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.