Folate deficiency and decreased brain 5-hydroxytryptamine synthesis in man and rat

FOLATE deficiency was once considered to belong exclusively to the field of haematology. However, recently there have been reports of neuropsychiatrie symptoms in folate-deficient patients1–7. Among the most frequent symptoms are mild poly-neuropathies, fatigue, mild depression and abnormal intellectual functioning. These symptoms, which can occur in the absence of any severe haematological changes at routine haematological testing, are responsive to folate therapy. Excess folate can also produce undesirable side effects. One study on the effect of pharmacological doses of folate (15 mg daily) had to be abandoned after 1 month because of side effects such as altered sleep patterns, malaise, irritability and overactivity5; the same clinical complaints were found in some of our patients who received folic acid therapy and in whom folate levels were very high (M. I. B., unpublished data). In studies on rats, behavioural deficits were found in animals fed diets that were either deficient6 or over-supplemented7 with folate. Both active and passive avoidance behaviour was affected. In this study we have looked for biochemical changes associated with folate deficiency and over-supplementation. Because the regional distribution of 5-methyltetrahydrofolate in the brain is similar to that of 5-hydroxytryptamine (5-HT)8 we looked at the latter. We found that the concentration of the 5-HT metabolite 5-hy-droxyindoleacetic acid (5-HI A A) is low in the lumbar cerebrospinal fluid (CSF) of folate-deficient patients who have folate-responsive neuropsychiatrie symptoms. We also found low brain 5-HT levels in the brains of rats fed folate-deficient or over-supplemented diets. Thus, there is a close association between folate-dependent behavioural effects and low brain 5-HT.