B12 supplementation

Why you might want high plasma levels if you need to supplement

My vet tech friend said whenever cats come in to the clinic, they are tested for B12, and most of them are deficient. So they get a B12 injection.

When I had serious fatigue 30 years ago, the first thing my semi-holistic Dr. did was give me IM B12 and magnesium, and some to take home and give myself.

My friend tested positive for pernicious anemia, but had high serum levels, so what’s up with that? Apparently the active form of B12, holotranscobalamin, is assembled inside the intestinal mucosal cells when the B12 is absorbed along with intrinsic factor in the natural way. If you jack up your blood levels with supplements, or with injections, it is converted to the active form at a much lower rate. So you need higher plasma levels for it to be effective.

Again, you really need to test MMA (good) and homocysteine (bad) to find out if your B12 is doing the job. Or, just go with a high dose and don’t worry about high levels. (Smart commenters welcome here…)

I confess I cheated on this assignment and asked Chatgpt. Here is what it said (all the rest of this article is from chatgpt, but I can’t figure out the formatting here) :

Great follow-up — holotranscobalamin (holoTC) can enter the plasma through two main pathways, only one of which is dependent on intrinsic factor. Here's a breakdown:

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1. Intrinsic Factor–Dependent Absorption (Primary Route)

• As we've discussed, this is the normal physiological route:

  • B12 binds to intrinsic factor (IF) in the small intestine.

  • The complex is absorbed in the terminal ileum via receptor-mediated endocytosis.

  • Inside the enterocyte, B12 binds to transcobalamin II (TCII), forming holotranscobalamin, which is released into the blood.

• This is the major route for getting holotranscobalamin into plasma in healthy people.

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2. Passive (Non–IF–Dependent) Diffusion — Supplemental B12

• At pharmacologic doses (oral doses ≥1,000 mcg), a small amount (about 1–2%) of B12 can be absorbed via passive diffusion, even without intrinsic factor.

• This absorption occurs along the entire intestine, not just the ileum, and does not require IF or receptors.

• Some of this B12 will still enter enterocytes and bind to TCII, forming holotranscobalamin.

Clinical relevance:

• This is why high-dose oral B12 therapy (e.g., 1,000–2,000 mcg/day) can still be effective for treating pernicious anemia, even though IF is absent.

• Some of that passively absorbed B12 will form holoTC and become bioavailable.

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3. Intramuscular (IM) or Subcutaneous B12 Injections

• In this case, B12 bypasses the gut entirely and enters the bloodstream directly.

• Once in circulation, some of the injected B12 will bind to TCII, forming holotranscobalamin.

• The rest will bind to haptocorrin (inactive) or be stored in the liver.

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Summary — How Holotranscobalamin Can Enter Plasma:

RouteRequires Intrinsic Factor?Efficient?Produces HoloTC?Normal dietary absorptionYesYesYesPassive diffusionNoLowSomeB12 injectionsNoHighYes

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Bottom Line:

You can get holotranscobalamin into plasma without intrinsic factor, but it typically requires:

• High-dose oral supplements (to leverage passive diffusion)

• Parenteral B12 injections (IM or subcutaneous)

Both approaches are commonly used to treat pernicious anemia and restore functional B12 levels, including holoTC.

Let me know if you'd like dosing examples or guidelines.

Excellent question — sublingual B12 lozenges (and other forms that dissolve in the mouth) offer a third alternative route for absorbing B12 without requiring intrinsic factor, and they can also lead to the production of holotranscobalamin in plasma.

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How Sublingual B12 Works:

• Absorption occurs through the mucous membranes of the mouth — primarily the sublingual (under the tongue) and buccal (cheek) areas.

• These membranes allow direct absorption into the bloodstream, bypassing:

  • The stomach

  • Intrinsic factor

  • Intestinal absorption

Once B12 is absorbed into the blood this way, it can bind to transcobalamin II in the same way as B12 from food or injections, forming holotranscobalamin.

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Does It Work?

• Yes, for many people, sublingual B12 can be effective, especially in high doses (e.g., 500–2,000 mcg).

• Studies suggest sublingual B12 is roughly as effective as oral B12, especially in people with absorption problems like pernicious anemia or atrophic gastritis.

• However, the majority of B12 may still be swallowed, so some absorption will still occur through passive diffusion in the gut, similar to high-dose oral pills.

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Advantages:

• Bypasses the need for intrinsic factor

• Non-invasive (unlike injections)

• Convenient for long-term therapy

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Limitations:

• Effectiveness varies based on formulation, time in contact with mucosa, and individual physiology

• Only a small amount is absorbed directly via mucosa; most still relies on passive gut diffusion, unless held under the tongue for a long time

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Bottom Line:

Sublingual B12 lozenges can raise holotranscobalamin levels and are a useful option for people with pernicious anemia or other causes of malabsorption. While they don't rely on intrinsic factor, their effectiveness depends on dose, form, and patient compliance.