Schizophrenia transmethylation hypothesis

The transmethylation hypothesis depended on the psychosis of mescaline as an example of how methylated compounds similar in structure to the monoamine neurotransmitters could be psychotogenic, and demonstrated how methionine, the precursor of the methyl donor S-adenosylmethionine, could exacerbate the psychotic symptoms of schizophrenia in patients. This theory was fed by studies of the now notorious pink spot, an amine found in paper chromatography of urine extracts from schizophrenics and thought to be 3,4-dimethoxyphenylethylamine (i.e., O-methylated dopamine). Subsequent studies eventually identified this as another compound or compounds, primarily of dietary origin. Another methylated derivative erroneously proposed to be found in higher quantities in schizophrenia was dimethyltryptamine. This compound is similar in structure to LSD, the hallucinogenic nature of which was the key to the serotonin deficiency hypothesis, which proposed that the known antagonism of serotonin (5-HT) by LSD indicated that psychotic disorders such as schizophrenia may result from a hypofunction of 5-HT. 

Noting the structural resemblance of serotonin to the hallucinogenic indoles dimethyl tryptamine (DMT) and bufotenin, researchers proposed that psychotic symptoms were caused by these or similar compounds generated in schizophrenics by the abnormal transmethylation of endogenous indoleamines (21). Unfortunately, studies were unable to confirm increases in methylated indole amines in the plasma or CSF of schizophrenic patients versus controls (22). The transmethylation hypothesis is also questioned by the recognition that LSD-induced psychosis differs significant ways from the signs and symptoms of schizophrenia (23). 

Another aspect of the transmethylation hypothesis involves the administration of methyl donors (L-methionine) or methyl acceptors (niacin, niacinamide) to schizophrenic patients in order to exacerbate or alleviate, respectively, the psychotic state. Although L-methionine appeared to intensify some schizophrenic symptoms (see Kety), it did not increase the urinary levels of N- or 0-methylated amines. Moreover, the beneficial results reported by Hoffer et al on the use of methyl acceptors in schizophrenia have not been confirmed by other investigators. ... 

In addition, GSH dysregulation might play a role in the framework of the Single-Carbon Hypothesis of schizophrenia originally proposed by Smythies et al. (Smythies et al., 1997). In the transmethylation pathway, methionine is converted to homocysteine providing methyl groups to DNA, lipids and proteins. 

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