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.

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

US-Russia cooperation has long been possible in Space, but not so often in Medicine. NASA reportedly pays Russia $85 million per astronaut to go the International Space Station (ISS).  The US Space Shuttle program ended in 2011, leaving a Russian Soyuz rocket the only way to the ISS.

This post comes ahead of the dietary autism post, awaited by Tanya.  It really is just a brief follow-on from the previous post. I have only just come across Anavex, which does add weight to the first post on sigma-1R.
                                                                                                               

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.

In the last post I wrote about a cheap OTC anxiety drug from Russia, called Afobazole, that appears to be a safe sigma-1R agonist.  This drug has also recently been trialed in autism and Parkinson’s - the same targets as Anavex.

I did make the point in my original sigma-1 post that I am interested in existing therapies, rather than potential ones, so I did not include Anavex, or any other research drug, in that post. Anavex is nonetheless interesting, because their research studies further support the suggestion that targeting ER stress via sigma-1 is an interesting avenue to pursue.  

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

Anavex is claiming precision medicine, but in fact sigma-1R agonists appear more like the opposite, at least in terms of who you target.  The majority of both common and rare neurological disorders look like they should benefit from reducing ER Stress (from whatever cause); it is a shared feature.  So it looks more like a shotgun approach; that is actually a good thing, if it were to drive the price down.

What is needed is an affordable, effective, mass market drug; not an ultra expensive pill just for Rett Syndrome and perhaps a different colour version for Angelman's Syndrome.

Which will prove effective - Anavex or Afobazole? Or perhaps neither.

Having already made the case for Soyuz in my earlier post, here is the case for NASA, and for those with NASA-sized budgets, courtesy of  https://www.anavex.com/

Animal Study Details Motor, Sensory and Respiratory Benefits of Anavex 2-73, Supporting Phase 2 Trials

Treatment with Anavex 2-73 was seen to improve motor skills, acoustic responses and visual acuity in a mouse model of Rett syndrome, supporting ongoing Phase 2 studies in patients.

Its use also helped to lessen abnormal movements and ease breathing in these mice, its researchers said.

The study, “ANAVEX®2-73 (blarcamesine), a Sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome,” was published in the journal Pharmacology Biochemistry and Behavior.

Anavex 2-73 (blarcamesine) is an oral investigational therapy developed by Anavex Life Sciences that works by activating the sigma-1 receptor (S1R), a protein involved in the correct folding of other proteins.

S1R activation results in reduced toxic accumulation of misfolded proteins, as well as lesser dysfunction in mitochondria (a cell’s “powerhouse”), oxidative stress and neuroinflammation, all involved in Rett syndrome. (Oxidative stress is an imbalance between the production of free radicals — potentially harmful molecules associated with a number of diseases — and the generation of antioxidant defenses.)

Researchers at Anavex, assisted by PsychoGenics, evaluated the potential treatment’s specific effects on Rett symptoms in a validated mouse model.

They assessed motor function (balance, motor coordination, locomotion, and abnormal movements or stereotypies), sensory function (reflex responses to sound stimuli and visual clarity), and respiratory function.

Motor and sensory functions were assessed in younger mice, while visual acuity and breathing were measured in older animals.

Results showed that Anavex 2-73 significantly eased motor dysfunction, and deficits in acoustic and visual responses compared to mice given a placebo.

Anavex 2-73 also induced a significant reduction in two distinctive features of Rett syndrome found in these mice: hind-limb clasping (an abnormal posture comparable to hand stereotypies in people with Rett), and apnea (involuntary breath-holding) that is the most concerning breathing abnormality in Rett syndrome, the researchers said. These improvements were mainly dependent on treatment dose and duration.

“In conclusion, the data demonstrate that [Anavex 2-73] is effective in ameliorating multiple neurobehavioral phenotypes in [Rett] mice,” the researchers wrote. “In line with previous animal and human studies [in other neurodegenerative diseases], [Anavex 2-73] also showed a good safety profile,” they added.

These data served as a proof-of-concept for an ongoing safety and efficacy Phase 2 trial called RS-001 (NCT03758924, still enrolling) in the U.S., and for the Phase 2 AVATAR study (NCT03941444) in Australia. These trials together will evaluate Anavex 2-73 in up to 51 women with Rett syndrome.

Conclusion

It may be that Anavex is far superior to the cheap Afobazole. Like the space shuttle was far more advanced than the Soyuz. 

But what if the cheap Afobazole is quite good enough?  Like the cramped, but reliable Soyuz rocket.

Anavex/Afobazole will not cure any severe neurological condition, just improve it, so it will need to be part of a polytherapy. That means the patient will need to be able to afford multiple drugs, somehow.

Coming back to those autisms, what if your daughter has Rett Syndrome, or son has Fragile-X Syndrome ?  Wait a few years for Anavex and for someone else to pay for it? or make do with some cheap Afobazole?