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What exactly is the connection between vitamin B2 (FAD) and the MTHFR enzyme?

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Bluelude1, Jan 10, 2018.

  1. Bluelude1

    Bluelude1

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    Vitamin B2 (specifically the active form FAD) plays a role with the MTHFR enzyme & folate but I haven't been able to find a good simplified explanation of what's actually going on, especially in relation to supplemental methylfolate.

    Does the supplemental methylfolate make up for the lack of FAD in the methylation cycle or does FAD make the methylfolate supplement more efficient?

    Maybe its brain fog, but I am having a bit of an issue getting my head wrapped around the topic.


    Riboflavin (in the form, FAD) is required as a cofactor for the key folate-metabolizing enzyme, MTHFR. A low status of riboflavin status may interfere with the metabolism of folate, particularly in individuals homozygous for the MTHFR C677T gene variant;

    http://lpi.oregonstate.edu/mic/vitamins/riboflavin

    Because the thyroid produces what is called T4, also known as thyroxine. Thyroxine helps produce the body’s most active form of vitamin B2, flavin adenine dinucleotide (FAD). Vitamin B2 must be converted into active FAD by thyroxine in order for the body to effectively use vitamin B2. The connection between FAD and MTHFR is that the MTHFR enzyme must have an ample supply of FAD in order to function. If FAD levels are low due to low levels of thyroxine, then the MTHFR enzyme slows down, causing low methylfolate levels. We now know from above that low methylfolate leads to low neurotransmitters and low SAMe.

    https://www.verywell.com/the-link-between-mthfr-gene-mutations-and-disease-3232709
     
  2. PinkPanda

    PinkPanda Senior Member

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    Vitamin B2 (FAD) is a cofactor for MTHFR, so too low vitamin B2 status reduces MTHFR activity and production of 5-MTHF.

    https://www.ncbi.nlm.nih.gov/books/NBK6145/

    Vitamin B2 status might be relevant for lowering homocysteine, especially when you have a homozygous mutation.
    I take 10mg of riboflavin and tolerate it well, but not everyone seems to tolerate it well and I have had the experience that it can increase anxiety.
    I think the chances are higher that B2 helps you with a homozygous mutation and I don't know if it is helpful at all, if you don't have any MTHFR mutation.

    In my experience, more folate cannot simply replace riboflavin, if you have low riboflavin status. I had folate deficiency for a while and responded more to vitamin B2 than methylfolate.
     
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  3. Hip

    Hip Senior Member

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    People on this forum get caught up and lost in all the complex pseudoscientific nonsense about methylation. These methylation complexities are a bit like astrology: a system of belief with little or no empirical evidence behind it, but nevertheless some people get totally caught up in astrology or methylation, thinking it will provide all their answers.

    Methylation pseudoscience is a distraction that I think prevents people from pursuing other good ME/CFS treatments that might be more fruitful in terms of improving health.

    Trying the methylation protocol is well worthwhile, but it is essentially very simple to do: see this post.
     
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  4. PinkPanda

    PinkPanda Senior Member

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    Don't really know what is pseudoscientific about the MTHFR-vitamin B2 issue, it seems rather well-founded to me.

    MTHFR is an enzyme, FAD its cofactor, if B2 status is low, this will reduce MTHFR activity.
    There are several studies linking vitamin B2 status to homocysteine levels in people with MTHFR mutation.

    One study finds that a mutated MTHFR 677C>T enzyme is more likely to dissociate and lose its cofactor, which might indicate that FAD plays a special role in MTHFR 677C>T mutations.

    Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase
     
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  5. Hip

    Hip Senior Member

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    That's why Rich Van Konynenburg's simplified methylation protocol includes a multivitamin tablet, to help ensure good vitamin status.


    What is pseudoscientific is suggesting to ME/CFS patients (as often done on this forum) that the reason they are not getting benefits from the methylation protocol is because of some obscure blockage in their methylation, and suggesting that if they tinker around with various vitamins or other supplements, they will finally get the methylation protocol to work, and then benefits will accrue.

    These suggestions seem to be pseudoscience, because I don't know of any case where a patient was not getting benefits from methylation protocol, but then suddenly started getting benefits after tinkering around with vitamin B2 or what have you.
     
  6. PinkPanda

    PinkPanda Senior Member

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    Like I said, I have had benefits from taking vitamin B2 that I didn't have on methylation protocol or from a multivitamin. I'm not saying that vitamin B2 will help everyone, but it might be beneficial for some.
    B2 I love you! is a thread where some people share benefits of supplementing vitamin B2.

    I agree that a lot of unfounded theories are around, regarding methylation and methylation protocols. I don't think supplementing vitamin B2 is one of these theories. Maybe it's doesn't work well for everyone, but there is at least sufficient scientific evidence.

    And I don't think this will 'finally get the methylation protocol to work' and make you healthy. Vitamin B2 deals with one isolated issue, cofactor presence of MTHFR. It can't solve the whole metabolism.
     
  7. Learner1

    Learner1 Forum Support Assistant

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    @Hip This is utter nonsense.

    Having a canned "one size fits all" methylation protocol can be very detrimental to people.

    The need for methylating nutrients depends on one's genes, level of toxicity, nutrient status, amount of oxidative stress, drugs one is taking, and what's going on in several other biochemical processes in the body.

    I have a family full of people who don't methylate well, have genetic testing and 9 years of regular lab testing, and the experience of supplementing over 9 years.

    Having a personalized nutrient protocol can make a huge difference in function and can make the difference between having a mental illness and cancer vs. avoiding them completely.

    Early on, I learned a great deal by reading Rich van Konynberg's and Freddd's discussion and recommendations.

    But, from 9 years of experience, what they recommend would make me and others I know quite ill. To give you an example, this is my current protocol, which I am stable on, under the care of an expert doctor:

    2.4mg 5-MTHF
    10mg MB12
    3.8g TMG
    350mg P5P (B6)
    300mg R5P (B2)
    600mg magnesium glycinate
    3g methionine
    4.5g glycine
    1.5g NAC (n-acetyl-cysteine)
    2mg molybdenum
    500mg benfotiamine

    I don't recommend that anyone take what I'm on, and my family members are on different proportions based on their needs.

    Many people on this site focus on folate and B12 and are on insufficient amounts of B6 and B2, as well as nothing supporting the transsulfuration pathway and end up with all kinds of symptoms.

    Then they think that they don't tolerate methylating nutrients, which is a big problem as methylation is essential to immune system function, neurotransmitter production, proper DNA replication, and many other essential functions.

    This can be avoided by getting comprehensive nutrient testing (Genova Diagnostics NutrEval or similar)and adapting a program to ones actual needs rather than guessing, and starting with digestion and elimination, then working backward through the transsulfuration pathway to the methionine cycle to the folate cycle.

    Much as I respect the roadmap work you've done, @Hip, this is an area that is not addressed as comprehensively as it should be. It can and does help tremendously.

    And understanding this better can alleviate the need for psychiatric drugs, and solve depression, anxiety, headaches, etc. (One family member had a serious mental illness resolved by methylation nutrients and resolving digestive issues.)
     
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  8. Bluelude1

    Bluelude1

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    @PinkPanda @Learner1 having had a similar experience I very much agree with your arguments.

    I know the effect I am looking for and what used to take 3mg of Methylfolate now takes 30+mg. This has gotten me to investigating other aspects of the methylation cycle that might need support to improve the efficiency of methylfolate. My dad has the exact same experience, so it's likely whatever is going on has some sort of genetic factor.

    I've tried the various pieces (methylfolate & sublingual active B2) separately previously, but as I am gaining a better understanding of how to they all work together it's nice to have additional context from people with the first-hand experience.


    Were you able to use less methylfolate to the same effect with the addition of the B2?

    1.) Any particular reason you use R5P vs a sublingual FMN?

    2.) Was 300mg R5P a trial an error dose?

    3.) On a side note, I am really interested in your experience on 350mg of P5P. I've always been under the impression that 100mg was the safe cut off, but at times I've had deficiency symptoms that indicate I could handle a higher dose.
     
  9. Hip

    Hip Senior Member

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    Certainly taking a vitamin or a supplement can provide benefits, and I have found benefit from quite a few supplements.

    Although when you do find one that helps, the reason that it helps is often unknown, or is at best a series of biochemical guesses. For example, I found high dose selenium greatly improved my brain fog and energy, but I was never really able to figure out why, although in my thread I listed various biological mechanisms that involve selenium, which might be responsible for the benefits I experienced.

    I am certainly not saying people shouldn't experiment with supplements or drugs. The very opposite: I think this often leads to discovering beneficial treatments.

    I am just saying that I don't know any example of someone not getting benefits from the methylation protocol because of some assumed blockage in their methylation, and then when that magic supplement is found to unblock the blockage, bingo, the benefits then start to appear. I have never come across that.

    In that sense, there is no evidence, not even anecdotal evidence, of what you might call "methylation tinkering" leading to benefits.

    But if you know of some good anecdotes, or have some evidence, I am more than happy to consider them.



    You are making bold statements, but can you back them up with evidence? Is there any scientific evidence for your above statement? Or even anecdotal evidence?

    I have been reading these forums for many hours a day ever since I first joined in 2009. When I first read about methylation, and all the complexities of "methylation tinkering", I was very open minded, and followed all the theory and practice of this tinkering, as I enjoy experimenting with new treatments, and am often curious about all sorts of treatment ideas.

    However, I have not seen a single case on this forum where "methylation tinkering" led to a positive result. That is to say, after reading these forums every day for nearly 10 years, I have yet to come across even just one anecdotal account of "methylation tinkering" paying dividends.

    So that is why I am pointing out that playing around with methylation has a very poor track record. In my experience, the methylation protocol either works, or it does not. If it does not, you may be best advised to move on to another treatment that may be more fruitful.

    I have often seen major benefits reported on these forums from other treatments, such as low-dose naltrexone, oxymatrine, Valtrex, Famvir, Valcyte, cholestyramine + BEG nasal sprays for those with mold illness, and then more minor benefits from things like transdermal magnesium, probiotics, prebiotics, Q10, D-ribose, melatonin, piracetam, and so forth.

    Thus for me it almost borders on unethical to promote "methylation tinkering" to new patients, when we know its success rate is very poor, yet it is incredibly time consuming, and requires you to spend weeks if not months trying to study it all, with the promise of a pot of gold at the end of the rainbow, but a pot of gold nobody ever seems to reach.

    Is that really the most productive use of time for us poor brain fogged ME/CFS patients, trying to reach the mythical end of the rainbow?



    There are certainly studies linking certain supplements to a reduced (and sometimes increased) rate of cancer, I agree. I have not seen any evidence for supplements or personalized nutrition ever preventing mental illness though.

    However, to blow my own trumpet, my N-acetyl-glucosamine anti-anxiety protocol often gets very good results, as lots of people trying it have reported on the thread.
     
    Last edited: Jan 11, 2018
  10. PinkPanda

    PinkPanda Senior Member

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    It's hard to tell, because I wasn't taking them at the same time. I would say though, that B2 had a different effect from folate. Folate gave me a bit more energy initially, while B2 helped with histamine symptoms, fatigue after meals and mood.
     
  11. Bluelude1

    Bluelude1

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    Getting some sublingual B2 (FMN) in today...should be interesting to see how it interacts with folate.
     
  12. pamojja

    pamojja Senior Member

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    In my experience with supplementation in general - not 'methylation tinkering' in particular - it's essential to tinker with doses of all nutrients. By starting with the lowest possible doses and gradually increasing over time. Not only over weeks or months, but realistically for many years to come. Because needs are just too individual for each person, and might change radically over time.

    Would love the more guidance-giving approach of Learner1, for example by using NutriEval test, but realistically can't afford such an expensive lab-test on a regular basis. None is giving recommendations here beyond relating very individual anecdotal evidences. But if one is supplementing, I considered it unethical not to point out, that the needs for individual nutrients is always very individual. And without 'tinkering' in the known of bio-chemical individuality probably not going very far. On the other hand saying:

    Buyer beware! Your needs may be higher of lower on each of those, and you wont know if you do not trial.

    By tinkering all the time I didn't reach the end of a mythical rainbow, but realistically could get my PAD and T2D in remission, and prevented a COPD and other conditions from progressing. All things which evidence based medicine told me in no uncertain terms wouldn't be possible at all.
     
    Last edited: Jan 12, 2018
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  13. Hip

    Hip Senior Member

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    I am always experimenting myself with supplements and drugs, and tinkering with doses, combinations, and so forth, and observing the effects. As I said, often benefits can be discovered by experimenting with supplements or drugs, sometimes just by accident. I have found many good treatments just by accident, when I took a supplement or drug for one purpose, but discovered it had benefits in a completely different area.



    But what is misleading is the narrative involved in methylation, a narrative that was not created by Rich Van Konynenburg, who thought that a "one size fits all" methylation was perfectly adequate, but rather by people on this forum, who approach methylation with a narrative they have created for themselves.

    This narrative says: "your health and wellness depends on you finding an addressing some obscure and hidden methylation blockage, and once you do this, your health will return".

    This narrative is not based on any evidence, not even anecdotal evidence, but by repeating the idea on these forums, the narrative has now become elevated to a status of what looks to the uninitiated like a science.

    But in fact it is just pseudoscience, and pseudoscience always needs to be called out for what it is.

    Every time I ask for evidence from people who vociferously support "methylation tinkering" that this approach leads to benefits, I am confronted with silence. Nobody can offer any examples of it ever working. But the supporters keep marching on, always headed towards the mythical end of the rainbow.

    I suspect the reason "methylation tinkering" has become a popular pastime of some ME/CFS patients is because it constantly offers a sense of hope, and provides a way to past the day. You keep exploring all these proverbial methylation blockages, leaving no stone unturned, until one day, according to the narrative of "methylation tinkering", you will find your answer under one of the stones. So it is a seductive narrative, that one draws people in, like being involved in your own "Indiana Jones and the Raiders of the Lost Ark" movie.

    We could call this movie "Indiana Jones and the Search for the Mythical Methylation Blockage".
     
    Last edited: Jan 12, 2018
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  14. Learner1

    Learner1 Forum Support Assistant

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    Yes, it can. But my point is not to experiment, but to use an informed, data driven approach. The metabolomics study definitely gave clues that PWME have abnormalities in our biochemistry. They also found that the bulk of the biochemistry was highly individual.

    So, making an individual investigation into ones biochemistry and righting what's abnormal can be beneficial.

    Sorry you haven't. I have. 3 examples:

    - I was asleep and non-functional and given a customized IV with a lot of B12, along with folate, B6, B2, B1, and molybdenum, and felt alert and clear headed 20 minutes later.

    - I began to feel depressed and edgy, even though nothing was wrong. My homocysteine was 3. My doctor had me take 3g of l-methionine, and my mood normalized within a day.

    - A family member was diagnosed with bipolar, PTSD, inattentive ADHD, and borderline personality disorder. Labs showed severe deficiencies of B6 and B12. Taking these provided a cure with no more psychiatric meds needed.

    Yes, there is ample evidence.

    For my cancer statement, extensive work has been done on the one carbon metabolism, aka methylation and cancer. It has been shown that cancer can be promoted at every step in the process, as shown in Figure 4 here:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3806315/#!po=8.82353

    It's a caution that just throwing random amounts of methylating nutrients at one's problem is unwise...too little or too much of methylating nutrients can promote cancer.
    Sorry you haven't. But there's a lot of good evidence, if you choose to look.

    For brain health, Dr. Carl Pfeiffer was hired by the state of New Jersey over 30 years ago to go into the mental institutions and prisons and find out what the matter was with the inmates. Building a database that now contains over 1,000,000 samples, he and his team found significant issues in methylation. You can read about it here:

    https://www.walshinstitute.org/nutrient-power.html

    As you're in the UK, I'm surprised you haven't heard of this guy, who interned with Dr. Pfeiffer and who runs a clinic in London. This book was extremely helpful in helping us understand the nutrient protocol our doctor was prescribing after all the psychiatrists failed:

    New Optimum Nutrition for the Mind https://www.amazon.com/dp/1591202590/ref=cm_sw_r_cp_apa_iLnwAbWEG6402

    It's complex. I certainly don't think brain fogged patients should be trying to guess their way through this.

    Getying rid of symptoms requires getting good lab work to guide treatment and ideally working with someone with knowledge of methylation. Here's a link to the kind of test that's useful - click on the sample test to see it:

    https://www.gdx.net/product/nutreval-fmv-nutritional-test-blood-urine

    I have 9 years of these tests done annually on multiple people, and can say that we've been able to confirm many of the theories we've read about regarding nutrients and methylation, detoxification, brain function, and ME/CFS studies.

    They've been very helpful and saved us from all the frustrating experimenting and guessing, and I will say the results have surprised us on more than one occasion.
     
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  15. Bluelude1

    Bluelude1

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    @pamojja I agree and would go so far as to say a lot of us have been tinkering for years and the benefit of these very nuanced discussions of personal experience with specific doses/forms of supplements is they provide far more granular first-hand insight than the glut of boiler plate info out there. In fact, I come here because it is one of the few places you can get such unique discussion.

    FWIW - on an aside rant. I get a little sick of being directed to have another test or to seek the wisdom of a doctor every time I want to fine tune something nutritionally. After having spent tens of thousands of dollars on tests and doctors of different stripes I have less respect for the accuracy of most lab tests and if possible even less respect for the greater majority of doctors ability to accurately read them and respond to the results.

    Let's face it being a doctor treating a CFS patient has very little accountability in real terms. If they don't figure it out & resolve the issue for you it doesn't matter because they still got paid for "trying", never have to account for their poor success rate and most of all don't have to live with the consequences of leaving the issue unaddressed.

    @Hip the above pretty much sums up in my experiance why people are let to "methylation tinkering". If they were getting the results they were looking for elsewhere they wouldn't have to fall back to the more subjective approachs.

    @Learner1 my above statement on testing is not directed at you as you seem to be one of the few that has had a far better experiance in this area then most. The average person can't find a knowledgable person anywhere close to them to do the tests and then actually know how to read them.

    BTW Learner1 I'd still really like to hear your thoughts on my previous questions.

    1.) Any particular reason you use R5P vs a sublingual FMN?

    2.) Was 300mg R5P a trial an error dose?

    3.) On a side note, I am really interested in your experience on 350mg of P5P. I've always been under the impression that 100mg was the safe cut off, but at times I've had deficiency symptoms that indicate I could handle a higher dose.
     
    Last edited: Jan 12, 2018
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  16. pamojja

    pamojja Senior Member

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    Maybe by re-framing this into: "your health and wellness depends to a certain degree on you finding and addressing some obscure and hidden nutrient deficiencies and/or imbalances. And once you do this, your health may return to a certain degree" - which basically expresses the same in less certain terms. So you may not throw out the baby with the bath-water?

    If one doen't agrees with Orthomolecular medicine, then there is no argument. But as someone who does and has benefited I see no other way than to trial. Whatever lack of science, or 'evidence based', or 'pseudoscience' one postulates - the practical approach doesn't change.
     
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  17. Hip

    Hip Senior Member

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    Certainly, I agree. But that's a general statement you are making, whereas I am talking about something very particular: the utility of "methylation tinkering."

    I get the impression you think that I am arguing against the use of vitamins and supplements in general. But I am not; in fact I used supplements a lot with good success long before I ever developed ME/CFS, and am a big fan of such approaches.

    So you should not generalize my comments into something of greater scope than intended; my comments refer just to "methylation tinkering." I am not criticizing the use of supplements in general. I have more supplements on my shelves, draws and cupboards than some vitamin stores!



    What have any of those examples got to do with the subject at hand?

    The subject is whether the many months ME/CFS patients spend tinkering with their methylation protocol ever leads to any benefits over and above the standard Rich Van Konynenburg methylation protocol.

    And I should point out again that when a supplement produces positive results, that does not necessarily mean it is due to its effects on methylation, which is the assumption you have made when giving the above examples. Supplements have effects on multiple biological pathways.


    It's also worth mentioning that in Rich Van Konynenburg's own informal study on his methylation protocol for ME/CFS, he found that the benefits of methylation took an average of 5 to 6 weeks before the protocol even started to work, and then up 9 months for the full benefits to manifest.

    What does that mean? It means that if you were to find one of these mythical methylation blockages and unblock it, it would likely take 5 to 6 weeks before the benefits for your ME/CFS symptoms start to appear. Because Konynenburg's study indicates that for ME/CFS, 5 to 6 weeks is the sort of timescale on which methylation benefits begin to manifest.

    Thus if ever you make a change to your methylation regimen, and you then observe benefits to your ME/CFS symptoms kicking in on a timescale of just days, or say a couple of weeks, then most likely those benefits will have nothing to do with methylation, because they have manifested too quickly. So the benefits you observed are more likely due to some non-methylation biochemical effects that the supplements have in your body.

    So keep that in mind when looking for any examples of "methylation tinkering" leading to benefits in ME/CFS: if the benefit is due to methylation kicking in, then you would expect the timescale to be 5 to 6 weeks. That may help you distinguish between methylation-based and non-methylation-based benefits.



    I agreed that supplements can help mental health; what I said was that I have not seen evidence of the preventative effects of supplements on mental health. In other words, does taking a daily multivitamin for example lower the risk of developing schizophrenia.
     
    Last edited: Jan 12, 2018
  18. Learner1

    Learner1 Forum Support Assistant

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    No, taking a multivitamin won't easily lower the risk of schizophrenia.

    Knowing the patient's microbiome status, food allergies, genetics, and nutrient status and having them on a comprehensive and individualized program can prevent symptoms.

    Tinkering is how one gets into trouble. Using a data driven approach, based in sound science is how one stays out of trouble.

    I have seen adjustments to protocols happen within hours or days, however, if someone is out of balance, getting into balance can very well take several months.

    It sounds like you would benefit greatly from reading the resources I provided, which are littered with references. I also find Dr. Roberts of Heartfixer to be interesting, as well as Ben Lynch, who has compiled a vast trove of studies into a body of knowledge on methylation - his Pathway Planner is a tremendous resource, as are his YouTube videos. I attended a multiday conference of his with about 300 doctors and found their case studies and knowledge they shared to be quite powerful.

    Methylation is worth working on. It is essential to proper immune system function, neurotransmitter production, DNA replication, and many other essential processes. Optimizing it is not in itself a cure, but it to difficult to get well without it.

    I also have found great help from the work of Martin Pall as well as Maes and Morris, discussed elsewhere around here... The idea that methylation defects can lead to limited tetrahydrobiopterin recycling and an increase in peroxynitrites which can damage mitochondrial membranes. In looking at my labs, genetics and how I use nutrients, my doctor and I believe that I've experienced this issue, and it underscores the importance of supporting my methylation as well as replenishing lipids in mitochondrial membranes.

    Then, there's the issue of toxicity. People who methylate well detoxify well. People who don't tend to pick up toxins, which get sequestered in mitochondria, and also can impact brain function. Lead toxicity has been documented to reduce IQ. The "mad as a matter" phrase comes from hatmakers who experienced mercury toxicity from their work. Arsenic impairs ATP production.

    Methylation is important, and more than a hobby to dabble in.

    Optimizing it should be data-driven, and individualized, and approached in the context of the rest of one's biochemistry.
     
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  19. Hip

    Hip Senior Member

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    I am aware of these resources: don't forget that I also paid for a cinema ticket so see the movie "Indiana Jones and the Search for the Mythical Methylation Blockage" when I first started reading about boosting methylation.

    I would wager that Ben Lynch has not gathered any empirical data on the medical benefits his Pathway Planner software. There are people offering all sorts of speculative medical treatments, but when they do not offer any empirical data or details of success rates, and just provide testimonials (which are worthless in terms of statistics), I am not impressed.

    The first thing any genuine scientist does it try to test whether his or her theories actually work in practice — ie, gather empirical evidence. If you don't do that, you are not a genuine scientist. But you may be great movie director.


    Also, why are there so little references to boosting methylation in the scientific literature?

    If you search on PubMed for the herbal extract curcumin, it finds over 10,000 studies that contain this term in the title/abstract. So we can't say that alternative treatments are not found in PubMed. But in my previous searches on PubMed for the benefits of boosting methylation, I found very little.

    If people like Ben Lynch are getting results, why aren't they publishing in scientific journals?
     
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  20. Bluelude1

    Bluelude1

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    @Freddd has talked about how B2 can drive the need for potassium. Does anyone know the underlying reason why that is?
     

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