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

Vevelstad, Merete; Øiestad, Elisabeth Leere; Nerem, Elisabeth; Arnestad, Marianne; Bogen, Inger Lise

doi:10.1124/dmd.117.077263

Cited by 3 publications

(1 citation statement)

References 61 publications

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“…But once PMA/PMMA enters in the brain they start to release serotonin (like MDMA does), but these drugs also block the breakdown of serotonin by monoamine oxidase so it can reach toxic levels leading to the serotonin syndrome with hyperthermia, seizures and death. Also, PMA is a metabolite of PMMA,making their effects, in combination, stronger and increasing the risk of neurotoxicity. This toxicity and that of MDMA is also in part mediated by inhibition of the presynaptic 5‐HT reuptake transporter, also leading to 5‐HT syndrome …”

Section: Salutary Tales From the Last 2 Decades: The Then New Psychoamentioning

confidence: 99%

New psychoactive substances: Pharmacology influencing UK practice, policy and the law

Nutt

2020

Brit J Clinical Pharma

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This review covers the last 20 years of UK drug control policy leading up to the recent Psychoactive Substances Act. It explores policy decision made in relation to MDMA and mephedrone that not only were associated with increased drug harms overall but also had a significant detrimental effect on the UK research base. The new UK legislation on synthetic cannabinoids and other novel psychoactive substances threatens to do the same, showing that there is still much to learn from the decisions of the past. In future input from academic societies such as the BPS could help improve policy evaluation and policy development and so help avoid such problems in the future.

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Section: Salutary Tales From the Last 2 Decades: The Then New Psychoamentioning

confidence: 99%

New psychoactive substances: Pharmacology influencing UK practice, policy and the law

Nutt

2020

Brit J Clinical Pharma

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Cellular Uptake of Psychostimulants – Are High- and Low-Affinity Organic Cation Transporters Drug Traffickers?

et al. 2021

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Psychostimulants are used therapeutically and for illegal recreational purposes. Many of these are inhibitors of the presynaptic noradrenaline, dopamine, and serotonin transporters (NET, DAT, and SERT). According to their physicochemical properties, some might also be substrates of polyspecific organic cation transporters (OCTs) that mediate uptake in liver and kidneys for metabolism and excretion. OCT1 is genetically highly polymorphic, with strong effects on transporter activity and expression. To study potential interindividual differences in their pharmacokinetics, 18 psychostimulants and hallucinogens were assessed in vitro for transport by different OCTs as well as by the high-affinity monoamine transporters NET, DAT, and SERT. The hallucinogenic natural compound mescaline was found to be strongly transported by wild-type OCT1 with a Km of 24.3 µM and a vmax of 642 pmol × mg protein−1 × min−1. Transport was modestly reduced in variants *2 and *7, more strongly reduced in *3 and *4, and lowest in *5 and *6, while *8 showed a moderately increased transport capacity. The other phenylethylamine derivatives methamphetamine, para-methoxymethamphetamine, (-)-ephedrine, and cathine ((+)-norpseudoephedrine), as well as dimethyltryptamine, were substrates of OCT2 with Km values in the range of 7.9–46.0 µM and vmax values between 70.7 and 570 pmol × mg protein−1 × min−1. Affinities were similar or modestly reduced and the transport capacities were reduced down to half in the naturally occurring variant A270S. Cathine was found to be a substrate for NET and DAT, with the Km being 21-fold and the vmax 10-fold higher for DAT but still significantly lower compared to OCT2. This study has shown that several psychostimulants and hallucinogens are substrates for OCTs. Given the extensive cellular uptake of mescaline by the genetically highly polymorphic OCT1, strong interindividual variation in the pharmacokinetics of mescaline might be possible, which could be a reason for highly variable adverse reactions. The involvement of the polymorphic OCT2 in the renal excretion of several psychostimulants could be one reason for individual differences in toxicity.

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Investigation of Biotransformation Products of p-Methoxymethylamphetamine and Dihydromephedrone in Wastewater by High-Resolution Mass Spectrometry

et al. 2021

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There is a paucity of information on biotransformation and stability of new psychoactive substances (NPS) in wastewater. Moreover, the fate of NPS and their transformation products (TPs) in wastewater treatment plants is not well understood. In this study, batch reactors seeded with activated sludge were set up to evaluate biotic, abiotic, and sorption losses of p-methoxymethylamphetamine (PMMA) and dihydromephedrone (DHM) and identify TPs formed during these processes. Detection and identification of all compounds was performed with target and suspect screening approaches using liquid chromatography quadrupole-time-of-flight mass spectrometry. Influent and effluent 24 h composite wastewater samples were collected from Athens from 2014 to 2020. High elimination rates were found for PMMA (80%) and DHM (97%) after a seven-day experiment and degradation appeared to be related to biological activity in the active bioreactor. Ten TPs were identified and the main reactions were O- and N-demethylation, oxidation, and hydroxylation. Some TPs were reported for the first time and some were confirmed by reference standards. Identification of some TPs was enhanced by the use of an in-house retention time prediction model. Mephedrone and some of its previously reported human metabolites were formed from DHM incubation. Retrospective analysis showed that PMMA was the most frequently detected compound.

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

Cited by 3 publications

References 61 publications

New psychoactive substances: Pharmacology influencing UK practice, policy and the law

New psychoactive substances: Pharmacology influencing UK practice, policy and the law

Cellular Uptake of Psychostimulants – Are High- and Low-Affinity Organic Cation Transporters Drug Traffickers?

Investigation of Biotransformation Products of p-Methoxymethylamphetamine and Dihydromephedrone in Wastewater by High-Resolution Mass Spectrometry

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