The de-diagnosis of autism begins? And calcium channel blockers considered for ADHD, which type of ADHD and which blocker?

Stockholm – an autism diagnosis hotspot according to the psychologist Sebastian Lundström

Nordic countries often lead the way and after apparently over-diagnosing autism and ADHD they are now eager to de-diagnose it.

I received an article from the British Medical Journal which drew my attention.

Autism and ADHD de-diagnosing services could be rolled out in Sweden—should the US and UK follow suit?

Swedish authorities are considering requests for “de-diagnosis services” for autism and attention deficit/hyperactivity disorder (ADHD) from a new patient group: adults who no longer want their diagnosis.

The proposals come against the backdrop of an ongoing study on around 100 patients, all of whom joined the trial with the hope of getting their diagnostic labels removed. It could see de-diagnosis services rolled out in several of Sweden’s clinics in a matter of months, the study authors told The BMJ.

While “de-diagnosis” is gaining traction in Sweden, clinicians and patient groups who spoke to The BMJ were divided as to whether similar services should be set up in the UK or the US.

What is a de-diagnosis service?

The psychologist Sebastian Lundström, one of the study’s researchers, told The BMJ that his work on this new patient group was prompted by “the sheer number of people with these diagnoses who now are turning into adult age and being told that they can’t join the military services [or] the draft.”

Historically, Swedish citizens with an ADHD or autism diagnosis have been barred from joining the military or working as train drivers without a specific doctor’s note. They must also provide a medical certificate when applying for a driving licence.

At the Preventing Overdiagnosis Conference in Oxford earlier this month, Lundström said that diagnoses had been “assigned by well meaning clinicians” to an increasing number of Swedish children in recent years but that the label could often be “sticky.”

 

Preventing Overdiagnosis Conference in Oxford

In September 2025 there was a conference about overdiagnosis across a wide range of conditions, it was not just about autism and ADHD.

https://www.cebm.ox.ac.uk/preventing-overdiagnosis

But, it did have presentations like:

THE TIDAL WAVE OF ADHD AND AUTISM: INSIGHTS FROM PATIENTS, PROFESSIONALS AND PUBLIC HEALTH

 

Sebastian Lundström’s presentation is available on YouTube. It is very interesting for anyone interested in the skyrocketing level of autism diagnosis.

I have mentioned previously that since in schools in many Western countries more than 20% of kids are now seen as having special educational needs, do not be surprised if autism/ADHD rates eventually hit 20%.  ADHD does look like autism-lite to me and the genetic studies also back this up. So, expect that autism/ADHD reaches 20% of boys.

Now look at Stockholm.

It turns out that in Stockholm 5.9% of teenage boys now have an autism diagnosis and 15% have an ADHD diagnosis. Some will have both.

 

 

Here is the full video for those who think this must be a mistake, or that doctors in Stockholm have gone insane.

 

Now, much to psychiatrists' surprise, adult Swedes are coming forward and trying to delete their autism/ADHD diagnosis from their records. Being Sweden, everything is recorded centrally. In the first 100 cases that were re-evaluated 90% were found to have no symptoms of autism/ADHD. In the video Professor Lundström gives the reasons for the misdiagnosis. It ranges from the parents insisting to have one, to the doctor giving one so that the child can access extra help at school. In many European countries the diagnosis qualifies the child/parents for various social security payments.

There are some downsides in Sweden to be an adult with an autism/ADHD diagnosis. It can affect employment, driving, or securing insurance.

The subject of ADHD leads to the second half of this post. Here we reconnect with the theme of treatable ion channel dysfunctions that have become somewhat a hallmark of this blog.

  

Calcium channel blockers now considered for ADHD treatment

 Blood pressure drug could be a safer alternative for treating ADHD symptoms, finds study

Repurposing amlodipine, a commonly used blood pressure medicine, could help manage attention-deficit/ hyperactivity disorder (ADHD) symptoms, according to an international study involving the University of Surrey.

 

Here is the full study

 

Validation of L-type calcium channel blocker amlodipine as a novel ADHD treatment through cross-species analysis, drug-target Mendelian randomization, and clinical evidence from medical records

ADHD is a chronic neurodevelopmental disorder that significantly affects life outcomes, and current treatments often have adverse side effects, high abuse potential, and a 25% non-response rate, highlighting the need for new therapeutics. This study investigates amlodipine, an L-type calcium channel blocker, as a potential foundation for developing a novel ADHD treatment by integrating findings from animal models and human genetic data. Amlodipine reduced hyperactivity in SHR rats and decreased both hyperactivity and impulsivity in adgrl3.1−/− zebrafish. It also crosses the blood-brain barrier, reducing telencephalic activation. Crucially, Mendelian Randomization analysis linked ADHD to genetic variations in L-type calcium channel subunits (α1-C; CACNA1C, β1; CACNB1, α2δ3; CACNA2D3) targeted by amlodipine, while polygenic risk score analysis showed symptom mitigation in individuals with high ADHD genetic liability. With its well-tolerated profile and efficacy across species, supported by genetic evidence, amlodipine shows potential to be refined and developed into a novel treatment for ADHD.

 

This is not an entirely new finding, but prior research shows that crossing the blood barrier is a key factor. Drugs like Verapamil win over Amlodipine.

 

Brain-penetrant calcium channel blockers are associated with a reduced incidence of neuropsychiatric disorders 

Calcium channel blockers (CCBs) differ in their ability to penetrate into the brain. Pharmacoepidemiological studies suggest that CCBs as a class may have beneficial effects on the risks and outcomes of some psychiatric and neurological disorders. It is plausible but unknown whether this effect relates to their brain penetrance. To address this, we used the TriNetX electronic health records network to identify people prescribed a brain-penetrant CCB (BP-CCB), or those given amlodipine, a CCB with low brain penetrability. We created cohorts of patients who, prior to first CCB exposure, either had to have, or could not have had, a recorded ICD-10 diagnosis in any of the following categories: psychotic disorder; affective disorder (including bipolar disorder and major depressive disorder); anxiety disorder; substance use disorder; sleep disorder; delirium; dementia, or movement disorder. Cohort pairs were propensity score matched for age, sex, race, blood pressure, body mass index, and a range of other variables. The outcomes were the incidence of these disorders measured over a two-year exposure period. Matched cohort sizes ranged from 17,896 to 49,987. In people with no prior history of psychiatric or neurodegenerative disorder, there was a significantly lower incidence of most disorders with BP-CCBs compared to amlodipine, with risk ratios ranging from 0.64 to 0.88 and an overall risk ratio of 0.88, i.e. a risk reduction of 12%. In people who did have a prior psychiatric or neurodegenerative diagnosis, differences were much smaller, but again showed lower risks for several disorders with BP-CCBs compared to amlodipine. The differences were somewhat more marked in women and in people less than 60 years old. Results were similar when comparing BP-CCBs with verapamil and diltiazem. We also compared BP-CCBs with angiotensin receptor blockers, and found an overall risk ratio of 0.94 in favour of BP-CCBs, but with differential effects across disorders including a higher risk of psychotic disorder and dementia, but a lower risk for anxiety and sleep disorders. In some analyses, there was evidence of residual confounding even after the extensive matching, in that negative control outcomes showed a reduced incidence with BP-CCBs relative to the comparator cohort. In summary, CCBs that readily penetrate the brain are associated with a lower incidence of neuropsychiatric disorders, especially first diagnoses, compared to CCBs which do not. This may reflect their blockade of neuronal voltage-gated calcium channels. The findings encourage repurposing trials using existing BP-CCBs, and suggest that novel BP-CCBs with enhanced and more selective central actions might have greater therapeutic potential for psychiatric and neurodegenerative disorders.

  

Conclusion

I do not think de-diagnosis of autism/ADHD will catch on in the UK or US. Few countries have a centralized register of who has autism/ADHD and in general there are few downsides to adults holding a diagnosis, unlike in Sweden. If it affected your rights to drive a car and what you pay for insurance, there would be a long queue for de-diagnosis.

In the Swedish military conscription/assessment medical guidelines, autism spectrum disorders are listed among psychiatric/neurological conditions that can lead to exemption from service. Some patriotic young Swedes with autism/ADHD actually want to serve.

As conscription may return to other less patriotic European countries, you can expect an additional demand for adult autism diagnosis to avoid the draft!

When it comes to calcium channels, I think all bases have already been well covered in this blog.

I know of several different calcium and other channel blockers being used by readers, the latest being Journavx/suzetrigine, a new one approved in 2025, which blocks Nav1.8. Nicardipine is more likely to block Nav1.8 in the brain. Journavx was developed specifically to have poor CNS penetration to avoid central side effects. It targets acute pain situations where short-term opioid use would normally be considered. It all depends which Nav1.8 channels you want to block. But, if the blood brain barrier is impaired (as we know it is in certain types of autism) then more of the drug will enter the brain than expected.

An impaired blood brain barrier would also help Amlodipine to cross.

 

Regular readers of this blog will already know that calcium channels are dysfunctional across a wide range of disorders from bipolar, schizophrenia, autism, intellectual disability to epilepsy.

I was nonetheless surprised that a university in the United Kingdom would propose repurposing Amlodipine (an L type calcium channel blocker) to treat ADHD. Even if they are mistaken, at least they are showing signs of curiosity!

There is no single perfect calcium channel blocker for the brain.

If you want to target Cav1.2 you have a great option in Verapamil, because it is relatively selective for this channel and it crosses the blood brain barrier easily.

If you want to target Cav1.2 and Cav1.3 then Amlodipine appears the best drug, but it does not cross the blood brain barrier as well as Verapamil.

I think the ADHD researchers should start with Cav1.2, because we know 100% it can be blocked in the brain using Verapamil. Then compare the result with taking Amlodipine.

 

Pleiotropic Association of CACNA1C Variants With Neuropsychiatric Disorders

 

From this blog we know that both verapamil and amlodipine can be safely used in autism. A small number of people do have side effects and discontinue, but most do not have issues.

The effect of the two drugs overlap but are not identical. This matches what we know about what channels they block. Verapamil also has other effects:

·        Verapamil partially blocks Cav1.3

·        Verapamil partially blocks T-type channels (Cav3.1–3.3) particularly at higher doses.

·        Verapamil partially blocks potassium Kv channels.

The big advantage of Amlodipine is that it has a long half-life, so you take it once a day.

Verapamil needs to be taken 3 times a day, or in the extended release version.

I did look on Reddit and plenty of people with ADHD were commenting that taking Amlodipine for high blood pressure had not improved their ADHD symptoms.

Note that ADHD is another umbrella diagnosis and there will be many sub-types. For some people Amlodipine might well help. For some people ADHD is just a consequence of being glued to a smartphone all day, every day, for years on end. Guess what, 60% of adults with ADHD report chronic sleep problems.

The over liberal diagnosis of autism in Stockholm does look crazy. Maybe it is the Greta effect?

It is as if Stockholm has developed a new version of the old “Stockholm syndrome” — an emotional loyalty to the very diagnostic culture now being questioned. When 90% of adults seeking de-diagnosis are found not to have autism or ADHD, it suggests that what began as a well-meaning effort to help children may have trapped an entire system in its own narrative. Fancy that.

 

(The term “Stockholm syndrome” comes from a 1973 bank robbery in Stockholm, when hostages ended up sympathising with their captors — a classic case of misplaced loyalty.)

 

From Conception to Early Childhood: Managing pain, fever, and neurodevelopmental risk. Time to apply some common sense? Time for NAC?

 

Donald Trump recently reignited debate about Tylenol (paracetamol/acetaminophen) in pregnancy. His comments drew attention to research linking prenatal use to higher rates of autism and ADHD.

A large review of 46 studies, including work from Harvard, found consistent associations between paracetamol in pregnancy and neurodevelopmental risks. The FDA now advises caution: use the lowest dose for the shortest time.

 

Tylenol in pregnancy linked to higher autism risk, Harvard scientists report

Researchers reviewing 46 studies found evidence linking prenatal acetaminophen (Tylenol) exposure with higher risks of autism and ADHD. The FDA has since urged caution, echoing scientists’ advice that the drug be used only at the lowest effective dose and shortest duration. While important for managing fever and pain in pregnancy, prolonged use may pose risks to fetal development. Experts stress careful medical oversight and further investigation.

 Why the concern?

• Paracetamol depletes glutathione (GSH), the body’s main antioxidant.
• This raises oxidative stress in both mother and fetus.
• The fetus has weak antioxidant defences, so damage may occur during critical brain development.

But here is the dilemma: the fever, pain, or inflammation that drives a mother to take paracetamol is itself risky. We have long known from maternal immune activation models that fever and cytokine surges in pregnancy can disturb fetal brain development and cause autism or schizophrenia. There is also evidence linking maternal immune activation to ADHD in the offspring.

So, what is the solution? Pair paracetamol with NAC.

Why NAC?

• NAC (N-acetylcysteine) is a precursor to glutathione.
• It’s used worldwide in emergency rooms to save lives after paracetamol/ acetaminophen overdose.
• In pregnancy, NAC has been shown to reduce miscarriage risk by 50%,

N-acetyl cysteine for treatment of recurrent unexplained pregnancy loss

• Increased pregnancy continuation: Women receiving NAC and folic acid were 2.9 times more likely to continue their pregnancies beyond 20 weeks compared to those receiving folic acid alone
• Higher take-home baby rate: The NAC group had a 1.98 times higher rate of delivering a live baby.
• These findings suggest that NAC, an antioxidant, may help mitigate oxidative stress, a factor implicated in pregnancy loss.

  

A combined Paracetamol/acetaminophen + NAC pill would:

• Prevent liver toxicity,
• Buffer oxidative stress in the fetus,
• Eliminate the overdose suicide risk that haunts current paracetamol use.

So far, no company has produced it. Perhaps the “rotten egg” smell of NAC is a barrier—but solid sustained-release tablets avoid this.

 

Why Paracetamol/acetaminophen use is problematic in under 5s

Paracetamol depletes glutathione (GSH), the body’s primary antioxidant, increasing oxidative stress. A fetus with some genetic predispositions might already be in a state of oxidative stress, as might the mother

Paracetamol is mainly metabolized in the liver. A small fraction is metabolized into NAPQI — a reactive toxic metabolite. Glutathione (GSH) neutralizes NAPQI by forming a harmless conjugate.

If GSH stores are low (or paracetamol is taken in high doses), NAPQI accumulates, causing liver toxicity and GSH is exhausted raising oxidative stress.

Acute oxidative stress can be very damaging to developing brains. The risk after 5 years old fades away, other than in those who have already exhibited a profound metabolic/mitochondrial condition.

Why Oxidative Stress Rises in Pregnancy

Placental development: Early pregnancy is low-oxygen; as blood flow increases, oxygen surges and generates reactive oxygen species (ROS).

High metabolic demand: The mother and placenta require much more energy, leading to increased mitochondrial ROS.

Immune adaptations: Pregnancy involves a shift in maternal immunity, with inflammatory cytokines contributing to oxidative stress.

Fetal growth: Rapid cell division and organ development naturally produce oxidative byproducts, while the fetus’s antioxidant defenses are immature.

Limited antioxidant reserves: Maternal antioxidants (glutathione, vitamins C & E, enzymes) are partly depleted as pregnancy progresses.

 

Compounding Risk Factors

Polycystic Ovary Syndrome (PCOS): Associated with high androgens, insulin resistance, and chronic inflammation. These increase oxidative stress and are linked to higher autism risk in offspring.

Gestational Diabetes: Maternal hyperglycemia and insulin resistance increase ROS, damage the placenta, and expose the fetus to oxidative and metabolic stress.

Other amplifiers: Obesity, infection, fever, or poor nutrition further elevate oxidative stress.

 

How Oxidative Stress Affects the Fetus

Neurodevelopmental disruption: ROS can damage neural stem cells, impair migration, and disturb synapse formation.

Epigenetic reprogramming: Oxidative stress alters DNA methylation and gene expression, shaping long-term brain function.

Immune activation: Inflammatory cytokines cross the placenta and disturb fetal brain development.

Mitochondrial dysfunction: ROS damage fetal mitochondria, reducing energy for developing neurons.

Neurotransmitter imbalance: Antioxidant depletion disrupts glutamate/GABA balance and monoamine systems.

 

Consequences for the Unborn Child

Most pregnancies manage oxidative stress without harm, thanks to maternal–fetal antioxidant defences.

When oxidative stress overwhelms these defences—especially in mothers with PCOS, GDM, or infections—the risk of complications rises:

Preterm birth, growth restriction, or preeclampsia

Higher vulnerability to neurodevelopmental disorders, including autism spectrum disorder (ASD) and ADHD.

Genetic predispositions in antioxidant or mitochondrial pathways may make some fetuses especially sensitive to these oxidative challenges.

Pregnancy naturally involves a controlled increase in oxidative stress, but when combined with maternal conditions like PCOS, gestational diabetes, or acute infections, the oxidative burden can exceed protective capacity. This imbalance may impair placental function and fetal brain development, increasing the risk of adverse outcomes, including autism. 

 

Pregnancy: Choosing safer options for pain and fever

• Paracetamol → Remains the best option if pain relief is absolutely needed, but should be paired with NAC.
• NSAIDs (ibuprofen, mefenamic acid) → Unsafe in later pregnancy due to fetal kidney damage and premature closure of the ductus arteriosus. Premature closure of the ductus arteriosus is a serious condition that occurs when the fetal blood vessel connecting the pulmonary artery to the aorta closes before birth. Do not use NSAIDs!
• NAC supplementation → Low-cost, safe, and evidence-backed for reducing oxidative stress.

 

Infancy and Early Childhood

• Paracetamol
• Licensed from birth.
• Effective for pain and fever, but still depletes glutathione.
• In at-risk infants (metabolic or mitochondrial issues), consider pairing with NAC.
• NSAIDs (ibuprofen, Ponstan)
• Suitable from 3–6 months (depending on guidelines).
• Do not deplete glutathione, making them safer for oxidative stress.
• Hydration matters to protect kidneys.

 

Vaccinations, Fever, and Oxidative Stress

Vaccines work by briefly activating the immune system. This triggers a short burst of oxidative stress—far smaller than that caused by actual infections.

• Healthy children clear this easily.
• At-risk children (mitochondrial disease, metabolic errors, weak antioxidant systems) may struggle, leading to fatigue, regression-like symptoms, or metabolic instability.

Medication choices around vaccines

• NSAIDs → Good for post-vaccine fever. Avoid routine pre-dosing to prevent dampening immunity, unless the child is in the at-risk group.
• Paracetamol → Pre-vaccine dosing can reduce antibody production and reduce GSH. Post vaccine should be paired with NAC.
• Montelukast → Anti-inflammatory, theoretically helpful in at-risk children, but not tested in trials, but is used at metabolic/mitochondrial clinics treating children.
• NAC → Biologically plausible support for antioxidant status, though not studied formally in this setting.

Mainstream pediatrics avoids routine prophylactic anti-inflammatories, but some specialists (e.g., Dr. Kelley, Johns Hopkins) do use them selectively in fragile children. Using paracetamol without NAC is a bad idea.

 

Metabolic Decompensation: The Hidden Risk

Some children with mitochondrial or metabolic disorders cannot handle stress from fever or illness. This can trigger:

• Energy failure (low ATP)
• Accumulation of toxic metabolites (lactate, ammonia)
• Seizures or regression

In developing brains, these crises can leave permanent autism-like features and/or intellectual disability. These symptoms are secondary to brain injury. Prevention is key:

• Hydration, glucose support
• Early fever control
• Antioxidant support (NAC, vitamins C & E)

 

Key Takeaways

• Pregnancy: If pain relief is needed, paracetamol + NAC is safer than paracetamol alone. Avoid NSAIDs.
• Infancy: Paracetamol is widely used, but NSAIDs are safer from 3 months onward when oxidative stress is a concern.
• Vaccination: Vaccines prevent far greater oxidative stress from infections. At-risk children may benefit from antioxidant or anti-inflammatory support, but this should be individualized.
• Metabolic decompensation: Recognize and prevent crises in vulnerable children—this reduces risk of secondary neurodevelopmental injury.

 

Conclusion

Paracetamol has been trusted for decades, but its link with oxidative stress and neurodevelopmental risk is becoming harder to ignore. A Paracetamol + NAC pill makes both medical and common sense—safer for mothers, safer for children, and suicide-proof.

Until then, thoughtful use of NAC, NSAIDs, and tailored fever management could make a real difference in protecting brain development from conception through early childhood.

 

My original draft post was rather long, so here is the “optional” part 2, for any avid readers out there!

 

 

Part 2: Vaccines, Oxidative Stress, and Children at Risk

Why some kids may react differently — and what parents and clinicians can do

Vaccines are one of the greatest public health achievements, protecting children from infections that would otherwise cause significant illness, hospitalization, or death. But for children with mitochondrial disorders, metabolic diseases, or weak antioxidant systems, even routine vaccination can temporarily stress the body.

How Vaccines Trigger Oxidative Stress

• Vaccination works by activating the immune system, prompting cytokine release, mild inflammation, and reactive oxygen species (ROS) production.
• In healthy children, this burst is short-lived. Antioxidant defences like glutathione, superoxide dismutase, and dietary vitamins C & E neutralize ROS quickly.
• In children with mitochondrial or metabolic vulnerabilities, baseline ROS is already elevated, and antioxidant defences may be limited. A small extra load from vaccination can feel disproportionately stressful.

 

Why Some Children React Differently

Mitochondrial Disorders

• Mitochondria produce ATP and ROS. Dysfunction means higher baseline oxidative stress and lower energy reserves.
• A vaccine-induced oxidative spike can linger longer, leading to fatigue, metabolic stress, or regression-like symptoms.

Metabolic Disorders

• Children with amino acid, fatty acid, or urea cycle defects have limited antioxidant capacity.
• ROS accumulation may overwhelm defences, causing secondary mitochondrial stress or toxic metabolite build-up.

Genetic Variants

• Some children carry variants that reduce glutathione production or antioxidant enzyme activity (e.g., GSTM1/GSTT1 deletions, MTHFR variants, impaired SOD/catalase).
• Even minor oxidative challenges can temporarily disturb synapse formation, neurotransmitter balance, and myelination in the developing brain.

 

Medications Around Vaccination

NSAIDs

• Symptom-driven use for fever or pain post-vaccine is generally safe.
• Routine prophylactic use is usually avoided because it can reduce antibody responses, but specialists consider this is likely minimal

Paracetamol

• Pre-vaccine dosing can modestly blunt antibody formation in some vaccines and is unwise because it reduces GSH just before it will be needed most.
• Post-vaccine, symptom-driven use is often considered safe, but is unwise due to the ruction in GSH when needed most
• High-risk children should always avoid paracetamol unless paired with NAC to protect glutathione and limit oxidative stress.

NAC (N-acetylcysteine)

• Biologically plausible support for antioxidant status in at-risk children.
• Safely used during pregnancy and by babies
• Not yet studied in formal vaccine trials, but safe and used in clinical settings for other oxidative stress conditions.

Montelukast

• Anti-inflammatory, may reduce oxidative stress, but not proven for vaccine prophylaxis.
• Used by children at vaccination time when already prescribed it for asthma/allergic disease.

 

Managing Vaccination in At-Risk Children

1.     Ensure good hydration, feeding, and metabolic stability before vaccination.

2.     Monitor closely for post-vaccine fever, fatigue, or regression-like symptoms.

3.     Have supportive measures ready:

o    NAC or other antioxidant support

o    Symptom-driven NSAIDs

o    Avoid paracetamol unless paired with NAC

o    Quick access to a specialist if metabolic stress occurs

 

Takeaways for Parents and Clinicians

• Vaccines do cause a small, transient oxidative stress, but it is far less than the oxidative burden from infections.
• Children with mitochondrial or metabolic vulnerabilities may need extra care before and after vaccination.
• NAC, hydration, symptom-driven NSAIDs, and careful monitoring can reduce risk without compromising immunity.
• Always coordinate with a metabolic or mitochondrial specialist when planning vaccination for high-risk children.

By understanding oxidative stress, supporting antioxidant defences, and tailoring care, parents and clinicians can protect both immunity and neurodevelopment.

Since most parents, in reality, do not have access a mitochondrial specialist it pays to do your homework in advance. All the needed resources are in plain view.

You do wonder why nobody makes a combined Paracetamol/acetaminophen + NAC pill.

Such a pill is perfect for pregnant women.

Nobody would be able to commit suicide with this pill. This pill blocks the harmful effect on the liver that ultimately can lead to death.

NAC does smell of rotten eggs. One argument against such a pill is that it would stink and pregnant women are often feeling nausea. If the pill is solid (like NAC Sustain) there is no smell of rotten eggs. So you certainly can have a combined pill.

Personally, I would ban all liquid formulations of Paracetamol, other than for babies under 3 months. Many countries have long used exclusively Ibuprofen or Ponstan for children. Once a child is 5 years old the potential for paracetamol to do neurodevelopmental harm should have faded.

You can give babies NAC, it is sold in a liquid form for this purpose. NAC acts as a mucolytic, meaning it thins mucus in the airways.

How common is Metabolic Decompensation as a cause of severe autism? We know it exists, but I think we will never know how common it is. Hannah Poling is the best-known example. Evidence of an inconvenient truth.

 

TRH and Rifaximin – an alternative to intranasal TRH or oral Taltirelin/Ceredist?

I think this is going to be one of my smarter posts. It may be more for our doctor readers and our motivated home-based researchers. It does remain a hypothesis and while it looks plausible it is certainly not 100% proven – so typical Peter stuff.

Many parents with autism regularly treat their child with the antibiotic Rifaximin. This drug is also the go-to therapy for SIBO (small intestine bacterial overgrowth) and is a key part of the Nemechek autism protocol to increase butyric acid production in the gut (and reduce propionic acid).

Some parents report that their child with completely normal GI function responds well behaviorally to Rifaximin.

Rifaximin is taken orally and stays in the gut, it does not enter the blood stream.

Our long-time reader Maja mentioned that she still uses Rifaximin in her now adult daughter.

I then did a quick Google and was surprised to see Rifaximin linked to the hormone TRH.

And, most surprising, you can use Rifaximin to treat prostate inflammation, via its effect on TRH.

TRH was the subject of an experiment I did 12 years ago. I suggested that an existing Japanese drug, an orally available TRH super-agonist, could be repurposed at a low dose to treat autism.

 https://www.epiphanyasd.com/2014/05/the-peter-hypothesis-of-trh-induced.html

I then noted that a well-known, but a little controversial, doctor in the US used intranasal TRH to treat his patients with chronic fatigue syndrome.

Another doctor had grant funding from the US military to develop intranasal TRH to reduce suicides in veterans.

In my old post I started by wondering why my son and some others with severe autism respond so well to sensory stimulation like standing on the upper deck of a ferry boat in the open sea on a windy day, or sitting in an open-top bus, driving in a convertible car etc.

Without be able to do any testing I looked for “similar” situations that haven been studied. The closest I found was people jumping out of a plan (with a parachute) where one of the key changes was a surge in the level of the hormone prolactin.

How to replicate the open-top bus effect? One of my doctor relatives suggested sitting Monty in front of a fan. Over course I wanted better than that. I found that stimulating TRH receptors in the brain would release prolactin.  It was already known that TRH is disturbed in autism.

It seemed to me that a Japanese orphan drug developed to treat spinocerebellar degeneration (SCD) – a group of progressive neurodegenerative disorders characterized by ataxia (poor coordination, gait disturbance, speech difficulties) could be repurposed.

I did discuss with a Japanese doctor in Osaka and he prescribed it.

It is a very expensive drug, even when bought with a prescription, and it has a very short expiry date. The idea was to use a micro-dose, to avoid undesirable side effects and this would also make the price less scary. I thought it provided a benefit without side effects, but was impractical. At the full dose it is potent and is the only drug I have trialed that had a near immediate profound effect on myself. I suddenly had hyper-acute vision. The micro dose had no effect on me.

Since Ceredist (taltirelin) is a TRH analogue, it could in theory affect the hypothalamic–pituitary–thyroid (HPT) axis.

TRH normally stimulates TSH release from the pituitary, which then increases thyroid hormone (T4/T3) secretion. Taltirelin was designed for CNS activity rather than endocrine use. Its clinical development in Japan for spinocerebellar degeneration focused on neurological symptoms, not thyroid stimulation. Animal studies showed that taltirelin has much weaker TSH-releasing activity than native TRH, but much stronger central nervous system stimulant effects (improved motor coordination, wakefulness).

Human data at therapeutic doses for spinocerebellar degeneration, significant changes in thyroid hormone levels (TSH, T3, T4) have not been a common clinical issue. Monitoring thyroid function is not part of standard Ceredist treatment.

 

So what is TRH?

TRH (thyrotropin-releasing hormone) serves as a master regulator of energy metabolism, mood, arousal, cognition, and immune balance.

Core Endocrine Role

Produced in the hypothalamus (paraventricular nucleus), but also found in other brain regions and peripheral tissues.

Main function is to stimulate the anterior pituitary to release TSH (thyroid-stimulating hormone), this increases thyroid hormone (T3, T4) production in the thyroid gland.

A secondary effect promotes prolactin release from the pituitary. TRH is a significant stimulator, especially when dopamine inhibition is reduced.

 

Effects on Other Hormones

Growth hormone & insulin: Some modulatory effects reported in stress and metabolism, though less central.

ACTH/cortisol: Minor indirect effects; TRH can modulate stress responses via cross-talk with the HPA axis.

 

Mood and Behavior

Antidepressant effects - TRH has rapid mood-elevating and activating effects in both animals and humans, independent of thyroid hormones. Some clinical studies have tested TRH or TRH analogs as rapid-acting antidepressants.

Arousal & vigilance - it increases wakefulness, motivation, and locomotor activity.

Anxiety - can produce mild anxiogenic effects at high doses, but generally associated with improved mood and alertness.

 

Cognition

Neurotransmitter modulation - TRH interacts with cholinergic, dopaminergic, and glutamatergic systems.

Memory & learning - TRH and TRH-like peptides enhance memory consolidation and counteract cognitive decline in animal studies.

Neuroprotection - shown to reduce neuronal injury in models of ischemia and trauma.

 

Inflammation & Immunity

 Anti-inflammatory - TRH dampens pro-inflammatory cytokine production (e.g., TNF-α, IL-1β).

Microglia modulation - TRH reduces microglial over-activation, relevant in neuroinflammation.

Systemic effects: TRH analogs show protective roles in sepsis and multiple organ injury in animal studies, likely via immune regulation and mitochondrial support.

 

Here is the recent study that showed the common antibiotic Rifaximin increases TRH in the brain and in peripheral tissues. Rifaximin itself stays within the gut when taken by mouth, it does not enter the blood stream. It changes the gut microbiota which then sends a signal via vagus nerve to the brain (clever, isn’t it?).

Caveat – rats are not humans.

 

Rifaximin modulates TRH and TRH-like peptide expression throughout the brain and peripheral tissues of male rats

 

The TRH/TRH-R1 receptor signaling pathway within the neurons of the dorsal vagal complex is an important mediator of the brain-gut axis. Mental health and protection from a variety of neuropathologies, such as autism, Attention Deficit Hyperactivity Disorder, Alzheimer’s and Parkinson’s disease, major depression, migraine and epilepsy are influenced by the gut microbiome and is mediated by the vagus nerve. The antibiotic rifaximin (RF) does not cross the gut-blood barrier. It changes the composition of the gut microbiome resulting in therapeutic benefits for traveler’s diarrhea, hepatic encephalopathy, and prostatitis. TRH and TRH-like peptides, with the structure pGlu-X-Pro-NH₂, where “X” can be any amino acid residue, have reproduction-enhancing, caloric-restriction-like, anti-aging, pancreatic-β cell-, cardiovascular-, and neuroprotective effects. TRH and TRH-like peptides occur not only throughout the CNS but also in peripheral tissues. To elucidate the involvement of TRH-like peptides in brain-gut-reproductive system interactions 16 male Sprague–Dawley rats, 203 ± 6 g, were divided into 4 groups (n = 4/group): the control (CON) group remained on ad libitum Purina rodent chow and water for 10 days until decapitation, acute (AC) group receiving 150 mg RF/kg powdered rodent chow for 24 h providing 150 mg RF/kg body weight for 200 g rats, chronic (CHR) animals receiving RF for 10 days; withdrawal (WD) rats receiving RF for 8 days and then normal chow for 2 days.

Results

Significant changes in the levels of TRH and TRH-like peptides occurred throughout the brain and peripheral tissues in response to RF. The number of significant changes in TRH and TRH-like peptide levels in brain resulting from RF treatment, in descending order were: medulla (16), piriform cortex (8), nucleus accumbens (7), frontal cortex (5), striatum (3), amygdala (3), entorhinal cortex (3), anterior (2), and posterior cingulate (2), hippocampus (1), hypothalamus (0) and cerebellum (0). The corresponding ranking for peripheral tissues were: prostate (6), adrenals (4), pancreas (3), liver (2), testis (1), heart (0).

Conclusions

The sensitivity of TRH and TRH-like peptide expression to RF treatment, particularly in the medulla oblongata and prostate, is consistent with the participation of these peptides in the therapeutic effects of RF. 

 

It turns out that other researchers have looked at Rifaximin’s effects on the brain, but they never understood the mechanism.

 

Effects of Rifaximin on Central Responses to Social Stress—a Pilot Experiment

Probiotics that promote the gut microbiota have been reported to reduce stress responses, and improve memory and mood. Whether and how antibiotics that eliminate or inhibit pathogenic and commensal gut bacteria also affect central nervous system functions in humans is so far unknown. In a double-blinded randomized study, 16 healthy volunteers (27.00 ± 1.60 years; 9 males) received either rifaximin (600 mg/day) (a poorly absorbable antibiotic) or placebo for 7 days. Before and after the drug intervention, brain activities during rest and during a social stressor inducing feelings of exclusion (Cyberball game) were measured using magnetoencephalography. Social exclusion significantly affected (p < 0.001) mood and increased exclusion perception. Magnetoencephalography showed brain regions with higher activations during exclusion as compared to inclusion, in different frequency bands. Seven days of rifaximin increased prefrontal and right cingulate alpha power during resting state. Low beta power showed an interaction of intervention (rifaximin, placebo) × condition (inclusion, exclusion) during the Cyberball game in the bilateral prefrontal and left anterior cingulate cortex. Only in the rifaximin group, a decrease (p = 0.004) in power was seen comparing exclusion to inclusion; the reduced beta-1 power was negatively correlated with a change in the subjective exclusion perception score. Social stress affecting brain functioning in a specific manner is modulated by rifaximin. Contrary to our hypothesis that antibiotics have advert effects on mood, the antibiotic exhibited stress-reducing effects similar to reported effects of probiotic

 

Effects of the antibiotic rifaximin on cortical functional connectivity are mediated through insular cortex

It is well-known that antibiotics affect commensal gut bacteria; however, only recently evidence accumulated that gut microbiota (GM) can influence the central nervous system functions. Preclinical animal studies have repeatedly highlighted the effects of antibiotics on brain activity; however, translational studies in humans are still missing. Here, we present a randomized, double-blind, placebo-controlled study investigating the effects of 7 days intake of Rifaximin (non-absorbable antibiotic) on functional brain connectivity (fc) using magnetoencephalography. Sixteen healthy volunteers were tested before and after the treatment, during resting state (rs), and during a social stressor paradigm (Cyberball game—CBG), designed to elicit feelings of exclusion. Results confirm the hypothesis of an involvement of the insular cortex as a common node of different functional networks, thus suggesting its potential role as a central mediator of cortical fc alterations, following modifications of GM. Also, the Rifaximin group displayed lower connectivity in slow and fast beta bands (15 and 25 Hz) during rest, and higher connectivity in theta (7 Hz) during the inclusion condition of the CBG, compared with controls. Altogether these results indicate a modulation of Rifaximin on frequency-specific functional connectivity that could involve cognitive flexibility and memory processing.

  

Probing gut‐brain links in Alzheimer's disease with rifaximin

Gut‐microbiome‐inflammation interactions have been linked to neurodegeneration in Alzheimer's disease (AD) and other disorders. We hypothesized that treatment with rifaximin, a minimally absorbed gut‐specific antibiotic, may modify the neurodegenerative process by changing gut flora and reducing neurotoxic microbial drivers of inflammation. In a pilot, open‐label trial, we treated 10 subjects with mild to moderate probable AD dementia (Mini‐Mental Status Examination (MMSE) = 17 ± 3) with rifaximin for 3 months. Treatment was associated with a significant reduction in serum neurofilament‐light levels (P < .004) and a significant increase in fecal phylum Firmicutes microbiota. Serum phosphorylated tau (pTau)181 and glial fibrillary acidic protein (GFAP) levels were reduced (effect sizes of −0.41 and −0.48, respectively) but did not reach statistical significance. In addition, there was a nonsignificant downward trend in serum cytokine interleukin (IL)‐6 and IL‐13 levels. Cognition was unchanged. Increases in stool Erysipelatoclostridium were correlated significantly with reductions in serum pTau181 and serum GFAP. Insights from this pilot trial are being used to design a larger placebo‐controlled clinical trial to determine if specific microbial flora/products underlie neurodegeneration, and whether rifaximin is clinically efficacious as a therapeutic.

 

Rifaximin and the prostate

For some reason one of the main areas where Rifaximin triggers the production of TRH is in the prostate, in males. There are studies showing how Rifaximin can be used to treat prostatitis (prostate inflammation).

Symptom Severity Following Rifaximin and the Probiotic VSL#3 in Patients with Chronic Pelvic Pain Syndrome (Due to Inflammatory Prostatitis) Plus Irritable Bowel Syndrome

This study investigated the effects of long-term treatment with rifaximin and the probiotic VSL#3 on uro-genital and gastrointestinal symptoms in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) plus diarrhoea-predominant irritable bowel syndrome (D-IBS) compared with patients with D-IBS alone. Eighty-five patients with CP/CPPS (45 with subtype IIIa and 40 with IIIb) plus D-IBS according to the Rome III criteria and an aged-matched control-group of patients with D-IBS alone (n = 75) received rifaximin and VSL#3. The primary endpoints were the response rates of IBS and CP/CPPS symptoms, assessed respectively through Irritable Bowel Syndrome Severity Scoring System (IBS-SSS) and The National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI), and performed at the start of therapy (V0) and three months after (V3). In IIIa prostatitis patients, the total NIH-CPSI scores significantly (p < 0.05) decreased from a baseline mean value of 21.2 to 14.5 at V3 , as did all subscales, and in the IIIb the total NIH-CPSI score also significantly decreased (from 17.4 to 15.1). Patients with IBS alone showed no significant differences in NIH-CPSI score. At V3, significantly greater improvement in the IBS-SSS and responder rate were found in IIIa patients. Our results were explained through a better individual response at V3 in IIIa prostatitis of urinary and gastrointestinal symptoms, while mean leukocyte counts on expressed prostate secretion (EPS) after prostate massage significantly lowered only in IIIa cases. 

Since SIBO is treated by rifaximin, some researchers linked SIBO with prostatitis: 

Chronic prostatitis and small intestinal bacterial overgrowth: is there a correlation?

Background: Clinical management of chronic inflammation of prostate and seminal vesicles is very complex. Among the causes of recurrent chronic prostatitis (CP), a possible malabsorption, such as lactose intolerance, in turn related to small intestinal bacterial overgrowth (SIBO), should be considered.

Methods: We have performed lactose and lactulose breath test (BT) in 42 patients with CP, in order to evaluate the prevalence of SIBO in this kind of patients and the concordance of the two tests.

Results: A positive lactulose BT was present in 33/42 patients and in 73% (24/33) was associated to lactose malabsorption. Five patients had positive response after lactulose, while only 4 had both negative tests.

Conclusions: Our data showed an association between lactose and lactulose BT positivity. They also indicated high prevalence of bacterial colonization of small bowel in patients with CP, possibly related to recurrence or chronicity of genitourinary tract inflammation. The research for these phenomena could be relevant in diagnostic route of infertile patients in whom slight gastro-enteric symptoms can be underestimated.

 

For those of you who still read books:

 

Betrayal by the Brain: The Neurologic Basis of Chronic Fatigue Syndrome, Fibromyalgia Syndrome, and Related Neural Network Disorders
This seminal work presents Dr. Goldstein's theory that CFS and fibromyalgia result from dysfunctions in neural networks. It integrates neuroscience research into the pathophysiology and treatment of these conditions.

A Companion Volume to Dr. Jay A. Goldstein's Betrayal by the Brain: A Guide for Patients and Their Physicians
Authored by Katie Courmel, this companion guide simplifies Dr. Goldstein's theories and treatment protocols for a broader audience, aiding patients and physicians in understanding and applying his methods.

 Tuning the Brain: Principles and Practice of Neurosomatic Medicine

In this book, Dr. Goldstein outlines the principles of neurosomatic medicine, a field he developed that combines neurology, psychiatry, and pharmacology to treat chronic illnesses.

In Tuning the Brain: Principles and Practice of Neurosomatic Medicine, Dr. Jay A. Goldstein discusses the use of thyrotropin-releasing hormone (TRH) in treating chronic fatigue syndrome (CFS) and related disorders. He describes TRH as a neuropeptide that can modulate neural network activity, particularly through the trigeminal nerve, which is involved in sensory processing. By stimulating this pathway, TRH may help "re-tune" the brain's response to sensory input, potentially alleviating symptoms associated with CFS and similar conditions.

The book outlines the principles of neurosomatic medicine, a field Dr. Goldstein developed that combines neurology, psychiatry, and pharmacology to treat chronic illnesses. It emphasizes the rapid modulation of neural networks through pharmacological means, aiming to restore normal sensory processing and alleviate symptoms.

 

Conclusion

It does look like Rifaximin has interesting effects beyond where it can reach itself.

Rifaximin → modifies gut microbiota → activates vagus nerve

Vagus nerve → signals to brainstem → hypothalamus → TRH release 

According to that rat study, TRH and TRH-like peptides are present in the prostate, and their levels change in response to rifaximin. The TRH (or TRH-like peptides) in the prostate is produced locally in the prostate tissue itself, not delivered there from the brain via the bloodstream. the level of production can be modulated by gut–brain signaling, such as after rifaximin treatment.

I have to say that this reminds me of using L-Reuteri probiotic bacteria to send a signal via the same vagus nerve to release oxytocin in the brain. Seems a better approach than intranasal oxytocin.

I think the study showing Rifaximin improves the response to social stress fits with Dr Goldstein’s use of intranasal TRH to “retune” the brain in the conditions he studied and the potential use to reduce suicide initiations. It is enough for me to see TRH as a possible common factor.

I think Goldstein and the US DoD scientists should have used the TRH super-agonist Taltirelin/Ceredist. It is 30x more potent and yet does not affect thyroid function. It also has a far longer half-life. The other alternative, we now see, would have been to use Rifaximin.

Goldstein has passed away and the US DoD gave upon TRH. Research indicates that intranasal esketamine can rapidly reduce suicidal thoughts. Esketamine was FDA approved in 2019.

Taltirelin was approved for use in humans in Japan in 2000 for spinocerebellar degeneration (SCD).

Note that spinocerebellar degeneration (SCD) has no drug therapy in the US/Europe, even though one has existed in Japan for 25 years. Looks pretty odd to me. In a perfect world low dose Taltirelin could be a useful add-on therapy for many neurological conditions and potentially even for prostatitis! Don’t hold your breath.

Taltirelin is now being researched in animal models of Parkinson’s and fatigue syndromes.

Unless you live in Japan and have a pal who is a doctor, I think autism parents are best off with Rifaximin.

As Maja just pointed out “Rifaximin is still very helpful. I repeat a ten-day course (2x400 mg) every two to three months”, in her adult daughter. We can never know for sure if increased TRH is mechanism, or reduced SIBO, or increased butyric acid, or something else. If it works, stay with it!