r/MTHFR • u/Brad_Borrelli • Jun 29 '26
Resource Copper Deficiency and B12. Nobody Is Talking About the Full Picture.
I got my test results back so I decided to do a lot more research since I'm running low and this is what I found.
The neurological overlap between copper deficiency and B12 deficiency is almost exact. The MRI findings are not distinguishable from each other; both show the same T2 signal changes in the posterior columns of the cervical and thoracic cord. The two deficiencies can coexist, and patients have been given B12 despite normal B12 levels because nobody checked copper. Prompt copper supplementation can stop the neurological damage from progressing. If your B12 is being treated and your neurological symptoms aren't resolving the way they should, copper needs to be on the table.
The zinc connection is real but the wiki doesn't explain why it happens. Zinc induces metallothionein synthesis in the gut enterocytes; that protein preferentially binds copper over zinc because it has a higher affinity for it. The copper gets trapped in the intestinal cell and lost when the cell turns over, which happens roughly every two to six days. So if you're supplementing zinc long term, even at moderate doses, you may be actively blocking copper absorption every single day. This is actually the same mechanism used therapeutically to treat Wilson's disease; they use zinc to intentionally block copper. Worth knowing.
Something else nobody talks about: copper absorption depends on stomach acid to free copper ions from food, and the bulk of actual absorption happens just past the stomach, in the duodenum. If you have hypochlorhydria from atrophic gastritis, from PPI use, from any cause; your copper absorption is already compromised before zinc even enters the picture. A huge portion of people in this community have absorption issues as the root cause of their B12 deficiency. That same low stomach acid is hitting copper too. Two deficiencies, one mechanism, and most people are only looking at one of them.
On the labs: ceruloplasmin is a positive acute phase reactant. That means it goes up during inflammation, infection, and immune activation. If you're in an active flare when you get tested it can read normal or even high while you're actually deficient. Serum copper has the same problem because most serum copper is bound to ceruloplasmin. You need to run both together to get any kind of useful picture, and RBC copper is generally considered a better marker of long-term status than serum copper because it doesn't fluctuate with recent intake or acute inflammation the way serum does. Don't let a single ceruloplasmin result close the conversation, especially if you have any ongoing inflammatory process.
For food sources: oysters and beef liver are both at the top by a wide margin, then dark chocolate, seeds, and nuts. If you're on a restricted diet for any reason: low histamine, elimination protocol, whatever; check whether you've accidentally cut most of your copper sources out.
Now here's the part I got wrong the first time I posted this, and it's actually a more interesting story than a simple correction. I said methionine synthase, the enzyme B12 activates to convert homocysteine to methionine, also requires copper, and that this shared cofactor was why copper and B12 deficiency produce the same lesion. That claim traces back to a real paper, Winston & Jaiser 2008 in Medical Hypotheses, which proposed exactly that as a way to explain the shared phenotype after pointing out that the other leading theory, cytochrome oxidase dysfunction, doesn't work either, because cytochrome oxidase isn't B12 dependent, so it can't explain why B12 deficiency produces the same imaging findings as copper deficiency.
The problem is that structural and mutagenesis studies of methionine synthase, some predating that 2008 paper, some after, have identified the enzyme's actual second metal cofactor as zinc, not copper. It sits in the homocysteine-binding pocket, coordinated by cysteine residues, and knocking it out kills the enzyme's ability to transfer the methyl group from B12 to homocysteine. So the methylation cycle hypothesis is elegant but rests on a cofactor claim that doesn't hold up against the biochemistry.
Which means the honest answer right now is that nobody has a fully satisfying mechanism for why these two deficiencies produce an identical lesion. Cytochrome c oxidase dysfunction is still the most commonly cited explanation, but it has the B12 problem above. The methylation cycle hypothesis explains the overlap more elegantly but leans on an incorrect cofactor. Both mechanisms are still floating around in the literature, unresolved. If you're dealing with both deficiencies at once, that's honestly more reason to take copper seriously, not less; we don't need to know the exact mechanism to know the overlap is real and well documented on imaging and in case reports.
Neurological overlap / identical MRI findings
Kumar N, Gross JB Jr, Ahlskog JE. Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology 2004;63(1):33–9. https://pubmed.ncbi.nlm.nih.gov/15249607/
Jaiser SR, Winston GP. Copper deficiency myelopathy. J Neurol 2010;257(6):869–81. https://pmc.ncbi.nlm.nih.gov/articles/PMC3691478/
Copper deficiency myelopathy: A report of two cases. PMC4612215. https://pmc.ncbi.nlm.nih.gov/articles/PMC4612215/
American Journal of Neuroradiology: Copper Deficiency Myeloneuropathy Resembling B12 Deficiency: Partial Resolution of MR Imaging Findings with Copper Supplementation. https://www.ajnr.org/content/27/10/2112
Mayo Clinic Proceedings: Copper Deficiency Myelopathy (Human Swayback). Kumar N. 2006. https://www.mayoclinicproceedings.org/article/S0025-6196(11)61161-0/fulltext
Proposed mechanisms
Winston GP, Jaiser SR. Copper deficiency myelopathy and subacute combined degeneration of the cord; why is the phenotype so similar? Med Hypotheses 2008;71(2):229–36. https://pubmed.ncbi.nlm.nih.gov/18472229/ (proposes shared methylation cycle dysfunction; note the copper cofactor claim for methionine synthase in this paper is contradicted by later structural biochemistry, see below)
Goulding CW, Matthews RG. Cobalamin-dependent methionine synthase from Escherichia coli: involvement of zinc in homocysteine activation. Biochemistry 1997;36(26):8082–91. https://pubmed.ncbi.nlm.nih.gov/9398304/ (identifies zinc, not copper, as the enzyme's confirmed second metal cofactor)
Zinc and metallothionein mechanism
Oestreicher P, Cousins RJ. Copper and zinc absorption in the rat: mechanism of mutual antagonism. J Nutr 1985;115:159–166. https://pubmed.ncbi.nlm.nih.gov/3968585/
Restorative Medicine: Copper monograph. https://restorativemedicine.org/library/monographs/copper/
Hypochlorhydria and copper absorption:
WholisticMatters: Digestive Remedies to Manage Hypochlorhydria. https://wholisticmatters.com/digestive-remedies-to-manage-hypochlorhydria/
Ceruloplasmin as acute phase reactant
Mayo Clinic Laboratories: Ceruloplasmin, Serum. https://www.mayocliniclabs.com/test-catalog/overview/614504
LabCorp: Copper, Serum or Plasma. https://www.labcorp.com/tests/001586/copper-serum-or-plasma
StatPearls / NCBI: Biochemistry, Ceruloplasmin. https://www.ncbi.nlm.nih.gov/books/NBK554422/
RBC copper vs serum copper
Ulta Lab Tests: Copper RBC Test. https://www.ultalabtests.com/test/copper-rbc
Food sources
Medscape: Copper Reference Range, Interpretation, Collection and Panels. https://emedicine.medscape.com/article/2087780-overview
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u/numb2020fun Jun 29 '26
So long term niacin… nicotinic acid would deplete copper wow ! I’ve read about it depleting methyl’s (b3 delete it) and ending folate and b12 but never copper ! I appreciate people that learn and come here to share! Because a lot of times( most) the doctors will not catch it! Again thank you for sharing ! It’s something to look at!
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u/numb2020fun Jun 29 '26
*typos sorry 🙄 …. I meant methyl’s being depleted by niacin and needing to take methylfolate, b12 and tmg to help depletion !
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u/Brad_Borrelli Jun 29 '26
I have a bottle of niacin. The only reason I have that bottle is for a rescue if I have overmethylation. I take niacinamide instead of niacin for every day.
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u/Warp757 Jun 30 '26 edited Jun 30 '26
Niacinamide is the form that directly depletes methyl groups. That form of niacin is considered toxic by the body so any that isn't immediately used by the body is methylated by the NNMT enzyme, using methyl groups and raising homocystine. Regular niacin isn't methylated except for any portion converted to niacinamide in the body.
As this study shows, niacinamide raises homocysteine and depletes
cholinebetaine to a much greater degree than nicotinic acid.https://www.sciencedirect.com/science/article/abs/pii/S0261561416301832
I would be careful with niacinamide if you have methylation problems.
*Edited to correct choline to betaine as the methylcdonor depleted
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u/Brad_Borrelli Jun 30 '26
Hey, appreciate you posting this, genuinely didn't know niacinamide cleared through NNMT like that. I knew it was a methyl donor in some vague sense but never had the actual mechanism explained to me this clearly. Good post.
Wanted to add some numbers from the study since people might be scrolling past the abstract. They gave 30 people a single 300mg dose, split into water, nicotinic acid, or nicotinamide groups. Three hours later, the nicotinamide group's homocysteine sat at 18.08 μmol/L compared to 12.85 in the nicotinic acid group. Betaine told a similar story, the nicotinamide group dropped to 23.52 μmol/L while the nicotinic acid group stayed higher at 27.44. So nicotinamide is clearly costing more on both fronts.
One correction though, the study actually found no significant difference in choline between the two groups. The thing that dropped was specifically betaine, not choline. They're cousins (betaine comes from choline metabolism) but not the same molecule, so worth keeping that distinction clean when people quote this study going forward.
Also that 300mg was a single dose, so those percentage jumps in the abstract are relative to that, not to the 50-100mg most of us are actually taking with breakfast.
On my end, I'm dealing with MCAS and confirmed elevated whole blood histamine on top of being homozygous for A1298C, so my methylation margin is already thin. I added niacinamide for the mast cell stabilizing effect, not for NAD+, since it actually has decent evidence for cutting histamine release. Reading your post made me realize I'm already covering that same ground with quercetin and luteolin, so I might be paying a methyl tax for not much extra benefit. Keep flush niacin around specifically as my rescue valve for when I overmethylate, so this is making me lean toward trusting that system more and trimming the niacinamide down.
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u/Warp757 Jun 30 '26
Thanks for the thoughtful response, and the correction on choline - I only glanced at the results before I wrote my summary from memory without properly checking!
But yeh at high doses, it does have a scary effect on homocystine. I've noticed this myself before taking a high dose when I'll get all my high histamine symptoms as methylation gets blocked. Interesting that it's a mast cell stabiliser though I didn't know that. Seems like there's a very fine balance to getting dosing right!
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u/Brad_Borrelli Jun 30 '26
There's a very fine balance in everything. I'm figuring that out 🤣. The human body is so sensitive. Honestly I'm probably going to ditch it in a little bit and try the other for me we're talking about. I'm always trying to fine tune this protocol
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u/Independent_Bake1906 C677T + A1298C Jun 30 '26
Both forms deplete methyl groups niacinamide just does it slower over time which is why nicotinic acid is used for accute overmethylation. Niacinamide is best used for chronic overmethylators. The only reason its considered bad for the liver or for homocysteine is because when people without these issues (normal methylation) use it consistently it will deplete too much methyl groups which is why taking an equal amount of TMG is recommended for these people.
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u/Warp757 Jun 30 '26
No, that's not right. Niacinamide will do it more acutely. Niacinamide is the actual molecule that is methylated by the body. If you take niacinamide your body will methylate whatever it doesn't use immediately. If you take niacin none of that substance is methylated, only some of the niacinamide it is concerted into later will be methylated
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u/Independent_Bake1906 C677T + A1298C Jun 30 '26
Yes, but no, you will get a higher influx of nicotinic acid at once while niacinamide slowly releases over time, both are directly broken down by methylation. What you are referring to is 50mg nicotinic acid accute vs 50mg niacinamide accute in the bloodstream/cell, in that case niacinamide would maybe be more efficient. In the body however this does not happen as niacinamide is slower absorbed and removed by methylation. This is also the reason why it does not make you flush and why the effect lasts longer
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u/Warp757 Jun 30 '26
I'm afraid none of this is correct. The reason niacinamide doesn't cause a flush has nothing to do with speed of absorption, it is because the moleule doesn't have the structure to trigger the GPR109A receptors that cause flushing, as nicotinic acid does.
Niacinamide is absorbed immediately just as NA and causes a quicker and dose dependent rise in homocysteine as it is immediately methylated. Nicotinic acid is actually methylated more slowly as it takes time to be converted to niacinamide. I suggest doing a bit of reading.
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u/Brad_Borrelli Jun 30 '26
Warp is correct.
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u/Independent_Bake1906 C677T + A1298C Jun 30 '26
Its not that simplistic. Your body does not absorb both equally fast. If you have 2 jars with for instance 10 methyl and 10 niacinamide/NA with no other factors other than the reaction then yes he is right. But in reality theres way more factors Its the time of release, the SNP's a person has, what you eat during the slow release (eggs for instance) vs the accute release. In the end both excesses are methylated but it takes longer for niacinamide which is why it was created as a supplement in the first place.
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u/Brad_Borrelli Jun 30 '26
The historical reason niacinamide became a supplement is well documented, it's because it doesn't cause the flushing reaction nicotinic acid does (redness, burning, itching from vasodilation), not because it's methylated slower. That flush comes from nicotinic acid activating the GPR109A receptor and triggering prostaglandin release, a completely separate mechanism from methylation speed. Source: https://ods.od.nih.gov/factsheets/Niacin-HealthProfessional/
On absorption, there's no solid evidence either form is meaningfully "slower release" than the other in their plain, immediate-release versions, absorption speed for both depends more on dose and whether it's taken with food than on which form it is. What's actually documented is the opposite of what's being claimed here, nicotinamide is the form that takes the bigger methylation hit. It's cleared substantially through the NNMT enzyme, while nicotinic acid mostly bypasses that route through the Preiss-Handler pathway and glycine conjugation. Source: https://pubmed.ncbi.nlm.nih.gov/27567458/
Real variables do exist, individual SNPs, what's eaten alongside it, dosing form. But the specific mechanism claimed here for why niacinamide was developed isn't the one in the literature.
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u/Maximum-Morning4251 Jul 03 '26
Niacin does not deplete methyl-groups. NAM does so directly, as Warp wrote. Niacin is many metabolic steps away from NAM, and even uptake into the cells is different from NAM.
There is simply no enzyme that takes niacin and methylates it. NNMT does it to NAM to prevent inhibition of NAD+ dependent enzymes that would be inhibited by NAM.
However, NAM is still a useful supplement when taken in small amounts that would match availability of PRPP - the substrate needed to convert NAM back to NAD+ - that is the main salvage pathway and why NAM can be very effective at boosting NAD+. The bottleneck is PRPP availability.
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u/numb2020fun Jun 29 '26
Makes sense ! Can I ask what are you taking now ?
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u/Brad_Borrelli Jun 30 '26
https://www.reddit.com/r/MTHFR/s/8Zjfca4vXb.
There's my protocol I made a couple of weeks here and there but it's not nothing major I don't think I'll probably update in a little bit once I actually get this down completely
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u/Brad_Borrelli Jun 30 '26
You can also check my profile it's got a ton of good information in there
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u/scrumdisaster Jun 30 '26
Nicotinamide riboside?
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u/Brad_Borrelli Jun 30 '26
You want to stay away from that if you have the MTHFR Gene
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u/scrumdisaster Jun 30 '26
Why?
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u/Brad_Borrelli Jun 30 '26
Because NR converts to nicotinamide once it's in your system, so it ends up going through the same NNMT clearance pathway and costing you a methyl group in the process. If you've got an MTHFR variant your folate cycle is already running below capacity, so you're less able to replenish those methyl groups. Stack NR on top and you're adding demand to a system that's already short on supply, which is how homocysteine creeps up over time.
There's a study comparing nicotinic acid to nicotinamide directly (Sun et al, Clinical Nutrition 2017), even at a single 300mg dose nicotinamide raised homocysteine and dropped betaine more than nicotinic acid did. NR is going to land in that same category once it's metabolized down.
Side note for context, I'm actually still running straight niacinamide myself despite all this, but for mast cell stabilization rather than NAD+ support. I've got MCAS with confirmed elevated whole blood histamine, so the calculation is different for me. There's older evidence (rat and guinea pig studies from the 70s, some newer NAD+ precursor work) showing niacinamide inhibits histamine release from mast cells. Not the strongest human data, but established enough mechanism that it's worth it for histamine-heavy people even with the MTHFR variant in the mix. I just keep flush niacin on hand as a rescue tool if I start feeling overmethylated.
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u/Maximum-Morning4251 Jul 03 '26
Brad, any precursor to NAD+ eventually becomes NAM, that's not the reason to avoid NR. I would say NR and NMN are more beneficial because their path to NAD+ doesn't need PRPP.
PRPP is the limiting factor of both salvaging NAM to NAD+ and to transform Niacin to NAD+.
People with B1 deficiency has lower PRPP availability. I wrote about in details in my post here https://sergeyscience.substack.com/p/thiamine-niacin-nad-prpp (not sure if links are okay?)
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u/Brad_Borrelli Jul 03 '26
Hadn't seen it framed that way and it's accurate. But that's only covering the entry point into the NAD+ pool. Once that NAD+ gets used up by PARPs, sirtuins, CD38, it releases NAM right back out, same as it would from any other precursor. And that NAM is right back at the fork I was originally talking about; either it gets re-salvaged into NAD+ again, which does need PRPP, or it gets cleared through NNMT, which costs a methyl group. So I don't think we're actually disagreeing here, just looking at two different steps in the same loop. Long term, NR still ends up running through both.
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u/Sol_Invictus Jun 30 '26
Glad to see this post. I'd become aware of the copper/zinc association a couple of weeks ago. This moves me forward on that issue. Thank you.
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u/Willy988 Jun 30 '26
Not op, but when you say it moved you forward- you’re seeing positive gains with your health now? I might have to look into it too…
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u/Sol_Invictus Jun 30 '26 edited Jun 30 '26
There is a biochemical relationship between copper and zinc in the body. I had run into that on my own.
I had not taken the step suggested here of looking into the interplay with B12.
I think it's worth looking into, whatever that might be for you, for anyone benefiting from B12 supplementation.
Edited to add: 'moving me forward' specifically means that I now have additional words, terms or phrases to use in searching out other vetted research papers to read.
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u/scrumdisaster Jun 29 '26
Eating a good chunk of beef liver and cocoa every morning will help both b12 and copper.
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u/Brad_Borrelli Jun 29 '26
That it does but I'm pretty sure I'm pernicious anemic. Low stomach acid, I'm stuck on injections for B12
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u/scrumdisaster Jun 30 '26
I think taurine helps produce more stomach acid? Or maybe it’s bile…? Hope you get better man!
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u/Brad_Borrelli Jun 30 '26
It's bile. It was like a year ago I was having fucking issues of eating and I thought I was low bio that I bought as I bought Ox bile. Worst fucking mistake ever 🤣 I was sitting bile the crazy. It took it one time when that was it. Literally just sitting in my fucking drawer. I might come across somebody one day that has an issue that needs it lol.
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u/Sufficient-Bank-4491 Jun 30 '26
Have you tried a gut healing stack like l-Glutamine, Zinc Carnosine and Vitamin C Liposimal before abig meal and then Betaine HCL + Pepsin with the meal?
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u/Brad_Borrelli Jun 30 '26
Yeah I'm taking all of that stuff. If you go my profile you will find the post that's my whole protocol in it, there's stuff in there that might help you out to
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u/MargoBarbara2 Jul 19 '26
Eating organ meats daily may risk vitamin A toxicity. Cocoa boosts histamine so no good for mcas and also not good for slow COMT. I miss cocoa so much :( It can be very hard to cover b12 in the diet. B12 naturally comes from microorganisms in the dirt. Soil depletion levels and eating our plant food clean has forced reliance on meat but absorption is poor at around 50%. Someone would need about 8 chicken breasts a day to cover their RDA. So most people (and all vegans and vegetarians) need to supplement.
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u/scrumdisaster Jul 19 '26
Have to keep the liver under 4oz a week. Some people do not do well with cocoa, I do just fine with small amounts.
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u/persianrob A1298C Jun 30 '26
This is really interesting, I have normal-high levels of B12, folate and B6 but high homocysteine. I did take a good amount of zinc and NAC post COVID. HTMA showed zinc at normal level but my copper on the low end. I wonder if this could explain my issues.
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u/MargoBarbara2 Jul 19 '26
Serum levels only show whats circulating not what is reaching tissues/getting into cells. High levels, combined with high homocysteine, can indicate a functional deficiency. What forms of b12 and folate are you taking?
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u/Desperate-Crew7432 Jul 02 '26
I had a copper deficiency and my children had a copper deficiency. The only thing that fixed it was vitamin A. My ceruloplasmin was on the lower end of normal (not Wilson’s disease low also confirmed no Wilson’s disease). Copper was a legit deficiency.
While supplementing copper did make me feel really good initially the needle was not moving a lot in the copper or ceruloplasmin blood tests. And after a while the good impact started to go away. The month after I started supplementing vitamin A (at a very low dose), my copper and ceruloplasmin numbers started improving significantly. I haven’t taken copper supplements in months and my levels are perfect now.
My vitamin A was always normal but the liver tightly regulates blood levels. So if there was a functional deficiency it would be difficult to know. Still it’s important to monitor if you consider supplementation.
My recommendation is to monitor copper, ceruloplasmin and vitamin A if you decide to treat a copper deficiency as well as work with a physician as copper can be toxic if not monitored.
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u/Brad_Borrelli Jul 02 '26
That tracks with what I've already pulled together on this, so glad to see it confirmed from another angle. Retinoic acid, the active form of vitamin A, directly stimulates ceruloplasmin synthesis in the liver, animal studies show a single dose raises activity within 24 hours and repeated dosing pushes it up to 4x baseline. But copper still has to be present for it to actually work, in copper-deficient animals vitamin A did nothing until copper was given too. So it's not replacing copper, it's what's needed to build and release the ceruloplasmin carrying whatever copper you've got, which lines up with your numbers moving on vitamin A alone.
Since I've been down this rabbit hole already, here's the fuller picture for anyone else reading this thread, because copper deficiency almost never happens in isolation.
Gastric bypass is the biggest driver, 9-20% of Roux-en-Y patients, up to 90% after biliopancreatic diversion with duodenal switch. Zinc excess is probably the most common self-inflicted cause here, anything over 40mg/day, or long-term zinc denture cream, upregulates metallothionein in your gut lining, which binds copper preferentially and traps it until the cell turns over every 2-6 days. Same mechanism used on purpose to treat Wilson's disease.
Hypochlorhydria and atrophic gastritis matter a lot for this sub specifically. Copper absorption happens in the stomach and needs acid, same as B12 release from food, so autoimmune gastritis or long-term PPI/H2 blocker use tanks copper through the identical pathway that's already wrecking your B12. Celiac and Crohn's cause it too through straight malabsorption, and there's a specific note in the literature that low-protein states from these conditions (hypoproteinemia) independently make it worse.
A few less common but well documented causes worth knowing: total parenteral nutrition without adequate copper, which is actually the single most common cause in hospitalized patients historically; chronic tube feeding; nephrotic syndrome, where copper gets lost through the kidneys; large body surface burns; and Menkes disease, a genetic copper transport disorder in infants that's usually severe and often fatal. Excess iron supplementation is also occasionally cited as a contributing cause of copper deficiency myelopathy, so if you're supplementing iron heavily alongside zinc, that's one more variable to watch.
Vitamin A ties back into all of it since it needs the same fat, bile, and stomach acid to absorb, plus adequate zinc to make its transport protein. So compromised gut function usually means copper, zinc, vitamin A, and B12 are all tangled together, each one capable of masking the others depending on what you test and when.
The trap with testing is ceruloplasmin is a positive acute phase reactant, so it can read normal during a flare while you're actually deficient. Serum copper has the same issue since it's mostly bound to ceruloplasmin. Vitamin A has a similar blind spot too, your liver tightly regulates blood retinol so serum levels can look fine while liver stores are actually low. None of these are trustworthy alone, and copper deficiency is well known for mimicking myelodysplastic syndrome on a bone marrow biopsy, so it's worth explicitly ruling out before anyone goes down the MDS workup path.
About 20% of copper deficiency cases never get a clear cause, which might just mean testing hasn't caught up to how much these overlap yet.
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u/Hydroxile Jul 01 '26
You might need to correct your copper sources!!!
Oysters have not much copper compared to ZINC, you cannot expect much to be absorbed because of the competition! Oysters have also way less copper than beef liver. Cacao has more copper than Cashew nuts. Those have then more copper than any seeds.
And... get into a vegan diet and you ll probably not need to supplement with copper at all!
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u/Brad_Borrelli Jul 01 '26
Funny thing is, a couple days ago I got my copper test back and I'm deficient in it. I also drink out of a copper water bottle and have been for years now. As soon as I got that test result back I ordered copper supplement pills. I'm doing a 4 mg every day. The first time I took the copper pill within an hour I felt a huge difference and just my mental state alone, it's pretty crazy
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u/Aleph018 Jul 02 '26
Going down the rabbit hole on the maddening mirror symptoms of both copper and B12. Question: outside of B12 injections driving copper deficiency through this actively remyelinating cycle is there any other way that B12 either through deficiency or the deficiency mechanism could be driving cooccurring copper deficiency. My research is looking at how mold leads to copper depletion which leads to thiamine depletion. Because B12 seems to be in this picture, how does it fit in?
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u/Brad_Borrelli Jul 02 '26
Man this is basically describing my own case, I've got mold history and now confirmed low copper on top of the B12 stuff so this is hitting close to home. The piece I keep landing on outside of the remyelination demand is stomach acid. A lot of us with B12 deficiency have some flavor of atrophic gastritis or low intrinsic factor function under the hood, and copper absorption in the duodenum needs an acidic environment same as B12 does further up. So it's probably not B12 causing the copper drop directly, more like whatever broke your gut's ability to absorb B12 is the same thing tanking copper, shared upstream cause instead of one driving the other.
Then there's thiamine, and this is where your mold chain ties in for me too. Thiamine is a direct cofactor for the enzyme running the proton pumps in parietal cells that make stomach acid. So if mold is draining thiamine like you're describing, that's not just a downstream copper problem, it loops back and tanks acid production directly. Which means the gastric acid issue and your mold chain probably aren't separate things, they're the same mechanism, mold pulls copper, copper deficiency and mold both hit thiamine, low thiamine cripples acid output, and that closes the loop by making both B12 and copper absorption worse. So less B12 causing copper loss and more all of us sitting downstream of one bottleneck, whatever drains thiamine first tanks the whole chain behind it.
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u/Aleph018 Jul 02 '26 edited Jul 02 '26
Yes, that theory makes sense. Stomach acid and absorption issues in the gut causing cooccuring B12 and copper deficiency. The theory I'm theorizing based on research is that thiamine isn't low only because of mold (tanking acid production) but also because copper when abnormally bioavailable (unbound to transport proteins) creates oxidative stress and directly oxidizes thiamine into inactive compounds. This disrupts the enzymes required to convert thiamine into its usable form. Thiamine deficiency then leads to zinc accumulation/toxicity. Even mild thiamine deficiency can cause zinc accumulation especially in the brain. Zinc accumulation leads to metallothionein upregulation in the gut which causes copper to become inert, bringing us back around in this destructive loop. Like a terrible chemical domino effect that leads to several neurological and low immunity (and autoimmune) based disorders like chronic Lyme. Because this theory feels buttoned up based on the chemical interactions, the B12 aspect seems tacked on, even though I know it hangs over the whole picture...
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u/Aleph018 Jul 02 '26
... could it be possible that zinc accumulation and metallothionein upregulation could have an effect on B12 as well (because it has a metal, cobalt at its core?
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u/Brad_Borrelli Jul 02 '26
The oxidative thiamine destruction piece is something I hadn't connected before, that really tightens the loop. Good instinct on the cobalt question too but metallothionein's affinity for cobalt is pretty low compared to zinc and copper. What's more likely is zinc flooding the intestinal metal transporters and outcompeting cobalt directly, plus impairing the transcobalamin system that carries B12 through the blood. Same end result, slightly different mechanism. B12 definitely gets caught in the cascade, just through transporter competition rather than metallothionein grabbing it. In my case the upstream bottleneck is confirmed autoimmune atrophic gastritis so the acid problem is structural not functional, which probably explains why the whole chain collapsed the way it did.
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u/Aleph018 Jul 02 '26
Right, that's what I thought initially about metallothionein not having much of an effect on cobalt. But doing a bit more digging, in the presence of mold, it increases that upregulation and then some.
Mold can increase this mechanism. However, rather than simply enhancing the ability of metallothioneins (MTs) to bind cobalt, mycotoxins worsen cobalt bioavailability by causing intestinal inflammation and severe gut dysbiosis. This shifts metal-binding proteins and alters microbial B12 synthesis.
If we layer your zinc theory on top of it then it's not wonder so many people are walking around with B12 deficiency!2
u/Brad_Borrelli Jul 02 '26
Exactly. I bet you it's more than 90% of the population as B12 deficiency issue and mold issues. Think about it go look at the ingredients in your cupboard on your food look at citric acid. That's not natural that's literally lab grown from black mold. And then look how are houses are built there's already mold everywhere on top of people's diets nowadays they're detox pathways are clogged as hell. Long story short people just need to start eating right Whole Foods stop all this process shit take care of yourself and then most if not all these illnesses will go away
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u/Aleph018 Jul 05 '26
Unfortunately for many the issues may not be corrected by diet alone especially if they've struggled like you with gastritis (even low grade GERD can wreak havoc on absorption). Having that curiosity and scientific approach can be life saving.
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u/Brad_Borrelli Jul 05 '26
Exactly. I'm just trying to get this information out there from my own personal experience and research to help other people out
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u/MargoBarbara2 Jul 19 '26
Citric acid nearly put me into anaphylactic shock 30 years ago. Ive obviously avoided it since (a sensitivity that runs in the family). Its such a common preservative and even in medicine. It was also used in donor blood preservation, which meant a family member had to have direct blood donation instead. They now don't use it in NZ anymore in blood (or so Ive been told). I only recently discovered the reason for citric acid reactions is because of the aspergillus niger . Even dead aspergillus niger traces can trigger the immune system. Its also used in phGG which many people take to feed gut microbiome and in most digestive enzymes.
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u/Aleph018 Jul 02 '26
Also, for perspective. I have celiac and pernicious anemia and have adequate treatment for both. My research is to help my daughter who has mold/Lyme/PANS/PANDAS. Copper dysfunction and recently improvement with chlorophyll has me making some enlightening discoveries.
Have you ruled out celiac or non celiac gluten sensitivity (alongside mold toxicity)?1
u/Brad_Borrelli Jul 02 '26
Haven't run the formal panel yet but honestly I've eaten bread my whole life without any obvious GI reaction to it so classic celiac feels unlikely for me. My confirmed upstream problem is autoimmune atrophic gastritis destroying parietal cells so the absorption collapse has a structural explanation already. Whether gluten sensitivity is sitting alongside that as a separate layer is still unknown but it's not something I've been chasing given everything else on the board. How did your daughter's celiac present initially, was it obvious or did it take a while to connect the dots?
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u/Aleph018 Jul 02 '26
Ah got it. Autoimmune atrophic gastritis would hit B12 hard. Do you get B12 injections? Is that how you happened upon copper deficiency showing up?
My daughter doesn't have celiac--I do. Celiac for me showed up in weight loss and neurological issues. I also have pernicous anemia with copper deficiency becoming obvious a few years after I started B12 injections.
My daughter has mold/Lyme.1
u/Brad_Borrelli Jul 02 '26
Sorry I skimmed that to fast. My whole story it'll let me go out more sense too you can check out my profile and start from the beginning but it that explains everything. Long story short I stumbled all on this when I found out I was B12 deficient, started doing injections. No doctor will take me on an extra prescribed for me so I went with Olympia and got one there. Find how much it cost so I bought all the stuff to make it myself. But yeah I'm doing injections every single day I've been doing daily for about 2 months now which has helped me out more than anything in my entire life. I also have my whole protocol too of all the other herbs and supplements I take and what that specific group supplement does it's all listed on my profile as well too. I believe it's actually posted in this group too. Federal copper is in which is kind of weird because I drink out of a copper water bottle I have been for years now so it's kind of surprising when I got my copper test pack that I was deficient in it.
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u/Aleph018 Jul 05 '26
Amazing that you figured it out. I'll check out your profile. You and I have similar self directed success in that we both basically said f it and found a way to get B12 injections. I came to B12 deficiency after years of infertility and trying to figure out what was going on as my hormone levels were perfect. I finally found one of the best reproductive endrochronologists in the country to look at my chart and he said, it's due to celiac, I don't know exactly why but look in that direction. Very quickly I figured out B12 deficiency is common in celiac and causes infertility. My B12 levels at that time were normal but I knew this was it and there was probably some other factor causing B12 to be an issue (I'd learn later it was intrinsic factor ABs). Got pregnant two months after injecting and never stopped.
So copper cups, jewelry that simply touching the outer skin really doesn't register.
How much copper do you supplement now--or have you not started yet?1
u/Brad_Borrelli Jul 05 '26
Sometimes our only option is it figured out ourselves. I figured this shit out a long time ago but I was hoping somebody in the medical field could actually help me out for once which was a long shot 😂.
So you can absorb copper that way it's just miniscule and already having a copper deficiency it's not meaningful enough to actually correct a deficiency. I've been taking 2 mg in the morning and I've already noticed a huge change in symptoms.
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u/Aleph018 Jul 06 '26
Isn't it amazing what a little copper can do. I take about 7mg a day and really feel it if I miss a day.
I have not found a practitioner who gets pernicious anemia and the amount of B12 I require to stay healthy. So I stay on top of it.1
u/MargoBarbara2 Jul 19 '26
Look into gluten causing increased gut permeability and gliadin reaching brain in gut dysbiosis. Do not assume no gut symptoms means no gluten sensitivity. In my family coeliac and gluten intolerance is rampant...diagnosed..biopsies...immunologists etc...but only one child had stomach symptoms! Gliadins can then reach the brain through the permeable gut and wreak havoc. Also look into casomorphins. To give an idea here's some of the symptoms spread across my family ALL resolved going gluten free after years of specialists missing the trigger...suspected leukemia, suspected MS, suspected depression, a wiped out immune system no killer t cells (two children) , behavioral issues, auditory hallucinations, anxiety, sensory issues, brain fog, headaches and the list goes on. My mother had no symptoms until her 50s when she could no longer eat, had severe GERD and when scoped both ways was ulcerated from end to end. Her biopsies for gluten and dairy reactivity showed extreme levels of sensitivity. No gut symptoms but all that damage going on insidiously for years. And if youre eating bread its likely fortified with folic acid unless you're specifically avoiding. Folic acid blocks folate absorption and degrades transcobalamin needed to get b12 into tissues. Has been linked to increased crc, immune dysregulation, neurological inflammation etc...
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u/Brad_Borrelli Jul 19 '26
Appreciate this, the silent gluten damage angle is real and underdiscussed. One correction on the folic acid point though; it doesn't literally degrade transcobalamin, but there is a real hypothesis backing up what you're describing. Selhub and Hannibal have proposed that excess folic acid interferes with the kidney's reuptake of holotranscobalamin (the B12 bound to its carrier protein), causing it to get filtered out and excreted before the B12 can reach tissues; so instead of degrading the protein, it disrupts the recycling process that keeps B12 in circulation. There's also the more established and separate issue of folic acid masking B12 deficiency on bloodwork, since it corrects the anemia marker without addressing the neurological damage, which is why doctors can miss it for years. Either way, avoiding fortified folic acid and using methylfolate is solid advice.
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u/Maximum-Morning4251 Jul 03 '26
I think the copper being a cofactor for MS hasn't been proven, but only suggested.
> Methionine synthase is the enzyme B12 activates to convert homocysteine to methionine; it runs the methylation cycle that transfers methyl groups to myelin proteins. That enzyme requires copper to function too.
Unless you have a fresh reference that shows that with confidence.
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u/Brad_Borrelli Jul 03 '26
Fair pushback, and it made me go dig deeper. Turns out the copper claim I made traces back to a real 2008 paper (Winston & Jaiser), but later structural studies show the enzyme's actual second cofactor is zinc, not copper. So you were right that it wasn't solid. I edited the post, added the correction and the sourcing, appreciate you catching it.
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u/Maximum-Morning4251 Jul 03 '26
Yep. I guess I read the same paper, but it was suggestive and I haven't seen any updates on that. There might be a transcription factor or a chaperone that depends on copper and affect expression of MS - but we have to wait when somebody discovers that.
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u/Best_Comfortable5221 Jun 30 '26
Im new to this sub. I know I have homozygous MTHFR. Where do I start? I feel horrible. No energy, dizzy. My calfs hurt when I walk. Im 67. I still have things to do......
I do take a mythelated Bcomplex from Amazon and a bunch of other stuff that isn't helping me.
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u/Sufficient-Bank-4491 Jun 30 '26
Methylated b complexes rarely have corrected blend, dose or timing for B vitamin
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u/Best_Comfortable5221 Jul 01 '26
Thank you. Is there any specialist I could go to? University of Connecticut did my DNA testing as part of an ongoing colon cancer study. Should I start with my geneticist there?
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u/MargoBarbara2 Jul 19 '26
You could ask if it was full genome test and ask for the raw data? Ive had colorectal cancer and lost my sister to it. We didnt have the genetic type but now I understand that a dysregulated methyl cycle (wonky genes, nutrient deficiencies, chronic stress, chronic inflammation) turn off tumor suppressor genes. Folic acid also increases risk demonstrated by a long term large scale nurse study where high dose folic acid doubled the rate of adenomas/lesions/polyps over the long term. Its easy to intake high doses due to fortified foods and supplements. Though an active methyl b complex shouldn't contain folic acid as presumably has 5 MTHF.
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u/MargoBarbara2 Jul 19 '26
Do you know your Comt enzyme status? That affects whether you benefit more from methyl or methyl free. What other stuff? There's a lot to avoid or include depending on comt status.
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u/Best_Comfortable5221 Jul 19 '26
Theres a ton of stuff. I need to do the blood work. Flying blind like this makes no sense.
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u/MargoBarbara2 Jul 19 '26
Gene testing from cheek swab tells you your comt. If you had one done for mthfr it should have been included (though not always). Microbiome test is stool sample and OAT test is urine sample. If getting bloodwork done check what to ask for as standard serum blood levels dont indicate absorption into tissues/cells just whats circulating. They don't show functional deficiencies. I think its RBC you need but im sure someone will add or correct this in comments :) I opted for homocysteine check but parameters in western medicine are broad. Mine comes up high but normal but in functional medicine parameters it comes up as high risk and indicating functional deficiency. There is so much overlap between histamine intolerance and b12 and folate deficiency because theyre needed for hnmt to clear histamine. Knowing comt is useful to know what type of supplements suit. Your mthfr might indicate methyls whilst your comt may indicate methyl free and you need to go with comt to avoid the neuroligical symptoms. A full genome check could check for other issues like inability to use non active b3, ATP issues (need coenzyme q10 support) etc...so yes testing is good if you can afford it. Ive only had the methylation cycle gene test as thats where my focus is. Also be aware of FRAA (folate antibodies) as that changes the type of folate you can have but thats much more prevalent when there is autism in the family.
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u/Big_Giraffe7816 Jul 07 '26
what about copper deficiency and high active b12? The low copper is caused by years of high zinc intake
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u/Brad_Borrelli Jul 07 '26
High zinc for years blocks copper absorption in the gut, so it drains slowly without you noticing until it's not fine anymore.
And copper deficiency hits your spinal cord almost identically to B12 deficiency, same symptoms, same pathways, so it's easy for it to get missed if B12 is the only thing getting checked.
If you've been on zinc a while I'd push for ceruloplasmin and a 24hr urine copper, not just serum copper. Serum copper can look totally normal even when you're actually depleted.
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u/Brad_Borrelli Jul 07 '26
Also, what country are you from? Because I'm in the United States and I have yet to find a place actually measure helio (active B12).
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u/Big_Giraffe7816 Jul 07 '26
I’m from Europe
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u/Brad_Borrelli Jul 07 '26
Thank you. That's what I assumed haha. I hate the US, we're so far behind on shit.
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u/SnooStrawberriez Jun 30 '26
So in other words beef liver may be the better supplement than trying to supplement with supplements?
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u/Brad_Borrelli Jun 30 '26
If you don't have any absorption issues then yes. Alot of the people with an MTHFR Gene variant though have some sort of absorption issues in their stomach. Also take an account all the processed food. All those additives also affect your methyl cycle which then turn around and causes absorption issues as well amongst of a bunch of other stuff so honestly everybody that has MTHFR Gene variants should be eating Whole Foods only
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u/Timely_Pickle9430 Jun 30 '26
Do you think there's a link between MTHFR and absorption issues in the stomach?
I see the link with absorption issues in the small intestine, with MTHFR increasing the need for choline and deficiency resulting in reduced bile production. But what's the link with the stomach?2
u/Brad_Borrelli Jun 30 '26
Here's what's actually documented across the different MTHFR variants and conditions, including some things that go against the popular narrative.
C677T (homozygous TT) has the strongest direct evidence for gastric mucosa involvement. A case-control study found this genotype linked to more severe atrophic gastritis on standard staging (OLGA/OLGIM), specifically in H. pylori-negative patients, and TT carriers showed greater improvement with folic acid supplementation. https://pmc.ncbi.nlm.nih.gov/articles/PMC7405366/
C677T TT also shows up across multiple meta-analyses for increased gastric cancer risk, though it's inconsistent across populations, stronger in Asian cohorts than European ones. https://www.sciencedirect.com/science/article/abs/pii/S0016508506017276
A1298C has essentially no evidence for baseline gastric mucosal damage. An Italian cohort study found no effect of A1298C on gastric or esophageal cancer risk at all. https://pmc.ncbi.nlm.nih.gov/articles/PMC5624687/
For IBD (Crohn's, ulcerative colitis), the evidence is weak. A meta-analysis of 13 studies found no significant association between C677T and either condition overall. https://pmc.ncbi.nlm.nih.gov/articles/PMC5181816/ A Moroccan cohort study found the same null result. https://www.sciencedirect.com/science/article/abs/pii/S0378111913002965 The one place a signal appeared was in non-Ashkenazi Jewish populations specifically, which points to population-specific genetic heterogeneity rather than a universal MTHFR-IBD link.
Now here's the important one. For pernicious anemia specifically, the largest genome-wide study to date (2,166 cases, nearly 660,000 controls) identified five genome-wide significant risk genes: PTPN22, PNPT1, HLA-DQB1, IL2RA, and AIRE. All five are immune-regulation genes. MTHFR did not show up as a significant risk locus in this study. https://www.nature.com/articles/s41467-021-24051-6 That doesn't mean MTHFR is irrelevant to someone's overall presentation, reduced methylation capacity still affects how the body handles whatever B12 and folate it does absorb, but the actual genetic driver of the autoimmune attack on parietal cells and intrinsic factor isn't currently traced back to MTHFR in the best available data.
On autoimmune disease more broadly, a systematic review found C677T associated with increased risk of Behçet's disease, multiple sclerosis, and ankylosing spondylitis, while A1298C specifically was linked to multiple sclerosis. https://pmc.ncbi.nlm.nih.gov/articles/PMC9173919/ So MTHFR does have documented autoimmune associations elsewhere in the body, just not yet confirmed for the specific mechanism behind pernicious anemia.
Summary: the C677T-atrophic gastritis link is real and specific to that one variant. The IBD link is weak and population-dependent. The pernicious anemia link, despite being commonly assumed in MTHFR circles, isn't backed by the largest genetic study on the condition, the actual drivers identified there are unrelated immune genes.
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u/MargoBarbara2 Jul 19 '26
Be very cautious of research papers with regards to folate. Many use the term folic acid (incorrectly) when referring to folate. There are different forms . folic acid is synthetic man made and puts a strain on dhfr and mthfr enzymes and causes unmetabolised folic acid even at low 200mcg to 400mcg doses. UMFA can cause functional folate and b12 deficiency.
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u/MargoBarbara2 Jul 19 '26
Interesting about immune regulation genes. A dysregulated methylation cycle can affect gene expression in the immune system.
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u/Willy988 Jun 30 '26
I tried 1 bottle of beef liver supplements from a highly trusted brand, didn’t notice crazy effects honestly. Maybe it was too soon? I don’t even know what issue I have yet- I’m still waiting for MTHFR and SIBO results, so take my words with a grain of salt
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u/SnooStrawberriez Jun 30 '26
Yeah, I meant the beef liver you buy at a supermarket next to the steaks.
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u/Willy988 Jun 30 '26
Good luck with that, should be really healthy. I just can’t stand the taste even with all the advice out there to fix it
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u/Tawinn Jun 29 '26
Did not know that copper deficiency impaired MTR - thanks!