MS, the gut, and Autism in males and females

 

There is quite a lot in this blog about MS (multiple sclerosis) because it is the classic myelin disorder and so is well researched. Many other neurological conditions, including some autism, also feature impaired myelination. 

One of the very cheap myelin therapies is the old anti-histamine drug Clemastine. I learnt this week that it will be trialed in children with Pitt Hopkins syndrome. It is a very logical choice and some parents have already trialed it. I used it for a few years and did feel there was a benefit. The key is to keep the dose low enough not to cause drowsiness. Very long term use may reduce acetylcholine in the brain, so it is not a forever medicine.

Then I saw some interesting research from Japan showing that it appears that multiple sclerosis starts in the gut.

We already know from interesting US research that you must have had the Epstein-Barr virus (EBV) to be able to develop MS. It also depends on the age at which you caught the virus. The older you were, the bigger the risk of later developing MS. So it is best to get EBV very young, or avoid it entirely by vaccination (expected to be available in 10 years). EBV is also known to increase the risk of certain cancers, so I guess the vaccination will get adopted.

 

The role of the gut

For years, researchers have suspected that the gut plays an important role in neurological conditions. What has been missing is a clear explanation, a step-by-step account of how something happening in the intestine could influence the brain.

A recent study provides exactly that for Multiple Sclerosis.

 

How Intestinal Cells Trigger Multiple Sclerosis

Summary: For years, scientists have suspected that the gut plays a role in Multiple Sclerosis (MS), but the “smoking gun” linking the two has been elusive. A landmark study has finally identified the cellular mechanism: Intestinal Epithelial Cells (IECs)—the cells lining your gut—are acting as “accidental” messengers.

The study found that in patients with MS, these gut cells abnormally express MHC II, a protein that “presents” antigens to the immune system. This interaction mistakenly transforms ordinary immune cells into pathogenic Th17 cells, which then migrate from the gut directly to the central nervous system to attack the brain and spinal cord.

Key Facts

·         The Accidental Messenger: IECs do not normally “talk” to the immune system in this way. In MS, they begin expressing MHC II, which “primes” CD4+ T cells to become aggressive.

·         The Th17 Migration: Using “Kaede” protein tracking (which changes colour under light), researchers proved that these gut-primed Th17 cells physically travel from the intestine to the spinal cord to drive neuroinflammation.

·         Human Connection: The team used single-cell RNA sequencing on human biopsies to confirm that the same inflammatory patterns seen in mouse models are present in the intestines of human MS patients.

·         New Treatment Target: Most current MS therapies target B cells in the blood; this study suggests that treating the gut environment or blocking the antigen-presenting activity of gut cells could stop MS at its source.

 

This new knowledge should shift the focus of treatment away from simply suppressing the immune system after damage has started, toward stopping the problem earlier at its source. Future therapies may aim to block these abnormal gut signals, target specific inflammatory pathways, and use gut-focused treatments such as microbiome modulation and diet. Overall, the goal is to prevent the immune system from being mis-trained in the first place, rather than just managing the consequences later.

  

The actual study:-

Intestinal epithelial MHC class II induces encephalitogenic CD4 T cells and initiates central nervous system autoimmunity

The gut as an immune training ground

The key finding is that cells lining the gut, intestinal epithelial cells, can act as unexpected immune instructors.

In MS, these cells begin expressing MHC class II, a molecule normally used by immune cells to “present” antigens. This abnormal behavior turns the gut lining into a kind of misguided training center.

The result is:

• Activation of Th17 cells
• These cells become highly inflammatory
• They migrate from the gut to the brain and spinal cord
• They drive autoimmune attack on myelin

This is a causal pathway from gut to brain.

 

A shared biological axis

The gut is not just influencing the brain, it is actively programming immune cells that control it.

This gut-immune-brain axis likely operates across multiple conditions, including autism, asthma, and ADHD.

 

Intestinal epithelial cells and autism

Intestinal epithelial cells sit at the center of the gut–immune interface and may also play a role in Autism.

They have three key functions.

 

1. Barrier control

IECs regulate what passes from the gut into the body.

If this barrier is altered, microbial products and metabolites may enter circulation and immune activation may increase

Some studies in autism report increased gut permeability, suggesting altered epithelial function.

 

2. Immune signaling

IECs actively communicate with the immune system. They release cytokines, influence T-cell behavior and potentially affect pathways like Th17 cells

In MS, abnormal IEC signaling directly drives inflammation.

In autism, similar immune pathways are implicated, though less directly established.

 

3. Microbiome interpretation

IECs “read” signals from gut microbes.

·        balanced microbiome produces healthy regulatory signals

·        dysbiosis produces inflammatory signals

 

In autism, microbiome differences are common, meaning IEC signaling may be altered.

 

Autism - same axis, different outcome

In autism, we see:

• altered microbiome
• gut inflammation
• immune activation (including Th17/IL-17 in some cases)

 

The difference is timing and target.

 

Step	MS (Adult)	Autism (Early Life)
Gut signal	IEC activation	Dysbiosis / gut inflammation
Immune response	Pathogenic Th17 cells	Altered immune signaling
Brain effect	Myelin attack	Developmental disruption
Timing	Adulthood	Early childhood

 

Why more females have MS

Multiple Sclerosis is 2–4 times more common in females.

Females have:

• stronger immune responses
• two X chromosomes (more immune genes)
• greater responsiveness to immune signals

When the gut sends the wrong signal, females are more likely to amplify it into autoimmunity.

Hormonal shifts (e.g., pregnancy/postpartum) further support an immune-driven mechanism.

 

Why more males have Autism

Severe autism is 3–4 times more common in males.

Males show:

• higher vulnerability during early brain development
• only one X chromosome (less genetic backup)
• less regulated early-life immune signaling

When the gut–immune system is activated early, males are more likely to cross the threshold into neurodevelopmental disruption.

Females appear more protected via:

• neural resilience
• better early immune regulation
• genetic redundancy

 

The EBV connection: a required trigger

One of the most important recent discoveries is the role of Epstein-Barr Virus infection in MS.

Large longitudinal studies show:

• individuals not infected with EBV almost never develop MS
• after EBV infection, the risk of MS increases dramatically (around 30-fold)

This suggests EBV is a necessary but not sufficient factor.

 

How EBV fits the model

EBV infects and persists in B cells, altering immune behavior. It may:

• create immune cells that recognize both viral proteins and brain proteins (molecular mimicry)
• keep B cells chronically activated
• prime the immune system toward autoimmunity

 

A multi-hit model of MS

The emerging picture is that MS requires multiple aligned factors:

1.     EBV infection
creates autoreactive immune potential

2.     Gut immune dysregulation
generates inflammatory Th17 cells

3.     Environmental modifiers (e.g., low vitamin D)
reduce immune regulation

Together, these drive immune attack on the brain

EBV loads the gun, the gut pulls the trigger, and the immune system fires at the brain.

 

Why MS varies by latitude

MS prevalence increases with distance from the equator.

• Lower rates near the equator
• Higher rates in northern regions

This reflects environmental effects on immune regulation.

 

Vitamin D and sunlight

Reduced sunlight lowers vitamin D, which normally:

• suppresses excessive Th17 cells activity
• promotes immune tolerance

Low vitamin D removes a key brake on autoimmunity.

 

Infection timing

Epstein-Barr Virus infection often occurs later in higher latitude regions, triggering stronger immune responses.

 

Microbiome differences

Geography affects diet and microbial exposure, shaping the gut–immune axis.

 

Hygiene effects

Reduced early microbial exposure may impair immune training.

 

Why some conditions improve with age

A striking observation across medicine is that many children “grow out of” certain conditions.

This includes:

• Mild autism (in some cases)
• Asthma
• Attention Deficit Hyperactivity Disorder

This reflects a shared biological pattern.

 

The dynamic regulation model

Early life is a period of high instability:

• the gut barrier is still developing
• the microbiome is fluctuating
• the immune system is learning tolerance
• the brain is highly sensitive

This creates a system that is:

• more reactive
• more inflammatory
• more vulnerable

 

What Changes Over Time

Three stabilizing processes occur:

1. Gut stabilization

• microbiome becomes more consistent
• fewer abnormal immune triggers

2. Immune regulation improves

• better control of inflammation
• reduced overactivation (including Th17 pathways)

3. Brain maturation

• circuits strengthen
• compensatory pathways develop
• regulation improves

 

The threshold effect

Symptoms can be viewed as crossing a threshold:

• Above threshold → visible condition
• Below threshold → mild or no symptoms

As stability improves:

• inflammation ↓
• regulation ↑

The individual may drop below the clinical threshold (unless they keep lowering the diagnostic threshold, as with autism)

 

Implications for Treatment

Focus on stabilizing the system, not just suppressing symptoms.

Potential approaches:

• improve gut health and microbiome stability
• reduce inappropriate immune activation
• support metabolic resilience
• ensure adequate vitamin D and environmental exposure
• minimize chronic inflammatory triggers

 

For MS:

• targeting EBV and gut immune programming may prevent disease at its source

 

For autism and related conditions:

• early stabilization of the gut–immune axis may improve outcomes

 

Does severe autism improve with age?

Severe autism is not a fixed condition where everything is determined at the start of life. While some children begin with greater challenges than others, what happens over time depends heavily on how skills develop during the long period of childhood and adolescence. These include communication, social interaction, emotional regulation, and daily living abilities. Early progress in these areas can create a positive ripple effect, making future learning easier and more natural.

If certain skills are delayed or missed early on, development may be slower—but this does not mean progress is impossible. The brain remains capable of learning and adapting, even later in life. This means that outcomes are not set in stone, much is up to the parents.

What shapes these outcomes is a combination of factors. Biology plays an important role—things like brain plasticity, energy levels, and overall health can influence how easily a child can learn. Biology can be modified pharmacologically, which is what EpiphanyASD is all about.

Biology is only part of the picture. Therapy, education, and the home environment are equally important. Structured teaching, repetition, encouragement, and meaningful interaction all create opportunities for skills to develop.

Importantly, these factors interact with each other. When a child’s biological state improves, they become more receptive to learning. In turn, effective therapy and support can help build new abilities, which further improves confidence, behavior, and engagement. This creates a positive cycle where progress builds on progress. Nothing changes over night, it is a slow process. Increasing skill acquisition rate by just 10% can lead to a massive difference over a decade.

This is why outcomes in autism are so variable. Two children who start at a similar level can follow very different paths depending on the opportunities they have and how their abilities are supported over time.

There are also important developmental windows, particularly in early childhood, when learning certain skills is easier. However, these windows do not fully close. Progress may become slower later, but it is still very much possible. Many individuals continue to gain skills well into adolescence and adulthood.

In this way, severe autism is better understood as a dynamic developmental process rather than a fixed outcome. The trajectory can be changed, sometimes substantially, depending on how biology, learning, and environment come together over time.

 

A note on EBV

Epstein–Barr virus (EBV), also known as human herpesvirus 4, is a common virus that infects most people and remains in the body for life. It is best known for causing infectious mononucleosis (“glandular fever”), especially when infection occurs in adolescence.

EBV spreads via saliva.

Childhood transmission is very common globally, but as hygiene increases it gets caught at older ages. In western countries kissing during adolescence is a major route.

90-95% of adults carry the EBV, the only question is at what age they were exposed.

Early exposure to EBV is less risky than late exposure. This fits the hygiene hypothesis, which has been covered in this blog and my book.

The hygiene hypothesis proposes that reduced exposure to microbes in early life results in less “training” of the immune system and causes higher risk of immune dysregulation in later life.

Exposure to pets at home will help train a young child’s immune system, but does not expose him/her to EBV, which is exclusively a human virus. 

Dihexa, Telmisartan (Candesartan, Losartan), PEPITEM, Cognitive Enhancement and the example of Pitt-Hopkins

 

A reader recently left an interesting comment on my earlier post about telmisartan. They wrote that they had been using Dihexa for a couple of months and had noticed new vocalizations and unexpected progress with toilet training in their child. They also mentioned another peptide, PEPITEM, which they had come across while reading about bone metabolism and inflammation.

This comment prompted me to look more closely at how several topics might intersect biologically: Dihexa, angiotensin receptor blockers such as telmisartan, the peptide PEPITEM, and conditions like Pitt-Hopkins syndrome.

 

What is a peptide?

Peptides are short chains of amino acids, the same building blocks that make up proteins. They act as signaling molecules in the body and regulate many biological processes. Examples of natural peptide hormones include insulin and oxytocin.

Scientists often design synthetic peptides to mimic or modify these natural signals. Some peptides have become successful medicines. A well-known example is semaglutide, used to treat diabetes and obesity.

In recent years peptides have become very popular in longevity and biohacking circles. This is partly because modern biology has discovered many new peptide signaling systems. These regulate metabolism, immune responses, tissue repair, and brain plasticity.

Another reason is that peptide manufacturing has become much cheaper. Automated peptide synthesis now allows laboratories to produce peptides easily. As a result, some research peptides are now sold online.

Many of these compounds are marketed as “research chemicals”. Examples often discussed online include BPC-157 and Dihexa. These compounds originated in laboratory research.

However, most of them have not gone through proper human clinical trials. Their long-term safety and effectiveness are therefore unknown.

Social media and podcasts have amplified interest in these substances. This has created a large grey market for experimental peptide therapies.

Scientists remain cautious because peptides can have strong biological effects. Problems can include uncertain purity, incorrect dosing, and lack of safety data.

Despite these concerns, peptides remain an important area of medical research. Many future medicines are likely to be peptide-based.

The reason is simple, biology uses peptides as a major language of cellular communication. They control processes ranging from metabolism to immune function and brain signaling.

This is why peptides sometimes appear in discussions of neurological conditions.

Many pathways involved in brain development and synaptic plasticity are regulated by peptide signals.

  

Dihexa and the angiotensin system

Dihexa was originally developed from angiotensin IV, a fragment of angiotensin II that belongs to the renin–angiotensin system. While this system is best known for regulating blood pressure, it also has important roles in the brain.

In the 1990s researchers noticed that angiotensin IV could improve learning and memory in animal experiments. This led scientists to design molecules that could mimic these effects but cross the blood–brain barrier and remain stable in the body. One of these molecules was Dihexa.

Interestingly, Dihexa does not appear to work primarily through classical angiotensin receptors. Instead it activates the HGF/MET pathway, which regulates neuronal growth, dendritic branching and synapse formation. In laboratory experiments Dihexa has shown very strong synaptogenic effects, meaning it can promote the formation of new synaptic connections between neurons.

This is why it sometimes appears in discussions of cognitive enhancement or experimental neurological treatments. However, it is important to stress that Dihexa has never undergone proper human clinical trials, so its safety profile and long-term effects remain unknown. It is somewhat surprising that it is sold online as a “supplement” or research compound, since it is really a laboratory-designed molecule rather than a traditional dietary supplement.

 

BDNF and synaptic plasticity

Some autism clinicians have experimented with approaches intended to increase brain levels of BDNF (brain-derived neurotrophic factor), a key regulator of synaptic plasticity and neuronal survival.

BDNF promotes dendritic growth, synapse formation and learning-related plasticity. In many ways it is one of the brain’s central “growth signals”. Dihexa became famous in neuroscience circles partly because some laboratory studies suggested it could stimulate synapse formation even more strongly than BDNF, although those findings were mainly from cell culture experiments.

The two pathways are different but converge on similar intracellular signaling networks that regulate synaptic growth.

Interestingly, one of the most reliable ways to increase BDNF is not a drug at all but physical exercise. Exercise stimulates BDNF production in the hippocampus through a combination of increased neuronal activity, metabolic signaling and muscle-derived molecules such as irisin. High-impact activity may also stimulate endocrine signals from bone, including osteocalcin, which can influence brain function.

 

Angiotensin receptor blockers and the brain

The drugs discussed in some of my previous articles—telmisartan, candesartan and losartan—belong to the class of angiotensin receptor blockers (ARBs). They block the AT1 receptor, which is activated by angiotensin II.

Although these drugs are prescribed for hypertension, the brain has its own local renin–angiotensin system. In the central nervous system angiotensin signaling influences neuroinflammation, oxidative stress, cerebral blood flow and neuronal excitability.

Blocking the AT1 receptor tends to reduce inflammatory signaling and shift the balance toward protective pathways.

Telmisartan is particularly interesting because it also activates the nuclear receptor PPAR-gamma, which influences mitochondrial function, metabolic signaling and inflammation in neurons.

Candesartan is often considered one of the more brain-penetrant ARBs and has shown neuroprotective effects in some experimental models.

Losartan has attracted attention because it can reduce excessive TGF-beta signaling, a pathway involved in inflammation and tissue remodeling.

Telmisartan might theoretically be more relevant in autism where metabolic stress and inflammation dominate (because of PPAR-γ activation). Losartan might be more relevant where excessive tissue-remodeling or TGF-β signaling plays a role. In the brain, tissue remodeling involves:

• synapse formation and elimination
• growth of dendrites and axons
• restructuring of the extracellular matrix around neurons
• activation of glial cells

Losartan is used to treat Marfan syndrome. Marfan syndrome is a systemic connective-tissue disorder that affects many parts of the body, particularly the heart.

Some studies have reported altered TGF-β signaling in certain forms of autism, suggesting that immune and tissue-remodeling pathways may contribute to aspects of neurodevelopment in at least some individuals. Losartan could theoretically influence these biological processes.

These mechanisms do not directly overlap with Dihexa’s synapse-forming activity, but they may influence the overall biological environment in the brain by reducing inflammatory and metabolic stress.

 

The peptide PEPITEM

The reader also mentioned PEPITEM, short for “PEPtide Inhibitor of Trans-Endothelial Migration”.

PEPITEM regulates the movement of immune cells across blood vessel walls. In simple terms, it helps control whether inflammatory immune cells leave the bloodstream and enter tissues.

This pathway has been studied mainly in inflammatory diseases. By limiting immune-cell migration, the PEPITEM pathway can reduce tissue inflammation.

Interestingly, the same pathway also influences bone metabolism because immune signaling strongly affects osteoclast activity and bone resorption.

 

Why bone biology keeps appearing

One surprising theme linking these topics is the intersection between inflammation, bone metabolism and the renin–angiotensin system.

Angiotensin II can stimulate osteoclast activity and promote bone resorption. Blocking the AT1 receptor with ARBs may therefore modestly reduce inflammatory bone loss. Some observational studies have suggested that ARB use may be associated with slightly higher bone density or lower fracture risk.

Given how closely immune signaling and bone metabolism interact, it is not surprising that peptides affecting immune-cell trafficking, like PEPITEM, also influence bone remodeling pathways.

 

Pitt-Hopkins syndrome as an example

Pitt-Hopkins syndrome is caused by mutations in the transcription factor TCF4. This gene regulates many downstream processes involved in neuronal development, synaptic maturation and network formation.

In experimental models of Pitt-Hopkins and related neurodevelopmental disorders, researchers often observe abnormalities in synaptic development and neuronal connectivity.

Because of this, some therapeutic ideas have focused on pathways that influence synaptic plasticity, neuronal growth or inflammatory signaling.

The HGF/MET pathway activated by Dihexa is one such pathway. The MET gene has also been linked to autism genetics in several studies, and reduced MET signaling has been associated with altered cortical connectivity.

This does not mean that Dihexa is a treatment for Pitt-Hopkins syndrome or autism, but it is certainly plausible.

We saw in previous posts that autism can be broadly divided in hypo/hyper (too little/much) active pro-growth signaling pathways. Pitt Hopkins would be in the hypo category, so increasing activity should be beneficial.

The unknown issue with Dihexa is that it has not be tested thoroughly in humans, so long term use might not be wise, particularly in older people.

The totally safe way to increase pro-growth signaling is via daily aerobic exercise, which comes up again in the next post, which looks at translating recent Alzheimer's research to autism. 

 

A broader pattern

What the reader’s comment illustrates is something that appears frequently in biomedical research, apparently unrelated compounds often converge on a small number of biological control systems.

In this case we see several different layers of regulation:

– the renin–angiotensin system influencing inflammation and metabolic signaling
– growth factor pathways such as HGF/MET and BDNF regulating synapse formation
– immune trafficking pathways such as PEPITEM controlling inflammatory cell migration
– transcriptional regulators such as TCF4 governing neuronal development

Each operates at a different level, but they all ultimately influence how neurons grow, connect and function.

This does not mean that compounds like Dihexa or peptides such as PEPITEM will become treatments for neurological conditions. Most remain at a very early stage of research.

But it does highlight how discoveries in cardiovascular biology, immunology, bone metabolism and neuroscience increasingly intersect.

 

Conclusion

Dihexa and telmisartan start from the same hormonal system but act very differently:

• Dihexa directly stimulates synapse formation through growth-factor signaling.
• Telmisartan reduces inflammation and metabolic stress that may impair neuronal function.

The overlap lies mainly in their potential downstream effects on neuronal plasticity, not in their primary mechanism of action.

In the case of Pitt Hopkins syndrome both might be potentially beneficial, although through very different mechanisms, but no clinical evidence exists.

Dihexa acts by activating the HGF/MET pathway, which promotes synapse formation, dendritic growth and neuronal plasticity. Since Pitt-Hopkins syndrome involves impaired neuronal network development caused by mutations in the TCF4 transcription factor, pathways that enhance synaptic growth should attract scientific interest.

Telmisartan works in a different way. By blocking the AT1 receptor of the renin–angiotensin system it reduces inflammatory signaling and oxidative stress, and it also activates the nuclear receptor PPAR-γ, which influences mitochondrial metabolism and cellular stress responses. These effects could potentially improve the cellular environment in which neurons function.

In simple terms, Dihexa attempts to directly stimulate synapse formation, whereas telmisartan may reduce biological stresses that interfere with normal neuronal signaling.

Both approaches therefore touch on biological processes that are relevant to brain development and plasticity.

Dihexa is used by some autism clinicians in the US.

 

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.

---

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.