As mentioned in the previous newsletter, this month we will go deeper into the book by Dr. Richard Frye, The Folate Fix. Now that you are familiar with CFD, cerebral folate deficiency, we will now discuss how to diagnose it and how to treat it. Additionally, I will explain Tylenol's link to this diagnosis. If you want to refresh the information from Part 1, click here.

The website www.fratnow.com sells the FRAT blood test. This test checks for blocking or binding antibodies and soluble folate receptor autoantibodies. These autoantibodies interfere with folate transport across the blood-brain barrier. This causes a folate deficiency in the brain and nerves discussed in Part 1. The test needs a blood draw and would require the additional cost of a mobile phlebotomist. The test is 295.00. Before taking the test, it is best to avoid taking folate supplements and cow and goat's milk for several days because dairy can raise antibody levels. Dr. Frye says that 75% of autistic individuals show a positive autoantibody result on the FRAT test.

Doctors perform a lumbar puncture test to collect cerebrospinal fluid to diagnose CFD, which will measure how much folate is in the cerebrospinal fluid. Although more invasive, this is the most precise method to assess central nervous system levels of folate before and after treatment.

In Part 1, we discussed the importance of healthy mitochondria for preventing CFD. These mitochondria must produce sufficient ATP to transport folate across the blood-brain barrier. Dr. Frye suggests testing both mitochondrial function and the FRAT blood test. The following blood/urine tests relate to poor mitochondrial health:

• Elevated lactate levels
• Elevated pyruvate levels
• Elevated lactate to pyruvate ratio
• Elevated alanine levels
• Elevated fatty acids
• Low carnitine
• Low CoQ10
• Elevated Creatine Kinase
• Decreased Glutathione (oxidative stress)
• Elevated fumarate, malate, or dicarboxylic acids in the urine

Leucovorin - the treatment for CFD

A side effect of chemotherapy drugs like methotrexate and 5-fluorouracil results in the inhibition of folate metabolism. Doctors also use methotrexate to treat some autoimmune diseases. Leucovorin, a high dose folinic acid drug, is prescribed to counteract anemia caused by these drugs. While generally well-tolerated, leucovorin can cause mild side effects like difficulty sleeping. Doctors have repurposed leucovorin to treat CFD and can prescribe it in 5, 10, 15, and 25 mg doses. It is common for children with severe problems such as profound autism or epilepsy with CFD to need up to 100 mg per day of leucovorin to see results. The RDA (recommended daily allowance) for folate is about 150-300 mcg for a child 3-9 years old. From the doses using leucovorin, you can see that the therapeutic dose based on this research can be hundreds of times higher. For CFD, the standard dosing measurement is 2 mg of leucovorin for each kilogram of body weight. A 55-pound child, or 25 kg, needs a 50 mg daily dose, or 25 mg twice a day. Doctors may sometimes prefer three doses daily. CFD patients should see results in weeks to months, after the right dose is used. Reaching a therapeutic folate dose through supplements might be hard. A liquid form of 5-MTHF, an absorbable folate that is gentle on the liver, is available in 15 mg doses. Frye feels leucovorin made at a compounding pharmacy is best. He criticizes some companies for using ingredients that reduce leucovorin's effectiveness. He plans to start a company that produces Levo Leucovorin, which he believes is the best form for children.

Naturally, leucovorin is not effective for all patients. According to Dr. Frye, of those with a positive FRAT test, fewer than two cases need to be treated to see one case improvement. If the FRAT test is negative, doctors need to treat about five cases to see one case improve. In his book, there are a dozen remarkable case histories ranging from children who were nonverbal, those with seizures, or other neurological issues, such as severe autism, who responded to this intervention. Statistics show that a significant percentage of the children on the autism spectrum responded to this treatment. Also, adults with cognitive or psychological conditions such as depression or suicidal ideation responded. This kind of success shows that leucovorin can be a monumental change for good.

Acetaminophen (Tylenol) and Paracetamol

On September 22, 2025, President Trump and several health officials announced a controversial link between acetaminophen (Tylenol) and autism. The health officials included Dr. Marty Makary, Jay Bhattacharya, and Robert Kennedy Jr. They also announced that children with autism spectrum disorders should pay more attention to the use of leucovorin, and that insurance will reimburse this therapy in the future.

The FDA approved acetaminophen in 1951. At first, it was marketed as a prescription drug for children, but by 1961, Johnson & Johnson (J&J) bought the company that first produced it and renamed it Tylenol. They then persuaded the FDA to approve it as an over-the-counter medication. Initially approved, the maximum daily dose was 4000 mg. However, many individuals, particularly those taking medications like Excedrin, DayQuil, NyQuil, Robitussin, Vicodin, and Percocet (which also contain acetaminophen), were consuming 6000 mg daily. Too much Tylenol can cause liver toxicity and death. Acetaminophen abuse sends over 50,000 people to emergency rooms each year, causing 500 deaths yearly. Lawsuits have rewarded plaintiffs for the damage caused by Tylenol toxicity, and in 2011, authorities lowered the maximal dose per day to 3000 mg because it is the leading cause of liver failure in the U.S. Too much acetaminophen produces excess NAPQI, a toxic byproduct that binds to and inactivates an important antioxidant named glutathione, that is protective of the liver.

There is evidence that as far back as 2008, J&J employees expressed concerns via internal emails about Tylenol's safety. Specifically, about a growing body of studies pointing to a link between the prenatal use of Tylenol and neurodevelopmental disorders like autism and ADHD.

Tylenol is effective in relieving pain and lowering a fever. High fevers in pregnant women or young children can harm a developing nervous system. Therefore, a young mother's caution seems justified in preventing a rampant fever by taking Tylenol. However, people must balance this with knowing the risks of Tylenol or acetaminophen and use it carefully or choosing another method of controlling a fever and pain. The media and the manufacturer of Tylenol: Kenvue - a spin-off from Johnson & Johnson since 2023, are trying to downplay the risks of Tylenol while pointing out its benefits. Due to liver effects, Tylenol and acetaminophen can reduce folate levels. Soon, the FDA will require warning labels on products containing these, stating they may cause autism and ADHD in children. A 2025 review from Harvard and Mount Sinai pooled 46 studies on acetaminophen use in pregnancy and outcomes of autism and ADHD. Of the 46 studies, 27 found some link, 9 found none and 4 suggested a protective effect. The remaining 6 studies showed a mixed response. Nevertheless, the authors concluded that there was "evidence consistent with an association" and recommended using acetaminophen at the lowest dose and shortest time possible.

Legal experts are now reviewing whether J&J spun off Kenvue with its Tylenol product to avoid litigation damage. In 2023, J&J held over half of Kenvue's stock but has since reduced its stake to under 10%. J&J did the same tactic when there was evidence of harm from its asbestos-containing baby powders. In that case, J&J’s subsidiary named Red River marketed and sold J&J's baby powder to protect J&J from lawsuits. The claimants rejected Red River's offer of 8.9 billion in settlements for ovarian and mesothelioma. Now the claimants have now surpassed 73,000, and there is an expectation they will reach 93,000, requiring an eventual settlement of 11 billion. Could something like this happen with Tylenol? Could we see extensive legal action from parents and children with autism or ADHD, or those who took too much Tylenol? Should we rethink adding synthetic folic acid to foods and supplements and use natural folate instead, considering its potential impact on mothers' and children's livers over the last 25 years? These questions will be answered eventually.

I would like to thank Dr. Richard Frye for his excellent book, and I encourage anyone interested in this topic to read The Folate Fix for yourself. His book is the source of most of the information in these two newsletters. If you would like to read more about Dr. Frye and hear more details about his work, I would also suggest visiting his website at www.drfryemdphd.com

Happy holidays, everyone, and a happy New Year!!