1. Twenty-one patients with pernicious anemia were maintained on synthetic folic acid (pteroylglutamic acid) therapy alone for periods ranging from eight to seventeen months. Satisfactory blood levels were maintained in all cases receiving daily oral doses of 1.25 to 15.0 mg. Severe hematologic relapse occurred within six months in a case treated with monthly injections of 30 mg.
2. Synthetic folic acid in oral doses of 15 mg. daily induced satisfactory hematopoietic responses in 3 patients with pernicious anemia in severe relapse, but only slight hematopoietic response in a fourth patient with mild pernicious anemia but severe subacute combined degeneration of the spinal cord.
3. Ten patients showed a significant improvement in blood values for a few months after substitution of folic acid for liver extract. With one exception these subsided after six or more months to pre-folic acid levels comparable with those previously maintained with liver extract alone.
4. These observations suggest that a combination of orally administered folic acid and parenterally injected liver extract may maintain a better hematologic status than either substance alone.
5. A previously untreated patient with severe subacute combined degeneration of the spinal cord failed to show improvement in neural disease during twentyeight days of folic acid therapy.
6. Eleven patients developed, or showed progression of, subacute combined degeneration of the spinal cord during folic acid treatment. Neurologic disease developed in most of these patients when the peripheral blood was normal.
7. One patient showed an extremely explosive onset and rapid progression of neural disease. The progression of the disease was rapid in 3 other cases.
8. The institution of liver extract therapy in adddition to folic acid in 5 patients who developed subacute combined degeneration during folic acid maintenance therapy failed to prevent progression of the disease in 4 cases, and only partially arrested the disease in the fifth, in which improvement occurred more rapidly when folic acid was discontinued.
9. Subacute combined degeneration occurred with greater frequency in patients on large daily doses of folic acid than it did in patients with small or intermittent doses.
10. The possibility is discussed that folic acid in large daily doses may actually precipitate or aggravate neurologic disease.
11. It is suggested that folic acid may interfere with the metabolism of 1(+) glutamic acid in the central nervous system and possibly disturb the formation or function of acetylcholine.