Independent Insights, a Health Mart Podcast

Navigating the Role of Leucovorin in Autism Care

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Recent FDA actions have brought renewed attention to leucovorin as a potential treatment for managing symptoms associated with autism spectrum disorder. This course explores the clinical distinctions between autism and cerebral folate deficiency, reviews key evidence behind leucovorin use, and outlines counseling considerations relevant to pharmacy practice. You will gain clarity on this complex and evolving topic to better support informed, evidence-based care.

HOST
Rachel Maynard, PharmD
GameChangers Podcast Host and Clinical Editor, CEimpact
Lead Editor, Pyrls

GUEST
Geoff Wall, PharmD, FCCP, BCPS
Professor of Pharmacy Practice
Iowa Methodist Medical Center

Rachel Maynard and Geoff Wall have no relevant financial relationships to disclose.


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CPE INFORMATION
 Learning Objectives
Upon successful completion of this knowledge-based activity, participants should be able to:
1. Describe current clinical evidence related to the use of leucovorin in autism and cerebral folate deficiency.
2. Identify key counseling considerations for pharmacists discussing leucovorin therapy with patients and caregivers.

0.05 CEU/0.5 Hr
UAN: 0107-0000-25-363-H01-P
Initial release date: 12/1/2025
Expiration date: 12/1/2026
Additional CPE details can be found here.

SPEAKER_00:

Hi Healthmart Pharmacist, from your education partner CE Impact, this is Game Changers. I'm your host, Jen Moulton, and each week we have a conversation on a hot clinical topic that will keep you current in practice and position you as a resource for prescribers and patients. Thanks for listening in.

SPEAKER_04:

Hey everyone, Josh here. It's been such an incredible journey sharing clinical updates that shape your pharmacy practice. I've truly enjoyed every minute of learning and growing alongside you through these conversations. But the time has come for me to pass the mic, and I couldn't be more excited about who's stepping in next. Dr. Rachel Maynard will be your new host moving forward. Rachel is a pharmacist with extensive experience across diverse areas of practice and more than a decade focused on developing engaging, evidence-based educational content. She's passionate about helping pharmacists translate knowledge into better patient care. You may also recognize Rachel's voice because she's joined me as a guest on a few past episodes. But don't worry, I'm not going anywhere. I'll still be in my same role here at CE Impact, just working on some new projects and initiatives to support pharmacists and promote lifelong learning. Rachel, it has been such a pleasure getting to know you over the past few months, and I can't think of anyone better to carry the conversation forward. So take it away, my friend.

SPEAKER_01:

Well, thanks so much, Josh. And hello, everyone. I'm so excited to be joining you as the new host of Game Changers Clinical Updates. I've admired this podcast for a long time, and I can't wait to continue the conversations that help us grow, learn, and make a real impact in pharmacy patient care. Over the upcoming episodes, we'll hear from practice leaders, explore fresh perspectives, and get practical insights that you can apply to your own practice. Josh, thank you so much for paving the way and for your dedication to creating meaningful dialogue in pharmacy practice. I'm thrilled to build on that foundation and to keep the momentum going. So let's dive in. The next chapter starts now. Alright, so today we've got a really interesting topic to tackle, which is looking at a decades-old drug, Leucovorin, and some recent FDA action to make it available for a new use. So the FDA recently put out a press release, and the headline is FDA takes action to make a treatment available for autism symptoms. And that treatment is Leucovorin, and we'll dig into what that autism symptoms phrase means a little bit more. But since that FDA press release, the American Academy of Pediatrics actually came out with their own interim guidance about the use of Leucovorin in pediatric patients with autism. And their guidance states, and I quote, at this time, the American Academy of Pediatrics AAP does not recommend the routine use of leucovorin folinic acid for autistic children. So I think you can tell from that this is a bit of a controversial topic. We're going to sort through the evidence and come to a bottom line about what all this means in your practice. And I'm so excited to welcome our guest today, Dr. Jeff Wall, who is no stranger to this podcast. But we're so excited to have your expertise on this challenging topic today, Jeff. So welcome.

SPEAKER_03:

Thank you very much. I appreciate it.

SPEAKER_01:

Awesome. So for our listeners who may not have heard you on the podcast before, and for me too, since it's my first time chatting with you, can you share a little bit about your background, your current role, and why you might be interested in this topic?

SPEAKER_03:

All right. I appreciate it. Yeah. So yeah, I'm a uh currently I'm on faculty at Drake University, have been for over 25 years now. I'm in the Department of Pharmacy Practice. My practice site is in internal medicine and critical care at Iowa Methodist Medical Center, which is the third largest hospital in Iowa. Have been practicing in internal medicine for about 25 years now, a little bit a little bit longer. I've been a pharmacist now for almost 35 years. Oh my lord. And so yeah, at this point I get routinely made fun of before for my age and stuff. So it's pretty good at this point. But and yeah, you know, uh uh I like internal medicine, kind of you know, Jack of all trades master of none. But I mean, this has certainly reached a lot of stuff because I'm also the director of the Director of Information Center. And so in that role, we actually have gotten already several questions about some of the recent uh announcements by FDA and by uh HHS about several topics in the world of autism, but this was certainly one of them, and uh we actually just completed a monograph for phlinic acid and its potential use in autism use disorder. So, you know, I feel I you know pretty comfortable with the data at this point.

SPEAKER_01:

So excellent. Well, then very happy to have you here to help sort through all that because I think it is a confusing topic, and even the the FDA sort of headline that I read um is open to a bit of interpretation depending on how much further you read into that news release. So I just gave a brief background and like I say, just basically the headlines. So if you could give a little bit more on what the FDA is doing and why maybe this is coming up now and what what's sort of spurring this, and you mentioned some other actions around autism too, and I think this you know falls in with that. So just a little more clarification on what FDA has said and what what they're planning to do.

SPEAKER_03:

Right. So, you know, uh autism spectrum disorder is is a controversial topic from really the word go. But for those who suffer from it and for parents of of children who have it, it can be a devastating diagnosis and is is just a real challenge because like so many disorders that we really don't understand the cause of, we don't really have a lot of effective treatments for. And so, you know, depending on the scale of symptoms that that patients have, it can be unbelievably challenging for day-to-day life, for you know, education and and all sorts of things like that. So as you might imagine, in a world where we've got you know patients where we don't really understand what's going on with them, but we kind of you know look around for for you know any treatments we can, right? And um and this is true for a variety of of disorders. And for autism spectrum disorder, there have been uh studies, very small studies, uh, both at the kind of the bench level as well as one randomized control trial that have suggested that thalinic acid may be beneficial in improving some symptoms in autism spectrum disorder. FDA has has basically announced that they're going to use that as kind of a pedestal to to look at approving thalinic acid for autism spectrum disorder, but also I think more importantly, as an impetus for designing and executing large-scale clinical trials, which is really what we need. And and I think so. I mean it's it's a twofold thing. I think I think they signaled I wouldn't say approval of of a non of an off-label use, because I'm not sure that's something the FDA can do. But I think I think uh a way to interpret the FDA's press announcement is that you know it's a signal to healthcare providers that hey, we're you know, plenary evidence is promising. We're taking a look at at maybe approving this either on its own merits from the studies we have, which I hope they I I'm not sure how smart that is to do, but that's a whole other issue. But also as a platform to help design and execute clinical studies. Polinic acid's been generic for a long, long time. So there's good it's gonna be challenging to find anyone who will do large-scale randomized control trials on this because they won't have anything really to benefit from it.

SPEAKER_01:

So yeah, but I I think you brought up a few great points. And one of the things that was confusing to me actually about that FDA press release was that they were initiating the the approval of this. As you said, it's a little bit it not our normal regulatory process for approving drugs. So that was yeah, so it's very interesting. But let's actually just take a step back for a second and actually look at what they were sort of starting this initiation of process for, and that specifically was for a condition called cerebrofolate deficiency. And so I think it would help all of us get on the same page around what is cerebrofolate deficiency, which maybe we can refer to as CFD going forward, just for simplicity and ease of use, but also what is that and how is that different or similar to autism? And you know, some distinctions there. Are are they sort of equivalent terms or what are the nuances there?

SPEAKER_03:

It's a good question. And and and from my reading, you know, they're not equivalent terms, but but they're clinical phenotypes. I mean, how they look and how and and how patients can have symptoms surrounding it are very, very similar, right? And since autism spectrum disorder is, you know, I mean, there's no there's no lab test, there's no imaging test that definitively diagnoses it. Um, like many of these disorders, it becomes difficult to tell one versus the other. But the former, uh CFD. Sorry, I'll take me a second.

SPEAKER_01:

You can use the full name if you'd like, either way.

SPEAKER_03:

No, no, that's fine. I think CFD is better. You know, yeah, it, you know, it it is basically just what it says it is, that that there's a small percentage of patients that have a basically a genetic disorder where they have a a mutation in their MTHFR gene, which is a gene that does a million things, but one of the things it's primarily responsible for is folic acid metabolism. And uh without that, you can't, yeah, uh folic acid doesn't get basically activated. And so you have basically unactivated folic acid with that um um physiologically active types of folic acid, which is folinic acid, basically are at very low levels. Your whole body needs folic acid, but in particular your brain needs folic acid, particularly when you're growing. And so this is a small percentage of patients that can have this mutation in their gene that leads to low levels of folic acid in the cerebral spinal fluid that has been thought to lead to some developmental issues that are very, very similar to autism spectrum disorder. Um, and again, just looking at a patient, uh you can't really say, you know, I mean, okay, well, this patient has met the diagnostic, you know, clinical criteria for autism spectrum disorder. Could they also have this, you know, uh uh uh cerebral folate deficiency? They may well have. It's relatively rare compared to overall ASD, but it it certainly could be a possibility. And this is an unusual, you know, folic folic acid deficiency or methylfolate deficiency, I suppose, at the at the brain level isn't just limited to the potential uses in autism second resort. We know that about 10% of patients with resistant depression also have this, you know, decrease in in activated folic acid in the brain. And in some of these patients, treatment with methylfolate has been found to be beneficial. So, you know, that there's certainly biological plausibility for the fact that that low levels of folic acid in in in the central nervous system can lead to issues. So it certainly stands to reason that that's what's going on.

SPEAKER_01:

Okay, got it. So uh just to clarify, so they are not one and the same autism and cerebral folate deficiency. And cerebral folate deficiency, it is a nice descriptive term because as you said, it it means that folate is not getting into the cerebrospinal fluid, it's not crossing that blood brain barrier as it should. And so even if they have normal blood levels, it's not getting into the that cerebrospinal fluid. Okay, so that's a great distinction. And the other distinction is that people with CFD may have symptoms similar to autism, um, but they may, you know, it may not be a diagnosis of autism spectrum disorder, and and vice versa also. So people with autism don't necessarily have CFD. They're sort of they are discrete, you know, there may be an overlap, but they're discrete terminologies.

SPEAKER_03:

So they're yeah, they're yeah, they're absolutely discrete entities. But again, the phenotypes clinically can be very, very similar. So that's I mean, that's the problem is that in a in a disorder where we don't have definitive testing, it can be very difficult to differentiate the two. And the only thing you can really kind of go off of is that as we understand it, the cerebelfolia deficiency is relatively rare.

SPEAKER_02:

Right.

SPEAKER_03:

Right. But that's but you know, that's really it. That's that that's you know, so it can be challenging to do. Yes, they're absolutely two different separate entities, but without advanced testing, it's it's difficult to tell between the two.

SPEAKER_01:

Right. I I I think in the American Academy of Pediatrics FAQs, it said it's it's either lumbar puncture or genetic testing is the way to actually diagnose CFD. So that's an important nuance. But again, thinking about that FDA headline to make a treatment available for autism symptoms, um, they then go on to say initiate the approval of leukobornin for patients with cerebrofoliate deficiency, which those patients may have autistic features. So again, there's sort of this blending, and I think it can be confusing, especially if you, like you say, you're looking for treatments for, you know, because there's not one proven target treatment. Um, and so this could be this is why I think it's of interest to a lot of people and and people looking for an answer. So maybe with that we can actually go into Lukeborin and and what it has typically been used for and sort of that mechanism. You touched upon that a little bit, I think, but maybe just clarifying what what that drug is and what it's been used for in the past and what the theoretical role might be for CFD and/or autism.

SPEAKER_03:

So, I mean, as I think everyone knows, you know, folic acid, right, is an essential vitamin. It's vitamin B9. It is responsible for a whole host of metabolic processes, not least of which is producing red blood cells, but also developing uh um the cerebral or the the um central nervous system, peripheral nervous system as well. Why it's why folic acid is so important to the developing fetus and why it's critical that that that that that uh pregnant women you know you know have enough folic acid. But folic acid is is not metabolically active. Folinic acid or leukoforin is the metabolically active form of folate that does not require um a an enzyme called dihydrofolate reductase for conversion. So if you're wondering why can't we just give people tons and tons of folic acid and won't that do the same thing, you know, the answer is probably no, because the theory behind all this isn't that people aren't eating enough folic acid, is that their body can't convert it to its active form, right? So folinic acid kind of bypasses that, right? It has been available, as you pointed out, for decades, but it's been primarily only used almost not all exclusively, but I'd say 80% of phalinic acid was used as a rescue treatment for methotrexate-based chemotherapy regimen. So we would give, especially for for non-tumer solid tumor cancers like lymphoma, leukemia that often had CSF infiltration, uh, you would actually give massive doses of of intrathecal methotrexate to knock out the cancer in the central nervous system. And those kind of doses were, you know, extremely could cause extreme sickness and even death in patients. And so we would perform what was called leukoborin rescue. So you just you'd you'd, you know, since methotrexate and all these drugs are fully uh reducers, we would just give massive amounts of active folic acid, folinic acid, to treat it. So that was that that's the primary use. Now I've used it for methotrexate overdoses a million years ago when when we were in the tail end of the AIDS crisis, we would occasionally be using high doses of of sulfonamide-based drugs for certain types of opportunistic infections, and we'd often require um uh a philic acid rescue in those patients because again, bacterum and sulfonamide-based drugs work by decreasing folic acid levels. So that's primarily where it's been used for. But in the 21st century, even though our use of a lot of these drugs has kind of gone by the wayside in traditional chemo, they still use quite a bit of methotrexate for for non-solid tumors. So you're still going to see a lot of that use for that.

SPEAKER_01:

And and that translates well into the theory around using Lucoboran for CFD, because as you said, it's sort of bypassing that it can get transported, right? Because it can be bypassing, it doesn't need to have that enzyme process to become its active form. It is sort of the active close to the active form already, and then you can more easily cross the political barrier and then manage replenish those levels. Is that the idea for okay, okay? And so, you know, thinking about potential risks of leukoporin, uh what what would you say are the concerns there, like in terms of for any, yeah.

SPEAKER_03:

Yeah, right. From a safety perspective, really there shouldn't be any side effects, right? Because you know, folic acid is a water-soluble vitamin, so is folinic acid. So theoretically, it should be impossible to overdose on it. And certainly we would give huge, huge doses of phinic acid to patients, and you know, for for leukoforan rescue back in the day, and we never saw anything from it. So I think from a safety perspective, you know, uh data on what where we used it traditionally has not found significant toxicity, but we're not going to be using it in those patients. Um, again, you know, biologically, you know, yeah, biologically, we shouldn't see big side effects, but we don't know because we haven't done randomized control trials in this population to really find out, right? Right. So I mean, you know, you know, you know, again, yeah, I the the theory that some terrible side effect could manifest, you know, it it I don't, you know, based on the mechanism of of Luke of Warren probably shouldn't happen, but you know, we we've been many times in the history of medicine that we'd be burned by saying, well, this really shouldn't happen, and then it does.

SPEAKER_01:

Right. You know, so yeah, so I think that's actually a great segue into thinking about what evidence is available for the role of this drug in either autism andor cerebral folate deficiency, and what FDA is using to support this action and what American Academy of Pediatrics has sort of said about the evidence, and really uh sifting through all that to think about given given the mechanism and potentially minimal risk, but as you said, maybe lack of data to support its use in these populations. Let's talk a little bit more about that evidence there and and what would you say?

SPEAKER_03:

Absolutely. So, so I mean, there's been a number of small retrospective or or or you know cases, case-code case series that have suggested this benefit. But really, when it comes down to it, there's only really a couple of papers that have any sort of scientific rigor to them, in my opinion. And and one of them is a paper that came out in nutrients actually just this year. And I think it it gave it gives us some of the biologic framework for for the possibility of using this. So this was a study done in China where they looked at patients who had autrect uh did who had um autism spectrum disorder, and now I now I can't speak about it, and but they also wanted to take a look at at um in these patients who did not have known uh cerebral folate deficiency, right? So, and they wanted to look and see just in and of itself whether or not they received folic acid or anything else that would patients who had all autism spectrum disorder have any sort of mutations in folinic in folic acid metabolism that might uh you know support the use of this drug, right? Because again, if if you have these mutations in full in in folic acid metabolism and you're not able to use that, is that one of the potential causes of autism spectrum disorder? And so they had 80 patients in the study, wasn't a large study, but none of these studies are really big, and basically just did a a very in-depth genetic profiling of them. And then they actually did give phalinic acid two milligrams per kilogram per day in these patients. And again, there was there there was a control group and intervention group about a total of 80 patients. And what they found was that only about 50, uh only about 60 percent of the 60 per patients in the study actually stayed in the study, and they found that patients who had significant mutations in folic acid deficiency. Now, again, these patients had not been diagnosed with uh cerebral folate deficiency, just that they had these mutations, right? So and they found that that the administration of folinic acid did seem to have some improvement in behavioral issues associated with autism spectrum disorder. And and they and it was certain combinations of mutations, because many times these patients had more than one uh mutation that was leading to stuff, and they found basically that folinic acid seemed to benefit a lot of patients who had these mutations or who had been diagnosed with autism spectrum disorder, but not necessarily with cerebral folate deficiency, if that kind of makes sense, right? I think that this study was trying to do two things. They were trying to point out that even if even if your LP, your lumbar puncture does not necessarily show that you have low levels of folic acid, that that patients who just have the mutations involved with with the potential of folate deficiency would still potentially benefit from folinic acid. So I think that's the framework that that that makes kind of makes sense and kind of kind of I understand. But the paper that really kind of got this really kind of launched, and it's the only RCT that's been done, was a paper done in the European Journal of Pediatrics in uh September of 2024 as well. Very small study, only 40 patients in the study. Patients had autism spectrum disorder, ages, ages of two to 10. So this was only done in children. Um they also received ophthalinic acid, two milligrams per kilogram per day, up to a maximum of 50 milligrams a day. And it was a randomized control trial, so there was a placebo group and an active RM group. The patients also receive kind of behavioral, standard behavioral care, et cetera, et cetera. Like so many disorders like this, there are a million outcomes that you can look at, right? The same, same with you know different types of neurologic and psychiatric disorders where we have kind of scales, we have endless scales where we measure you know behavioral disorders and sensory disorders and learning issues and things along those lines. These, the, the main outcome they used in this study was something called the child behavior checklist, which is is is one of the outcomes commonly used in autism spectrum disorder. But they also looked at a wide variety of other of these secondary ones as well. They did look to see if the patients had antibodies to folate receptors. And again, their theory was that okay, so some of these patients have that as well. They did find at the end of the study that there was an improvement in this child behavioral checklist score. Um, and it and it it there was it the overall improvement was relatively modest. I mean, it did improve things, but it wasn't like, you know, gangbusters. Oh my goodness, I can't believe this sort of thing. But in particular, they found that that some of the behavioral issues that they were associated, some of the sensory issues that that are associated with autistic spectrum seemed to improve in these patients. Um they also found, not surprisingly, that this was particularly true in patients who had antibodies to folic acid receptors, that that that was where they got the most most benefit. Again, we're we're realizing that that that uh impairments in folic acid activation and metabolism, you know, may be an issue behind this that goes beyond just this cerebral folate deficiency. Again, they're two different things, but there there may be there may be kind of an overlapping role. So that's basically what they found. And the conclusion of that study was all your oral folinic acid supplementation is effective and safe. Again, it was a small study, so it's kind of hard to say that, in improving ASD symptoms with more pronounced benefits in children with high titers of folate receptor autoantibodies. And so those are that that's that's kind of the the limit. So I mean, we're we're looking at small studies, and the only randomized control trial was not long acting or not not long going on, and it was only in 80 patients. So as you might imagine, I think uh the American Academy of Pediatrics took a look at that and said, uh kind of hard to believe that we're going to approve you know a drug for of a relatively common disorder. I mean, it's not like ASD is something that we, you know, you don't hardly ever see or anything. I mean, yes, we're duper duper rare diseases, 40 patients maybe is as good as you get, but we certainly could could could do a much larger study and should do a much larger study, I think, to to really show the benefit of this.

SPEAKER_01:

Right. And I I think you you mentioned something earlier on about you know part of the the impetus with FDA is to not only you know try to find treatments for this very common condition and you know try to provide treatment, but also spur additional research, right? Because if if we are trying to work with what we have right now and we're what you just described is, as you say, not what we would normally see rising to the level of getting this drug approved for this use. So I think that's that's sort of the interesting part here is that FDA has taken this action to initiate the approval, but we don't have those phase three large, you know, multi-center randomized control trials with a large population of patients, short duration, as you say, you know, so there's what we would typically expect to see supporting evidence for in terms of safety and efficacy. Um, we just currently don't have. And I know in the in the FDA press release too, there was a discussion around a systematic analysis, including published case reports. But again, case reports are different than randomized controlled trials, as you're saying. And so, you know, yeah, go ahead.

SPEAKER_03:

Yeah, I mean, yeah, no, I mean I mean you're exactly right. I mean, it's always tough, you know, you know, using systematic review and meta-analyses is is is always an issue anyway. But it, I mean, it is it is emblematic of the whole garbage in, garbage out sort of sort of thing. I mean, if you have, you know, poor research going into a systematic review, uh, you're gonna get, you know, I wouldn't say poor outcomes, but you're certainly gonna get non-definitive outcomes, right? And if you decide to do a systematic review, it says all we'll do we'll take case series, we'll take case reports, we'll take retrospective cohort studies, and we'll also sneak in the one randomized control trial, you know, it's gonna be difficult to interpret the the the results. So yeah, I I don't I'm not sure at this point we have enough evidence base that even systematic reviews and meta-analyses are really gonna help us come up with the answer.

SPEAKER_01:

Yep, that makes perfect sense. Okay, so I think you've summarized sort of where we are now with the evidence. And and so what would you if I was to ask you point blank, is Lucovorin an effective and safe treatment for autism? How would you answer that if I was a patient asking or a parent asking?

SPEAKER_03:

I I would say that, you know, right now nobody knows, right? Right now we have one small study that suggests a benefit, but it suggests a benefit in particular in patients whose own body has a difficult time either absorbing folic acid or converting folic acid to its active form so the brain can absorb it, right? And and I and I think if I was talking to a patient, that's exactly how I would phrase it. You know, we don't know what percentage of patients with autism disorder have this issue because we really haven't even explored that yet, not to say nothing about this. So then the question becomes, you know, well, you know, my child has this, and I really am right, you know, anything that isn't particularly harmful, I'm willing to die. And that's really who we're gonna be talking about, right? I think the we we the way we phrase it to him is I can't tell you if it's safe in these patients because we just haven't studied it. And I think that's why the American Academy of Pediatrics has come kind of come out against it and said, you know, we need more data, you know. You know, again, theoretically it shouldn't. Theoretically, it should be fine, but we just don't know. We don't know the dose, we don't know the duration and and all those things. Now, does that mean that people aren't gonna be, you know, getting philanthropic acid by hook or crook just to try it? I'm sure they will, right? You know, families, parents are are, you know, they're desperate for any sort of treatment that's going to improve things. I get it, I totally do. But I think as healthcare providers and as pharmacists, I think we need we need to be honest with patients. And I have heard people say, well, I can't hurt them. Oh we don't know that though.

SPEAKER_01:

Right, right, right.

SPEAKER_03:

You know, I sometimes I think we forget that phase three studies are designed to to evaluate efficacy and safety in the population with the disease. We we focus on the efficacy part, right? But but uh, you know, we need to focus on the safety part. The other big problem that that oncologists have have raised, which I think is totally reasonable, is you know, there's the you know, in in a drug that wasn't mass-produced to begin with, because again, how you know how many patients are we going to use philinic acid rescue, leukovoran rescue in patients with chemo? The the oncology groups have raised the issue. It's like, well, okay, hold a bit. If every um family with with with a pay with a child with autism spectrum disorder starts asking for the stuff, what happens when we need it for actually leukovorin rescue in patients if we can't get it, you know.

SPEAKER_01:

Great point.

SPEAKER_03:

So, you know, and and I mean, and and I think that's a very valid point because you know, there's actually only a couple of companies that even make right philinic acid. I mean, it's not like every company makes it because A is a generic and B, it's got a very narrow indication. So, you know, I think I think that's a real concern for cancer patients and oncologists is you know, when when I when we need this stuff, we need it. You can't wait for a month for it to come back, you know. You know, to get it, we we need to be able to use it. So I think there's also a supply issue argument to be made.

SPEAKER_01:

Yeah, yeah.

SPEAKER_03:

So, you know, you know, again, it's an unsatisfactory. Answer, you know, to patients and parents who are very desperate, and I get it. But as of now, I can't recommend it based on the evidence we have. Now, if a if a you know, again, if a patient you know insists or harangues their their primary care provider, because you don't have to be an oncologist to prescribe this, I think that they will, I think that that people will get a hold of it and they will try it irrespective in many cases, if if because again, you know, you know, we want an active treatment. And it's like, well, you know, I'm I'm hearing you say this is just basically a vitamin. So it's gonna hurt anybody, so let's let's let's give it a shot, sort of thing.

SPEAKER_01:

Right. I mean, there are sort of the the unaccounted for downsides too, like additional pill burden, right? And and depending on what else they're taking, does that affect adhere and cost too? We don't really cost, especially if demand does go up as a result of all this, and cost and pill burden and potentially impact on other medication adherence. And I know you phrase it very well, you know, that this is something we we obviously want to provide solutions, but we also don't want to provide false hope and have people be thinking it's going to be you know a cure all and not yeah, when we don't have good data to support even for even that limited subset of patients where where it's being proposed for use now. So yeah, it's a challenging one. And and I guess like uh even outside of the prescribing aspect, what about people who might be asking about folic acid over the counter? And again, like using as a as just a supplement harmless. What are what would you say in that context?

SPEAKER_03:

And I mean, and and your your your discussion about you know a pill burden costs. I mean, you know, again, little things add up. You may say, well, you know, folic acid is probably only five bucks for a hundred pills at at a at a community pharmacy, but that adds up when you start you know adding on in patients, you know, families who have you know children with autism sex disorder are already paying uh money in a wide variety of areas, right? Again, I think we we we focus that, you know, in even in patients where we have okay data again in this in this cerebral folate deficiency, folic, the the the fact that they're not eating enough folic acid is not the issue, right? It's that the body doesn't know what to do with it. And and it's the same argument I usually give for patients with B12 deficiency, right? B12 deficiency anemia. It's like, why are we giving these shots to people? Or we're giving these shots to people because it isn't that most patients aren't eating enough B12, it's that their body can't absorb it or activate it. And then that's the same thing here. So, you know, if yeah, you're right, folic acid is probably not going to hurt, you know, someone to take an extra folic acid pill at A or something, right? Again, because it's a water-soluble vitamin, but it you do have the pill burden, you have the cost, and there's no reason to think it would work because we have exactly zero data. We don't even have these little tiny studies to suggest that there's any benefit in folic acid, and there's no biologic plausibility that it would.

SPEAKER_01:

Yeah. And I think that can be a compelling argument, you know, when helping redirect some of those conversations to, you know, because a patient who's who's maybe looked this up and sort of has some background about what leukoborin is and maybe why it's different, I think explaining that, you know, it's it is this different form of folic acid. And so if the idea is that your body isn't able to use that active form, then folic acid isn't going to be any better for you either. So I that's at least something we can help rationalize. How would we help redirect patients? What other what other options can we provide if we're going to not be encouraging use?

SPEAKER_03:

Right. I mean, you know, there are all sorts of little tiny studies out there looking at all sorts of pharmacotherapy to improve symptoms. Again, in a disorder that we don't really understand the causes of and don't, and because of that, have a hard time targeting therapy on. And I mean, and they can be pretty disparate stuff. I was asked the DI Center got a question probably less than six months ago about mamantine for patients with severe autism disorder. And we actually looked it up, and and gee, just like polinic acid, there's one little teeny tiny study that suggests that it may have a benefit. But again, you know, and my my reply was again, you know, it's a small study, we you know, it is it it was a very short-term study, we just don't know. And mamantine probably, you know, very well may have long-term side effects in especially a developing child. So, you know, I unfortunately I you really can't point to pharmacotherapy that is going to address the root cause of the issue. I think we can use pharmacotherapy as adjunctive treatments to treat some of the behavioral issues, especially in severe autism patients. But unfortunately, as it stands now, we don't have good pharmacotherapy to treat this. And until we figure out the the the pathophysiology behind autism suction disorder, we are going to struggle to find treatments for it because if you don't know the cause of something, it's very difficult to target treatments for them. So, and of course, you know, as you pointed out, you know, there that's that's that's corollary to another announcement that was recently made by the federal government about causes of autism. That could be a whole nother uh podcast. But uh so yeah, I don't know. You know, yeah, unfortunately we we direct them back to hopefully their child psychiatrists, child neurologists who are experts in treating autism and say we're we're doing the best we can with what we have. But unfortunately, as it stands now, pharmacotherapy does not play a role in the treatment of autism. It can improve some of the side symptoms, but that's about it.

SPEAKER_01:

Or comorbidities like anxiety, depression. But yeah, absolutely, in terms of treating the condition, this the autism spectrum disorder itself, there is no one, and part of it is just because it is a spectrum, right? And so there's varying symptoms, and uh patients are all it's going to be a very individualized sort of management.

SPEAKER_03:

So Yeah, yeah, yeah. And that and that's I mean, you you know, you you you you bring a good point that you know, you know, uh because autism spectrum disorder can kind of fall into the whole whole whole area of neurodivergence, you know, you know, millions of people have some level of neurodivergence and they lead perfectly happy, healthy lives, right? And and so, you know, do we target, do we focus all our energies on the the the most severe symptoms, the most severe behavioral problems, the most severe sensory problems? You know, that makes sense to me. You know, if if we're gonna if if we're going to do a large randomized control trial on this, do we do we seek out the patients who probably need treatment the most? That makes sense to me, or will that actually happen is anybody's guess. But you know, because of course uh, you know, there's a pro and a con, right? You know, I mean, uh if you have very, very severe symptoms, it's you know, uh because the the improvements will be probably highest in patients with the most severe symptoms, it's probably gonna be easiest to find a clear a statistically significant difference, right? But also in the very severe patients, nothing or very little, you know, very few things may actually help, right? So so it's it's gonna be tricky. But I really, you know, I I really do hope that this becomes the impetus for somebody, uh probably the federal government, to to fund a decent sized phase three study looking at this. I really do hope if if that's gonna be the end game of this, that's what real what really we should be looking at. There is the potential for benefit. There is, you know, there's there are signals that it's gonna work. We need to confirm that.

SPEAKER_01:

Yeah. Yep. And and just to clarify that that this move for the approval is a very limited indication it would be for the cerebral folite deficiency, and so not the broad population that we think of with autism spectrum disorder. So well, fantastic. This has been a super interesting discussion. And and just to wrap up our our our thoughts and sort of summarize where we are, you know, we always end this podcast with a game changer. What are what were the game changers from this discussion? And so what would you summarize as our game changers and that listeners can take away and apply in their practices? What would you break that in?

SPEAKER_03:

I'd say, you know, the the the bullet point summary of this is that you know uh um FDA has has announced that that they're going to look at and the philinic acid, which is the activated form of bufolic acid, as a potential treatment for a condition similar to autism spectrum disorder, um, and that that may provide the startup, you know, or the jump start to get an actual study done. That current studies in patients with autism spectrum disorder and high dose of linic acid have been small, they've been short-term, and they aren't really even close to the level of what we would expect for any other drug to get approved by the FDA. But the good news is that they have you know shown some benefit. In particular, patients who have some sort of difficulty either activating folic acid to its active form or getting the drug into the central nervous system. So that's you know, that's what we found. And the American Academy of Pediatrics believes that that that this is that's not enough information, that we don't have enough information to look at efficacy or safety, and that um even though theoretically there should be few side effects, there are a lot of unintended consequences. And again, to me, not least of which is running out of full in a getting people who we know absolutely will benefit from it. So I would I would not recommend its use at this time.

SPEAKER_01:

Okay. Well, fantastic. Thanks for that nice bottom line. You summarized it very well. And really appreciate your expertise on this, Jeff. I mean, this is a tricky topic, lots of you know, interest and desire for useful treatments, but gotta go with where the evidence leads us. And in this case, yeah, it sounds like we don't have what we need, so not yet. Yeah, yeah. All right. Well, thank you so much for your time. Appreciate it, Jeff.

SPEAKER_03:

Thank you.