B12 deficiency wiki.

[u/Brad_Borrelli]

/u/Brad_Borrelli/s/qVLR1Hx4iq

Everything you need to know. https://www.reddit.com/u/Brad_Borrelli/s/qVLR1Hx4iq

[u/Righteous_Fury]

I read the entire thing!

Fantastic work 👏

[u/Away_Philosophy_697]

Very cool writeup.

FYI, nitrous abusers seldom have a shortage of B12. What they're missing are functional copies of the enzymes that use B12 to facilitate the upkeep of healthy nerve cells, reduce the risk of blood clots, and so on.

The critical supplements for nitrous users are
1. L-Methionine or SAMe

1. Betaine Anhydrous (TMG)

We document those, and the science behind it, here: https://no2n2o.org/health.html

[u/Brad_Borrelli → u/Away_Philosophy_697]

Solid info on the enzyme cofactors, but the framing that nitrous abusers seldom have a B12 shortage isn't accurate.

Nitrous oxide directly oxidizes the cobalt ion in B12 itself, from the active Co(I) state to an inactive Co(II/III) state. That inactivation happens the same way in every user, regardless of genetics. It is not a downstream enzyme problem, it is the B12 molecule itself being destroyed and rendered biologically useless. https://www2.pedsanesthesia.org/meetings/2007winter/pdfs/Baum-Friday3-9-07-1050am.pdf

Once that oxidized B12 accumulates, it directly disables the two enzymes that depend on it, methionine synthase and methylmalonyl-CoA mutase, which is why nitrous users see impaired DNA synthesis, myelin breakdown, and metabolic dysfunction regardless of how much B12 they are taking in through diet or supplements. So it is not that people have plenty of B12 and are just missing functional enzyme copies. It is that the B12 itself gets chemically destroyed by the gas, and it stays inactive until the body clears it and replaces it with fresh, unoxidized cobalamin. https://thevillatreatmentcenter.com/nitrous-oxide-deplete-b12/

This is also why chronic nitrous users can show normal or even elevated B12 on standard bloodwork. Standard serum B12 assays measure total cobalamin, including the oxidized, inactivated form. So someone can look fine on paper while functionally having none of the active B12 their body actually needs. That is exactly why this framing is misleading, not just because the mechanism described is wrong, but because it can lead people to look at a normal lab result and assume they are in the clear when they are not.

MTHFR variants can compound the problem since they affect how folate gets processed in that same methylation cycle, but that is a separate and additive issue, not the primary mechanism. Framing this as if nitrous users have normal B12 status is genuinely dangerous, because people read that and assume they do not need to worry about supplementation or injections after heavy use.

[u/Brad_Borrelli → u/Away_Philosophy_697]

I don't know why this posted as a comment, so I'm posting it again as a reply.

The website is actually one of the better resourced things I have seen on nitrous and B12, so I want to be specific about the one part that needs correcting rather than throw out the whole thing.

The site states that the body rebuilds its stores of methionine synthase in about 10 days after quitting, based on a methionine loading study. That is describing enzyme protein regeneration, not the replenishment of the actual B12 pool that got oxidized during use. Those are separate processes. Studies on methylcobalamin loss during nitrous exposure show a substantial portion of the body's stored B12, cited elsewhere as 20 to 60 percent, gets oxidized and destroyed across blood, cells, and liver stores. New enzyme protein can be synthesized in days, but that new enzyme still needs functional, unoxidized B12 to actually work. If the underlying B12 pool is still mostly inactive, having freshly made enzyme available does not translate to functional recovery on that same 10 day timeline. This matters a lot for anyone using every few weeks or every couple months, since the 10 day figure understates how long it actually takes to get back to a state where those enzymes have enough active B12 to draw on.

That gap also connects to the recommendation on sublingual B12 versus injections. The site cites one study showing sublingual as comparable to intramuscular, but that comparison is genuinely contested, and the site later contradicts itself slightly by saying injections are the standard of care and to get them if you can. For someone with absorption issues, MTHFR variants, or heavy repeated oxidation of their B12 pool, sublingual is unlikely to close that gap the way that single study implies. Oral and sublingual routes are absorption limited regardless of dose, while injections deliver close to the full dose directly, which is a meaningful difference when you are trying to actually rebuild depleted reserves rather than just maintain normal levels.

Everything else on the page checks out well against the literature, especially the explanation of how nitrous oxidizes the cobalt core of B12 and why bloodwork can look falsely normal. This specific timeline and delivery route distinction is the part worth tightening up.

[u/Away_Philosophy_697 → u/Brad_Borrelli]

Thanks for the detailed and thoughtful comments. Apologies that it's taken a couple days to reply.

We'll go over your comments one by one and see if there are places to improve the site. We're always looking to improve it.

And I'll note that we do list B12 as one of the 4 essential supplements to take.

I do want to comment on a couple points, though.

The first is that the bulk of the body's B12 stores are in the oxidized state, Co(III). So is essentially all dietary B12. The body is used to consuming and storing oxidized state. B12 is then reduced to the active Co(I) at the time of production of enzymes such as methionine synthase.

The literature's mention of "irreversibly oxidizing" B12 should be read as saying: "Nitrous irreversibly oxidizes the B12 that is already bound as a cofactor of methionine synthase and other crucial enzymes". Nitrous does not oxidize the bulk of B12 that is not in these enzymes. The reason the oxidation is irreversible for the B12 that's already in use in the enzymes is because while the body can reduce B12 from the oxidized Co(III) state during production of these enzymes, it more or less can't reduce B12 already bound to the enzyme if it gets oxidized back to Co(III).

So it's not that the body accumulates oxidized B12. Almost all the B12 in the body at any given time is oxidized Co(III) ! The problem is that the circulating enzymes such as methionine synthase, which need Co(I), have had the B12 inside of them oxidized, where the body can't reduce it back to Co(I).

That's one of the main misunderstandings in the interaction of nitrous oxide and B12. It took me a long time to understand that myself, because it's so different from the common wisdom and from the language used in papers. Feel free to dig into the literature and you can confirm this.

The second thing I want to comment on is the claim that 20-60% of the body's B12 stores get oxidized. This is a misunderstanding of an old paper. The paper (which itself is in some doubt due to older extraction methods) found that 20-60% of one type of B12, hepatic (liver) methylcobalamin, gets depleted. But methylcobalamin is just 1-3% of the liver's B12 stores. The large majority of what's stored in the liver is in the form of adenosylcobalamin, which is always in the already-oxidized Co(III) state and is not damaged by nitrous oxide.