bacteria that reside in the intestines and play a key role in health. Research indicates that microflora in people with IBS might differ from microflora in healthy people.

Triggers

Symptoms of IBS can be triggered by:

• Food. The role of food allergy or intolerance in IBS isn't fully understood. A true food allergy rarely causes IBS. But many people have worse IBS symptoms when they eat or drink certain foods or beverages, including wheat, dairy products, citrus fruits, beans, cabbage, milk and carbonated drinks.
• Stress. Most people with IBS experience worse or more frequent signs and symptoms during periods of increased stress. But while stress may aggravate symptoms, it doesn't cause them.
• Hormones. Women are twice as likely to have IBS, which might indicate that hormonal changes play a role. Many women find that signs and symptoms are worse during or around their menstrual periods.

Research shows that some people with IBS report improvement in diarrhea symptoms if they stop eating gluten (wheat, barley and rye) even if they don't have celiac disease.

Rezular – Patent for Oral Treatment for IBS

http://www.google.com.na/patents/WO2009090453A2?cl=ko

  

Conclusion

I guess we may never know why some people’s IBS responds to Verapamil. It is likely because of one of the following:-

The experts suggested:-

     ·      Cav1.2
·      Melatonin MT1
·      Serotonin 5-HT2b

I earlier proposed (in addition to Cav1.2)

•   ·      Kv1.3

R-Verapamil failed in its trial for IBS-D (IBS that causes increased diarrhoea is often called IBS-D).

But Verapamil clearly does help some types of IBS, you would just have to try it. I did try it on myself and it worked for me.

This post again shows the limitations of clinical trials, because we actually do know Verapamil does resolves the GI problems of some people.

Perhaps they got it all wrong and should have trialed S-Verapamil, or indeed just the regular mixture of Verapamil. They did not do the latter because how do you patent/make money out of an existing ultra-cheap generic drug? One pack costs $1.

It looks strange to me that people with Type-2 diabetes are not prescribed Verapamil, it might save a lot of insulin injections later in their lives. 

The Autism PolyPill 5 years on from December 2012

2^nd WOW!

Still autistic, but less so, and no longer cognitively challenged.

It is exactly five years since Monty, now aged 14 started his Polypill therapy. At first it was just bumetanide, but shortly thereafter NAC and atorvastatin were added, more followed later.  All without any side effects.

I received Monty’s end of term school report just before Christmas and it bears little resemblance to what he received back in 2012. Now it does not look like the report of someone who is cognitively challenged. Almost all the grades are As; these are his best ever results and unlike 5 years ago, these are the same tests as taken by his NT peers, not an easy version. 

At the beginning of this first year in high school, there was a view that Monty should not be there, that he would fail to cope and later have to leave; he has proved otherwise.  None of this was malicious; it was just that the head of the high school used to teach in the junior school and has known Monty since he was four years old. Back then, and until he was nine years old, he was seriously challenged, academically. The post-Polypill Monty came as a big surprise, he is still autistic, but now academically functional.  He is now never disruptive and behaves like an attentive model student, just one that does not talk much.

Monty’s assistant recently asked me why, since some doctors do read this blog and apply it, don’t more doctors now treat their kids with autism? She mentioned a top local neurosurgeon who has twins with severe autism; why isn’t he treating his own kids? If you can do it, why can’t he? My answer was that a neurosurgeon is not a neuroscientist.   His job is quite primitive; he drills holes in people’s skulls and pokes around for visible defects in the brain. Treating autism is about tweaking tiny things like ion channels that you cannot even see. Being a neurosurgeon does not really help much, unless you read the neuroscience literature, which he likely does not.  

Wow Moments

I do like “Wow moments”. They do not come very often, the last one was four years ago when I first saw a little yellow pill (Verapamil) make an extended episode of self-injury, melt away in front of my eyes. That was like winning the Lottery and this therapy continues to have the same effect.

A “Wow moment” occurred in late December when I opened the end of term report, of Monty’s NT big brother, who attends the same school.  Monty’s grades are better. Yes, Monty is in year 7 and big brother is in year 13, his final year of school. You should not compare one sibling with another sibling, but nobody would have dreamt that a boy with classic autism would ever outshine his intelligent NT brother academically, under any circumstances. I think that deserves a “Wow”. Even big brother was impressed by little brother.

Nowadays an autism diagnosis usually is not associated with MR/ID; it is much more likely to be better described as a variant of Asperger’s. If you have Asperger’s there is no reason you should not aim for College/University. Unfortunately that is not Monty’s case, he has strictly defined autism (SDA), meaning more severe biological dysfunctions and his school reports from 5 years ago reflected that. He could not function academically; school was more for “socialization”.  People with SDA usually do not make it past the basics of school academically.  Where we live, autism = SDA and severe autism means something extremely challenging, so I find it very strange to read comments on the internet written by people claiming to have severe autism themselves.

One medical researcher recently asked me how effective is sodium benzoate (NaB) proving as a cognitive enhancer. All I could say was the current level of academic performance is shocking everyone. We had teachers thinking the assistants were boosting his test performance, so we all agreed to be super careful not to give help during tests. So now they are 100% his work, before I think it was 90% his work with some “hinting”.  I cannot say with certainty whether NaB helps or not. I stopped for a week over Christmas, and I concluded that there may well be a difference.

The extreme case of “hinting” is so-called facilitated communication, when the assistant ends up doing 90% of the work. The result is an illusion of what you would like to think the child is capable of, rather than reality. We do not need any of that.

There are also prompting methods like RPM, but at the end of the day what matters is what the child can eventually achieve entirely unaided. It does not matter if they type their work, or handwrite it.

Is the OAT3 inhibitor helping? For the last few weeks I have used coffee flavanols to boost the pharmacodynamics of bumetanide (by delaying its excretion). 

There are still plenty of ideas I have not yet implemented (RORα, PDE4 etc.) but the current PolyPill has delivered results far beyond my expectations. I do not think it is realistic to go from strictly defined autism (SDA) to entirely NT. The target I mentioned long ago was to go from SDA to something like Asperger’s. Monty is never going to be quite like his older brother, but after 5 years he now evidently has a typical level of IQ, and most importantly he can apply it at school and in daily life.

This Christmas Monty made his way through the self-scanning passport control at the airport and when randomly selected for the whole body scanning machine, he coped without incident.  Air travel is now a highlight of a trip and the more turbulence the better.

Now to the next five years.

The open question is whether Monty can obtain formal educational qualifications. In the English system there are externally assessed exams at age 16 (year 11) and at age 18 (year 13). Monty’s class group are two years his junior, so he will be 18 at the year 11 assessment. Years ago our piano teacher, who only teaches people with special needs, was pretty blunt about the fact that none of her kids leave school with formal qualifications, except sometimes in music. 

The situation varies greatly depending on where you live.  In the US things are very different and if you have an IEP (Individualized Education Program) and attend high school, you automatically seem to “graduate” high school with some kind of diploma. Many people with an IEP in the US do not have severe learning disabilities and they graduate with the standard diploma.

Monty has never had an IEP because he does not go to a school that offers them. In effect he has had a very customized education program for more than a decade, just it was run from home.

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