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Friday 6 March 2020

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:-

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.



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.





40 comments:

  1. Hi Peter, too bad that Afobazole didn't work out. I am not going to give it more either because my son entered high school with many subjects such as physical sciences and Maths. Regarding Clemastine, what benefits do you find?Any side effect?
    Valentina

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    Replies
    1. Valentina, Clemastine has had no negative effects. It has the bonus effect of being an antihistamine, so it helps with allergies.

      The effects it has had relate to cognition and specifically opinions, so these are higher level areas, where the changes are subtle and will vary by how "autistic" you are at the start.

      Many people with more severe autism, and indeed many with mild autism, are unable to think in a "broad way". They can complete clearly specified tasks, but struggle when the task is not well defined. One teacher at our school called this "higher level thought".

      A good first step towards higher level thought is to have your own opinions and later on to recognize that other people have opinions, that may differ from yours. Finally, you might be able to enter a discussion which might result in you changing your own opinion; this is a step not achieved by many people with high IQ and autism.

      Monty is now at the stage of having his own opinions, this seems to be the result of Clemastine. Clearly there is still a long way to go.

      In effect I have just substituted Clemastine for the Ceterizine, I had been giving.

      Delete
    2. Hi Peter-- I am re-trialling Clemastine ...largely for horrible allergies this year, but also for any other beneifits I might get. Like Monty, I have always struggled with tasks that are not well-defined ... parents and teachers have helped me with this.
      But my question is about the long-term safety of Clemastine. I have searched Pubmed and other sites to find instances that Clemastine is not safe --but I am not finding anything to indicate this. A friend (whose husband is a doctor) says that Clemastine could cause dementia.... but does not give any research to support this idea.
      I also have a rough time taking Clemastine--- a quarter of a tablet makes me very sleepy (like many other antihistamines I've tried). So, I take about 1/8th of a pill every third day or so at bedtime... and don't drive the next day.
      I would be grateful for any thoughts or comments you might have.
      Jan

      Delete
    3. My daughters allergy doctor didn't seem concerned at all about Clemastine. I think it is fine to use 6 months a year for a couple of years. One doctor who favoured new antihistamines mentioned something about possible effects on the heart, but didn't seem overly concerned.
      I think trialing it for a few months is a good idea, and then decide if the benefits overweigh the (comparably) low risks.

      /Ling

      Delete
    4. Jan, Clemastine is a first generation antihistamine, so it crosses into the brain and makes you sleepy, some people more so than others.

      All drugs and supplements can have side effects. Below is an answer I have another reader to the same question.

      Clemastine is an anticholinergic drug, so it does reduce the amount of an important neurotransmitter, acetylcholine, and it blocks some muscarinic receptors.

      Most antihistamines also block muscarinic receptors. This causes side effects like a dry mouth. The ideal antihistamine would have minimal effect on muscarinic receports.

      Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H1 receptors in the cerebral cortex.

      An antihistamine that enters the brain, like clemastine, will reduce the amount of acetylcholine present as well as affecting the muscarinic receptors.

      As we age the number of cholinergic neurons or receptors in the brain decreases. As we age there is also less acetylcholine in the brain.

      Giving a potent anticholinergic drug to an older person would not be wise. There is an association between long term use of anticholinergic drugs, like an antidepressant, and increased risk of dementia.

      Piracetam and α-GPC are claimed to activate the cholinergic system and alleviate cognitive symptoms caused by extended use of anticholinergic drugs.

      I think if I had multiple sclerosis and took a jumbo dose of Clemastine every day, I would combine it with Piracetam.

      The dose of Clemastine my son takes (1mg) is half the hay fever dose, the MS dose varies from 5 to 36mg in trials.

      The good news is that even at the 1mg dose, there is a cognitive effect. This might be due to more myelin, or it might be calming (ramification) of microglia.

      If there was no clear benefit, I would not give Clemastine.

      Delete
  2. Peter, good to hear about Monty. My son is happy with the great change, the assistant is 28 and is psychologist, she helped an adolescent with Asperger for 2 years with his library career. My son told me today with this words:"I almost die, when I found out that Paul left the school". Paul was one of his best friends. Regarding Cetrizine, do you think it works the same as Clemastine? For me it is easier to get Cetrizine of course.
    Valentina

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    Replies
    1. Ceterizine is a very good antihistamine, but will not improve myelin or calm activated microglia.

      Delete
    2. Peter, are there any other anti-histamines that help calmmactivated microglia? I have a seizure kid and I want to be sure of the safety profile for epilepsy.T
      Rahul

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    3. Rahul, the only one I am aware of is Clemastine.

      Delete
    4. Low dose naltrexone is good for calming microglia and is available easily from many online doctors, both in a transdermal lotion form, a syrup, or pill. I use 2mg for 30kg child and it helps a lot especially combined with 0.5-0.75mg clemastine. Just google "online LDN doctor prescription".

      Delete
  3. Ouch, I was so hoping you would know the reason why calcium folinate helps speech. It is on my agenda to find out, but I don't even know where to start. I'm not convinced it is all about folate receptor autoantibodies.

    /Ling

    ReplyDelete
  4. Peter, Prof Theoharides recommended buateron for colonic acid.. he said it is a liquid preparation and is absorbed much better and you need much less amount. We have been using around 2-3 mg a day with good effect. Also Dr Frye's collaborator who is a basic scientist on this project mentioned that these side effects should go away over time.. so it might make sense to find a dose where you have minimal side effects and slowly increase the dose

    ReplyDelete
    Replies
    1. Rahul, Buateron is the Greek version of Leucoverin (Theoharides is Greek). In Frye's new trial he will use a liquid, since it is for young children.

      Does Buateron include something to improve bioavailability? Somebody should know; maybe it does and maybe it does not.

      It is easy to take the capsule of calcium folinate acid, open and mix with a drink.

      In trials the dosage of folinic acid varies hugely from 400 mcg/day to 2-3 mg/kg/day.

      In your case 2mg is enough.

      For our reader tpes, the 20kg child took 15mg a day for a year with not effect.

      I think it is yet another case where different people react in completely different ways to the same therapy.

      Delete
    2. @rahul I wonder where did you get Buateron, i have been looking for it online since we do not live in Greece but within the European Union and some pharmacies answered they have it but they don't sell it online. I'd be grateful if you could tell where you get it from

      Delete
  5. Peter, it may be that afobazole is not a potent sigma 1 receptor agonist for Monty.
    From behavioral studies sigma 1 receptors were shown to be involved in higher ordered brain functions including memory. I clearly remember my son's academic skills improved.
    The thing that made me stop and switch to another sigma 1 receptor agonist was that he also became angry with unpredictable changes of mood. At that point I suspect the dopamine effect because I know my son has a dysfunctional drd2 inhibition.
    It's great clemastine helps Monty's cognition. Remyelination is something I really want to pursue. Again here, sigma 1 receptors are supposed to help as they are predominantly localized at the endoplasmic reticulum of both neurons and oligodendrocytes and seem to play an important role in the pathogenesis of certain demyelinating diseases.
    Anavex still seems interesting to me.
    Petra

    ReplyDelete
    Replies
    1. Petra, what other sigma 1 agonist did you change to?
      /Ling

      Delete
    2. Ling, it's the SSRI fluvoxamine.
      Cognition and depression: the effects of fluvoxamine, a sigma‐1 receptor agonist, reconsidered
      PMID: 20373470 DOI: 10.1002/hup.1106
      Petra

      Delete
    3. Rats' MS gets better when treated with antidepressant Luvox... The study shows that the antidepressant Luvox promoted the production of the protective coating by helping stem cells evolve into oligodendrocytes or cells that generate myelin sheath.
      Petra

      Delete
    4. That sounds highly interesting Petra , I will have to look at it closer. Thank you! :-)

      /Ling

      Delete
  6. Petra is sigma 1 receptor or sigma 1 receptor agonist supposed to help memory? Or is it the same thing? Thanks, PM

    ReplyDelete
    Replies
    1. PM, I understand sigma 1 receptor agonists may improve memory deficits in multiple diseases. For example the anavex research determines that activating the receptor with an agonist can potentially stop, slow or reverse the disease.
      I should tell you that my adult asperger's son in ideal conditions has very high IQ but practically his executive functions became progressively really worse, so he possibly fits a depression like model of cognitive impairment.
      Best wishes, Petra

      Delete
  7. One other piece of info that might be relevant is that my son's appetite has decreased or at least his willingness to eat food that is in front of him.
    Edginess is noticeably visible at these times.
    My son has a very distended abdomen and has for a long time.
    With butyric acid with cal/mag, it went down.
    Can the amino acids intervention create or aggravate gut issues?
    Again, thanks for all the help. I don't know where we would be without this guidance. Everything that has been supporting him for the past couple years has come from this blog.
    Nancy

    ReplyDelete
  8. Nancy, it sounds like severe gut issues. Possibly with an effect on serotonin (linked to aggression), though I think pain and discomfort would make anyone edgy. Either try interventions for the gut, or something like tryptophan/5-HTP?
    /Ling

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  9. Nancy, Maybe it is from the amino acids revealing some overgrowth of sulfate reducing bacteria that has been triggered by the AA being metabolized ? You could try a dose of pepto bismol - the bismuth neutralizes the hydrogen sulfate gas - until you get things figured out. Also zinc acetate form helps neutralize the gas as well (this form is usually found in zinc lozenges). And maybe brush border enzymes would help? I give my son Klaire Labs Sibb Zymes - it helps
    https://onlinelibrary.wiley.com/doi/full/10.1111/1541-4337.12401

    ~Tanya

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  10. Peter,
    First, thank you for all of this. I've written before about my minimally verbal 20 year old who spells or types to communicate and is a successful university student. His IQ is high but he struggles with serious motor issues and anxiety and sensory overload on any given day. He can keep it all together at Uni but can have tough times with verbal OCD and restlessness at home.
    I've bought some Afobazole and am going to trial it and am about to get a script for Clemastine which I'll start after I see if the Afobazole is taking the edge off his early evening anxiety. My question is what dose did you try? My box (written in Russian and English : )) says 10mg three times a day but could it be used just in the late afternoon when he seems to get more anxious and he doesn't have school to take his mind off things?
    Appreciate your thoughts.
    PS you helped me cure his GERD this summer with one small comment!)
    Brooke

    ReplyDelete
    Replies
    1. I used 10 mg twice a day. The effect is gradual and it is not dependent on the time you took the last pill. When you stop taking the pills the effects takes a week to fade away.

      Other anxiety treatments used in autism, like Propranolol, have a near immediate effect, which just lasts a few hours. So a low dose of propranolol in afternoon might be worth discussing with your doctor.

      Delete
  11. Roger, maybe it will give you some protection, I doubt it will harm you.

    Many of the new Covid therapies are from MS, arthritis and even HIV. It will be interesting to see how these people, who are an at-risk group, react to Covid-19. Will their daily medication give a degree of protection, or will the underlying immune problem still catch them out.

    ReplyDelete
  12. Hi Peter. I have not posted in a few years. My son is currently being treated by Dr Frye who relocated to my city (Phoenix, AZ) a couple years ago. We did try Leucovorin, but no improvement was seen. He is also prescribing Bumetanide now, and we are trying it at 0.5mg twice a day. I noticed your PolyPill dose is about 3x that amount. Where did you come up with that dose and do you believe 0.5mg is not enough?

    ReplyDelete
    Replies
    1. JB, I have tried various doses since I started in 2012. The bigger the dose, the bigger the effect, as was also shown in the clinical trials. At higher doses there is a greater chance of side effects and that is likely why Dr Frye uses a small dose. The problem is that for some people the small dose has no effect, whereas the larger dose does.

      The side effects of bumetanide are entirely manageable for most people, if they take care.

      In my son 0.5 mg twice a day had no effect, but 1mg once a day did show effect. Very little bumetanide crosses the blood brain barrier (BBB) and you may need a certain level for any of the drug to cross the BBB. I discussed this with the French researchers and their pharmacology adviser.

      Delete
  13. Dear PLT,

    My sister with a brain disorder (not autism) had a positive FRAAT result. I’m her guardian and she takes an over-the-counter form of calcium folinate, Designs for Health's Super Liquid Folate.

    This generic form of Leucovorin does not require a prescription, but an MD approved its use for her. This product also contains a very small amount of Vitamin B12 as Methylcobalamin.   

    Her total daily dose is about 27 mg calcium folate (DFE - dietary folate equivalent). This is less than the highest doses used in Dr. Frye's treatment of autism.  I am using 'augmenting' strategies in the hope that they will boost transport to the brain. At higher doses she became angry, agitated and hit staff at group home.
      
    Calcium folinate (0.6 ml) is administered three times a day at least 30 minutes before or after meals.   Rationale for this regimen is there is a limit to how much folate absorption can take place over a given amount of time and % absorption is higher when NOT taken with food. My sister still consumes some milk and cheese, but not much.  She is also on vitamin D 3000 IU. Based on rat research article (link below) this may help transport folate to the brain.  


    Additional NOTES:

    Calculations of dose based on Designs for Health product info:  660 drops x 680 mcg = 448.8 mg /30 ml = 14.9 mg per ml

    14.9 x 0.6 ml= 8.9 mg DFE per dose.  TOTAL daily dose (8.9 x3) =  26.82 mg DFE

    A month's supply of Super Liquid Folate (at this dose) costs about $70 (US) on Amazon.

    She also takes daily 13 drops of a Methyl B complex (low dose) made by Biocare in the UK.  She uses two bottles per month.  https://www.biocare.co.uk/nutrisorbr-liquid-methyl-b-complex-15ml
     
    To help digestion she takes 3 capsules/day of zinc carnosine (Doctor's Best PepZin) w/ 8 mg zinc per capsule and a Senior probiotic containing 6 Billion CFU-- Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium longum, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus helveticus, Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus lactis, and Streptococcus thermophilus. 

    There are other supplements and pharmaceutical drugs — too numerous to mention here. Whenever my sister starts new medications/vitamins I try to start low and go slow.  It can take weeks or months to show benefits, but if doses are too high the bad results are usually evident pretty quickly. 

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952265/

    https://tspace.library.utoronto.ca/handle/1807/101300

    https://www.pnas.org/content/116/35/17531

    ReplyDelete
    Replies
    1. Virginia, that is interesting. Adding vitamin D should increase folate transport.

      My son also got aggressive at high doses of calcium folinate. I am not sure if adding vitamin D to 27 mg calcium folinate is going to be better than a higher dose of calcium folinate. I assume the aggression is triggered by the amount of folate that crossed into the brain.

      What benefit does your sister show from the calcium folinate?

      Some people report that aggression from calcium folinate may fade. Some people get headaches as a side effect. Some people take taurine with leocovorin/calcium folinate to minimize side effects. Here was one comment in this blog.

      "Dr.Rossignol recommended it. We give 750 mg l taurine with 10 mg leucovorin calcium in the morning, 325 mg with 5mg leucovorin in the afternoon and 325 mg with 5mg leucovorin at night."

      Delete
  14. Hi Peter,

    Can this supplement form of calcium folinate (in the link below) be same as Leucovorin? i just ordered, but not sure if it is same Calcium Folinate being talked about here.

    https://bigvits.co.uk/product/folic-acid-megafolinic-800mcg-x-120tabs-bioavailable/?gclid=Cj0KCQiA8vSOBhCkARIsAGdp6RT8egm9ankXgR1FgFK5K58-gcjXY3I_-x_964jM_rKg1jv_vwrDzJAaAsjcEALw_wcB

    i see the most of the references above refers to Leucovorin, but being in UK i can only get supplement form and one in the above link looks to be one?

    P.S. also noticed the most of the calcium folinates in the supplement hubs have become either "not available" or "out of stock", presume some linkage to it being used as drug perhaps. Even kirkman had DMG plus folinate and is now out of stock everywhere.

    thanks
    Teymur

    ReplyDelete
    Replies
    1. The best supplement version is the liquid calcium folinate from iHerb because you can easily give large doses. It is currently out of stock, but this happens often. They email you when it is back in stock. They ship everywhere.

      Delete
  15. This is connecting so many dots for me. Had no idea Dr. Frye's research indicated folate receptor antibodies could be related to cow's milk exposure. My daughter absolutely reacts to cow's milk and has for as long as I have been able to give it to her. She was also very colicky/constipated as an infant (maybe exposure via breast milk?). Our main concern with her has been speech and I have only recently been trialing folinic acid with her, albeit at small doses compared to what Dr. Frye uses in his trials. She definitely seemed to improve since I started using it with her. She especially seems to sleep better and seems less hyperactive before bed when she does take it.

    However, the most dramatic improvement I've noticed has been with L-carnitine. She is speaking more and more clearly, shows more interest in not only speaking and conversing with us but in the emotion we show when speaking, and seems more receptive of / motivated by positive reinforcement. So, there definitely seems to be a mitochondrial component unless the L-carnitine is compensating for an unrelated issue. Nonetheless, folinic acid seems to be helpful!

    Trialling inulin for the last few days has also seemed to have an added, but small benefit. My guess is that a more dramatic effect, if any, would be visible after more regularity (as it seems her issue has been constipation, which could be increasing harmful gut metabolites).

    ReplyDelete
    Replies
    1. Nice to hear improvements for your child. can i ask which brand you use for folinate and what dose?

      I tried inulin before but not a good response (perhaps FODMAP sensitivity), we switched to psylium husk (1 teaspoon in the morning at the end of cereal) and it works, although she still tends to hold it as much as she can but constipation is gone. I tried OptiFibre from Nestle, didnt work as good as psyllium either.

      Delete
  16. What are the options to obtain calcium folinate (higher dose) in Eruope, either as a a drug but preferably as a liquid supplement? Looking for trademarks, links or stores...

    ReplyDelete
    Replies
    1. iHerb have stopped selling their OTC liquid version, which is a pity.

      The drug version is inexpensive but you will need a prescription in most countries. Calciumfolinat Ebewe is a common version.

      Delete
    2. Hi, there is still Folinoral (5 mg or 25 mg caps.) available OTC at French online pharmacies.

      Sandoz quit Calciumfolinat production for Ebewe last year and the Greek liquid Buateron has been stopped few weeks ago.

      It seems like there is Lederfolin 2.5 mg oral solution sold as a prescription drug in Italy.

      Delete
  17. Hello Peter, do you know if there is any scientific backing to anecdotal improvements on speech using intranasal C peptide? Has anyone from parents in this blog tried it for speech improvement? Thanks.

    ReplyDelete
    Replies
    1. Intranasal c peptide and intranasal insulin are both plausible therapies for those with cognitive dysfunctions.

      I do not have any reports of people using c peptide. It is not a crazy idea, but there seems to be no published evidence yet to support its use in autism.

      You would have trouble knowing that you have actually bought genuine c peptide. So beware of fakes.

      Delete

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