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The Brain Boosting and Fatigue Fighting B-12

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Vitamin B-12 Hydroxocobalamin

Hydroxocobalamin is a natural and uniquely powerful form of vitamin B-12. Clinical studies and practice have demonstrated its ability to help improve cognitive functioning, fight fatigue, promote heart health, aid in detoxification and more.

Vitamin B-12 is an essential nutrient – one that your body needs but cannot produce itself. It is necessary to make: the red blood cells that carry oxygen throughout the body, the myelin sheath that surrounds nerve cells, and various proteins. B-12 also plays an important role in fat and carbohydrate metabolism. Yet, despite its importance to overall health, vitamin B-12 deficiency is relatively common. It is estimated that up to 15% of the general population may be deficient in B-12 – and even more among those with chronic illnesses like fibromyalgia, ME/CFS and chronic Lyme disease.

Causes of Vitamin B-12 Deficiency

In order for the B-12 obtained from food to be absorbed, it must attach to a protein called intrinsic factor, which is secreted in the stomach. Unfortunately, a number of things can inhibit the secretion of intrinsic factor, which in turn blocks the absorption of B-12 and results in a vitamin B-12 deficiency.

A deficiency of vitamin B-12 is not usually caused by insufficient dietary intake but rather by a lack of intrinsic factor secretion. Without intrinsic factor, vitamin B-12 cannot be absorbed. This situation can occur with:

  • Digestive disorders such as celiac disease, Crohn’s disease, bacterial overgrowth in the small intestine or a parasite.
  • Surgery to remove or bypass part of the stomach or the part of the small intestine called the ileum.
  • Certain medications, particularly diabetes medications like metformin, and long-term use of proton pump inhibitors (such as Prilosec, Prevacid, Nexium, etc.) commonly prescribed for heartburn, acid reflux and GERD.
  • Vegetarian or vegan diets, since B-12 is found almost exclusively in animal foods.
  • Pernicious anemia – a decrease in red blood cells that develops when the body lacks the intrinsic factor necessary to naturally absorb vitamin B-12 from food.

Vitamin B-12 Deficiency Symptoms

Early symptoms of a B-12 deficiency may be overlooked, diagnosed as another illness, or attributed to “just getting older” because many of them mimic classic signs of aging. Of course, this isn’t surprising since low serum levels of vitamin B-12 are fairly common in elderly patients.(1) Some of the symptoms of a vitamin B-12 deficiency may include:

  • Fatigue
  • Weakness
  • Memory loss
  • Cognitive functioning problems
  • Diarrhea or constipation
  • Loss of appetite
  • Shortness of breath
  • Beefy, red, smooth and sore tongue
  • Sore mouth and/or bleeding gums
  • Numbness and tingling of hands and feet
  • Poor sense of balance
  • Depression
  • Confusion
  • Insomnia
  • Vision problems
  • Loss of hearing and tinnitus
  • Pale, possibly yellowish pallor in light-skinned individuals; blotchy pigmentation in dark-skinned individuals

A vitamin B-12 deficiency can be difficult to diagnose because serum blood levels of B-12 may test normal. Having circulating B-12 in the blood doesn’t mean it is being utilized properly by the body’s cells. Some doctors suggest that a test measuring methylmalonyl coenzyme A levels in the blood or urine gives a more accurate reading of B-12’s availability in the body.

Vitamin B-12 in Food

Vitamin B-12 is produced exclusively in the digestive tracts of animals. Therefore, the richest dietary sources of B-12 are organ meats like liver or kidney. Other good natural sources include meat, fish, eggs and dairy products. Although some beverages, nutritional yeasts and food products like cereals may be enriched with B-12, they generally do not contain adequate amounts to be used as the sole source of this essential nutrient.

Since the only natural source of B-12 is from animals, it is particularly important for vegetarians and vegans to pay special attention to how much vitamin B-12 they are getting. It is strongly recommended that they consider taking a B-12 supplement.

Which Form of Vitamin B-12 is Better – Hydroxocobalamin or Cyanocobalamin?

The name vitamin B-12 is used for a group of cobalt-containing enzymes called cobalamins. (It’s the cobalt that gives B-12 its red color.) There are several members of the cobalamin family, but cyanocobalamin and hydroxocobalamin are two of the best known.

  • Cyanocobalamin is the type of B-12 found in most supplements and in prescribed injectible forms – largely because it is inexpensive and the most stable form of B-12.
  • However, studies have found that hydroxocobalamin raises B-12 levels higher and lasts longer than cyanocobalamin.(2)(3)

Another interesting fact – cyanocobalamin contains cyanide. It’s actually a cyanide molecule attached to a cobalamin. Although the amount of cyanide is miniscule enough that it is not thought to be harmful to most people, it could be dangerous for those who have cyanide metabolism defects or kidney failure. There is also the possibility that it could be toxic if taken in extremely large doses.

On the other hand, hydroxocobalamin has a high affinity for cyanide. It pulls the cyanide out of the mitochondria of the cell and combines with it to form cyanocobalamin, which is then excreted in the urine. In fact hydroxocobalamin is so effective at this process that in 2006 it was approved by the FDA as an antidote for cyanide poisoning.

Since cyanide is present in cigarette smoke (and essentially reduces the cells’ ability to use oxygen), hydroxocobalamin would be a good option for smokers seeking a B-12 supplement.

Hydroxocobalamin’s Relationship to Fibromyalgia and ME/CFS

Several of the symptoms of a vitamin B-12 deficiency are remarkably similar to some of the fibromyalgia symptoms and ME/CFS symptoms reported by patients – cognitive functioning problems, memory loss, and fatigue to name a few. Is that merely a coincidence or is there a connection?

In a 1997 study of 12 patients with fibromyalgia and ME/CFS: Most had little or no detectable B-12 in their cerebrospinal fluid – despite the fact that all had normal B-12 blood levels. Conversely, they had high levels of homocysteine in their cerebrospinal fluid.(4)

Homocysteine is an amino acid, too much of which can be toxic to nerves and blood vessels, and may result in increased pain sensitivity and/or heart disease. When there is not enough vitamin B-12, homocysteine levels increase; as B-12 levels rise, homocysteine levels decrease.

ME/CFS specialist and researcher Dr. Paul Cheney, MD, PhD, utilizes large doses of hydroxocobalamin as part of his treatment protocol. He believes it is a potent brain detoxifier and says data suggests that megadoses in the range of 10,000 mcg or more per day, given before bedtime, may be effective. He also notes that hydroxocobalamin is superior to cyanocobalamin as a detoxifier of the brain.(5)

Another researcher, Dr. Martin L. Pall, PhD, hypothesizes that elevated levels of nitric oxide and peroxynitrite (affecting brain function and pain sensitivity) may be the common etiology of ME/CFS, fibromyalgia, multiple chemical sensitivity and post-traumatic stress disorder.(6)  He believes hydroxocobalamin’s ability to “mop up” excess nitric oxide may be why it has proven to be so useful in treating those illnesses.(7)

Hydroxocobalamin’s Effect on Other Conditions

Studies have shown hydroxocobalamin to have positive effects on a variety of different diseases and disorders.

  • In a 2001 study, hydroxocobalamin improved cognitive function in older cobalamin-deficient persons.(8)
  • A study conducted at a VA Medical Center found that hydroxocobalamin inhibited HIV-1 infection of normal human blood monocytes and lymphocytes in vitro.(9)
  • In three case studies of childhood asthma, the use of hydroxocobalamin resulted in remarkable improvement in asthma wheezing.(10)

There are also individual or small case reports indicating a possible correlation with vitamin B-12 deficiency in some cases of infertility, dementia, diabetic neuropathy, neuromyelopathy, multiple sclerosis, autism, motion sickness, and even psychosis to name a few.

Vitamin B-12 Injections vs. Pills – Is There a Difference?

Most hydroxocobalamin studies have used the intramuscular injection form. However, that requires patients to return to the doctor’s office for every dose (unless they learn to do it themselves). Therefore vitamin B-12 injections are a more time-consuming, expensive and – let’s face it – painful way to go. But are they more effective?

Two studies addressing that question concluded that oral supplementation with large doses of B-12 was as effective, if not more effective, than injections.

  • A 1997 study showed that oral supplementation with 2,000 mcg per day was three times as effective as vitamin B-12 injections in increasing B-12 levels in pernicious anemia patients.(11)
  • Another study done in 2005 concluded that 2,000 mcg doses of oral B12 was as effective as intramuscular administration in vitamin B-12 deficient patients. (12)

When it comes to oral supplementation of B-12, sublingual tablets are the best option because they are absorbed directly into the mucous membrane and don’t have to go through the digestion process, which is often the cause of the deficiency to begin with.

How Much Vitamin B-12 Is Enough? …Too Much?

There is no set upper dose limit for hydroxocobalamin because there are no known toxic effects, even at extremely high dosages Many of the studies used 1,000 or 2,000 mcg/day. Dr. Cheney generally prescribes 10,000 mcg/day for ME/CFS patients. Dr. Susan Solomon, MD, recommends at least 5,000 mcg/day sublingual for chronically ill patients. Dr. Sarah Myhill, MD, usually starts with 5,000 mcg/day for ME/CFS and then adjusts the frequency according to the response.

In Summary

Clinical research and practice strongly supports the use of hydroxocobalamin as a safe and highly effective method for correcting a vitamin B-12 deficiency.

This article, originally published on December 23, 2010, was updated on October 21, 2019.

Karen Lee Richards is ProHealth’s Editor-in-Chief. A fibromyalgia patient herself, she co-founded the nonprofit organization now known as the National Fibromyalgia Association (NFA) in 1997 and served as its vice-president for eight years. She was also the executive editor of Fibromyalgia AWARE magazine. After leaving the NFA, Karen served as the Guide to Fibromyalgia and Chronic Fatigue Syndrome for the New York Times website About.com, then worked for eight years as the Chronic Pain Health Guide for The HealthCentral Network before coming to ProHealth. To learn more about Karen, see “Meet Karen Lee Richards.


1.  Stott DJ, et al. “Prevalence and haemopoietic effects of low serum vitamin B-12 levels in geriatric medical patients.” Br J Nutr. 1997 Jul;78(1):57-63. doi: 10.1079/bjn19970118

2.  Hall CA, et al. “The availability of therapeutic hydroxocobalamin to cells.” Blood. 1984 Feb;63(2):335-41. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/6692038

3.  Glass GBJ, et al. “Hydroxocobalamin V. Prolonged Maintenance of High Vitamin B-12 Blood Levels following a Short Course of Hydroxocobalamin Injections.”  Blood, 1966, Vol. 27, No. 2, pp. 234-241. doi: 10.1182/blood.V27.2.234.234

4.  Regland B, et al. “Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome.” Scand J Rheumatol. 1997;26(4):301-7. doi: 10.3109/03009749709105320

5.  Hoh D. “Treatment at the Cheney Clinic.” The CFIDS Chronicle. July/August, 1998:13-14. Retrieved from: http://www.vitasearch.com/get-clp-summary/20655

6.  Pall ML. “Common etiology of posttraumatic stress disorder, fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity via elevated nitric oxide/peroxynitrite.” Med Hypotheses. 2001 Aug;57(2):139-45. doi: 10.1054/mehy.2001.1325

7.  Pall ML. “New theory on explanations for chronic fatigue syndrome. ProHealth.” February 13, 2001. Retrieved from: https://www.prohealth.com/library/new-theory-on-explanations-for-chronic-fatigue-syndrome-19645

8.  vanAsselit DZ, et al. “Cobalamin supplementation improves cognitive and cerebral function in older, cobalamin-deficient persons.” J Gerontol A Biol Sci Med Sci. 2001 Dec;56(12):M775-9. doi: 10.1093/gerona/56.12.m775

9.  Weinberg JB, et al. “Inhibition of productive human immunodeficiency virus-1 infection by cobalamins.” Blood. 1995 Aug 15;86(4):1281-7. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/7632933

10. Wright, JV. “Treatment of childhood asthma with parenteral vitamin B-12, gastric re-acidification, and attention to food allergy, magnesium and pyridoxine: three case reports with background an integrated hypothesis.” Journal of Nutritional Medicine, 1990; 1:277-282. Retrieved from: http://www.vitasearch.com/get-clp-summary/5624

11. Journal of the American Geriatrics Society. January, 1997; 45(1):124.

12. Butler CC, et al. “Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B-12 deficiency: a systematic review of randomized controlled trials.” Fam Pract. 2006 Jun;23(3):279-85. Epub 2006 Apr 3. doi: 10.1093/fampra/cml008

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4 thoughts on “The Brain Boosting and Fatigue Fighting B-12”

  1. BobSmiley says:

    Such a source of vitamin B-12 is easily found in easily attainable foods like meat, fish eggs. I would rather get them from natural sources than taking multivitamins.

  2. IanH says:

    Bob, one cannot argue against “natural (food/sun) sources of nutrients are best”. However when a person suffers an illness which affects the levels of those nutrients or their intracellular metabolism then natural sources may not be enough or impractical.

    In addition, in the case of B12 as people age and stomach release of intrinsic factor decreases, as well as many of those who are on PPIs will have low levels of B12 which cannot be corrected by diet.

    In ME/CFS and FM the serum levels of B12 are abnormally low. This has been shown in many laboratories/studies. I advise all people with ME/CFS or FM to take sublingual B12 in addition to their diet. The benefits of taking the supplement far outweigh any disadvantages.

  3. LAJLG says:

    also true for those with barrier dysfunction, intestinal impermeability, Leaky Gut ….
    there is an absorption problem and supplements are crucial.

  4. meowzietung says:

    I recently began taking 500 mcg of B12 and developed a very sore tongue and broke out heavily in rosacea-like lesions on my face. I also have lost my sense of taste. I’m back down to 125 mcg.

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