“The treatment didn’t fail, the trial did.” Here we go again with Memantine

They are all pizza, but each slice (sub-group) is very different. Only one has pepperoni 😋 and that’s the one memantine helps!

Older regular readers will be familiar with the large, well-funded trial that started a decade ago of Memantine/Nameda for autism. It had been a widely used off-label therapy for autism in the US. The regulator asked the producer to fund a large clinical trial.

The trial failed because Memantine was shown to be no more beneficial than the placebo. That trial had 400 participants and really should have been able to identify any large sub-groups that did respond. But, it did not.

I saw that a new Memantine trial has just been published, and guess what, they found that Memantine was beneficial and they used a special kind of MRI to try and identify that sub-population.

What struck me was the type of autism population they used to make the trial. You can look at IQ, comorbid diagnosis and even what other drugs the trial subjects are already on.

Here are some stand outs:

·        The average IQ in the placebo group was 110. That is top 25% by IQ.

·        Three quarters have ADHD and multiple anxiety disorders.

·        More than half have major depression.

·        In the treatment group 20% have psychosis.

That has very little in common with my son’s presentation of “autism.”

I think it would have been better to summarise this as a trial of Aspies with ADHD, who are also likely to be very unhappy.  That is a very valid treatment group, but the word autism does not fully capture it. These could be described as “lost souls.” 

The 2025 JAMA trial shows that memantine is not a failure for autism — it’s effective for a biologically distinct, high-glutamate subgroup, often corresponding to high-IQ, emotionally dysregulated “Lost Souls” autism.

My blog was always targeted at severe types of autism, but many of the messages I receive are from people with normal to high IQ, fully verbal but deeply troubled.

You can slice the autism pizza however you like. Here are some possible slices:

·        Classic autism / Profound autism / Kanner’s autism

·        Lost souls

·        Quirky autism, Aspies, some super-brainy, but most not

·        Sub-threshold autism, self-diagnosed autism, attention-seeking diagnosis

Back to the recent trial

·        All Memantine responders had high glutamate levels, and 80% of participants with  high glutamate levels were memantine responders. 

·        Notably, the abnormally high levels of glutamate were not universal but were limited to 54.0% (n = 20 of 37) of participants with ASD 

So applying some common sense:

·        Half of “Lost souls” autism (high IQ) are likely to have high glutamate when measured in the special MRI

·        80% with this biomarker are likely to find their social impairments are reduced by Memantine. 

Hurrah !!!!  

(particularly if that Lost souls definition applies to you, or your child)

The researchers themselves summarise the results as

“In this study, treatment with memantine was superior to placebo in improving social behaviors. Youths who received memantine had 4.8 times the odds (95% CI, 1.1-21.2) of responding to treatment compared with placebo. The NNT statistic was robust (NNT = 3), indicating that 1 in 3 memantine-treated youths with ASD would respond to treatment.” 

I think the autism sample in the trial is a little odd, so I will stick to my interpretation.

If about 40% of this lost souls autism really do respond to well to 20mg a day of Memantine, why did this not show up in the 2018 trial that costs many millions of dollars? That trial excluded kids with IQ ≤70 and also required at least moderate severity of social impairment.

The IQ cut off at 70 would exclude all profound autism and about 70% of Classic/Kanner’s autism.  There really should have been plenty of responders in the 2018 trial. Was the dose too low? Somebody may have wasted $20 million in trial costs.

Memantine to Treat Social Impairment in Youths With Autism Spectrum Disorder

A Randomized Clinical Trial

Several glutamate-modulating agents, including lamotrigine, amantadine, and N-acetylcysteine, have been evaluated as potential treatments for the core symptoms of ASD, demonstrating only modest efficacy.^26-30 In contrast, preliminary data from retrospective and prospective uncontrolled trials of memantine hydrochloride, with its unique mechanism of action as a moderate-affinity noncompetitive NMDA receptor antagonist, have been promising, reporting an acceptable safety and tolerability profile and substantial improvements in SCI and RRBs in youths and adults with ASD.^31-33 However, the only controlled trial of memantine in children to date, while showing improvements in ASD behaviors, failed to demonstrate superiority over an equally robust placebo response; this is likely due to the low dosing and inclusion of participants with intellectual disability, which did not adequately assess memantine’s efficacy in individuals with ASD without intellectual disability.³⁴ Addressing these limitations, preliminary findings from an uncontrolled trial of memantine at dosages of up to 20 mg/d in adults with ASD without intellectual disability demonstrated substantial improvements in social behaviors.³⁵

Spectroscopic glutamate levels in the pgACC were significantly elevated by a large magnitude in youths with ASD compared with healthy control participants, replicating previous findings by Joshi et al²⁵ of glutamate dysregulation in individuals with ASD. Notably, the abnormally high levels of glutamate were not universal but were limited to 54.0% (n = 20 of 37) of participants with ASD, with the remainder of participants without any glutamate abnormality.

Treatment response differed based on pgACC glutamate levels in participants with ASD. A significantly greater response rate to memantine compared with placebo was observed in the high-glutamate subsample, whereas no such difference was observed in the medium-glutamate subsample. All memantine responders had high glutamate levels, and the majority of participants with ASD with high glutamate levels were memantine responders (8 of 10 [80.0%]).

 

Why is Memantine used for Alzheimer’s?

In a healthy brain, glutamate is the main excitatory neurotransmitter and is crucial for learning and memory and normal neuronal activation.

In Alzheimer’s, damaged and dying neurons start to leak glutamate into the extracellular space.
This causes chronic, low-level overactivation of NMDA receptors.

That chronic stimulation:

• lets in too much calcium (Ca²⁺)
• triggers oxidative stress and mitochondrial dysfunction
• leads to progressive neuron death — a process called excitotoxicity

Memantine’s mechanism is a partial NMDA block without shutting down normal signaling.

• It binds inside the NMDA receptor channel, only when it’s open (i.e., during overactivation).
• It blocks excessive Ca²⁺ entry, protecting neurons from excitotoxic damage.
• Because its binding is voltage-dependent and rapidly reversible, it does not block normal glutamate transmission needed for learning and memory.

Unlike strong NMDA blockers (e.g. ketamine), memantine is neuroprotective without being sedating or hallucinogenic.

Why are Alzheimer’s drugs so ineffective to treat Alzheimer’s

People start treatment for Alzheimer’s disease 25 years too late.

The biological processes start two decades before the severe symptoms appear and at that point the damage is already done.

For Memantine to be truly effective you would need to start it in your 50s.

Target people very likely to develop Alzheimer’s 25 years early

We already know who is very likely to develop Alzheimer’s. There are the 3% of the general population carrying a double copy of the risk gene, so APOE ε4/ε4.

Then we have everyone with Down syndrome. Amyloid plaques have developed by their 30s and Alzheimer’s is nowadays the leading cause of death in DS.

Why not give the option of preventative treatment? Since it is very cheap and safe.

Elevated extracellular glutamate in autism?

Many studies suggest that extracellular glutamate levels are elevated in autism, at least in certain brain regions and in subgroups of individuals.

Magnetic Resonance Spectroscopy (MRS) — often called MR Spectroscopy — is a non-invasive imaging technique that is closely related to MRI, but instead of showing brain structure, it measures brain chemistry.

MRS studies show elevated glutamate or glutamine + glutamate levels have been found in regions such as:

• Anterior cingulate cortex (ACC / pgACC)
• Basal ganglia
• Hippocampus
• Thalamus

In today’s study the biomarker for responders was elevated glutamate in the Anterior cingulate cortex (ACC / pgACC)

Excluding people from autism trials based on IQ

It is increasingly common to exclude children from autism trials based on low IQ.

The right approach is probably to have separate trials for those with IQ less than 80. Then you can adapt the assessment process to suit people with limited communication and cognitive skills.

As more and more people want to get diagnosed with level 1 autism, the relevance of those at level 3 tends to get minimized. This does upset many parents.

I actually believe that raising IQ should be an endpoint in some autism trials. It is meaningful and measurable. I was very surprised to discover that you can raise IQ. Raising IQ by just 10 points is a big deal in classic/profound autism, it then makes all that expensive 1:1 therapy in childhood much more effective.

Conclusion

Memantine is a really cheap Alzheimer’s drug that can help some autistic people with high glutamate in their brain. It has been shown to be very safe.

There are much more expensive drugs like Riluzole.

Riluzole acts on multiple glutamate-related pathways:

·        ↓ Glutamate release from presynaptic neurons

·        ↑ Glutamate reuptake by astrocytes (enhancing EAAT2 transporter activity)

·        Blocks voltage-dependent sodium channels, reducing neuronal overactivation

·        Modulates NMDA and AMPA receptors, dampening excessive excitatory signaling

This results in lower extracellular glutamate, less calcium influx, and protection from oxidative stress and excitotoxicity — a key mechanism in ALS, Alzheimer’s, and possibly some autism.

I did try both Memantine and Riluzole a long time ago. Riluzole caused lethargy, which makes sense.

In Memantine clinical trials, social responsiveness is the measure the researchers always like to focus on.

Some people think the big expensive 2015-2018 trial had the wrong primary endpoint — Memantine might have modestly improve cognitive flexibility or irritability, but those were secondary measures.

The cost of the special MRI scan to diagnose high glutamate in the PgCC (Pre-genual Anterior Cingulate Cortex) is $1000 to $2000. This is way too expensive to be used at a wide scale as a biomarker.

20mg a day of Memantine costs $20 a month in the US and even less everywhere else.

Peter’s approach would be: “don’t overthink it, just try it!”

Do not expect it to be a silver bullet. If it helps, add it to your polytherapy. If there is no positive response, stop the therapy. A good investment of $20, either way.

ARBs and ACE inhibitors for Autism, an old Peter idea finally explored in a research model

 

 A home run? Certainly worth further consideration. 

When I was doing my review of unexplored potential autism therapies several years ago, I did look at two closely related classes of drugs. ARBs and ACE inhibitors.

I wrote about it in blog posts and set out why I thought the ARB telmisartan was the best one to trial first.

 

           Targeting Angiotensin in Schizophrenia and Some Autism          

Just when you thought we had run out hormones to connect to autism and schizophrenia, today we have Angiotensin.

Angiotensin is a hormone that causes vasoconstriction and a subsequent increase in blood pressure. It is part of the renin-angiotensin system, which is a major target for drugs (ACE inhibitors) that lower blood pressure. Angiotensin also stimulates the release of aldosterone, a hormone that promotes sodium retention which also drives blood pressure up.

Angiotensin I has no biological activity and exists solely as a precursor to angiotensin II.

Angiotensin I is converted to angiotensin II  by the enzyme angiotensin-converting enzyme (ACE).  ACE is a target for inactivation by ACE inhibitor drugs, which decrease the rate of Angiotensin II production.  

It turns out that Angiotensin has some other properties very relevant to schizophrenia, some autism and quite likely many other inflammatory conditions. 

Blocking angiotensin-converting enzyme (ACE) induces those potent regulatory T cells that are lacking in autism and modulates Th1 and Th17 mediated autoimmunity.  See my last post on Th1,Th2 and Th17. 

In addition, Angiotensin II affects the function of the NKCC1/2 chloride cotransporters that are dysfunctional in much autism and at least some schizophrenia.

Then I wrote another post and made a trial of Telmisartan.

Angiotensin II in the Brain & Therapeutic Considerations

I was pleased to see that some researchers have recently published a paper on this subject. They chose an ACE inhibitor called Captopril.

 

Captopril restores microglial homeostasis and reverses ASD-like phenotype in a model of ASD induced by exposure in utero to anti-caspr2 IgG

Microglia play a crucial role in brain development, including synaptic pruning and neuronal circuit formation. Prenatal disruptions, such as exposure to maternal autoantibodies, can dysregulate microglial function and contribute to neurodevelopmental disorders like autism spectrum disorder (ASD). Maternal antibodies targeting the brain protein Caspr2, encoded by ASD risk gene Cntnap2, are found in a subset of mothers of children with ASD. In utero exposure to these antibodies in mice leads to an ASD-like phenotype in male but not in female mice, characterized by altered hippocampal microglial reactivity, reduced dendritic spine density, and impaired social behavior. Here, we studied the role of microglia in mediating the effect of in utero exposure to maternal anti-Caspr2 antibodies and whether we can ameliorate this phenotype. In this study we demonstrate that microglial reactivity emerges early in postnatal development and persists into adulthood following exposure in utero to maternal anti-Caspr2 IgG. Captopril, a blood-brain barrier permeable angiotensin-converting enzyme (ACE) inhibitor, but not enalapril (a non-BBB permeable ACE inhibitor) ameliorates these deficits. Captopril treatment reversed microglial activation, restored spine density and dendritic arborization in CA1 hippocampal pyramidal neurons, and improved social interaction. Single-cell RNA sequencing of hippocampal microglia identified a captopril-responsive subcluster exhibiting downregulated translation (eIF2 signaling) and metabolic pathways (mTOR and oxidative phosphorylation) in mice exposed in utero to anti-Caspr2 antibodies treated with saline compared to saline-treated controls. Captopril reversed these transcriptional alterations, restoring microglial homeostasis. Our findings suggest that exposure in utero to maternal anti-Caspr2 antibodies induces sustained neuronal alterations, microglial reactivity, and metabolic dysfunction, contributing to the social deficits in male offspring. BBB-permeable ACE inhibitors, such as captopril, warrant further investigation as a potential therapeutic strategy in a subset of ASD cases associated with microglial reactivity.

 

So here is an update that incorporates all these ideas and the new study.

 ___ 

Targeting the Brain Renin-Angiotensin System: From Schizophrenia to Autism (2025 Update)

By Peter Lloyd-Thomas, Epiphany ASD Blog

In 2017, I wrote about the idea that drugs targeting the renin–angiotensin system (RAS)—ACE inhibitors and ARBs—might have therapeutic effects beyond blood pressure, including in schizophrenia and autism. At that time, the discussion was mostly mechanistic. Today, new evidence strengthens the rationale and provides translational plausibility.

 

Why the Brain RAS Matters

While angiotensin II is best known for regulating blood pressure, the brain has its own RAS, which regulates:

·         AT₁ receptors → oxidative stress, neuroinflammation, microglial activation

·         AT₂ and Mas receptors → neuroprotection, mitochondrial function, anti-inflammatory signaling

·         ACE → converts Angiotensin I → II and degrades bradykinin, affecting cerebral blood flow

Shifting the balance from AT₁-dominated to AT₂/Mas signaling can normalize microglial function, improve neuronal energy metabolism, and support synaptic plasticity.

 

New Autism-Relevant Evidence (2025)

A recent study (Spielman et al., Molecular Psychiatry, 2025) used a mouse model of maternal anti-Caspr2 antibodies, a risk factor for some forms of autism. Male offspring showed:

·         Hyperactive microglia

·         Reduced hippocampal dendritic spines

·         Impaired social behavior

Captopril, a BBB-penetrant ACE inhibitor, reversed these deficits. In contrast, enalapril, which poorly crosses the BBB, was ineffective. Single-cell RNA sequencing revealed captopril restored microglial metabolic homeostasis (mTOR, oxidative phosphorylation, eIF2 signaling), linking microglial function directly to behavioral outcomes.

 

ACE Inhibitors vs ARBs: CNS and Immune Effects

Feature	ACE inhibitors (e.g., captopril)	ARBs (BBB-permeable, e.g., telmisartan)
↓ Ang II	Yes	No (blocks AT₁ receptor)
↑ Bradykinin / NO	Yes	No
BBB penetration	Variable — captopril high, enalapril low	Most low; telmisartan high
Microglial activation	↓ via less Ang II & more NO	↓ via AT₁ blockade
NKCC1/2 chloride cotransporters	Normalized via ↓ Ang II	Normalized via AT₁ blockade
Regulatory T cells (Tregs)	Strong ↑	Moderate ↑ (telmisartan strongest among ARBs)
Th1/Th17 autoimmunity	Modulated ↓	Modulated ↓
PPAR‑γ activation	No	Yes (telmisartan)
Evidence in ASD model	Captopril reversed phenotype (2025)	Mechanistically promising; anecdotal human benefit

Both classes modulate neuroinflammation, chloride signaling, and immune function, but ACE inhibitors and ARBs differ in mechanisms and potency.

 

Clinical Evidence in Schizophrenia

Telmisartan has been trialed in adults with schizophrenia (NCT00981526), primarily for metabolic side effects of antipsychotics (clozapine, olanzapine). Secondary observations included:

·         Improvement in negative symptoms

·         Modest cognitive benefits

·         Good tolerability over 12 weeks

This demonstrates CNS activity in humans, beyond metabolic effects, supporting translational plausibility for neuropsychiatric conditions.

 

Personal Observation in Autism

Years ago, I trialed telmisartan in my son. The effect was striking: he began singing spontaneously—something no other therapy had achieved. Singing engages emotion, motivation, and executive coordination, all dependent on healthy microglial and neuronal metabolism. While anecdotal, this observation aligns with mechanistic insights from both the mouse autism model and schizophrenia trials.

 

Safety and Accessibility

ACE inhibitors and ARBs are:

·         Widely prescribed globally for hypertension and heart protection

·         Generic, inexpensive, and safe in adults

·         Typically well-tolerated (ACE-i cough, hypotension, mild electrolyte changes)

This makes them practical candidates for drug repurposing in neurodevelopmental and neuropsychiatric disorders.

 

Mechanistic Summary

1.     Microglial hyperactivation contributes to synaptic and behavioral deficits in some autism subtypes.

2.     Brain RAS modulation (ACE-i or ARB) restores microglial homeostasis, improves energy metabolism, and supports synaptic plasticity.

3.     NKCC1/2 chloride cotransporter regulation: By reducing Ang II (ACE-i) or blocking AT₁ (ARB), these drugs normalize intracellular chloride, restoring proper GABAergic inhibition.

4.     Immune regulation: ACE inhibition induces regulatory T cells (Tregs) and modulates Th1/Th17 autoimmunity. BBB-penetrant ARBs like telmisartan also modulate these pathways, enhanced by PPAR‑γ activation.

5.     Behavioral outcomes: In mice, captopril reverses ASD-like phenotypes; anecdotal human reports suggest telmisartan may improve engagement, motivation, and communication.

 

Next Steps for Research

·         Carefully designed biomarker-driven pilot trials in humans, selecting individuals with evidence of neuroinflammation or maternal autoantibody exposure.

·         CNS-focused outcome measures (microglial imaging, inflammatory markers, synaptic function).

·         Behavioral endpoints relevant to autism (social interaction, expressive communication).

Or skip that and maybe make an n=1 trial?

 

Take-Home Message

Drugs long used for cardiovascular health may have untapped potential in neurodevelopmental and neuropsychiatric disorders. BBB-penetrant ACE inhibitors and ARBs, particularly telmisartan, can modulate:

·         Microglial activity

·         Neuronal chloride gradients

·         Immune regulation

Recent mouse data (Spielman et al., 2025) and human observations in schizophrenia support mechanistic plausibility and safety, making these drugs promising candidates for further study in selected autism subgroups.

 

References and Further Reading:

Spielman et al., Molecular Psychiatry, 2025: Captopril restores microglial homeostasis in anti-Caspr2 ASD model

NCT00981526, Telmisartan in schizophrenia (Fan X, 2018)

Lloyd-Thomas, 2017: Angiotensin II in the Brain

Lloyd-Thomas, 2017: Targeting Angiotensin in Schizophrenia and Some Autism

Human Psychology — The Limiting Factor in Dealing with Autism

 

 

When it comes to autism, perhaps the biggest obstacle is not scientific knowledge, but human psychology itself.

We want certainty: lab tests, clear causes, definitive diagnoses, and effective treatments. Yet autism resists all of them. It exists at the intersection of biology, behavior, and more recently culture. It exposes how much of medicine is still filtered through the lens of human perception.

 

The power of belief: Placebo and Nocebo

Autism clinical trials reveal a striking pattern, the placebo group often does surprisingly well. Parents, teachers, and clinicians report improvements in social engagement, eye contact, or irritability even when the child receives no active compound.

That is not fraud — it is psychology. Expectations shape observations. Parents want to see improvement; clinicians want to believe their interventions work (some clinicians even seem to want the interventions of others not to work!). The placebo effect amplifies hope into perceived progress.

The opposite is also true. If a therapy is expected to fail, or cause side effects, people tend to notice negative changes. That is the nocebo effect — our beliefs shaping our biology, or at least our perception of it.

 

Beyond placebo and nocebo: other human effects that shape perception

The placebo and nocebo effects are just the beginning. Human psychology is full of subtle forces that can make a treatment appear to work, or fail, even when biology remains unchanged. These effects are especially powerful in autism research, where progress is measured through behavior rather than lab tests.

 

1. The Hawthorne effect

People often change their behavior simply because they know they are being observed. Parents in a trial may interact more positively with their child, or teachers may give extra encouragement. The child then behaves better—not because of the therapy, but because the social environment has changed.

The Hawthorne effect is a type of human behavior reactivity: individuals modify their behavior simply because they know they are being observed. It was first described in studies during the 1920s at the Hawthorne Works, a Western Electric plant in Illinois, where workers’ productivity appeared to improve under different lighting conditions and work structures. Later analysis suggested that the apparent gains were likely due to the novelty of being studied and the extra attention workers received, rather than the experimental changes themselves.

 

2. Observer expectancy

Researchers and clinicians, consciously or not, tend to see what they expect to see. A therapist who believes a treatment is promising may rate ambiguous behaviors more favorably. Even small cues like tone, enthusiasm or body language can subtly influence outcomes.

 

3. The caregiver effect

When parents believe something is helping, they naturally act differently: calmer, more patient, more hopeful. The child senses this, and behavior improves. The apparent “treatment effect” is really a change in the social dynamic, not the biology of the child.

 

4. Regression to the mean

Children may join studies when their behaviors are at their worst. Over time, things tend to return toward their usual level, whether or not any treatment was effective. Without biological markers, this natural recovery can look like success.

 

5. Confirmation bias

We notice what confirms our hopes and ignore what does not. A parent who wants to see progress will remember good days vividly, while quietly forgetting setbacks. Over time, that bias creates a story of steady improvement—even when change is uneven or minimal.

 

6. Natural maturation

Children grow and change. Speech, self-regulation, and awareness can all improve simply with time and development. Without objective measures, it is hard to tell whether improvement came from therapy or from ordinary maturation.

 

7. The therapeutic alliance

Sometimes, what helps most is the sense of being understood. A caring professional who listens and offers hope can have a measurable calming effect on both parent and child. It feels like progress because it is, psychological progress, but it’s not necessarily biological.

 

8. The expectancy cycle

These forces often combine. Parents, teachers, and researchers all expect improvement, and those expectations subtly reinforce each other. Everyone feels encouraged, interactions improve, and the child responds in kind.

 

Taken together, these human effects can create the illusion of treatment success without any measurable biological change.

They do not make research meaningless, but they remind us that, in autism, we are often studying human perception as much as human biology.

 

Measuring what can’t be measured

Unlike diabetes or infections, autism lacks objective biological markers. There is no blood test, no scan, no lab value that confirms progress. Autism trials rely almost entirely on soft behavioral endpoints like eye contact, social reciprocity, verbal skills, repetitive behaviors.

But these are all subjective judgments. One parent’s “huge improvement” is another’s “slight change.” Even trained clinicians often disagree. This introduces a layer of human variability that overwhelms any small biological signal a treatment might produce.

 

A contrast: When biology speaks clearly

Imagine your nine-year-old child with autism becomes irritable, withdrawn, and starts covering his ears. His behavior worsens rapidly.

You take him to the doctor, who looks in his ear and immediately sees the problem — an infection. The diagnosis itself does not make the pain go away, and the child’s behaviors do not improve simply from being told what is wrong. But after a week on antibiotics, the infection clears. The pain disappears. His sleep normalizes. His behaviors return to baseline.

Here, biology is clear. The cause was physical, the treatment targeted it, and the outcome was measurable. There is no placebo interpretation involved, just the cause-and-effect precision that medicine aspires to.

That clarity is what is usually missing in autism research.

 

The comfort of a diagnosis

By contrast, many adults receiving a mild autism diagnosis report feeling relief,  they finally “understand themselves.” Yet nothing physical has changed. No inflammation has resolved, no neurotransmitter has been balanced. What changed was self-perception.

A diagnosis can provide comfort, identity, and even community. It answers the deeply human need to make sense of who we are. But it is a psychological event, not a biological one.

 

The paradox of mild autism

My mother, a doctor, once remarked how curious it is that so many people are now diagnosed with mild autism — yet there is no therapy or even structured follow-up. The diagnosis is meant to help, but what comes next?

Parents of children with severe autism often feel alienated by this trend. They watch celebrities and influencers describe themselves as autistic for being introverted or socially anxious, while their own children are non-verbal, incontinent, and dependent for life. They feel that the term autism has been stretched so far that it risks losing meaning.

 

When autism is severe, there is less room for subjectivity

In cases of severe autism, the boundaries between perception and reality become clearer. There is less room for interpretation because the behaviors are so obvious, so measurable, and often so disabling that they cannot be mistaken for personality differences.

When a child is non-verbal, does not respond to their name, cannot feed or toilet independently, and shows self-injurious or highly repetitive behaviors, progress can be tracked in concrete ways. A therapy either helps the child communicate a few new words, reduces self-harm, improves sleep, or it does not. There is far less ambiguity.

A parent of a severely autistic child does not need rating scales to know whether their child’s aggression or anxiety has improved, they can see it in daily life. If the child goes from sleeping two hours a night to sleeping eight, that is not a placebo effect. If self-injury stops after an antibiotic or anti-inflammatory, that is a biological clue, not a subjective impression.

Because of this, severe autism may actually offer better opportunities for scientific understanding. The behaviors are consistent and pronounced, and measurable improvements can point to real biological mechanisms—whether immune, metabolic, or neurological.

However, these children are also the most neglected by research. Most autism trials exclude them, preferring verbal, higher-functioning participants who can follow instructions and complete rating scales. Ironically, this biases autism science toward the most subjective end of the spectrum, the very group where human psychology most distorts perception.

If we want to understand autism’s biology, it may be wiser to focus more on those with clear and measurable impairments, where psychology plays a smaller role and biology has a chance to reveal itself.

 

Diagnosis as identity

There is a broader cultural pattern at work. Increasingly, psychiatric labels like ADHD, bipolar disorder, and autism have become identity markers — especially among younger adults. They bring belonging, validation, and sometimes even social capital.

But it raises a question, does the diagnosis help because it changes biology, or because it reshapes how a person feels about their life story?

For some, the label provides understanding. For others, it becomes a kind of permission, a way to explain why life did not turn out to plan. Yet life rarely does, for anyone, neurodiverse or not.

Real life is messy and unpredictable, not like the polished arcs of old Hollywood movies. The narrative a diagnosis provides can feel comforting, but it is ultimately a false framework — an excuse to explain the story, without altering the underlying biology or changing the ending.

 

A broader cultural shift

The rise in self-diagnosed autism overlaps with another social trend, more young people identifying as LGBTQ+. Both movements challenge norms and offer belonging to those who feel different. Both provide a ready-made narrative that transforms uncertainty into identity.

In that sense, autism today has become as much a social phenomenon as a medical one.

 

The human factor in science

Biology is rarely black and white, especially in neuroscience. Each brain is unique, and behavior reflects countless interacting systems. But when objective biomarkers are absent, psychology fills the void — through expectation, perception, and interpretation.

That is why autism remains so difficult to “treat.” Our understanding is constrained not only by biology, but by human psychology — the biases, hopes, and needs that color how we define and measure improvement.

Until we learn to separate biological change from psychological interpretation, human psychology will remain the limiting factor in how we deal with autism.

 

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.)