Wednesday, 21 March 2018

Amino Acids Disturbed in Autism? Very Likely

Amino acids in your body are the building blocks for making proteins. There are essential Amino Acids that you must obtain from diet and semi-essential amino acids that in young children are body is still not able to produce and non-essential amino acids that your body can produce. 

There was an earlier post on Amino Acids:- Amino Acids in Autism 

There are also sub-groups, Branch Chained Amino Acids (BCAAs) and aromatic.  The branched chained amino acids (BCAAs) compete with the aromatic amino acids for entry into the brain. Therefore, altering BCAA levels can affect the levels of the neurotransmitters serotonin, dopamine, epinephrine and norepinephrine in the brain. 

Arginine (essential)
Aspartic acid
Glutamic acid
Histidine (essential) Aromatic
Isoleucine (essential) BCAA
Leucine (essential) BCAA
Lysine (essential)
Methionine (essential)
Phenylalanine (essential)  Aromatic
Threonine (essential)
Tryptophan (essential) Aromatic
Tyrosine  Aromatic
(essential)  BCAA 

Taurine is not an amino acid, but often gets treated as if it was one.

Arginine and its derivatives appear to play a critical role in some types of cognitive impairment including Alzheimer's and other forms of dementia.

I am writing new posts about certain individual amino acids that look interesting. Aspartic acid is next and the post looks like getting rather complex, so I decided to highlight an interesting very simplistic study that I stumbled across, that would otherwise get lost in other complex papers.  
I call it simplistic because it compares a control (NT) group with two groups of children with autism, one group has no intervention and the other group is made up of kids with some intervention, of any kind, under the umbrella of digestive/dietary/enzyme/antifungal. The control group was siblings of the children with autism. So three groups in total.
Nonetheless, this Disney science does show something quite surprising. In most cases it looks like any intervention produced results much closer to the reference range than no intervention. The study did not measure whether the intervention had any effect on the severity of autism, or compare the different interventions.
Since I am currently researching Aspartic acid I was drawn to the fact that Aspartic acid was nearly three times higher for the female controls compared with the males.  This I find notable, given the sex difference in autism, which is the biggest clue nature has left us. 

A total of 63 subjects were recruited, consisting of 34 autistic children with 31 males and three females aged 5–15 years (mean ± SD, 6.9 ± 2.5 years), and 29 controls with 13 males and 16 females also covering a range of 5–15 years (mean ± SD, 8.9 ± 3.3 years). The controls were derived primarily from siblings of the autistic group, where the sex ratio was more reflective of the general population compared to the sex balance of the autistic population which is recognised as approximately 4:1 (male:female).15 Measures were taken to account for the uneven sex-distribution in the interpretation of the results.

Twenty-two of the autistic children were receiving therapeutic treatments related to digestive function and nutritional uptake. These treatments included antifungal medication, to treat confirmed or suspected Candida infection of the digestive tract, probiotics for maintenance of gut microflora, dietary intervention (gluten- and/or casein-free diet), nutritional supplements, or the hormone secretin; this has been shown to be responsible for regulating pH of the duodenum and is, therefore, pertinent to the functioning of digestive enzymes. On this basis, the autism group was further subdivided into two groups for evaluation of urinary metabolites: treated autistic patients (n = 22; range, 5–15 years; mean, 6.9 ± 2.4 years; 91% male) and untreated autistic patients (n = 12; range, 5–12 years; mean, 7.0 ± 2.5 years; 91% male). To account for any sex-associated differences in urinary output, resulting from the disparity in the sex matching of the autistic and control groups, the control population was first subdivided on the basis of gender.

Two compounds emerged as significantly different on a gender basis for the control group: (i) glucose excretion was of a significantly higher mean concentration for the female control group compared with the males (P <0.05); and (ii) aspartic acid was nearly three times higher for the female controls compared with the males (P < 0.05). No other urinary metabolite concentrations proved to be significantly different between the female and male controls. On this basis, the data from the entire control group were compared with the treated and untreated autistic cohorts.

Plasma amino acids vs urinary amino acids 

There are numerous other studies and they do tend to use a blood test rather than a urine sample. Below is a relatively recent study from Egypt. 

Twenty autistic children were compared to twenty healthy age and sex matched normal children serving as control, where serum amino acids, urea, ammonia and protein electrophoresis were estimated.

As regards essential amino acid levels, autistic children had significant lower plasma levels of leucine, isoleucine, phenylalanine, methionine and cystine than controls (P < 0.05),while there was no statistical difference in the level of tryptophan, valine, threonine, arginine, lysine and histidine (P > 0.05). In non-essential amino acid levels, phosphoserine was significantly raised in autistic children than in controls (P < 0.05). Autistic children had lower level of hydroxyproline, serine and tyrosine than controls (P < 0.05). On the other hand there was no significant difference in levels of taurin, asparagine, alanine, citrulline, GABA, glycine, glutamic acid, and ornithine (P > 0.05).

There was no significant difference between cases and controls as regards the levels of urea, ammonia, total proteins, albumin and globulins (alpha 1, alpha 2, beta and gamma) (P > 0.05).

Autistic children had lower levels of some plasma amino acids except for glycine and glutamic acids and phosphoserine were increased with normal serum levels of urea, ammonia, total proteins, albumin and globulins (alpha 1, alpha 2, beta and gamma). 
In conclusion, autistic children may have dysregulated amino acids metabolism as all amino acids except for glutamic acid, phosphoserine and glycine are decreased in patients than in control; the raised glutamic acid may suggest involvement of an altered glutamate transporter and is consistent with a biochemical basis for autistic disorders. Also, the lower amounts of essential amino acids are correlated with more severe autism.


The fair conclusion is that both excreted and plasma amino acids look to be disturbed in autism. Does this tell you anything actionable? Should you become obsessed by trying to reach the reference ranges?
The answer depends on who you ask and I guess who is paying.

The derivatives of some amino acids may indeed be disturbed as a protective mechanism in which the body is adapting to specific effects of that person's autism. This was suggested in the research as one explanation of why agmatine, a derivative of arginine, is elevated in schizophrenia.  In other words elevated agmatine is a good thing in that person, it may well be a biomarker for schizophrenia, but possibly a "good" biomarker. 
If normalizing amino acids does improve autism, then expect the CM-AT treatment from Curemark to pass its phase 3 trials and become an FDA approved therapy for autism. Interestingly when I looked into the Curemark patents a long time ago, secretin appeared and it made another appearance earlier in this post. Secretin is now viewed as a false hope for autism treatment and those who still use it are seen as quacks. In trials secretin was shown not to help most people with autism, but regular readers will know that this is different from saying nobody responds. 
Irrespective of what finally happens to CM-AT, it looks like individual amino acids do have a place in some personalized autism therapies. This may, in some cases, be irrespective of the reference ranges, in other words in some cases an abnormally high level of one amino acid may be required to get a specific beneficial therapeutic effect.  Staying within the reference range is clearly the safer option.
Now I am back to my complicated post about Aspartate and N-acetylaspartate (NAA), which does look very relevant to autism.

Thursday, 15 March 2018

PolyPill Updated with Agmatine

After several months of testing Agmatine, including stopping and then re-starting, it is time to add it to my PolyPill.
The idea to trial Agmatine came from our reader Tyler. It ticks all the boxes, it really does have a benefit; that benefit continues for at least several months. When you stop taking it, the benefit stops and when you restart you see the same benefit return. It is safe, inexpensive and widely available if you live anywhere outside the EU. Since it is relatively recent to the market as a supplement, it can no longer be sold in the EU until someone applies for it to be approved; long established supplements bypass this recent legislation.
There were earlier posts evaluating why it might help some types of autism and now there even is one study on an animal model of autism. 

I think the positive effect very likely comes from the vasodilatory effect produced by the increased eNOS, there is also increased BDNF.  This I believe is why it also effective in two models of dementia. Agmatine is also an NMDAR antagonist, like Memantine and this is the mode of action proposed by autism researchers in the animal model above.  My opinion is that at this "bodybuilder's" dose the mode of action is not NMDAR antagonism.

The effect of Agmatine?

The energetic bunny on the left is the one taking 0.7g a day of Agmatine.
In the case of Monty, aged 14 with ASD, Agmatine gives him boundless energy, which in his case is beneficial.
I think the effect will manifest itself slightly differently in different people. In animal models it improves cognitive function.  
If you have autism + ADHD, then it might not be helpful. When I tried it on myself it made me feel slightly nauseous. In Monty's big brother it made him feel "different", but not better or worse and certainly not more energetic.

Other People’s PolyPills
Other readers of this blog have developed their own science-based “Polypill” therapies, for their specific type of autism. What works for my son may not help your child, but other  things discussed in this blog just might help.
High doses of the immuno-modulating Biogaia Gastrus probiotic bacteria clearly help some people greatly; but others get a negative reaction.
Immunomodulation by antibiotic is used successfully by some, but has some drawbacks. 
PAK1 inhibition ticks the science boxes and if you can obtain a potent PAK1 inhibitor it helps some people.

Butyric acid (from sodium butyrate, Miyairi 588 bacteria, more fiber or even rancid butter) is an HDAC inhibitor and is also required for gut wall integrity and likely BBB integrity. It is widely used in animal feed and some humans respond well to it, but the effect is dose dependent. HDAC inhibition can work epigenetically to change the expression of hundreds of "autism" genes, as highlighted in recent research using a potent cancer drug HDAC inhibitor.
Numerous individual amino acids (glutamine, taurine, methionine, aspartic acid etc) seem to help in some people. These tend to be OTC bulk powders like Agmatine.

In a sub-group of people with autism it is clear that digestive issues, unusual gut bacteria or food sensitivity is a major problem that is treatable relatively easily.

People with regressive autism may have (had) mitochondrial disease and this has a very specific therapy to protect from further regression and to allow for remyelination and mitochondrial biogenesis in the short term and hope for neurogenesis in the long term.

Saturday, 10 March 2018

A Thinking Person’s Brief Guide to Autism

I wrote this list because most people visit this blog and do not go any further into the details, either because they think this blog is nonsense, or it is just too complicated.

It certainly does sometimes get complicated, but complex subjects require detailed attention. There is little point in looking superficially.  Understanding autism science is not beyond most people’s ability, but it does take time. It will not cost you a penny. Then you can make up your own mind as what is a novel therapy and what is likely a quack therapy.

Some doctors do know best.  While your family doctor no doubt was taught autism is untreatable, some doctors who have a child with autism think differently and I do not mean MAPS/DAN doctors. Some mainstream doctors read the same research as me and successfully treat their child – an example of personalized medicine. In the ideal world they would all publish their experiences, but most keep it private.

Autism is not a biological medical diagnosis, it is just an observational diagnosis based on guidelines published in a book called the Diagnostic and Statistical Manual of Mental Disorders (DSM). These guidelines have changed substantially over time. We are currently on DSM 5; in 1987 it was DSM3 Revised. Most people diagnosed today with autism would not have been given that diagnosis under DSM 3. This is one key reason for the autism diagnosis “epidemic”, but there are other reasons.

A vast amount of scientific research already exists about autism. More is published every day and very helpful lay summaries are available for free on the internet on medical news websites and blogs like Paul Whiteley's Questioning Answers. There is also the Simon’s Foundation’s excellent website for non-scientists at

There are hundreds of different known biological causes of autism.  Scientists have already created 267 different genetic mouse models of autism and 78 types of induced autism. 192 rescue models exist, where the scientist could reverse autism in the mouse.  If you can reverse it in a mouse, perhaps you can treat it in a child? Not crazy to at least try.

Some autism/MR/ID caused by rare errors of the metabolism is treatable today, by mainstream medicine. Clinicians in Vancouver maintain a database; they focus on Mental Retardation (MR) / Intellectual Disability (ID), but many of these conditions can also be diagnosed as autism.

Science and medicine are not the same. Medicine applies drugs that are shown effective in large clinical trials on people with the same biological disorder.  This is evidence-based medicine.  Where a disorder exists with multiple causes, medicine struggles to cope. Many illnesses have multiple causes, or unknown causes, for example dementia, depression, epilepsy, multiple sclerosis etc. and even conditions outside the brain like chronic prostatitis.

Medicine has many poorly effective drugs for neurological conditions. There are drugs for dementia, ALS (motor neuron disease), Parkinson’s, Huntington’s, Schizophrenia, Bipolar etc., but they are not curative - they are better than nothing, but sometimes not by much. Drugs for autism should be seen in this perspective; generally they will be partially effective and only in specific people with the same particular biological dysfunction. Drugs for ALS, Alzheimer’s etc. currently just treat some features of the disease, they do not address the cause; some of these features are shared by others brain disorders. So using an ALS drug to treat autism or schizophrenia is not a crazy idea, if the same biological features are present.

There are numerous well-researched biological features present in some autism. Some of these same features are present in unrelated, better-researched, medical conditions where often they are treated. For example:- oxidative stress, elevated pro-inflammatory cytokines and reduced anti-inflammatory cytokines, activated microglia, disturbed growth factors (BDNF, NGF, IGF-1, VEGF etc.), numerous ion channel and transporter dysfunctions (NKCC1, KCC2, Cav1.2 etc.), NMDA hypofunction or hyperfunction, reduced estrogen and ERβ, excitatory-inhibitory imbalance, glutamate excitotoxicity, impaired autophagy, unusual myelination etc. 

Autistic brains are not just “wired up differently”. Brains are not computers and while some things are fixed as in a computer, much inside your brain is changing all time and so can potentially be modified.  You can induce even “autism” in a perfectly normal brain (with propionic acid) and then reverse it.  A slightly better analogy might be an old out-of-tune piano; tuning the strings (wires) is a complex process, but results in much improved function. Autistic brains can be tuned to improve their function and the person’s wellbeing.

Vaccines can trigger mitochondrial disease in children, which will appear as autism. This was proved by Dr Jon Poling a US neurologist trained at Johns Hopkins, who won $1.5 million in compensation for his daughter. Here interviewed on CNN:-

Vaccines caused one little girl's autism, but that does not mean they caused it in your child. How widespread this problem might be is something Dr Poling does comment on, but it is not something anybody would research.  Johns Hopkins is home to some of the best autism and mitochondrial disease researchers and clinicians. They even developed a cheap therapy to minimize the risk of possible damage from vaccinations to their young patients who already have mitochondrial disease. 

Autism does not kill you?
Vaccines save millions of lives and even Dr Poling does not suggest avoiding them. People with severe autism do have a life expectancy of less than 40 years mainly due to death from seizures, drowning and other accidents. People with the Asperger's type of milder autism have a nine times elevated risk of suicide and a disturbingly a high proportion of the tiny number of mass killers have an Asperger's/autism diagnosis (the other large group have suffered a previous head injury). So autism clearly can have troubling consequences.  Teaching anyone to shoot a gun who has a neurological disorder (autism, bipolar, schizophrenia, even ADHD, Intermittent Explosive Disorder etc), severe enough to get a medical diagnosis, is asking for trouble.

Does Autism need to be treated?
Some of the people with the newly included mild autism protest about the idea of treating autism. A significant minority of deaf people think their children born without hearing should not receive cochlear implants and so remain with them in silence, but most hearing people would likely want their child disabled by hearing loss to be treated. Medically diagnosed autism is currently based on guidelines from a book of mental disorders (DSM5). Most people probably think disorders in a psychiatrist’s manual should be treated, even if the very people with those disorders think they are just fine - they do after all have a disorder potentially clouding their judgement. If their autism is so mild and not troubling at all, then it does not warrant a medical diagnosis. You can be different without needing a medical diagnosis to support it.

Many observational diagnoses like Autism, ADHD, Bipolar and Schizophrenia are overlapping biologically
. Genetic studies have shown people can have biological elements of more than one diagnosis. So you can have autism with a little Bipolar and a touch of ADHD.  This means that some therapies trialed in Schizophrenia may show a positive effect in some autism, for example.

Clinical trials in Autism have all ultimately failed. All of the many clinical trials in autism to date have been viewed as failures and part of the reason is that there is more than one autism. There is no easy way to tell which person has which type, so trials include many people who are bound not to be responders.

People treating autism are all quacks? There undoubtedly are many people making money out of the families affected by autism and where money is involved, you will always find quack therapies of one kind or another.

Personalized medicine is one way forward. In cancer care personalized medicine is already being used, where drugs are tailored to exactly what is wrong in a specific person.  With hundreds of different variants of autism personalized medicine would be the ideal solution, but it is many decades away for most people.

Autism clusters and nexus where multiple dysfunctions converge.  The realistic way to treat autism in the 2020s will be to group people into similar clusters, not perfect matches, and treat by cluster.  This is possible because it seems that multiple different dysfunctions converge at a manageable number of so-called nexus. This means that rather than several hundred unique therapies you have just a few tens of therapies. Each person is then matched with their Polypill of a handful of those few tens of therapies.

Autism is a condition of opposites. In autism very often both extremes of the same condition exist, making the average meaningless. On a simple level the research finds many big heads, but also a fair number of tiny heads. There is very high cholesterol and very low cholesterol. There are very high levels of a particular growth factor and then some with virtually none.   So do not expect what works for someone else’s autism, to necessarily work for your child’s autism.

Many drugs have multiple modes of action. Lay people assume that drugs do just one thing, be it lower blood pressure, lower cholesterol or act as a diuretic.  This is not the case; most common drugs have multiple effects. For example many antibiotics have completely unrelated anti-inflammatory effects. A diuretic that affects one ion channel in your kidneys can also affect a related one in your brain, so yes a diuretic can treat some people’s autism, it is not crazy.

Many existing drugs can be repurposed. Many drugs already exist that can potentially be repurposed to treat neurological conditions. Big drug firms like to develop new drugs because their patents allow them to charge very high prices. Existing drugs are often now cheap generics, with well-known safety profiles, that can potentially be used off-label in personalized medicine, based on intelligent use of the vast wealth of autism research.

Off-label prescribing used to be widespread; it is when a drug is used for an application other than that for which it has been officially approved. For example, the diuretic Spironolactone is widely used off-label to treat acne in females.  Modern doctors are less willing to prescribe off-label either because they insist on strictly following the rules, or do not want to take a risk of being blamed for an adverse reaction.  Treating autism will inevitably require off-label prescribing.

Personalized therapy for the few? Hopefully the mainstream doctors who currently successfully treat their own children will persuade more of their peers to try and treat others. Until then, or until a drug like Bumetanide finally passes its stage 3 clinical trials for autism, I do not think much will change.  A small number of parents do read the research and persuade their physician to help them and others evidently self-treat. For those who are truly motivated there are options, which is what really matters.

Monday, 5 March 2018

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.

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.

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. 

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 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.

[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. 

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

You can measure DAO levels in your blood.

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.

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.

Wednesday, 28 February 2018

Winter Olympics

Today’s post is about the non-academic benefits of treating classic autism, which mainly seem to come from raising cognition (IQ).

Our reader Liz from Australia, whose five year old daughter has been using Bumetanide for two years, was telling us recently in her comments how her daughter can now go surfing with her four brothers.
While we do all want success at school and mastering practical skills like doing up shoe laces, the importance of being able to actively participate with siblings should not be underestimated.
Some siblings may be angels, but quite often there is resentment about having a sibling with special needs. One way to compensate is to have cool talents like surfing, skiing, fencing - something you can do well.

When I started this blog I was contacted by an Australian doctor who has a son with autism, she went to the same university as me. Her son was diagnosed early with severe autism with MR/ID, but progressed remarkably well and attended a mainstream school. His chosen sport at school was fencing (sword fighting). At that time Monty’s big brother was also having fencing classes and had all the equipment. I recall at the time thinking there is no way Monty could ever do that. Five years later though, Monty and his big brother are fighting together with homemade swords.
Fencing can look very impressive and certainly seems to count as a cool activity by modern day teenagers.

The main sport of Monty, now aged 14 with autism, is swimming - particularly underwater. While people with classic autism are at a greatly elevated risk of drowning, that is no longer something we have to worry about. Monty is more likely to be the rescuer than the one in trouble. If we lived in Australia, he too would be going to the beach to surf.
We did have swimming lessons, but only post-Polypill did Monty get competent. Now he swims really well and can swim a very long way underwater.

I do think that things that improve exercise endurance may be helpful to those with a neurological condition like autism. Just look what Nordic skiers, cyclists and tennis stars get into trouble for taking - much relates to getting more output from your mitochondria.  High altitude training is not an option for us, but swimming underwater may have a similar effect. There actually is research about what changes biologically in endurance divers (holding their breath) and people who train at high altitude. I suspect that moderate diving may improve brain perfusion, extreme diving is different because they are functioning when a typical person would have lost consciousness due to lack of oxygen. Moderate diving, like high altitude training, should increase how much oxygen your blood can carry.
Native Andean and Himalayan populations have better oxygenation at birth, enlarged lung volumes throughout life, and a higher capacity for exercise. Tibetans demonstrate a sustained increase in cerebral blood flow, but a typical hemoglobin concentration, whereas in the Andes they have significantly elevated levels of hemoglobin. Hemoglobin/haemoglobin is the protein in your blood that transports the oxygen around your body.  How do the Tibetans manage without extra hemoglobin?

“The Tibetan hemoglobin distribution closely resembled that from a comparable, sea-level sample from the United States whereas the Aymara (Andes) distribution was shifted toward 3-4 gm/dl higher values.”

The performance-enhancing effect of altitude training appears not to be due to increased red blood cell count or increased hemoglobin, as thought until recently, but rather something called Red Blood Cell (RBC) Hypoxic Metabolic Reprograming.
In essence, the hemoglobin becomes better at holding on to oxygen. Perhaps this is what Tibetans do.
Lay people suggest that:
More hemoglobin = More oxygen delivery.
It appears that you do not need more hemoglobin, you just need to make your existing hemoglobin work better.  And for that you need to give it a challenge; perhaps regularly swimming a long way on a single breath counts?

When scientists examined the oxygen-carrying proteins, known as hemoglobin, in volunteers’ red blood cells, they found multiple changes affecting how tightly it hung onto its oxygen load. Roach says a simplistic analogy is comparing this to what happens when baseball players loosen their grip on a mitt. “If I relax my hand, it will let go of the ball,” he says. Such changes had been observed before in the lab, but never in humans, and never at high altitude, the team reports this month in the Journal of Proteome Research. The scientists also found that the metabolic processes producing these changes were considerably more complex than suspected. And because red blood cells live for about 120 days, the changes last as long as the cells do.

Skiing is popular where we live and most children from our school go once a year, either with school or with their family. 

Unless you live in the mountains, skiing is not a sport people do very often and so you could question whether it is worth all the expense. 
Monty started skiing when he was five with a couple of instructors who had recently started a ski school in Zell am See in Austria, just for children with disabilities like autism.

In the beginning just putting on all the equipment and riding up the mountain in the cable car was a big challenge.  It certainly was a case of stepping out of his comfort zone.  Having started we did persevere, in part so that big brother also had his chance to learn to ski.
2018 was the first week of skiing without any lessons.

This year big brother was concerned that he would have no one to ski with and was planning to make new friends on the slopes.
He did agree that he would ski with little brother, but much to his surprise spent the whole week skiing with him. It was not at all what he had expected. They could ski all over the resort using multiple types of ski lift. Who lost his ski while on a chair lift and had it fall into the trees? Not Monty, who had to ski by himself to the bottom of the slope while big brother retrieved his ski.
Being left alone at the top of the mountain, might have been a cue for one of those old-time “meltdowns”, but much to big brother’s surprise, Monty just skied alone down the mountain and waited for him, once he had found his missing ski. No awkward explaining to parents what had happened to Monty was required.
So then big brother decided to teach Monty how to do ski jumps, just like any regular teenager.
Both have been skiing for 8 years. Monty skis on red slopes (medium difficulty), whereas his brother would also go on the black slopes (the hardest).

Regarding myelination from a recent post, many people (like me) who learn skiing in adulthood often never myelinate their “skiing neuronal pathways” and so each year you come back as a near beginner. This is clearly not the case with Monty, he now retains his skiing skills, even though he has not used them for a year. 

Other Sports
Trampolining is something remarkably popular among people with severe autism. I suppose this is all about seeking sensory stimulation. Monty loves water slides and we used to know twins with autism/Asperger’s who were obsessed with roller coasters.

There is a common view that if you have a mental disability you must have a physical disability. Monty’s new teachers at high school were surprised when they learnt he skis just like a regular boy. Of course he showed the ski jump video to his classmates.

While you can ski with an IQ less than 70, as in Down Syndrome and most Classic Autism, it goes even better when you boost IQ.
I imagine the same applies to surfing and other water sports like sailing.
Clearly raising IQ means parents have far less safety issues to worry about.
Music of course is another great potential area for people with autism and Asperger’s. I wrote a post a long time ago about talents and savants, suggesting that people with autism really should be encouraged to use their abundant free time to develop such skills. Many people already do. Most of the Asperger’s people I have come across are now very talented musicians, practising hours every day. One is also an excellent skier on black slopes.

Friday, 23 February 2018

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 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.

The L-type calcium channels (LTCCs) Cav1.2 and Cav1.3, 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 Cav1.2 and Cav1.3. 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 Cav1.2- and Cav1.3-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.

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


"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-HT2b 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:-


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.

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


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.