In 1946 the journal Blood called the new pill a "miracle drug". A few milligrams a day, and the worst anemias melt away: the blood count normalizes in front of the doctors' eyes. The tablet is called folic acid, synthesized a year earlier, and it quickly pushes aside the treatment used until then, injections of liver extract. It is cheaper, it is easier, it does not hurt.
Only a year later the same journals begin to publish another kind of report. The patients' blood is fine. The patients are not.
The blood gets better. The nerves do not.
The disease that the doctors then call pernicious anemia is in fact a vitamin B12 deficiency: the body has lost the ability to take it up. The shortage strikes on two fronts. In the bone marrow it stops the normal production of blood cells. In the nervous system it slowly damages the spinal cord and the peripheral nerves.
Folic acid in a high dose can unblock the first front: it hands over a detour for DNA synthesis, and blood formation starts again. The second front, though, is of no interest to it. The nerves want B12 and nothing else.
The result is the most treacherous combination possible: a treated blood marker and an untreated disease. The anemia, the old loud alarm bell of the deficiency, has gone quiet. The damage goes on in silence.
The window 1947–1951
In 1947 the first reports appear of patients who lose remission or develop neurological damage on folic acid. Only months after the excitement, an editorial in the New England Journal of Medicine rules that in this disease folic acid brings "no new benefit, only risk to the patient", and insists that it not be used as the sole treatment.
The numbers from the later review of the cases mark out the window with frightening precision. Of the 155 documented cases with neurological signs, almost all were diagnosed and treated between 1947 and 1951. In exactly those years vitamin B12 is not yet there as a medicine: it is isolated only in 1948, and quantities sufficient for routine treatment come only in the early 1950s. A whole profession was treating B12 deficiency with the one modern pill on the market that holds no B12.
The argument that is not over
Whether folic acid only failed to help, or actively sped up the damage, is disputed to this day. A review from 1995 finds that the nerve damage advanced at the same speed in patients treated with and without folic acid. An analysis from 2018 finds no link between the dose and the worsening, and declares the historical case unfounded. Against it stands the 1998 position of the US Institute of Medicine, which stands on exactly these cases from the 1940s to bring in an upper limit of 1 mg a day for folic acid: a limit that the food fortification programs in more than 80 countries still work to today.
History has no control group, and the argument will hardly be settled for good. But the lesson the two sides do not argue about is big enough.
The lesson that stayed
The blood count can be put right without the disease being treated. That is why normalized blood on folate intake does not rule out a B12 deficiency, and why modern diagnostics measure the two vitamins separately, and not their combined effect on the blood.
There is an older clue too, hidden at the very start of the story. The liver extracts that treated "pernicious anemia" for decades worked because they carried both substances at once: the folate and the B12. The natural packaging never separated them. The tablets separated them.
That is why the two vitamins are still read together: one writes the blood, the other guards the nerves, and the true picture shows only when both are on the table.
Sources
- Robert J. Berry, Lack of Historical Evidence to Support Folic Acid Exacerbation of the Neuropathy Caused by Vitamin B12 Deficiency, The American Journal of Clinical Nutrition 110(3), 2019: 554–561.
- C. J. Dickinson, Does Folic Acid Harm People with Vitamin B12 Deficiency?, QJM 88(5), 1995: 357–364.
- Institute of Medicine, Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline, National Academies Press, 1998.
- NIH Office of Dietary Supplements, Folate: Fact Sheet for Health Professionals.
