Methamnetamine (PAL-1046), an amphetamine-based new psychoactive substance that causes excessive serotonin release, is not regulated in most countries and had no prior metabolism studies. Using human liver microsomes and flavin-containing monooxygenase analyzed by liquid chromatography-quadrupole time-of-flight mass spectrometry, eight phase I metabolites were identified. Metabolic processes include N-demethylation, N-hydroxylation, and aromatic hydroxylation. N-hydroxylated metabolites were confirmed using expressed FMOs. The major metabolite results from hydroxylation of the naphthalene ring. These findings may help detect methamnetamine ingestion by users.
Two synthetic tryptamines, 4-AcO-DET and 4-HO-MET, are abused as recreational hallucinogens and may pose unknown health risks. In laboratory tests, both substances increased the proliferation of rat heart cells in a concentration-dependent manner, prolonged QT intervals in rats, and inhibited potassium channels in hamster cells, indicating potential cardiotoxicity. Expression of the PAK1 protein, involved in cardiovascular function, did not change. The findings suggest these new psychoactive substances could cause adverse cardiovascular effects, supporting evidence for their legal scheduling.