pH and Neuronal Excitability - Therapy in Autism, Epilepsy, Mitochondrial Disease and ASIC mutations. Plus GPR89A

 

Diamox or Meldonium would make it easier

 

Several times recently the subject of pH (acidity/alkalinity) has come up in my discussions with fellow parents. It is not a subject that gets attention in the autism research, so here is my contribution to the subject.

If your child has a blood gas test a day after a seizure and it shows high pH, this is not the result of the seizure, but a likely cause of it. Treat the elevated pH to avoid another seizure and likely also improve autism symptoms. It may be respiratory alkalosis which is caused by hyperventilation, due to stress, anxiety etc.

The regulation of pH inside and outside brain cells is a delicate balance with far-reaching consequences. Subtle shifts toward acidity (low pH) or alkalinity (high pH) can alter calcium handling, neuronal excitability, and ultimately drive seizures, fatigue, or even inflammation. This interplay becomes especially important in conditions like autism, epilepsy, and mitochondrial disease, where metabolism and excitability are already dysregulated.

You can measure blood pH quite easily, but within cells different parts are maintained at very different levels of pH and this you will not be able to measure. Blood pH is about 7.4 (slightly alkaline) the gogli apparatus is slightly acidic, whereas the lysome is very acidic (pH about 4.7).

 

pH and Calcium Balance

Calcium (Ca²⁺) is central to neuronal excitability. Small pH changes shift the balance between intracellular and extracellular calcium:

• Alkalosis (↑ pH): reduces extracellular calcium availability, destabilizes neuronal membranes, and promotes hyperexcitability and seizures.
• Acidosis (↓ pH): activates acid-sensing ion channels (ASICs), leading to Na⁺ and Ca²⁺ influx and further excitability.

Thus, both too much acidity and too much alkalinity can increase seizure risk, though through different mechanisms.

Your body should tightly regulate its pH. You can only nudge it slightly up or down. Even small changes can be worthwhile in some cases.

When extracellular (ionized) calcium enters neurons through ion channels it can drive inflammation, excitability, and mitochondrial stress. Calcium needs to be in the right place and in autism it often is not, for a wide variety of reasons.

 

 

Mitochondrial Disease and pH

Mitochondria produce ATP through oxidative phosphorylation. Dysfunction can impair this process and lead to accumulation of lactate (acidosis) or, paradoxically, reduced proton flux (relative alkalosis). In autism, mitochondrial dysfunction is reported in a significant minority (10–20%) of cases.

 

Hyperventilation and Alkalosis

Another often-overlooked contributor is hyperventilation. By blowing off CO₂, blood pH rises (respiratory alkalosis), leading to reduced ionized calcium and increased excitability. This is the reason why hyperventilation is used during EEG testing to provoke seizures in susceptible individuals.

 

Therapeutic Approaches - Adjusting pH

Several therapies—old and new—intentionally alter pH balance:

1. Sodium and Potassium Bicarbonate

• Mechanism: Buffers acids, increases systemic pH (alkalinization).
• Applications: Beneficial in some cases of autism and epilepsy, as reported in blogs and small studies.
• Note: Raises extracellular pH, which can reduce ASIC activation but may increase excitability if alkalosis is excessive.
• Beyond buffering, sodium bicarbonate (baking soda) has been shown to trigger anti-inflammatory vagal nerve pathways. This effect may be especially valuable in neuroinflammation seen in autism and epilepsy.

 

2. Acetazolamide (Diamox)

• Mechanism: A carbonic anhydrase inhibitor that causes bicarbonate loss in the urine, lowering blood pH (mild acidosis).
• Neurological Effects: Used as an anti-seizure drug, especially in patients with channelopathies and mitochondrial disorders.
• In Climbers: At altitude, the body tends toward alkalosis due to hyperventilation (blowing off CO₂). Diamox counteracts this by inducing a mild metabolic acidosis, which stimulates ventilation, improves oxygenation, and prevents acute mountain sickness (AMS). This is why mountaineers often describe Diamox as helping them “breathe at night” in the mountains.

3. Zonisamide

• Mechanism: Another carbonic anhydrase inhibitor, with both anti-seizure and mild acidifying effects.
• Benefit: Often used in refractory epilepsy.

 

ASICs: Acid-Sensing Ion Channels

ASICs are neuronal ion channels directly gated by protons (H⁺). Their activity is pH-sensitive:

• Low pH (acidosis): Activates ASICs → Na⁺/Ca²⁺ influx → excitability and seizures.
• High pH (alkalosis): Reduces ASIC activity, but destabilizes calcium balance in other ways.

 

ASIC Mutations

Mutations in ASIC genes can alter how neurons respond to pH shifts. In theory, modest therapeutic modulation of pH (via bicarbonate or acetazolamide) could normalize excitability in patients with ASIC mutations.

 

ASIC2 is seen as a likely autism gene. There is even an ASIC2 loss of function mouse model.

Give that mouse Diamox!

 

Meldonium vs Diamox — Two Paths to Survive Altitude

During the Soviet–Afghan war in the 1980s, Russian troops were supplied with meldonium, while American soldiers and climbers commonly used acetazolamide (Diamox) for altitude adaptation. The Mujahideen and Taliban need neither, because they have already adapted to the low oxygen level.

Meldonium is a Latvian drug made famous by the tennis star Maria Sharapova who was found to be taking it for many years. It is a very plausible therapy to boost the performance of your mitochondria and so might help some autism. I know some people have tried it.

Although both drugs were used to improve performance under hypoxia, they worked in almost opposite ways:

 

At high altitude without Diamox

• You hyperventilate to compensate for low oxygen.
• Hyperventilation ↓ CO₂ in the blood → respiratory alkalosis (↑ pH).
• The alkalosis suppresses breathing (since the brainstem senses “too alkaline, slow down”), which is why people breathe shallowly at night, leading to periodic apnea and low oxygen saturation.

With Diamox

• Diamox blocks carbonic anhydrase in the kidneys → you excrete more bicarbonate (HCO₃⁻).
• This causes a metabolic acidosis (↓ pH).
• The brainstem now senses blood as “acidic,” which stimulates breathing.
• So, you hyperventilate more, but this time it’s sustained, because the metabolic acidosis counterbalances the respiratory alkalosis.

The net effect

• Without Diamox: hyperventilation → alkalosis → suppressed breathing → poor oxygenation.
• With Diamox: hyperventilation + mild metabolic acidosis → balanced pH → sustained ventilation and better oxygen delivery.

 So, the key is that Diamox shifts the body’s set point for breathing, letting climbers breathe harder without shutting down from alkalosis.

The Irony

• Meldonium - indirect alkalinization to reduce stress on cells.
• Diamox - deliberate acidification to stimulate respiration.
• Both approaches improved function under low oxygen, but they pulled physiology in opposite pH directions.

 

Another irony is that not only is Meldonium banned in sport, but so is Diamox. Diamox is banned because it is a diuretic and so can be used to mask the use of other drugs.

Now an example showing the impact of when pH control within the cell is dysfunctional.

 

GPR89A - the Golgi “Post Office” gene that keeps our cells running

When we think about genes involved in neurodevelopment, most people imagine genes that directly control brain signaling or neuron growth. But some genes quietly do their work behind the scenes, keeping our cellular “factories” running smoothly. One such gene is GPR89A, a gene that plays a critical role in regulating Golgi pH — and when it malfunctions, the consequences can ripple all the way to autism and intellectual disability (ID).

 

The Golgi Apparatus: The Cell’s Post Office

To understand GPR89A, it helps to picture the cell as a factory:

• The endoplasmic reticulum (ER) is the protein factory, producing raw products — proteins and lipids.
• The Golgi apparatus is the post office, modifying, sorting, and shipping these products to their proper destinations.

Just like a real post office, the Golgi must maintain precise conditions to function. One key condition is pH, the acidity inside the Golgi.

 

GPR89A: The Golgi’s pH Regulator

Inside the Golgi, acidity is carefully balanced by:

• V-ATPase pumps, which push protons (H⁺) in to acidify the lumen.
• Anion channels like GPR89A, which allow negative ions (Cl⁻, HCO₃⁻) to flow in, neutralizing the electrical charge and keeping the pH just right.

Think of GPR89A as the electrical wiring in the post office: without it, the machinery may be overloaded or misfiring, even if the raw materials (proteins) are fine.

 

When Golgi pH Goes Wrong

If GPR89A is mutated:

1.     The Golgi cannot maintain its normal acidic environment.

2.     Enzymes inside the Golgi — responsible for adding sugar chains to proteins (glycosylation) — cannot work properly.

3.     Proteins may become misfolded, unstable, or misrouted. Some may be sent to the wrong destination, while others are degraded.

This is akin to a post office with wrong sorting labels: packages (proteins) either go to the wrong address or get lost entirely.

 

Consequences for the Brain

Proteins are not just passive molecules; many are receptors, ion channels, adhesion molecules, or signaling factors essential for brain development. Mis-glycosylated proteins can lead to:

• Disrupted cell signaling
• Impaired synapse formation
• Altered neuronal communication

The end result can manifest as intellectual disability, autism spectrum disorders, or other neurodevelopmental conditions, because neurons are particularly sensitive to these trafficking and signaling errors.

 

Could Modulating Blood pH Help?

Since Golgi pH depends partly on cellular bicarbonate and proton balance, I have speculated whether small changes in blood pH could indirectly influence Golgi function:

• Sodium/potassium bicarbonate
• Increases extracellular bicarbonate and buffering capacity.
• Might slightly influence intracellular pH and indirectly affect Golgi pH.
• Acetazolamide (Diamox):
• Inhibits carbonic anhydrase, altering H⁺ and bicarbonate handling in cells.
• Could theoretically shift intracellular pH including Golgi pH

 

Systemic pH changes are heavily buffered by cells, so the impact on Golgi pH is likely to be modest at best.

Neither approach has been validated in human studies for improving glycosylation. Currently, there is no established therapy for GPR89A mutations.

Because there is no treatment, a reasonable option is a brief, carefully monitored trial.

• Try both interventions (bicarbonate then Diamox) for a short period.
• Observe for any measurable benefit in function or clinical outcomes.
• If there is no benefit, stop the trial — nothing is lost.

This approach allows cautious exploration without committing to a long-term therapy that may be ineffective.

 

The Bigger Picture

Even though GPR89A itself is not classified as a major autism or ID gene, its role in Golgi ion balance and glycosylation highlights how basic cellular “infrastructure” genes can profoundly affect brain development.

GPR89A reminds us that neurodevelopment is not only about neurons or synapses but also about the tiny cellular logistics systems that make them function. Maintaining Golgi pH is not glamorous, but without it, the entire cellular supply chain collapses, illustrating a pathway from a single gene mutation → cellular dysfunction → potential autism and ID outcomes.

Manipulating blood pH with bicarbonate or Diamox is an intriguing idea, will it provide a benefit?

 

Conclusion

pH regulation is a critical but underappreciated factor in autism, epilepsy, and mitochondrial disease. Subtle shifts in acidity or alkalinity affect calcium handling, ASIC activation, and neuronal excitability. Therapeutic strategies—from bicarbonates to carbonic anhydrase inhibitors—show that intentionally modulating pH can be both protective and symptomatic. Understanding the individual’s underlying metabolic and genetic context (eg mitochondrial function, ASIC mutations etc) will help determine whether a person might benefit more from raising or lowering pH.

For people with inflammatory conditions like some autism, or even MS, the simple idea of using baking soda to activate the vagus nerve is interesting.

·      Sodium bicarbonate → slight systemic alkalization.

·      Alkalization → reduced acidosis-related inflammatory signals.

·      Sensory neurons detect the pH change → activate vagus nerve.

·      Vagus nerve triggers cholinergic anti-inflammatory pathway → lowers pro-inflammatory cytokines.

We saw this in an old post and the researchers even went as far as severing the vagus nerve to prove it.

Potassium bicarbonate is a better long-term choice than sodium bicarbonate (baking soda) since most people lack potassium and have too much sodium already. It is cheap and OTC.

Diamox, Meldonium and Zonisamide are all used long term.

If you mention any of this to your doctor, expect a blank look coming back! Unless he/she is a mountaineer or perhaps a Latvian sports doctor!