V M. ANDREOLl, A. AGNOLI, and C. FAZIO The transfer of a methyl group
from a donor to an acceptor compound is a fundamental biochemie al
process long since known to biologists; the process is involved, for
instance, in the metabolism of porphyrins, nuc1eic acids, and fatty
acids. Only recently, however, did transmethylation processes reveal
their decisive role in CNS biochemistry - namely with the discovery that
such processes are linked with the biogenie amines that have been
conc1usively identified as the chemical mediators of neu- ronal
transmission and, more broadly, of behavior. The first suggestion that
transmethylation processes might be involved in the origina- tion of
certain mental diseases came from Harley-Mason (1952), who noticed that
many of the hallucinogenic substances known at that time contained
methyl radicals, and par- ticularly that mescaline represented the
product of O-methylation of dopamine in posi- tions 3, 4, and 5. This
hypothesis was put forward when the O-methylation of catechol- amines by
catechol-O-methyltransferases had not yet been described. Harley-Mason
further proposed that in the living organism the process of O-methyla-
tion might follow a "deviant" metabolie pathway, and that the
accumulation of abnor- mal methylated metabolites endowed with
hallucinogenic properties might be responsi- ble for the implementation
of some mental diseases, notably schizophrenia. He also called attention
to a substance, 3,4-dimethoxyphenylethylamine (3,4-DMPEA) as a possible
psychotogenic moleeule, on the strength of its capacity for producing
cata- tonia in experimental animals.