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.)

 

Autism Research Merry-go-round Keeps Turning

 

Today’s post again shows that many issues raised in previous posts keep on coming back – is that good news? Only you can decide.

I start with the “old chestnut” (English idiom to imply “a tired old story”) of the Autism Tsunami. 

Then we see what has come up in the world of autism interventions in the research in the last 3 weeks, most of which regular readers will already be aware of.

·        Autism Tsunami – real or not?

·        Vitamin D

·        Bumetanide

·        Ibudilast

·        Niclosamide

·         Non-invasive brain stimulation

·         Simvastatin 

I noted the research about autism incidence coming from Northern Ireland because it was published in the Belfast News Letter.  These days it has a tiny subscription, but I am one of those who know it is the world's oldest English-language general daily newspaper still in publication, having first been printed in 1737. In 1972 a bomb warning was called in to the paper's office and, as people evacuated, an explosion went off nearby killing several people and injuring many more. Back in the early 1990s, when some people in Northern Ireland were still blowing up others with bombs, I made a visit to Northern Ireland to meet the management of this newspaper. 

Their recent article on autism incidence is very well researched considering how only about 8,000 copies are published. Keep up the good work!

Idea that 5% of all Northern Ireland's children are autistic is 'a fantasy' claims international expert

Professor Laurent Mottron was speaking to the News Letter following a claim that the rate of autism in Northern Ireland is double the rate in the rest of the UK.

Back in 2019 Prof Mottron had authored a report warning about a tsunami of over-diagnosis, saying that soon "the definition of autism may get too vague to be meaningful, trivializing the condition"

“If this trend holds, the objective difference between people with autism and the general population will disappear in less than 10 years," he had said then – and has now indicated that this “fuzziness” is what’s helping swell the numbers in Northern Ireland.

Meanwhile Jill Escher, the president of the National Council on Severe Autism, takes a different view.

She says that evidence indicates the "skyrocketing" rate of autism in Northern Ireland is real, adding: "It boggles my mind that it is not the subject of the highest possible alarm and inquiry."

"One in 20 children in Northern Ireland of school age has a diagnosis of autism," he told MPs.

"[It is] one in 57 in the rest of the UK. The need in Northern Ireland is significantly different."

To put that in perspective, that would mean 5% of Northern Irish children are diagnosed with autism, compared with 1.8% in the rest of the UK.

Prof Mottron, a psychiatrist based at Montreal University, told the News Letter "numbers such as 5% are pure fantasy... these numbers correspond to the part of the general population which has less overt socialisation, which has minimally to do with prototypical autism". 

There is a "current fuzziness of autism diagnosis and over-inclusivity," he said, leading to "a situation of perfect confusion between autistic traits and prototypical autism" (that is, mixing up people who exhibit some tendencies of autistic people with people who actually have the full-blown condition). 

"The scientific 'quasi consensus' would be around 1% everywhere on the planet,” he added.

 

So on one side we have Jill Escher and her NCSA and on the other we have a French/Canadian researcher.  This time Laurent Mottron but in my blog posts I quoted Éric Fombonne.

A paper that was mentioned both in my blog and critiqued by Jill about autism incidence and cost just got retracted.  In reality a better word is “cancelled.”  The 3 authors are very much in the politically incorrect camp of the autism debate.

I was surprised it ever got published.  

Controversial ‘cost of autism’ paper retracted 

Citing methodological issues and undeclared conflicts of interest, an autism journal has retracted a paper that forecast the prevalence and cost of autism.

The retraction note, posted last week, comes two years after Spectrum reported on backlash surrounding the paper, which was published in the Journal of Autism and Developmental Disorders in July 2021. A month after publication, the journal added an editor’s note that the study was under investigation because of criticisms of its conclusions. 

“I am glad to see that it was retracted, although at a pace that maybe is a bit frustrating in terms of how long it took. But it was the right choice,” says Brittany Hand, associate professor of health and rehabilitation sciences at Ohio State University in Columbus.

Outside experts who reviewed the paper on the journal’s behalf found that it misrepresented the rise in autism diagnoses and gave “insufficient attention” to some potential causes of the increase, such as improved surveillance and changes to the diagnostic criteria. The authors also used “higher estimates and assumptions that inflated costs,” according to the retraction note.

The authors — Mark Blaxill, Toby Rogers and Cynthia Nevison — all disagree with the journal’s decision, the note also says.

The cancelled paper is here:-

Autism Tsunami: the Impact of Rising Prevalence on the Societal Cost of Autism in the United States

 

I assume Blaxill was the driving force behind all the math, because he is the ex- management consultant, with a son with severe autism that his dad attributes to vaccines.

What I found bizarre in their paper was that they has a prevention scenario, based on what they think has already happened in rich parts of California, where they think autism incidence is falling.  It is not falling, all that is happening is that wealthy Californians are paying for treatment using insurance or their own money, and no longer burdening the State.

The “rainbow” researchers that wanted the paper retracted think that preventing autism is akin to eugenics and Dr Mengele. According to Peter, treating autism is good, while Dr Josef Mengele, byname Todesengel (German: “Angel of Death”) was as bad as you can get.    

Jill Escher and her NCSA think that you cannot prevent autism.  According to Peter, you can both minimize the incidence and severity of autism. 

A bugbear of our reader Tanya is that the NCSA have a pet hate of facilitated communication and in particular the rapid prompting method (RPM). This method worked for Tanya’s son and it opened the door to independent, un-facilitated communication. 

Always keep an open mind.

 

 

 

“our Prevention scenario is based on real rates observed among wealthy white and Asian children in the California DDS.  Severe ASD prevalence has flattened and even declined among these children since birth year 2000, suggesting that wealthy parents have been making changes that effectively lower their children’s risk of developing ASD. The Prevention scenario assumes that these parental strategies and opportunities already used by wealthy parents to lower their children’s risk of ASD can be identified and made available rapidly to lower income children and ethnic minorities, who are currently experiencing the most rapid growth in ASD prevalence”

 

New Paper Makes Case that Autism Tsunami May Threaten American Economy

A major weakness in the analysis was the “Prevention Scenario” in which future costs were projected based on “what might be possible if strategies for reducing ASD risk are identified and addressed in the near future.” As I think everyone knows, at this time there is no way to prevent autism. But the authors use the observation that autism in the DDS is declining among wealthier white families, and thus “suggesting that wealthy parents have been making changes that effectively lower their children’s risk of developing ASD.” No, it’s far more likely that wealthier families are not entering their children into the system because they access services through insurance and school districts instead.

 

Vitamin D as a cause of autism has been discussed for decades.  As the title below puts it – a never-ending story. Our reader Seth Bittker even wrote a paper about it. He later wrote a paper about the use Acetaminophen/Paracetamol in children under two as a risk factor in developing autism. Good work Seth!

 

Maternal Vitamin D deficiency and brain functions: a never-ending story 

A large number of observational studies highlighted the prevalence rates of vitamin D insufficiency and deficiency in many populations as pregnant women. Vitamin D is well known to have a crucial role in differentiation and proliferation, as well as neurotrophic and neuroprotective actions in brain. Then, this micronutrient can modulate the neurotransmission and synaptic plasticity. Recent results from animal and epidemiological studies indicated that maternal vitamin D deficiency is associated with a wide range of neurobiological disease including autism, schizophrenia, depression, multiple sclerosis or developmental defect. The aim of this review is to provide a state of the art on the effect of maternal vitamin D deficiency on brain functions and development.

4.2.2. Autism

Autism spectrum disorder (ASD) is a complex neurodevelopmental disease with repetitive behaviour and difficulties in social interaction, communication and learning. Several murine studies and cohorts have demonstrated that early exposure to low levels of VD during pregnancy could be a risk factor for ASD. In 2019, Ali et al. aimed to find out the impact of a maternal VDD on early postnatal, adolescent and adult offspring. By assessing righting reflex and negative geotaxis, they found out that the pups from deficient dams showed a delay in their motor development. P12 rats from deficient females also exhibited increased ultrasound vocalization indicating an alteration in their vocal communication. Adolescent and young adult rats displayed an altered stereotyped repetitive behaviour as they had a reduced digging behaviour. Adolescent rats had less social interaction with longer latency to interact, which was not found in adult rats; however, adults were more hyperactive but showed no anxiety like behaviour.  In another animal study, maternal VDD induced an increase in the vocalizations of the pups accompanied with a decrease in cortical FoxP2, decrease in social behaviour and impaired learning and memory were observed in adult males (Table 1). Using data from the Stockholm youth cohort, Magnusson et al. examined a population of 4-17-year-old children exposed to low levels of VD during gestation and was able to report a positive association between maternal VDD and ASD. Analysing the same cohort, Lee et al. suggested that high levels of VD during pregnancy were associated with a moderate decrease in risk of ASD in the offspring. A prospective study of a multi-ethnic cohort in the Netherlands (generation R study) has also shown an association between maternal mid-gestation VDD and a two-fold increase in the risk of autism in children (Table 2). Interestingly, VD supplementation seems to clinically improve ASD symptoms of affected children.

 

People do associate this blog with Bumetanide.  Yet another paper has been published showing the benefits of this therapy for autism.

 

EEG-based brain connectivity analysis in autism spectrum disorder: Unravelling the effects of bumetanide treatment 

Highlights

 

·        We investigated the nonlinear brain connectivity and topological changes in brain networks of people with autism spectrum disorders (ASD) after a three-month course of bumetanide treatment.

·        We found statistically significant differences between pre and post intervention in the connectivity patterns using repeated measures analysis of variance (ANOVA).

·        We found that the number of strong connections in response to sad image stimuli seem to be less compared with that of the other two stimuli, especially in the central area.

·        We found that the changes in brain connectivity between pre and post intervention is more significant in response to sad image stimuli.

 

Emerging evidence suggests that cognitive impairment associated with brain network disorders in people with autism could be improved with medications such as bumetanide. However, the extent to which bumetanide is effective in improving brain function in these individuals has not been adequately studied. The main purpose of this study is to investigate the nonlinear brain connectivity and topological changes in brain networks of people with autism spectrum disorders (ASD) after a three-month course of bumetanide treatment. We used electroencephalography (EEG) data of nine participants recorded during the face emotion recognition activity in two stages before and after bumetanide treatment. Brain connectivity matrix was calculated using a neural network-based estimator. Graph criteria and statistical tests have been used to determine the effects of bumetanide treatment on children and adolescents with autism. Bumetanide treatment significantly alters the brain connectivity networks based on stimuli type. Differences in brain connectivity related to the sad stimuli are more significant. The most of the significant changes of the strength graph metric was in the occipital electrodes and electrodes related to the right hemisphere. These results suggest that bumetanide may affect effective connectivity and be used a promising treatment for improving social interactions in patients with autism. It also suggests that brain connectivity patterns can be considered as a neural marker to be used in the development of new therapies. 

I have also covered in sometimes painful details the potential to treat autism and increase cognitive function using PDE (Phosphodiesterase) inhibitors. One of our psychiatrist readers is a huge fan of Pentoxifylline and takes it himself.

I was recently asked how to obtain Ibudilast.  It is approved in Japan as an asthma drug. Sometimes it is called Ketas and you can get it from an “International Pharmacy” in Germany/Switzerland if you have a prescription. 

I also wrote about repurposing Roflumilast, which as Daxas is approved all over the world as a therapy for severe asthma (COPD). This drug at a 1/5^th dose has been patented as a cognitive enhancer.

 

Phosphodiesterase inhibitor, ibudilast alleviates core behavioral and biochemical deficits in the prenatal valproic acid exposure model of autism spectrum disorder

 

Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder, presenting with a variety of aetiological and phenotypical features. Ibudilast is known to produce beneficial effects in several neurological disorders including neuropathic pain, multiple sclerosis, etc. by displaying its neuroprotective and anti-inflammatory properties. Here, in our study, the pharmacological outcome of ibudilast administration was investigated in the prenatal valproic acid (VPA)-model of ASD in Wistar rats.

Methods

Autistic-like symptoms were induced in Wistar male pups of dams administered with Valproic acid (VPA) on embryonic day 12.5. VPA-exposed male pups were administered with two doses of ibudilast (5 and10 mg/kg) and all the groups were evaluated for behavioral parameters like social interaction, spatial memory/learning, anxiety, locomotor activity, and nociceptive threshold. Further, the possible neuroprotective effect of ibudilast was evaluated by assessing oxidative stress, neuroinflammation (IL-1β, TNF-α, IL-6, IL-10) in the hippocampus, % area of Glial fibrillary acidic protein (GFAP)-positive cells and neuronal damage in the cerebellum.

Key findings: Treatment with ibudilast significantly attenuated prenatal VPA exposure associated social interaction and spatial learning/memory deficits, anxiety, hyperactivity, and increased nociceptive threshold, and it decreased oxidative stress markers, pro-inflammatory markers (IL-1β, TNF-α, IL-6), and % area of GFAP-positive cells and restored neuronal damage.

Conclusions

Ibudilast treatment has restored crucial ASD-related behavioural abnormalities, potentially through neuroprotection. Therefore, benefits of ibudilast administration in animal models of ASD suggest that ibudilast may have therapeutic potential in the treatment of ASD.

 

 

I have also written widely about repurposing certain anti-parasite medicines to treat autism. This is not because I think parasites cause autism, it is the secondary modes of action.

 

 

Repurposing Niclosamide as a plausible neurotherapeutic in autism spectrum disorders, targeting mitochondrial dysfunction: a strong hypothesis

 

 

Autism Spectrum Disorders (ASD) are a complex set of neurodevelopmental manifestations which present in the form of social and communication deficits. Affecting a growing proportion of children worldwide, the exact pathogenesis of this disorder is not very well understood, and multiple signaling pathways have been implicated. Among them, the ERK/MAPK pathway is critical in a number of cellular processes, and the normal functioning of neuronal cells also depends on this cascade. As such, recent studies have increasingly focused on the impact this pathway has on the development of autistic symptoms. Improper ERK signaling is suspected to be involved in neurotoxicity, and the same might be implicated in autism spectrum disorders (ASD), through a variety of effects including mitochondrial dysfunction and oxidative stress. Niclosamide, an antihelminthic and anti-inflammatory agent, has shown potential in inhibiting this pathway, and countering the effects shown by its overactivity in inflammation. While it has previously been evaluated in other neurological disorders like Alzheimer’s Disease and Parkinson’s Disease, as well as various cancers by targeting ERK/MAPK, it’s efficacy in autism has not yet been evaluated. In this article, we attempt to discuss the potential role of the ERK/MAPK pathway in the pathogenesis of ASD, specifically through mitochondrial damage, before moving to the therapeutic potential of niclosamide in the disorder, mediated by the inhibition of this pathway and its detrimental effects of neuronal development.

 

Note that in earlier posts I explored RASopathies as potentially treatable types of intellectual disability (ID). We also have RAS-dependent cancers as a discrete treatable sub-type of cancer.

The ERK/MAPK pathway is known to interact with multiple genes that have been implicated in autism, and genome-wide association analysis of the same have supported these findings. As such, a dysregulation of this pathway has been found to result in many CNS disorders, including ASD-related syndromes, in many studies. These syndromes are collectively known as Rasopathies, due to the fact that the affected genes include those encoding for elements which function together with Ras, a G-protein responsible for activating ERKs (Levitt and Campbell 2009; Tidyman and Rauen 2009). It has been found that ASD is linked to the occurrence of many Rasopathies, and there have been multiple reports suggesting the possible relation of ERK/MAPK pathway defects with the incidence of ASD (Vithayathil et al. 2018; Aluko et al. 2021)⁠⁠. Moreover, a detailed study has found that single nucleotide polymorphisms (SNPs) in the ERK/MAPK-related genes are more common in subjects presenting with idiopathic ASD.

 

Niclosamide is an FDA-approved antihelminthic drug which is routinely used to treat tapeworm infections by inhibiting their mitochondrial oxidative phosphorylation and ATP production. In addition, it has long been known to have significant immunomodulating activity, and has been shown to inhibit a number of signaling pathways, including the Wingless-related integration site (Wnt)/β-catenin, nuclear factor kappa B (Nf-κB), signal transducer and activator of transcription 3 (STAT3), and mammalian target of rapamycin (mTOR) (Chen et al. 2018). However, while these targets are known to be rather well-characterized in terms of the effect that niclosamide has on them, there are also other targets, including the phosphoinositode 3 kinase/Akt (PI3K/Akt) and ERK/MAPK pathways, that are seen to be downregulated by the agent. Hence, given the possible relation of the ERK pathway in autism, there has been interest in the potential role of niclosamide in the management of the prognosis of ASD. This article aims to discuss the possible therapeutic benefit of niclosamide in the treatment of autism spectrum disorders.

 

Now I know that parents like the idea of treating autism with various gadgets you can strap on to your head – things like Transcranial Magnetic Stimulation (TMS). I must say I liked my old post on Photobiomodulation/cold laser/low level laser therapy.

Epiphany: Low Level Laser Therapy (LLLT) for Autism – seems to work in Havana

From China we have a new round-up paper, but the full text does not yet seem to be ready.

 

Non-invasive brain stimulation for Patient with Autism： A Systematic Review and Meta-Analysis

Objective: To comprehensively evaluate the efficacy of non-invasive brain stimulation (NIBS) in patients with autism spectrum disorder (ASD) in randomized controlled trials (RCT),providing reference for future research on the same topic.

Methods:Five databases were searched (Pubmed,Web of science,Medline,Embase and Cochrane library) and track relevant references,Meta-analysis was performed using RevMan 5.3 software.

Results: Twenty-two references(829 participants) were included. The results of meta analysis showed that, NIBS had positive effects on repetitive and stereotypical behaviors, cognitive function and executive function in autistic patients. Most of the included studies had a moderate to high risk of bias, Mainly because of the lack of blinding of subjects and assessors to treatment assignment, as well as the lack of continuous observation of treatment effects.

Conclusions: Available evidence supports an improvement in some aspects of NIBS in patients with ASD. However, due to the quality of the original studies and significant publication bias, these evidences must be treated with caution. Further large multicenter randomized double-blind controlled trials and appropriate follow-up observations are needed to further evaluate the specific efficacy of NIBS in patients with ASD.

Unfortunately, the Chinese have concluded that most of these studies are not reliable. So no laser for me to go out and buy just yet.

No need to dent your bank balance with the next therapy.  We are back to one of the world's most prescribed and therefore affordable drugs, its Simvastatin (Zocor). 

There is masses of information in this blog about the potential to treat sub-types of autism with Atorvastatin, Simvastatin or Lovastatin. They are each slightly different.

 

Effect of simvastatin on brain-derived neurotrophic factor (BDNF)/TrkB pathway in hippocampus of autism rat model 

Purpose: To study the effect of simvastatin on behavioral performance in a rat model of autism, and its effect on hippocampal brain-derived BDNF-TrkB pathway. 

Methods: Twelve rats with valproic acid (VPA)-induced autism were randomly divided into model group and simvastatin group, while six healthy rats served as normal control group. Rats in the simvastatin group received the drug (5 mg/kg) via i.p. route, while rats in model group and normal control group were injected with equivalent volume of normal saline in place of simvastatin. Capacity for interaction and repetitive stereotyped behavior, as well as results of Morris water maze test were determined for each group. The expressions of BDNF-TrkB proteins were assayed with immunoblotting. 

Results: The frequencies of sniffing normal saline, alcohol and rat urine were significantly higher in model and simvastatin rats than in normal rats, but they were significantly lower in simvastatin-treated rats than in model rats (p < 0.05). There was higher duration of turning, jumping and grooming in the model group and simvastatin group than in the normal rats, but the duration was significantly reduced in simvastatin rats, relative to model rats. Escape latency times was significantly longer in model and simvastatin rats than in controls, but number of target quadrant crossings was significantly reduced. However, escape latency time was lower in simvastatin rats than in model rats, but number of target quadrant crossings was significantly higher. The model and simvastatin rats had down-regulated levels of BDNF and TrkB protein, relative to control rats, but there were markedly higher levels of these proteins in simvastatin-treated rats than in model rats. 

Conclusion: Simvastatin improves the behavioral performance of autistic rats by regulating BDNF/TrkB signal axis. This finding may be useful in the development of new drugs for treating autism.

  

Conclusion

What is the conclusion? Well, I could say give up reading the new research and just read my old posts.  It seems you are not going to miss very much.

Of course, back in the real world, it is true that things do take time to change and after a few decades the leap might be taken from the research to the doctor’s office.

There already is plenty of research on the causes of autism and what steps can be taken by those who want to treat aspects of it.  It is far from a complete picture, but it is enough to get started.  There are no guarantees of success, but if you want 100% certainty you will wait forever.

Are any autism statistics credible? Most are not.

The best place for many statistics

In 2021 the UK government carried out a census and in that census there were some voluntary questions about sexual orientation. A surprisingly large 92.5% of respondents, aged 16 or over, answered the question on sexual orientation and just 3.2% identified as gay, lesbian, bisexual, or another sexual orientation (LGBT+). 

Even in the gay capital of the UK, a city called Brighton, only 14% identified as L or G. 

2021 census: What do we know about the LGBT+ population?

Go back 40 years and many LGBT people would have undoubtedly lied about their orientation, or just refused to answer the question. In most Western countries this is no longer the case – the pendulum has swung very much in favour of all minorities.

When my elder son was applying for jobs, the first part was always online and one of the first questions he faced is what is your sexual orientation – that is meant to be a sign of progress, apparently.  Having started work he discovered that the real key factor of the selection was, not surprisingly, whether you will fit in and what you like to drink down at the pub. I guess they want meat-eating colleagues who like a drink, or two.  Not a place for teetotal vegetarians.

If you watch CNN, the BBC or read news from a liberal source you might think that 20% were LGBT.  I would have guessed 10%.  In research targeting young people you also get vastly inflated figures, because their views are shaped by social media which rarely reflects reality.

 

Back to Autism

In the current diagnostic framework autism is split into level 1 (least affected), level 2 (moderate) and level 3 (most affected).

In some countries only a small number of very specific people can make a diagnosis, whereas in others a much broader group can hand out a diagnosis. In some countries you can effectively buy the diagnosis you are seeking.

In some countries only kids with an autism diagnosis can get free early intervention. Some doctors are diagnosing autism in a toddler with an intellectual/development delay because they know he is likely to benefit, even though he does not technically qualify.

In Australia having a level 1 diagnosis does not automatically entitle you to any free services and it was recently reported that doctors are changing the diagnosis to increase the child’s entitlements. 

Children are being diagnosed with autism more severely to secure NDIS funding

When I visited our local special school many years ago to meet their piano teacher, I learned that the school had a large Roma population and so some autism parents did not want to send their children there.  I asked why there were so many Roma kids. I was told they do not have autism, they are classified as having MR/ID, which then entitles the parents to financial support.

Many readers of this blog told me that if they improve their child’s cognition they will lose supports, so they keep on using an old IQ test result.  

 

So do I believe this recently published chart from the US?

 

It tells us that in 4 just years the number of kids with autism and MR/ID has doubled to  more than 1%.

It is not credible.

Here is the source:

 

AUTISM AND DEVELOPMENTAL DISABILITIES MONITORING (ADDM) NETWORK

 

Here is a chart showing autism prevalence in specific states in the US in 2020.

California leads the pack.

 

“Only” 22% of kids with ASD in California also had intellectual disability (MR/ID) compared to 48% in Arkansas.

But, that is because kids are twice as likely to get an autism diagnosis if they live in California.  This is because they are diagnosing many minor cases that would not get diagnosed in Arkansas.

 

California:

 

Arkansas:

 

Current incidence of autism

If 4.5% of 8 year old Californians have autism, that likely equates to something like 7% of boys and 2% of girls.

We know that about 20% of school children have some special educational need.  We know that about 4% of Americans will develop bipolar disorder, about 0.5% will develop schizophrenia and approximately 9% of adults in the U.S. have some type of personality disorder.

Let’s assume 10% of Americans are LGBT, well maybe better say Californians, to keep the peace.

We know that many LGBT people experience bullying and exclusion which will give some people symptoms that do indeed overlap with those of mild autism and hence they may choose to identify as autistic, get a diagnosis, join the autism club and make TikTok videos.

 

Future incidence of “autism”

I would predict the published incidence of “autism” in 8 year old Californian boys will reach 20% in the next decade.

Am I worried? Not really. It’s nonsense.

Any increase in genuine, severe, non or limited-verbal autism, with IQ<70 is a problem.  It could and should be addressed, but it will not be.

By the way, this kind of autism does not need the new name “Profound Autism”, that has been proposed by the Lancet Commission.  It already has several names, including Classic Autism and Autistic Disorder.  It just needs medical treatment! Go from level 3 to level 2, maybe passing some Australians going the other direction, seeking more money from NDIS.

  

Statistics in Autism Clinical Trials

All clinical trials involve statisticians, lots of data and hence lots of charts.

Unfortunately, almost all autism clinical trials are flawed from the outset.  There is no singular autism, but rather hundreds of biological variations that produce symptoms that appear to overlap with this fuzzy autism spectrum.  

Lump in all these different types of autism and of very different levels of severity and give all the kids the same therapy.

When a subgroup does respond, ignore it because it is too small; the overall clinical response does not satisfy the goal/endpoint of the trial.  The trial is branded a failure.

In the bumetanide trial as an example, what percentage of parents actually gave the pill every morning to the kids for the duration of the trial?  If the trial was during the school term, there will have been problems with needing to pee on the way to school and for the first 2 hours at school. After complaints from school and accidents in the car, what percentage really gave the pill every day?

As some readers of this blog have proposed, “I’ll just give it at the weekend”.

Combine the behavior of the parents, the school bus driver and the class teacher with the trial using a dose 50% too low, is it a surprise the statistics show that the phase 3 trial failed? Not to me and many others.

Statistics on Treatable ID and single gene autisms

We are told that syndromes leading to treatable types of intellectual disability (MR/ID) are so rare that it is not cost effective to screen children for them.

We are also told that there are numerous single gene autisms, but that they are ultra rare.

Since almost no children with autism are routinely screened using genetic testing, there is no way to know just how rare treatable ID or single gene autism actually are. 

The current statistics on the incidence rates are nonsense.

Conclusion

Garbage in, garbage out.

Since it was first coined in the world of computer science in the 1950s, the phrase “garbage in, garbage out” has been a popular metaphor for flawed, or nonsense data input that produces flawed or nonsense output, aka “garbage.”

Mark Twain popularised the phrase "lies, damned lies, and statistics" to describe the persuasive power of statistics to bolster weak arguments.

Or, as I would say, if you need a statistician to prove your point, you probably don’t have one.