How Recommendations Were Formulated
by Jack Norris, RD | Last updated: August 2013
Chew 2,000 µg once a day, for 2 weeks. You can break the remaining tablets in half or quarters for Step #2. It's okay to take more than recommended. Then follow the advice under Step #2.
The Step 1 recommendations geared to replenish one's B12 stores are based on the success that people with B12 malabsorption problems have had with oral B12 supplements (as described next).
Intramuscular injections (IMI) of B12 are the typical way to treat B12 deficiency. The injections can be painful and expensive. Norberg (1) (1999, Sweden) points out that investigations in the 1950s and 60s showed that oral B12 is absorbed by an alternative pathway not dependent on intrinsic factor or an intact ileum. Approximately 1% of an oral dose in the range of 200-2000 µg/day was absorbed by the alternative pathway in those investigations. Based on this research, oral treatment, rather than IMI, has been in use for the majority of B12 deficiency cases in Sweden since the early 1970s.
|Table 1. B12 Oral Administration Vs. Injection (Kuzminski et al.)|
|Serum B12 (pg/ml)||Serum MMA (µmol/l)||HCY (µmol/l)|
|After 4 months|
|Oral 2000 µg/day||1005a||.169b||10.6|
a,b - Statistically significant difference between groups with same letters
In a literature review encouraging the use of oral B12 therapy over injections for patients with pernicious anemia, Lederle (2) (1991, USA) reported that Swedish investigators recommend 2000 µg of oral B12 twice a day or injections to replenish B12 stores. After initial therapy, doses of 1000 µg/day appear to be enough.
Kuzminski et al (3). (1998, USA) studied 33 newly diagnosed B12-deficient patients (almost all had malabsorption) who received cyanocobalamin as either 1 mg intramuscularly on days 1, 3, 7, 10, 14, 21, 30, 60, and 90; or 2000 µg orally on a daily basis for 120 days (4 months). See Table 1.
Kuzminski et al. conclude that 2000 µg/day of oral cyanocobalamin was as effective as 1000 µg injected intramuscularly each month, and may be superior.
Delpre & Stark (4) (1999, Israel) studied patients with B12 deficiency to see if B12 can be absorbed by holding a tablet under the tongue, known as sublingual. The theory behind sublingual is that the mucous membranes under the tongue are efficient at absorbing certain molecules, particularly if combined with something fat soluble such as a cyclodextrin. 5 patients had pernicious anemia, 7 were vegetarians, and 2 had Crohn's disease (which can prevent the absorption of B12 in the ileum). The patients held two 1000 µg B12 tablets (equaling 2,000 µg/day), made by Solgar, under their tongues for 30 minutes until completely dissolved. This was done for 7 to 12 days. Average serum B12 levels went from 127.9 ± 42.6 to 515.7 ± 235. All patients' serum B12 normalized. There were no side effects and all patients preferred this to injections. Unfortunately, Delpre & Stark did not include a control group who chewed the B12 tablets, so there is no way to know if taking the tablets sublingually was more effective than chewing and swallowing them. On the basis of Kuzminski et al. above, chewing seems to be as effective if done for 3 months.
Please note that the large doses mentioned in this section are for people with B12 malabsorption (or vegans who have neglected their B12 intake for a few months). People without malabsorption problems or current B12 deficiency do not need such large doses; hence Step 2 of the recommendations.
The current U.S. RDA for vitamin B12 is 2.4 µg (6). However, this RDA was based on how much B12 is needed to prevent macrocytic anemia rather than how much is needed for ideal homocysteine or methylmalonic acid levels. Recently, research has been indicating a need for more B12 than the current RDA.
A 2010 paper by Bor et al. (13), showed that in healthy people aged 18-50, a vitamin B12 intake of 4 to 7 µg/day was associated with the lowest methylmalonic acid and homocysteine levels (6). They reviewed other research from the past 10 years, primarily on older populations, that indicates the ideal B12 intake is 6 to 10 µg/day. Their review covered the following papers:
Vogiatzoglou A, Smith AD, Nurk E, et al. Dietary sources of vitamin B-12 and their association with plasma vitamin B-12 concentrations in the general population: the Hordaland Homocysteine Study. Am J Clin Nutr 2009;89:1078-87.
Bor MV, Lydeking-Olsen E, Moller J, Nexo E. A daily intake of approximately 6 micrograms vitamin B-12 appears to saturate all the vitamin B-12-related variables in Danish postmenopausal women. Am J Clin Nutr 2006;83:52-8.
Kwan LL, Bermudez OI, Tucker KL. Low vitamin B-12 intake and status are more prevalent in Hispanic older adults of Caribbean origin than in neighborhood-matched non-Hispanic whites. J Nutr 2002;132: 2059-64.
Tucker KL, Rich S, Rosenberg I, et al. Plasma vitamin B-12 concentrations relate to intake source in the Framingham Offspring study. Am J Clin Nutr 2000;71:514-22.
Vitamin B12 is more easily absorbed from fortified foods (because it is not bound to protein), so vegans will not need quite as high an intake as meat-eaters. Because of this, I will not distinguish between the ages for vegans, who are getting all their B12 from fortified foods or supplements.
Of the papers above, Bor et al. (2006) and Vogiatzoglou et al. (2009) correlated B12 intake to methylmalonic acid (MMA) and homocysteine (HCY). They found that 6 and 6-10 µg/day, respectively, were associated with the lowest levels of MMA and HCY. Because these were older populations whose protein-bound B12 ability was probably decreased, and because, according to the Institute of Medicine, absorption of non-protein-bound B12 does not appear to decrease with age (6), I will stick with Bor et al.'s 2010 finding which were on people ages 18 to 50.
Note: Fortified foods represented 29% of intake in the Bor et al. (2010) study.
According to the Institute of Medicine, the second of two doses of B12 eaten 4-6 hours apart is absorbed as well as the first (6).
Therefore, a straight calculation that vegans need at least 2 doses of 2 µg per serving per day is easy to make. If you cannot find fortified foods with 2 µg per serving, you should eat more servings or take supplements.
Unlike the studies above that measured B12 intakes from food and compared it to MMA and HCY levels, there is little research looking at what level of supplements people need.
|Table 2. B12 Levels in India (2010) Study|
|2 µg B12 / day||10 µg B12 / day|
|Plasma Hcy (µmol/l)|
Instead, we will have to primarily extrapolate from known absorption rates to get the ideal levels of small-dose supplements that will be linked to the lowest MMA and HCY levels.
There is one study from India (2010) in which subjects, who were vegetarian and somewhat B12-deficient with high homocysteine levels, were given doses of either 2 µg or 10 µg of B12 each day for a year (12). See Table 2.
While both doses lowered homocysteine, neither 2 µg nor 10 µg was enough to lower it to an ideal level of less than 8 mmol/l.
|Table 3. B12 Absorption Rates|
|Food / Oral Dose||% absorbed||µg absorbed (avg)c|
|.1 µg 7||77%||0.08|
|.5 µg7,8||71-90%||.35-.45 (.4)|
|1 µg6-9||50-80%||.5-.8 (.6)|
|2 µg7-9||40-50%||.8-1 (.9)|
|5 µg6-10||20-55%||1-2.8 (1.7)|
|50 µg8,9||3%||1.5 (1.5)|
|1,000 µg6,8||1-1.5%b||10-15 (12.5)|
|aNumber represents only the fortified portion of B12 in the milk | bEven without intrinsic factor | cAverage of all measurements (i.e., not the mid-range)|
Absorption rates of different doses of cyanocobalamin have been measured and appear in Table 3.
The data in the table is somewhat mixed. A 5 µg supplemental dose of cyanocobalamin appears to saturate the intrinsic factor absorption mechanism. Thus, B12 absorption drops to 1-1.5% for any additional B12 ingested above 5 µg. But in the results in the table, the total amount absorbed from 5 to 50 µg is all about the same.
Considering all the evidence, I think we should assume that absorbing 2 to 3 µg per day is ideal. Depending on how you calculate the absorption rates, to get the same absorption rates from supplements in one dose, you would need 25 µg to 240 µg per day (11).
Because these extrapolations are imprecise and because it seems much too high that someone would need 240 µg per day (based on anecdotal evidence and the fact that vegans getting an average of 5.6 µg of B12 per day had healthy homocysteine levels on average (14)), I have adjusted the upper limit down to 100 µg.
Some people like to take large dose supplements, so let's do the math on those. The people in Bor et al. (2010) were absorbing 14 to 24.5 µg of B12 per week. If you assume a 1.25% absorption rate from high dose supplements, you would need 1,120 to 1,960 µg per week. To be safe, I would recommend 1,000 µg twice per week.
A 2003 study compared 500 µg per day via the sublingual and oral routes (15). The results were that sublingual was no better than oral B12 at raising vitamin B12 levels or improving B12 activity (as measured by homocysteine and methylmalonic acid levels). The report did not specifically state whether the tablets were chewed or not (it's probably safe to assume they were swallowed whole). If someone has any reason to believe their stomach acid is not strong enough to dissolve a B12 table or capsule, or for any other reasons believes it is not dissolving, then chewing a tablet is advised.
Summary: Based on the studies below, it appears that 500 - 1,000 µg per day of cyanocobalamin is the ideal amount for people over 65 years of age to take in a daily dose.
There have been at least four relevant studies for how much vitamin B12 people over 65 years need, based on a once daily supplement. To my knowledge all of these supplements were cyanocobalamin.
A 2005 clinical trial from the Netherlands found that among people aged 70-94, who had vitamin B12 deficiency but were otherwise healthy, 16 weeks of 500 µg/day of cyanocobalamin was required to get MMA levels in the healthy range. Other doses tested were 2.5, 100, 250, and 1,000 µg (16).
A 2002 observational study from Canada of 242 people aged 70-94 without vitamin B12 deficiency found that those taking a daily supplement had significantly lower MMA levels (173 vs. 188 µmol/l; p = .042). However, there were many even in the daily supplement group who had elevated MMA levels. The range of supplements was from 2.6-37.5 µg/day with intakes being spread out about evenly over the range (17).
In a 2013 clinical trail from the UK in 100 people aged 65-86 with poor B12 status, 500 µg/day of cyanocobalamin was required to normalize MMA levels in 75-85% of the participants over 8 weeks. 500 µg was significantly better than 10 or 100 µg (18).
In a 2002 study from Seattle on 23 people 65 years and older with B12 deficiency but otherwise healthy, 1,000 µg of B12 was required to get the average MMA level into the normal range, as compared to 10 and 100 µg. This study was continuous in that first they put everyone on 10 µg for 6 weeks (moved average MMA from 581 to 400 nmol/l), then 100 µg for 6 weeks (moved average MMA from 400 to 380 nmol/l), and then 1,000 µg for 6 weeks (moved average MMA from 380 to 200 nmol/l). The final 6 weeks resulted in a big drop after the 2nd six weeks resulted in only a small drop (19).
6. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 1998.
10. Heyssel RM, Bozian RC, Darby WJ, Bell MC. Vitamin B12 turnover in man. The assimilation of vitamin B12 from natural foodstuff by man and estimates of minimal daily dietary requirements. Am J Clin Nutr. 1966 Mar;18(3):176-84.
12. Deshmukh US, Joglekar CV, Lubree HG, Ramdas LV, Bhat DS, Naik SS, Hardikar PS, Raut DA, Konde TB, . Wills AK, Jackson AA, Refsum H, Nanivadekar AS, Fall CH, Yajnik CS. Effect of physiological doses of oral vitamin B12 on plasma homocysteine: a randomized, placebo-controlled, double-blind trial in India. Eur J Clin Nutr. 2010 May;64(5):495-502.
13. Bor MV, von Castel-Roberts KM, Kauwell GP, Stabler SP, Allen RH, Maneval DR, Bailey LB, Nexo E. Daily intake of 4 to 7 microg dietary vitamin B-12 is associated with steady concentrations of vitamin B-12-related biomarkers in a healthy young population. Am J Clin Nutr. 2010 Mar;91(3):571-7.
14. Haddad EH, Berk LS, Kettering JD, Hubbard RW, Peters WR. Dietary intake and biochemical, hematologic, and immune status of vegans compared with nonvegetarians. Am J Clin Nutr. 1999;70(suppl):586S-93S.
15. Sharabi A, Cohen E, Sulkes J, Garty M. Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route. Br J Clin Pharmacol. 2003 Dec;56(6):635-8. | link
16. Eussen SJ, de Groot LC, Clarke R, Schneede J, Ueland PM, Hoefnagels WH, van Staveren WA. Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial. Arch Intern Med. 2005 May 23;165(10):1167-72. | link
17. Garcia A, Paris-Pombo A, Evans L, Day A, Freedman M. Is low-dose oral cobalamin enough to normalize cobalamin function in older people? J Am Geriatr Soc. 2002 Aug;50(8):1401-4. | link
18. Hill MH, Flatley JE, Barker ME, Garner CM, Manning NJ, Olpin SE, Moat SJ, Russell J, Powers HJ. A vitamin B-12 supplement of 500 μg/d for eight weeks does not normalize urinary methylmalonic acid or other biomarkers of vitamin B-12 status in elderly people with moderately poor vitamin B-12 status. J Nutr. 2013 Feb;143(2):142-7. | link
19. Rajan S, Wallace JI, Brodkin KI, Beresford SA, Allen RH, Stabler SP. Response of elevated methylmalonic acid to three dose levels of oral cobalamin in older adults. J Am Geriatr Soc. 2002 Nov;50(11):1789-95. | link