In the late 1980s, Dr. Paul Cheney and I heard several anecdotal reports of chronic fatigue syndrome (CFS) patients who improved when their primary care physicians administered B-12. Given the scarcity of effective treatment options for CFS, we set out to try various doses and preparations in our own patients.
This treatment was based on three articles that appeared in the New England Journal of Medicine demonstrating that persons with CFS-like neurological
symptoms and normal blood counts could benefit from the administration of vitamin B-12 injections.
In these patients, problems such as numbness or tingling in the extremities, abnormal gait, memory loss, weakness of the limbs, changes in mood and personality and even fatigue were improved, and even resolved, with B-12 therapy. In addition, during this period of time Dr. Les Simpson was describing how changes in the red blood cells in persons with CFS reversed when high doses of B-12 were administered. With this in mind, we began treating patients with cyanocobalamin (a form of vitamin B-12 that is readily available in the U.S.) at doses from 1000 mcg weekly to 5000 mcg three times weekly, given subcutaneously (through injections under the skin).
Patients appeared to have a significant response at approximately 2000-2500 mcg, and reported increased energy levels, improved stamina or an enhanced sense of wellbeing within 12-24 hours of administration. The effects lasted two to three days on average. However, many patients required up to six weeks to achieve regular, consistent results, and a wide range of dosing proved to be effective, from 1000 mcg injected daily to 5000 mcg injected three times per week. To obtain a continuous and satisfactory level of improvement, we now recommend injections of 3000 mcg of cyanocobalamin every two to three days.
An informal poll of our patient population revealed that 50-80% improved to some extent with this simple therapy. However, we found that oral or nasal spray preparations of B-12 did not produce a demonstrable effect.
The vast majority of our patients had normal serum B-12 and folate levels prior to the start of therapy, which indicates that routine laboratory tests may not reveal a deficiency. It also suggests that our therapy was effective because vitamin B-12 was not being absorbed or utilized properly by individual cells.
Difficulties can arise at any point during metabolism of B-12, resulting in many negative effects on the body, including nerve damage. Potential problems can include:
–Transport failure-the B-12 does not make it through the cell wall from the bloodstream. This is problematic because once inside the cell, B-12 functions as a cofactor, which means that it helps start important chemical reactions that allow the cell to function.
–Failure to degrade completely-if the process of metabolism is working correctly, the B-12 compound is broken down in a series of reactions. When the enzymes (synthetase and reductase) that facilitate those reactions do not do their job, chemical byproducts can build up and nerve cells can be damaged.
–Dietary insufficiency-this rarely happens because many of today’s processed foods are supplemented with vitamins, including B-12.
Studies from SpectraCell Laboratories using the EMA technique (which measures the metabolic response of a patient’s blood cells to individual nutrients) demonstrated that more than 70% of 66 individuals with chronic fatigue-not necessarily CFS-demonstrated B-12 deficiency, compared to about 40% of the normal population. It follows logically that individuals with chronic fatigue syndrome would also experience abnormalities in B-12 metabolism.
At The Cheney Clinic, we measured homocysteine and methylmalonate (organic acids that are elevated when B-12 is not metabolized properly by cells) in CFS patients. Homocysteine was elevated in 33% of the individuals tested, methylmalonate in 38%, and both were elevated in 13%. Thus, about one third of CFS cases could perhaps have symptoms attributable to B-12 deficiency.
Researchers have hypothesized that the B-12 deficiency seen in CFS may be due to a genetic abnormality. The enzyme reductase, which plays a key role in B-12 metabolism, is controlled by multiple genes. Genes for a trait or enzyme occur in pairs, and how they act in combination determines how active the enzyme is. Dominant genes are expressed or translated more fully than recessive genes. Half of the population has two dominant genes for reductase, which causes normal activity of the enzyme. Approximately 40% have only one dominant gene, resulting in only 50% enzymatic activity. And 10% are homozygous (two recessive genes) with only 30% enzymatic activity. Swedish researchers examined the genetic makeup of 11 CFS patients with abnormal B-12 metabolism and determined that those who responded best to B-12 injections had normal reductase activity, and those that responded poorly had one or no dominant genes for reductase.
However, my experience suggests that inability to transport B-12 across the cell membrane is the major cause of abnormal B-12 metabolism in persons with CFS, because large doses of B-12 markedly improve cognitive ability, mood, irritability and numbness and weakness in a majority of patients. Those who respond poorly to high doses of B-12 may have low reductase activity. The latter should improve somewhat if they supplement their diet with folic acid,
which helps improve the action of this crucial enzyme. I generally recommend 1 mg of folic acid daily, in tablet form, for those individuals who do not respond well or at all to B-12 injections.
Two forms of B-12 are available to consumers: cyanocobalamin and hydroxycobalamin. Of the two, I have always preferred cyanocobalamin because it is less likely to cause adverse reactions and stings much less than hydroxycobalamin when injected. The cost of high dose B-12 therapy is approximately $8 to $10 per month.
Patients can be taught to administer their own injections of B-12 using the same lcc insulin syringes diabetics use. They will need to obtain a supply of the B-12 solution from their physician – cyanocobalamin is typically prepared in 10 ml or 30 ml multi-dose vials, and should be stored in a cool dark place because both heat and light degrade the product rapidly. A cabinet or refrigerator are satisfactory.
Large doses of B-12 could theoretically compete with other B-vitamins in the cell, so to prevent deficiencies I always recommend that patients starting injections supplement their diet with multivitamins containing B-vitamins as well as folate.
Toxicity and adverse effects
Toxicity or “poisoning” from cyanocobalamin, a form of B-12 that is combined with very small amounts of cyanide, has been the major cause of patient concern about high-dose B-12 therapy. I have not encountered any evidence of cyanide toxicity. The amount of cyanide administered is so minuscule that it affords wide margin of safety even at doses of 15,000 mcg per week. Although this dose may seem inordinately large, medical textbooks have long recommended doses of 1000 mcg per day (or 7000 mcg per week) for the treatment of nerve problems due to B-12 deficiency. The only exception is in individuals with kidney failure. In patients with normal B-12 levels and intact kidney function, excess cyanide and B-12 are simply excreted through the urine.
Subscribe to the World's Most Popular Newsletter (it's free!)
I have recommended high-dose B-12 to thousands of patients over the past 10 years and have seen no serious adverse effects. The major complaint about B-12 from patients is bruising at the injection site. This is harmless, goes away quickly and can usually be eliminated by inserting the needle perpendicular to the skin or using a longer needle. The “bruise” may actually be accidental leakage of the crimson-colored B-12 solution under the skin.
Although some drug references indicate that idiosyncratic reactions are not uncommon with B-12, I have only had one patient who developed hives and chills after an injection, and even that person could tolerate occasional small doses.
A rare individual will develop a raised red bump at the injection site, but this is usually attributable to agents added to the B-12 solution to inhibit the growth of bacteria in the vial and not the B-12 itself. In such cases, the pharmacist can prepare small vials of B-12 without the bacteria-inhibiting agent. With high doses of B-12, an acne-like rash also may occur, but the rash usually responds promptly to a reduction in dosage.
Some patients respond so well to B-12 that they become hyperactive-nervous and excitable-but this too can usually be resolved by reducing the dose. Because of this excitatory effect, I recommend that B-12 be administered in the morning, so that it will not interfere with sleep.
Very rarely, a patient’s urine will be faintly pink-tinged following a dose of B-12. This “cobalaminuria” occurs intermittently, and although it looks alarming, seems to be entirely benign.
Is B-12 therapy for you?
B-12 injections are an effective, safe and inexpensive treatment in the management of CFS. There is evidence that B-12 metabolism at the cellular level is abnormal in persons with CFS, possibly due to reduced transport of the vitamin across the cell membrane or abnormalities in the enzymes that help break it down inside the cell. The mechanism has yet to be defined, but in my clinical experience, large doses of B-12 provide improvement in energy and well-being in a majority of CFS patients. Persons with CFS who are interested in B-12 therapy and are willing to take an injection two to three times a week should consult with their physician.
Things to keep in mind about B-12 therapy
1. Don’t rule out therapy because of test results. Blood serum levels do not necessarily reflect a deficiency, so you may need more B-12 even if your test results are normal.
2. You must be comfortable with injections. Many individuals are not willing to get a shot two or three times a week. Unfortunately, the oral or nasal spray preparations are less effective than injections.
3. You can administer the shots yourself. If it is more convenient for you to inject yourself with B-12 at home, you can ask your physician to show you how and provide the injection solution.
4. Report adverse reactions. Be sure to tell your physician immediately if you experience a rash, skin discoloration, chills or any other reaction following an injection.
5. B-12 does not interact. There have been no reported instances of B-12 interacting in a negative way with medications or other nutritional supplements, so you can rest easy if you are taking other substances to treat your CFFDS.
6. Take a multivitamin a day. B-12 can potentially hinder your absorption of other vitamins-taking a supplement can help prevent additional deficiencies.
7. Results might not be immediate. It takes up to six weeks to see improvement with B-12 therapy, so be patient.
1. Lindenbaum J, et al., “Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis,” NEIM 1998; 318(26):1720-1728.
2. Beck WS, “Cobalarnin and the nervous system,” NEJM 1988; 318 (26):1752-4.
3. Carmel R, et al., “Hereditary defective cobalamin metabolism presenting as a neurological disorder in adulthood,” NEIM 1988; 318(26):1738-1741.
4. Simpson LO, “CIBA Symposium on Myalgic Encephatomeylitis,” Cambridge University, England, April 1990.
5. Personal communication with Dr. Luke R. Bucci, Director of Science and Quality at SpectraCell Laboratories, Houston, Texas, in a letter dated August 12,1994.
6. Regland B et al., “One-carbon metabolism and CFS,” presented at The Clinical and Scientific Basis of Chronic Fatigue Syndrome (international symposium), Sydney, Australia, February 1998.
7. Communications from Dr. Paul Cheney and the Department of Biochemistry at the University of North Carolina, 1994.
8. Sherertz EF, “Acneiform eruption due to megadose B-6 and B-12,” Cutis, 1991; 48: 119-120.