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I detailed in my first thread how I came down with severe ME/CFS symptoms starting in November 2022 which for the next year or so would continuously evolve in intensity to the point of me being relieved of most of my major bodily functions by summer 2023.
I however found a lifeline solution in December 2023 which sort of came as a culmination of all my research on bodily functions, nutrients, co factors, etc. A large part of that research coming from posts on this forum during the time I was lurking.
I tried many solutions, ranging from basic vitamins to chelation to amino acids, etc. I used the entire kitchen sink in an effort to save myself. But nothing worked until recently, which left me in a reduced state of health. Even basic breathing was starting to become incredibly laborious despite me just being 22 years old and for the majority of this crisis, 21.
The solution that would come to help me was b6 and magnesium, which is most likely down to me having a b6 deficiency. A deficiency induced by excessive folate, biotin and thiamine usage in 2023, alongside usage of metformin in 2022.
But b6 on the many occasions I would use it prior to my recent discovery would give me the most intense neuropathy and brain fog, alongside cracking tinnitus in my ear. I tried p5p but it wasn’t pushing the needle on addressing my symptoms. In-fact, Pyridoxine HCL was more effective in addressing my b6 deficiency symptoms, probably due to it being dosed higher.
The point of this thread however isn’t really just b6, or magnesium. It’s co-factors and the delicate relationship they have with each other. I spent a year reading threads on this website from people desperately trying to seek a fix and one thing which pretty much all their plans lacked was a consideration for co-factors.
For example, if you take b12, or folate, you will have increased demand for potassium. But your body needs magnesium in order to hold onto potassium. Meaning that a cofactor for potassium is magnesium. This alone is what I suspect to be causing the “insatiable hypokalemia” that many people on this forum have during methylation protocols.
You however cannot absorb magnesium without b6, as the homocysteine to cysteine, and furthermore the cysteine to taurine pathway are b6 dependant. Meaning that to solve the magnesium issue needed for solving the potassium issue, you need b6.
A lot of people here would say but you need b2 for b6. Whilst this is true, it’s only half the story. Your body actually uses b6 for the usage and transport of selenium in the body. Selenium is vital for the thyroid hormone necessary to properly convert and utilize B2. Which means that b2 technically is B6 dependant, alongside b6 being b2 dependant.
To absorb B6 in the first place however, regardless of it being pyridoxine, or Pyridoxial-5-phosphate, one needs zinc. Without zinc your body cannot engage in the uptake of b6, as Pyridoxial kinase is zinc dependant.
This is probably why so many people either get little effect from p5p, or negative effects from b6. The threshold for actual b6 toxicity is very high. Iirc it is upwards of 1000mg daily for toxicity to become relevant.
Despite this, people get toxicity on doses as low as 4mg a day. This obviously indicates a co-factor problem, as high blood levels due to your body not being able to engage in uptake of said vitamin, will mimic the symptoms of your blood stream being saturated from extremely high doses of said vitamin being taken, or in other words toxicity.
You also need zinc for riboflavin usage and uptake, as riboflavin kinase is also zinc dependant. Meaning that without zinc you will not absorb b2, b6, and by extension, magnesium, potassium, b12, folate, etc.
Folate also increases the need for b6 alongside b6 increasing the need for folate. They are interdependent in the context of needing each other in order to avert a deficiency.
This is probably one of the reasons why many get depression or other negative symptoms from high doses of methylfolate. You are basically depleting your b6 through increased need, leading to magnesium and therefore potassium deficiency. b2 will also shut down due to the b6 dependant selenium step mentioned before.
Another reason is copper, as you need copper for the conversion of folate to its end products.
Those who take chelation drugs here, like alpha lipoic acid, are also in a world of hurt when it comes to this. I myself took large amounts of alpha lipoic acid towards the end of 2022 which not only depleted many necessary metals like copper, or zinc, or manganese, it also outright depletes Biotin, molybdenum, iodine, etc.
Molybdenum and iodine are necessary cofactors for b2. A deficiency of either leads to b2 shut down and therefore lack of ability to convert most of the B vitamins. Biotin is necessary for the cycling and creation of Adenosylcobalamin, which is the critical form of b12 used in many of the bodies cells. This means Alpha lipoic acid through biotin deficiency can cause functional b12 deficiency.
If you however use biotin however, it can compete with not only Pantothenic acid but also B6 through depletion of lysine. Lysine is important for both the transport and utilization of b6 and b7. If biotin depletes lysine then b6 cannot be transported adequately which leads to b6 toxicity-like symptoms.
B6 through its magnesium absorption effect therefore allows you to absorb both b1 and vitamin D. Which means that you cannot fix either a b1 or vitamin D deficiency without vitamin B6 being adequate. It was listed in studies how b6 deficient groups took longer to correct vitamin D deficiency, which probably is due to lower ability to actually absorb and utilize magnesium.
B1 can also compete with and deplete b6. B6 can deplete b1. Excess b6 will cause beriberi, excess b1 will cause b6 deficiency and magnesium depletion which only means you will be less able to actually utilize b1 in future supplementation.
Folate apparently lowers zinc absorption, which is probably one of the ways it depletes b6 and by extension b2.
B12, without the selenium transport and therefore thyroid hormone effect of b6 activating b2 cannot itself be used. Meaning b6 deficiency will cause functional b12 deficiency.
Taking manganese can possibly deplete your b6 through increased alkaline phosphatase activity which will use up your b6, which should be a worry to those supplementing manganese and riboflavin together.
Copper deficiency will increase need for vitamin D, albeit I’ve yet to discover exactly how.
B6 as mentioned before is necessary for vitamin D. This means that vitamin b6 deficiency by proxy will lead to calcium and phosphorus deficiency.
B1 is also important for thyroid hormone production which is vital to b2.
Niacin, which many people here take, is a vitamin that in excess depletes b6 and b12. By extension from that b6 depletion you will deplete b2.
Depletion of b2 means you will not be able to properly convert niacin. You also need b6 to convert tryptophan to niacin, which means b6 deficiency will drastically increase the requirement for niacin as one critical pathway for niacin production has been effectively shut down.
“overmethylation”, which is something I’ve seen discussed a lot on this website, alongside me believing it for a time and basing my plans on it, is a myth. Overmethylation in the context of a methylation system going into overdrive is actually extremely rare. Feeling the symptoms typically tied to “overmethylation” would prevent such a thing from even occurring in the first place.
One has to remember that the methylation system is dependant on a wide range of cofactors in order to function at all. You are much more likely to be suffering from an induced deficiency somewhere after taking some b12, rather than actual “overmethylation”. I’ve even seen people here claim overmethylation symptoms from b1 and b2, which actively makes no sense.
B2 alone is what stabilizes the MTHFR enzyme and is necessary for the nutrients necessary for methylation to be converted. B1 on its own has little to do with methylation at all.
If you’re taking a bunch of b12 and feel the typical “overmethylation” symptoms of depression, or rapid heart beat, or insomnia, it’s much more likely that you instead have an increased demand for b1 and b2, as b12 places extra demand on those vitamins. Magnesium, potassium, selenium and iodine are also very important.
“overmethylation” from methylfolate isn’t actually overmethylation albeit there’s a higher risk for it as methylfolate actively inhibits methylation regulatory enzymes (like GNMT).
Methylfolate and folate in general as mentioned before increases the need for b6, which therefore increases the needs for a bunch of things related to b6, like magnesium. Folate will also increase demand for zinc which now means the nutrient necessary for even basic uptake of b2 or b6, which folate depletes, is now also in shortage.
If you take a huge gob of folate exceeding a milligram you likely have now just depleted b6, zinc, b2, etc. there’s also a high chance of you depleting b12, as excess folate in relation to b12 will cause b12 deficiency.
I then see people use stuff like niacin in huge dosages to “fix” the overmethylation. Whilst niacin will quench some symptoms, it will only make the issue worse in the long run as niacin depletes b6 and b12. An even lower level of b6 and b12 means your tolerance to folate the next time around will be minimal which will make you reach for the niacin bottle again which only makes things worse until you totally crash. How do I know? Because I’ve been through all that for basically an entire year.
If you’re trying to correct methylation, it’s best to take a B complex. Nobody needs 20mg of folate, it makes no sense. You can tell if you need something when the effect is SUSTAINED.
A need to take huge gobs of folate repetitively with no actual end goal in sight means you’re not actually fixing anything. You’re compensating with a high risk of crash. You’re treating a vitamin like a drug, which is a bad call. Vitamins unlike drugs do not have a guaranteed effect. If you took adderall it’s pretty much guaranteed to make you amped up. If you took Valium it’s pretty much guaranteed you’ll feel more calm and sleepy. When it comes to vitamins, or nutrients in general, effect is nutrient status based. Fixing a deficiency will make you feel amped and relieved. Topping up on normal levels will make you feel normal. Creating an excess will make you feel sick.
If you need folate, take a methylated complex with FOLATE. Do not take folate alone. One of the worst mistakes is taking supplements in isolation when these supplements are interdependent on so many factors. Even if your nutrient levels are ok, it doesn’t matter, as your demand for nutrients will skyrocket the minute you take a pill.
The body only stores so much and you can as a result burn through your reserves very fast when subjecting said reserves to constantly increased demand.
Focus on non B vitamin cofactors as they’re necessary for the entire end goal you’re working towards. Don’t just take a multi mineral either. 5mg of zinc will become nothing in comparison to a bunch of folate, a bunch of b6, a bunch of riboflavin, etc. You need at least 20-30 daily to justify the supplementation you commonly see on this website.
This however does not mean taking a crazy dose of co-factors, like 100mg of zinc, as that just creates an excess which now will deplete other important stuff like copper and magnesium.
Cofactors whilst very complicated on the surface are very simple. You have no place taking any vitamin or supplement if you do not have the necessary cofactor for it. Your body doesn’t care if you supplement a bunch of b6 but say don’t have enough zinc to justify it. It’s the equivalent of putting a pot on the stove, dumping in some water and expecting a 5 course fine dining meal from boiling the water.
Whilst a pot and some water can act as the foundation for creating something delicious, more needs to be added to justify putting the pot on the stove in the first place. Otherwise you’re wasting time and in the case of many on this website, widening the distance between you and your much desired goal of recovery.
There’s also people on this website who gained a following and I myself used to follow like Freddd who said stuff like drastically limiting your b2 intake in relation to folate, which to me before made sense but now comes off as complete madness.
No disrespect to him, as he was correct on a fair bit of what he said, but one who deals in the hand of methylation should always understand that b2 is literally the backbone for all methylation nutrients. Folate and b12 become useless or even detrimental when your b2 isn’t up to par. B1 is also very important as it assists b2 and b12 absorption in the first place.
If you have an issue tolerating b1 and b2, that does not mean that these nutrients are bad. Remember that they co-occur in pretty much all major nutrient dense foods. B1 and B2 intolerance rather as elaborated on throughout this thread, means you have a co-factor issue, which spells a very dangerous situation for your methylation goals considering direct methylation factors like b9 and b12 have b2 as a cofactor and share cofactors with b2. If b2 doesn’t work, b9 and b12 likely won’t either. This is also in my opinion likely why people need huge doses of folate to feel something, as deficiencies in cofactors will drastically increase the need for vitamins.
The links for the studies and proof for what I said in this thread will be listed below.
Homocystiene to Cystiene being B6 dependant:
https://www.sciencedirect.com/topics/medicine-and-dentistry/homocysteine
Taurine biosynthesis being B6 dependant (Taurine is derived from Cystiene which is also relevant to above):
https://www.sciencedirect.com/science/article/abs/pii/S0271531705803562
"a vitamin B-6 deficiency of the lactating dam resulted in reduced biosynthesis of taurine in the dam and pup without influencing the availability of endogenous or exogenous taurine in milk."
Selenium usage being dependant on B6:
https://pubmed.ncbi.nlm.nih.gov/1802975/
"A significant decrease of GSH-Px activity in liver was found in vitamin B6-deficient animals fed Se-Met compared with vitamin B6-supplemented animals, whereas no significant decrease was observed in those fed SeL. These results suggest that this vitamin is involved in the transport and deliverance of Se in plasma to the other tissues and the incorporation of Se from Se-Met to GSH-Px in liver. "
B6 and B2 Absorption being Zinc dependant:
B6 article -
https://www.google.com/url?sa=t&rct...usg=AOvVaw3zOqjhjSJaHwDfDELk8s5X&opi=89978449
B2 article -
https://www.sciencedirect.com/topics/medicine-and-dentistry/riboflavin-kinase
"At physiological concentrations, zinc stimulates the activity of pyridoxal kinase, enhancing the formation of pyridoxal phosphate, which in turn enhances the activity of glutamic acid decarboxylase."
"Conversion of riboflavin to coenzymes occurs within the cellular cytoplasm of most tissues, but particularly in the small intestine, liver, heart, kidney, and brain. The obligatory first step is the adenosine 5'-triphosphate (ATP)-dependent phosphorylation of the vitamin catalyzed by flavokinase, which utilizes Zn2+"
"The FMN product can be complexed with specific apoenzymes to form several functional flavoproteins, but the major portion is further converted to FAD in a second ATP-dependent reaction catalyzed by FAD synthetase, which utilizes Mg2+"
B2 is B6 dependant through magnesium and selenium. It is Zinc dependant through flavokinase.
Folate inhibiting zinc absorption:
https://pubmed.ncbi.nlm.nih.gov/6711464/
"Fecal zinc was significantly (p less than 0.001) higher in the group that received folic acid supplements during the initial control and low zinc intake periods. No significant differences were seen during the period of high zinc intake. During all dietary periods urinary zinc excretion was reduced by about 50% by folic acid supplementation. No apparent changes occurred in iron or copper excretion. These data indicate that supplemental folate influences zinc homeostasis, perhaps through formation of an insoluble chelate and impairment of absorption."
Folate increasing B6 need and vice versa:
B6 Lowering folate article - https://www.jstor.org/stable/48507382
Folate increasing B6 need article - https://pubmed.ncbi.nlm.nih.gov/11592449/
"Plasma vitamin B₁₂ and basal homocysteine levels remained unchanged (234.0 ± 27.8 vs. 217.1 ± 50.4 pg/ml and 10.9 ± 4.8 vs. 10.1 ± 3.6 µmol/l). There was no significant effect of vitamin B₆ supplementation on the area under methionine and homocysteine concentration versus time curve. Significant correlations were found between pre- and post-supplement levels of folate as well as PLP levels (r = 0.73, p < 0.05; r = 0.75, p < 0.05). These data suggest that a dose of 25 mg vitamin B₆ supplemented for 10 days reduces plasma folate but did not affect basal and post-prandial homocysteine levels suggesting (1) a normal cellular availability of folate or (2) a compensation of impaired homocysteine remethylation by increased transsulfuration."
"In a pilot study we measured the effect of three different combinations of the vitamins B6, folate and B12 on the serum concentrations of homocysteine, cystathionine and methylmalonic acid in five healthy young men without hyperhomocysteinemia. The results indicate that there are still undescribed interactions between vitamin B6 and folate, suggesting that these two vitamins should be given together to avoid depletion of the one not given. With regard to the well known metabolic pathways of methionine and cysteine, this confirms the hypothesis that a combined supplementation with the vitamins B6 and folate (and B12) is superior to folate alone in order to lower homocysteine."
Niacin depleting B6 and b12:
https://pubmed.ncbi.nlm.nih.gov/11895163/
"Supplementation with niacin (1,000 mg/kg diet) for 3 months resulted in a significant increase in plasma and urinary total homocysteine levels; this increase was further accentuated in the presence of a high methionine diet. The hyperhomocysteineaemia was accompanied by a significant decrease in plasma concentrations of vitamins B6 and B12, which are cofactors for the metabolism of homocysteine."
A lowering of blood concentration of b6 and b12 alongside hyper-homocystieneaemia means that b6 and b12 is being wasted by Niacin, rather than Niacin increasing the absorption of these nutrients into tissues and therefore lowering blood concentrations.
In terms of supplementing and what worked for me, I succeeded with a stack based around B6, zinc and magnesium. All the co-factors needed were also taken with the B6. The stack is as follows:
Part 1 - Lysine 500mg (First), Zinc bisglycinate 30mg (Second), B6 HCL 300-500mg (Third), P5P 50mg (Last).
In the first two days of me trying to correct my B6 deficiency, I took a loading dose. Starting with 500mg of HCL and 50mg of P5P for 550mg total of B6, followed by 400mg HCL and 50mg P5P for 450mg total of B6. For the next 12 Days after these initial two days, I took 300mg of B6 HCL alongside 50mg of P5P for a combined total of 350mg B6. For the next two weeks I plan to lower this total to 250mg of total B6, with me taking 200mg HCL and 50mg P5P.
Part 2 - Selenomethionine 200mcg (First), Iodine from kelp 800-1600mcg (Second), Riboflavin 200mg (Third), Benfotiamine 160mg (Last).
Part 3 - Magnesium Bisglycinate 200-600mg (First), Hydroxo B12 1-2mg (Second), Methylfolate or folic acid 1-2mg (Last).
From viewing this stack some might ask why the B6 dose is so high, and the answer to that would be to of course correct B6 deficiency. However the necessity of other vitamins and nutrients cannot be overstated. As said before, B6 without B1 for any duration of time will give you a one way to ticket to beriberi very fast.
For that reason i'm taking 160mg of benfotiamine with every B6 supplement. When trying to fix a deficiency of a certain B vitamin, you want to take that vitamin with all it's cofactors whilst ensuring that the dose of the supplement for the nutrient you're deficient in is the highest dosed supplement in your stack. If for example you took 100mg of B6 to fix your B6 deficiency but also took 200mg of benfotiamine or Allithiamine with your B6, your B6 deficiency won't actually be fixed, since your B1 will be inhibiting any significiant increase in B6.
You however should not take way more of one supplement than the other. For example if you have a folate deficiency and as a result take all it's cofactors but take 20mg of folate in comparison to maybe 1mg in B12, you will still run into problems due to cofactors being depleted by the sheer demand induced by high intake of folate. Take more but not much more.
The high magnesium intake is for increasing my blood level of magnesium which was depleted as a consequence of b6 deficiency. Lysine is necessary for transport of B6 and without sufficient lysine, you will have a much greater buildup of b6 in your blood stream after even minimal supplementation of B6. Zinc as elaborated on earlier in this post is necessary for Pyridoxial kinase. Any B6 taken without sufficent zinc is effectively a sugar pill as the enzymes needed to convert b6 will not have the nutrients to convert the b6 you are taking.
Riboflavin is of course to help the B6, Folate and b12 along.
This doesn't mean you should take B6, as with everything health wise, this is a deeply personal issue. If you do not have a B6 deficiency and take a huge amount of b6 you're not only wasting time, but you are potentially hurting yourself with B6 Toxicity. You should however use this as a framework for how and why you supplement. Or why and how you fix health problems in general. Focus on CO-FACTORS above all when trying to fix potential deficiencies. The lack of care for this on this site is why I think many either do not find a solution in time before symptoms become totally disabling, or instead are stuck taking huge doses of one nutrient which inevitably leads to a crash and ultimately a regression to square one.
I however found a lifeline solution in December 2023 which sort of came as a culmination of all my research on bodily functions, nutrients, co factors, etc. A large part of that research coming from posts on this forum during the time I was lurking.
I tried many solutions, ranging from basic vitamins to chelation to amino acids, etc. I used the entire kitchen sink in an effort to save myself. But nothing worked until recently, which left me in a reduced state of health. Even basic breathing was starting to become incredibly laborious despite me just being 22 years old and for the majority of this crisis, 21.
The solution that would come to help me was b6 and magnesium, which is most likely down to me having a b6 deficiency. A deficiency induced by excessive folate, biotin and thiamine usage in 2023, alongside usage of metformin in 2022.
But b6 on the many occasions I would use it prior to my recent discovery would give me the most intense neuropathy and brain fog, alongside cracking tinnitus in my ear. I tried p5p but it wasn’t pushing the needle on addressing my symptoms. In-fact, Pyridoxine HCL was more effective in addressing my b6 deficiency symptoms, probably due to it being dosed higher.
The point of this thread however isn’t really just b6, or magnesium. It’s co-factors and the delicate relationship they have with each other. I spent a year reading threads on this website from people desperately trying to seek a fix and one thing which pretty much all their plans lacked was a consideration for co-factors.
For example, if you take b12, or folate, you will have increased demand for potassium. But your body needs magnesium in order to hold onto potassium. Meaning that a cofactor for potassium is magnesium. This alone is what I suspect to be causing the “insatiable hypokalemia” that many people on this forum have during methylation protocols.
You however cannot absorb magnesium without b6, as the homocysteine to cysteine, and furthermore the cysteine to taurine pathway are b6 dependant. Meaning that to solve the magnesium issue needed for solving the potassium issue, you need b6.
A lot of people here would say but you need b2 for b6. Whilst this is true, it’s only half the story. Your body actually uses b6 for the usage and transport of selenium in the body. Selenium is vital for the thyroid hormone necessary to properly convert and utilize B2. Which means that b2 technically is B6 dependant, alongside b6 being b2 dependant.
To absorb B6 in the first place however, regardless of it being pyridoxine, or Pyridoxial-5-phosphate, one needs zinc. Without zinc your body cannot engage in the uptake of b6, as Pyridoxial kinase is zinc dependant.
This is probably why so many people either get little effect from p5p, or negative effects from b6. The threshold for actual b6 toxicity is very high. Iirc it is upwards of 1000mg daily for toxicity to become relevant.
Despite this, people get toxicity on doses as low as 4mg a day. This obviously indicates a co-factor problem, as high blood levels due to your body not being able to engage in uptake of said vitamin, will mimic the symptoms of your blood stream being saturated from extremely high doses of said vitamin being taken, or in other words toxicity.
You also need zinc for riboflavin usage and uptake, as riboflavin kinase is also zinc dependant. Meaning that without zinc you will not absorb b2, b6, and by extension, magnesium, potassium, b12, folate, etc.
Folate also increases the need for b6 alongside b6 increasing the need for folate. They are interdependent in the context of needing each other in order to avert a deficiency.
This is probably one of the reasons why many get depression or other negative symptoms from high doses of methylfolate. You are basically depleting your b6 through increased need, leading to magnesium and therefore potassium deficiency. b2 will also shut down due to the b6 dependant selenium step mentioned before.
Another reason is copper, as you need copper for the conversion of folate to its end products.
Those who take chelation drugs here, like alpha lipoic acid, are also in a world of hurt when it comes to this. I myself took large amounts of alpha lipoic acid towards the end of 2022 which not only depleted many necessary metals like copper, or zinc, or manganese, it also outright depletes Biotin, molybdenum, iodine, etc.
Molybdenum and iodine are necessary cofactors for b2. A deficiency of either leads to b2 shut down and therefore lack of ability to convert most of the B vitamins. Biotin is necessary for the cycling and creation of Adenosylcobalamin, which is the critical form of b12 used in many of the bodies cells. This means Alpha lipoic acid through biotin deficiency can cause functional b12 deficiency.
If you however use biotin however, it can compete with not only Pantothenic acid but also B6 through depletion of lysine. Lysine is important for both the transport and utilization of b6 and b7. If biotin depletes lysine then b6 cannot be transported adequately which leads to b6 toxicity-like symptoms.
B6 through its magnesium absorption effect therefore allows you to absorb both b1 and vitamin D. Which means that you cannot fix either a b1 or vitamin D deficiency without vitamin B6 being adequate. It was listed in studies how b6 deficient groups took longer to correct vitamin D deficiency, which probably is due to lower ability to actually absorb and utilize magnesium.
B1 can also compete with and deplete b6. B6 can deplete b1. Excess b6 will cause beriberi, excess b1 will cause b6 deficiency and magnesium depletion which only means you will be less able to actually utilize b1 in future supplementation.
Folate apparently lowers zinc absorption, which is probably one of the ways it depletes b6 and by extension b2.
B12, without the selenium transport and therefore thyroid hormone effect of b6 activating b2 cannot itself be used. Meaning b6 deficiency will cause functional b12 deficiency.
Taking manganese can possibly deplete your b6 through increased alkaline phosphatase activity which will use up your b6, which should be a worry to those supplementing manganese and riboflavin together.
Copper deficiency will increase need for vitamin D, albeit I’ve yet to discover exactly how.
B6 as mentioned before is necessary for vitamin D. This means that vitamin b6 deficiency by proxy will lead to calcium and phosphorus deficiency.
B1 is also important for thyroid hormone production which is vital to b2.
Niacin, which many people here take, is a vitamin that in excess depletes b6 and b12. By extension from that b6 depletion you will deplete b2.
Depletion of b2 means you will not be able to properly convert niacin. You also need b6 to convert tryptophan to niacin, which means b6 deficiency will drastically increase the requirement for niacin as one critical pathway for niacin production has been effectively shut down.
“overmethylation”, which is something I’ve seen discussed a lot on this website, alongside me believing it for a time and basing my plans on it, is a myth. Overmethylation in the context of a methylation system going into overdrive is actually extremely rare. Feeling the symptoms typically tied to “overmethylation” would prevent such a thing from even occurring in the first place.
One has to remember that the methylation system is dependant on a wide range of cofactors in order to function at all. You are much more likely to be suffering from an induced deficiency somewhere after taking some b12, rather than actual “overmethylation”. I’ve even seen people here claim overmethylation symptoms from b1 and b2, which actively makes no sense.
B2 alone is what stabilizes the MTHFR enzyme and is necessary for the nutrients necessary for methylation to be converted. B1 on its own has little to do with methylation at all.
If you’re taking a bunch of b12 and feel the typical “overmethylation” symptoms of depression, or rapid heart beat, or insomnia, it’s much more likely that you instead have an increased demand for b1 and b2, as b12 places extra demand on those vitamins. Magnesium, potassium, selenium and iodine are also very important.
“overmethylation” from methylfolate isn’t actually overmethylation albeit there’s a higher risk for it as methylfolate actively inhibits methylation regulatory enzymes (like GNMT).
Methylfolate and folate in general as mentioned before increases the need for b6, which therefore increases the needs for a bunch of things related to b6, like magnesium. Folate will also increase demand for zinc which now means the nutrient necessary for even basic uptake of b2 or b6, which folate depletes, is now also in shortage.
If you take a huge gob of folate exceeding a milligram you likely have now just depleted b6, zinc, b2, etc. there’s also a high chance of you depleting b12, as excess folate in relation to b12 will cause b12 deficiency.
I then see people use stuff like niacin in huge dosages to “fix” the overmethylation. Whilst niacin will quench some symptoms, it will only make the issue worse in the long run as niacin depletes b6 and b12. An even lower level of b6 and b12 means your tolerance to folate the next time around will be minimal which will make you reach for the niacin bottle again which only makes things worse until you totally crash. How do I know? Because I’ve been through all that for basically an entire year.
If you’re trying to correct methylation, it’s best to take a B complex. Nobody needs 20mg of folate, it makes no sense. You can tell if you need something when the effect is SUSTAINED.
A need to take huge gobs of folate repetitively with no actual end goal in sight means you’re not actually fixing anything. You’re compensating with a high risk of crash. You’re treating a vitamin like a drug, which is a bad call. Vitamins unlike drugs do not have a guaranteed effect. If you took adderall it’s pretty much guaranteed to make you amped up. If you took Valium it’s pretty much guaranteed you’ll feel more calm and sleepy. When it comes to vitamins, or nutrients in general, effect is nutrient status based. Fixing a deficiency will make you feel amped and relieved. Topping up on normal levels will make you feel normal. Creating an excess will make you feel sick.
If you need folate, take a methylated complex with FOLATE. Do not take folate alone. One of the worst mistakes is taking supplements in isolation when these supplements are interdependent on so many factors. Even if your nutrient levels are ok, it doesn’t matter, as your demand for nutrients will skyrocket the minute you take a pill.
The body only stores so much and you can as a result burn through your reserves very fast when subjecting said reserves to constantly increased demand.
Focus on non B vitamin cofactors as they’re necessary for the entire end goal you’re working towards. Don’t just take a multi mineral either. 5mg of zinc will become nothing in comparison to a bunch of folate, a bunch of b6, a bunch of riboflavin, etc. You need at least 20-30 daily to justify the supplementation you commonly see on this website.
This however does not mean taking a crazy dose of co-factors, like 100mg of zinc, as that just creates an excess which now will deplete other important stuff like copper and magnesium.
Cofactors whilst very complicated on the surface are very simple. You have no place taking any vitamin or supplement if you do not have the necessary cofactor for it. Your body doesn’t care if you supplement a bunch of b6 but say don’t have enough zinc to justify it. It’s the equivalent of putting a pot on the stove, dumping in some water and expecting a 5 course fine dining meal from boiling the water.
Whilst a pot and some water can act as the foundation for creating something delicious, more needs to be added to justify putting the pot on the stove in the first place. Otherwise you’re wasting time and in the case of many on this website, widening the distance between you and your much desired goal of recovery.
There’s also people on this website who gained a following and I myself used to follow like Freddd who said stuff like drastically limiting your b2 intake in relation to folate, which to me before made sense but now comes off as complete madness.
No disrespect to him, as he was correct on a fair bit of what he said, but one who deals in the hand of methylation should always understand that b2 is literally the backbone for all methylation nutrients. Folate and b12 become useless or even detrimental when your b2 isn’t up to par. B1 is also very important as it assists b2 and b12 absorption in the first place.
If you have an issue tolerating b1 and b2, that does not mean that these nutrients are bad. Remember that they co-occur in pretty much all major nutrient dense foods. B1 and B2 intolerance rather as elaborated on throughout this thread, means you have a co-factor issue, which spells a very dangerous situation for your methylation goals considering direct methylation factors like b9 and b12 have b2 as a cofactor and share cofactors with b2. If b2 doesn’t work, b9 and b12 likely won’t either. This is also in my opinion likely why people need huge doses of folate to feel something, as deficiencies in cofactors will drastically increase the need for vitamins.
The links for the studies and proof for what I said in this thread will be listed below.
Homocystiene to Cystiene being B6 dependant:
https://www.sciencedirect.com/topics/medicine-and-dentistry/homocysteine
7.5.4 Homocysteine
"Homocysteine (HCy) is formed from SAH following the removal of the adenosyl group by the enzyme SAH hydrolase. The two major methyltransferases that contribute to the formation of HCy are phospatidylethanolamine N-methyltransferase (PEMT), which synthesizes phosphatidylcholine, and guanidinoacetate N-methyltransferase (GAMT), which synthesizes creatine. Collectively, PEMT and GAMT account for roughly 85% of SAM-dependent transmethylation [47]. Interestingly, in bladder cancer PEMT polymorphisms are associated with the degree of global DNA hypomethylation [48]. HCy can be converted into cysteine by the vitamin B6-dependent enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase, or recycled by two separate remethylation pathways."Taurine biosynthesis being B6 dependant (Taurine is derived from Cystiene which is also relevant to above):
https://www.sciencedirect.com/science/article/abs/pii/S0271531705803562
"a vitamin B-6 deficiency of the lactating dam resulted in reduced biosynthesis of taurine in the dam and pup without influencing the availability of endogenous or exogenous taurine in milk."
Selenium usage being dependant on B6:
https://pubmed.ncbi.nlm.nih.gov/1802975/
"A significant decrease of GSH-Px activity in liver was found in vitamin B6-deficient animals fed Se-Met compared with vitamin B6-supplemented animals, whereas no significant decrease was observed in those fed SeL. These results suggest that this vitamin is involved in the transport and deliverance of Se in plasma to the other tissues and the incorporation of Se from Se-Met to GSH-Px in liver. "
B6 and B2 Absorption being Zinc dependant:
B6 article -
https://www.google.com/url?sa=t&rct...usg=AOvVaw3zOqjhjSJaHwDfDELk8s5X&opi=89978449
B2 article -
https://www.sciencedirect.com/topics/medicine-and-dentistry/riboflavin-kinase
"At physiological concentrations, zinc stimulates the activity of pyridoxal kinase, enhancing the formation of pyridoxal phosphate, which in turn enhances the activity of glutamic acid decarboxylase."
"Conversion of riboflavin to coenzymes occurs within the cellular cytoplasm of most tissues, but particularly in the small intestine, liver, heart, kidney, and brain. The obligatory first step is the adenosine 5'-triphosphate (ATP)-dependent phosphorylation of the vitamin catalyzed by flavokinase, which utilizes Zn2+"
"The FMN product can be complexed with specific apoenzymes to form several functional flavoproteins, but the major portion is further converted to FAD in a second ATP-dependent reaction catalyzed by FAD synthetase, which utilizes Mg2+"
B2 is B6 dependant through magnesium and selenium. It is Zinc dependant through flavokinase.
Folate inhibiting zinc absorption:
https://pubmed.ncbi.nlm.nih.gov/6711464/
"Fecal zinc was significantly (p less than 0.001) higher in the group that received folic acid supplements during the initial control and low zinc intake periods. No significant differences were seen during the period of high zinc intake. During all dietary periods urinary zinc excretion was reduced by about 50% by folic acid supplementation. No apparent changes occurred in iron or copper excretion. These data indicate that supplemental folate influences zinc homeostasis, perhaps through formation of an insoluble chelate and impairment of absorption."
Folate increasing B6 need and vice versa:
B6 Lowering folate article - https://www.jstor.org/stable/48507382
Folate increasing B6 need article - https://pubmed.ncbi.nlm.nih.gov/11592449/
"Plasma vitamin B₁₂ and basal homocysteine levels remained unchanged (234.0 ± 27.8 vs. 217.1 ± 50.4 pg/ml and 10.9 ± 4.8 vs. 10.1 ± 3.6 µmol/l). There was no significant effect of vitamin B₆ supplementation on the area under methionine and homocysteine concentration versus time curve. Significant correlations were found between pre- and post-supplement levels of folate as well as PLP levels (r = 0.73, p < 0.05; r = 0.75, p < 0.05). These data suggest that a dose of 25 mg vitamin B₆ supplemented for 10 days reduces plasma folate but did not affect basal and post-prandial homocysteine levels suggesting (1) a normal cellular availability of folate or (2) a compensation of impaired homocysteine remethylation by increased transsulfuration."
"In a pilot study we measured the effect of three different combinations of the vitamins B6, folate and B12 on the serum concentrations of homocysteine, cystathionine and methylmalonic acid in five healthy young men without hyperhomocysteinemia. The results indicate that there are still undescribed interactions between vitamin B6 and folate, suggesting that these two vitamins should be given together to avoid depletion of the one not given. With regard to the well known metabolic pathways of methionine and cysteine, this confirms the hypothesis that a combined supplementation with the vitamins B6 and folate (and B12) is superior to folate alone in order to lower homocysteine."
Niacin depleting B6 and b12:
https://pubmed.ncbi.nlm.nih.gov/11895163/
"Supplementation with niacin (1,000 mg/kg diet) for 3 months resulted in a significant increase in plasma and urinary total homocysteine levels; this increase was further accentuated in the presence of a high methionine diet. The hyperhomocysteineaemia was accompanied by a significant decrease in plasma concentrations of vitamins B6 and B12, which are cofactors for the metabolism of homocysteine."
A lowering of blood concentration of b6 and b12 alongside hyper-homocystieneaemia means that b6 and b12 is being wasted by Niacin, rather than Niacin increasing the absorption of these nutrients into tissues and therefore lowering blood concentrations.
In terms of supplementing and what worked for me, I succeeded with a stack based around B6, zinc and magnesium. All the co-factors needed were also taken with the B6. The stack is as follows:
Part 1 - Lysine 500mg (First), Zinc bisglycinate 30mg (Second), B6 HCL 300-500mg (Third), P5P 50mg (Last).
In the first two days of me trying to correct my B6 deficiency, I took a loading dose. Starting with 500mg of HCL and 50mg of P5P for 550mg total of B6, followed by 400mg HCL and 50mg P5P for 450mg total of B6. For the next 12 Days after these initial two days, I took 300mg of B6 HCL alongside 50mg of P5P for a combined total of 350mg B6. For the next two weeks I plan to lower this total to 250mg of total B6, with me taking 200mg HCL and 50mg P5P.
Part 2 - Selenomethionine 200mcg (First), Iodine from kelp 800-1600mcg (Second), Riboflavin 200mg (Third), Benfotiamine 160mg (Last).
Part 3 - Magnesium Bisglycinate 200-600mg (First), Hydroxo B12 1-2mg (Second), Methylfolate or folic acid 1-2mg (Last).
From viewing this stack some might ask why the B6 dose is so high, and the answer to that would be to of course correct B6 deficiency. However the necessity of other vitamins and nutrients cannot be overstated. As said before, B6 without B1 for any duration of time will give you a one way to ticket to beriberi very fast.
For that reason i'm taking 160mg of benfotiamine with every B6 supplement. When trying to fix a deficiency of a certain B vitamin, you want to take that vitamin with all it's cofactors whilst ensuring that the dose of the supplement for the nutrient you're deficient in is the highest dosed supplement in your stack. If for example you took 100mg of B6 to fix your B6 deficiency but also took 200mg of benfotiamine or Allithiamine with your B6, your B6 deficiency won't actually be fixed, since your B1 will be inhibiting any significiant increase in B6.
You however should not take way more of one supplement than the other. For example if you have a folate deficiency and as a result take all it's cofactors but take 20mg of folate in comparison to maybe 1mg in B12, you will still run into problems due to cofactors being depleted by the sheer demand induced by high intake of folate. Take more but not much more.
The high magnesium intake is for increasing my blood level of magnesium which was depleted as a consequence of b6 deficiency. Lysine is necessary for transport of B6 and without sufficient lysine, you will have a much greater buildup of b6 in your blood stream after even minimal supplementation of B6. Zinc as elaborated on earlier in this post is necessary for Pyridoxial kinase. Any B6 taken without sufficent zinc is effectively a sugar pill as the enzymes needed to convert b6 will not have the nutrients to convert the b6 you are taking.
Riboflavin is of course to help the B6, Folate and b12 along.
This doesn't mean you should take B6, as with everything health wise, this is a deeply personal issue. If you do not have a B6 deficiency and take a huge amount of b6 you're not only wasting time, but you are potentially hurting yourself with B6 Toxicity. You should however use this as a framework for how and why you supplement. Or why and how you fix health problems in general. Focus on CO-FACTORS above all when trying to fix potential deficiencies. The lack of care for this on this site is why I think many either do not find a solution in time before symptoms become totally disabling, or instead are stuck taking huge doses of one nutrient which inevitably leads to a crash and ultimately a regression to square one.
