Para-methoxymethamphetamine (PMMA): A study of risk factors for fatal intoxication with emphasis on metabolite pattern and CYP genetics

PMMA (para-methoxymethamphetamine) is, for unknown reasons, more toxic than MDMA (ecstasy). This thesis assessed risk factors for a fatal PMMA intoxication, with emphasis on CYP enzyme genetics, PMMA metabolite pattern, and active metabolites. This was accomplished by analyzing blood samples from fatal PMMA intoxications and non-fatal PMMA abuse cases for CYP genotypes, PMMA, and relevant metabolites, and by studies using human liver microsomes (HLM). During 2010-2012, 27 fatal PMMA intoxications were registered in Norway. The CYP2D6 enzyme was vital for the formation of most metabolites. We found no association between CYP2D6, 2C9, 2C19, or 3A5 enzyme genotypes and fatal outcome. PMMA was partly metabolized to the reactive catechol dihydroxymethamphetamine in HLM, but in lower amounts than formed from MDMA. The main risk factors were high/repeated doses of PMMA, concomitant use of (meth)amphetamine or heroin, unattended sleep, and unwitting intake of PMMA. Witnessed signs of poisoning were severe hyperthermia, convulsions, respiratory failure, unconsciousness, and cardiac arrest, attributable to a pronounced increase in serotonin and noradrenalin neurotransmission