Keeping ahead of the curve in Autism (and Pitt Hopkins syndrome) treatment - the placebo effect, clinical trials, and a promising case study

Since AI is a trending tool in this blog, I decided to let ChatGPT rewrite today's post. It did rather strip out the science bits.  It added the "don't wait for permission at the end"—a little cheeky, I think. It does like to use dashes.

 

Keeping out in front of the pack is not always easy

Today’s post highlights a compelling new case study—one that turns theoretical research into a real therapy.

About time too! That was my reaction when a reader sent me the paper.

This case study reports on the repurposing of a cheap, well-known drug—Nicardipine—to treat Pitt Hopkins syndrome (PTHS). The drug had already shown promise in earlier mouse models.

So why aren’t we doing this more often? Because the system misunderstands risk.

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What About the Risk?

When it comes to trying new treatments, people often fixate on the risk of the therapy itself. But that’s only half the equation. The risk of doing nothing is often much greater—especially in autism.

Most conventional drug repurposing therapies pose minimal long-term risk. Things change only when you start injecting compounds or using untested chemicals. But even then, there’s surprisingly little harm on record.

Only one death has ever been clearly attributed to a therapy for autism:

A 5-year-old autistic boy from the UK died in the US while undergoing chelation therapy. The wrong form of EDTA—disodium EDTA instead of calcium EDTA—was used. The result was fatal hypocalcemia-induced cardiac arrest. The doctor administering the therapy didn’t understand the pharmacology.

Lesson: Always read the label.

Meanwhile, the risk of death from untreated autism is well established:

• In severe autism, common causes include drowning, accidents, and seizures.
• In milder cases, the biggest risk is suicide.

Another overlooked danger, mentioned previously in this blog, is polydipsia—excessive water drinking—which can cause hyponatremia (low blood sodium), leading to seizures, coma, and even death.

Bottom line?

The risks from untreated autism far exceed the risks from science-based, carefully applied therapies.

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The Nicardipine Case Study

A newly published study builds on promising mouse results and shows real benefit in a young child with PTHS. The drug used—Nicardipine—has been around since 1988 and is commonly prescribed to older adults for high blood pressure or angina.

🔗 Read the case study

Highlights:

• Pitt Hopkins syndrome involves loss of function in the TCF4 gene, leading to overactivity of Nav1.8 sodium channels in neurons.
• Nicardipine inhibits Nav1.8, making it a logical therapy.
• In this case study, the child received oral nicardipine for 7 months (0.2–1.7 mg/kg/day).
• Result: Mild to moderate improvement in all developmental areas, and reduced restlessness.
• No significant side effects reported.

It’s not a magic bullet—but it’s a start.
Used as part of polytherapy, this could become a powerful tool for treating PTHS.

And there’s more coming: Vorinostat, another potential therapy, is entering human trials.

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Why Don’t More Therapies Get Adopted?

A recent paper by Antonio Hardan sheds light on this. He’s the researcher who showed that the OTC antioxidant NAC benefits many with autism, and later explored the hormone vasopressin.

This time, he tackled the placebo effect—a real barrier in autism research.

🔗 Placebo Effect in Clinical Trials in Autism: Experience from a Pregnenolone Treatment Study

What They Did:

• A two-week placebo lead-in before the main trial.
• The drug tested was pregnenolone, a neurosteroid.
• They used parent-reported ABC-I scores to measure irritability.

What They Found:

• A 30% reduction in irritability—just from placebo.
• Also improvements in lethargy, hyperactivity, and repetitive speech.
• The placebo effect was strongest in the first two weeks, then plateaued.
• Clinician-rated scores (CGI) did not show this placebo response.

The Takeaway:

Parent expectations strongly shape trial results—at least in the early stages.
A placebo lead-in is a clever way to measure and filter out this noise.

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Early Adopters, Take Note

It pays to be ahead of the curve.

Some Pitt Hopkins parents are already trying nicardipine at home based on this case study. Good luck to them—I hope they find the right specialists and support.

Let’s not forget: the big autism trials of recent years—Bumetanide, Memantine, Balovaptan, Oxytocin, Arbaclofen—all officially “failed.”

But the drugs didn’t fail—the trial designs did.

Each of these drugs helped some individuals. The problem?
The trials weren’t structured to identify responder subgroups. We wasted time, money, and hope by not tailoring inclusion criteria more carefully.

Consider Trofinetide, the first FDA-approved drug for Rett syndrome (2023). It helps only 20% of patients, but was still approved.

I’d argue that Bumetanide has an even higher response rate in severe autism, particularly with intellectual disability—and that the best outcome measure is IQ, not a generalized autism scale.

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My Own Example: No Placebo Here

How do I know I wasn’t misled by the parental placebo effect?

Simple. No one knew I was trialing treatments—not even the teachers or therapists. That meant their feedback was objective and uninfluenced by my hopes.

My son Monty went from being unable to do basic subtraction at age 9, to later passing his externally graded IGCSE high school math exam.

Not bad for a therapy that mainstream medicine still ignores.

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Final Thoughts

• Drug repurposing is safe, smart, and often effective.
• The placebo effect is real—but it’s measurable and manageable.
• If we want progress in autism treatment, we need smarter trial designs, not just more of them.
• Being ahead of the curve isn’t risky—it’s essential.

💡 Stay informed, stay curious, and don’t wait for permission.

Thanks for the guest post, ChatGPT !!

One point to add to the risk assessment: by my estimation, each year in the US, around 200 to 300 people die from drowning, seizures, accidents, and suicides related to autism. In living memory, only one person has died as a result of visiting an autism doctor in the US and that death was entirely preventable.

Vorinostat, a potent HDAC inhibitor trialed in several autism models, was mentioned in the above post. Interestingly, there is a recent comment from a reader who finds it resolves 80% of his autism but only for about 2 hours. The half-life of this drug is about 2 hours. There are discussions on Reddit by people using it for autism, anxiety, PTSD etc. It is about 1,000 times more potent than HDAC inhibitors people typically might try at home. Perhaps there should be trials of micro-dosing Vorinostat? I think daily use of high-dose Vorinostat may not work well, due to side effects.  Human trials will soon inform us better. It is often older people who struggle with drug side effects, not children.  

Vorinostat may not only correct Differentially Expressed Genes (DEGs) but also:

• Increase synaptic plasticity
• Improve synaptic morphology (the shape and function of neuronal connections)
• Improve memory and cognition 

The main research interest is in single gene autisms, where one specific gene is under-expressed (eg Pitt Hopkins, Rett, Fragile-X etc) but the general ideas are equally applicable to broader autism. 

Clinical Trials – Bumetanide and Memantine & Making Sense of it all in a Single Book

This week I received a message: -

“Your Bumetanide treatment is on trial among 25 teenagers here and parents are loving it”

My reply, brief as usual (unlike my blog posts)

“Great!”

I did not mention that in the first phase of the trial 50% of the teenagers are going to be on the placebo.  It is Dr Ben-Ari’s treatment.

A clinician told me that all the parents of children, to whom she has prescribed bumetanide, think their children are responders and is wondering how to deal with the parental placebo effect.

I had another clinician telling me, “I guess from your experience with the blog, most people are not responders to Bumetanide”.  Then came an analysis of the recent tiny study in China that showed on average there was a measurable improvement on the CARS scale (Childhood Autism Rating Scale), but the question arose was “is this response large enough for parents to notice?”

Memantine (Namenda)

A few years ago, Memantine was also trialled at the University Hospital where we live, the same one that is part of the current Bumetanide study.

Memantine was subject to a rigorous multi-center study of nearly one thousand children a few years ago.  The FDA did not like all the off-label prescribing of Memantine for autism and asked the producer to carry out a serious clinical trial.

The first phase of the trial was to identify the responders, those responders then were to be enrolled to two follow-on trials to collect additional useful data.  The trial was terminated after the first phase was completed because in the subsequent trials the placebo produced as good results as Memantine.

So, we should assume memantine is no good for autism?

Or

In spite of spending millions of dollars and liaising with the FDA on the detailed structure of the trial, the producer did not know how to organize an autism trial properly?

I was just writing a part of my autism book that reviews all the drugs trialed to date in autism and I noted that Antonio Hardan (for me, Dr NAC from Stanford) has published a review of data from those expensive Memantine trials.

Efficacy and safety of memantine in children with autism spectrum disorder: Results from three phase 2 multicenter studies

… the considerable improvements in mean Social Responsiveness Scale scores from baseline in the open-label trials were presumed to be clinically important.

I think that is Hardan-speak for “I think Memantine can be a useful therapy, for some people”.  I am not totally sure and I can see why Barney Rubble might be left scratching his head. 

Hardan is about to become Stanford's Dr Nexium, as he runs a clinical trial of the acid lowering drug esomeprazole (Nexium).  I am not sure why he thinks this will improve autism.  I think it will make some people's autism worse, because over time it will cause intestinal dysbiosis.

https://stanfordhealthcare.org/trials/a/NCT03866668.html

Intestinal Dysbiosis Secondary to Proton-Pump Inhibitor Use

Autism for Dummies?

Writing a comprehensive book about autism is quite a task.  If it is too complicated nobody will read it, but if you do not go into the how and why of autism, you have not contributed very much.

My elder son has suggested calling it “Autism for Dummies”; but that was not helpful suggestion.  We probably all count as Dummies, when it comes to autism, even Dr Naviaux, who I think knows the most.

I like the book written by a US Academic who treated his "untreatable" brain cancer (Gioblastoma, life expectancy 14 months), by reading the research and applying off-label therapies, using cheap generic drugs.  He has lived long enough to publish a second edition.  The first edition has a cover that looks like a medical textbook; he learned his lesson and the second edition looks more like a cookery book.

Before using pharmaceuticals to treat autism, we used a Peter-created, ABA-inspired, home therapy program.  Amongst many resources, we had two old, but excellent books - they were published nearly 40 years ago.  One was blue and one was yellow (code named by me and therapists as the yellow and blue books), one was about increasing good behaviors and the other was about reducing bad behaviors.  I could not leave them lying around at home, because in the tittle of these use cute looking books was in large print “SEVERE RETARDATION”.  The books are great and of course they should have been combined into a single book. 

I am not a fan of giving a nice name to somethings that is bad.

To me, intellectual disability sounds like not being very good at playing chess.

Accept bad news and move on.

Peter’s Book

I decided to have three sections in my book and have a nice cookery book style cheerful cover, so nobody can be embarrassed.  I will not be citing endless complicated research papers. 

I start with all the general issues that are relevant to understanding autism, that do not relate to complicated science.  I finish with a section on how autism can be treated based on applying the research findings to date, what ideas I came up with myself and other people’s ideas shared on this blog. 

Sandwiched in between easy reading section 1 and practical section 3, is a more heavy-going section 2; it is a simplified review of the biology and chemistry that is relevant to autism.  These are things you need to know to make any sense of those tens of thousands of published autism papers, that most people do not know exist.

Section 2 is not going to be a favourite for Roger, but I think he will like sections 1 and 3.  To really judge what to do in the therapy part (section 3), understanding at least part of section 2 is advisable and that is why it has to be there.

It is just like fixing your car, it does help to know a little bit about how it works, before you start tinkering with it.  Even the mechanic at the dealership does not know everything about how it works, but hopefully he knows enough.

If the mechanic cannot fix your car, you just sell it. You may feel a pain in your wallet, but no long-term guilt.

The autism is equivalent is putting your child into an institution, or group home.  You either feel guilty at this point, or later on when something goes terribly wrong. 

I am forever having to fix things - from cars to computers, to solar panels, air conditioners, blocked drains, a leaking swimming pool etc.  Once you realize the "experts" are often not so expert, you engage yourself to solve the problems; or at least tell the expert what you want him to do, like “I found the leak, here it is, now fix it like this”.

Don’t skip section 2, invest time to learn some biology.

Parental Placebo Effect in Autism

I have not met that many parents of kids with ASD; from those that I have met it, is clear that often the therapies applied are limited by the more skeptical parent.  There really are no therapies that everyone agrees on.

So it is no surprise that sometimes my wife doubts the value of the therapies I am sharing in this blog.  She would far rather have a homeopathic wonder cure, than use drugs or ABA.  I saw today as an opportunity.  Monty, aged 10 with ASD, had been up half of the night with a virus and his Mum said "don't give him any of your medicines"; "OK" I replied.

By 2pm Monty was in an increasingly bad mood, frustrated,  exhibiting obsessive repetitive behaviours and showing warning signs of mild self injury.

So I mixed him up a Peter cocktail (1.2g NAC, 10 mg atorvastatin and 1mg of bumetanide) in orange juice.  Within 10 minutes things started to change.  Facial expression switched from anger to contented and, most telling of all, he sat at the piano and started to play.  I could not have hoped for a better result. 

After an hour I asked Mum, if she noticed the transformation.  Yes she had and agreed it was remarkable.


Placebo Effect

It is clear that the more involved the parent becomes, the greater is the risk of seeing what you want to see, rather than what is there.  This why nobody generally listens to parents and indeed why doctors are not supposed to treat their children.

It is always good to have a reality check.

I can now move forward to my serotonin and acetylcholine interventions, in the knowledge that previous interventions have past their critical test.

Placebo Effect in Autism

 

Placebo effect in autism - Parent/Child Matrix      

A big problem in autism research is the placebo effect.  It could be because the child found the therapy fun and liked all the attention and so showed improved behaviors; or it could be that the parents so desperately wanted to see an improvement, that they imagined it.

In good research, half of the kids receives the trial drug and the other half receive a placebo.  But what happens when both groups show an improvement?  Well if both groups show equal improvement then the therapy has no value.  In almost all the research I have seen, the placebo group shows an improvement.  In one study the placebo group improved 70% on the behaviour rating scale.

We need to conclude several things:-

• Good studies rely on assessment by clinicians, not parents
• If the therapy was fun and included lots of 1:1 attention, then the kid's behavior will improve, regardless of the medical value of the therapy.
• Do not reject a study because the placebo group improve moderately
• Always focus on the relative improvement of the group on the trial therapy vs the control group on the placebo.

Behavioural rating scales

In autism there are many different behavioural rating scales, including :-

• CGI (clinical global impression) Physician and Parental version 
• ABC (abherrant behaviours checklist)
• CARS (Childhood Autism Rating Scale)
• ADOS (Autism Diagnostic Observation Schedule)

Researchers can pick and choose which scale to use and which scale to emphasize.  All these scales are highly subjective.  Different people assessing the same child will get a slightly different answer.  The same person assessing the same child a week later will also get a slightly different answer. 

Tiny Studies and Not so Objective Researchers

Many studies in autism have a tiny number of subjects, sometimes fewer than ten. Often researchers have a vested interest in the research, this is not always a bad thing. As a result it is best to focus on research that has been frequently cited by other researchers, this should mean that they buy into it.

Example - Secretin Research

In a 2003 study of the hormone secretin, 62 children participated. At that time there were stories that secretin was a "wonder cure" for autism. Half received a one-off injection of secretin, the other half received a placebo. The clinicians' tests showed that there was no behavioral improvement in either group; the parents however saw things differently. The parents of 48 children saw an improvement. When asked to guess whether their child had received the placebo or the secretin, 27 guessed correctly and 27 guessed wrong. Six families would not guess and two families dropped out.