The Vitamin B12 Shot


By Douglas Lobay, B.Sc, ND

Why do we do what we do? Sometimes we get too comfortable and complacent in our daily practices whereupon we forget what we give and why we do it.

I have been happily practicing as a licensed naturopathic physician in British Columbia for twenty-eight years.  I have a busy practice that integrates natural and western medicine. I utilize injection treatment, including intravenous vitamin and chelation therapy. In my tenure I have administered thousands of intramuscular injections of vitamin B12 and hundreds of Myer’s intravenous nutrient cocktails.

At a recent roundtable discussion with other doctors, the topic of vitamin B12 shots came up for discussion. The questions asked included why do we give vitamin B12 shots and which form of vitamin B12 is the best? I realized that I really didn’t know much about vitamin B12 therapy. I had my opinions based on observations in my practice, but I had shortcomings in my scientific understanding. I decided to research vitamin B12 therapy and try to better understand why I am giving vitamin B12 shots to some patients.

I reflected back to when I graduated from Bastyr College (now University) of Naturopathic Medicine in Seattle in 1991. One of the rights of passage from student clinician to full fledged doctor was the administration of the vitamin B12 shot. With the tenets of naturopathic medicine in mind, including identifying and treating the cause, treating the whole person and doing no harm, I was unleashed to heal the world. From the drawing of the deep red solution from a sterile vial into a syringe, to the appropriate location on the shoulder, thigh, or derriere, with the proper aseptic swabbing technique, the vitamin B12 shot was then administered with proper trajectory and momentum. The patient winced and complained of slight pain, but the shot was quickly dispensed and released. It was natural and safe and made a lot of people feel better for a while.

What I knew thus far is that vitamin B12 is the largest and most complex water-soluble vitamin. Humans cannot produce it, except for maybe some bacterial production in the large intestine. Vitamin B12 is required for energy production and DNA synthesis, including production of red blood cells. The adult recommended dietary allowance (RDA) of vitamin B12 for an adult is 2.4 micrograms per day.  Vitamin B12 from food is bound to proteins and must be broken down first before intestinal absorption can occur.  Hydrochloric acid from the stomach breaks down the protein bonds and allows vitamin B12 to bind to intrinsic factor. Vitamin B12 bound intrinsic factor can then be absorbed across the intestinal lumen.

A lack of dietary sources of B12, decreased stomach acid production and consumption of drugs that inhibit stomach acid production, autoimmune decrease of intrinsic factor production leading to pernicious anemia, celiac disease, specific genetic polymorphisms, and other causes can lead to vitamin B12 deficiency. Up to 20% of the adult population in western societies may be deficient in vitamin B12.  Older adults, vegetarians, and those with compromised digestive systems have an even higher rate of vitamin B12 deficiency.

Vitamin B12, like hemoglobin, consists of a large heavily nitrogenous corrin ring structure that envelopes a central cobalt molecule. There are six bonding sites on the cobalt atom, consisting of four bonds to the sites on the corrin molecule, one to an azole group, and one to a R group. The R group can be an alkyl or methyl, adenosyl, hydroxyl, or cyano group. The R group bond determines what type of vitamin B12 is created.  For medical purposes in humans, there are four types of vitamin B12: methylcobalamin, adenosylcobalamin, hydroxycobalamin, and cyanocobalamin. 

It has been argued that the first three types of B12 (methylcobalamin, adenosylcobalamin, and hydroxycobalamin) are naturally occurring in humans, while cyanocobalamin has been suggested to be synthetic. However, cyanocobalamin is produced in nature by certain bacteria and is found in humans at low levels as a byproduct of cyanide ingestion from certain foods and smoking. While all types of B12 have the same basic core structure, the R group attachment confers unique structural and functional aspects.1,2

Only methylcobalamin and adensylcobalamin are believed to functionally active in humans. Each form of B12 has a singular unique function. Firstly, methylcobalamin is necessary for transferring a methyl group from 5-methyltetrahydrofolate (MTHF) to homocysteine.  Methylcobalamin is a cofactor for enzyme methionine synthase, which catalyzes the conversion of toxic homocysteine to stable methionine. This leads to the formation of tetrahydrofolate (THF), which is important in cellular DNA synthesis in bone marrow, nascent red blood cell formation, and intestinal wall production. In turn the methylated homocysteine is inactivated to methionine. Methylation is also an important method that is used to turn different genes on and off.  In the bone marrow, vitamin B12 in combination with folic acid acts as a methyl donor.  This turns on purine and thymidylate synthesis of deoxyribonucleic acids, which leads to the production of nascent red blood cells. The utilization of methylcobalamin only occurs inside the cell cytosol.

Adenosylcobalamin participates in the reaction that converts methylmalonyl-coenzyme A to succinyl-coenzyme A. Succinyl-coenzyme A is a key part of the tricarboxylic acid or Kreb’s cycle. This conversion is an important step in energy production from protein, fats, and carbohydrates. The utilization of adenosylcobalamin only occurs in the mitochondria of cells. Other functions of vitamin B12 have also been described but are believed to be a consequence of these two main functions namely the methylation pathway and the tricarboxylic energy generation. For example, an increased concentration of methylmalonyl-coenzyme A leads to a decrease in myelin sheath production of nervous tissue.1,2

Oral vitamin B12 supplements have notoriously low intestinal absorption rates. For instance, the absorption rate of a 1000 microgram tablet has been determined to be between 1 to 2%.  That is, only 10 to 20 micrograms of the original 1000 microgram dose is actually absorbed into systemic circulation. Sublingual delivery is believed to have a slightly higher absorption rate.  All forms of vitamin B12 appear to be absorbed at nearly the same rate. It is important to point out, however, that this easily meets the required adult RDA of 2.4 micrograms per day or higher optimal dosage requirements suggested by some health experts. Some studies show that a high dose of 500 to 2000 micrograms of vitamin B12 per day also forces passive diffusion in addition to transluminal protein bound absorption across the small intestinal wall. Hence, enter the vitamin B12 shot.1,2

Intramuscular injection of vitamin B12 delivers a high dose of vitamin B12 into systemic circulation thereby bypassing intestinal absorption. Once delivered to the bloodstream, vitamin B12 is strongly protein bound. All forms of B12 are bound to protein carriers transcobalamin 1 and transcobalamin 2.

Transcobalamin 2 has a higher affinity for intracellular transport of vitamin B12. All forms of vitamin B12 participate in lysosomal transport inside the cell. Once inside the cell all forms of B12 are believed to be reduced to the core cobalamin molecule less the R group inside the cytosol. Then the cobalamin molecule is reassembled into one of the two active forms, namely methylcobalamin and adenosylcobalamin. The active form of B12 produced does not depend so much on the initial form of B12 that is ingested or injected.

The formed B12 then participates in the unique biochemical pathway for which it is intended either for methylation pathways in the cytosol or active co-enzyme A pathways inside the mitochondria. Additionally, it is important to point out that once formed inside the cell it does not appear that active B12 types can interchange with each other once produced. That is to say that methylcobalamin cannot be converted to adenosylcobalamin and vice versa.1,2,3

Cyanocobalamin is the semi-synthetic version of vitamin B12 that is made by substituting a cyanide molecule for the hydroxyl R group.  Cyanocobalamin is relatively cheap to produce and is more stable compared to the other forms of B12. Yes, there is a small amount of cyanide in this commercially available form of B12.  Like other forms of vitamin B12, cyanocobalamin is broken down and converted into one of the two active forms of B12 inside the cell cytosol. The cyanide is converted to thiocyanate and is then excreted through the liver and kidneys.  To put things in perspective, the molecular weight of cyanocobalamin is 1355 grams per mole. The molecular weight of cyanide is 26 grams per mole. Therefore, the cyanide content of cyanocobalamin is calculated to be approximately 1.9%. Then the cyanide content of a 1000 microgram dose of cyanocobalamin is calculated to be about 19 micrograms.   

The Center for Disease Control reports that cyanide is considered mildly toxic when blood levels are between 0.5 to 1.0 milligrams/liter of blood is reached. Moderate toxicity is considered to be 1.0 to 2.0 milligrams per liter and severe toxicity is between 2.0 to 3.0 milligrams per liter. It is important to remember that small amounts of cyanide are found in over 2000 plants and foods, including apples, apricots, cherries, peaches, cassava root, lima beans and soybeans.1,2,3,5

Hydroxycobalamin is a bio-identical form of vitamin B12 that occurs in food and humans.  It is not considered biologically active and must be converted to the active forms of B12 inside the cell cytosol. It is slightly less stable than cyanocobalamin and is slightly more expensive.  Methylcobalamin is a more expensive form of B12 and as mentioned is broken down in the cytosol and reassembled to one of the two active forms. 

There was some argument in commercial advertising that methylcobalamin cannot be converted to the other active form adenosylcobalamin. A combination of different vitamin B12 types was therefore suggested, but this hasn’t been proven to be any more effective than any of the other types of B12 alone. All types of vitamin B12 have similar absorption rates, but once inside the body behave slightly differently. The human body can store between 2 to 5 milligrams of vitamin B12 with up to 50% stored in the liver alone.  In one study methylcobalamin increased liver storage capacity more than cyanocobalamin.  Furthermore, cyanocobalamin showed increased urinary excretion compared to methylobalamin and less tissue retention. In another study adenosylcobalmin showed decreased intracellular activity compared to methylcobalamin. Hydroxycobalamin appears to be more protein bound than cyanocobalamin. The clinical significance of these findings are not known.1,2,4

Vitamin B12 is considered generally safe and non-toxic. The 50% lethal dose of LD 50 in mice has been calculated to be 5000 milligrams per kilogram. Peak blood levels are reached 8 to 12 hours following oral consumption.  Peak levels are reached quickly after intramuscular or intravenous administration. Vitamin B12 is distributed widely to liver, bone marrow, brain, the placenta, and other tissues following absorption.  The half-life in the blood is estimated to be between 2 to 6 days. Fifty to 90% of cyanocobalamin was excreted through the kidneys via glomerular filtration. Vitamin B12 does not appear to be mutagenic or teratogenic.  The use of B12 in normal physiologic doses during pregnancy showed no adverse side effects.  High dose vitamin B12 supplementation during pregnancy appears to be safe but is still unproven.  Side effects of vitamin B12 supplementation include nausea, upset stomach, diarrhea, itching, skin rash, headache and other relatively benign symptoms.  Rare cases of anaphylactic reactions to vitamin B12 shots have been reported.  As the case with injecting any substance, precautionary measures should always be taken.5.6

Over the years I have administered vitamin B12 shots to many patients.  In some patients with unexplained fatigue, I have measured vitamin B12 levels as part of chemistry panels, including CBC, ferritin, thyroid, and other markers. In some patients I have measured the statistical increase in serum vitamin B12 levels following a shot.  In other patients I have simply given a B12 to see if it “helps” them and makes them “feel” better. The cost of B12 remains cheaper than the price of a blood test to measure B12 levels.

I have recommended sublingual B12 to many patients with varying results.  Some patients say the oral supplements help, and a lot say they don’t help.  I have tried to switch many patients from getting B12 shots back to oral supplements. In many cases, patients tell me they “feel” better with getting intramuscular shots.  I have tried to deter some patients from coming in for shots too often, by either supplementing them between visits or trying to stretch the duration between shots.  If I think a patient needs a B12 shot for the first time, I try to explain the pros and cons and possible side effects of intramuscular administration.  I usually tell the patient if it helps improve their energy level and makes them “feel” better they will usually come back and ask for another shot. 

At least 50% of patients I give a B12 shot notice no difference and no improvement in clinical symptoms.  However, I believe there is a subset of the general population, estimated to be somewhere between 25 to 35% of general population that just “feel” better from a vitamin B12 shot. This appears to be true for patients with lower normal levels of B12 but also is true for some patients with high levels of B12.  Through the years I have experimented with the various types of injectable vitamin B12 available.  In my clinical experience, I have not found any substantial difference in any of the types of B12 I use, including methylcobalamin, adenosylcobalamin, hydroxycobalamin or cyanocobalamin alone or in combination. 

In addition, to energy, vitality and wellbeing, I have seen vitamin B12 shots help some patients with shingles, poor memory, back pain, neurological conditions, chronic fatigue syndrome, fibromyalgia, depression,  eczematous neurodermatitis, and other conditions.  I believe that vitamin B12 therapy is an important supplement and cornerstone of my natural medical practice.

References

  1. Paul C and Brady D. Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Polymorphisms. Integr Med (Encinitas). 2017 Feb; 16(1):42-49.
  2. Author Unknown. Vitamin B12. Linus Pauling Institute. Micronutrient Information Center. Oregon State University.www.lpi.oregonstate.edu/mic/vitamins/vitamin-B12. Dec 2019.
  3. Kamath A and Pemminati S. MethylCobalamin in Vitamin B12 Deficiency: To Give or not to Give? J Pharmacol Pharmacother. 2017 Jan-Mar; 8(1):33–34.
  4. Thakkar K and Billa G. Treatment of Vitamin B12 Deficiency-Methylcobalamine? Cyanocobalamine? Hydroxycobalamine? Clearing the Confusion. Eur J Clin Nutr. 2015 Jan 69(1):1-2
  5. Author Unknown. Prescribing Information Cyanocobalamin Injection, USP (Vitamin B12). Product Monograph. Mylan Pharmaceuticals ULC. 2014 May 14;1-6.
  6. Author Unknown. Vitamin B12. Drug Bank. Dec 2019. www.drugbank.ca/drugs/DB00115.


About the Author

Douglas G. Lobay is a practicing naturopathic physician in Kelowna, British Columbia. Dr. Lobay graduated with a Bachelor of Science degree from the University of British Columbia in 1987. He then attended Bastyr College of Health Sciences in Seattle, Washington, and graduated with a Doctor of Naturopathic Medicine in 1991. While attending Bastyr College, he began to research the scientific basis of natural medicine. He was surprised to find that many of the current medical journals abounded with scientific information on the use of diet, nutrition, vitamins, and botanical medicines. Besides practicing naturopathic medicine Dr. Lobay enjoys research, writing and teaching others about the virtues of good health and nutrition. He has authored several books, numerous articles, and papers and has taught many courses at seminars and colleges throughout his career. He is married to Natalie and has two daughters, Rachel and Jessica. He also enjoys hiking, hockey, skiing, tennis, travelling and playing his guitar.