Ethosuximide to increase speech in some autism? and PTHS?

I have previously proposed the use of calcium T channel blockers to treat some types of autism. I did suggest that language might be a good target.

Time for T? Targeting language-associated gene Cntnap2 with a T-type calcium channel blocker corrects hyperexcitability driving sensory abnormalities, repetitive behaviors, and other ASD symptoms, but will it improve language? Will it also benefit Pitt Hopkins syndrome (PTHS) and broader autism?

I recently received a question from a reader who read an abstract from a paper presented to the Brain Foundation, that suggested Ethosuximide can increase speech in autism. She also asked what the effective dosage might be.

This subject has come up before in this blog. Ethosuximide is a very specific T channel blocker, commonly used to treat absence seizures. Some readers of this blog have already trialed it. The other interesting one is Zonisamide, which blocks T channels but also has other effects. We have reports that the starting low dose of Zonisamide had some interesting beneficial effects that were lost at the regular higher doses.

I did not expect to find much new information, but that changed when I found the patent document submitted by Charles Niesen. So here is a blog post dedicated to this specific subject.

Here is the full patent:

Method of treating expressive language deficit in autistic humans

Here is an easy-to-read summary:

 

A New Patent Claims an Unusual Approach to Autism Language Deficits

A recent patent proposes a novel pharmacological method for improving expressive language in individuals with autism. Rather than introducing a new drug, the invention repurposes a class of existing anticonvulsant medications—specifically succinimides such as ethosuximide, methsuximide, and phensuximide.

These drugs have long been used to treat epilepsy, particularly absence seizures. However, the patent suggests they may also address one of the most challenging aspects of autism: the inability to initiate and sustain meaningful verbal communication.

 

Understanding the Problem

Autism is often characterized by difficulties in social interaction, but a core feature—especially in more severe cases—is expressive language impairment. Many individuals with autism may speak only in short phrases or single words. Others may respond to questions but rarely initiate conversation or engage in back-and-forth dialogue.

This is distinct from related conditions like Asperger syndrome, where language is typically intact but social communication is impaired. In classic autism, the issue is not just how language is used—but whether it emerges spontaneously at all.

Currently, there are no FDA-approved medications specifically designed to improve expressive language in autism. Most available treatments focus on associated symptoms such as irritability, seizures, or attention deficits.

 

The Core Idea Behind the Patent

The patent proposes that daily administration of a succinimide anticonvulsant—most notably ethosuximide—over an extended period (typically several months) can significantly improve expressive language abilities.

Patients are treated for at least one month, with stronger effects reported after three to six months or longer. The goal is not just increased vocabulary, but a progression toward spontaneous speech and true conversational ability.

 

How Might This Work?

Ethosuximide works by blocking T-type calcium channels in the brain. These channels play a role in regulating neuronal activity and rhythmic signaling.

While the exact mechanism in autism is unknown, the patent speculates that modulating these channels may help normalize communication between brain regions involved in language. Another hypothesis is that the drug may “activate” previously underused or dormant neural circuits.

These ideas remain theoretical and are not yet confirmed by broader research.

 

Dosage and Treatment Approach

The proposed dosing follows standard epilepsy guidelines, typically ranging from 10 to 60 mg per kilogram of body weight per day. In many cases, a range of 20–40 mg/kg/day is used for children, while adolescents and adults may receive fixed doses between 150 mg and 1000 mg twice daily.

Treatment is administered consistently over months, with periodic evaluation of language and behavioral progress.

 

How Speech Was Measured

To evaluate improvement, the patent uses a simple but structured 7-point expressive language scale. This scale attempts to quantify how advanced a person’s spoken communication is, ranging from no speech at all to full conversational ability.

The scale is defined as follows:

• 0 — Nonverbal: No meaningful spoken language
• 1 — Echolalic: Repeats words or phrases (echoing others)
• 2 — Single words: Uses isolated words to communicate
• 3 — Phrases: Combines words into short phrases
• 4 — Sentences: Forms complete, understandable sentences
• 5 — Spontaneous speech: Initiates speech independently
• 6 — Mutual speech: Engages in true back-and-forth conversation

This scale is central to the patent’s claims. Improvements are measured as movement upward along these stages—for example, progressing from single words (2) to phrases (3), or from sentences (4) to spontaneous speech (5).

The inventors argue that even a 1–2 point increase represents a meaningful functional gain in real-world communication.

 

Summary of the Reported Study

The patent describes a small observational study involving 24 patients with autism. Participants were treated with ethosuximide for periods ranging from one month to over six months.

Patients were grouped based on cognitive level, including normal IQ, borderline, mild impairment, and moderate impairment. Language ability was assessed using the 7-point scale described above.

 

Reported Outcomes

Across all groups, improvements in expressive language were observed. The most significant gains occurred in individuals with higher baseline cognitive function.

On average, patients improved by approximately two points on the language scale. This often meant progressing from single words to phrases, or from phrases to full sentences and occasional spontaneous speech.

In some documented cases, children who initially spoke only in isolated words were able to form sentences within six months and engage in basic conversation within a year.

 

Timeline of Improvement

Initial changes were sometimes observed within the first month of treatment. More consistent and substantial gains were reported after three months, with the most pronounced improvements occurring after six months or longer.

Interestingly, the progression of language development in treated patients appeared to mirror typical early childhood language acquisition—albeit delayed.

 

Persistence After Treatment

One of the more striking claims is that improvements persisted even after the medication was discontinued. In several cases, language abilities continued to develop beyond the treatment period.

This suggests the possibility of longer-term changes in neural function, rather than temporary symptom management.

 

Additional Observations

Beyond language, some patients also showed improvements in social interaction and mood. Increased engagement, better eye contact, and reduced irritability were noted in certain cases.

However, many participants were also receiving speech therapy and applied behavioral analysis (ABA), making it difficult to isolate the effects of the medication alone.

 

Safety Profile

Ethosuximide was generally well tolerated in the study. Known side effects include gastrointestinal discomfort, fatigue, and behavioral changes. Rare but serious risks—such as blood or liver abnormalities—are also associated with the drug and require medical supervision.

 

Age Range and Cognitive Profile of Participants

The patent provides limited but useful information about the participants’ ages and cognitive abilities.

Age Range

• The study included both young children and adolescents.
• Specific examples mention children as young as 3 years old and others up to around 12–15 years old.

Cognitive (IQ) Groups

Participants were divided into four categories based on cognitive level:

• Normal IQ (NIQ)
• Borderline IQ (BIQ)
• Mild intellectual impairment (mMR)
• Moderate intellectual impairment (moMR)

 

Key Takeaways

• The strongest language improvements were reported in children with normal IQ.
• Children with lower cognitive levels also improved, but to a lesser degree.
• The results suggest that baseline cognitive ability may influence response to treatment.

 

Final Thoughts

This patent presents an intriguing hypothesis: that a well-established epilepsy medication may have the potential to improve core language deficits in autism.

The reported results are promising, particularly the magnitude of language gains and their persistence after treatment. However, the evidence is limited by the small sample size, lack of a control group, and reliance on a subjective rating scale.

As it stands, this work should be viewed as exploratory rather than definitive. Larger, controlled clinical trials would be needed to determine whether this approach truly offers a reliable and reproducible benefit.

Still, the idea highlights an important direction for future research—targeting the underlying neural mechanisms of communication itself, rather than just managing associated symptoms.

 

Critical periods and CNTNAP2

Another factor to consider is the role of developmental “critical periods,” when brain circuits involved in language are particularly plastic. Disruption of CNTNAP2 has been linked to altered neuronal connectivity and delayed circuit maturation, which may extend or shift these windows of plasticity. If so, interventions that stabilize network activity—such as T-type calcium channel modulation—might help enable more effective language development during these periods. This could potentially explain why some improvements, once initiated, continue even after treatment is stopped.

This also raises the possibility that timing may be critical. If language development depends on sensitive developmental windows, and pathways involving CNTNAP2 alter the timing of circuit maturation, then the age at which a treatment is given could determine its effectiveness. Interventions such as T-type calcium channel modulation may be more beneficial when applied during periods of higher neural plasticity, and less effective once circuits have become more established. This could help explain why any signal of benefit has been difficult to detect in routine clinical use.

 

Conclusion

The study did not have a placebo group. We know from many previous small studies that in most cases everyone improved in autism studies, including those who were assigned the placebo.

Has Niesen identified a simple therapy that will improve speech in autism?

If ethosuximide strongly improves language, why has this not already been noticed?

Neurologists have used ethosuximide for decades for autistic children with absence seizures, but it is not widely recognized as a language-enhancing drug.

I expect there likely is a subgroup of responders, but it will not be a silver bullet for all.

Ethosuximide is cheap, but it can have some unusual side effects.

Zonisamide is more predictable than Ethosuximide, but still can have problematic side effects, more so than drugs like bumetanide or atorvastatin.

It may be the case that responders to Ethosuximide do not need to take it permanently and that has to be factored into the side effect assessment.

Any potential benefit is likely limited to a specific subgroup, such as children with subtle absence seizures, epileptiform activity, or abnormalities in calcium channel signaling. One candidate subgroup involves mutations in the CNTNAP2 gene, which are associated with language impairment, autism, and increased neuronal excitability. Preclinical studies suggest that targeting T-type calcium channels in such models can reduce hyperexcitability and improve behavioral features, raising the possibility that drugs like ethosuximide may be more effective in individuals with similar underlying biology.

CNTNAP2 is also regulated by TCF4, the gene mutated in Pitt-Hopkins syndrome, a condition marked by profound speech deficits. This points to overlapping biological pathways underlying language impairment across different neurodevelopmental disorders and reinforces the idea that identifying responders will be key to determining clinical value.

So, another idea for Pitt Hopkins parents is to consider is Ethosuximide. Maybe the parents’ organisation should contact Charles Niesen to make a small clinical trial, like the forthcoming Clemastine one.

There’s nothing boring about boron – why 3mg of boron should be in multivitamins and some could take 6-10mg

 

Contents of a common multivitamin for adults

I wrote this post a while back and, the more I think about it, the more I see boron as a potentially useful autism therapy. It is safe, OTC, very cheap and has several mechanisms that should be beneficial. Notably, it reduces inflammation (CRP can fall as much as 50% in 10 days) and it increases estrogen receptor beta signaling (relevant to the brain and bones); both these factors are very relevant in severe autism. It has no effect on estrogen receptor alpha, so avoids the side effects of phytoestrogens and estradiol. I started taking it myself.

Believe it or not, even with a strange subject like boron, there is an autism angle.

I originally stumbled upon boron while researching bone metabolism. I expected it to be relevant only for bones and joint pain. Instead, I was surprised by the sheer breadth of its biological effects: inflammation, hormones, detoxification, memory, immunity, even cancer risk.

Boron is one of those nutrients that no one thinks about because it has not yet been officially classified as essential for humans. That means:

·         No recommended daily intake

·         Almost no multivitamin includes it

·         Most people are taking in less than 1 mg/day through diet

And yet clinically meaningful benefits only begin at least 3 mg/day.

This is especially relevant to people with restricted diets. Many autistic individuals eat the infamous “beige diet” of pasta, bread, chips/crisps, and nuggets. Telling them that avocados contain boron or that leafy greens contain manganese goes nowhere.

Even Monty, now 22, who eats very well, does not reach 3 mg/day of boron from food. He would need to drink half a bottle of high-boron Pinot Noir a day to get close!  

This post has some of the science at the back as non-essential reading.

If you are male, make sure to read the part about male hormones. It looks like a potentially good way to avoid benign prostate enlargement as you age. Prostate size was reduced by about 35% in those with high boron in their drinking water. Not surprisingly, this potential therapy has not been seriously followed up.

If you are female take a note of the female hormone effects.

 

What Boron Actually Does

From the open-access paper Nothing Boring About Boron just click on it to read the full paper

Boron influences multiple systems simultaneously. Benefits documented at 3+ mg/day include:

1. Bone health

·  Essential for bone growth and mineralization

·  Improves calcium and magnesium use

·  Synergistic with vitamin D and estrogen

2. Collagen health (Joints, bone matrix, intervertebral discs, eyes etc)

Remarkably, studies show that adults with a high boron intake seem protected from getting osteoarthritis in later life. Boron is even therapeutic in people who already have this type of arthritis. 

·   Boron improves collagen cross-linking, making fibres stronger, more elastic, and more resistant to breakdown.

·   Enhances vitamin D and magnesium biochemistry, both required for hydroxylating proline/lysine — the two amino acids that give collagen structural strength.

·   Reduces collagen-degrading enzymes (MMP-2 and MMP-9), protecting connective tissue from inflammatory destruction.

·   Boosts bone collagen quality, improving bone strength independently of calcium intake.

·   Supports joint cartilage and reduces arthritis symptoms, likely via improved collagen structure and reduced inflammation.

·   May slow collagen degeneration in the vitreous, explaining why boron sometimes helps with eye floaters.

3. Hormone regulation

·  Increases free testosterone in men

·  Normalizes estrogen metabolism in women

·  Enhances vitamin D activation

·  Reduces SHBG (sex hormone–binding globulin)

4. Anti-inflammatory effects

·  Reduces CRP, TNF-α, IL-6

·  Lowers oxidative stress

·  Raises glutathione peroxidase, catalase, and SOD

5. Detoxification

·   Reduces toxicity of heavy metals

·    Mitigates pesticide-induced oxidative stress

·    Improves cell membrane stability

6. Brain health

·    Improves electrical activity in the brain

·    Enhances short-term memory

·    Supports NAD⁺ and SAM-e pathways

·    Has neuroprotective properties

7. Anti-cancer activity

·     Signals against prostate, breast, lung cancer

·     Reduces tumor growth in models

·     Enhances chemotherapy efficacy

·     Protects normal tissue from chemo damage

Across dozens of studies these effects do not appear at <3 mg/day.

Safety is extremely high, with an upper limit of 20 mg/day for adults.

Boron and Autism — Small Study, Big Signal

A 2024 study examined boron in a rat autism model induced by propionic acid (PPA). 

Effects of Boron on Learning and Behavioral Disorders in Rat Autism Model Induced by Intracerebroventricular Propionic Acid

This model replicates:

·   neuroinflammation

·   microglial activation

·   elevated cytokines

·   reduced Purkinje cells

·   learning/social behaviour deficits

·   increased BDNF (a maladaptive elevation)

What 4 mg/kg boron (boric acid) did:

• improved learning and social interaction
• significantly lowered TNF-α, IL-6, IL-1β
• reduced microglial & astrocyte activation
• restored Purkinje cell numbers
• normalised BDNF
• provided broad neuroprotection

This lines up with boron’s known biology:

• anti-inflammatory
• antioxidant
• mitochondrial support
• hormone modulation
• detoxification
• microglial regulation

This does not mean boron is a cure for autism, but it clearly has biological relevance.

Given the low cost, excellent safety, and widespread deficiency, 3+ mg/day makes sense for most people, especially those with restrictive diets or systemic inflammation.

Boron and Hormones — Very Interesting Male vs Female Effects

Boron’s effect on hormones is surprisingly strong and well documented. This is where things get very interesting because the effects differ between men and women.

In Men: Free Testosterone Booster

Studies show that 6 mg/day of boron for 1 week:

• ↑ free testosterone by 25%
• ↓ estradiol by 50%
• ↓ SHBG (sex hormone-binding globulin)
• ↓ inflammatory markers (CRP dropped by 60%)

Why does this matter?

Reduced SHBG means more biologically active testosterone. This is not like taking steroids; it is allowing your existing testosterone to circulate freely.

Results seen:

• increased libido
• improved mood
• better energy
• increased muscle response to training
• reduced inflammation
• possibly lower prostate cancer risk 

There was a Turkish observational study (from the 1990s, often cited in boron research summaries) looking at a village with very high natural boron levels in soil and drinking water.

Men in this village consumed boron intakes around 6–30 mg/day (far above typical Western intake of 1 mg/day).

Compared with men from nearby normal-boron areas, they had:

·         Significantly smaller prostate volumes

·         Lower PSA levels

·         Lower rates of prostate enlargement (BPH)

No increase in adverse effects was detected in these high-boron consumers.

Boron has several effects relevant to prostate size:

·         Lowers inflammation (↓ NF-κB, ↓ cytokines)

·         Improves androgen–estrogen balance

·         Mild increase in free testosterone

·         Mild decrease in estradiol

This combination tends to lead to smaller prostates and lower PSA, especially in older men.

Does This Apply to Supplement Use?

Probably, but not to the same magnitude unless the dosage is comparable.

BORON SUPPLEMENT EFFECTS:

3 mg/day → measurable anti-inflammatory and hormonal effects

6–10 mg/day → stronger hormonal shift

10–12 mg/day → studied in athletes for testosterone effects

Does this explain why boron helps older men?

Yes. Older men typically develop:

·         Low free testosterone

·         Higher estradiol

·         Chronic prostate inflammation

Boron improves those three issues at once.

 

In Women: Estrogen Metabolism & Menopause Support

Boron helps women balance estrogen in a very different way:

·         increases estrogen when estrogen is too low

·         reduces “bad” estrogen metabolites (16α-hydroxyestrone)

·         increases “good” metabolites (2-hydroxyestrone)

·         improves response to vitamin D

·         reduces menstrual pain

·         supports bone density after menopause

In post-menopausal women:

·         urine calcium loss drops dramatically

·         vitamin D activation improves

·         bone turnover markers improve

Women deficient in magnesium or vitamin D benefit especially.

Why the Sex Difference?

Boron seems to act primarily by:

·    lowering SHBG (men see a larger effect), Sex Hormone–Binding Globulin is a protein made in the liver that binds tightly to sex hormones, mainly Testosterone, Dihydrotestosterone (DHT) and Estradiol

·    shifting estrogen metabolites (women see a larger effect)

·    enhancing vitamin D activation (beneficial for all)

·    reducing inflammation (universally helpful)

This dual effect is rare—few minerals have male/female divergence.

Boron-Rich Foods and Typical Intake Levels

Food	Boron (mg per 100 g)	Notes
Avocado	2.1 mg	One of the richest natural sources
Raisins	2.5 mg	Dried fruit is consistently high
Prunes	1.9 mg	Very dense source
Almonds	2.8 mg	Nuts are excellent
Hazelnuts	2.7 mg	Similar to almonds
Peanuts	1.4 mg	Lower but common
Peanut butter	1.9 mg	Higher concentration
Beans (various)	0.5–1.5 mg	Good but variable
Chickpeas	0.7 mg	Decent source
Lentils	0.7 mg	Regular intake helps
Dates	1.1 mg	Very effective
Red wine	0.5–0.7 mg per glass	Grapes are boron-rich
Apples	0.3 mg	Everyday source
Pears	0.4 mg	Another fruit source
Vegetables (general)	0.1–0.6 mg	Depends on soil content

Typical Daily Intake From Diet

·         Developed countries average 0.8–1.4 mg/day

·         Mediterranean diet: 2–3 mg/day

·         Vegan diets: 3–6 mg/day (high fruit/nut consumption)

Nearly all Western omnivorous diets fall below the 3 mg/day threshold associated with documented benefits.

Conlusion

Boron is one of the few nutrients where:

·         the safety is high

·         the benefits are large

·         the deficiency is common

·         the cost is trivial

And because modern diets (and nearly all multivitamins) provide little to none, 3 mg/day is a simple, evidence-based upgrade for anyone—especially those with osteopenia, inflammation, hormonal imbalance, or restrictive diets such as those often seen in autism.

Higher doses like 10mg would seem appropriate for specific groups that are likely to benefit from the effects described in this post.

How much boron did they give the rats with autism?

One thing you very quickly learn when reading animal studies is that the dose used in rats is almost always huge. The same is true in the recent study looking at boron in a propionic-acid model of autism. On paper, the researchers used “2 mg/kg and 4 mg/kg of boric acid.” That sounds modest, rats are small.

In toxicology, a rat “mg/kg” is not the same as a human “mg/kg.” Rats have a much faster metabolism, and their surface-area-to-body-weight ratio is different. If you dose a human the same way you dose a rat, you will rapidly enter “please call poison control” territory.

To make sense of rodent studies, you have to convert the dose using the FDA’s body-surface-area formula. When you do that, the “4 mg/kg” rat dose becomes roughly the human equivalent of:

45 mg/day of boric acid

which equals 7–8 mg of elemental boron, a dose that’s above normal diet but within the range of commercially available supplements.

But, that is a conservative conversion. There are other conversion models that give an equivalent human dose much higher, in the 35-80 mg/day range.

In reality, nobody knows the human dose that would give the same benefits as found in the rat study. Those rats with autism were essentially on very high pharmacological boron, not the gentle nutritional 3 mg/day found in health-food circles.

No wonder the effects were dramatic:

·         inflammation markers (IL-6, IL-1β, TNF-α) crashed

·         microglia and astrocytes calmed down

·         Purkinje cell loss reversed

·         learning and social behaviours improved

All good news — just not at “one avocado per day” boron levels.This is the same situation as resveratrol, curcumin, sulforaphane, luteolin, quercetin, and a dozen other compounds: the rodent study shows us mechanism and potential, but not a directly usable human dose. Still, what is remarkable is that even at low human doses (3–10 mg/day), boron does show measurable changes in humans: reduced inflammation, altered SHBG, higher free testosterone, better vitamin D handling, and nicer bone and joint metabolism.

So the take-home message is that the autism rat study used a boron dose equivalent to well above what humans safely take as a supplement — but it confirms that boron is a potent anti-inflammatory and neuroprotective micronutrient, and that even low doses may be biologically meaningful.

Perfectly reasonable to include boron in a multivitamin. It would save people a lot of bother.

Not reasonable to copy rat dosing, unless you happen to be a rat!

Different L-type Calcium Channel Blockers Repurposed for Different Types of Autism

 

 A Purkinje Neuron, home of P-type calcium channels

Today’s post was prompted by a reader who saw a very positive response from the L-type calcium channel blocker, Amlodipine.

So we return to the subject of calcium channels.

The good news about calcium channel defects is that many are easy to treat.

In most single gene autisms (Rett, Fragile-X, Pitt Hopkins etc) the underlying problem is that a faulty gene does not do its job of producing the expected protein.  This is a problem of too little.

In many ion channel dysfunctions the problem is not too little, it is too much expression. For example, in Timothy Syndrome the mutation in the gene produces too much of the protein, in this case the L-type calcium channel Cav1.2.

Ion channel dysfunctions can be the result of a faulty gene, or just that the on/off switch for that gene is faulty.  Fortunately, the problem is usually that it is stuck “on”.

In people who develop Type-1 diabetes we have seen how the disease process can be halted by blocking Cav1.2 in the pancreas.  This halts the decline in the beta cells that produce insulin.

Once all the beta cells are dead, the person cannot produce insulin and has type-1 diabetes. Treating the person after this point with a Cav1.2 blocker will provide no benefit; the damage has already been done

Something similar happens in Parkinson’s disease, but this time you need to block Cav1.3.  In the early stages of the disease Cav1.3 is over-expressed in a key part of the brain, which triggers a slow process of degeneration. Treating a person with all the visible symptoms of Parkinson’s with a Cav1.3 blocker will provide no benefit; the damage has already been done.

 

Calcium channel blockers are not very specific

The current drugs used to block calcium channels were mainly developed to treat heart conditions.

When treating neurological disorders like autism we are primarily focused on the brain, what goes on elsewhere can also be very relevant, but in an indirect way.

In the brain the important calcium channels are: -

L type

N type

P type

R type

T type

Plus, Inositol trisphosphate receptor (IP3R) and Ryanodine receptors. IP3R has been covered in previous posts.

Verapamil (a Phenylalkylamine class drug)

Verapamil blocks L type channels and T type channels, plus some potassium ion channels.

When it comes to specific L type channels there are 4, Cav1.1, Cav1.2, Cav1.3, and Cav1.4.

In the brain we have just Cav1.2 and Cav1.3. Verapamil mainly affects Cav1.2.

 

Amlodipine (a Dihydropyridine class drug)

Amlodipine blocks L type channels and N type channels.

Amlodipine mainly affects Cav1.3.

 

Nicardipine (a Dihydropyridine class drug)

Nicardipine blocks L type channels and N type channels.

As a Dihydropyridine, it should mainly affect Cav1.3.

In addition, it blocks the sodium ion channel Nav1.8.

The effect on Nav1.8 is why it has been proposed as a therapy for Pitt Hopkins. In this syndrome Nav1.8 is over expressed as a downstream consequence of a mutation in the TCF4 gene.

 

Effect on P channels

To some extent Verapamil, Amlodipine and Nicardipine all block P channels.

P channels are called P after the Purkinje neurons, where they are located. These Purkinje cells likely define some aspects of autism, because of their absence. Purkinje neurons are among the largest in the brain, with elaborate dendritic arbor.  I imagine this makes them vulnerable.

In the people with severe autism most of the Purkinje cells appear to have died.

Blocking P channels might have protected Purkinje cells from death.

 

The effect of too much L-type calcium channel signaling on behavior 

You can both turn on self-injury via activating L type calcium channels and extinguish it by blocking the same channels.  It is proven in mice and seems to apply to at least some humans.

Calcium channel activation and self-biting in mice

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

The self-biting provoked by (±)Bay K 8644 can be inhibited by pretreating the mice with dihydropyridine L type calcium channel antagonists such as nifedipine, nimodipine, or nitrendipine. However, self-biting is not inhibited by nondihydropyridine antagonists including diltiazem, flunarizine, or verapamil.

(±)Bay K 8644 functions as an L type calcium channel activator that increases calcium fluxes in response to depolarizing stimuli (19–21). In rodents, this drug has been reported to produce characteristic motor abnormalities including impaired ambulation, twisting and stretching movements, transient limb extension, back arching, spasticity, ataxia, or catatonia (22–28). Some studies have anecdotally noted the occurrence of SIB with this drug (23–25, 27), though this phenomenon has received little attention. The current study shows that (±)Bay K 8644 will reliably provoke SB and SIB under certain conditions in mice, providing a tool to study the neurobiology of this unusual behavior.

 

When I first encountered the above study, I did wonder why Verapamil did not extinguish the self-injury.

It turns out that Bay K 8644 is a modified version of the common drug nifedipine, which is a Cav1.3 blocker.  Verapamil is mainly a Cav1.2 blocker.  Bay K 8644 is like the opposite of nifedipine.

In the trial they have activated Cav1.3 causing excess calcium inside neurons. The only way to block this process is to block Cav1.3. Blocking Cav1.2 with Verapamil could not solve the problem. 

Note that activation of Cav1.3 can cause motor abnormities in mice and this might be seen as ataxia in a human. One particular reader of this blog will see the relevance of this. 

I did write extensively in earlier posts about the large amount of research that links L type calcium channels to neuropsychiatric disorders.

I did mainly focus on Cav1.2 using Verapamil, but the evidence for the role of Cav1.3 is clear as day. 

L-type calcium channels as drug targets in CNS disorders

 L-type calcium channels are present in most electrically excitable cells and are needed for proper brain, muscle, endocrine and sensory function. There is accumulating evidence for their involvement in brain diseases such as Parkinson disease, febrile seizures and neuropsychiatric disorders. Pharmacological inhibition of brain L-type channel isoforms, Cav1.2 and Cav1.3, may therefore be of therapeutic value.

 

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

The L-type calcium channels (LTCCs) Ca_v1.2 and Ca_v1.3, encoded by the CACNA1C and CACNA1D genes, respectively, are important regulators of calcium influx into cells and are critical for normal brain development and plasticity. In humans, CACNA1C has emerged as one of the most widely reproduced and prominent candidate risk genes for a range of neuropsychiatric disorders, including bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder, autism spectrum disorder, and attention deficit hyperactivity disorder.

Here, we provide a review of clinical studies that have evaluated LTCC blockers for BD, SCZ, and drug dependence-associated symptoms, as well as rodent studies that have identified Ca_v1.2- and Ca_v1.3-specific molecular and cellular cascades that underlie mood (anxiety, depression), social behavior, cognition, and addiction.

 

Was I surprised that Amlodipine, that targets Cav1.3 rather than Cav1.2, was very beneficial in someone with severe autism?  Not at all.

I was interested that the effect was more pro-cognitive than anti-anxiety.  Is that the effect on Cav1.3 or is it via that N channel Cav2.2?

N-type calcium channels are important in neurotransmitter release because they are localized at the synaptic terminals. Piracetam, the original cognitive enhancing drug, is also a N type channel blocker.

  

Statins and L type calcium channels blockers – it matters which one you choose

We previously saw how the statin class of drugs can be beneficial in autism, but it depends which one you chose. For example, in SLOS (Smith-Lemli-Opitz syndrome), where both copies of the gene DHCR7 are mutated, you need to push the gene to work. To increase expression of this gene you need Simvastatin. This is hard for people to understand because SLOS features very low cholesterol and statins are thought of as cholesterol lowering drugs. The body needs the enzyme DHCR7 to make cholesterol and Simvastatin increases DHCR7 expression.

In the case of L type channel blockers, the selection is very important.  The effect will not be the same.

If you have a mutation in Cav1.2, you would expect Verapamil to be a good choice.  If the mutation is in Cav1.3, you would expect Amlodipine to be better.

If you have over expression of T channels (Cav3.1, Cav3.2 or Cav3.3) then you would expect a benefit from Verapamil and none from Amlodipine.

If you have over expression of the N channel (Cav2.2) then you would want Amlodipine

If you have over expression of the sodium channel Nav1.8 then you would want Nicardipine

  

Conclusion

It is likely that many people with autism, bipolar, ADHD or schizophrenia might benefit from treating their ion channel dysfunctions.  The required drugs are cheap generics that have been in your local pharmacy for a few decades.

Back in 2019 I wrote the post below:

Cheap common drugs may help mental illness

I highlighted a new study, using historic data from Sweden, that looked at the secondary effects of statins, calcium channel blockers and metformin on psychiatric hospitalization.

 

Association of Hydroxylmethyl Glutaryl Coenzyme A Reductase Inhibitors, L-Type Calcium Channel Antagonists, and Biguanides With Rates of Psychiatric Hospitalization and Self-Harm in Individuals With Serious Mental Illness

 

Question  Are drugs in common use for physical health problems (hydroxylmethyl glutaryl coenzyme A reductase inhibitors, L-type calcium channel antagonists, and biguanides) associated with reduced rates of psychiatric hospitalization and self-harm in individuals with serious mental illness?

Findings  In this series of within-individual cohort studies of 142 691 patients with bipolar disorder, schizophrenia, or nonaffective psychosis, exposure to any of the study drugs was associated with reduced rates of psychiatric hospitalization compared with unexposed periods. Self-harm was reduced in patients with bipolar disorder and schizophrenia during exposure to all study drugs and in patients with nonaffective psychosis taking L-type calcium channel antagonists. 

We found that periods of HMG-CoA RI (statin) exposure were associated with reduced psychiatric hospitalization in all subgroups of SMI (Serious Mental Illness) and with reduced self-harm in BPD and schizophrenia.

Exposure to LTCC (L type calcium channel) antagonists was associated with reduced rates of psychiatric hospitalization and self-harm.

Periods of metformin (a type 2 diabetes drug) exposure were associated with reduced psychiatric and nonpsychiatric hospitalization across all SMI subgroups.

 

Use of L type calcium channel blockers reduces self-harm.

How much more evidence is needed?

I took an educated guess several years ago that Verapamil would tame summertime raging in my son.  It was the only calcium channel blocker I tried and it worked. This year we had the emergence of extreme sound sensitivity. My educated guess was that blocking potassium channels with Ponstan (Mefenamic acid) would resolve the problem, and it did.  

Treating ion channel dysfunctions (channelopathies) in autism clearly is not rocket science; it is just waiting to be attempted.

Modulation of IP3 receptors in Autism – Pancreatitis and Caffeine?

This post stems from our Greek reader Petra's original observations about the combined effects of coffee and bumetanide.

In earlier posts we learned that one likely nexus in autism is the IP3 receptor that releases calcium from a store within each cell.

It turns out that too little/too much activity from IP3 receptors is a feature of a wide range of disease, some of which you may not have heard of, including:-

·      Gillespie syndrome, a genetic condition leading to MR/ID, ataxia and notably part of the iris to be missing

·      Spinocerebellar ataxias, genetic conditions that cause loss of movement control

·      Glioblastoma, an aggressive and “untreatable” brain cancer

·      Alzheimer’s disease

·      Huntington’s disease

·      Pancreatitis, inflammation of the pancreas where your body makes its digestive enzymes and insulin 

For detail, refer to this Japanese paper:- 

IP3 receptor mutations and brain diseases in human and rodents

Of the three types of IP₃Rs, the type 1 receptor (IP₃R1) is dominantly expressed in the brain and is important for brain function. Recent emerging evidence suggests that abnormal Ca²⁺ signals from the IP₃R1 are closely associated with human brain pathology. In this review, we focus on the recent advances in our knowledge of the regulation of IP₃R1 and its functional implication in human brain diseases, as revealed by IP₃R mutation studies and analysis of human disease‐associated genes. 

I suspect that both hyper and hypo-active IP3 receptors will be found in different types of autism. I assume the variant I deal with in my son is more likely to be hyperactive. The research by Gargus suggested “dysregulated IP3R” in autism in 3 single gene autisms; he found depressed Ca²⁺ release through inositol trisphosphate receptors (IP₃Rs) in patient-derived fibroblasts.

Shared functional defect in IP3R-mediated calcium signaling in diverse monogenic autism syndromes

Your body contains a lot of calcium, but almost all of it is in your bones, as calcium phosphate.  Only the residual amount (about 1%) of calcium is present in solution as the ion Ca²⁺. Ca²⁺ plays an important role in many physiological functions.  An excessive elevation of Ca²⁺ inside cells will kill them. Cells must maintain the intracellular Ca²⁺ concentration at the low level of ~10⁻⁷ mol/L, against the much higher extracellular Ca²⁺ concentration (~10⁻³ mol/L).

Cells must be able to rapidly and dynamically change the intracellular Ca²⁺ concentration in response to extracellular stimuli to regulate physiological functions such as cell proliferation, fertilization, immune response, and brain functioning.

To dynamically change the intracellular Ca²⁺ level, cells use two sources of Ca²⁺:

·      Ca²⁺ influx from outside (the extracellular space)

·      Ca²⁺ release from inside (the intracellular Ca²⁺ store, the endoplasmic reticulum – ER)

Many Ca²⁺ handling molecules (Ca²⁺ ion channels, Ca²⁺ pumps, Ca²⁺ sequester proteins) work to maintain the correct balance. The IP3 receptor is a key protein in the regulation of the intracellular Ca²⁺ dynamics, because it  controls the release of intracelluar Ca²⁺.

If IP3R is left open, Ca²⁺ levels inside cells become too high; if it is left shut Ca²⁺ becomes too low.

No medical therapy currently exists to inhibit/block IP3 receptors, but today’s post considers one potential therapy – caffeine. 

Caffeine

Caffeine is a drug, although it is not regulated as one.  At high doses caffeine is toxic, but at non-toxic doses caffeine does have some potent medical effects and it does protect against certain diseases.

It protects against pancreatitis, for example.

It would be very hard to drink yourself to death with coffee. Just like eating numerous bananas does not cause death by having too much potassium in your blood. Supplements have more risks than food. 

Pancreatitis IP3R and Caffeine 

Caffeine protects against experimental acute pancreatitis by inhibition of inositol 1,4,5-trisphosphatereceptor-mediated Ca2+ release 

Significance of this study

What is already known on this subject?

·       Acute pancreatitis is a major health problem without specific drug therapy.

·       Coffee consumption reduces the incidence of acute alcoholic pancreatitis.

·       Caffeine blocks physiological intracellular Ca²⁺ oscillations by inhibition of inositol 1,4,5-trisphosphate receptor-(IP₃R)-mediated signalling.

·       Sustained cytosolic Ca²⁺ overload from abnormal Ca²⁺ signalling is implicated as a critical trigger in the pathogenesis of acute pancreatitis.

What are the new findings?

·       Caffeine and its dimethylxanthine metabolites inhibit IP₃R-mediated, sustained cytosolic Ca²⁺ elevations, loss of mitochondrial membrane potential and necrotic cell death pathway activation in pancreatic acinar cells.

·       Neither specific phosphodiesterase inhibitors nor cyclic adenosine monophosphate and cyclic guanosine monophosphate inhibit sustained Ca²⁺ elevations in pancreatic acinar cells.

·       Serum levels of xanthines after 25 mg/kg caffeine administration are sufficient to inhibit IP₃R-mediated Ca²⁺ overload in experimental acute pancreatitis.

·       Caffeine but not theophylline or paraxanthine administered at 25 mg/kg significantly ameliorated pancreatic injury in experimental acute pancreatitis through IP₃R-mediated signalling inhibition.

How might it impact on clinical practice in the foreseeable future?

·       These findings support an approach of inhibition of Ca²⁺ overload and of its consequences as novel potential therapy for acute pancreatitis.

·       Methylxanthine-based structures are suitable starting points for drug discovery and development to treat acute pancreatitis. 

The Pancreas and Autism

The biomarker proposed by Joan Fallon/Curemark for her autism treatment (CM-AT) is low fecal chymotrypsin level. Chymotrypsin is a digestive enzyme produced in the pancreas and it can be used as a test for early cystic fibrosis. In adults low chymotrypsin indicates a pancreatic disease like pancreatitis.

Many people with autism have GI problems, but there are several distinct sub-groups. Some people have inflammatory bowel disease (IBD) potentially leading to ulcerative colitis, but most do not. Some people with autism have GI dysfunctions that remain undiagnosed, for some it is as if they do not digest food the same way as other people.

If IP3R hyperactivity is a feature of some autism and IP3R hyperactivity is inherent in pancreatitis, is it a surprise that some people with autism do not seem to digest their food properly? Or is it just a coincidence?

Brain Cancer

We did come across glioblastoma in a previous post that looked at off-label therapies for some cancers. In that post we came across an academic from San Diego, who decided to read the research and try and reverse his incurable aggressive brain cancer. This involved driving across the border to Mexico to freely acquire the prescription drugs he used to treat himself.  Two decades later he is still very much alive. 

More Wnt Modulation for Autism and More Inexpensive Potential Cancer Therapies

According to the study below, a hot cup of strong Greek coffee might be a good choice to maintain Professor Williams in good health.

Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival.

IP₃Rs are known to be difficult to study especially due to the lack of suitable inhibitors and subtype specific blockers. We found that caffeine paradoxically inhibited IP₃R-mediated Ca²⁺ responses in a subtype 3 specific manner (Figure 5). Using caffeine as a tool to inhibit IP₃R3-mediate Ca²⁺ release, we have demonstrated that inhibiting IP₃R3 effectively reduced the migration, invasion, and survival of glioblastoma cells (Figure 2). The gene silencing of IP₃R3 by shRNA also effectively reduced the caffeine sensitivity of Ca²⁺ signaling and invasiveness in the Matrigel invasion assay (Figure 5). Our results are the first to demonstrate the involvement of IP₃R3 in glioblastoma Ca²⁺ signaling and invasion. Furthermore, we suggest that IP₃R3 can be specifically targeted for therapeutic intervention in glioblastoma patients with minimal influence on normal glial as well as neuronal functions.

Whether caffeine can directly affect the gating of IP₃R3 channels or not is still unknown. However, according to previous studies demonstrating that caffeine can compete with ATP binding to IP₃Rs (21) at millimolar concentrations (20), caffeine could selectively bind to IP₃R3 and affect the gating of IP₃R3. Further work is required to investigate the direct role of caffeine on IP₃R3 gating in comparison to other subtypes of IP₃R.

In summary our study provides IP₃R3 as a novel therapeutic target for glioblastoma treatment. Our study also provides new insights into the detailed molecular mechanism of caffeine action on migration and invasion of glioblastoma. The apparent beneficial effect of caffeine suggested by our study should trigger future investigations of the therapeutic potential for caffeine to treat this deadly disease that otherwise has no cure. 

Conclusion

Caffeine is the most obvious modulator of IP3R in your kitchen or at the local pharmacy.

cAMP plays a complex role in IP3R, PKA is involved so PDE4 should be. Parathyroid hormone (PTH) is also important. PTH is secreted to tell your bones to release Ca²⁺ into the bloodstream, but it has multiple roles. PTH causes the release of IP3 and DAG and hence release of calcium from the store within cells (the ER). PTH release is stimulated when Ca²⁺ is low but also by other things, such as notably by histamine. PTH also is reported to increase the sensitivity of IP3R receptors, so too much PTH would clearly be a bad idea.

Primary Hyperparathyroidism (PHPT) is characterized by hypercalcaemia and elevation of parathyroid hormone.  Children with PHPT may present with non-specific complaints such as behavioural change and deteriorating school performance.  As we know, behavioural change in the form of aggression sometimes occurs in autism, ADHD and various other mood disorders. It may also present as a psychiatric manifestation of an endocrine disorder such as Primary Hyperparathyroidism (PHPT).

It is not surprising that histamine can cause aggression in the same way that Primary Hyperparathyroidism does. Aggression in all psychiatric disorders very likely has a biological cause, you just have to look for it. 

Aggression and Homicidal Thoughts in a Patient with Primary Hyperparathyroidism: A Case Report.

How about checking kids with aggression/SIB for PHPT, or just high levels of calcium (hypercalcaemia). Or perhaps:-

Going Loco? Think histamine, calcium and hyper-parathyroidism, before taking antipsychotics.

Back to caffeine.

In people with hyperactive IP3 receptors, such as those who damaged their pancreas by drinking too much alcohol, caffeine looks a smart therapy. The same would apply to people with autism and hyperactive IP3 receptors. So for those people, drink coffee, preferably Greek coffee (or Turkish coffee, which is the same thing). Some Latin American countries also make potent coffee drinks. Your cup of instant coffee, or chain store coffee is not going to do much.

There are numerous interesting substances in less processed coffee, not just caffeine. The key is to process it as little as possible, as we saw cocoa. In instant coffee only the caffeine is going to have much effect.

Chlorogenic acid, an OAT3 inhibitor, that should enhance bumetanide, is there in coffee.

Coffee contains small amounts of Caffeic acid. What we would really like is Caffeic Acid Phenethyl Ester (CAPE), which is a substance found in some bee propolis. CAPE acts as a PAK1 inhibitor, among other potentially beneficial effects.

Catechin, epicatechin, and surprisingly vanillin are present in coffee.

Roasting coffee makes big changes to its chemical composition and of course to its taste. Green coffee bean extract, used as a supplement for weight loss, is a rich source of chlorogenic acid.

Perhaps someone should do a study on adults with autism using 2 cups of Greek coffee a day.  Alternatively you could just use caffeine pills, with or without coffee bean extract for those interesting flavanols.