Jacob Schor, ND, FABNO
January 10, 2020
Vitamin B-12 may not be as safe as we once thought. Our routine of injecting vitamin B-12 indiscriminately into anyone who wants more energy just might not be the great idea that many of us think it is. That’s the thought that keeps arising in the back of my mind ever since reading a colleague’s offer to sell patients “B-12 gift packages” to share with friends and family.
There has been a long standing and widespread belief that B-12 is completely safe and that there is no harm in raising B-12 in the body to high levels. Believing this, we have happily injected B-12 into a range of patients and in high doses to see if it would help. This is a classic example of our practice refrain, “It won’t hurt, but it might help” that many of us routinely fall back on. And it does seem to help now and then. There is a widespread belief that B-12 acts as a pick me up, providing an invigoration and an increase of energy that will sustain a patient for days, weeks or even months. From time to time it resolves odd neuropathies. And of course, pernicious anemia. B-12 often works for that. At least when the cause is B-12 deficiency. Sometimes it’s folic acid deficiency or folinic acid but let’s not get stuck on the details.
This concern about B-12 not being totally safe is brought to mind by a paper written by Harvard researchers that was published in JAMA Network last year, which suggested the risk of hip fracture was worsened by vitamins B-12 and B-6. These researchers had seen hints of this in an earlier pair of randomized clinical trials. In this prospective cohort study, 75,864 women enrolled in the Nurses’ Health Study, were followed from 1984 to 2014. These women were interrogated extensively about food and supplements. Cumulative intakes of vitamins B-6 and B-12 were used to calculate relative risk of hip fractures. During this time period, 2,304 of the 75,864 women experienced a hip fracture. Median age at which they fractured their hips was 75.8 years. Average total intake of B-6 was 3.6 mg/day and B-12 was 12.1 μg/day. This included intake from all sources, both food and nutritional supplements. Women who took in more than 35 mg/day of B-6 had a 29% higher risk of having a hip fracture compared to women who had taken in less than 2 mg/day (RR, 1.29; 95% CI, 1.04-1.59). Women who received more than 30 μg/day of B-12 had a 25% higher risk of a hip fracture than those who received less than 5 μg/day. The risk of a hip fracture was almost 50% higher in women who had high intakes of both vitamins (B6 ≥35 mg/d and B12 ≥20 μg/day (RR, 1.47; 95% CI, 1.15-1.89). 
This should give all of us pause as many of the daily supplements our patients swallow far exceed these levels. Vitamin B-12 injections typically contain 1000 μg each.
Over the years we’ve certainly seen patients with high B-12 levels. Often as not the assumption is that their levels have risen because they are taking high doses and again, the past assumption is that this is fine. Sometimes their levels are high even without taking supplements. A concern about increased fracture risk should now be weighed against this.
There’s another concern that is less clearly defined that gives me an even greater pause. Circulating levels of B-12 in the blood tend to go up in some patients with cancer. A 2013 report published by that National Cancer institute told us that high plasma B-12 levels appear to be a marker for this disease.
Johan Arendt and several colleagues went through the Danish national medical registries and identified people with B-12 levels above the lower reference limit (≥200 pmol/L) during the period of 1998 and 2009. They then obtained data on cancer incidence of these people from 1998 to 2010. Cancer risks were calculated as standardized incidence ratios (SIR). In total, they looked at 333,667 people who started out without cancer and who were not being treated with B-12. Six percent had B-12 levels above the reference range (≥601 pmol/L). Cancer risk increased with B-12 levels. SIR more than tripled for people with moderately elevated B-12 levels (601-800 pmol/L). For people with more elevated levels, incidence was increased more than six-fold (greater than 800 pmol/L : RR: 6.27, 95% CI = 5.70 to 6.88; both P < .001).
For patients diagnosed with cancer, discovering that they have high B-12 levels is bad news. A second paper by Arendt and colleagues published in 2016 informs us that high B-12 levels in cancer patients are also associated with higher risk of mortality compared to patients with normal B-12 levels.
This study included 25,017 cancer patients whose B-12 levels had been measured up to a year prior to diagnosis. These patients were compared to just under 62,000 cancer patients whose B-12 levels were unknown.
Those with moderately elevated B-12 levels had a lower probability of 1-year survival (49.6%) than patients with normal levels (69.3%) or compared to the cohort with unknown levels (72.6%]). The higher the B-12 level, the lower the odds of survival. One-year survival was only 35.8%. in those with serum B-12 levels >800 pmol/L.
This obviously doesn’t mean that high B-12 killed these patients. These data just show us an association but not causation. A plausible explanation is that ‘bad cancers’ trigger the liver to release an abundance of B-12 into the blood and the worse the cancer is, the more B-12 is released into circulation. But still numbers like these should give one pause. It is possible that B-12 release is engineered by the cancer as B-12 is essential for rapidly growing cells to replicate their DNA and divide. Giving excessive doses of B-12 to cancer patients could conceivable aid and abet tumor growth. Not what we want to do.
Note: US labs report B-12 in ng/ml not in these nanogram per mole numbers as in Denmark. A few relevant conversions
800 pmol/liter = 1084 ng/ml
600 pmol/L = 813 ng/ml
200 pmol/L = 271 ng/ml
Normal range for B-12 is 200-900 ng/ml 
Now don’t get me wrong. Vitamin B-12 is useful for treating a broad range of conditions. In fact, the Natural Medicine Journal as I write this is in the process of reviewing a study by Polytarchou et al that suggests B-12 might be useful in heart failure.  So, like many things in life, there is a time and place where B-12 can be useful. But there are times when supplemental B-12 might not be a good idea. Our assumption that B-12 is always good and never bad is, in hindsight, myopic. Too little is an obvious problem. It’s looking like too much may also be a problem. Is that a surprise to anyone?
 Meyer HE, Willett WC, Fung TT, Holvik K, Feskanich D. Association of High Intakes of Vitamins B6 and B12 From Food and Supplements With Risk of Hip Fracture Among Postmenopausal Women in the Nurses’ HealthStudy. JAMA Netw Open. 2019 May 3;2(5):e193591.
 Arendt JF, Pedersen L, Nexo E, Sørensen HT. Elevated plasma vitamin B12 levels as a marker for cancer: a population-based cohort study. J Natl Cancer Inst. 2013 Dec 4;105(23):1799-805.
 Arendt JF, Farkas DK, Pedersen L, Nexo E, Sørensen HT. Elevated plasma vitamin B12 levels and cancer prognosis: A population-based cohort study. Cancer Epidemiol. 2016 Feb;40:158-65.
 Polytarchou K, Dimitroglou Y, Varvarousis D et al. Methylmalonic Acid and Vitamin B12 in Patients with Heart Failure. Hellenic J Cardiol. 2019 Nov 15. pii: S1109-9666(19)30286-6.