Episode 281 — Clarify The Leucovorin Confusion
Guest: Nicole Rincon • Date: November 13, 2025
Episode Overview
Nicole Rincon, PA-C, returns to provide clarity on folinic acid and the confusion surrounding Leucovorin, especially in light of recent headlines. As a physician assistant and mom of triplets with autism, she blends medical insight with lived experience to help parents cut through the noise.
About Nicole Rincon
Nicole Rincon, MS, PA-C, is a board-certified Physician Assistant with a background in microbiology and genetics. She received her Master’s Degree from Western University of Health Sciences and has been working with children with autism—including her own triplets—for over a decade. Nicole offers functional and integrative care, combining deep clinical knowledge with personal insight.
🔗 More about Nicole at Rossignol Medical Center
You’ll Discover
Why Leucovorin Is Suddenly Getting National Attention (4:23)
Signs of Cerebral Folate Deficiency (8:11)
How To Know If Pharma Or Supplement-Based Support Is Right For Your Child (12:15)
Why Supporting The Folate Pathway Can Improve Speech, Focus, and Behavior (18:28)
What Parents Should Ask Before Starting Leucovorin (24:17)
Whether Leucovorin Is A Short-Term Fix Or Long-Term Support (33:13)
Referenced in This Episode
Full Transcript
Nicole Rincon [00:00:00]:
It treats several things, and the studies have shown that it helps with speech significantly, attention significantly, repetitive behaviors, but also hyperactivity and irritability. So a lot of parents come to me and say, I'm scared to do it, Nicole. I don't. I don't want these side effects for my child. My child's already hyper, already irritable. So I don't think this is the drug for us or the medication supplement. But really, when you look at it, it treats a lot of these things. And for a lot of kids, like my son is an example, it reversed those symptoms in him.
Nicole Rincon [00:00:27]:
He was very hyper and it calmed him down.
Len Arcuri [00:00:30]:
If you're a parent of a child with autism, you are being called to rise with love, courage, and clarity. This journey isn't easy, and most parents aren't equipped, but you can be. This podcast is your invitation to rise higher because how you navigate matters. I'm Len, and this is Autism Parenting Secrets, where you become the parent your child needs now. Hello and welcome to Autism Parenting Secrets. If you're a parent who's heard of leucovorin, which is definitely in the headlines lately, it goes by a few different names, folinic acid or calcium folinate. But basically, if you're like most parents, you're a little bit confused because. And you're not alone in this because there's a lot of information, a lot of people talking about this.
Len Arcuri [00:01:19]:
Some of the information that you hear about it is a little bit conflicting. So right now is the best time to get clearer on what leucovorin is, how it might help, and again, all in the spirit of helping you to make better decisions for your child. So this week's guest returns to the podcast to help clarify this. Nicole Rincon is a board certified physician assistant, a microbiologist by training, and a deeply committed parent who's been supporting children with autism, including her own triplets, for over a decade. She brings both clinical and lived experience to this topic. And today we dig into the nuances of folate metabolism, pharma versus supplement forms, and the specific use cases for leucovorin and related supports. The secret this week is clarify the leucovorin confusion. Welcome back, Nicole.
Nicole Rincon [00:02:11]:
Perfect. Thank you so much for having me. I really appreciate coming back on. I know I was just on a few months ago, but this is such an exciting topic. I mean, it's. It's wonderful that it's becoming mainstream. And, you know, I reached out to you because a lot of people are having a lot of confusion out there. Reaching out to me.
Nicole Rincon [00:02:27]:
And it's so much easier to disseminate accurate information on this podcast. So I really appreciate you. I'm Nicole. Like you mentioned, I'm a physician assistant. I work at Rossignol Medical center with Dr. Frye and Dr. Rossignol. I did want to plug this book.
Nicole Rincon [00:02:40]:
I have zero financial benefit from this, but this is Dr. Frye's new book, so it's. Let's see if I can get it here. The folate fix. Sorry, my camera is a little blurry here. But in either case, it is his new book, published this year, about folate. And honestly, a lot of metabolic issues associated with autism too. But this is where us clinicians, we drive, derive a lot of our information from.
Nicole Rincon [00:03:05]:
So fantastic book. Really easy for the layman to read, too. So, anyway, great book. So thank you for letting me plug that, because I have a lot of parents that have actually clarified a lot of information just that from that.
Len Arcuri [00:03:17]:
If you didn't plug it, I would have. It's right behind me. And again, real resources are key. And in this case, Dr. Frye has been at the forefront of this. So taking the time to read his book to better understand this topic is definitely not a bad move.
Nicole Rincon [00:03:31]:
Yeah, thank you. Yeah, perfect. I'm glad. And, you know, and I wanted to bring this up because, you know, just as a clinician, obviously, I've been prescribing this for nine years, but my kids, we'd mentioned on the last podcast, I have triplets. Both of my boys regressed and were diagnosed at 2 with autism. And we had started leucovorin, I think, when they were about just over four years old. So took me a couple years to get to it. But they've been on it for almost nine years, not consecutively, but on and off, and I'll talk about that in a minute.
Nicole Rincon [00:04:03]:
But this is a near and dear topic to me because my family's on Leucavor, and all three of my children, I am actually on it as well because we're all positive for folate receptor antibodies, which, of course, I'll talk about in a second for testing. So I just wanted to bring that up because we've. We had really good gains for my one son in particular. And so this is not some far off. Oh, I had a patient that benefited, you know, once upon a time. Personally, I noticed that my son, it increased his cognition within, you know, weeks of starting it. His speech, his hyperactivity improved his attention. All the kind of the landmark symptoms that we see in the studies that it improves My son had that.
Nicole Rincon [00:04:44]:
So, yes, And I do see this clinically as well. So I don't believe this is snake oil. I believe in the clinical trials and I see it in my own family and also in the patients that I treat in clinic. So. So this is why I'm here. I really wanted to. To bring up the fact that the initial study that was done for leucovorin, it's not a new drug. I mean, people are saying, oh, this new cure, but it's not at all.
Nicole Rincon [00:05:05]:
Exactly. One of the landmark studies was done by Rayma in 2007 and he took 25 children with what he called low functioning autism, and he confirmed that they had cerebral folate deficiency, which is that low folate in the brain. So even though in the blood it's normal, it's not crossing into the blood brain barrier and getting folate into the brain. And in those kids, the study showed that the two youngest kids in the trial, because there were various age of kids, the one that was age two and then two years, eight months, and then three years, two months after taking leucovorin for a year, they completely recovered their autism, both of the children. So the two youngest ones in the trial recovered autism. So this idea that autism is treatable is not a new one. And even in the trial, leucovorin was a game changer for these two kids. So I just wanted to bring that up because a lot of parents, not everybody's gonna get these kind of results, but these results are possible.
Nicole Rincon [00:06:04]:
And that's why this is a drug that's worth talking about. Right? This is a clinical trial. This isn't from somebody's uncle's brother's sister's cousin. It's really potent. And they did use leucovorin in the prescription in this trial. We can talk about the doses, but this specific trial used 1 to 3, up to 3 milligram per kilogram per day. So it was a little bit of higher dose. And they did measure it over a year.
Nicole Rincon [00:06:26]:
I wanted to give that intro to just know that it is a potent and there is the studies out there and that there is a reason why this is such a widespread recommendation now and FDA approved, which is amazing.
Len Arcuri [00:06:37]:
It is amazing. And I think that's worth just focusing on for a second where the news flash and the big development is that this is something that's now approved for use where within, especially with asd, there's nothing really approved that's helpful. So it's noteworthy that this passed the bar that it is something that's approved for use, but that doesn't necessarily mean that everyone should run out and go down this road. Right. So it's not new. There's a lot of track record on this, a lot of science, and they wouldn't be able to make this recommendation unless this was something that very well can be beneficial. But again, for a parent to hear that and then say, okay, what do I do now? And I know that's why your phone's ringing off the hook. I've gotten so many questions on this, and I am not a clinician, but the key message is it's not new.
Len Arcuri [00:07:30]:
It's been around for a while. There's a huge track record with this. So now, with that in mind, and it's not a cure for anything. It's just something that has been shown to be effective with addressing what might be happening for these kids or for these adults. And so again, with that framework, it's been approved. That's significant. What would you say now in terms of. For parents assessing, is this worth moving on? Let's focus on that before we get to dosing and the options that parents may have.
Nicole Rincon [00:08:05]:
Absolutely. And I was just going to get there. So that's perfect, because I was going to talk about really what they're treating with leucovorin. Like, what is it? So not every child. You know, autism is a heterogeneous disease, Right. That means that not all autistic kids have the same problems. You know, some have issues with fatty acid metabolism or gut microbiome or mitochondrial issues. And those are all obviously separate podcast topics.
Nicole Rincon [00:08:31]:
But for this topic, we're looking specifically at cerebral folate deficiency. So a lot of kids they found with autism have cerebral folate deficiency, but not all of them. So Dr. Frye and Dr. Rossignol did a meta analysis a few years ago and found that almost half, I believe the percentage was in the 40s. But almost half of kids with autism do have cerebral folate deficiency, but not all. So when we're treating this leucovorin, it's important to note that this is active folate, and it's different. So what everyone's asking me is, are they treating this MTHFR gene mutation and what that is? There's a gene that activates folate, but that is a completely separate issue from what we're treating here with leukovorin.
Nicole Rincon [00:09:16]:
It's like apples and oranges. It sounds the same because the treatment is actually the same drug, ironically, or the same supplements, which is folinic acid. But the dosing is way different. So same, same supplement, same medication, but different dosing for different conditions. So this is not for MTHFR and that active methylation. This is actually just for cerebral folate deficiency and getting folate into the brain. So to answer your question, what are symptoms of specifically of cerebral folate deficiency that are kind of separate from autism? I mean, they definitely run together, but there are kind of characteristics, cerebral folate deficiency symptoms. So the big ones that you see, and a big clue is actually smaller head circumference.
Nicole Rincon [00:09:57]:
So if you have a child that's maybe when they're growing, like their head is small on that growth curve, smaller than it should be, or it's decelerating, that can be actually a big sign of cerebral folate deficiency. Things such as irritability, anxiety, obviously those are very general symptoms that have a lot of causes, but we find that frequently, especially irritability, poor sleep is a symptom of cerebral folate deficiency. And also another big one is motor issues. So they have a lot of movement disorders. They may have gross motor problems. So like they're clumsy, they're tripping, they're not able to coordinate their body, you know, to catch a ball or things like that. And then the fine motor. Some kids will actually get things like tremors.
Nicole Rincon [00:10:39]:
I know that was actually my son who responded well to Leucavorin. He actually started with a tremor at 18 months old. And I now, looking back, I think that was cerebral folate deficiency. And I think that's why he responded so well. And so there's things like another big point is seizures. So if you have a child that has autism and seizures, I have high suspicion of cerebral folate deficiency. So if that's your child, definitely talk to your doctor or your neurologist about that because they found that 75% of kids with cerebral folate deficiency and autism improved with leukovorin. So big, big numbers.
Nicole Rincon [00:11:16]:
And some of these are more general, like developmental delays and, or slow developing children can be a sign as well of cerebral folate deficiency. So again, it's not all the symptoms. It's not necessarily specific for speech or whatnot. But these are, again, these are symptoms you may want to look at. And if you're checking a lot of these boxes for your kids, they may be a better candidate. So I don't know if that helps clarify kind of what you're looking at.
Len Arcuri [00:11:41]:
For me, that's very useful. What are some signs that this might be more of an issue? Right. If you haven't done a test, let's say to confirm cerebral folate deficiency. And my guess is if somebody does have functional genomic information and they know that they have an impairment in mthfr. Right. That that's yet another not proof that you have this issue, but that's another indicator that this very well may be applicable for your child. Correct.
Nicole Rincon [00:12:08]:
It compounds the issue. So, yes. So basically, if you. You don't have to have MTHFR issues, you can have no problems there and still have cerebral folate antibodies and deficiency. But if you have both, it means that even if you may have enough folate in the brain, but it's not getting methylated. So if you have that MTHFR and. Or if you have both, you're not getting enough in the brain and it's not being activated with those methyl groups. So, yeah, I mean, the more problems you add on, the worse it tends to the severity of symptoms, certainly.
Nicole Rincon [00:12:41]:
So, yeah, it's a good question.
Len Arcuri [00:12:44]:
That's helpful. And again, the way my brain works as I'm hearing you talk, is that I feel like the biggest move for a parent to make is to really have a great plan that addresses a handful of really specific root causes, guesses of what's going on with their child. So to me, this whole thing comes down to, do you have enough evidence as a parent, the warning signs like you mentioned that say that cerebral folate deficiency for your child is a key root cause to focus on. And if you do, and if you identify that, then that's where this comes into play. And you answered the question I was going to ask before, which is generally with kids on the spectrum, and I know that's a large, very diverse crowd, but you're saying what Dr. Frye's research is that of that population, about half have this deficiency, some perhaps greater than others. And so this particular intervention with leucovorin or something similar has demonstrated improvement for that population that has this deficiency. Is that fair to say?
Nicole Rincon [00:13:54]:
That is exactly right. And there are. There's a couple studies that have shown that the severity of cerebral folate deficiency does correlate with the severity of autism symptoms. So if you have a little CF cerebral folate deficiency, then you might have milder symptoms. So, yes, that. That's. That's a fair assessment. That's good summary.
Len Arcuri [00:14:11]:
Okay, good. I just wanted to me that clarifies it in my mind, but for any of the people listening, you know, I think that's a helpful way of looking at it, because if you have no evidence, and maybe even. Even if you do a frat test that says this isn't an issue specifically for your child doesn't mean you can't go down this road and see what happens. But is this the primary place to focus? Perhaps not for your child, because there may be some more fundamental causes that are going on that need to be addressed first, which is why a practitioner like Dr. Frye or Dr. Rossignol or yourself and your unique ways of serving parents can help you know better where to aim.
Nicole Rincon [00:14:51]:
You can have negative folate receptor antibodies and still have cerebral folate deficiency, which is kind of a complicated concept, but a lot of that is because of mitochondrial dysfunction. So we. We know that most of the cerebral folate deficiencies due to these antibodies, which we can test for with the folate receptor antibody test. But mitochondrial dysfunction is an independent and separate risk factor. So like you said, even if they're negative and. But we're seeing a ton of mito dysfunction, energy production, dysfunction markers. We may start this anyway as a clinician because it doesn't necessarily rule out cerebral folate deficiency if the antibodies are negative. So, yeah, it's definitely good to work with a provider because we may want to do this anyway, depending on the clinical presentation.
Nicole Rincon [00:15:37]:
And again, just. I didn't say this, but the definitive in. And we have actually done this in some patients, but the definitive for looking at cerebral folate deficiency is a spinal tap. So. So it's actually doing a spinal tap and looking at folate levels in the. In the fluid, in the. Around the brain. So.
Nicole Rincon [00:15:54]:
But we rarely do it in any kids. Cause it is invasive. They have to go under sedation. But that would be the only way to actually know for sure. So.
Len Arcuri [00:16:03]:
Right. Which. Which is why there's a general view that, hey, go down this road. There's, you know, you don't need to have that proof just to try this and see if it's beneficial. Because by and large, the downside to going down this road. What are the negative things that can happen? Things are always possible, but it's a relatively low downside in terms of trying this. You might see an uptick in behaviors and other things, particularly if you maybe go too fast. But generally speaking, it's a pretty safe road to go down to experiment to see if this is beneficial for your child.
Nicole Rincon [00:16:39]:
Absolutely. I never want to downplay symptoms and there are some side effects, and I've had a couple cases of kids that have worsened with it. But in general, I don't want to discourage people because it treats several things. And the studies have shown that it helps with Speech significantly, attention significantly, repetitive behaviors, but also hyperactivity and irritability. So a lot of parents come to me and say, I'm scared to do it, Nicole. I don't want these side effects for my child. My child's already hyper, already irritable. So I don't think this is the drug for us or the medication supplement.
Nicole Rincon [00:17:10]:
But really, when you look at it, it treats a lot of these things. And for a lot of kids, like my son is an example, it reversed those symptoms in him. He was very hyper and it calmed him. So it's not fair to assume that every kid's gonna get worsening side effects. And they are less than 10% of kids. So it's not. It's not like. I mean, it's not likely, you know, statistically speaking, but it is possible.
Len Arcuri [00:17:31]:
So you're saying less than 10% have. Have some. Okay, because I think that's really good. Because generally speaking, whether it's this road or other interventions that you might do for your child, my experience has been usually things get worse before they get better. Whatever you're doing, like if you're doing chiropractic adjustments, things can kind of get worse as that child is kind of re regulating themselves. So I've gotten used to seeing things perhaps quote, unquote, worsen before. Before the uptick. If something's going to be helpful.
Nicole Rincon [00:18:00]:
Well, and that comes back to the guidance I was going to talk about. Is that what we do? There are several things you can do to minimize side effects. And I think it's important for parents to know it's not just, okay, try this, and fingers crossed, you know, start praying. You know, there are things we can do beforehand. The first steps, I tell parents, is to eliminate folic acid from your diet. So again, there is folic, F, O L, I C. It's. It's a synthetic form.
Nicole Rincon [00:18:25]:
It is inactive. It is oxidized, which means that it's. It's basically your body has to work really hard metabolically to. To activate it. And for people with mthfr, like we mentioned, it's. That can be very detrimental. And there was a study that showed that it actually competitively binds methylfolate at the folate receptor 1. At the receptor.
Nicole Rincon [00:18:48]:
At fully receptor 1. So what that means is that basically if you're taking in folic acid, it's making your problem worse. It's actually not. It's not only. It's not helping, it's not only neutral, but it's probably making these antibodies worse. So eliminating folic acid from any supplements, from any breads, cereals, anything you're taking in can actually help in and of itself. So just removing that from your diet. And so I counsel patients on that.
Nicole Rincon [00:19:12]:
I also counsel patients to eliminate cow's milk because reducing cow's milk stimulates these antibodies for both blocking and binding folate receptors. So just a lot of patients just reducing those two things, stopping dairy entirely and stopping folic acid, their symptoms improve even without trying leucovorin. So if you're really scared at home and you're a parent and you're wondering what you can do, I mean, those are first good steps, even independent, because it will treat. The underlying cause of what we're doing are a folate receptor of folate receptor antibodies and downstream cerebral folate deficiency.
Len Arcuri [00:19:45]:
And you're saying to eliminate milk and cow's milk and the like, even if you may have test results that say that your child's not allergic or, or sensitive to cow's milk, you're saying it can still be problematic, Correct?
Nicole Rincon [00:19:58]:
Yeah. And unfortunately, I mean, that's a hard one. I mean, we all love our dairy and I understand that a lot of these kids are picky and that's one of the few foods they have. But I have great results from some of my patients that are like, man, we just were really strict. We weren't strict before. We were having cheese pizza and we were doing this and that. But when they eliminated it, that the child, the hyperactivity improved, the cognition improved. So I do hear this, and I think there's various reasons we can talk about in another podcast, but part of it is definitely it lowers these antibodies and that's been studied in trials.
Nicole Rincon [00:20:27]:
And unfortunately, when you go back on dairy, those antibodies go back up. And that's what, that's what the trials show. So those are first good things to start. The other things that we do in our clinic to minimize those side effects is we will put them on. Like you said, it's not a standalone. This is not the one, one shot treatment. You can do it that way. But there's more side effects typically, so we will often add it with.
Nicole Rincon [00:20:49]:
First, I do calming things like magnesium, which can help with the mitochondrial function. It's very calming. We'll do things like Omega 3, which can decrease inflammation in the gut and also help receive and metabolize the, the folinic acid, the leucovorin. And another one that I really like is broccoli extract, which is sulforaphane. I add that a lot because a, it's calming. And B, it helps with that detox. It's sulfur support, liver support. So for a lot of these kids, I think you're kind of starting to stimulate these metabolic pathways and the folate pathways that, that kind of downstream go to the methylation pathways and essentially you're kind of stimulating detox, if you think about it that way.
Nicole Rincon [00:21:26]:
And you need to make sure that you're supporting these things Dr. Frye talked about in his book the Folate fix. Adding in B12 as well is very important to prevent what's called folate trapping. So basically we, every patient I have, I put them on some form of folate. I'm sorry, B12. Methyl B12 is typically the form before we start leucovorin. And I find that actually really minimizes side effects. I think some kids, they're a little B12 deficient to start, and then once you push that folate, it triggers a lot of reactions.
Nicole Rincon [00:21:59]:
So adding the B12 before the folate can be helpful.
Len Arcuri [00:22:02]:
Great. No, that, that, that's very comprehensive. Great suggestions. Just one clarific clarifying question with magnesium, if you're adding that from a calming standpoint, is there any particular form of magnesium?
Nicole Rincon [00:22:14]:
Yeah, I mean, typically we prescribe magnesium glycinate because it has kind of dual calming action. I know some practitioners use threonate, obviously. Like, I don't use the. There's the oxides and citrates for the constipation, but we're trying to get this actually into the brain and the central nervous system. So usually glycinate's the form that we go for. But yeah, like, again, there's primag and things like that. But, but that's a good question. And it's great because if kids are constipated too.
Nicole Rincon [00:22:38]:
Before you start any intervention with autism, I always recommend treating constipation. You know, that is the first, first, first thing we have to do before we do anything else because then kids will also react. And that's across the board of whatever intervention you do. If they're not pooping, then they're going to react to anything you give them, pretty much including Lucavorin.
Len Arcuri [00:22:56]:
Right. I love that you brought that up, because a lot of times, especially when I'm helped walking alongside parents and that idea of them guessing on which root causes to focus on, it's easy to focus on things that you think are bigger, but if you don't focus on that root cause of your child's constipation and address that first, it's hard for Anything, let alone leucovorin, again, for that to really benefit. So that's where there's some root causes that are worth and, and really require your focus first before you move on to higher level things.
Nicole Rincon [00:23:28]:
Yeah. So. And then the last thing is just if, if they're still having issues sometimes. Some kids do require some B vitamins as well. So B2 and B6 are also co factors for some of these, the folate process and methylation. So I usually do like to combine it with some kind of a methylated, good quality B vitamin. So B complex.
Len Arcuri [00:23:48]:
Okay, well, yeah, I think this might be a good time to start to talk about dosing. And specifically, again, what are your options in terms of going down this road? And I know when at the MAPS conference a couple months ago, Dr. Frye was talking about, because even before this announcement, there was a huge run on Leucavorin because it was being so prescribed. And I can only imagine what it is now. But even with this, I think it's important to not only get the dosing right, which Dr. Frye talks at length about in his book, but where you're getting your supply from is also important because some manufacturers, if they're kind of filling this prescription, they may add stuff to that pill for a variety of reasons that may actually be problematic and maybe negate its efficacy. So the form of leucovorin, I know there's a few options is really important to consider. My son is so highly sensitive to everything we have to have anything that he takes compounded.
Len Arcuri [00:24:55]:
Now, not every parent needs to do that, but for us, we have a higher bar. So can you talk a little bit about dosing and exactly the form of Leucovorin, what the options are for parents?
Nicole Rincon [00:25:06]:
Yeah. So just to talk about how we base dosing on. So I test every patient in my clinic for folate receptor antibodies. It is a specialty test that only one lab in the US does. I, I hope that more labs do it because I know they're really impacted. It's taking about six weeks, eight weeks now to get results, unfortunately. But nevertheless, it's extremely useful to get these antibody results. It tests for binding and blocking, and that really does help guide our treatment and our.
Nicole Rincon [00:25:32]:
On our dosing here at our clinic. So when a patient comes to me, I will put them on the few calming things, see how they're doing. I will start them on a very small dose of leucovorin, maybe 5 milligrams, just to see how they're responding again, even if they have MTHFR issues. That will help. So a lot of kids, even if they don't have antibodies, I'm putting them at such a low dose that it will be helpful for them. But as we wait for the antibodies to come back, when we see the results, we tailor it to the results. So there was a study done actually last year by Dr. Fry, and they looked at folate receptor antibodies and response to treatment.
Nicole Rincon [00:26:07]:
So what they found was that the higher the binding, specifically the binding titers were a, the higher the irritability in the child. So it correlated with symptoms. They, these kids responded to leucovorin well, so it can help guide who might respond. And then B, it improved their social skills more. So clinically, we took a step back, and basically we see, okay, these antibodies are very high. This child's more likely to respond. Let's be more aggressive with this. So normally, we're gonna get at least 2 milligrams per kilogram per day of leucovorin.
Nicole Rincon [00:26:44]:
And you divide it into two doses. So the kid's about 50 pounds. Let's just say it's gonna be about 50 milligrams of lucavorin a day. We divide it 25 in the morning. And also an important factor, we do it in the afternoon. For the second dose. You don't want to do it right before bed. Giving it right before bed can interrupt sleep.
Nicole Rincon [00:27:02]:
So when we do the dosing, we do morning, afternoon. And if the child is a high titer, let's say for binding, we may increase that to 4 milligrams, 6 milligram per kilogram per day. We go a lot higher because the studies are showing that it may be more beneficial for those kids. So this is why I emphasize it's important to get a test, and it does guide our treatment. But in most clinical trials, it's 2 milligram per kilogram per day. And that's kind of the standard dose where I shoot most kids for if they're positive for antibodies. If they're negative for antibodies, we may. I'm still going to try it, but I will be less aggressive.
Nicole Rincon [00:27:36]:
I go a lower dose. Normally I start at 5 milligrams of leucovorin, and we increase it weekly up until about to get about 10 milligrams, twice a day. And then I assess response. Was it good, neutral, or bad? And if it's good or neutral, then we kind of keep going up because they may have mito issues, especially if they have mitochondrial dysfunction issues. So we tend to treat as long as the kids are tolerating. It, because I do see benefit at higher doses. And this is where leucovorin is helpful versus supplements. You can use supplements, and I think a lot of practitioners provide that.
Nicole Rincon [00:28:11]:
But a lot of our kids are on 100 milligrams a day, 150 for the larger kids. So it can be difficult to supplement at that high of a dose. And to your point, the leucovorin that we get commercially, they do. Some of them have lactose, which a lot of kids can react to, because if they have a hard time digesting that, that sugar from milk, a lot of them have dyes in it, the food colorings and things that a lot of kids react to as well. So, yeah, a lot of kids get more. If they're having a lot of irritability, especially early on, then that, to me is an indication they're reacting to the supplement or the actual specific med. So if I put them on 5 milligrams and the kid's doing well with it, I'm thinking that maybe it's a filler or a reaction to some kind of ingredient in it. And as you mentioned, that's when I typically will go to compounded leucovorin.
Nicole Rincon [00:28:58]:
And I'm sure your listeners know, because they're brilliant, but it's that specific. It's that pharmacy that actually makes medications, and they make it to our specifications without dyes and fillers. And it's just a pure ingredient, and a lot of kids do much better with that. So, I mean, half my kids, I probably start out compounded just to begin with, just to bypass problems. If people are willing to pay for it and they want to go all in, it's a good place to start as a clinician.
Len Arcuri [00:29:23]:
Yeah, yeah. No, that there. It's just the price point, you know, if you are able to get a cleaner where there's no guesswork. So I think that makes a lot of sense. You mentioned mitochondrial dysfunction, though, earlier. Just out of curiosity, because it popped into my head, what percent of kids on the spectrum would you suggest in some way, shape or form have a mitochondrial dysfunction?
Nicole Rincon [00:29:46]:
There was a contribution, yeah, actually, in the meta analysis from Fryeand Rossignol, and I don't have the specific number, but I believe it was something like 41% of cerebral folate deficiency was contributed to mitochondrial dysfunction. So, but don't quote me on that. I'd have to look it up. But I know that it was around a third maybe, of kids that have MITO contributing to cfd. So mitochondrial dysfunction is very common in autism. And it's a third, maybe half of kids, depending on which trials you look at in the meta analysis. It's, it's, it's highly common. So the reason it's important is that ATP, which is energy, that energy molecule, is needed to push folate into the brain.
Nicole Rincon [00:30:26]:
So it has to actively be pushed in through the folate 1 receptors. So basically when you have low energy, it's not pushing folate into the brain. And so like we talked about earlier, that's a, that's a contributing problem. And leucovorin is actually interesting because that's why folinic is such a good form, because it actually can backdoor through what's called the reduced folate carrier. And so it's a way to bypass those antibodies in a passive way. But in order to do that, you need to flood those receptors with a lot of folate and a lot of active folate. So like I said, the folic won't work and the, the methylfolate, if you get the doses high enough, it may be too many methyl groups. The clinical trials don't look at high dose methylfolates for kids with cerebral folate deficiency.
Nicole Rincon [00:31:12]:
It's only really looks at folinic. So that's why we focus specifically on folinic, because it's been studied the most in the trials and it's been found to be very safe overall, considering side effects. So, yeah, it's a good form. You can get it compounded, you can do it as a supplement, but really to treat cerebral folate deficiency, you got to do folin, leucovorin, not methylfolate, and certainly not folic acid.
Len Arcuri [00:31:36]:
Got it. And as you're titrating up, which you alluded to, I think what is in the literature, what's in Dr. Fry's book, and is that ultimately the goal is to keep increasing to like 50 milligrams seems to be like the target. But as you just alluded to, that might be something that's too high for some kids. And for some kids, that may not be enough if they're older or larger. So again, it can go much higher than that. But I think the key thing for parents to keep in mind is the goal is to titrate up and increase. Watch what's going on.
Len Arcuri [00:32:11]:
And for some kids, maybe it is about getting to that level or it may be lesser, more. That's why it's so individualized.
Nicole Rincon [00:32:17]:
Correct? Yeah. And like I said, if the antibodies are negative, I'm not typically going to push it higher than 50mg but if they're very high, I've had kids that are positive for both and they're both really high, Then yeah, we're going to just ramp it up until, see if the high as a child will tolerate it because that usually is the upper level where we see the gains in certain kids, not all kids. So again, this is why you need a clinician. But, but yeah, the studies do. Like you said, they ramp, they stop at 50, and that's not a bad place. Like I tell parents, you know, if you can get your kid to 25 twice a day, you can convince your neurologist and your kid's doing okay with it. That's where the clinical trials are showing that there's a lot of benefit there. So it would be a good place to start, I think, for a lot of.
Nicole Rincon [00:33:02]:
Lot of kids.
Len Arcuri [00:33:03]:
Perfect. Well, I think we covered a lot of ground. Is there anything else I think that you'd like to add that might just be useful for parents to understand? The one thing that pops to my mind is, you know, the question I get a lot is if I do this, is it like my child's gonna need this forever? Like, is this something that's gonna be a perpetual supplement or is there some window where you can back off? So can you touch on that and anything else you think that might be helpful?
Nicole Rincon [00:33:28]:
Yeah, yeah. And that goes to the, my very intro. Start at the earlier the better. If you can get the child on it at 2 or 3 years old, that's where the best benefits are made. But again, there's benefits made at any age, even in your 20s and 30s, even into adulthood. So it's not like there's a window and then the window closes. My son, just to share my story, my son, we were on it for years. He responded really well.
Nicole Rincon [00:33:52]:
We ended up testing negative for antibodies. After several years we were dairy free. So I stopped it because after like five years you're like, okay, let's try it, let's try it. He's doing very well. Speech, social. So we stopped it. And then I reintroduced it because he's getting to 13, he's hitting puberty. And when I restarted it, he got a huge jump in gains again.
Nicole Rincon [00:34:11]:
And now he's actually, he jumped in from his, he was grade level and now he's two grade levels ahead in reading. He's now Mr. Social Popular. So I, I kind of kicked myself thinking, man, maybe I should have kept him on it and because he was doing well, but I guess he could do even better. So I guess the point is, if they're tolerating it well, it looks like it's safe to be on long term. Now, there's not huge long term studies, again, not decades long, but especially if your child was a responder and you found that that was really beneficial for him. Him or her, yeah. Kids can be on it for life.
Nicole Rincon [00:34:42]:
And again I mentioned I'm on it as well. So I tested positive because I thought, well, all three of my kids are positive. So I tested myself. I'm positive. So I take it every day. And I find that my sleep is improved, my anxiety, just cognition, my ability to work and juggle my billion hats in my life. So I love it. I miss it.
Nicole Rincon [00:35:00]:
When I don't take it metabolically, I mentally feel it. So I think you can take it for life if you're feeling good with it and you're not having side effects. That's what we're kind of doing. I know Dr. Fryein his practice, he won't stop any on it, anybody on it, unless they've tested negative for antibodies and for some reason they don't want to continue it. But it's kind of one that we keep kids on. So, yeah, I mean, it's, it's, it's bummer, but it's, but it's a great thing at the same time too, you know, like we having something that's been shown in trials to really help and, and it's helping. So let's leave them on it.
Len Arcuri [00:35:31]:
Yeah. If that's the case, it's just kind of, that's the way it is. But otherwise, if it's helping, it's helping. And, and that is exciting and something to celebrate. So with all the confusion, maybe that might be out there with a lot of people talking about this. It is all just very hopeful that something that absolutely can help many kids is more widely available, better understood. And I think for people who are listening, yeah, I think the key moving forward or the opportunity is just to move forward with confidence, with more awareness. So this episode, I think helps answer a lot of questions I know that were in my mind.
Len Arcuri [00:36:06]:
And if you're listening and you have a practitioner that you're working with, share this episode with them. And I know you, you and the, all the people at Rossignol have a lot of demand now. So I know you're not necessarily looking for new clients, but if people do want to work with you, I know they can. We'll include in the show notes where they can reach out to you and you're in California. But otherwise, again, there's definitely with more awareness, you can definitely incorporate this into your plan for your child in a much smarter way, in a way that, you know, definitely stacks the deck for you to get benefits from. Going down this road. There's definitely some do's and don'ts, and I think you touched on a lot of them.
Nicole Rincon [00:36:44]:
Nice.
Len Arcuri [00:36:44]:
Perfect.
Nicole Rincon [00:36:45]:
Thank you for having me on. I appreciate your time.
Len Arcuri [00:36:47]:
Well, you're welcome back anytime. Thanks, Nicole.
Nicole Rincon [00:36:49]:
Thank you.
Len Arcuri [00:36:50]:
Your child needs you running on all cylinders now. And the fastest way to rise is with personalized one on one support. Get started today. Go to elevatehowunavigate.com
