This BILD article led me to the suggestion that some autistic individuals may have an underlying methylation disorder.

Furthermore, there is the indication from Dr. Costantini – a late Italian neurologist – that most neurological diseases benefit from higher doses of Vitamin B1. I have now researched this topic in more detail.

Here is the current state of science, based on the studies that likely formed the basis for the media reports. The studies are linked below.

Background: The Folate Hypothesis

Research suggests that some children with autism possess so-called folate receptor autoantibodies (FRAA). These antibodies block the transport of folic acid from the blood into the brain. Since folic acid is essential for brain development and the production of neurotransmitters, this deficiency leads to neurological symptoms.

The Key Study (Dr. Richard Frye et al.)

The most frequently cited study was conducted at the Arkansas Children’s Research Institute and published in the journal Molecular Psychiatry.

• Participants: Children with ASD and confirmed folate receptor autoantibodies.
• Result: A placebo-controlled double-blind study showed that children receiving high-dose leucovorin demonstrated significant improvements in verbal communication and social interaction compared to the placebo group.
• Effect: Leucovorin can bypass the blocked receptors and supply the brain directly with the required folate.

Important Facts for Context

Conclusion of the Leucovorin Hypothesis

The results are promising, but one must remain realistic: it is not a “cure” for autism itself. Rather, it appears to be a targeted treatment for a biological peculiarity (the folate transport defect) that occurs in a subset of those affected.

Then there is Thiamine by Dr. Costantini – in the context of Parkinson’s, I wrote about the book by Daphne …. regarding Thiamine.

Leucovorin and Thiamine in Autism

The Therapeutic Approach: TTFD and Benfotiamine

At the center of these reports is usually not conventional Vitamin B1 (thiamine hydrochloride), but fat-soluble derivatives such as TTFD (thiamine tetrahydrofurfuryl disulfide) or benfotiamine.

The reason: These forms can cross the blood-brain barrier more easily and raise thiamine levels in the brain more effectively than the water-soluble standard variant.

1. The Pilot Study by Dr. Lonsdale (2002)

The most well-known investigation is a (very small) pilot study by Dr. Derrick Lonsdale:

• Participants: 10 children with autism.
• Treatment: They received TTFD for two months.
• Result: Clinical improvement was observed in 8 out of 10 children, particularly in the areas of language, social interaction, and cognitive attention.
• Hypothesis: The researchers suspected that the children had a type of “functional thiamine deficiency” in the brain that was resolved by the vitamin.

2. Thiamine and Energy Metabolism (Mitochondria)

Recent reports (e.g., review articles from 2023/2024) often link thiamine to mitochondrial function.

• Many children with autism show signs of mitochondrial stress (the “power plants” of the cells do not function optimally).
• Thiamine is an absolutely critical cofactor for enzymes that convert carbohydrates into energy for the brain. A deficiency or transport disorder can lead to symptoms resembling autistic behaviors.

Comparison: Leucovorin vs. Thiamine

What You Should Consider

• No Self-Medication: High-dose Vitamin B1 (especially TTFD) can lead to a temporary worsening of symptoms (often described as a “paradoxical reaction”) before improvement occurs.
• Non-specific Symptoms: Thiamine deficiency often manifests through extreme fatigue, irritability, or digestive problems. If these are present in a child with autism, doctors sometimes investigate this path.
• Lab Values: A normal Vitamin B1 level in the blood does not necessarily rule out a deficiency within the cells or the brain.

Potential laboratory tests to ensure targeted rather than blind therapy

If you wish to follow the lead of leucovorin or thiamine in autism, standard blood tests at a GP often do not suffice. These usually only measure whether enough of the vitamin is circulating in the blood, but not whether it reaches the cells or the brain.

Here are the specific tests relevant to biomedical diagnostics (often performed in specialized laboratories such as Eurofins, LADR, or Ganzimmun):

1. Tests for Thiamine Status (Vitamin B1)

A simple B1 level in blood serum is often unreliable, as thiamine is primarily active within the cells (erythrocytes).

• Transketolase Activity (with TPP effect): This is the “gold standard” for finding a functional deficiency.
• What is done? The activity of an enzyme (transketolase) in the red blood cells is measured once with and once without the addition of thiamine (TPP).
• Result: If the activity increases by more than 20% after addition (the so-called TPP effect), it indicates a significant deficiency in the cells – even if the blood value appears normal.
• Whole Blood Analysis: Here, the blood is measured including the cells. This is more meaningful than the value in the serum (the liquid part without cells).

2. Tests for Folate Status (Leucovorin Context)

If you want to know if leucovorin makes sense, the primary concern is the transport pathway.

• Folate Receptor Autoantibodies (FRAA): This is the test that was decisive in the US studies (Dr. Frye).
• Background: The goal is to find antibodies that block the transport of folate into the brain (Cerebral Folate Deficiency).
• Note: Only a few specialized labs in Germany offer this test. Often, the sample must be sent to specialized institutes (sometimes even abroad).
• Homocysteine: A high homocysteine level can be an indirect indication that folic acid metabolism (methylation) is not running smoothly.

3. Supplementary Diagnostics (Mitochondria & Metabolism)

Since thiamine and leucovorin are closely linked to energy production, specialists often look at the following values:

Important Tips for Proceeding

1. Specialized Labs: Specifically ask your doctor about laboratories specialized in “environmental medicine” or “biomedicine.”
2. Pre-analytics: Vitamin tests are sensitive. The blood must often be sent protected from light (wrapped in aluminum foil) and chilled; otherwise, the result is worthless.
3. Costs: Many of these special tests are not standard services of statutory health insurance and must often be paid for privately (IGeL service).

This research was conducted based on the Bild article. We do not perform this in our practice – at least not yet!

References

1. Leucovorin (Folinic Acid) in Autism

These studies examine the effect of folinic acid (not to be confused with normal folic acid) on language development in children with autism and folate receptor antibodies.

• Frye, R. E., et al. (2016). Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Published in: Molecular Psychiatry. Content: This landmark study showed that high-dose leucovorin significantly improves verbal communication, especially in children who tested positive for folate receptor autoantibodies (FRAA).
• Frye, R. E., et al. (2013). Cerebral folate receptor autoantibodies in autism spectrum disorder. Published in: Molecular Psychiatry.
  Content: This is the foundational work that established the link between antibodies (FRAA) and autism.
• Frye, R. E., et al. (2016). Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Published in: Molecular Psychiatry.
  Content: This is the main study often cited in newspapers (placebo-controlled).
• Frye, R. E., et al. (2018). Folate metabolism abnormalities in autism spectrum disorder: Review and relevant mechanisms. Published in: Current Pharmaceutical Design.
• Rossignol, D. A., & Frye, R. E. (2012). Cerebral folate deficiency in autism spectrum disorders. Published in: Molecular Genetics and Metabolism. Content: An earlier, very important review on folate deficiency in the brain.
• Rossignol, D. A. & Frye, R. E. (2021). The Efficacy of Leucovorin (Folinic Acid) in Children with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. Published in: Journal of Personalized Medicine. Content: A summary of several studies confirming safety and efficacy.

2. Thiamine (Vitamin B1) in Autism

Research here is more fragmented and focuses on specific forms of B1 (TTFD).

• Lonsdale, D., Shamberger, R. J., & Audhya, T. (2002). Treatment of autism spectrum children with thiamine tetrahydrofurfuryl disulfide: a pilot study. Published in: Neuro Endocrinology Letters.
• Content: A pilot study with 10 children, 8 of whom showed clinical improvement in autistic symptoms under the administration of TTFD (a fat-soluble form of B1).
• Kern, J. K., et al. (2011). Thiamine deficiency in autism spectrum disorder. Published in: Medical Hypotheses.
• Content: Theoretical analysis of why thiamine deficiency could contribute to the metabolic problems in ASD.

3. Dr. Antonio Costantini: High-Dose Thiamine (HDT)

Dr. Costantini (Italy) was a pioneer in the use of high-dose thiamine for neurodegenerative diseases. His theory: many of these diseases are actually a “local Vitamin B1 deficiency” in the brain that can be overcome by extremely high doses (often intramuscular).

• Costantini, A., & Fancellu, R. (2016). An open-label pilot study with high-dose thiamine in Parkinson’s disease. Published in: Neural Regeneration Research.
• Content: Investigation of 50 Parkinson’s patients. Motor symptoms improved by an average of 31% to 77% (measured on the UPDRS scale).
• Costantini, A., et al. (2013). High-dose thiamine improves fatigue in multiple sclerosis. Published in: BMJ Case Reports.
• Content: Case reports on the drastic reduction of chronic exhaustion (fatigue) in MS patients through B1.
• Costantini, A., et al. (2013). High-dose thiamine improves the symptoms of Friedreich’s ataxia. Published in: BMJ Case Reports.
• Content: Shows improvements in coordination disorders (ataxia).
• Costantini, A., et al. (2014). High-dose thiamine improves fatigue after stroke: a report of three cases. Published in: Journal of Alternative and Complementary Medicine.
• Content: Translation of the fatigue protocol to patients after a stroke.

Book by Daphne Bryan on Thiamine in Parkinson’s

Summary of Evidence

While the Leucovorin studies (Frye) have already reached the “gold standard” (double-blind, placebo-controlled), the works of Costantini and Lonsdale are primarily based on pilot studies and case reports (“open-label”). They are medically highly interesting but not yet part of official guidelines.