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 2 mg/ kg per day (maximum 50 mg 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 (2 mg kg−1 per
day, maximum 50 mg 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 = 2 mg/ 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?
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.
ReplyDeleteThis 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.
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.
DeleteRoger and his Facebook group who have used this dosage for years will be a reliable source of safety info.
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.
ReplyDeleteInterventions 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?)
Thanks Roger. In the US the test costs $200.
ReplyDeleteHere is a link:-
http://iliadneuro.com/index.html#faqs
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.
ReplyDeleteRoger, 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.
ReplyDeleteI really appreciate your in-put.
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).
ReplyDeleteWe 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.
ReplyDeleteRoger,
ReplyDeleteHow 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?
Salempeacock, if they have an expensive test for FRAA and give leucovorin regardless of the result, you do have wonder what is going on.
ReplyDeleteYou might as well save the $200+ for the test and spend the money on generic calcium folinate and do your own trial.
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
ReplyDeleteThank 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.
ReplyDeleteThe 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?
DeleteNat,
DeleteNo. 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?
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
ReplyDeletethanks 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.
ReplyDeletePeter,
ReplyDeleteYes. 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 .
OK here is the math for trialing this:
ReplyDelete(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.
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.
DeleteTyler, 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.
DeleteOh 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??
ReplyDeleteHere is some new research on NAC and aging (Open Access):
ReplyDeletehttp://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.
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.
ReplyDeleteDoes 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.
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.
DeleteMonty 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
Thank you Petra, this is very interesting.
DeleteRunning 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.
I've found an article about PTSD and the role of NOX2 and parvalbumin interneurons(PV) in the development of the disease.
ReplyDelete"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.
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.
DeleteAlso 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.
Thank you.
DeleteKutki 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.
Petra it is expensive 200g costs EUR 46 on Amazon, but the "normal" dose is 1-2 g a day.
Deletesalemapeacock, do you know the dosages/kg in the triple shot and how often it is given?
ReplyDeleteSorry, I don't know.
ReplyDeletehttps://issuu.com/arkansastimesvisitorsguide/docs/arkansas_times_july_21_2016
Came to know about it from this article.
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?
ReplyDeleteThere 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.
DeleteThe 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.
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.
ReplyDeleteI 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
Asma, there are some comments in another post that may be useful regarding side effects of leucoverin.
Deletesalempeacock21 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.
Asma, I am sorry to hear about osteosarcoma in your daughter.
DeleteMy 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.
Agnieszka, what dosage of LDN do you use?
DeleteIt was 3-4 mg daily.
DeleteAlso 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 ?
ReplyDeleteAsma
I think you may find that the autism-cancer connection is not folate deficiency, but the FOSB osteosarcoma viral oncogene.
DeleteIt 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.
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.
ReplyDeleteI 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 ?
Asma, perhaps when taken orally some other substance is produced that is not present when given I/V. There must be a reason.
DeleteIntranasal 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.
Asma, I wish the best for your daughter and family. So tough what you are going through.
ReplyDeleteIs 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.
Asma,
DeleteFirst, 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.
Hi Tanya thanks for your response do you use anything for the histamine ?
ReplyDeleteAsma, 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.
DeleteTanya, 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?
DeleteV
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?
DeleteI am not using D Serine. It can cause seozures. But I am considering Sarcosine. Can you share what DAO snp he has.
Deleteoh, 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).
DeleteVladimir and Tanya, I am using L Serine, is a safer alternative to D Serine .
DeleteValentina
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.
ReplyDeleteI 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.
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.
ReplyDeleteAsma, 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.
DeleteHi 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.
ReplyDeleteI 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
Asma, I am very sorry about your loss. It would be a nice way to help remembere her by helping others.
DeleteDear Asma,
DeleteSomehow Sabina and her fight was very personal to me. Please know that your sorrow is shared.
Radhe
Hi Peter my daughters FRA test by Iliad came back negative and her MTHFR cheek swab came back heterozygous for A1298C.Did not get a chance to do tests for mitochondrial disease.
ReplyDeleteI was wondering if your wife or any moms out there had epidurals and or pitocin during labor and if so was there any fetal declearations/bradycardia/hypoxia.
I am reflecting upon all the events during labor. I did get pitocin for no other reason than the OB wanted to speed it up and then got an epidural and just before birth my daughter had fetal distress and I was given oxygen. The following when my daughter was with me she had increased respiratory secretions/foaming she was rushed for suctioning to the nursery. Now I am thinking could that have been seizure activity.
I am reading about Hypoxic ischemic injury to the neonatal brain
Any feedback is appreciated.
Asma, we understand and share your anguish. Time alone can heal it.
DeleteMy daughter in law had both epidural and oxytocin. At 40 weeks the baby passed maconium and her membranes ruptured and NHS staff tried to induce labour. She had prolonged labour for more then 48 hours. NHS Refused to do cesarean. It was too late to go for private medical care. She had intrapartum fever and fetal distress and then emergency Cesar was done. The baby was fine with Apgar score 9. Next day my grandson was diagnosed with enterococcus sepsis and was kept in neonatal ward with antibiotics for nine days and then discharged. At 20 months he was diagnosed with ASD.
Every single day we regret our decision for not coming to India for delivery. Here doctors never take such a risk. With membrane rupture and maconium they never wait more than 24 hours for fear of infection and neonatal complication.
Nowadays in Indian cities some modern doctors give epidural if the patient wants. Old fashioned doctors refuse outrightly even if the patient requests.
Asma, I think most people who benefit from Leucoverin will be FRA negative. I think they have nitrosative stress, likely from mitochondrial disease/dysfunction.
DeleteMany things contribute to the risk of autism, some of those relate to what happens during childbirth, but many others relate to what happened in the previous 9 months (and before that for epigenetic effects). For most people it appears to be an accumulation of small risks that when taken together with the parent's genes, prove to be too much. Except for people with single gene autism, you will never really be able to blame one single factor.
I don't know if my son has a FRAA mutation; his dna test shows he's compound heterozygous for MTHFR and his mitochondria are not good at all, so his doc prescribed folinic acid, among other things. Trouble is that these drops also have B12, which my son tolerates very badly, he gets more irritable. So I am going to try a new product from Neurobiologix called Methyl Folate Plus, which has 2mg folinic acid and B2 and see what happens. It's £34, so not that expensive and will see what happens.
ReplyDeleteHI Roger, Tyler, Peter et al, My college age son is high functioning but always wondered if trial of folinic acid would help. The doses here are high -- would you be able to tell if there could be a response with much smaller does like 800 mcg of folinic acid? Would I need to get the Rx at a higher dose to see.? Since some things are different at dosage levels I am wondering if that is the case here too? Thanks, KM
ReplyDeleteKM, the high dose that Roger takes requires a prescription. I very much doubt the 800 mcg dose would help him at all. There are all kinds of deficiencies that can occur in autism and a small dose of folinic acid probably would benefit someone, but it would not address the issues Dr Frye is targeting.
DeleteI respond very dramatically to 5mthf at even 400mcg, think extreme headaches, anxiety, painfull muscles, it causes some kind of methionine/histamine overload in those who have the folic acid mutations (which is extremely common in autism).
ReplyDeleteI would suggest to open a capsule and take a quarter of a 400mcg pill, if possible even less to address response.
folic acid activates dna methylation, once you activate that by using 5mthf or other forms of folic acid the only thing that can stop the possible side effects is niacin, which works by slowing down dna methylation.
Thanks Aspie and Peter. I do find it interesting that he seemed to have responded with 800 mcg with less negative thinking and cleared up acne. I don't know if it is another reason -- but no other change to regimen-- but it seems more than coincidental. I think Peter if I understand you correctly, he could have had a small deficiency (like someone needing iron, etc) and it could help in minor ways. Aspie, If it activated the DNA methylation would you expect it to make lasting changes? thanks for both of your feedback. KM
ReplyDeleteHi, I really need some help/clarification! I ended up here when I went looking for reasons why taking 25mg of Leucovorin (prescribed because of intensive Lyme treatment) has been so good for my mental and physical ASD issues, but taking a 5-MTHF supplement gives me insane, unrelenting, migraines and mood swings.
ReplyDeleteI was so surprised to find this posts that confirmed what I had been experiencing, with the positives of leucovorin. But I’m still trying to understand why the 5-MTHF is causing blinding migraines, even though the leucovorin doesn’t induce any headaches and actually makes me feel better. Aren’t they both forms of folate, I don’t have the MTHFR gene mutation, so I really thought either should be pretty benign.
Can anyone help me to understand this better? I really need to be able to explain it to my doctor, (who is a Lyme specialist, not someone familiar with ASD research) because he’ll be extremely skeptical and resistant to my stopping the 5MTHF. I need a clear enough understanding so I can effectively push for a higher dose of leucovorin if he insists that I need more folate with my other meds, rather than have to continue the combination of leucovorin AND a high dose 5MTHF supplement. If I can point to the science behind my bodies issues with 5 MTHF I’ll get much farther with him. Thank you all for sharing you experiences, without these posts, I’d be completely at sea about what is happening in my body and brain!
If you live in the US, contact Dr Frye ideally, or Dr Rossignol.
DeleteJust google "leucoverin Dr Frye". You can read what they have to say about this subject.
Dr Frye does reply to emails from doctors, so you can always have your doctor explain your case and ask for advice.
Hi Peter, I think I'm going to try Verapamil before venturing to helminthic therapy. Do you think the mucosal effects of Verapamil could reduce intestinal permeability or "leaky gut" in the small bowel or are the effects primarily focused on the colon?
ReplyDeleteIf folate could cross the BBB would it work just as well as the folinic acid?
ReplyDeleteIn terms of what I am currently working on, it keeps becoming more clear how sensitive I am to pretty much all medications. I think even a tiny dose of Verapamil causes low blood pressure like 100/60 (but it could be a combination of things where verapamil is the trigger). I think the verapamil also works for me as a mast cell stabilizer so its a shame how it dramatically lowers my blood pressure, I am not sure I can take it.
My last 3 blood tests show low RBC, low hemocrit, low neutrophils... I wonder where this fits in to my autism? Maybe this is why agmatine has been so positive for me because of the low RBC...
My current understanding of my autism:
definately allergy related + over active immune system
weakened blood brain barrier
this post has been predictive of a lot my characteristics so I find it pretty interesting:
https://epiphanyasd.blogspot.com/2017/07/targeting-dendritic-spines-to-improve.html
I have had several days where I feel great lately... I really wish I didn't have all this inconsistency... inconsistency where I cannot explain it... but it is hard to complain... things are infinitely better than where I was at the start
Thanks Peter, I don't know if you have any thoughts to any of this?
Hello, after reading this post, I began the search in my country for folinic acid, and I found it, in its 15 mg calcium folinate form (ETAMOLIN AC PHARMA) (without a prescription, South American advantage), each mg would be costing me 0.2 €, unfortunately california gold from iherb is sold out, it is also possible for me to get it in injectable (50mg/5ml)
ReplyDeleteMy 3.7-year-old son weighs 15.5 kg, he can say a few words if you ask him to repeat it, he can't do it functionally or spontaneously, he has ASD and ADHD, so I'm interested in giving him a boost with folinic acid .
Now, after reading all the comments, the following is not clear to me:
- Apart from taurine, what else could counteract the possible effects of aggression? In case he is not aggressive.
- How to start the dosage and frequency?
- In my country there is no FRAA test, but there is an analysis of serum folic acid, would this tell me something interesting?
- Would it be like the bumetanide that should always be taken?
Regards, Nicolas from Peru
Nicolas, serum folic acid would not tell you much. The level in spinal fluid would tell you a lot. If you want to do the FRAA test you can send a sample to the US by FedEx or DHL. Just contact the lab in the US and ask for instructions.
DeleteA typical dose is 1-2 mg/kg but you can gradually build up to this dose to minimize side effects. This therapy would become permanent.
A significant minority do get side effects and that may well be because they already have enough folate in the brain.
Give it a try and see how well it is tolerated and whether you see an improvement in speech.
hi Peter.
ReplyDeletejust sharing our experience with Spectrum Needs , which is a supplement endorsed by some prominent names in the ASDworld
I would like to highlight that this is just my own experience and that the supplement might work for others.
RT started taking the lemon version of the supplement about 2 months ago. at first we noticed he was more hyper in general . he had more energy and was jumping around . Eventually, the his sleep started to get more disturbed and was agitated just before falling asleep as if he just couldn't wind down. we had a similar experience with leucovorin and DMG supplement.
We stopped the neuro needs about 7 days ago and he has been more calm and is sleeping better since. like a lot of parents with a child on the spectrum there is a lot of trials and errors , I have come to the conclusion that anything with folinic acid or some types of vitamin bs only make my son more hyper. We are continuing with Bumetanide and it definitely does have a positive effect on concentration and focus. Anyone else with similar experiences ?
Yes, all those medications you are giving are stimulants. Try balancing them out with "downers." Melatonin, benadryl, clemestine, emodin, hydroxyzine. Just trial and error till you figure out which works.
Deleteanji
ReplyDeletePeter, did Monty ever test positive for the FRAA? Just curious.
ReplyDelete-Stephen
No we did not do it. I did have a discussion with Prof Ramaekers in Belgium, who is a very nice person, and he offered to do it.
DeleteI did trial calcium folinate on more than one occasion and following Ramaeker's advice to slowly increase the dose. It always caused aggressive behavior. This is quite a common reaction.
I think the really useful test is folate in spinal fluid. Most people cannot access this but it is the only way to potentially open the door to I/V calcium folate, which can be a gamechanger to those affected.
Thank you 😊
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