We’ve already talked about the benefits of vitamin B12, but one big question remains: what is the best form of B12 for absorption for anyone deficient looking to supplement and actually get those benefits?
We’ll explore that now.
Types of B12: Methylcobalamin vs Cyanocobalamin vs Hydroxocobalamin vs Adenosylcobalamin
Vitamin B12 (cobalamin) is the largest and most complex vitamin out there. It is unique, because it is the only vitamin that contains a metal ion, cobalt (hence its name). The vitamin is a cofactor for two enzymes in mammals like us, one is methionine synthase, the other methylmalonyl-CoA mutase.
The molecule that is attached to the cobalamin is called a donor. The two most common donors in supplements are cyanide (making cyanocobalamin B12, or cyano B12), and methyl (making methylcobalamin B12, or methyl B12). Other forms you might find are hydroxocobalamin and adenosylcobalamin.
All those forms are present to some degree in the foods you eat, but the predominant forms are adenosylcobalamin and hydroxocobalamin. Another vitamin B12 form found in foods is sulphitocobalamin. It won’t be covered here because it’s irrelevant, and no sulphitocobalamin supplement exists.
Anyway, only adenosylcobalamin (AdeCbl) and methylcobalamin (MetCbl) are active within the human body. You’ll find MetCbl mainly in your blood plasma, cytosol cells, and certain body fluids (like cerebral spinal fluid), and AdeCbl in cellular tissues where it is stored in the mitochondria. In fact, the benefits of B12 all boil down to two biochemical reactions:
But all types of B12 can be converted in the body, so let’s take a look at each to examine which is the best form of B12 to supplement with.
(Also CN-Cbl, or Cyano B12)
Cyano B12 is a cheap, synthetic, slightly-toxic, inactive form of B12 that is made with a cyanide donor and is used commercially. It is the most stable form, because the cyanide molecule has the greatest attraction to the cobalamin and protects it from extreme conditions (like high temperatures). However, it doesn’t absorb well and requires methyl groups to detoxify it.
When cyano B12 does absorb, it converts to hydroxocobalamin (hopefully discarding of the cyanide in the process) and then to methylcobalamin and adenosylcobalamin. When taken orally, absorption of this form is drastically reduced if you have any gastric acid problems.
I can never recommend this form to anyone.
Sure, it’s cheap, but it does come with a price. The body must use a methylation reaction to cleave the cyanide out of this form so that it can be converted to a usable, absorbable form. This is a demanding process. Check out this paper (it does come from a questionable site, but I confirmed its content):
Although the amount of cyanide is considered toxicologically insignificant, humans must remove and detoxify the cyanide molecule, reduce the cobalamin to its usable +1 oxidation state, and then enzymatically convert the cobalamin into one of two metabolically active coenzyme forms. Nutritional inadequacies, enzyme defects, and pathological changes to tissues can all contribute to a reduced ability of the body to accomplish the synthesis of the active forms of vitamin B12 from CN-Cbl (Cyanocobalamin).
Methylation is one way in which your body detoxifies. But it requires methyl groups, which are often in low supply because of our modern life which is full of toxins. To remove the cyanide out of cyanocobalamin, the body uses a methyl molecule. This is why people with methylation problems (like autistic children) can get worse on CN-Cbl but not on other forms of vitamin B12.
You see, commercial cyanocobalamin only exists because after creating hydroxocobalamin from bacteria, some cobalamins bind to cyanide during the charcoal filtration process. Check out this paper from 1992:
If the indiscriminate dumping of industrial cyanide waste continues unchecked with the inherent risk of pollution of food and water supplies there may well come a time when more widespread chronic cyanide neurotoxicity occurs in the Western hemisphere from a dietary source in persons with a genetic or acquired error of cyanide or vitamin B12 metabolism.
And don’t get me wrong, we all get cyanide into our systems (barbecues, bonfire, second hand smoke, even almonds!), but the body always has to detoxify it. By taking cyano B12, you’re further depriving your body of a natural antidote, an antagonist for toxins.
Because of that detoxification process, cyanocobalamin usage could potentially deplete glutathione (GSH), an important anti-oxidant that helps decrease lipid peroxidation associated with oxidative stress. Once glutathione stores are depleted, high dose cyanocobalamin might theoretically cause cyanide toxicity, especially in renal failure patients.
Also, some people may have clinical or sub-clinical conditions which inhibit them from being able to convert this form of B12 to the active forms, and eventually absorb it. In these cases, you will see your serum B12 levels increased (it counts both active and inactive B12), but you’ll have a functional deficiency of AdeCbl and MetCbl in tissues and other body fluids.
Besides, it takes more than 48 hours for cyanocobalamin B12 to eventually convert to usable methylcobalamin, and even then only a small amount is converted. And remember, even when it does convert, it requires the interaction (possibly depletion) of glutathione and other agents.
Despite all that, cyanocobalamin B12 is the most commonly prescribed form for vitamin B12 deficiency. Reason? It’s available and it’s cheap. But it’s also the least safe, least effective, and most demanding type of B12.
Not natural to mammals whatsoever.
Why would you try to improve your health with something that, to become absorbable, requires the depletion of other crucial substances in your body?
It makes no sense, especially when the alternatives are so affordable.
(also Mecobalamin, MeCbl, MetCbl, MetB12, MeB12, or Methyl B12)
Methylcobalamin, the kingpin, one of the two active, natural forms of B12. It helps reduce homocysteine concentrations and generates SAMe (S-adenosyl methionine), the most important methyl donor in your body, supplying methyl groups for crucial chemical reactions to help maintain your health.
Where methyl B12 shows its greatest utility is with people suffering form degenerative neurological symptoms, where it’s often the only promising treatment. It bypasses several potential issues in the absorption cycle and helps relieve or completely reverse symptoms.
High doses of methylcobalamin have been used to treat multiple sclerosis (improved visual and auditory symptoms, not motor ones), amytropic lateral sclerosis, Parkinson’s, and may help regenerate nerves and treat peripheral neuropathies. People with Alzheimer’s noticed an improvement in memory and intellectual function when given this form of B12.
In fact, MetCbl is so effective — in numerous areas — that it is used almost exclusively in Japan to treat B12 deficiency. The science is breathtaking:
It may dramatically improve recovery time for facial nerve function in Bell’s palsy patients. In high doses, it may promote neuronal function, enhance nerve regeneration, and even protect cortical neurons against neurotoxicity.
For diabetic neuropathy patients, it may improve burning sensations, numbness, loss of sensation, muscle cramps, reflexes, vibration sense, lower motor neuron weakness, and sensitivity to pain. The improvement seem to be enhanced by combining methyl B12 with ginkgo biloba extract.
When hemolytic hyperchromic anemia and impairment of hematopoiesis in the bone marrow were induced in rabbits, a decrease in methylcobalamin in the blood serum was observed during spontaneous recovery. Methyl B12 administration completely normalized some blood and hematopoiesis patterns, improved the ratio between the cobalamin forms, and completely regenerated total B12 content. Adenosylcobalamin, which is the other active form, exhibited a distinctly lower effect on the patterns studied.
In both in-vitro and in-vivo experiments, methylcobalamin inhibited the proliferation of malignant cancerous cells. It also reduced tumor growth and enhanced survival time of mice with Ehrlich ascites tumor cells.
Methylcobalamin (along with adenosylcobalamin) had also been shown to increase survival time of leukemic mice, whereas cyano B12 was inactive under the same conditions. Experimental evidence suggests it may also enhance the efficacy of methotrexate.
Now, eye function. Chronic administration of methylcobalamin may protect cultured retinal neurons against N-methyl-D-aspartate-receptor-mediated glutamate neurotoxicity. It may also improve deterioration of accommodation following visual work.
As you see, its applications are limitless.
Methylcobalamin even produces improvements in several components of heart rate variability, suggesting a balancing effect on the sympathetic and parasympathetic nervous systems. Under experimental conditions, methyl B12 (adenosyl and hydroxo B12 too actually) also inhibited HIV-1 infection of normal human blood lymphocytes and monocytes.
One study reported a case of a 48 year old woman with motor weakness, dementia, sensory disturbances, and widespread coarse hair. Classic B12 deficiency symptoms. In response to methyl B12 injections (500mcg every other day), her paresthesia resolved, hand grip strengthened, dementia reduced, hair texture normalized, and she was now able to walk on tiptoe.
Let’s talk about male impotence now, shall we.
In one study, methylcobalamin at a dose of 6,000mcg a day for four months improved sperm count by 37.5%. In another one, methyl B12 at doses of 1,500mcg a day for 4-24weeks increased sperm concentrations in 38% of cases, total sperm count in 54% of cases, and sperm motility in 50% of cases.
I see you getting excited over there.
Now, as I said, methyl B12 converts homocysteine to methionine. This is why high levels of homocysteine can be a sign of low methylcobalamin levels. In one study, high homocysteine levels were reduced from 14.7 to 10.2 nmol/ml following methylcobalamin injections. Because of its effect on homocysteine, it has been found useful in treating children with autism and in reducing cognitive decline and cardiovascular outcomes in older patients.
That is not all.
The science on methylcobalamin B12 and sleep disturbances is especially promising. The exact mechanism isn’t completely understood yet, but it seems like this type of B12 could modulate the synthesis of melatonin, a hormone involved in your sleep-wake cycle regulation. It makes sense, because the biosynthetic formation of melatonin requires a methyl group. See this:
Eight young males were subjected to a single blind cross-over test to see the effects of vitamin B12 (methylcobalamin) on the phase-response of the circadian melatonin rhythm to a single bright light exposure. VB12 (0.5 mg/day) or vehicle was injected intravenously at 12:30 h for 11 days, which was followed by oral administration (2 mg x 3/day) for 7 days. A serial blood sampling was performed under dim light condition (less than 200 lx) and plasma melatonin rhythm was determined before and after a single bright light exposure (2500 lx for 3 h) at 07:00 h. The melatonin rhythm before the light exposure showed a smaller amplitude in the VB12 trial than in the placebo. The light exposure phase-advanced the melatonin rhythm significantly in the VB12 trail, but not in the placebo. These findings indicate that VB12 enhances the light-induced phase-shift in the human circadian rhythm.
Another study reported that intravenous (IV) injections of methylcobalamin increased rectal temperature in later hours of the day and improved alertness (assessed with visual analog scale), suggesting that “these results may provide evidence of an effect of vitamin B12 on the circadian clock.”
One study investigated the effects of both methyl and cyano B12 on circadian rhythms, well-being, alertness, and concentration in healthy subjects. Sleep time was significantly reduced in the MeB12 group, reporting improvements in subjective parameters of sleep quality, concentration and refreshed feel. The authors concluded that “only methylcobalamin has a positive psychotropic alerting effect with a distribution of the sleep-wake cycle toward sleep reduction.”
Here’s another case, this time of a 13 year old boy with adrenoleukodystrophy who had developed a sleep-wake disorder following a complete loss of vision. His sleep-wake cycle had been 25 hours, but normalized after being given methyl B12. MetCbl therapy caused his plasma melatonin and beta-endorphin levels to approximately match those of healthy volunteers, and his peak cortisol time shifted backwards. That is amazing.
Two adolescent patients suffering from persistent sleep-wake schedule disorders appear to have responded to treatment with vitamin B12 (methylcobalamin). A 15-year-old girl with delayed sleep phase syndrome (DSPS) and a 17-year-old boy with hypernychthemeral syndrome complained of not being able to attend school despite many trials of medication. The improvement of the sleep-wake rhythm disorders appeared immediately after the administration of high doses (3,000 micrograms/day) of methylcobalamin. Neither patient showed any laboratory or clinical evidence of vitamin B12 deficiency or hypothyroidism (which can cause B12 deficiency). Serum concentrations of vitamin B12 during treatment were in the high range of normal or above normal.
As you see, the science is there. Is your sleep-wake schedule messed up? Can’t you fall asleep before it’s 2 or 3 AM? Then methyl B12 supplementation may help modulate your melatonin secretion, enhance your light sensitivity, and normalize your circadian and sleep-wake rhythm.
What else? Any other benefits to the methylcobalamin form?
In one randomized study of stroke patients, 67 received doses of 1500mcg methyl B12 daily for 2 years, and the remaining 68 remained untreated. After two years, electrophysiologic parameters in sensory nerve in the treated group significantly improved compared to the untreated group.
Speaking of strokes, combined treatment of methylcobalamin and folate was found safe and effective in reducing the risk of hip fractures in elderly patients following stroke. Add clonidine and moxonidine to the mix and you improve baroreflex function in stroke-prone, spontaneously hypertensive rats.
Some Chinese studies found methylcobalamin to be helpful in treating lumbar disc herniation, thalamic pain, glaucoma, cervical spondylosis, and cubital tunnel syndrome. They also found acupoint methylcobalamin injections with acupuncture to be effective in treating intractable facial paralysis.
Now, how does methylcobalamin compare to cyanocobalamin when it comes to absorption and bio-availability? Is it any better?
Because of the effort it takes to reduce it to the active form, cyanocobalamin absorption varies greatly between individuals. Methylcobalamin is significantly better utilized and is around 2.5 times more potent (about 1/3 less is excreted in the urine) than cyanocobalamin. Yes, similar doses are “absorbed”, but once absorbed, MetCbl is accumulated and retained in the body much better.
In any form, methylcobalamin has higher bioavailability than cyanocobalamin. It is so efficient that even orally it was found effective in pernicious anemia:
A 73-year-old Japanese man with Hashimoto’s disease and diabetes mellitus received regular medical checkups for type 2 diabetes care. Blood tests indicated macrocytic anemia. The laboratory data demonstrated a normal folic acid level with a low vitamin B12 level. An endoscopic examination indicated no signs of gastric or intestinal bleeding. Positive results for anti-intrinsic factor antibodies were strongly suggestive of pernicious anemia. The patient refused cobalamin injections to treat the anemia. However, the oral administration of mecobalamin for the treatment of diabetic neuropathy was simultaneously initiated. Subsequently, the anemia gradually improved. Oral mecobalamin was presumably effective for pernicious anemia management.
Now, I’m not suggesting you treat pernicious anemia with oral MetB12. Vitamin B12 injections should always be used in that case (their absorption and efficiency are far superior, and with PA you can’t take any risks). But it still goes to show you the power of methylcobalamin.
(Also Hydroxycobalamin, Hydroxy B12, OH-Cbl, or B12a)
Hydroxocobalamin, a predominant form in vitamin B12 rich foods, is an inactive form of vitamin B12, but it has an advantage over cyano B12 in that it doesn’t contain cyanide and bypasses the need for decyanation.
Compared to cyano B12, it has a higher affinity to plasma protein and a longer half life, retaining longer in the blood. This may help reduce injection frequency. Again, it doesn’t contain a toxic donor, so no detoxification reaction is required for it to be absorbed, and the glutathione source is preserved.
Hydroxocobalamin reacts chemically with cyanide (CN), nitric oxide (NO) and nitrous oxide (N2O). In fact, this form of B12 is commonly used as an antidote for cyanide toxicity. Therefore, it can be used safely in tobacco amblyopia cases and in pernicious anemia patients with optic neuropathy.
Like cyanocobalamin, hydroxy B12 eventually has to be converted in the body to both methylcobalamin and adenosylcobalamin. But it converts much easier. Cyanocobalamin doesn’t react easily to anything else — the cyanide makes it very stable — so expensive energy expenditure is needed for it to convert.
So, who is hydroxocobalamin good for? Mainly patients with intrinsic cobalamin metabolic diseases, B12 deficiency cases with tobacco amblyopia, and pernicious anemia patients with optic neuropathy. But be careful:
Suppressing nitric oxide could have adverse affects (elevated blood pressure, digestive disturbances, impotence, susceptibility to infection, even increased risk of cancer), especially during pregnancy where NO helps controlling the feto-lacental circulation. Therefore, anyone who could utilize methyl or adenosyl B12 would be better off with one of them.
(Also AdeCbl, cobamamide, cobinamide, dibencozide, or AdoB12)
Adenosylcobalamin is the mitochondrial form of B12. It is used by the enzyme methylmalonyl-CoA mutase to convert methylmalonyl-CoA to succinylcholine CoA (used in the synthesis of porphyrin). This is why methylmalonic acid (MMA) levels get high when you’re low on AdeCbl.
Adenosylcobalamin also acts as an intermediate in the degradative pathway for valine, threonine, methionine, thymine, isoleucine, cholesterol and odd-chain fatty acids. Most of our B12 reserves are actually stored in the liver as adenosylcobalamin, and are converted to methylcobalamin whenever needed.
But what about supplementing with adenosylcobalamin?
In one study, carnitine and adenosylcobalamin promoted cerebral mass growth, pyramidal neuron volume, neocortical layer thickness, and fully restored normal structure of the neocortex in an experimental model of anorexia nervosa. In the patients, carnitine and AdeCbl accelerated body weight gain and gastrointestinal function normalization. Latent fatigue disappeared and mental performance sharply increased.
Speaking of anorexia, another study found that the combined use of carnitine and adenosyl B12 eliminated fluctuations in work rate and normalized the scope and productivity of intellectual work in patients with anorexia nervosa in the stage of cachexia. Latent fatigue wasn’t fully eliminated though.
One Italian study treated 37 persons suffering from viral hepatitis with either adenosylcobalamin or cyanocobalamin. The researchers found that AdeCbl was significantly more efficacious than CN-Cbl in normalizing total bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), and alkaline phosphatase values.
The AdeCbl administered was intramuscular injections at a dose of 1,000mcg per day for the first 12 days, and then orally for the next 12 days. Overall, 13/18 of subjects receiving the adenosylcobalamin had their total bilirubin normalized, 15/18 had their SGOT normalized, 10/18 had their SGPT normalized, and 18/18 (all) had their alkaline phosphatase normalized.
So, is it adenosylcobalamin or methylcobalamin? Which one should you supplement with? Remember, the two inter-convert in the body.
The main benefit methylcobalamin has over adenosylcobalamin is that it comes with a very beneficial methyl group, further enhancing your health in a myriad ways. Also, adenosylcobalamin isn’t available as injections, making it ineffective for pernicious anemia. However, if you can absorb B12 through the stomach, adenosyl B12 tablets can be a great option.
If you’re chronically fatigued and seem to get better only from AdoCbl (and not MetCbl), it is possible that you have some rare condition preventing your body from successfully converting B12 forms into others. In these case, you should supplement with a mixture of MetCbl and AdeCbl.
Verdict: What Is The Best Form of Vitamin B12? Cyanocobalamin vs Methylcobalamin vs Adenosylcobalamin vs Hydroxocobalamin
If you’re confused by all the text and the mass of studies, or if you’re simply a more visual person, this chart should give you a good picture:
So, which is the best type of B12?
Let’s summarize things.
Cyanocobalamin is an inactive, slightly toxic form of B12. It contains a cyanide molecule, which your body will have to remove through methylation, a reaction that requires precious methyl groups. Glutathione seems to be the substance performing the decyanation.
Only then can the cobalt atom be reduced from an oxidative state of +3 to the biologically active +1, eventually forming methylcobalamin in the cytosol and adenosylcobalamin in the mitochondria. This demanding process can be significantly hampered in a range of conditions.
Cyanocobalamin is especially dangerous to those with liver problems, renal failure, and smokers, because in those people the cyanide can’t be eliminated effectively. It’s also dangerous for pernicious anemia patients or anyone else with high homocysteine levels, because it may deplete the body of glutathione, a substance needed to lower homocysteine.
Recommended to no one.
Hydroxocobalamin is also an inactive form of B12, but it is better than cyanocobalamin because it doesn’t contain any cyanide, therefore bypassing the need for decyanation and preserving the glutathione. It also has to be reduced from state +3 to +1 before it can become either MetCbl or AdeCbl.
Recommended to B12 deficiency patients with tobacco amblyopia, cyanide toxicity, and/or early hereditary optic nerve atrophy (Leber’s disease). Nitric oxide levels should always be monitored during administration.
Adenosylcobalamin and methylcobalamin are the native forms, bypassing several reactions in the absorption cycle. They both retain in the body and increase tissue concentration much better, and often produce clinical results far superior to what cyano or hydroxy B12 can offer.
The use of AdeCbl/MetCbl offers significant benefits and should be considered first line of defense against conditions that may benefit from B12.
Which of them is the superior choice?
Remember, the two inter-convert. But if you have a rare condition preventing your body from inter-converting them (you’ll know this if you’re chronically fatigued and only AdeCbl — and not MetCbl — seems to benefit your energy levels), you’ll have to use a combination of MetCbl and AdeCbl.
For everyone else, which is more than 99% of people in need of extra B12, methylcobalamin is better. It exhibits distinct neuroprotective effects, improving nerve regeneration while bringing synaptic transmutations and diminished neurotransmitters back to normal levels.
Plus, methylcobalamin donates an extremely valuable methyl group that further enhances your health (and doesn’t steal any, like cyano does). This is especially important for pernicious anemia patients or anyone suffering from high homocysteine levels. This donation of methyl groups may be the reason why methylcobalamin is helpful to so many conditions.
This article is part of a larger guide: Vitamin B12.