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Thursday, 20 October 2016

Clinical Trial of Mega-dose Folinic Acid in Autism



The common form of Leucovorin Calcium is for injection, but it exists in 
tablet form. Maybe another opportunity for intra-nasal delivery?


As pointed out by Tyler, Richard Frye has published his trial on the effect of mega-dose folinic acid in children with autism and language impairment.

FRAA (folate receptor-αautoantibody) status was predictive of response to treatment.  This means that people who are FRAA positive are likely to really benefit from folinic acid treatment.

There are different types of folinic acid.  Dr Frye uses Calcium Leucovorin (Calcium Folinate), which is used in chemotherapy.  It is given by intramuscular injection or orally.

Dr Frye uses the oral form.

Folinic acid should be distinguished from folic acid (vitamin B9). However, folinic acid is a vitamer for folic acid, and has the full vitamin activity of this vitamin.

The dose is huge by normal standards of vitamin B9.  It was 2mg/kg per day (maximum 50mg per day) in two equally divided doses with half of the target dose given during the first 2 weeks. 

Biomarkers
Two folate-related biomarkers were investigated. FRAA titers, both blocking and binding, were analyzed. Plasma free reduced-to-oxidized glutathione redox ratio was determined. Folate-related vitamins and minerals were measured. Serum total folate and vitamin B12 were measured 

Of 93 children with ASD, 60% and 44% were positive for blocking and binding FRAAs, respectively.
  




We sought to determine whether high-dose folinic acid improves verbal communication in children with non-syndromic autism spectrum disorder (ASD) and language impairment in a double-blind placebo control setting. Forty-eight children (mean age 7 years 4 months; 82% male) with ASD and language impairment were randomized to receive 12 weeks of high-dose folinic acid (2mgkg−1 per day, maximum 50mg per day; n=23) or placebo (n=25). Children were subtyped by glutathione and folate receptor-αautoantibody (FRAA) status. Improvement in verbal communication, as measured by a ability-appropriate standardized instrument, was significantly greater in participants receiving folinic acid as compared with those receiving placebo, resulting in an effect of 5.7 (1.0,10.4) standardized points with a medium-to-large effect size (Cohen’s d=0.70). FRAA status was predictive of response to treatment. For FRAA-positive participants, improvement in verbal communication was significantly greater in those receiving folinic acid as compared with those receiving placebo, resulting in an effect of 7.3 (1.4,13.2) standardized points with a large effect size (Cohen’s d=0.91), indicating that folinic acid treatment may be more efficacious in children with ASD who are FRAA positive. Improvements in subscales of the Vineland Adaptive Behavior Scale, the Aberrant Behavior Checklist, the Autism Symptom Questionnaire and the Behavioral Assessment System for Children were significantly greater in the folinic acid group as compared with the placebo group. There was no significant difference in adverse effects between treatment groups. Thus, in this small trial of children with non-syndromic ASD and language impairment, treatment with high-dose folinic acid for 12 weeks resulted in improvement in verbal communication as compared with placebo, particularly in those participants who were positive for FRAAs.

Separate analyses were conducted for each biomarker of folate metabolism (Table 2A). In general, improvement in verbal communication was significantly greater in participants on folinic acid as compared with those on placebo for participants with abnormal folate metabolism (i.e., FRAA positive, low glutathione redox ratio). For participants with biomarkers indicating more normal folate metabolism (i.e., FRAA negative, high glutathione redox ratio) improvement in verbal communication was not significantly different between groups.

This study suggests that FRAAs predict response to high-dose folinic acid treatment. This is consistent with the notion that children with ASD and FRAAs may represent a distinct subgroup.61 Other factors such as genetic polymorphisms in folate-related genes or mitochondrial dysfunction may be important in determining treatment response but were not examined in this study. When methylcobalamin was combined with folinic acid, improvement in communication as well as glutathione redox status was found.48 Indeed, future studies will be needed to define factors that predict response to treatment, investigate optimal dosing and help understand whether other compounds could work synergistically with folinic acid.


Conclusion

This study, and previous ones, suggest that > 50% of people tested have what Frye is calling positive Folate Receptor Antibody Status.  This combined with oxidative stress, as measured by low glutathione redox ratio, looks a like a good predictor of who will benefit from Calcium Folinate.

Clearly using tablets, as opposed to the usual injections, means that less of the folinic acid actually reaches the brain.  As was discussed in an earlier post, there are other forms of folate, like Metafolin, that are OTC.

Can Metafolin perform the same function as  Calcium Leucovorin?

It would be useful to know how much Metafolin = 2mg/kg of Calcium Leucovorin.  

The only way to find out would be to ask someone taking Calcium Leucovorin.


Metafolin® is a proprietary ingredient directly usable by the human organism, involved in lowering homocysteine blood levels, and the only form of folate able to cross the blood-brain barrier. In addition, Metafolin® does not mask a vitamin B12-deficiency and presents no risk of an accumulation of unmodified folic acid in the body.”



I suppose readers will now want to measure Folate Receptor Antibody (FRA) status and look for Calcium Leucovorin.  Our regular reader Roger may want to give his insights; perhaps he wants to see if Metafolin can do the job of Calcium Leucovorin?


Any side effects, Roger, after long term use of Calcium Leucovorin?








62 comments:

  1. Hummmmm... I was under the impression oral ingestion of calcium folinate (the brand I have is Source Naturals Folinic Acid) would eventually be metabolized into a form that crossed the BBB. Each tablet is 800mcg. My son is probably about 45kg so that puts him at the max 50mg limit for 2mg/kg. This means in theory if I am even giving him the right form of folinic acid (by all accounts it appears to be the same as Metafolin) he would need 62.5 tablets which is a lot of pill crushing and then I would also have to figure out how to make it palatable. Then there is the issue of safety as well (I am assuming the Dr. Frye treatment is safe, but there may be caveats not mentioned in the study which would make do-it-yourself trialing risky). Then there is the obvious question of why folinic acid over methylfolate.

    This is all great news, but the frustrating thing here is that the pessimist side of me says that this research will end up never getting into the mainstream pipeline for pediatricians here in the United States because this is not a patented drug treatment, as well as the fear inducing term "MEGADOSE" being used to describe the treatment.

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    1. The clever thing to do, since you are in the US, might be to get tested for FRAAs. In many countries I think this will be a big challenge.

      Roger and his Facebook group who have used this dosage for years will be a reliable source of safety info.

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  2. No side effects at all.I see Paul Whiteley is blogging about this study too.It's nice to see children with higher functioning autism being tested for FRAAs,and given folinic acid.I don't think anybody uses the IV form of folinic acid for autism.The effects of each dose only lasts about six hours.

    25 mg pills are what are usually used.I dose three times a day,as do most of the parents I know from Facebook.I weigh about 105 lbs,and take 150 mg a day.I know of one parent whose kids take almost double my dose,3-4 mg/kg based on body weight.

    I am just the reverse,syndromic ASD,with no language impairment.Before the leucovorin I was moderate to low functioning.I had many other brain and medical issues.I now have pathogenic gene mutations,but no diagnosis yet.I suspect it may be a cancer gene.I have both types of FRAAs and MTHFR Deficiency as well.

    The older articles by Drs. Ramaekers,Frye,and Rossignol suggest FRAAs may only be present in more severe,syndromic autism.

    Metafolin is 5-MTHF.I have heard it will not work if there are FRAAs.Anything in micrograms is much too low a dose to work either.

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    1. Roger, based on your experience and what you have seen on your Facebook group, how long do you think somebody, who will be a responder, needs to take folinic acid to see an effect.

      Interventions that are effective can show effect very quickly, is this the case with folinic acid? or does it take months? (even years to peak effect?)

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    2. Thank you Roger. Also, where do you find 25mg folinic acid tablets? The 800mcg dose is the highest I have found (maybe I have not looked hard enough).

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    3. 25 mg tablets are prescription only.It is intended as a cancer drug.Autism and CFD are still off-label uses.It is very expensive.The cost for a month's supply is in the high hundreds or low thousands of dollars.Many doctors would be reluctant to prescribe it for this reason.

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  3. I think a lot depends on the age of the patient,and the severity of the condition,but initial improvements are usually seen in a matter of weeks.In a very young child,or someone with a mild disorder,reversal may be seen in a couple of months.I started out as an adult,with an autism diagnosis severe enough to have put me in residential treatment under 24-7 supervision.I had never held a job,and had lived with my mother all of my life,who did much of the basics of everyday living for me.It took 3 1/2 years for me to become more or less neurotypical.

    In the last couple of years,Dr. Ramaekers has found there are some cases of schizophrenia where there are FRAAs.These cases also respond to folinic acid.Something you have blogged about.Schizophrenia is pretty much always diagnosed in adults.I would imagine reversal of symptoms can take just as long here as well.

    People with mitochondrial disease also have FRAAs.

    I was tested for FRAAs during the initial clinical trials at SUNY Downstate.I tested positive after I had been on leucovorin a couple of years.This is not unusual.Edward Quadros,who came up with the test,sold the rights to Iliad Neurosciences in Pennylvania,who are the only ones in the USA that can do FRAA testing.FRAA testing is also done at Centre Hospitalier Universitaire de Liège in Belgium.This is Vincent Ramaekers' hospital.Parents in my Facebook group in the UK and Europe have gone to Belgium to be tested.I know of one woman and her son,who traveled from Singapore to Belgium to be seen.

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    1. Thanks Roger. In the US the test costs $200.

      Here is a link:-

      http://iliadneuro.com/index.html#faqs

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    2. We did FRAA for my grandson with illiadneuro and the result was negative. His MTHFR is ok. We showed the result to Dr.Rameakers. We were already on CFGF diet. He suggested to give tolerable amount of milk for 2 weeks and again take the FRAA. Also take FRAA of parents for more clarification. He suggested using leucovorin calcium only after positive FRAA. We tried milk and immediately bloating was there. So stopped. Meanwhile our appointment with Dr.Rossignol came. We told him about this. He suggested to give leucovorin calcium without FRAA. He gave prescription for it from Hopewel pharmacy (in India it is available OTC at 1/3 price but only 15mg tablet) and we have to start it slowly from 5 mg per day and to reach 20mg (12kg). He said without optimum dosage you can not judge the effect. We give 5mg at night. During day even 1.5mg makes him more cranky, more irritable and more hyper. But he has some ongoing cold and Dr.Rossignol said to try it after his cold is better. I remember reading somewhere Dr.Fry commenting 'Triple shoot' for autism with MB12, leucovorin calcium and vitamin E.

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    3. Salempeacock, if they have an expensive test for FRAA and give leucovorin regardless of the result, you do have wonder what is going on.

      You might as well save the $200+ for the test and spend the money on generic calcium folinate and do your own trial.

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    4. Peter,
      Yes. From few other parents whose children are treated by Dr.Rossignol I gather that he gives leucovorin calcium without testing FRAA. And the 'Triple shot' by Dr.Fry consists of MB12, leucovorin and NAC .

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    5. salemapeacock, do you know the dosages/kg in the triple shot and how often it is given?

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    6. Sorry, I don't know.
      https://issuu.com/arkansastimesvisitorsguide/docs/arkansas_times_july_21_2016
      Came to know about it from this article.

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  4. Thanks Roger and Peter for the info...Roger, congrats on the recovery! Gives me so much hope for my child...may I ask which FB group you run and is it open to all asd parents...thanks.

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  5. Roger, just out of curiosity, which mthfr mutation do you have? and in regards to FRAA treatment, is it just folinic Dr Frye recommends or will 5mthf work? We had labs drawn for Dr Quadros, ready to ship, then hurricane Sandy hit and the lab was closed indefinitely. I ended up putting this on the back burner and moving on to other things. I could never get my son to tolerate folinic then anyway. But perhpas since other things are in place he would now.
    I really appreciate your in-put.

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  6. Tanya,I am a compound heterozygote for MTHFR one mutation each of C677T and A1298C.I have megaloblstic anemia,high homocysteine,and methylmalonic acid,as well as very low stomach acid.I have been on betaine for years,and have mentioned it on this blog before.This was why I was put on folinic acid and B12 in the first place.This was 2009.The improvement in my autism was not expected by either me or my doctor.

    As for other types of folate,the only one I know of that Dr. Frye and Dr. Rossignol seem to accept as a substitute,is L-Methylfolate,or Deplin.

    The Facebook group is called Cerebral Folate Deficiency and Folate Receptor Autoantibodies.I do not run it.

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    1. Hi again Roger, Iam homocygote for MTHFRC677T and hetero A1298C, thought you were homocygote for C677T, know I have a seriuous condition. I only take 400 mcg methylfolate and 1000b12. Also take betaine anhydrous, do I have to add betaine HCL for low stomach acid? My son has HFA,he is not taking folinic acid or methylfolate,he had parasites and tend to have yest/bacterial issues. Valentina

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    2. thanks so much Roger. My son has no mutation on c677t but he is homozygous for a1298c. I have read conflicting information on whether or not methylfolate helps with that mutation, but i realize that is just one gene and many others at play that metylfolate can benefit. it is so complicated.

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  7. Roger,
    How did you start betaine? How did you know that you had very low stomach acid? What were the symptoms? Did you have a diagnosis? How? How is low stomach acid related to MB12 and folinic acid?

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  8. High homocsyteine levels are a result of inborn errors of folate metabolism,such as MTHFR deficiency.My homocsyteine was very high when it was first tested,within diagnostic range for severe MTHFR deficiency.I had blood tests for both MTHFR and a megaloblastic anemia panel,that tests methylmalonic acid and homocysteine.

    One of the results of high homocysteine is low stomach acid.Low stomach acid is also associated with autoimmune disease,which I have as well.

    This has been covered on this blog.Both autoimmune disease and inborn errors of folate metabolism are well documented with autism.I have both metabolic and autoimmune diseases.I am very complex both medically and genetically.I have many diagnoses.

    I still don't know if CFD from FRAAs isconsidered a metabolic or autoimmune disease.

    The symptoms of low stomach acid are many.

    http://drmyhill.co.uk/wiki/hypochlorhydria_-_lack_of_stomach_acid_-_can_cause_lots_of_problems

    https://branchbasics.com/do-you-have-enough-hcl-stomach-acid/

    http://bodyecology.com/articles/low_stomach_acid_symptoms.php


    Like leucovorin,betaine can be very expensive when bought as a prescription,between $700 and $1500 a month.Many insurance plans will not cover it.I found that high dose pharmaceutical grade betaine can be bought as supplements or bodybuilders.The stuff made for bodybuilders is so high dose,that one package,usually under $40,can last several months.It is not pleasant tasting,children would not like it.

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    1. Roger, did you develop any mood disorders related to your mthfr mutations and/or elevated homocysteine? Did you ever use TMG as a betaine source? And last question - did you use a higher dose of b6 to help with homocysteine? thank you

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    2. I'm sure mood disorders may have been part of the picture.They often are with autism.

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    3. Oh sorry what I meant to ask was by treating your mthfr mutations/homocysteine did that effectively treat mood disorder/anxiety etc. or were other pharmacologic medicines necessary??

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  9. Thank you Roger. I think my grandson has low stomach acid. First he had colick. Then mild to moderate reflux till one year. Cried and cried a lot. Poor sleep. Doctors said he was ok. From the age of 3 months he has feeding problem and bloating. We literally had to force feed him. But his bowel movements and stool are always normal. With CFGF diet and digestive enzyme his bloating is better. But still he has no appetite. It takes 1 and half hours for every meal. Periactin makes him more irritable. He is skinny and small for his age. He has wheezing, low cholesterol (132)and low ferritin(25ng/ml.) and high irritability. Our nutritionist said betaine HCL has to be swallowed in capsule and so give him lemon juice before every meal. Lemon juice gives him cankersores. Now Dr.Rossignol suggested 'Creon' instead of Kirkman DPP IV enzyme. Blood homocysteine and glucose level are normal. No mutation in MTHFR.For the past 6 months we give him MB12 injections. Now started leucovorin calcium. Craved salt and so started adrinal cortex supplement and after that he sleeps whole night. Looking for ways to improve his appetite. Hence the questions about betaine.

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    1. The symptoms you describe can be caused by achalasia of oesophagus or even esophilic esophagitis, has he been checked and have those things been ruled out?

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    2. Nat,
      No. we haven't. We have consulted pediatricians and ENT specialists and they did not suggest for further tests. We need to consult a pediatric gastroenterologist for this no?

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  10. OK here is the math for trialing this:

    (1) Cheapest form of folinic acid I could find happens to be the same brand I use which will get you 1 800mcg tablet for 6.7 cents (120 for $8.00).

    (2) To get 50mg of folinic acid would require 62.5 tablets (lets round down to 62).

    (3) 62 x $0.06667 = $4.13 per day

    When the tablets are crushed, there is a rather bitter taste (I recall this but will need to recheck) to them. Since my son won't do tablets or pills yet, this is the route I would probably have to go. I suppose the pills would probably dissolve somewhat in water or some other liquid but that is still a lot of folinic acid you need to mask.

    So that is still about $124 a month to do folinic acid this way which is a lot less than the amount cited by Roger Kulp (around $1000 a month) for the prescription 25mg tablets which are sold as a cancer drug.

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    1. So I just crushed one of the 800mcg folinic acid tablets using a pill crusher and then put it in my mouth and to my surprise it was pretty much tasteless, though it did have a pasty texture that might be offputting to some people though this minor issue could easily be addressed via masking the texture with a sticky food like peanut butter or jelly.

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    2. Tyler, if you use generic calcium folinate the cost of a 15 mg tablet is about EUR 0.5 ($0.5), but it is a prescription drug. It does seem that some people do not tolerate the 2mg/kg leucoverin, although this is not reported in the study. I think using your method you will establish whether your son tolerates this high dosage and whether it helps. Deplin 15 contains 15mg of Metafolin, but this is also a prescription drug. If you find your son is a responder, generic calcium folinate from Mexico/Europe/Asia might be the long term choice.

      Delete
  11. Here is some new research on NAC and aging (Open Access):

    http://www.sciencedirect.com/science/article/pii/S2213231716301434

    Of particular note is the suggestion that low-dose NAC might be good for helping minimize cellular damage from Glutathione depletion in older people, even though high dose NAC is generally considered safe (the only study I have found to the contrary suggests suggested if the redox ratio is too skewed from aggressive NAC treatment, then stem cells may get poisoned and die).

    Since aging at the cellular level has a lot in common with what happens in the stressed cells in many autism animal models, I have tried to look for interventions that seem to improve geriatric health generally and then see if it might be good for at least attenuating some of the worst cellular stress issues in autism.

    There are probably about a dozen compounds off the top of my head that are being looked at seriously for helping the aged stay healthy, but have been given little to no attention with respect to autism (very frustrating) even though the cellular symptoms with aging overlap significantly.

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  12. Speaking of antioxidants... Peter, I know that you are interested in asthma treatments and would like to say that NADPH oxidase inhibitor, apocynin, looks good as a strategy in managing asthma.
    Does Monty consume spinach? Have you ever seen improvement with it?
    Spirulina is also a good source of apocynin.
    I can't be sure but after just one spirulina tablet my son shows mood improvement.

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    1. Thanks Petra, apocynin is indeed interesting. It affects a specific type of oxidative stress (there are many), apparently it may be useful in the treatment of inflammatory diseases induced by oxidative stress through NOX activity.

      Monty loves spinach. Broad leafed dark green vegetables are extremely good for you and are part of the very healthy Mediterranean.

      NOX2 inhibitors (NADPH oxidase inhibitors) are a good avenue to investigate.


      Design of dual inhibitors of ROCK-I and NOX2 as potential leads for the treatment of neuroinflammation associated with various neurological diseases including autism spectrum disorder

      https://www.ncbi.nlm.nih.gov/pubmed/25465055

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    2. Thank you Petra, this is very interesting.

      Running a quick search on apocynin one of the first articles I got mentions the role of apocynin as NADPH oxidase inhibitor to promote osteogenesis and increase bone mass (in old rats but its a start). As my son is a responder to vitamin K, the osteogenesic + anti-inflammatory effects seems promissing.

      I won't try right now because at school he was moved from kindergarden to grade 1 despite his age, so I have to give him some adaptation time, but I'll look into it and add to our pipeline :)

      And here is the link "Apocynin suppression of NADPH oxidase reverses the aging process in mesenchymal stem cells to promote osteogenesis and increase bone mass"
      http://www.nature.com/articles/srep18572

      I'm happy it helps your son.
      Thanks again for sharing.

      Jane.

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  13. I've found an article about PTSD and the role of NOX2 and parvalbumin interneurons(PV) in the development of the disease.

    "Early, but not delayed, treatment with apocynin reversed all abnormalities after single prolonged test. In conclusion there is evidence that NOX2 activation in the hippocapus, at least in part, contributes to oxidative stress and neuroinflammation which further results in PV interneurons loss and consequent PTSD symptoms in a rat model of PTSD induces by single prolonged test."

    Obviously I am on the PTSD delayed phase treatment options and I don't even know how much apocynin I need or get through spirulina to inhibit NoX2.

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    1. Petra, it looks like Picrorhiza Kurroa (also known as kutki) is the most potent source of apocynin. It comes from India, but is now an endangered species. This appears to be what the labs use to produce apocynin.

      Also look at this paper, this suggests that the antioxidant effect of your spirulina may also be achieved using the mega dose folate that we have recently been discussing, or at least they are complementary.

      Practical prevention of cardiac remodeling and atrial fibrillation with full-spectrum antioxidant therapy and ancillary strategies.
      https://www.ncbi.nlm.nih.gov/pubmed/20083360

      Abstract
      A wealth of research data points to increased oxidative stress as a key driver of the cardiac remodeling triggered by chronic pressure overload, loss of functional myocardial tissue, or atrial fibrillation. Oxidative stress is a mediator of the cardiomyocyte hypertrophy and apoptosis, the cardiac fibrosis, and the deficits in cardiac function which typify this syndrome, and may play a role in initiating and sustaining atrial fibrillation. Nox2- and Nox4-dependent NADPH oxidase activity appears to be a major source of this oxidative stress, and oxidants can induce conformational changes in xanthine dehydrogenase, nitric oxide synthase, and the mitochondrial respiratory chain which increase their capacity to generate superoxide as well. Consistent with these insights, various synthetic antioxidants have been shown to suppress cardiac remodeling in rodents subjected to myocardial infarction, aortic constriction, or rapid atrial pacing. It may prove feasible to achieve comparable benefits in humans through use of a "full-spectrum antioxidant therapy" (FSAT) that features a complementary array of natural antioxidants. Spirulina is a rich source of phycocyanobilin, a derivative and homolog of biliverdin that appears to mimic the potent inhibitory impact of biliverdin and free bilirubin on NADPH oxidase activity. Mega-doses of folate can markedly increase intracellular levels of tetrahydrofolates which have potent and versatile radical-scavenging activities - including efficient quenching of peroxynitrite-derived radicals Supplemental coenzyme Q10, already shown to improve heart function in clinical congestive failure, can provide important antioxidant protection to mitochondria. Phase 2 inducer nutraceuticals such as lipoic acid, administered in conjunction with N-acetylcysteine, have the potential to blunt the impact of oxidative stress by boosting myocardial levels of glutathione. While taurine can function as an antioxidant for myeloperoxidase-derived radicals, its positive inotropic effect on the failing heart seems more likely to reflect an effect on intracellular calcium dynamics. These measures could aid control of cardiac modeling less directly by lowering elevated blood pressure, or by aiding the perfusion of ischemic cardiac regions through an improvement in coronary endothelial function. Since nitric oxide functions physiologically to oppose cardiomyocyte hypertrophy and cardiac fibrosis, and is also a key regulator of blood pressure and endothelial function, cocoa flavanols - which provoke endothelial release of nitric oxide - might usefully complement the antioxidant measures recommended here.

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    2. Thank you.
      Kutki is good with NAFLD and upper respiratory infections, which my son seems prone to.
      I read that they used up to 25mg in humans.
      Next step is where to find it. I viewed some products online but just in case you have a suggestion, please let me know.

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    3. Petra it is expensive 200g costs EUR 46 on Amazon, but the "normal" dose is 1-2 g a day.

      Delete
  14. I tried folinic acid on my son, he is 7 and weighs 23kg. I gave him 1mg a day for only two days but he developed a headache and became quite irritable, so I stopped. I had tried in the past with b12 and had the same result, he becomes really aggressive. Yet I read that all asd kids need b12 sups. Do I need to lower the dose even more?

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    1. There are no universal therapies for autism. A significant minority (15% ?) do seem to respond to high dose B12, but some respond negatively and for the rest it has no effect.

      The same is true with folinic acid. If you have central folate deficiency, some types of oxidative/nitrosative stress or mitochondrial disease you may respond well to high dose (50mg/day) calcium folinate/folinic acid. However a large group react negatively.

      If your son has autism with stereotypy, try NAC. If that helps, it is highly likely that oxidative stress is an issue for him.

      Delete
  15. Hi Peter hope you are well and your son is doing well. My daughter is undergoing chemo as I had mentioned for her Malignant Osteosarcoma left distal femur. She has gotten IV Methotrexate which caused terrible side effects which I observed including joint pains all over . However when they gave her the IV Leucovrin rescue which was 50mg infused over 15 minutes I noticed she instantly became more verbal. I did tell the pediatrician who thought it was interesting. I did look up Dr. Fryes study. I did get injectables but she would not tolerate me giving her IV fluids . So I did get leucovorin tablets 25 mg and notice a change in mood she is much happier and definitely more verbal within 30 minutes . I am starting with 12.5 mg bid. I did order kits to test her for MTHFR and FRAA but did not want to stress her will do it soon. We will be seeing orthopedic surgeon Monday to see about amputation surgery date. I did give he 25mg of the leucovrin which worked really good I gave it to her at 8 am and noticed she had a severe headache around 3 pm so I decided to go slow and split that dose am and pm.
    I am not using B12 since in the past I used a sublingual form of methylcobalamin which seemed to make her behavior and aggression worse. She has definitely responded positively to leucovrin both with IV and oral. Still using clonazepam low dose . Has anyone experience with Low Dose Naltrexone ?

    Asma

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    1. Asma, there are some comments in another post that may be useful regarding side effects of leucoverin.

      salempeacock21 March 2017 at 09:06

      With leucovorin calcium (folinic acid) we also experienced the same problems. We added l taurine and now tolerance is no problem.


      Peter Lloyd-Thomas21 March 2017 at 19:45

      Salempeacock, how much taurine did you add? Whose idea was this?

      In cancer care leocoverin is sometimes combined with Tauromustine, a taurine-based compound.


      salempeacock22 March 2017 at 13:39
      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. My grandson is 3 years old and weights 12 kg. Dr.Rossignol suggested to try 20mg leucovorin for at least 3 months. We have been gradually increasing from 5mg and only recently reached 20mg.
      He has MTR, MTRR and COMT but no MTHFR issue. FRA test negative. But we follow CFGF diet and Dr.Ramekar suggested FRA test after taking milk for a week. He didn't agree to prescribe leucovorin without positive FRA result.

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    2. Asma, I am sorry to hear about osteosarcoma in your daughter.
      My Low Dose Naltrexone experience is n=1 only, but quite encouraging as I found LDN use resulted in anxiety and SIBs reduction (this is in line with some papers as far as I remember), but also improvement in communication. By the last one I mean more verbal communication instead of behavioural one. No adverse effects during few months of use.

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    3. Agnieszka, what dosage of LDN do you use?

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  16. Also Peter I noticed Mr Roger said something about Folate deficiency and Cancer is there a link? Since my daughter has both autism and now a horrible cancer ?

    Asma

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    1. I think you may find that the autism-cancer connection is not folate deficiency, but the FOSB osteosarcoma viral oncogene.

      It is referred to in this paper:

      Genes Controlling Affiliative Behavior as Candidate Genes for Autism
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2386897/

      The folate-cancer link is more about people who have poor diet, having higher cancer incidence.
      Responding well to leucoverin could mean folate deficiency, but could mean nitrosative stress (peroxynitrites) which cause mitochondrial dysfunction. This dysfunction seems to be rather common in autism and when you treat it, autism improves.

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  17. Hi Peter, I gave my daughter IV leucovorin 50 mg once she got home from surgery and rehab every 2 days for about one and a half weeks.After returning home she was screaming a lot,throwing things,digging her nails into her hands and was constantly rubbing her hands . My other daughter said we dont know what chemo did to her brain and I immediately thought she probably has neuropathy from the High dose Methotrexate. Childrens motrin 600mg tid was not working . The effects of IV leucovorin were wonderful and instantaneous, I gave it IV push over 30 minutes in 20 cc of lactate ringers. The beneficial effects lasted 48 hours. It was like Jekyll and Hyde. She was calm,cooperateive, happy whilst the Leucovorin was in her system and as soon as it wore off the aggression returned. I had compounded leucovorin made up at a lower dose 5 mg bid but she still gets headaches. I will try the taurine.
    I have sent out for MTHFR and FRA testing will be sent out next week. I eamiled Dr Frye to see if other parents reported the headaches and how he treated them. I was just stumped to why the oral would cause headaches when less would reach the brain with oral absorption vs IV administration. I would definitely be curious about the intranasal route. Do you have any ideas on this topic?

    Also wanted to know from Mr. Roger what the status of his autism was before he started on leucovorin was he minimally verbal, did he have seizures,and how was his behavior? He reported things improved for him after taking leucovorin for 3 and a half years.
    I read that Cerebral folate deficiency is present in over 90% of autistic people and that giving leucovorin changes the biochemistry of the brain increasing serotonin,dopamine and norepineprhing. any comments on this ?

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    1. Asma, perhaps when taken orally some other substance is produced that is not present when given I/V. There must be a reason.

      Intranasal is a very interesting route to the brain. This assumes your doctor will give to the IV type of leucoverin long term. You would have to experiment, since nobody will have done this. It may have no effect, or it may work great.

      With insulin it is very easy. In some of the trials they use a standard spray dispenser like you might find in a pharmacy and match the dose to the amount the spray dispenses. You do not want to start diluting the substance because that makes it complicated. You either use multiple puffs or look at several different dispensers. You need to know what dose (in ml) is each puff. Maybe your doctor will take an interest and help you.

      I do not think that cerebral folate deficiency is present in 90% of autism. I think it likely quite rare.

      However, leucoverin has been shown to be very effective in quenching nitrosative stress. This is similar, but different to oxidative stress, and I think likely to be very common in autism, particularly when mitochondrial dysfunction is present.

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  18. Asma, I wish the best for your daughter and family. So tough what you are going through.
    Is it possible the leucovorin is raising histamine and your daughter has issues with that? Maybe taking the oral version there was a DAO histamine issue at play? I mention this bcause my son has these issues and folinic was always tricky for him - once we went over a threshhold with it, we had problems. With my son's histamine/mast cell issues, he gets pins and needles tngling sensation that for the longest time we thought was due to his nerve tumor - he has a ganglioneuroblastoma. But getting histamines under control, this goes away....
    I hope you get some answers soon! Best of luck to your dear daughter.

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    1. Asma,

      First, accept my sincere wishes for your daughter...may she regain good health soon.

      Secondly, what Tanya has mentioned in the comment above is very important as I also noticed this pins and needles sensation in my sons extremeties...hands and feet when on folinic acid which I gave to him as a very low dose, less than 400mcg, once in three or two days. He also experienced some gas issues, which could be a cause behind the headache. I also noticed symptoms of histamine problems as Tanya has mentioned which is always dfficult to ascertain as it manifests as and is linked to so many other issues. But most disturbing was a feeling I got that following every dose, after an initial positive response to folinic, as the effect waned, my sons irritability quotient was much higher than his normal...he went lower than the baseline here as if suffering from a hangover or as if he got addicted to it. I am only giving a very crude example here.

      Do keep sharing your experiences...I feel they are very helpful to others.

      And once again, best wishes for your daughter.

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  19. Hi Tanya thanks for your response do you use anything for the histamine ?

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    1. Asma, we are using P5P,in a b complex without folinic and b12 to support DAO enzyme and just started SAM-e for HMNT support. My son also has food triggers that we avoid. And of course benadryl and allegra helps when things get overwhelming. Also holy basil, nigella oil, and a mixture of potassium bicarbonate and sodium bicarbonate.

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    2. Tanya, can you explain what you are trying to do with DAO, suppresz or encourage? My son has a DAOA mutation which makes DAO overactive, reducing D Serine, making him 3x more probable to develop schizophrenia (D Serine is low in scizophrenic patients, which is responsible for low cognition and mood). Do you know if you child has a DAOA mutation and what it does to DAO activity?
      V

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    3. trying to boost DAO enzyme for gut. I know Peter has written about DAO levels in the brain, but I still have no real understanding of that. Just working with what I know for sure is going on with my son as gut issues and allergies were the first obvious crisis signs of my son's "autism". He does have an MAO-A mutation, and I did try respen-A in the past for it, with no luck. So I am supporting it with riboflavin now - it's all I know to do. Also heard copper and iron is needed to support this too..Maybe I shouldn't be trying tiny amounts of zinc without copper? He does have DAO snps per a 23andme test. I have never tried d-serine. How is that going?

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    4. I am not using D Serine. It can cause seozures. But I am considering Sarcosine. Can you share what DAO snp he has.

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    5. oh, sorry Vladimir - when you typed DAOA I assumed it was a typo and you meant MAOA ... I had to look up the DAAO gene for him: he has a homozygous snp on daoa rs 2893229 (GG genotype).

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    6. Vladimir and Tanya, I am using L Serine, is a safer alternative to D Serine .
      Valentina

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  20. Hi I did email Dr Frye in Arakasas, he replied and said that this was the 2nd case of Leucovorin rescue after HighDose IV methotrexate that he knows of that showed improvement in cognitive skills whilst receiving leucovorin IV, the other case is a Downs Syndrome Child.
    I am now using a compounded Leucovorin 5 mg suspension bid that I had the pharmacist make , seems to be working much better and she has not complained of headaches for the past 2 days will keep you updated. I am still using the low dose clonazepam bid , the only other change I did was give the VSL#3 in the morning before breakfast for the past 2 days.

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  21. Hi Peter and friends, I have my daughter on VSL#3 in the morning before giving 5 mg leucovorin compounded suspension with the clonazepam and same at 3 pm after she returns from school. I am having a 10 mg suspension made for next week . So far no headaches and behaviors have been excellent. She has been very affectionate and calm. No SIB. Her verbal skills are slightly better I hope they continue to improve with increased dosage. I will update you all on verbal and behavior improvement. I do have her on very LDN at night mostly as a prophylaxis to prevent cancer recurrence and metastasis which also helps her to sleep. However on LDN without the leucovorin her behaviors during day were unbearable. Shes not angry any more. Hallelujah.

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    1. Asma, that is great. I am no cancer expert, but you might ask your oncologist to read the recent research about Simvastatin's benefit in osteosarcoma and indeed many other cancers. Just google "simvastatin osteosarcoma". I use the very similar Atorvastatin, as does at least one medical reader of the blog. It is very well tolerated.

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  22. Hi Peter my daughter Sabina passed away last Thursday July 13th at 6:15 pm at home. Her cancer spread to her lungs, she had fluid in her lungs and I believe it went to her brain because she lost all use of her right leg and fine motor skills in both hands and at the end could not even sit up without falling to the left. Things are very surreal right now.
    I am still waiting on Iliad labs FRA test apparently its taking longer because more people asking for test. I sent it out in the middle of June. I would like to do my own study on lecuvorin ; I know it helped my daughter tremendously. My daughter died at age 14 but I am still so connected to autism and will be in touch with you. Have to find a new purpose in life.

    Asma

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    1. Asma, I am very sorry about your loss. It would be a nice way to help remembere her by helping others.

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