Showing posts with label Hypokalemic sensory overstimulation. Show all posts
Showing posts with label Hypokalemic sensory overstimulation. Show all posts

Sunday, 26 March 2017

Sensory Gating in Autism, Particularly Asperger's

Sensory gating is an issue in autism, schizophrenia and ADHD.   It is the neurological process of filtering out redundant or unnecessary stimuli in the brain; like the child who sits in his classroom and gets bothered by the noise of the clock on the wall.  He is unable to filter out and ignore this sound. He becomes preoccupied by the sound and cannot concentrate on his work.
There are also sometimes advantages to not filtering out environmental stimuli, because you would have more situational awareness and notice things that others miss.
An example of sensory gating is the fact that young children are not waken by smoke detectors that have high pitched siren, but are waken by a recorded human voice telling them there is a fire and to wake up.
There may be times when sensory overload in autism is not a case of too much volume from each of the senses, but rather too many inputs being processed by the brain, instead of some just being ignored.  It is more a case of information overload.
Note that this blog has already covered hypokalemic sensory overload in some depth, which is treatable.
Much is known about sensory gating because it has long been known to be a problem in schizophrenia.
An EEG (Electroencephalography) test measures your brain waves / neural oscillations. Many people with autism have EEGs, but mainly those in which epilepsy is a consideration.
In the world of the EEG, the P50 is an event occurring approximately 50 millisecond after the presentation of an auditory click.  The P50 response is used to measure sensory gating, or the reduced neurophysiological response to redundant stimuli.
Abnormal P50 suppression is a biomarker of schizophrenia, but is present in other disorders, including Asperger’s, post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI).
In more severe autism abnormal P50 suppression was found not to be present in one study.  This might be because cognition and the senses are dimmed by the excitatory-inhibitory imbalance.
More broadly, sensory gating is seen as an issue in wider autism and ADHD.

Correcting P50 gating
It is known that α7 nicotinic acetylcholine receptor (α7 nAChR) agonists can correct the impaired P50 gating. It is also known that people with schizophrenia have less expression of this receptor in their brains than typical people.

One short term such agonist is the nicotine released from smoking.  This likely contributes to why people with schizophrenia can be heavy smokers.  The effect is thought to last for about 30 minutes.
Clinical trials using Tropisetron, a drug that is a α7 nAChR agonist and used off-label to treat fibromyalgia, have shown that it can correct defective P50 gating and improve cognitive function in schizophrenia.

An alternative α7 nAChR agonist that is widely available is varenicline, a drug approved to help people stop smoking.
So you might expect varenicline to improve P50 gating and improve cognition. You might also expect it to help people with fibromyalgia and indeed some other people with chronic inflammation, as shown by elevated inflammatory cytokines.

You may recall that the α7 nAChR is the key to stimulating the vagus nerve and this should be beneficial to many people with inflammatory conditions (from arthritis to fibromyalgia).

Abnormalities in CHRNA7, the alpha7-nicotinic receptor gene, have been reported in autism spectrum disorder. These genetic abnormalities potentially decrease the receptor’s expression and diminish its functional role. This double-blind, placebo-controlled crossover study in two adult patients investigated whether an investigational receptor-specific partial agonist drug would increase the inhibitory functions of the gene and thereby increase patients’ attention. An electrophysiological biomarker, P50 inhibition, verified the intended neurobiological effect of the agonist, and neuropsychological testing verified a primary cognitive effect. Both patients perceived increased attention in their self-ratings. Alpha7-nicotinic receptor agonists, currently the target of drug development in schizophrenia and Alzheimer Disease, may also have positive clinical effects in autism spectrum disorder.

A role for H3 and HI histamine receptors
It has also been suggested that histamine plays a role in sensory gating via the H1 and H3 receptors.

It had also been thought H3 receptors could be targeted to improve cognition in schizophrenia, but that research really did not go anywhere.

Histamine H1 receptor systems have been shown in animal studies to have important roles in the reversal of sensorimotor gating deficits, as measured by prepulse inhibition (PPI). H1-antagonist treatment attenuates the PPI impairments caused by either blockade of NMDA glutamate receptors or facilitation of dopamine transmission. The current experiment brought the investigation of H1 effects on sensorimotor gating to human studies. The effects of the histamine H1 antagonist meclizine on the startle response and PPI were investigated in healthy male subjects with high baseline startle responses and low PPI levels. Meclizine was administered to participants (n=24) using a within-subjects design with each participant receiving 0, 12.5, and 25 mg of meclizine in a counterbalanced order. Startle response, PPI, heart rate response, galvanic skin response, and changes in self-report ratings of alertness levels and affective states (arousal and valence) were assessed. When compared with the control (placebo) condition, the two doses of meclizine analyzed (12.5 and 25 mg) produced significant increases in PPI without affecting the magnitude of the startle response or other physiological variables. Meclizine also caused a significant increase in overall self-reported arousal levels, which was not correlated with the observed increase in PPI. These results are in agreement with previous reports in the animal literature and suggest that H1 antagonists may have beneficial effects in the treatment of subjects with compromised sensorimotor gating and enhanced motor responses to sensory stimuli.

The aim of this study was to investigate an established rat model of decreased PPI induced by administration of the NMDA antagonist, dizocilpine and the reversal of this PPI impairment by the histaminergic H1-antagonist, pyrilamine. H1-antagonism is a potential mechanism of the therapeutic effects of the atypical antipsychotic, clozapine, which improves PPI following dizocilpine administration in rats as well as in patients with schizophrenia. In the present study we show that chronic pyrilamine administration prevents the PPI impairment induced by chronic dizocilpine administration, an effect that is correlated with a reduction in ligand-binding potential of H1 receptors in the anterior cingulate and an increase in nicotinic receptor α7 subunit binding in the insular cortex. In light of the functional anatomical connectivity of the anterior cingulate and insular cortex, both of which interact extensively with the core PPI network, our findings support the inclusion of both cortical areas in an expanded network capable of regulating sensorimotor gating.

The brain histamine system has been implicated in regulation of sensorimotor gating deficits and in Gilles de la Tourette syndrome. Histamine also regulates alcohol reward and consumption via H3 receptor (H3R), possibly through an interaction with the brain dopaminergic system. Here, we identified the histaminergic mechanism of sensorimotor gating and the role of histamine H3R in the regulation of dopaminergic signaling. We found that H3R knockout mice displayed impaired prepulse inhibition (PPI), indicating deficiency in sensorimotor gating. Histamine H1 receptor knockout and histidine decarboxylase knockout mice had similar PPI as their controls. Dopaminergic drugs increased PPI of H3R knockout mice to the same level as in control mice, suggesting that changes in dopamine receptors might underlie deficient PPI response when H3R is lacking. Striatal dopamine D1 receptor mRNA level was lower, and D1 and D2 receptor-mediated activation of extracellular signal-regulated kinase 1/2 was absent in the striatum of H3R knockout mice, suggesting that H3R is essential for the dopamine receptor-mediated signaling. In conclusion, these findings demonstrate that H3R is an important regulator of sensorimotor gating, and the lack of H3R significantly modifies striatal dopaminergic signaling. These data support the usefulness of H3R ligands in neuropsychiatric disorders with preattentional deficits and disturbances in dopaminergic signaling.


Other than nicotine, varenicline would seem a good potential therapy for sensory gating.  There are α7-nicotinic acetylcholine receptor agonists in development.
There are many H1 histamine antagonists.  Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H1 receptors. Centrally acting H1 antihistamines are sedating.

H3 antagonists have stimulant and nootropic effects. Betahistine is an approved drug in this class, there are many research drugs.

The aim of this study is to investigate the role of the neurotransmitter histamine in sensory and cognitive deficits as they often occur in schizophrenia patients (e.g. hearing voices, planning and memory problems). The ideal location to conduct the study and to obtain a unique learning experience is at the Institute of Psychiatry, London, United Kingdom, where staff comprises of leading experts in the field of schizophrenia and Magnetic Resonance Imaging of pharmacological effects. Current pharmacological treatment of psychotic symptoms including sensory and cognitive deficits remains partially unsuccessful due to side effects and treatment resistance. The neurotransmitter histamine seems to be a very promising target for new treatments. It has been found that histamine neurotransmission is altered in brains of schizophrenics, which may contribute to both the hallucinatory and cognitive symptoms. However, this specific role of histamine has not been investigated before. I will assess the effects of increased histaminergic activity, by administration of betahistine to healthy volunteers, on performance (sensory gating, executive functioning or planning and memory) and associated brain activity using fMRI. Altered performance and brain activity would support the importance of histamine in schizophrenia and would provide a research model and target for new treatments.

Friday, 11 March 2016

Treating Adults with Autism?


Almost the entire focus of treating autism is targeted at young children; only rarely do you hear about clinical trials involving adults, yet we are often reminded that autism is a lifelong condition.

For those of you that read the proposed guidelines to drug companies developing autism therapies, this issue raised its head again.  Will therapies effective in children be effective in adults (and vice versa)?

There are many issues here.  On the one hand there is great caution about giving drugs to very young children, but there is the realization that many therapies may only be effective if given at an extremely young age.

I only started treating the biological dysfunctions in Monty, now aged 12, when he was 9 years old.  By good fortune the first therapy (bumetanide) I tried was highly effective, otherwise this blog would not exist.

Had that Bumetanide clinical trial been published 5 years earlier, would I have given my then 4 year old son that same drug?  Probably not.

With what I now know, I would be happy to give Bumetanide as soon after birth that autism was even suspected.  (To the trained eye, this is but a few months old)

The effect of no treatment

For three years I have been developing a personalized autism treatment, Monty’s Polypill, and I think it works well, but a few weeks ago we decided to see what happens with no treatment at all.

This did provide some useful insights into treating young adults, as opposed to young children.

The first thing is that all the new skills that have been acquired, at close to neurotypical speed, in the last three years, did not just fade away. 

The old obvious repetitive behaviors/stimming/stereotypy did not return, but more subtle new ones did.  (no NAC)

He could still play his piano nicely with his teacher, but his interest in playing out of lessons faded away as did his skill level out of lessons.

He showed an occasional aversion to doing anything new, for example when his assistant came in the afternoon, I told him to go outside and meet her.  He could happily open the front door (his normal routine) but was not able to walk though it and meet her by the gate.  (no statin)

When I offered to go with him, he had a brief tantrum. 

He started asking permission to do things he knew how to do, which some people saw as a positive.  When lying in bed at 9pm he called out “Mum can I read a book”, rather than just picking one from the shelf by his bed and when at a small birthday party he had to bend down to light the candles, he turned round and said “can I squat?”  Most people thought that was good use of vocabulary, I was thinking “just do it”.  (statin effect)

I received comments like “how patient he is”, or at school  words like “peace” and “peaceful”.  I was thinking how passive he was. (no bumetanide/low dose clonazepam)

While there was no glaring loss of cognitive function and spelling tests and maths test at school were not showing any deficit, I noticed a loss of ability to develop new skills. 

We use an excellent online program called Math Whizz and one thing we were learning was to how to use the calendar.

Typical questions would be:-

“What date is the second Friday in May?”
“What date if the first Monday in December?”
“What day (of the week) is the last day in June?”

You first have to click on “May” to get the calendar to turn to the correct month and then you can figure out the answer.

To my surprise, while still on the Polypill, Monty was getting pretty good at this exercise, on his first attempt.

However, a few days later, when we tried with no Polypill, he was struggling and as the days passed he got worse and worse.  (chloride levels gradually rising?)

There was even a return of the sensory overload that causes many problems for some people with autism and also Asperger’s.  Even the sound of a crow became disturbing.  Both Acetazolamide and Bumetanide are used to treat Hypokalemic Periodic Paralysis, which is a more severe form of Hypokalemic Sensory Overload and at least some types of Autistic Sensory Overload are a subset of this.

After two weeks of Bumetanide and Potassium the sound over-sensitivity has gone again.  It did not go away immediately.

Pleiotropic effect of Verapamil

While I initially identified the calcium channel blocker, Verapamil, as an effective inhibitor of aggression and SIB triggered by allergy/mast cell degranulation, I was once asked if I thought Verapamil might have pleiotropic effects in Monty.  Having stopped using Verapamil and then restarted it, all outside of the problematic allergy season, I have all the proof I need in my n=1 case.  Life is better with a little Verapamil; his calcium channel dysfunction goes beyond those in mast cells.

Verapamil was the last element of the Polypill that I re-started; I was rather hoping it would show no effect outside the allergy season.  Only after adding it back did things really return to what has become our "normal".

There is after all a vast amount of evidence linking calcium ion channel dysfunction and autism.

My Verdict

I think many people would be very happy to have a passive child, who can sit for two hours in restaurant.

Most people do not notice the fading of good behavior, because their overriding concern is the lack of any “bad” behavior.  So a bad behavior is followed by a “is this better?”, rather than a “Wow, do you know Monty did today …”.

I prefer a child who can learn, even if that means he may get fed up from time to time, and show it.

I was pleased to come home earlier this week and find Monty sitting alone playing his piano beautifully (no prompting, no reinforcement needed), with his music book laid out in front of him, playing one melody, turning the page and playing the next one, while his big brother had gone upstairs to play his computer games, because little brother does not need him. 


Intervention in Adults

Other than halting self injurious behavior (SIB), I am far from convinced that most people would even notice the difference if you took an adult with classic autism and started to treat him.

At that age, passive and patient is what most caregivers want.

So I see little prospect that “corrective biological therapy” will ever be initiated in many adults with more serious autism;  they will continue to be “tranquilized”.

Many adults with Asperger’s and high IQ do their own research and self-treat; some even read this blog. For them, even a small biological "improvement" can have a welcome effect on well-being. Good for them.

Intervention in Young Children

The best way forward is to intervene immediately after diagnosis.  In the US/Canada that might be two years old, but more like four years old in Europe.

If I was a Roche or Novartis, this would be my target:- non-verbal, non toilet-trained toddlers who make no eye contact, possibly cry a lot and tend to be kept at home.

Wednesday, 27 May 2015

Diamox & Bumetanide, Ion Channels Nav1.4 and Cav1.1, HypoPP, Autism and Seizures

Today’s post links together subjects that have been covered previously.

It does suggest that there are multiple therapies that may be effective in the large sub-group of autism that is characterized by the neurotransmitter GABA being excitatory (E) rather than inhibitory (I).  The science was covered in the earlier very complicated post:-

The growing list of potential therapies is:-

·        Bumetanide (awaiting funding for Stage 3 clinical trials in humans)
·        Micro-dose Clonazepam (trials in mouse models of autism)
·        Diamox (off-label use in autism)
·        Potassium Bromide  - to be covered in a later post (in use for 150 years)

Not surprisingly, all of these drugs also have an effect on certain types of seizure.

The optimal therapy in people with this E/I imbalance will likely be a combination of some of the above.

Periodic paralysis

Periodic paralysis (Hypokalemic periodic paralysis or HypoPP) is a rare condition that causes temporary paralysis that can be reversed by taking potassium.  A similar condition is hypokalemic sensory overload, when someone becomes overwhelmed by lights or sounds, but after taking potassium all goes back to normal. Autistic sensory overload, experienced by most people with autism, can also be reduced by potassium.

Though rare, we know that HypoPP is caused by dysfunction in the ion channels Nav1.4 and/or Cav1.1.

For decades one of the treatments for HypoPP has been a diuretic called Diamox/Acetazolamide.

Other treatments include raising potassium levels using supplements or potassium sparing diuretics.

Bumetanide is a diuretic, but rather than raising potassium levels, it does the opposite.  So I always thought it was odd that bumetanide would have a positive effect on HypoPP.  But the research showed a benefit.

Autism and Channelopathies

We know that autism and epilepsy are associated with various ion channel and transporter dysfunctions (channelopathies).  In a recent post I was talking about Cav1.1 to Cav1.4.

Today we are talking about Cav1.1 and Nav1.4.

We know that Nav1.1 is associated with epilepsy and some autism (Dravet syndrome).

Nav1.4 is expressed at high levels in adult skeletal muscle, at low levels in neonatal skeletal muscle, and not at all in brain

Nav1.1 expression increases during the third postnatal week and peaks at the end of the first postnatal month, after which levels decrease by about 50% in the adult.

We saw with calcium channels that a dysfunction in one of Cav1.1 to Cav1.4 can cause a dysfunction in another dysfunction in another one of Cav1.1 to Cav1.4.

We also so that in autism the change in expression of NKCC1 and KCC2 as the brain matures failed to occur and so in effect they remain immature and therefore malfunction.

So it is plausible that sodium channels may also malfunction in a similar way. 

Hypokalemic periodic paralysis (hypoPP) is an autosomal dominant neuromuscular disorder characterized by episodes of flaccid skeletal muscle paralysis accompanied by reduced serum potassium levels. It is caused by mutations in one of two sarcolemmal ion channel genes, CACNA1S and SCN4A1-3 that lead to dysfunction of the dihydropyridine receptor or the alpha sub-unit of the skeletal muscle voltage gated sodium channel Nav1.4. Seventy to eighty percent of cases are caused by mutations of CACNA1S and ten percent by mutations of SCN4A4. 

There are no consensus guidelines for the treatment of hypoPP. Current pharmacological agents commonly used include potassium supplements, potassium sparing diuretics and carbonic anhydrase inhibitors (acetazolamide and dichlorphenamide). Dichlorphenamide is the only therapy for hypoPP to have undergone a randomized double blind placebo controlled cross over trial. This trial showed a significant efficacy of dichlorphenamide in reducing attack frequency but the inclusion criteria were based on clinical diagnosis of hypoPP and not genetic confirmation.


Cav1.1 also known as the calcium channel, voltage-dependent, L type, alpha 1S subunit, (CACNA1S), is a protein which in humans is encoded by the CACNA1S gene


Sodium channel protein type 4 subunit alpha is a protein that in humans is encoded by the SCN4A gene.

The Nav1.4 voltage-gated sodium channel is encoded by the SCN4A gene. Mutations in the gene are associated with hypokalemic periodic paralysis, hyperkalemic periodic paralysis, paramyotonia congenita, and potassium-aggravated myotonia.


Ranolazine is an antianginal and anti-ischemic drug that is used in patients with chronic angina. Ranzoline blocks Na+ currents of Nav1.4. Both muscle and neuronal Na+ channels are as sensitive to ranolazine block as their cardiac counterparts. At its therapeutic plasma concentrations, ranolazine interacts predominantly with the open but not resting or inactivated Na+ channels. Ranolazine block of open Na+ channels is via the conserved local anesthetic receptor albeit with a relatively slow on-rate.

Muscle channelopathies:does the predicted channel gating pore offer new treatment insights for hypokalaemic periodic paralysis?

Beneficial effects of bumetanide in a CaV1.1-R528H mouse model of hypokalaemic periodic paralysis
Transient attacks of weakness in hypokalaemic periodic paralysis are caused by reduced fibre excitability from paradoxical depolarization of the resting potential in low potassium. Mutations of calcium channel and sodium channel genes have been identified as the underlying molecular defects that cause instability of the resting potential. Despite these scientific advances, therapeutic options remain limited. In a mouse model of hypokalaemic periodic paralysis from a sodium channel mutation (NaV1.4-R669H), we recently showed that inhibition of chloride influx with bumetanide reduced the susceptibility to attacks of weakness, in vitro. The R528H mutation in the calcium channel gene (CACNA1S encoding CaV1.1) is the most common cause of hypokalaemic periodic paralysis. We developed a CaV1.1-R528H knock-in mouse model of hypokalaemic periodic paralysis and show herein that bumetanide protects against both muscle weakness from low K+ challenge in vitro and loss of muscle excitability in vivo from a glucose plus insulin infusion. This work demonstrates the critical role of the chloride gradient in modulating the susceptibility to ictal weakness and establishes bumetanide as a potential therapy for hypokalaemic periodic paralysis arising from either NaV1.4 or CaV1.1 mutations.

Mode of action

The research does state that nobody knows why Diamox is effective in many cases of hypoPP.

My reading of the research has already taken me in a different direction.  While researching the GABAA receptor that is dysfunctional in some autism, it occurred to me that in addition to targeting the NKCC1 receptor with bumetanide, another way of lowering chloride levels within the cells might well exist.

I suggested in an earlier post that Diamox could be used to target the AE3 exchanger.

What Diamox (acetazolamide) does is lower the pH of the blood in the following way.

Acetazolamide is a carbonic anhydrase inhibitor, hence causing the accumulation of carbonic acid Carbonic anhydrase is an enzyme found in red blood cells that catalyses the following reaction:

hence lowering blood pH, by means of the following reaction that carbonic acid undergoes

In doing so there will be an effect on both AE3 and NDAE, below.  This will change the intracellular concentration of Cl-, and hence give a similar result to bumetanide.

This would also explain the phenomenon cited below that pH affects the excitability of the brain.

Over excitability of the brain is the cause of some of the effects seen as autism and clearly Over excitability of the brain will be the cause of some people’s seizures/epilepsy.

Not surprisingly, then one of the uses of Diamox is to avoid seizures.


Anion exchanger 3 (AE3) in autism

Anion exchange protein 3 is a membrane transport protein that in humans is encoded by the SLC4A3 gene. It exchanges chloride for bicarbonate ions.  It increases chloride concentration within the cell.  AE3 is an anion exchanger that is primarily expressed in the brain and heart

Its activity is sensitive to pH. AE3 mutations have been linked to seizures

Bicarbonate (HCO3-) transport mechanisms are the principal regulators of pH in animal cells. Such transport also plays a vital role in acid-base movements in the stomach, pancreas, intestine, kidney, reproductive organs and the central nervous system.


Chloride influx through GABA-gated Cl channels, the principal mechanism for inhibiting neural activity in the brain, requires a Cl gradient established in part by K+–Cl cotransporters (KCCs). We screened for Caenorhabditis elegans mutants defective for inhibitory neurotransmission and identified mutations in ABTS-1, a Na+-driven Cl–HCO3 exchanger that extrudes chloride from cells, like KCC-2, but also alkalinizes them. While animals lacking ABTS-1 or the K+–Cl cotransporter KCC-2 display only mild behavioural defects, animals lacking both Cl extruders are paralyzed. This is apparently due to severe disruption of the cellular Cl gradient such that Cl flow through GABA-gated channels is reversed and excites rather than inhibits cells. Neuronal expression of both transporters is upregulated during synapse development, and ABTS-1 expression further increases in KCC-2 mutants, suggesting regulation of these transporters is coordinated to control the cellular Cl gradient. Our results show that Na+-driven Cl–HCO3 exchangers function with KCCs in generating the cellular chloride gradient and suggest a mechanism for the close tie between pH and excitability in the brain.


During early development, γ-aminobutyric acid (GABA) depolarizes and excites neurons, contrary to its typical function in the mature nervous system. As a result, developing networks are hyperexcitable and experience a spontaneous network activity that is important for several aspects of development. GABA is depolarizing because chloride is accumulated beyond its passive distribution in these developing cells. Identifying all of the transporters that accumulate chloride in immature neurons has been elusive and it is unknown whether chloride levels are different at synaptic and extrasynaptic locations. We have therefore assessed intracellular chloride levels specifically at synaptic locations in embryonic motoneurons by measuring the GABAergic reversal potential (EGABA) for GABAA miniature postsynaptic currents. When whole cell patch solutions contained 17–52 mM chloride, we found that synaptic EGABA was around −30 mV. Because of the low HCO3 permeability of the GABAA receptor, this value of EGABA corresponds to approximately 50 mM intracellular chloride. It is likely that synaptic chloride is maintained at levels higher than the patch solution by chloride accumulators. We show that the Na+-K+-2Cl cotransporter, NKCC1, is clearly involved in the accumulation of chloride in motoneurons because blocking this transporter hyperpolarized EGABA and reduced nerve potentials evoked by local application of a GABAA agonist. However, chloride accumulation following NKCC1 block was still clearly present. We find physiological evidence of chloride accumulation that is dependent on HCO3 and sensitive to an anion exchanger blocker. These results suggest that the anion exchanger, AE3, is also likely to contribute to chloride accumulation in embryonic motoneurons.


So the science does confirm that “chloride accumulation following NKCC1 block was still clearly present”.  This means that bumetanide is likely only a partial solution.

We also see that “anion exchanger, AE3, is also likely to contribute to chloride accumulation in embryonic motoneurons” and “that chloride accumulation that is dependent on HCO3”.

This is a subject of some research, but it is still early days.

I suggest that Diamox, via its effect on HCO3, may affect anion exchanger AE3 and further reduce chloride accumulation within cells.  This may have a further cumulative effect on GABA.

As we saw earlier, bumetanide does indeed shift GABA from excitatory to inhibitory in people who neurons remain in an immature state (like those of a typical two week old baby).  To my surprise, the use of micro-dose Clonazepam, as proposed by Professor Catterall, but in addition to Bumetanide, has a further effect on GABA’s excitatory/inhibitory imbalance.

Taken together this would highlight the possible further benefit of Diamox.

Normal blood pH is tightly regulated between 7.35 and 7.45.  I do wonder if perhaps in some people with autism, the pH of their blood is slightly elevated (alkaline), this would contribute to excitability of the brain.

Since Diamox increases the oxygen carrying capacity of the blood, I further wonder if this additional oxygen may also be beneficial in some cases.  Since some people are adamant that hypobaric oxygen therapy has beneficial (although not sustained) effects in autism, surely a better treatment would be Diamox?

Since the body is controlled via so-called feedback loops, perhaps in a small subset of people with autism who respond to extra O2, they actually have blood pH that is higher than 7.45.  In which case measuring blood pH would be a biomarker of who would respond to hypobaric oxygen therapy.  Not surprisingly then, trials of hypobaric oxygen therapy in autism fail, because most of the trial subjects do not have elevated blood pH.
So there are many reasons that Diamox should be trialed in autism.  I did find one (DAN) doctor currently using it, but they do not really explain why.

Biomedical Treatment of the Young Adult with ASD