Vitamin B12: You Should Probably Be Injecting Hydroxocobalamin

Vitamin B12 (cobalamin) is an interesting one, because many people (including doctors, and including me until recently!) don’t know much about it.

Let’s take a look, and let me explain why you might want to be injecting hydroxocobalamin. But let’s not get ahead of ourselves!

Before we get started: What the hell is Vitamin B12? Well, the most severe kind of deficiency of B12 leads to a blood disorder called “pernicious anemia” which is characterized by your red blood cells becoming abnormally large. But that’s probably the least of your problems, as you might subsequently be affected by “fatigue, decreased ability to think, lightheadedness, shortness of breath, frequent infections, poor appetite, numbness in the hands and feet, depression, memory loss, confusion, difficulty walking, blurred vision, irreversible nerve damage, and many others” (Wikipedia).

So far, so bad. But the good news is that this is somewhat easy to diagnose for physicians as pernicious anemia is easy to spot in a blood lab.

However, it gets more interesting when you move from huge B12 deficiency (pernicious anemia) to slight B12 deficiency. This is apparently really tricky to diagnose. How tricky? Let’s see!

In this super interesting paper, Bruce Wolfenbuttel and his colleagues describe some of their case reports of patients with B12 deficiencies. It’s a great read, almost like a thriller! Based on those case reports, they clear up some common misconceptions about B12. Here’s the TLDR, check this out. I went ahead and summarized them and translated them to Easy Human English for you:

• Vegetarians and vegans are often deficient.
• Even if you have a normal B12 value in your blood lab, you could be deficient.
• There are other lab values you can check which are related to B12 deficiency: Methylmalonic acid (MMA) and homocysteine.
  But even if those are normal, you could still be deficient.
• Some guidelines suggest to supplement B12 orally (= dropping a liquid in your mouth). However, the evidence for this actually working out is not very strong. The only proven way with good evidence is via intramuscular injection.
• When injecting B12, hydroxocobalamin is better than cyanocobalamin.

Now, if you read those bullet points and know nothing about B12, you might shrug and say “so what’s so crazy about all of this?”. Let me tell you, because here’s how most doctors (at least here in Germany) would typically treat you:

• You’re a vegetarian dude oder dudess and go to a doctor.
• You complain about fatigue.
• The doctor won’t even think about B12 deficiency and tells you to get a good night’s sleep, reduce your stress at work and go home.

End of doctor’s visit. You both just wasted your time and your problem remains unsolved. So now you see my point that doctors don’t know much about B12.

Let’s try that again. Let’s assume you point your doctor towards B12 deficiency:

• You’re a vegetarian dude oder dudess and go to a doctor and complain about fatigue.
• You mention B12 deficiency as possible cause. Reluctantly, the doctor might order a lab test.
• The lab test comes back normal, at the lower end of the normal range.
• The doctor tells you it’s not B12 deficiency and tells you to get a good night’s sleep, reduce your stress at work and go home.

End of doctor’s visit. Still a terrible outcome!

We just learned that a normal B12 lab value can still mean you’re deficient (= it’s essentially useless). But people don’t know this, because they didn’t read the paper from 2019 linked above by Mr. Wolfenbuttel.

Okay, let’s try again. This time, you insist that your doctor treats you for B12 deficiency.

• You’re a vegetarian dude oder dudess and go to a doctor and complain about fatigue.
• You mention B12 deficiency as possible cause. Reluctantly, the doctor might order a lab test.
• The lab test comes back normal, at the lower end of the normal range.
• The doctor tells you it’s not B12 deficiency and tells you to get a good night’s sleep, reduce your stress at work and go home.
• You insist on treatment.
• The doctor says it’s not necessary.
• You insist again.
• The doctor reluctantly injects you once with cyanocobalamin, with the main goal of you finally leaving his doctor’s office.
• For the future, the doctor tells you to supplement B12 orally.

End of doctor’s visit. And this is still a terrible outcome, because as we’ll see below, one injection of cyanocobalamin is close to nothing, and oral supplementation doesn’t have great evidence and might not work.

So even if you convince your doctor to treat you (thats a big if!), you end up getting screwed, because the only actual great treatment is intramuscular injections with hydroxocobalamin, but hardly anyone knows this.

Okay. Let’s backtrack a bit here, shall we?

Let’s Backtrack A Bit

Why Does Oral B12 Supplementation Suck?

First off, why do oral supplementations don’t have great evidence? That’s because the way your body absorbs B12 is somewhat complicated: First, you need to ingest adequate levels of B12. That typically only happens when you ingest animal products, so vegetarians and vegans are already at risk of being deficient here.

Once the B12-containing-animal-product enters you mouth, a complicated dance of various proteins and locations leads to its absorption. I’ll skip that for simplicity here, check out the Wikipedia article. Suffice to say, a lot of moving parts have to work properly, so there’s a lot which can go wrong here: If you have any sort of bowel “situation” (irritable bowel disease, Crohn’s disease, malabsorption, etc.), that might already be enough. Also, there are more rare diseases like atrophic gastritis with similar effects.

So.. it’s somewhat “easy” to be in a situation where you’re deficient because your absorption is not working properly. This review ($) by Ralph Green et al. estimates that between 2.5% and 26% of the general population might be deficient. Umm, regardless of what the actual number is (it’s a large range), that’s pretty huge!

Now! Back to the question why oral supplementations might not work well. When you inject B12, you typically inject 1mg of it. And pretty much all of that ends up in your blood stream, and the (hugely) limiting factor now is that your body can only absorb a tiny amount of it at once. But you’re still in a good situation here because you’ve “saturated” your body for a while and now it’s busy absorbing it. Cool.

Okay. What’s the typical dose of oral supplementation? It’s also 1mg. Now this is pretty crazy because of the following facts: If the “intricate protein absorption dance” mentioned above works well in your body, then you can likely absorb a significant chunk of that. Then you’re in a good situation. But wait.. then you wouldn’t be B12-deficient in the first place, right? So if you’re B12-deficient, there’s a fair chance you’re not absorbing B12 well orally, and the solution is.. to supplement orally? Even though that doesn’t work? Wait, what?

There’s a saving grace here: There’s another mechanism of absorbing B12 which is referred to as “passive diffusion”. It’s as simple as it sounds: Because you throw a huge chunk of B12 (well, technically, a few drops of liquid) in your body, some amount of it simply diffuses through your stomach linings etc. and ends up in your blood. However! It is estimated that this only amounts to an absorption of around 1% of what you ingested. A tiny amount. Crazy!

So, worst case, you’re only absorbing 1% of your oral supplementation – while consuming the same dose as when injecting it. So oral supplementation might only be 1% as effective as injections – again, in a worst-case scenario.

Okay, so we’ve established that oral B12 supplementation sucks. What about injections? Earlier, I mentioned that hydroxocobalamin is better than cyanocobalamin. Yet, cyanocobalamin is sold much more often, at least in my subjective experience shopping as a German doctor in pharmacies. Why? Let’s take a look.

Cyanocobalamin vs. Hydroxocobalamin

Finding a paper analyzing the differences between these two substances when injected in humans was surprisingly hard. Like, super hard – like searching for that one YouTube video you saw 15 years ago. Maybe researchers didn’t care much about the differences because there’s no such thing as a Vitamin B12 pharma lobby (chuckle) to fund such studies.

However, I found this ancient paper from 1962 (use the magic site to find the PDF – yes, that site) by Tauber et al. which did exactly what I was looking for: Injecting people with cyanocobalamin or hydroxocobalamin and comparing their B12 levels over time. Awesome! I love old-school papers as they’re usually written in simple English and straight to the point, and this one is no exception.

(By the way, this was brutally hard to find as people in 1962 apparently didn’t consider Google Search Engine Optimization when writing their paper titles – its titled “Parenteral Studies with Vitamin B₁₂ Complexes”, how the hell will anyone find this when searching for “cyanocobalamin vs hydroxocobalamin”?)

Back to topic – in their study, they injected healthy people either with cyanocobalamin, hydroxocobalamin or “normal” cobalamin. The latter is super interesting, because it requires the researcher to inject it in a darkroom as “normal” B12 degrades pretty quickly when exposed to light. Just imagine that: A researcher standing next to a courageous volunteer in the dark, trying to inject B12. Man, those old-school researchers.. mad props. Sounds tricky. And, in fact, it was tricky. Here’s my favorite quote which made me laugh out loud:

Since the subject from whom we recovered 0.2 per cent exhibited essentially a homeostatic serum level throughout the study, we are inclined to believe she represents a dark room casualty and that perhaps a substantial portion of the dose leaked from the site of injection or from the syringe.

So what they’re saying here is that they had one subject in their study whom they injected in the dark, and that person seemed to have no resulting increase in their B12 blood values at all. So they call this a “dark room casualty”, meaning that the B12 was injected somewhere, but not where it belonged (= in the muscle of the person). Nervous chuckle. I wonder where that B12 went. Anyway!

Here’s the super-interesting (and hand-drawn, old school, awesome) plot you’ve been waiting for:

This is, in my opinion, pretty crazy: The hydroxocobalamin injection elevates the B12 level for 4 weeks or even more. So that’s cool – you get a good bang for your buck!

The cyanocobalamin injection, however, only seems to elevate the B12 level for ~2-4 days, after which it returns close to its baseline again.

Remember: Your body can only absorb a tiny B12 amount per time, so you really want your injected B12 to hang around in your body for as long as possible.

So when the injected B12 concentrations are going down over time as in the chart above, they actually end up in the patient’s urine, and not in their body. This is bad!

So, in other words: The effect of cyanocobalamin might only last a few days, while that of hydroxocobalamin lasts at least 4 weeks!

That’s crazy!

And yet most doctors don’t know this difference, and pharmacies are still happy to sell cyanocobalamin instead of hydroxocabalamin.

I think this is borderline insane.

Conclusion

So we learned a lot about B12 today. What does this mean for you?

Let’s summarize:

• If you suspect you are B12-deficient, e.g. due to a vegetarian / vegan diet, bowel problems or other symptoms (fatigue etc.), try supplementing B12.
• You could get lab work done, but it’s essentially useless as normal values are of no consequence:
  • If your lab values for B12 + MMA + homocysteine are normal: Useless outcome, because you could still be deficient.
  • If your lab values for B12 + MMA + homocysteine indicate B12 deficiency: Well, now you know for sure you’re deficient, but you were already suspecting that, so this is also a useless outcome.
• The only way of supplementing B12 with good evidence is via intramuscular injections.
• Hydroxocobalamin is way better than cyanocobalamin. So much better that you should probably skip cyanocobalamin entirely if you have the choice.

So that’s it on B12.

Ah, and as always, don’t trust my writing without actually discussing this with your physician, even if they have no clue about B12.

Technically, at least here in Germany, you can just walk into a pharmacy and buy hydroxocobalamin and needles, but that doesn’t mean you should do it. At least talk to a Healthcare professional first, and it’d probably be a good idea to let them show you how to do intramuscular injections if you’re considering doing them yourself.

Don’t learn it from YouTube like I did – I’m a doctor, so I’m allowed to learn from YouTube.. right?