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🚨Instagram just SUSPENDED Children’s Health Defense. Hey Mark Zuckerberg, what happened to “no more censorship”? @finkd No clear explanation. No specific post identified. Just a vague claim that we violated “Community Standards.” What exactly did we violate? If you’re going to silence a non profit organization that is sharing the truth, the least you can do is tell us why. Thank you, @elonmusk, for providing a platform where we can continue speaking freely and share vital information so parents can make informed decisions. We will not be silenced. Tag @finkd and let him know if you stand with CHD.

Important Considerations Regarding Escalating Leucovorin Doses My concern comes from observing a small number of physicians who have been progressively increasing leucovorin doses over time without clear evidence supporting this approach. At the same time, I have heard reports of less-than-ideal outcomes, including regressions, from patients who subsequently leave these practices and seek care elsewhere. Beyond these observations, I believe several important points deserve discussion in a broader clinical and scientific context. 1. Today's Leucovorin Doses When my child was first prescribed leucovorin many years ago, the starting dose was 5 mg. This was later increased to 10 mg and eventually 15 mg, which, at the time, was considered a high dose. For context, these amounts are already orders of magnitude higher than the quantities of folate the body would typically obtain through dietary sources or microbial production. Today, however, we are seeing more individuals who have not improved at these doses being advised to increase their intake further—to 25 mg, 50 mg, 100 mg, and, in some cases, even 200 mg over the course of a day. The absence of definitive long-term safety data at these increasingly high doses should not automatically be interpreted as evidence of safety. We also need to consider what imbalances prolonged supplementation might introduce. This is a page straight out of the vaccine mantra? I believe one of the fundamental principles of health should be maintaining balance. It is difficult to assume that administering extremely high doses of a biologically active compound indefinitely will have no consequences for other systems in the body. This does not even address the possibility that the treatment may be compensating for an underlying problem rather than correcting it. The reason this discussion is important is simple: 5 mg, 10 mg, or even 25 mg is not equivalent to 100 mg. There has been a noticeable shift in prescribing practices among some physicians, with increasing pressure to escalate doses higher and higher. We should be asking whether this escalation is scientifically justified and whether the potential consequences are being adequately considered. 2. Absorption Profile We already have pharmacokinetic data from oncology regarding leucovorin absorption. These data indicate that oral absorption becomes limited at higher doses, particularly above approximately 25 mg, where the fraction absorbed can decline considerably. This blurb below is available from the published pharmacological data “Following oral administration of leucovorin in adults, the apparent bioavailability of levoleucovorin is 97% for 25 mg, 75% for 50 mg, and 37% for 100 mg” For instance 50mg twice per day will yield 75mg for the day, but 25mg three times per day will also yield about 75mg. Which is better? Read on From a logical standpoint, does escalating the oral dose make sense when absorption becomes increasingly limited? Is this being taken into consideration when physicians recommend progressively higher doses? If, under certain dosing conditions, only approximately 37% of the administered dose is absorbed, that seems like a significant consideration. At a minimum, the nonlinear absorption profile should be part of any discussion regarding dose escalation. 3. Why Do Folate Receptor Autoantibodies Exist in the First Place? FRA Immunity and the Microbiome Folate receptor autoantibodies (FRAs) represent an immune-mediated process rather than simply a genetic deficiency. But why do these antibodies develop in the first place? We have personally observed cases in which previously positive FRA tests became negative following interventions targeting the microbiome. This raises an important question: Could indefinite leucovorin supplementation be compensating for an underlying problem rather than addressing the factors contributing to FRA production? For example, Bifidobacterium species are important producers of biologically active folates, and restoration of these organisms has been associated with improvements in certain clinical and microbiome-related outcomes. Another issue that receives very little attention is the potential effect of high-dose folinic acid on the microbiome itself. I have personally observed several individuals taking high-dose leucovorin whose microbiome profiles showed significantly elevated Clostridium levels. There is also literature suggesting that folate availability can influence the growth of certain Clostridium species. This raises another important question: Could continuous high-dose folate supplementation, or progressive dose escalation, contribute to an unfavorable microbial environment in susceptible individuals? Consider a hypothetical example. Suppose the microbiome is normally exposed to approximately 400 micrograms of folinic acid under a particular set of conditions. Now imagine increasing that exposure by 100-fold or more. If excessive folate availability negatively influences certain microbial populations, we could unintentionally create a larger problem while attempting to correct another. Of course, the actual exposure of intestinal bacteria to orally administered leucovorin would depend on absorption, intestinal distribution, and other pharmacokinetic factors. Nevertheless, the possibility deserves investigation. We already know clostridium can be really non ideal in autism pubmed.ncbi.nlm.nih.gov/3643… tandfonline.com/doi/full/10.… Does any of this mean leucovorin is bad? Absolutely not. It means we should consider whether an optimal therapeutic dose exists—one that preserves the clinical benefits while minimizing unintended effects on other biological systems. More is not necessarily better. 4. The FRA Test: Where Has the Logic Gone? This is one of the issues I have the greatest difficulty rationalizing. Based on the collective experiences reported by parents, we frequently encounter the following situations: Individuals who test positive for FRA binding or blocking antibodies are recommended leucovorin. Individuals who test negative for FRA binding or blocking antibodies are also recommended leucovorin. Furthermore, parents report all four possible combinations of test results and treatment outcomes: FRA test result Leucovorin response Positive Improvement Positive No improvement NegativeImprovement NegativeNo improvement Every one of these outcomes has been reported. Yet leucovorin is frequently recommended regardless of the test result. To me, this raises a fundamental question regarding the clinical utility of the FRA test. I have heard MAPS clinicians chuckle and agree when I bring this up If both positive and negative individuals may improve, and both positive and negative individuals may fail to improve, how reliably does the test predict who will benefit from leucovorin? I am not suggesting that the test has no biological significance. Rather, I am questioning its specificity and predictive value for guiding treatment decisions. If the test result does not substantially change the treatment recommendation, what is the practical purpose of ordering it? And for an individual who has not demonstrated meaningful improvement at, say, 25 mg, what is the scientific rationale for doubling the dose? Shouldn't there be a clearly defined reason to expect that increasing the dose will produce a different outcome? 5. High-Dose Leucovorin and the Left-Handed Versus Right-Handed Isomers Now we come to the point I raised with Dr. Bogner. I believe this is one of the most overlooked aspects of the discussion. There are several important pharmacological considerations that deserve much greater attention. Does everyone know that conventional leucovorin is generally supplied as a mixture of two stereoisomers—the left-handed and right-handed forms? Does everyone know that the naturally occurring, biologically active form is the left-handed isomer (6S), while the right-handed isomer (6R) is not utilized in the same way? Does everyone know that these two isomers have substantially different pharmacokinetic profiles? The active 6S form has a relatively short reported half-life in certain pharmacokinetic studies, approximately 30 minutes, while the 6R form has been reported to persist considerably longer, with a half-life of approximately 7 hours or more under certain conditions. Does everyone know that there is evidence suggesting that both stereoisomers can interact with folate-binding systems, potentially with different binding affinities? The extent to which the 6R form competes with the active 6S form at clinically relevant folate receptor sites, however, requires further investigation. Does everyone know that a purified left-handed form, known as levoleucovorin, was developed and is used in oncology? Levoleucovorin contains the biologically active 6S isomer without the accompanying 6R isomer present in conventional racemic leucovorin. Does everyone know that a similar stereochemical distinction exists with L-methylfolate? Commercial L-methylfolate preparations generally use the biologically relevant stereoisomer rather than an equal mixture of stereoisomers. Does everyone know that microbial folate biosynthesis is stereoselective, producing naturally occurring biologically relevant folate forms rather than the synthetic racemic mixture found in conventional leucovorin? These are important distinctions. The Potential Problem With Accumulation of the Right-Handed Isomer We now have a situation in which increasingly high doses of conventional leucovorin may result in greater systemic exposure to the longer-lasting 6R isomer. This raises a potentially important pharmacological question: Could accumulation of the 6R isomer interfere with the availability, receptor binding, or transport of the biologically active 6S form? If the 6R form competes for relevant folate-binding sites, even with a lower affinity, its prolonged presence could theoretically influence the kinetics of folate transport. This possibility becomes particularly interesting when we consider the substantial differences in elimination rates between the two isomers. Remember, much of the original pharmacological development and clinical experience with these compounds comes from oncology, where high-dose folate rescue and precise dosing considerations are critically important. Levoleucovorin was developed to provide the active stereoisomer without administering the inactive 6R component. That distinction alone should prompt us to ask whether the same considerations might become increasingly relevant when conventional leucovorin doses are escalated substantially. Could We Be Creating Fluctuations in Folate Availability? A common counterargument is that there is insufficient evidence demonstrating that the right-handed form causes clinically meaningful harm. But once again that is the same mantra used by the vaccine pushers. We didn’t have an autism epidemic before 1986 when there were a few vaccines. What happened? If you speak to experts like Dr. Boles (MAPS) believe it is TOO many TOO soon among other contributors. Isn’t that a similar boat we are riding on here, there has to be a cost to dosing too high particularly with a product that contains a form that is unusable? Check out his logic, youtu.be/BasFYUXr6dc The absence of definitive clinical evidence does not eliminate the need to investigate a biologically plausible mechanism. We know that the two isomers have different pharmacokinetic properties. There is also evidence of interactions with folate-binding systems that warrant further examination. What happens when these differences are considered together? Could we be creating a dynamic in which an initial surge of active 6S folinic acid provides a therapeutic benefit, followed by a much longer period in which the 6R form remains present? If the longer-lasting 6R isomer competes for relevant transport or binding mechanisms, could that alter the availability of biologically active folate over time? Could this theoretically contribute to fluctuations in folate availability and, potentially, changes in clinical or behavioral responses? These are hypotheses, not established clinical outcomes. But they are questions that deserve investigation, particularly as doses continue to increase. We cannot assume that a person experiencing an initial improvement necessarily demonstrates an optimal pharmacokinetic response throughout the remainder of the dosing interval. An Analogy Imagine I gave you $100 to cover your expenses for an entire day, but imposed a rule that you could only spend that money during the first 30 minutes. How well would that arrangement work for most people? The point is that total availability is not necessarily equivalent to sustained functional availability. You need folate all day, not just at one point in time. If FRA are really at the core of the issue - they are going to be all the time. So if you help the issue out with the Left handed version which gets used up quickly version but then make the Folate status worse for the next several hours before the next dose because the Right handed also competes with the active folates you get from diet or your microbiome, you could be forcing the body to operate through non ideal conditions that are time dependent. You wouldn’t give a diabetic their insulin up front at the start of the day. In fact checking glucose is a consistent part of that ailment. Timing matters. Distribution matters. Receptor interactions matter. And pharmacokinetics matter. If there is evidence that the 6R form interacts with relevant folate-binding systems, if a purified active-isomer drug exists, and if other clinically used folate preparations preferentially contain the biologically active stereoisomer, then there is a reasonable scientific basis for questioning whether simply increasing the dose of a racemic mixture is always the most appropriate approach. We should not automatically assume that increasing the total dose is equivalent to increasing the desired biological effect. Falling back on the argument that there is no definitive evidence of harm is not sufficient by itself to establish that progressively higher doses are appropriate. The burden should also include demonstrating that the additional dose provides meaningful clinical benefit. 6. To be clear This Should Be a Scientific Discussion, Not an Attack on MAPS. None of these concerns should be interpreted as an attack on MAPS or on physicians who prescribe leucovorin. The purpose should be to encourage a thoughtful scientific discussion about several important issues that may not be receiving sufficient attention. I do not believe every MAPS physician is necessarily familiar with all of these pharmacokinetic and microbiome-related considerations. I also have no doubt that some knowledgeable physicians are already aware of them. The goal should be to improve our collective understanding, not to criticize individuals. We should be discussing: The scientific rationale for progressively escalating leucovorin doses. The limitations of oral absorption at higher doses. The underlying causes of folate receptor autoantibody production. The potential relationship between the microbiome, folate production, and FRA status. The possible effects of prolonged high-dose folate supplementation on microbial populations. The clinical predictive value of FRA testing. The pharmacokinetic differences between the 6S and 6R isomers. Whether prolonged exposure to the 6R isomer could influence folate receptor binding or transport. Whether purified 6S folinic acid might offer advantages over conventional racemic leucovorin, particularly at higher doses. Shouldn't we at least investigate whether these stereochemical differences become increasingly important as doses rise? My position is not that leucovorin should be avoided. I personally believe that treating the gut not only improves the FRA status and the need for leucovorin. I do believe that lower dosings of leucovorin can be really helpful for many. I don’t believe the recent dose escalations that keep crreeping always have rationale behind them. I don’t believe that everyone is aware of the people that have non ideal effects from the higher dosing leucovorin. My position is that dose escalation should be guided by pharmacology, clinical evidence, and an understanding of the broader biological consequences—not simply by the assumption that more must be better. I don’t think this isomer issue has been explored enough an in particular a threshold for A TIME DEPENDENT inhibition of FRA from high dose stereoisomers of folinic acid (Meaning worsened folate status over the day due to the extreme differences in the half lives of these isomers) There may be an optimal therapeutic window in which the benefits of leucovorin are maximized without unnecessarily increasing exposure to the inactive stereoisomer or disrupting other biological systems. That is a discussion worth having. And finally, if a purified version exists that provides the biologically active isomer without the additional 6R component, shouldn't we be advocating for more research into its potential advantages and improved access to appropriate formulations? Lets add these as discussion points so that we can better understand what is needed for our children.

What happens when 25mg Leucovorin doesn't work? Put them on 50mg.. What happens when that doesn't work? Put them on 100mg? What happens when the FRA test comes back negative.. Put them on Leucovorin.. Insane.. This is the only tool in your tool box and your completely abusing it and for $1500 consults??? WTF is going on. Do they realize this?--> Oncology and pharmaceutical guidelines note that the apparent bioavailability of oral leucovorin is 97% for a 25 mg dose, but falls sharply to 37% for a 100 mg Do they understand that these doses feed clostridium and pseudoclostridium Overgrowths?? Do they realize that FRA is caused from intestinal permeability in the first place and can be reversed or significantly mitigated with with Microbiome Balancing? Do they realize that important genus like bifidobacterium is a significant producer of folate. Does anyone even check for MTHFS mutations? We are now seeing recommendations for 200mg of leucovorin in a single day. Kids regressing on these doses.. This is insane. Not anti leucovorin.. this is just getting ridiculous.