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Leucovorin Study for Autism

Lee SIlsbyManaging Editor's Note:  We are proud to share with you that  Lee Silsby Compounding Pharmacy in Cleveland, Ohio, is supplying the Leucovorin for this study below. Alan Israel, lead pharmacist, has been a leader in our community to ensure safe, effective biomedical treatments for our children. On a personal note, Lee Silsby was the first pharmacy I ever used for girls' back in 2001 and I've never forgotten their customer care and attention.  Thank you, Alan and the staff at LS.  KRS

A Folinic acid intervention for ASD

Dr. Richard Frye is conducting an exciting study on the impact of a daily treatment of folinic acid on ASD-related symptoms. The hypothesis is that an folinic acid will improve folate metabolism in the brain, oxidative stress and mitochondrial function in children with autism, resulting in specific health improvements for patients with autism, a discovery that would be very welcome by the autism community.

Lee Silsby Compounding Pharmacy has been selected as the sole supplier of Leucovorin (folinic acid) for the study. Alan Israel, R. Ph., the lead pharmacist at Lee Silsby, stated that the biomedical community can benefit greatly from more research and that he is willing to help out as much as possible. To his credit, Lee Silsby Compounding Pharmacy has agreed to provide folinic acid for both the double-blind placebo-controlled portion of the trial as well as the open-label portion of the trial at no cost to the patients in the trial.

Dr. Frye’s current proposal can potentially provide strong evidence for a folinic acid intervention and will provide insight into the subgroups of children with ASD who would benefit from folinic acid.  The primary goal is to improve language for those with ASD (which is measured by the receptive and expressive CELF language index). Preliminary studies have suggested that a folinic acid intervention is associated with receptive and expressive language improvements. For example, in a case-series of 44 children with ASD and the folate receptor alpha autoantibody, treatment with high-dose folinic acid (2 mg/kg/day divided twice a day; maximum dose 50mg / day) improved communication, attention, and stereotypical behavior in many children with ASD.

Folate is an essential B vitamin required for normal neurodevelopment.  Defects in folate metabolism can cause secondary physiological abnormalities, some of which have been associated with ASD.  In this study, Dr. Frye and his team aim to study several physiological mechanisms associated with folate abnormalities in children with ASD: the folate receptor alpha autoantibody that reduce folate transport across the blood-brain barrier, low glutathione redox status, mitochondrial dysfunction and genetic polymorphisms. Most importantly, ASD patients with these physiological mechanisms have shown improvement in ASD symptoms with a folinic acid intervention.

The goal of the study is to extend these preliminary findings by documenting response to a folinic acid intervention in a double-blind placebo-controlled manner and test whether the folinic receptor alpha autoantibody titers, glutathione status, mitochondrial function and genetic polymorphisms predict response to a folinic acid intervention. If any of these measures of physiological dysfunction predict response to the intervention, such titers could provide a biomarker to identify a subset of children with ASD that may benefit from a folinic acid intervention and may even predict the development of ASD symptoms in high risk siblings during the presymptomatic period.

Using these biomarkers, it may be possible that children with ASD who optimally respond to the folinic acid intervention can be readily identified early after diagnosis or even during the pre-symptomatic period.

The study is being conducted at the Arkansas Children’s Hospital and it has S. Jill James, PhD and Stepan Melnky, MD, PhD as co-investigators and in collaboration with Dr Edward Quadros, Ph.D. at SUNY Downstate in Brooklyn, NY.

Lee Silsby Compounding Pharmacy specializes in autism and is determined to make a difference in the lives of patients with autism. Please contact [email protected] for more information.



Lee Silsby logo 09 The treatment category is sponsored by Lee Silsby, the leader in quality compounded medications for autism.



My son is 3 years old and we have bought folonic on the back of this theory, I was wondering if anyone could help me on the dose to give my son. I have small bottles 30 ml and one droplet contains 400 mcg. Any help would be appreciated. Thank you


I will like to know if young adults on the spectrum that has never use medication for autism treatment can take leucovorin or Deplin? and how do I know it is okay to do so.?
I believe son (21yrs) has language, but has problems with receptive and expressive language. Prompts is used to pull words out of him. He is very quite, but short attention span/ not making eye contact Please enlighten if leucovorin will be helpful. Thanks

Jessica Baker

My son is 3 years old and just started a supplement study with Arkansas Children's Hospital and we started the Folinic Acid today. I am very anxious to see how this will help my son!


Also Lisa as an adult with ASD I was excited to hear about your actual experience with Folonic Acid & now Deplin. You are the person that can give us sooooo much insight especially when my 3 year old can not tell me. Thank you so much for sharing your experience and knowledge. I truely appreciate all the people on this site who take the time to share information! :-)


Can someone please explain the difference to me of Leucovorin & 5-MTHF. I am just finding out about this research and am very interested. I have a son who is autistic. He is 3 years old. I thought that when I got rid of all his yeast problems he would begin to talk. They have now been addressed & I am givng him oral Methy B-12, enzymes & zinc..... He seems like he is going to talk but something is holding him back, maybe this is it. He does have a problem with milk. I took him off of milk 5 months ago. We have no DAN doctors here where I live. I had 3 days of complete testing done here at the hospital & they said EEG, MRI, CT were all 100% normal. I would like to try giving him Leucovorin or 5-MTHF but don't know which one.


Also remember some pharmacy sold Leucovorin has casein


Hands down one of the best treatments I've done. Be sure to work with your doc on proper dose. For 8 years I had the wrong dose. The right dose combined with Levo carnitine made a night and day difference in many ways.

Thanks Lee Silsby and Drs Frye and Rossignol.

For more info read http://www.rossignolmedicalcenter.com/app/download/5857490604/Cerebral+Folate+Deficiency+ASD.pdf

Ben's mom

My son is another ASD child with multiple MTHFR mutations who has benefitted from Leucovorin. Of interest is that when previously we trialed MB12 injections and saw no results, the combination of Mb12 and Folinic acid is very powerful. My understanding is that for some people the Leucovorin will only be of benefit of the other Bs are balanced as well. Also of interest is that the MTHFR mutations lead to impaired ability to clear toxins- thus explaining his initial descent into autism following thimerosol laden vaccines in the late '90s and additional regressions with Depakote for seizures.


My son has cerebral palsey and might be on the spectrum as well he is 5. He's been taking leukovorin calcium as well as p5p his dosage is higher than mentioned on this page or comments at 7500mg a day and 200mg of p5p a day and it is increasing monthly til his body has normal dosage. I've seen huge responses he's more aware and is walking in walker and is a different child. He gets lumbar checked every 3 months to check how much his brain is taking in as well as being monitored if dosage is too high but so far so good I'm very excited to see what my little guy will be on full dose!


Glutamate carboxypeptidase II and folate deficiencies result in reciprocal protection against cognitive and social deficits in mice
Dev Neurobiol. 2011 Nov 10. doi: 10.1002/dneu.21000. [Epub ahead of print]
Glutamate carboxypeptidase II and folate deficiencies result in reciprocal protection against cognitive and social deficits in mice: Implications for neurodevelopmental disorders.
Schaevitz L, Picker J, Rana J, Kolodny N, Shane B, Berger-Sweeney J, Coyle J.
Department of Biology, Tufts University, Medford, MA 02155.



Interestingly, the folate receptor autoantibodies are flared up by milk, because milk products contain a folate binding protein that is a close analog to human folate receptors located on the brain.

So for people with this condition, removing dairy products from the diet is a must. Note that researchers have found that a majority of kids with autism have these antibodies (see links below).

Folic acid is not a good choice in that case, it is better to use higher forms of folate like folinic acid (Leucovorin) or 5-MTHF (Deplin). Both forms are also available over-the-counter, though folinic is only available on prescription in large dose:


Here are publications on this topic, MUST-READ:

Cerebral folate receptor autoantibodies in autism spectrum disorder
Molecular Psychiatry (2012), 1–13

Folate receptor alpha autoimmunity and cerebral folate deficiency in autism spectrum disorders
J Ped Biochem 2012;2(4):263-271

Cerebral folate deficiency in autism spectrum disorders
Autism Sci Dig 2011;2:9-15


My son has the MTHFR mutation so I imagine that might have something to do with his low folic acid.
The neurologist tried to supplement my son with folic acid, but a month later he had bad blood work(ammonia etc...) so she decided to lower the seizure medication and agreed with me to stop the folic acid as well. After she informed us that she was throwing those lab results out because the lab was contaminated, I asked if we should resume the folic acid, but she wanted to wait until he was stable. Under her care he never became stable and so she ended up referring him to a brain surgeon whom helped us by taking him off drugs since he should never have been put on them and I simultaneously found that milk increased his tics.
Now 6 plus years later I still have no treatment for low D3 and folic acid from the doctors. Is this his immune system reacting to folic acid and D3 (mounting a fight)? With supplementation of either he becomes extremely sick the next day. The solution I came up with was fortified orange juice with D3 and calcium. He also takes B vitamin supplement. I have heard people are sensitive to D3 and they do have different D3 supplements for those sensitive, but I have yet to find one for him.
Thanks for the information.


Thank you both you little sweet dears, I do appreciate the information.

Six hours - got it.


Yes Leucovorin is 25 mg tablets from the pharmacy. They are easy to cut in quarters or crush. With insurance it costed me $10.00/month.

Or it can be compounded.

I found my best dose to be 18 mg/day. So I would take two quarters in the morning and one quarter in the afternoon.

At the beginning I found out it was very important that I take it at least twice a day to minimize ups and downs in mood (the lifetime of folinic in the body is about 6 hours). After a few weeks, I guess as my brain levels were normalizing, it became OK to skip doses, though I still prefer to take it twice a day.

Donna L.

It's given orally. Ours is in tablet form from a regular pharmacy, but some are getting theirs through compounding pharmacies, so could also be capsule and even liquid, I believe.


Karen, Donna L, Lisa

How was this folinic acid given?

Donna L.

Very helpful info! I think it was your postings on another forum about Leuco that prompted me to really try this for my son, so thank you!! We're seeing some slight language and cognitive gains, better mood,etc. The only downside is my son has been waking up incredibly refreshed after only 2-3 hours of sleep per night for months now...and I am ready to drop dead! Always a trade-off, no way around it I guess. We seem to be a magnet for every possible nasty side effect of anything!


I don't have ASD (my son does), but I do have a long history of depression and heavy physical fatigue, and Leucovorin also was a true MIRACLE for me.

When I started, it felt litterally like someone had just plugged batteries into the Duracell Bunny: instead of slowly dragging my heavy weight around, I felt like I was flying; instead of sleeping 9 hours and waking up brain-fogged and zombie-like, I was sleeping 3 hours and waking up feeling refreshed, with a crystal-clear brain.

It was A-M-A-Z-I-N-G. After a while, one gets used to feeling better, but at the beginning, it is breath-taking.

My son's biomed doctor found I had significant levels of folate receptor autoantibodies. I can't tell how grateful I am to him for all he's done for our family.

Donna L.

Thank you so much for sharing your experience with leucovorin. My son has been on it for almost a year and it definitely seems to have increased his awareness - something like your description of your brain 'lighting up' - but he is mostly nonverbal so I can never be sure how he feels. It helps so much to hear from others on the spectrum who can describe how our kids might be feeling. Thank you!


I am an adult with a diagnosis of ASD. Way back in the 1980's I was part of a research study using leucovorin for my neurological issues. The effect was really extreme, in a good way, but like my whole brain was lighting up. i was told that I had folate in my blood but it wasn't being metabolized. I now take Deplin. I no longer notice anything from taking folate, but I remember the initial effect lasted for about three years. My brain tissue must have been severely deficient. It did not eliminate that many symptoms but I know it has been a good thing, because I could really feel it A LOT.


One issue is that some of us moms, and many kids with autism, have both folate metabolism issues and/or autoimmunity issues against folate receptors. In such cases, it might be better to use higher forms of folate than just plain folic acid, for instance take supplemental folate in the form of folinic acid or 5-MTHF.

Leucovorin is high dose folinic acid, and Deplin is high dose 5-MTHF. Both forms are also available OTC as supplement in lower dose.

Folic acid levels in blood might be fine and yet it might be very deficient in the brain and elswhere in cells, if there are any autoimmunity problems or metabolic problems.


A series of videos and articles are out right now on yahoo!:

Personally, my folic acid levels were fine for my first pregnancy, but something changed with my second. My son had low folic acid. The only difference between the two pregnancies is that I was given a flu shot while I was carrying my second baby.
I think prevention would go a long way here, rather than just supplementing the Moms and hoping the children won't be injured, they should look at what is causing this injury to the Mother's. I don't think we had a need to supplement pregnant women with folic acid until they started vaccinating pregnant women.

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