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.

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 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.


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.


  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?

    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.

    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.

    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.


    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.

  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.

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

    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

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

    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".

  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.


  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

    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.

  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.

    1. Petra, what other sigma 1 agonist did you change to?

    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

    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.

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


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

    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

  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.

  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?

  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


  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!)

    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.

  11. Peter,you know I am both a patient of Dr.Frye,and have been on leucovorin for years.It was first given to me,along with B12,when I was diagnosed with pernicious anemia,one of multiple autoimmune diseases I lived with for decades undiagnosed,that were all diagnosed when I was in my late forties.I had a childhood autism diagnosis,that was verbal,but otherwise low functioning,as well as experiencing multiple regressions from acute illness,like meningitis,and pneumonia.It was after I had been on the treatments several months,that my autism began to improve,the first thing I noticed was the blackouts that led to my wandering went away.I wonder if these episodes were not due to undiagnosed seizures.It took a while for me,about 3 1/2 years,but I was able to reverse the severity of my autism,by about 75%,and develop the life skills for independent living.

    It was after I had been on treatment almost two years,when I learned about the antibody test,when it was still in clinical trials.I had both the blocking and binding autoantibodies,at high levels.

    As you know Peter,there are many types of disorders that can be diagnosed as autism.Even severe autism,without regression,can have multiple causes.As you say on this blog,regressive autism and severe autism are not the same conditions,but regressive autism is not always mitochondrial,it can also be autoimmune,and a result of inborn immune dosorders,as is the case with me.In my case,I have a collection of autoimmune,neurological,neurodevelopmental,and other diagnoses.I also have these rare and de novo gene mutations,I have been trying for years to find an over-arching diagnosis for.I have recently discovered the work of a young researcher,at Massachusettes General,who is doing work that is the closest to my unique case.

    I know Dr. Frye,and Dr. Rossignol want to apply this ressearch to all autism,but I do think leucovorin may work best for regressive autism,with GI,and other underlying diseases,either immune or mitochondrial.

  12. Thought on this,Peter? Would it be applicable to COVID-19?

    1. 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.

  13. 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?

    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.


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