Out with the old and in with the new? Maybe for iPhones but not for Autism therapies

 

It is important to move with the times, but it is equally important to realize that some old ideas remain better than some new ideas.

I was both pleased and surprised that my new car came with a full sized spare wheel in the boot/trunk. Where we live you can expect at least one puncture a year. In theory you do not need a spare wheel because cars rarely have punctures and you can carry an aerosol spray that will temporarily inflate the tire and fill a small hole. Some cars have skinny space-saver spare wheels. Neither of these is actually a good alternative.  

Old vs new autism therapies

People definitely are interested in new and “cutting edge” therapies for autism.

I was recently contacted again by a reader of this blog who has been struggling to control self injurious behaviors in her child for years. I have provided many ideas that have each worked a sub-group of those with SIB. One idea I had not yet suggested was Memantine/Namenda.

Memantine is a cheap, old, and not very effective Alzheimer’s drug.

It blocks NMDA receptors in the brain to prevent excessive stimulation by glutamate. It does actually have many other modes of action.

It has weak inhibitory effects on L-type calcium channels that add to its neuroprotective profile. This secondary mechanism helps regulate calcium influx, protect neurons from excitotoxicity, and mitigate oxidative stress, making it beneficial for managing various neurodegenerative and excitotoxic conditions.

Memantine has mild inhibitory effects on AMPA receptors, reducing overall excitotoxicity.

Memantine may block certain sodium ion channels, which can reduce neuronal excitability and help prevent excitotoxicity.

Memantine has been found to interact with serotonin (5-HT3) receptors, modulating their activity, which might contribute to cognitive and mood improvements.

Memantine reduces microglial activation, which is associated with neuroinflammation. This anti-inflammatory action can protect against secondary neuronal damage in neurodegenerative conditions.

By preventing excessive calcium influx through NMDA receptors, memantine reduces the production of reactive oxygen species (ROS), protecting neurons from oxidative damage.

Memantine's ability to stabilize calcium homeostasis helps maintain mitochondrial function, reducing energy deficits and apoptosis (programmed cell death).

Memantine may enhance synaptic plasticity by reducing pathological over activation of glutamate receptors. This improves synaptic connectivity and cognitive function.

Some studies suggest that memantine may partially activate or modulate nicotinic acetylcholine receptors, which are important for attention and memory.

Memantine may increase brain-derived neurotrophic factor (BDNF) levels, promoting neuronal survival and plasticity.

Memantine as a treatment for SIB in some, but a cause of it in others

It is clear from the above summary of Memantine’s modes of action that it should indeed be effective for some people’s SIB (self injurious behavior). Unfortunately, all these changes in the excitatory-inhibitory balance can cause problems in some other people where Memantine actually causes SIB.

Too much glutamate can be very damaging

Glutamate excitotoxicity refers to the pathological process in which excessive activation of glutamate receptors, particularly NMDA and AMPA receptors, leads to over-excitation of neurons. This over-excitation can result in cellular dysfunction, oxidative stress, and ultimately neuron death. It is a common mechanism underlying many neurological and neurodegenerative conditions.

NMDA and AMPA receptors, over activated by the high levels of glutamate, trigger a massive influx of calcium (Ca²⁺) ions into neurons.

High intracellular Ca²⁺ levels disrupt cellular homeostasis. It activates enzymes that damage cellular structures it causes oxidative stress, mitochondrial dysfunction and eventually cell death.

Elevated intracellular Ca²⁺ from allergy causing elevated glutamate and SIB

As we know from this blog, some SIB is triggered by allergy. You can halt it via treating the allergy, blocking the L-type calcium channels or targeting other inflammatory pathways.

In this allergy-driven self injurious behavior (SIB), glutamate is likely a significant downstream effector. Allergic reactions and inflammation can disrupt calcium homeostasis and activate pathways that increase glutamate signaling, leading to heightened excitotoxicity and contributing to behaviors such as SIB.

Allergic reactions significantly impact calcium homeostasis, primarily through the activation of immune cells, release of inflammatory mediators, and systemic effects on calcium metabolism. These disruptions contribute to the symptoms and complications of allergic diseases and highlight potential therapeutic targets to restore calcium balance.

When allergens bind to IgE on mast cells or basophils, they activate receptors that trigger intracellular calcium release from the endoplasmic reticulum (via IP3 signaling). Recall Prof Gargus proposed IP3 signaling as a nexus point in autism.

Is dysregulated IP3R calcium signaling a nexus where genes altered in ASD converge to exert their deleterious effect?

This calcium influx promotes the degranulation of histamine, serotonin, and other inflammatory mediators.

Abnormal calcium levels may trigger unregulated, spontaneous release of glutamate, even in the absence of an action potential.

Elevated calcium levels can impair the function of glutamate transporters (e.g., EAATs), responsible for clearing excess glutamate from the synaptic cleft.

Dysfunctional transporters exacerbate extracellular glutamate accumulation, amplifying excitotoxicity.

Memantine in broader autism

Memantine was extensively studied in a large clinical trial in autism that concluded that it was no better than a placebo.

You might well conclude that the matter should end there.

Memantine for Aspies

While looking for information about Memantine for SIB I came across some very positive reviews from Aspies.

If you believed social media you would think that people with level 1 autism are all anti-treatment and see autism as their superpower. In fact the majority of people contacting me about treating autism are actually those with level 1 autism and their parents.

I am really much more familiar with treatments for level 3 autism.

The symptoms may be slightly different, but the potential therapies are exactly the same.

 

https://www.drugs.com/comments/memantine/for-autism.html

"A life saver. I have autism. It is pretty bad autism. I saw help on day one. But it isn't a fix-it-all for me. Being able to understand nonverbal communication and verbal communication is huge improvements. This helps me with social interaction. This helps me with anxiety. Helps my expressive myself and respond better. Less meltdowns. Helps my cognitive functions. Helps me think. Helps my thought issue due to my autism and auditory processing disorder. Helps me slow down my mind to pay attention more and can respond to changes and sensory problems. Not a full fix for me but huge help. I am more polite. I can talk about others' interests not just my needs or wants or questions that I had trouble asking. Better behavior." 

"I was first prescribed this for Asperger's syndrome at the age of 24. I've been on numerous types of medications since I was a teenager, but this is the first one that I've been on that has significantly helped. My quality of life is much better. I don't have as many ruminating, obsessive thoughts that make me miserable." 

"I take 20 mg of memantine for my slight autism! And this has been a miracle drug! It helps me in social interactions, I can recognize social cues and skills that I couldn't before! It also helps with my obsessive and aggressive problems! Thank you to whoever made this drug." 

"I take 10 mg twice daily for autism spectrum disorder. It stops the intrusive thoughts, rumination, and repetitive thinking, which is a godsend. It also reduces repetitive behavior/stereotypes. I haven't noticed any side effects, maybe a little brain fog, but that has disappeared with continued use."

"Memantine has helped my social anxiety greatly, not through direct anxiolysis, but indirectly through dissociation from reality, albeit mild. It works perfectly for sensory overload as the autistic brain does not filter out unnecessary external stimuli due to NMDAR current blockade, similar to endogenous magnesium. Amazing, wonderful."

 

Conclusion

Don’t ignore all the therapies from the last 50 years and jump to the latest expensive therapy that is trending. You may after all find one of the oldies like Propranol, Pentoxifylline, Zoloft, Baclofen or Memantine is your Gamechanger. They each worked for some people.

Even though it failed in its phase 3 clinical trial, Memantine continues to have its believers. It is a cheap safe drug that clearly does provide a benefit to a sub group of autism that includes all levels of severity. It clearly does not work for all Aspies, but it certainly is worth trialing.

I think understanding glutamate excitotoxicity is very useful if you are trying to figure out a case of self injurious behavior.

In individuals where the GABA developmental switch has not occurred, oral GABA supplementation could potentially exacerbate glutamate excitotoxicity and trigger/worsen self injurious behavior. These are the people who react badly to benzodiazepine drugs and should respond very well to bumetanide.

No Wegovy/Mounjaro moment likely for autism – Lithium etc

 

Semaglutide, marketed under brand names like Wegovy, Mounjaro and Ozempic, is a GLP-1 receptor agonist originally approved for treating type 2 diabetes and more recently for obesity. The global semaglutide market is $27 billion in 2024. The broader market for GLP-1 receptor agonists, which includes semaglutide, is expected to experience significant growth. Analysts project that this market could reach between $150 billion and $200 billion by the early 2030s.

Semaglutide is a dream for pharmaceutical companies. The overweight can forget about diets and exercise; they just need a weekly self-administered dose and wait to lose 20% of their bodyweight in the first year. If they stop taking the drug all the weight will just come straight back, so the patient needs to take the drug for life.

Semaglutide is expensive, but nothing like the price hoped for by those developing elusive autism drugs.

Some obese people save so much money on food it covers the cost of their semaglutide.

Obesity is so damaging that semaglutide should have a transformative impact on healthcare.

On the other hand, the idea that society might increasingly rely on pharmaceutical solutions instead of encouraging lifestyle changes feels rather Orwellian, with a shift away from personal responsibility, fostering dependency on external control. In a society where health problems like obesity are "fixed" by a drug, self-regulation through lifestyle choices will be de-emphasized, giving the impression that human behavior is best managed through a weekly shot.

In the novel Brave New World by Aldous Huxley, published in 1932, people in a highly controlled society all take a drug called soma to feel good, maintain emotional stability, and suppress negative feelings.

 

No Wegovy/Mounjaro moment likely for autism

For people who get their information from social media it appears that such an effortless Wegovy/Mounjaro moment exists for autism. You just send a reply to Facebook post and get a message back telling you where to buy the miracle cure to autism.

Looking at the world of pharmaceuticals many parents hoped that Suramin would be the cure to autism.

Recently I saw yet another rather misleading headline:

Lithium restores brain function and behavior in Autism

Really, what it should say is:

Lithium may restore brain function and behavior in Autism caused by Dyrk1a mutation if given while a baby.

 

Here is the article.

Lithium Restores Brain Function and Behavior in Autism

Lithium, a drug widely used for bipolar disorder, may also treat autism spectrum disorder (ASD), according to new research. The study found that lithium restored brain function and reduced behavioral symptoms in mice with Dyrk1a gene mutations, a known ASD risk factor.

Administered during the juvenile period, lithium normalized brain size, improved neural connectivity, and eased anxiety and social deficits, with benefits persisting into adulthood.

This breakthrough highlights lithium’s potential to address core ASD mechanisms through its action on Kalirin-7, a molecule critical for synaptic function. The findings underscore the importance of early intervention and targeted treatments for ASD.

The team discovered that lithium’s therapeutic effects are partly mediated through its action on Kalirin-7, a molecule essential for synaptic structure and function.

By targeting this molecule, lithium helped to restore balance in the brain’s signaling networks, addressing one of the core mechanisms of ASD.

“This is an exciting breakthrough,” said Dr. Roh Junyeop, a senior researcher and co-first author of the study.

“Dyrk1a mutations disrupt neural connectivity, much like a traffic jam or roadblocks in a city. Lithium helps to clear the congestion, restoring smooth communication between neurons.”

Director Kim Eunjoon emphasized the potential impact of these findings, stating, “Our research shows that lithium, a widely used drug for bipolar disorder, could also serve as a treatment for ASD. The fact that its effects persist long after treatment ends underscores the importance of early intervention during critical developmental windows.”

This study, published in the journal Molecular Psychiatry on December 5, not only paves the way for new therapeutic approaches for ASD but also underscores the critical importance of early diagnosis and intervention.

It offers hope to families and individuals affected by ASD, suggesting that targeted treatments may one day reduce the burden of this complex disorder.

 

Too little Dyrk1a leads to small brains, autism and low IQ. In Down syndrome there is too much Dyrk1a expression and this is a contributing factor to low IQ. You need just the right amount of Dyrk1a for optimal brain development and then a higher IQ. Too much Dyrk1a also leads to Alzheimer’s which is why there can be early onset in those with Down syndrome.

Don’t give lithium to someone with Down syndrome.

 

GSK-3β and Dyrk1a

In previous posts we did look at something called GSK-3β, which plays a role in autism.

GSK-3β  and DYRK1A  are two enzymes that play significant roles in regulating cell signaling, neurodevelopment, and brain function. They also interact with each other. Both play a role in the Wnt signaling pathway, which is disturbed in much autism and some cancer.

 

Lithium in Autism

Lithium carbonate is a prescription drug used to treat bipolar.

Lithium orotate is an OTC product that some people do use to treat autism. The dosages are usually very low compared to what is used in bipolar.

It is not uncommon to be diagnosed with bipolar and autism.

 

Is Lithium a game changer for Autism?

While some people may well benefit, the usage to date shows that lithium is not a game changer for most autism.

 

Mebendazole for some Autism and indeed Down syndrome

I did propose years ago that Mebendazole/Vermox, the cheap drug used to treat pinworms in children, might have potential to treat some autism. Mebendazole is a Wnt inhibitor (the opposite of Lithium). I did receive a message recently that Mebendazole was beneficial in one reader’s son. Not much Mebendazole is absorbed into the bloodstream but you can maximize it by taking it with a fatty meal. It does cross the blood brain barrier.

Mebendazole has been shown to inhibit DYRK1A in laboratory settings, which could potentially address the effects of DYRK1A overexpression seen in conditions like Down syndrome. Since Down syndrome is diagnosed very early, treatment could start very early, which is critical to optimize the developing brain.

 

Mebendazole - Wnt Inhibition and other effects

Mebendazole is known to inhibit components of the Wnt signaling pathway. Inhibition of Wnt could potentially normalize overactive or dysregulated pathways, leading to more balanced dendritic spine dynamics in individuals with autism. In autism, there is often an imbalance in dendritic spine formation and pruning, leading to either excessive or insufficient connectivity. Modulating Wnt signaling could potentially restore this balance, improving synaptic function and related behaviors.

Mebendazole has been shown to have anti-inflammatory properties. Since neuroinflammation is often elevated in autism, this could indirectly improve symptoms.

Mebendazole also stabilizes microtubules, which are critical for intracellular transport and synaptic function. This might indirectly benefit neuronal communication in autism.

  

Conclusion

Autism is far more complicated and heterogeneous than obesity so sadly there can never be a simple Wegovy/Mounjaro moment.  Best not to listen to Autism Moms telling you otherwise on Facebook.

On the plus side there are numerous partially effective therapies, sitting on the shelf in the pharmacy that do benefit specific types of autism. You just have to find what works in your very specific case.

I was recently asked a German mother if I have a spreadsheet listing all the possible therapies, what the benefits are, and in what order to try them. It is a very rational request, but there is so much variation that this would not be a simple task.