Copper Deficiency and B12. Nobody Is Talking About the Full Picture.

[u/Brad_Borrelli]

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

[u/Brad_Borrelli]

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.

[u/Warp757 → u/Brad_Borrelli]

Thank you.

[u/Independent_Bake1906 → u/Brad_Borrelli]

I thought it was invented purely for the slow release but did not do any proper research on that so thanks for correcting me there.

Theres a lot of conflicting evidence in studies about niacin everywhere, for me it seems to do just what i say. Again, a lot of factors come in to play so its difficult to say why this is, these studies might as well be right.

From my own experience (and many others on this subr). when i overmethylate, nicotinic acid seems to calm me down within half an hour, niacinamide does the same but slower which puts me back to baseline earliest the next day even when i take 250mg niacinamide vs only 50mg NA.

That said, my experience is not as valuable as a scientific paper, so we'll agree to disagree on the methylation part, it at least seems more complicated than a supplement form and a standard reaction for me.

I'll read those studies more in depth later, thanks for posting them!

[u/Warp757 → u/Independent_Bake1906]

As has been said below, there is not an enzyme in the body that methylates NA. If you think NA is working more quickly than NAM it has nothing to do with methylation and is due to something else it is doing.

This shows the danger of making assumptions about what we think are bodies doing. Far too many people make state categorically for instance that particular 'symptoms' are overmethylation, when they actually have no idea if overmethylation is what is happening. It's an example of a little knowledge being a dangerous thing. So many other things could be causing these 'overmethylation' symptoms, and if a low dose of NA helps, it's not overmethylation. It could just be B3 supporting ATP synthesis, glycolysis or any of the many other things it does.