Studies on distribution and metabolism of para-methoxymethamphetamine (PMMA) in rats after subcutaneous administration

Rohanová, Miroslava; Balı́ková, Marie

doi:10.1016/j.tox.2009.02.003

Cited by 27 publications

(14 citation statements)

References 32 publications

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“…The metabolite originating from hydrolysis is the para-methyl derivative of norephedrine, a psychoactive drug that is used as a stimulant, decongestant, and anorectic agent (Flavahan, 2005), suggesting that the M3 metabolite might have similar activities. Furthermore, both oxidations and aromatic hydroxylation are metabolic pathways typical of amphetamine-like compounds (Alleva, 1963;Dring et al, 1966;Ellison et al, 1966;Theobald and Maurer, 2007;Rohanova and Balikova, 2009;Maurer, 2010;Welter et al, 2014). However, the main metabolite found in both the plasma (A-C) Analysis was done in the same rats after the first dose (A), after the 14th dose (B), and after a 15th dose given after 48-hour washout (C).…”

Section: Discussionmentioning

confidence: 99%

Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4′-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects

Lucchetti

Marzo

Passoni

et al. 2017

J Pharmacol Exp Ther

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para-Methyl-4-methylaminorex (4,49-DMAR) is a phenethylamine derivative with psychostimulant activity whose abuse has been associated with several deaths and a wide range of adverse effects. We recently validated a high-performance liquid chromatography-tandem mass spectrometry method to measure the compound's concentrations in plasma, and we applied it to describe the pharmacokinetic properties of 4,49-DMAR after a single dose in rats. In this study, we investigated the brain disposition and metabolism of cis-4,49-DMAR after intraperitoneal injection as well as its central behavioral effects. Locomotor activity increased after a single injection of 10 mg/kg, peaking at 2 hours and disappearing at 5 hours; in these conditions, brain absorption was very rapid, (t max 5 30-60 minutes) and large (brain-to-plasma ratio 5 24); the half-life was approximately 50 minutes. After 14 daily doses, the compound's effect on locomotor activity was greater (approximately 20% compared with the effect after the first dose), but not for pharmacokinetic reasons. Using high-resolution mass spectrometry, we also identified four metabolites of cis-4,49-DMAR in the plasma and brain of treated rats. Semiquantitative analysis indicated low brain permeability and very low brain concentrations, suggesting that these metabolites do not contribute to central behavioral effects; however, the metabolite originating from oxidation of the paramethyl group (M2) persisted in the plasma longer and at higher concentrations than the parent molecule and could be used to evaluate drug intake in human consumers. Finally, we describe the rewarding effect of cis-4,49-DMAR in the conditioning place preference test, suggesting a high risk of addiction in humans.

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Section: Discussionmentioning

confidence: 99%

Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4′-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects

Lucchetti

Marzo

Passoni

et al. 2017

J Pharmacol Exp Ther

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“…The adverse subjective effects reported in this study after ingestion of tablets containing MDMA with PMMA largely support the existing toxicological findings by others of casualties and fatalities after consumption of PMMA or its metabolite PMA (Caldicott et al 2003;Johansen et al 2003;Becker et al 2003;Lin et al 2007). Extreme hyperthermia was described as one of the symptoms of PMMA intoxication, especially in crowded environments (Rohanova and Balikova 2009;Páleníček et al 2011). PMMA showed a more gradual peak concentration in the brain compared to MDMA, leading to a delayed pattern of activation and prolonged endurance of effects of the drug, with increased toxicity as consequence (Páleníček et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Linking the pharmacological content of ecstasy tablets to the subjective experiences of drug users

Brunt

Koeter

Niesink³

et al. 2011

Psychopharmacology

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“…PMR is particularly significant for drugs with a volume of distribution (Vd) above 3-4 L/kg [22]. Although the human Vd is not known for PMMA, 6.4 L/kg is reported in rats [23], and structurally related amphetamines have Vd's in the range of 3-6 L/kg. A PMMA heart/ peripheral blood ratio of 2.5 is reported (n = 1) [8].…”

Section: Comparison Of Blood Drug Concentrations In Fatal and Non-fatmentioning

confidence: 99%

“…With repeated PMMA use or overdosing, the MAO inhibition leads to greatly increased discharge of catecholamine in response to whatever dose of stimulants or stimuli [3]. The severely increased extraneuronal and peripheral serotonin levels result in acute serotonin syndrome [23], while the increased levels of other monoamines are responsible for most of the serious effects on the cardiovascular system [3].…”

Section: Cause Of Deathmentioning

confidence: 99%

The PMMA epidemic in Norway: Comparison of fatal and non-fatal intoxications

Vevelstad

Øiestad

Middelkoop

et al. 2012

Forensic Science International

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During a 6 month period (July 2010-January 2011) we observed 12 fatal intoxications and 22 non-fatal cases related to the drug paramethoxymethamphetamine (PMMA) in Norway (4.8 mill inhabitants). This toxic designer drug, also known as "Death", is occasionally found in street drugs offered as "ecstasy" or "amphetamine". The present study aimed to evaluate the cause of death, and to compare the PMMA blood concentrations in fatal and non-fatal cases. Methods for identification and quantification of PMMA are presented. The median age of fatalities was 30 years (range 15-50) with 67% males; in non-fatal cases 27 years (20-47) with 86% males. In the 12 fatalities, the median PMMA blood concentration was 1.92 mg/L (range 0.17-3.30), which is in the reported lethal range of 0.6-3.1 mg/L in peripheral blood and 1.2-15.8 mg/L in heart blood. In the 22 non-fatal cases, the median PMMA concentration was 0.07 mg/L (range 0.01-0.65). Poly-drug use was frequent both in fatal and non-fatal cases. The PMA concentrations ranging from 0.00 to 0.26 mg/L in both groups likely represented a PMMA metabolite. Three fatalities were attributed to PMMA only, six to PMMA and other psychostimulant drugs, and three to PMMA and CNS depressant drugs, with median PMMA concentrations of 3.05 mg/L (range 1.58-3.30), 2.56 (1.52-3.23) and 0.52 mg/L (0.17-1.24), respectively. Eight victims were found dead, while death was witnessed in four cases, with symptoms of acute respiratory distress, hyperthermia, cardiac arrest, convulsions, sudden collapse and/or multiple organ failure. In summary, all fatalities attributed to PMMA had high PMMA blood concentrations compared to non-fatal cases. Our sample size was too small to evaluate a possible impact of poly-drug use. A public warning is warranted against use and overdose with illegal "ecstasy" or "speed" drugs.

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Studies on distribution and metabolism of para-methoxymethamphetamine (PMMA) in rats after subcutaneous administration

Cited by 27 publications

References 32 publications

Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4′-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects

Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4′-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects

Linking the pharmacological content of ecstasy tablets to the subjective experiences of drug users

The PMMA epidemic in Norway: Comparison of fatal and non-fatal intoxications

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