The CDC Suggests People with Severe Autism are at Elevated Risk from Covid-19 – Time to ACE it?

Elvin Jail in Iran, a hotbed for Covid-19 transmission. Iran has released 70,000 prisoners on furlough, including some foreign political prisoners

I was a little surprised to hear that people with neurodevelopmental disabilities are on the US Center for Disease Control (CDC) list of those at risk from the current Corona virus (Covid-19).  I can see no biological reason for this, but I can see the elevated risks for anyone living in an institution rather than at home, rather like cruise ships and prisons not being safe places to be living right now.

I did check that the CDC have such a list and indeed they do:

Appendix A: Underlying medical conditions that may increase the risk of serious COVID-19 for individuals of any age.

• Blood disorders (e.g., sickle cell disease or on blood thinners)

• Chronic kidney disease as defined by your doctor. Patient has been told to avoid or reduce the dose of medications because kidney disease, or is under treatment for kidney disease, including receiving dialysis

• Chronic liver disease as defined by your doctor. (e.g., cirrhosis, chronic hepatitis) Patient has been told to avoid or reduce the dose of medications because liver disease or is under treatment for liver disease.

• Compromised immune system (immunosuppression) (e.g., seeing a doctor for cancer and treatment such as chemotherapy or radiation, received an organ or bone marrow transplant, taking high doses of corticosteroids or other immunosuppressant medications, HIV or AIDS)

• Current or recent pregnancy in the last two weeks

• Endocrine disorders (e.g., diabetes mellitus)

• Metabolic disorders (such as inherited metabolic disorders and mitochondrial disorders)

• Heart disease (such as congenital heart disease, congestive heart failure and coronary artery disease)

• Lung disease including asthma or chronic obstructive pulmonary disease (chronic bronchitis or emphysema) or other chronic conditions associated with impaired lung function or that require home oxygen

• Neurological and neurologic and neurodevelopment conditions [including disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy (seizure disorders), stroke, intellectual disability, moderate to severe developmental delay, muscular dystrophy, or spinal cord injury].

Treating Covid-19

There are well established strategies in place to treat flu pandemics, but Corona virus is different, although there are similarities.

There is already a great deal of research published, thanks to very fast working Chinese researchers.

In simple terms there are two strategies:-

1.     Inhibit the spread of the virus

2.     Halt the cytokine storm that triggers pneumonia and respiratory failure, should the disease progresses that far

If you fail in these two steps you are left with the same situation as occurred in the Spanish flu epidemic, where you treating what has become a bacterial infection in your lungs and hoping for the best. Nowadays we have antibiotics and a small number of ventilators.

Fortunately, initial studies have already been completed and show positive results in both (1) and (2) above.

Some of the drugs used to inhibit the spread of the virus are cheap generics, while one is a Japanese drug originally developed to treat the flu.

The last time the world was worried about a pandemic people stocked up with an antiviral drug called Tamiflu.  Tamiflu does not work for Coronavirus.

What does work are some old drugs originally used to treat malaria that include:-

1.     Hydroxychloroquine (HCQ), sold under the brand name Plaquenil
2.     Chloroquine, a 70 year-old drug sold under names including Resochin

In France Sanofi is offering to donate millions of doses of Plaquenil to the Government and in the US Bayer has offered to donate Resochin. 

It appears that Plaquenil works better and has less side effects.

In Japan they have a drug developed to treat flu called Favipiravir (also known as Avigan).  In trials it has the same effect as the old malaria drugs, it shortens the duration of the disease by about half and so reduces severity.

In all cases the drugs that target the replication of the virus need to be taken early on in the disease progression, to give any benefit.  This makes perfect sense.

What kills people in Covid-19 is the same thing as in the Spanish flu of 1918, it is a cytokine storm when the body’s immune system over-reacts and attacks your lungs.

If the disease progresses to this point you have to look at therapies to treat cytokine storms associated with severe influenza.

Here we have at least two interesting approaches:

1.     IL-6R antibodies (Roche’s Actemra)   
2.     S1P1 receptor agonist like Fingolimod (Gilenya)

Actemra is already in trials to treat Covid-19, but is injected.

Gilenya is an immunomodulating drug, mostly used for treating multiple sclerosis, taken by mouth.

One feature of Covid-19 is hypokalemia.  When sick these people excrete potassium in urine and become hypokalemic, they may need 3,000mg a day of potassium supplement.  As they get better, they stop losing potassium. This all relates to the angiotensin system, disturbed by the virus.

If you take bumetanide you excrete potassium, so if you get Covid-19 you would be wise to stop bumetanide, but keep taking potassium supplements. 

ACE2 Coronavirus and Italians

The reseach has already identified how the Covid-19 virus spreads in humans.  It uses Angiotensin converting enzyme 2 (ACE2) and ACE2 receptors.

To inhibit the spread of the virus you want less ACE2.

In normal times ACE2 is a very good thing to have and it is a marker for a healthy person. In some people they have variations of the gene that produces ACE2 or its receptor.  This variation is seen in Italians and also in sportsmen - not a good time to be an Italian sportsman.

Certain drugs increase ACE2 and certain drugs you might expect to lower ACE2 appear not to.

You might think Grandma’s ACE inhibitor, she takes to lower blood pressure would inhibit ACE2, but ACE inhibitors inhibit ACE1.  It appears they increase ACE2 receptor expression and ACE2 itself.

There are two issues, the number of receptors and the amount of the enzyme, both are relevant.

Chinese research on real patients found that those taking ACE inhibitors and ARBs had elevated levels of ACE2.

Ibuprofen has been reported to increase ACE2.  In children treated in France, there condition became much worse after treatment with Ibuprofen.

Glitazone drugs, that can help treat a cytokine storm, unfortunately seem to increase ACE2.  These drugs are used to treat type 2 diabetes.

ACE inhibitors and ARBs are also useful un treating a cytokine storm, but raise ACE2 and so must be avoided.

Practical Strategies

I should start by pointing out that researchers at Imperial College in London, who have analysed the data from a town in Northern Italy where 100% of the residents were tested for Covid-19, suggest that only one in eight people with the virus actually show symptoms.

German researchers think that over the next two years 60-70% of their population will catch the virus.

It is only the at-risk groups where mortality is going to be widespread.

I started writing this post when I heard some of Donald Trump’s “experts” standing beside him talking about the virus. I was not very impressed.  Then I read a newspaper interview with an “expert” in England saying how they would treat a new patient with Covid-19.  He would use Tamiflu and later antibiotics.

Where we live, they have very few ventilators and so it really makes sense to change the course of the disease so that you will never need one.

The generic drugs to stop the virus replicating are cheap, while the modern immunomodulatory drugs to halt the cytokine storm are extremely expensive.

My choice is Hydroxychloroquine (Plaquenil).  In France the published adult dose used is 600mg for 10 days. UPDATE I would also add Azithromycin, based on the chart at the end of this post.  In a small French trial the combination is remarkable, after 5 days the virus has gone in 100% of patients. This a cheap macrolide antibiotic, with long known immunomodulatory effects. 

If you look at the half-life of this drug, it is extremely long, over one month.  If I was treating myself for Covid-19 I would start with a higher dose and then taper it.  You need the greatest effect at the start, not the end of the therapy.

I do not actually believe that a healthy boy with autism, living at home, is at elevated risk of Covid-19, but if I am wrong, I will be giving Hydroxychloroquine (Plaquenil) immediately, should Covid-19 be confirmed.

These drugs have side effects and you would not want to use them when it is just a cold or flu.

Since Ibuprofen is reported to increase ACE2, I certainly will not be using it.

Paracetamol/acetaminophen has the big problem of depleting the body’s key antioxidant GSH.

GSH itself has a benefit on inhibiting virus replication.

Since I already give a large daily dose of NAC (N-acetylcysteine) to boost GSH levels, I would use paracetamol to treat a very high temperature in Covid-19.

I think Monty’s grandparents are the ones that might need the anti-cytokine storm therapy.

People with autism often have potent immune systems.  In the Spanish flu, it was young adults with good immune health that died.  They died because they generated potent cytokine storms in their lungs, which express ACE2 receptors and then they developed bacterial pneumonia. In medical jargon they developed acute respiratory distress syndrome (ARDS) and sepsis, causing death. 

In the first stage of Covid-19 a potent immune system should be an advantage, if it identifies the virus.  In the final stage of the disease, which most people avoid, an overactive immune system might not be a good thing.

I think that Hydroxychloroquine (Plaquenil) is a good insurance policy.

If I was a US Presidential candidate, or any other rich elderly person, I would put my order in for Actemra, just in case I needed it.

Actemra (Tocilizumab) is an expensive drug to treat arthritis in adults and children.  It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many disease.  IL-6 is a key player in the cytokine storm in Covid-19.  It is taken by I/V infusion.

An advantage of the S1P1 agonists is that they are taken as tablets.

The following paper is very good and has links to the latest research papers from China, which are also very relevant:-

Are patients withhypertension and diabetes mellitus at increased risk for COVID-19 infection?

The most distinctive comorbidities of 32 non-survivors from a group of 52 intensive care unit patients with novel coronavirus disease 2019 (COVID-19) in the study by Xiaobo Yang and colleagues  were cerebrovascular diseases (22%) and diabetes (22%). Another study  included 1099 patients with confirmed COVID-19, of whom 173 had severe disease with comorbidities of hypertension (23·7%), diabetes mellitus (16·2%), coronary heart diseases (5·8%), and cerebrovascular disease (2·3%). In a third study, of 140 patients who were admitted to hospital with COVID-19, 30% had hypertension and 12% had diabetes. Notably, the most frequent comorbidities reported in these three studies of patients with COVID-19 are often treated with angiotensin-converting enzyme (ACE) inhibitors; however, treatment was not assessed in either study.

Human pathogenic coronaviruses (severe acute respiratory syndrome coronavirus [SARS-CoV] and SARS-CoV-2) bind to their target cells through angiotensin-converting enzyme 2 (ACE2), which is expressed by epithelial cells of the lung, intestine, kidney, and blood vessels.

The expression of ACE2 is substantially increased in patients with type 1 or type 2 diabetes, who are treated with ACE inhibitors and angiotensin II type-I receptor blockers (ARBs).

 Hypertension is also treated with ACE inhibitors and ARBs, which results in an upregulation of ACE2.

ACE2 can also be increased by thiazolidinediones and ibuprofen. These data suggest that ACE2 expression is increased in diabetes and treatment with ACE inhibitors and ARBs increases ACE2 expression. Consequently, the increased expression of ACE2 would facilitate infection with COVID-19. We therefore hypothesise that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19. 

The cytokine storm of severe influenza and development of immunomodulatory therapy

Severe influenza remains unusual in its virulence for humans. Complications or ultimately death arising from these infections are often associated with hyperinduction of proinflammatory cytokine production, which is also known as ‘cytokine storm'. For this disease, it has been proposed that immunomodulatory therapy may improve the outcome, with or without the combination of antiviral agents. Here, we review the current literature on how various effectors of the immune system initiate the cytokine storm and exacerbate pathological damage in hosts. We also review some of the current immunomodulatory strategies for the treatment of cytokine storms in severe influenza, including corticosteroids, peroxisome proliferator-activated receptor agonists, sphingosine-1-phosphate receptor 1 agonists, cyclooxygenase-2 inhibitors, antioxidants, anti-tumour-necrosis factor therapy, intravenous immunoglobulin therapy, statins, arbidol, herbs, and other potential therapeutic strategies.

  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711683/figure/fig1/?report=objectonly

Cytokine storm in the lung following severe influenza infection. (1) Viruses infect lung epithelial cells and alveolar macrophages to produce progeny viruses and release cytokines/chemokines (mainly contains interferons). (2) Cytokine/chemokine-activated macrophages and virally infected dendritic cells lead to a more extensive immune response and the initiation of cytokine storm. (3) Released chemokines attract more inflammatory cells to migrate from blood vessels into the site of inflammation, and these cells release additional chemokines/cytokines to amplify cytokine storm.

Summary of immunomodulatory therapy or strategies against severe influenza

Therapeutic agents or strategies	Summary
Corticosteroids	Alleviated the 2009 pandemic H1N1 influenza-infected patients with pneumonia.30 Ineffective as monotherapy in H5N1 influenza-infected mice.29 Increased long-term mortality in influenza-infected patients with pneumonia.27
PPARs agonists	Ciglitazone and troglitazone decreased the mortality of influenza-infected mice.34 Bezafibrate partially protected patients with influenza-associated encephalopathy.33 Gemfibrozil also decreased the production of IL-1, IL-6, and IFN-γ, but has no effects on the mortality of H5N1-infected mice when administered 48-h post-infection.31,32
S1P1 receptor 1 agonists	Reduced mortality of 2009 pandemic H1N1 influenza-infected mice over 80%, compared with 50% protection of oseltamivir.36
COX inhibitors	Ineffective as monotherapy in H5N1 influenza-infected mice, while effective when in combination with neuraminidase inhibitors.32
Antioxidants	N-acetylcysteine and glycyrrhizin inhibited H5N1 replication and pro-inflammatory gene expression in vitro39,40 but ineffective as monotherapy in vivo.45
Anti-TNF therapy	Effective in reducing the cytokine production and inflammatory cell infiltrates in influenza-infected murine lung but ineffective in improving survival of infected mice.47,48
IVIG therapy	Reduced 26% to 50% mortality of 2009 pandemic H1N1 and 1918 Spanish H1N1 influenza-infected patients.50,52
ACEIs or ARBs	Combined with caffeine or antivirals, alleviated lung injury and inhibited viral replication in H1N1, H3N2, and H5N1 influenza-infected mice.54 Ineffective in protecting 2009 pandemic H1N1-infected patients.55
CCR inhibitor	Increased survival of influenza-infected mice by 75%.58
AMPK activators	Increased survival for influenza-infected mice by 40%, while a combination with pioglitazone improved survival by 60%.59
OX40	Imparted a survival signal to the T cell via upregulating anti-apoptosis gene expression and eliminated weight loss in influenza-infected mice.60
SOCSs	Participated in a negative feedback loop in the JAK and epidermal growth factor receptor pathway to protect against severe cytokine storm during severe influenza.61
Macrolide	Decreased mortality, pro-inflammation, and inflammatory cell counts of influenza-infected mice.62
Arbidol	Reduced the mortality, lung lesion formation, and inflammation of severe influenza-infected mice.64
Herbs	Favorable in laboratorial data but limited clinical data for severe influenza.65,66,67,68,69,70,71

Polytherapy - Hydroxychloroquine plus Azithromycin (a macrolide, from the table above)

Click on figure below to enlarge it

Should you treat Severe Autism yourself? Consider what may happen if you do not

RMS Carpathia  picked up Titanic survivors from life boats, the others had drowned

I was recently asked by some friends of ours, how come Monty, now aged 16 with autism, has changed so much over the last ten years. It turns out they have a relative with a 12-year-old son, who has autism and does not speak.

A few weeks later I was asked to have a chat with the boy’s mother and tell her what I have been doing, regarding treating autism, for the last 13 years.  Following the standard practice where we live does not give good results.  The boy does not talk, was not taught sign language, or to use any augmentative communication device, he cannot write and cannot read.  He goes to mainstream school and has a 1:1 assistant, but what does he learn there?

When we started treating Monty after his diagnosis aged three, he was entirely non-verbal, cried a lot and was not interested in anything.  From the age of four he was sitting at a little table being instructed at home, as well as going to kindergarten four hours a day.   Only from the age of 11 did he become full time at school. 

A couple of weeks ago Monty was skiing on black slopes (the hardest ones) in Slovenia and Austria, with his elder brother. He had to read a very dull 220-page book during the school break. We are practicing quite hard maths at home, using an online teaching resource.  When getting fitted for ski boots, Monty’s mother explained to the guy in the ski rental store, “he’s autistic … but he can ski”.  Yes, he can ski, but it was not a simple road to get there. He started when he was 6 years old with a special needs instructor; when he was eight he fell on the ski slope and broke his collar bone - a perfect opportunity to give up for good, but we did not.  Now he skis all week without a fall. It did not just happen, ditto playing the piano, ditto tying shoelaces, learning to cross roads and everything else.

I explained to the mother of the 12 year old how much easier it became to teach Monty, after starting his Polypill therapy, but that you still need to use personalized education alongside personalized medicine.  If you use neither, the result is what it is.

Instruction at home does not have to cost anything, it just requires a vast amount of perseverance.  All the books you might need have existed for decades.  The advent of the internet and touch screens makes everything so much easier.

Even in rich countries like the US and UK, the outcomes in severe autism are usually pretty terrible and yet could be so much better.

Some parents seem to be waiting to be extracted from their “autism hell”, but nobody is coming to help them.

I recall visiting Romania after the fall of communism and being told how many people endured a pretty tough life in the 1980s.  Some people actually believed during Communism that “the Americans will come” and liberate them; they never came and Romanians liberated themselves in 1989. It took them 42 years and a little prompting from a man in Gdansk (Lech Wałęsa). 

Below is an excerpt from Thinking Autism’s current blog post.

https://www.thinkingautism.org.uk/autism-disability-consequences-of-polarised-debate/?fbclid=IwAR2TJb-mH1vn2AM_t0SJttPgvRX7K5am3EHOka7VfVw2A7AziYafRF_6XBA

What autism means for my son

My son is 20, has very high support needs, minimal speech, and his communication is limited to basic requests. His sensory processing difficulties are severe enough to have a significant impact upon his attention, focus and learning. He can’t hold a conversation, talk about past experiences, or tell me if he is in pain. He has little awareness of danger, and needs round-the-clock supervision.

Unless an effective medical treatment is found, he will never be able to keep himself safe or make any important decisions for himself, and will eventually require some form of closely supervised residential care for the rest of his life.

That is the stark reality of the impact of autism on my son.

Clearly, if my son’s disability were cured or corrected, then all the barriers to his full participation in society would be completely removed, and he would have no need for societal accommodations. If his disability were managed or diminished, he may well have greater independence and freedom; for example, improved communication skills might enable him to exercise a greater degree of choice and control over his life.

A drug called bumetanide has also been shown to ameliorate symptoms of ASD in a number of trials … The first bumetanide studies were carried out in 2010, but ten years later, translation into clinical practice still seems a long way off.

In the intervening decade, my son’s childhood and teenage years have passed by, and he has entered adulthood, with no prospect of accessing any of these potentially life changing treatments.

When the Titanic sank in the Atlantic Ocean, those without a place in the lifeboats waited 160 minutes for the ship to sink.  120 minutes after Titanic sank, the rescue ship, Carpathia, appeared.  Do you stand on the deck listening to the band playing as the ship sinks, or at least try and build yourself a raft?

My suggestion to those left on the deck of the Titanic, or parents enduring their “autism hell”, is to do something about it.  If your child learns nothing at school, then teach him at home.  If you want bumetanide, go and buy some.  If you want a doctor to help you, go and find one.

Why do some autism parents, particularly those dealing with severe autism, not help themselves? 

This recent study suggests something that we probably already knew. Some people call it denial, others depression.  I actually think it is best described as the "freeze" response, which does actually exist in psycho-babble speak. In the freeze response to a shock there is no fight, no flight, just nothing.

https://www.psychologytoday.com/us/blog/evolution-the-self/201507/trauma-and-the-freeze-response-good-bad-or-both 


According to new autism research, we can now call it post traumatic stress disorder (PTSD).   

Challenging child behaviours positively predict symptoms of post-traumatic stress disorder (PTSD) in parents of children with Autism Spectrum Disorder and Rare Diseases

·        18.6% of the sample of parents of children with ASD met criteria for a provisional diagnosis of PTSD.

         

·        Health professionals should screen parents for PTSD when potentially traumatic challenging behaviours are present in children with ASD.

In reality, if health professionals do not want to treat children with autism, they are unlikely to want to treat post-traumatic stress disorder (PTSD) in their parents. but it is a nice idea.

It does not help that autism organisations often give very poor advice (advice proven not to yield good results) and doctors are usually taught nothing about autism; only a very few can help you.

Mainstream schools should not accept children if they cannot teach them at least basic skills.  The most basic skill is some form of communication, be it sign language or some form of augmentative communication.

Special schools that do not at least try to teach some form of augmentative communication should not exist, but they do.

Calcium Folinate (Leucovorin) and Afobazole for Autism? Good, but …

Dr Frye is embarking on a multi-million dollar trial of Calcium Folinate (Leucovorin) to improve speech in autism.  I just completed my much humbler trial of a cheap generic Calcium Folinate.

I determined it was far cheaper and simpler to make a trial, than arrange for the blood test.  The other reason is that I note in the US they are prescribing Leucovorin, even if you test negative in the test for autoantibodies.

http://iliadneuro.com/order-a-kit.html

Dr Frye thinks many people with autism have low levels of folate inside their brain due to antibodies blocking folate crossing the blood brain barrier.  He even suggests that perhaps the source of these antibodies is your gut and they are produced as a reaction to cow’s milk.

I wondered why speech would be so directly affected by folate, but speech is something that is very noticeable and measurable.

I used 30mg of calcium folinate at breakfast and 15mg in the evening.

After a few days there was very clearly more speech. On several occasions I asked Monty a question, even without facing him eye to eye, and he gave a very much longer response than usual. The response was more like what he would produce if writing with a pencil and paper.

The problem was that three times during the trial he hit me, which is not his typical behavior. Aggression is a listed side effect of high dose calcium folinate.

Excerpt from Dr Frye’s colleague, Dr Dan Rossignol:

Dan Rossignol’s  Presentation at Synchrony 2019 | November 8, 2019

Folinic acid

• The good: Improvements in expressive speech, play skills, social skills, receptive language, attention, stereotypy

• The bad: Hyperactivity, self-stimulatory behaviors, aggression

Calcium Folinate (Leucovorin) is expensive in the US, but very much cheaper in some other countries, so it would be a viable therapy for many people.

Is there a lower dosage where you get the speech benefit without getting hit? I rather doubt it. It did actually try 15mg a day, a while back and saw no effect at all.

Since we do not really know why Calcium Folinate improves speech in particular, I doubt we can say why it produces aggression.

My old post from 2016:-

Clinical Trial of Mega-dose Folinic Acid in Autism

The new trial that is planned:-

Early Treatment of Language Impairment in Young Children With Autism Spectrum Disorder With Leucovorin Calcium

The primary objective of this study is to evaluate the cognitive and behavioral effects of liquid leucovorin calcium on young children with autism spectrum disorder (ASD) and determine whether it improves language as well as the core and associated symptoms of ASD. The investigators will enrol 80 children across two sites, between the ages of 2.5 and 5 years, with confirmed ASD and known language delays or impairments. Participation will last approximately 26 weeks from screening to end of treatment.

  

Afobazole

Afobazole is the cheap Russian OTC treatment for anxiety that works as a sigma-1R agonist.  It has an effect on NMDA receptors.

Afobazole was covered in two recent posts.

ER Stress and Protein Misfolding in Autism (and IP3R again) and perhaps what to do about it -Activation of Sigma-1 Chaperone Activity by Afobazole?

Afobazole is primarily used to treat mild anxiety.  Indeed it appears that sigma-1 receptor activation ameliorates anxiety through NR2A-CREB-BDNF signalling.  NR2A is a sub-unit of NMDA receptors.

Will Anavex for “Autisms” be worth the wait and the price, compared to Russian OTC Afobazole?

Hundreds of millions of dollars are being spent in the US to develop a safe sigma-1R agonist (Anavex 2-73). This drug is being trialed in various autisms (Rett, Fragile X and Angelman syndromes), Parkinson’s and Alzheimer’s.

Afobazole should reduce ER Stress and protein misfolding, making it an interesting potential therapy for many neurological conditions.

I did raise the issue as to whether Afobazole may affect the Excitatory-Inhibitory (E/I) imbalance that is present in bumetanide-responsive autism.

It turns out that in my trial, Afobazole was beneficial in reducing anxiety, it just takes the edge off - nothing drastic.  After several weeks I did notice a slight reduction in cognition, this was only really evident when working on maths. It was more noticeable on cessation.  If I did not teach Monty maths, all I would have noticed was the reduction in anxiety.  When I stopped Afobazole, Monty’s assistant commented how clever he was at school.

Since we are trying to keep up with typical children in academic work at mainstream school, cognitive function is the priority and so no more Afobazole.

Conclusion

I hope the millions of dollars spent on the Calcium Folinate (Leucovorin) trials produce some tangible results. Speech clearly is the area where it shows an effect, I think it has other effects that are less measurable.  It did seem to have an effect on what I would describe as “initiative”, which is completing tasks independently that otherwise you might ask for help to complete.

If you could have the benefits of Calcium Folinate (Leucovorin) without the negative effects, that would indeed be very interesting.

Perhaps giving Calcium Folinate (Leucovorin) to very young non-verbal children will give them a nudge to start speaking.  In those little children you would likely be less concerned by some aggression - they do not hit very hard.

Afobazole also has a place; anxiety is a problem in much autism and for many people a small drop in cognition, if it indeed occurs, is not such a problem.  Long term Afobazole use might produce benefits relating to reduced ER stress and less protein misfolding.

If I had a child with Rett, Fragile X or Angelman syndromes, I would definitely trial Afobazole, since the new American sigma-1R agonist (Anavex 2-73) is not yet available and I suppose will cost 100-200 times more than the Russian drug.

I think you need to find therapies free of any troubling side effects; otherwise in trying to solve one problem, you just create two new ones.