The Antemortem Neurobehavior in Fatal Paramethoxymethamphetamine Usage

Abstract

Paramethoxymethamphetamine (PMMA) is an emerging and prevalent psychoactive drug with a structure analogous to amphetamine and related psychostimulants. However, the neurobehavioral effect is only studied in experimental animals and is barely mentioned in human. The authors report the antemortem neurobehavioral manifestations in 8 patients with PMMA use. There were 2 different antemortem presentations. The first group of patients showed delirium, hypertalkativity, and incoherence speech and then turned into convulsion and death. They did not exhibit the typical hyperdopaminergic movement disorder. The second group of patients gradually fell asleep and then suffered respiratory or cardiovascular collapse. The heart blood PMMA level was higher in the second group than in the first group of patients. Forensic autopsy showed variable findings, ranging from no remarkable change to significant pathological damage similar to serotonin syndrome in both groups of patients. PMMA seems to enhance serotoninergism than dopaminergism, and exerts a concentration-related dual effect on human.

Studies on Para-Methoxymethamphetamine (PMMA) Metabolite Pattern and Influence of CYP2D6 Genetics in Human Liver Microsomes and Authentic Samples from Fatal PMMA Intoxications

“…The main PMMA metabolite formed in our HLM study was OH-MA (pholedrine), constituting 87% of the metabolized PMMA, whereas the minor metabolites PMA, OH-A, and di-OH-MA constituted only 1.0%-2.9% after 4 hours of incubation. In the fatal PMMA intoxications, which all exhibited PMMA levels within the lethal range above 2.8 mM (Chen et al, 2012;Vevelstad et al, 2012Vevelstad et al, , 2016aKronstrand et al, 2015;WHO, 2015), the detected metabolites were in general consistent with the results in HLMs. The formation of the metabolite PMA was, however, more pronounced in vivo compared with the in vitro HLM experiments.…”

“…The low concentrations of PMMA metabolites observed in the blood samples may, however, indicate that death occurred within a few hours after PMMA exposure. This hypothesis is in keeping with the available case information and the existing literature on PMMA toxicity (Chen et al, 2012;Vevelstad et al, 2012Vevelstad et al, , 2016b.…”

“…A substrate concentration of 100 mM PMMA and MDMA was chosen to enable detection of metabolites present at low concentrations. The PMMA concentrations measured in fatal intoxications are usually 3-40 mM in blood (Lin et al, 2007;Chen et al, 2012;Lurie et al, 2012;Nicol et al, 2015;Vevelstad et al, 2016b) and probably 2-6.5 times higher in liver tissue based on findings for similar drugs like PMA and methamphetamine/amphetamine (Felgate et al, 1998;McIntyre et al, 2013), which suggests that PMMA concentrations of 100 mM in liver tissue may be representative for fatal PMMA intoxications. Similar drug concentrations and liver/blood ratios have also been reported in fatal MDMA intoxications (Elliott, 2005).…”

“…ABBREVIATIONS: 2C-B, 4-bromo-2,5-dimethoxyphenethylamine; COMT, catechol-O-methyl-transferase; di-OH-A, 3,4-dihydroxyamphetamine (dihydroxyamphetamine, a-methyldopamine); di-OH-MA, 3,4-dihydroxymethamphetamine (dihydroxymethamphetamine, N-methyl-a-methyldopamine); EM, extensive metabolizer; HLM, human liver microsome; HM-A, 4-hydroxy-3-methoxyamphetamine; HM-MA, 4-hydroxy-3-methoxymethamphetamine; HPLC, high performance liquid chromatography; IS, internal standard; LC-MS, liquid chromatography mass spectrometry; MDA, 3,4-methylenedioxyamphetamine; MDMA, 3,4-methylenedioxymethamphetamine; ME, matrix effect; MQ water, Milli-Q water; NADPH, nicotinamide adenine dinucleotide phosphate; OH-A, 4-hydroxyamphetamine; OH-MA, 4-hydroxymethamphetamine; P450, cytochrome P450); pHLM, pooled human liver microsome; PM, poor metabolizer; PMA, para-methoxyamphetamine (4-methoxyamphetamine); PMMA, paramethoxymethamphetamine (4-methoxymethamphetamine); QC, quality control; SULT, sulfotransferase; UGT, uridine diphosphate glucuronosyltransferase; UHPLC-MS/MS, ultra-high-performance liquid chromatography-tandem mass spectrometry; UM, ultrarapid metabolizer. considered lethal (Chen et al, 2012;Vevelstad et al, 2012Vevelstad et al, , 2016aKronstrand et al, 2015;WHO, 2015). PMMA toxicity usually manifests as serotonin syndrome.…”

“…PMMA toxicity usually manifests as serotonin syndrome. Intoxication symptoms range from mild hyperthermia, neuromuscular hyperactivity and confusion, to fatal hyperthermia, convulsions, coma, respiratory distress, hypoglycemia, cardiac arrest, and multiple organ failure (Chen et al, 2012;Vevelstad et al, 2012;Nicol et al, 2015). Fatal PMMA intoxications have also been associated with PMMA concentrations in the low "recreational range."…”