I want to address a topic that’s gaining traction on social media, especially TikTok, where parents are sharing their experiences with leucovorin, also known as folinic acid, for their autistic children. This post is specifically for medical professionals who want to understand the science behind these stories.
About me
I have a PhD in computational chemistry from Yale University, and I have spent over a decade translating the science of autism for parents and healthcare professionals. Autism became my focus when my daughter was diagnosed. My daughter benefited so much from me knowing the science that I felt I needed to teach others. So here I am.
Parents come to me because they want trustworthy information. Healthcare professionals follow my work because I translate complex research into clear, actionable science and hopefully make your jobs easier. That’s my goal anyway.
Why is the spotlight on leucovorin
Today, I want to talk to you about something parents are bringing into your offices more and more often: leucovorin, also known as folinic acid, and autism.
In the past year, TikTok, especially, but other social media platforms, have exploded with parents sharing personal stories of their autistic children experiencing breakthroughs in speech, engagement, motor control, daily living, and interactions after starting the prescription, folinic acid, or leucovorin.
This means you, as a physician, may be getting more questions and maybe even more pressure about prescribing it. You might have some resistance, which is totally fair. Some of your colleagues are writing the prescription, and others are hesitant, often because they haven’t seen the body of research for themselves. And that is totally understandable.
There is no pharma rep walking into your offices with a nice prepackaged summary. Folinic acid is generic. There’s no sales push, there’s no sponsored CME, there’s absolutely no profit engine for anyone to come into your office and explain the science on folinic acid and autism.
That’s why I spent hours in PubMed reading and compiling, and fact-checking the data so that you can see exactly what’s been studied without bites or cherry-picking.
The science and studies behind leucovorin
Here’s what the peer-reviewed research shows. I’ll give you a high-level summary, and then we’ll go into studies.
Cerebral folate deficiency is present in a subset of children with autism. Many of these children test positive for folate receptor alpha autoantibodies. What they do is they block the folate transport into the brain.
The key thing here is if you have any doubt, any uncertainty, do the FRAT test. That’s the folate receptor alpha autoantibody test. So FRAT test. You can order it. It’s a specialized test. The greatest starting point is to do a test to confirm whether there is an autoantibody or not.
If the FRAT test comes back positive, many doctors feel much more comfortable prescribing leucovorin. There are still some doctors who, if the FRAT test comes back negative, do a trial of low-dose leucovorin just because they have a bit more experience with when the test is positive and seeing the different benefits.
Let us go through some of the studies that summarize the research that has been done on leucovorin and kids with autism worldwide. We’ll start with James et al.
James et al, 2009
| Design | Size | Intervention | Duration | Outcomes | Adverse effects |
|---|---|---|---|---|---|
| Open-label | 40 children with ASD | Methylcobalamin + folinic acid (0.4 mg 2x/day) | 12 weeks | Improved metabolic markers, glutathione redox status | 20% reported increase in hyperactivity |
It is an open-label design of the clinical trial. And this was basically the first one.
There are 40 children with autism. The intervention was methylcobalamin, B12 shots, with folinic acid. The folinic acid dose here was very, very small – 0.4 milligrams twice a day.
Duration, 12 weeks. Twelve weeks is the common amount of time that it’s been studied. When you’re looking at your patients and you’re starting to analyze if there’s a benefit, just make sure to keep that 12-week duration in mind.
The key outcome was that they were able to see improved metabolic markers and glutathione redox status. They’re measuring blood tests. They’re actually quantifying things.
There was a 20% reported increase in hyperactivity. That commonly happens with B12 and also folinic acid. B vitamins tend to do that, as you know, so no surprise there.
Frye et al, 2018
| Design | Size | Intervention | Duration | Outcomes | Adverse effects |
|---|---|---|---|---|---|
| Double-blind RCT subtyped with glutathione | 48 children with ASD, language issues | Folinic acid (2 mg/kg/day, max 50 mg) vs. placebo | 12 weeks | Better verbal communication, especially FRAA+ (d=0.91); improved VABS, ABC | No difference vs. placebo |
This study is what a lot of people will say is the pivotal study that really got people interested and was more of a jumping-off point. Dr. Frye and his associates in 2018 in the United States did a double-blind, placebo-controlled study, and they did subtype it with glutathione, so they were getting very specific.
It was 48 children, folinic acid. The dose was 2 milligrams per kilogram per day, and the duration was 12 weeks.
In this, they were able to see better verbal communication, especially if the child was positive for the FRAT. Again, doing the test really helps to have focus as to whether this is a priority for your patient.
Adverse effects across the board are very, very minimal. So folinic acid, vitamin B9, it’s water-soluble. Excess is going to get peed out.
Renard et al, 2020
| Design | Size | Intervention | Duration | Outcomes | Adverse effects |
|---|---|---|---|---|---|
| Double-blind RCT | 19 children (3–10y) | Folinic acid (5mg 2x/day) vs. placebo | 12 weeks | Improved ADOS scores (global: P=0.003, social: P=0.004, communication: P=0.022) | None reported |
Then there was another study in 2020, this time in France. I definitely want to highlight that this is not just being studied in the US. These are worldwide studies that are ongoing.
Again, double-blind. 19 children, so it’s on the smaller side. Dosing about the same, 12-week duration. And you see improvement, adverse effects, none reported.
Batebi et al, 2021
| Design | Size | Intervention | Duration | Outcomes | Adverse effects |
|---|---|---|---|---|---|
| Double-blind RCT | 55 children (mean 13.4y) | Folinic acid (2 mg/kg/day, max 50 mg) + risperidone vs. placebo | 10 weeks | Improved ABC-C scores (speech: P=0.044, stereotypy: P=0.036, hyperactivity: P=0.003) | None reported |
This is in Iran. Double-blind, 55 children. Again, dose is the same. This was with risperidone. It is important to keep in mind that it’s not as if it’s folinic acid or nothing. You have options here.
The duration here was 10 weeks. You see improvement in speech and a variety of other things, and no reported adverse effects.
Panda et al, 2024
| Design | Size | Intervention | Duration | Outcomes | Adverse effects |
|---|---|---|---|---|---|
| Double-blind RCT | 80 children (2–10y) | Folinic acid (2 mg/kg/day, max 50 mg) + standard care vs. placebo | 24 weeks | Reduced CARS scores, better in FRAA+; improved CBCL scores | None repported |
Now we have a study done in 2024 in India. Again, double-blind, 80 children this time. Very nice number. We’re increasing in that. The dose is the same. The duration here is 24 weeks, so again, it’s great to see this studied longer and longer.
They saw a reduction in CARS scores, and it’s better if the FRAT test is done, and it’s positive. Those are the children who seem, based on the research, to really benefit from it. That’s why doing the FRAT test makes sense, so that you can understand, does this child really need this intervention or not?
Wong et al, 2025
| Design | Size | Intervention | Duration | Outcomes | Adverse effects |
|---|---|---|---|---|---|
| Open-label, within-subjects | 10 children (4–8y, 9M/1F) | Folinic acid (2 mg/kg/day) | 24w (12w control, 12w treatment) | Improved PDDBI scores (p=0.103, medium-large effect); trends in communication, CGI | None reported |
The last study I’ll cover here is from 2025 in Singapore. This was open-label, 10 children, so a small sample size. Again, dose is the same, 2 milligrams per kilogram per day. The duration here is 24 weeks, so very nice. They had a 12-week control and a 12-week treatment arm. And again, they saw improvements with no adverse effects. And that’s what you’re really looking for, the improvements and the adverse effects that have been shown.
Summary
The science shows that adverse effects are really minimal. Now, if you go too fast with dosing, this is where conversations need to be had. Hyperactivity, aggressiveness, irritability, these can all happen if the dose is given too quickly, too much. There is a little bit of an art to titrating this up so that there is minimal disruption.
That’s the summary of the research that’s been done on leucovorin in clinical trials with kids with autism worldwide. It gives you, hopefully, a larger perspective of leucovorin in autism. These aren’t anecdotes. You can see it’s peer-reviewed clinical research. I have the references below. You can certainly go pull all the publications and read that yourself.
Mainstream medical education hasn’t caught up yet. It’s because folinic acid is generic. There’s no large-scale marketing or sponsored conference session. All of the things that you’re familiar with in how cutting-edge research gets to you is not going to happen in autism for a generic drug.
So this leaves busy physicians like you to rely on your own limited time to do research and investigate it. And I certainly know how impossible that can be in the middle of a packed clinical schedule. There are so many demands on your time.
So this post is really meant to be a helpful summary. And this is where my work comes in, translating the science so you have the full picture without losing hours of research that you, quite frankly, don’t have, but would love to have. So if you decide to explore this with patients, here’s what the literature shows.
Who benefits from leucovorin?
The benefit is most likely in children with the folate receptor alpha autoantibodies. Do the FRAT test. It’s a blood test, not anyone’s favorite thing to do on a child, but it really helps to be able to focus and get specific.
Leucovorin dose
Dosing is hugely important to get it right in order to see the benefit. I’m not going to go into dosing too much here. That’s definitely a conversation for parents to have with their doctors
Leucovorin duration
Most studies were 12 weeks. You want to set parents’ expectations because they’re seeing these TikTok videos, and are saying, “Oh my gosh, my child’s talking overnight!” So they give one dose of the leucovorin, and they’re expecting every single thing to change.
Managing their expectations is important. I wanted you to see how long the clinical trials were done, so you can really manage their expectations as well as you can. It’ll be great to have monthly check-ins with your patients to see how they’re doing, so that you get a lot more familiar with prescribing the dosing and things like that.
Leucovorin side effects
Adverse side effects are very minimal. However, like I’ve mentioned, hyperactivity, some GI symptoms do occur, and they certainly can be intense if dosing is not correct. So just keep that in mind. But overall, adverse side effects from leucovorin are very, very minimal.
My mission
I am not providing a protocol here. I am just ensuring that your medical decision-making is informed by the most complete and current evidence available.
My mission is to make high-quality autism science accessible to both parents and healthcare professionals so that decisions are based on quality facts, not trends, not fears, not hype.
If you’re a physician, you already know the weight of the decisions you make. I respect that deeply. That’s why I’m committed to being your go-to resource for clear, trustworthy, fully referenced autism research. If you want to get in touch with me, you certainly can send me an email.
I’m turning autism complexity into clarity for families and clinicians, for better outcomes for kids with autism. There’s a lot of great research out there, but it’s hard to stay up to date. Let me help.
