SINCE hallucinogenic drugs, mostly N-methylated compounds, can induce in human subjects psychotomimetic effects which markedly resemble certain symptoms encountered in schizophrenic disorders, it was natural to suspect that such N-methylated compounds could be produced in schizophrenic patients through an abnormal metabolism. This consideration taken together with the role of methionine in this phenomenon, gave rise to the methylation theory according to which schizophrenia should be due to an excessive N-methylation process. Although this concept has received some indirect support, certain limiting and unknown factors have perhaps prevented this idea to be developed in a more extensive manner. It seems to us now that one of the main reasons for it lay in the choice of the methyl donor. Up to now, S-adenosylmethionine was believed to be the only cofactor for Nmethylation reactions in the adrenal medulla as well as in the brain. Recently an unusual methyl donor for biogenic amines, 5-methyltetrahydrofolic acid was found to be involved in the reaction of an N-methylating enzyme from the rat brain (LADURON~). This new N-methyltransferase has already been characterized and appears to be quite different from the N-methylating enzyme (PNMT) of the adrenal medulla, namely in the specificity of its methyl donor (LADURON et ~1.~). Furthermore it has been demonstrated also that 5-methyl tetrahydrofolic acid is the most specific methyl donor for the N-methylation of catecholamines and indoleamines in the brain (LEYSEN and LADURON~). Our new working hypothesis is based mainly on the fact that folic acid and its main metabolite %methyltetrahydrofolic acid, rather than methionine, should be responsible for the enhanced N-methylation process assumed in schizophrenia. In this regard, it must be recalled that at least 65 % of folic acid is converted in the liver into 5_methyltetrahydrofolic acid which is preferentially retained in neural tissues (for reference see LADURON~). It is postulated that, in schizophrenic disorders, an excess of folate congeners could give rise to an increased or unusual formation of N-methylated amines like bufotenin, Nmethylserotonin, N,N’-dimethyltryptamine or others. In this regard, some dopamine derivatives, like epinine or N,N’-dimethyldopamine which have never been reported as being hallucinogenic, could play an important role, more especially as it seems at present well established that the antipsychotic action of neuroleptics is related to their dopamine receptor blocking activity (cf. this symposium). Our hypothesis has already received an indirect support in a preliminary clinical trial where folic acid was given to psychotic patients (VAN LOMMEL 1972: unpublished results quoted by LADURON~. 257