Nonlinear Pharmacokinetics of (±)3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) and Its Major Metabolites in Squirrel Monkeys at Plasma Concentrations of MDMA That Develop After Typical Psychoactive Doses

Abstract

At certain doses, the psychoactive drug (Ϯ)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") destroys brain serotonin axon terminals. By causing increases in plasma MDMA concentrations that exceed those predicted by the increase in dose, nonlinear pharmacokinetics has the potential to narrow the range between safe and neurotoxic doses of MDMA. The present study sought to determine whether the pharmacokinetics of MDMA in nonhuman primates are nonlinear and, if they are, to identify plasma concentrations of MDMA at which nonlinear accumulation of MDMA occurs. Four different oral doses of MDMA were tested in the same six squirrel monkeys in random order. At each dose, pharmacokinetic parameters for MDMA and its metabolites 3,4-dihydroxymethamphetamine (HHMA), 4-hydroxy-3-methoxymethamphetamine (HMMA), and 3,4-methylenedioxyamphetamine were determined. Doses were selected to be equivalent to 0.4, 0.8, 1.6, and 2.8 mg/kg doses in humans. The maximal concentration (C max ) and area under the curve (AUC) of MDMA increased nonlinearly with dose, whereas the C max and AUC of the metabolites HHMA and HMMA remained relatively constant. Nonlinear MDMA pharmacokinetics occurred at plasma MDMA concentrations of 100 to 300 ng/ml and above. The half-life (T 1/2 ) of MDMA and its metabolites also increased with dose. These results firmly establish nonlinear pharmacokinetics for MDMA in squirrel monkeys and indicate that nonlinear MDMA accumulation occurs at plasma MDMA concentrations that develop in humans taking typical doses. By raising MDMA concentrations and prolonging its action, nonlinear pharmacokinetics and T 1/2 prolongation, respectively, may influence the likelihood and severity of MDMA toxicities (including brain serotonin neurotoxicity).

In vivo Effects of Abused ‘Bath Salt’ Constituent 3,4-methylenedioxypyrovalerone (MDPV) in Mice: Drug Discrimination, Thermoregulation, and Locomotor Activity

“…The pattern of responding after administration of 1.0 mg/kg MDPV was quite similar, and it seems likely that a higher dose of MDPV would look very similar indeed to what we have previously seen with 3.0 mg/ kg MDMA. We have also reported that cumulative doses of MDMA lead to higher concentrations of MDMA in plasma, 3,4-Methylenedioxypyrovalerone in mice WE Fantegrossi et al as compared with administration of an equivalent bolus dose, revealing that, consistent with previous studies in rats (Chu et al, 1996), squirrel monkeys (Mechan et al, 2006;Mueller et al, 2008), and humans (de la Torre et al, 2000), metabolism is also decreased when the dose is administered cumulatively in the mouse . Analogous studies have not yet been performed with MDPV, but it is possible that this compound also displays nonlinear pharmacokinetics, which may explain the apparent potency differences here observed when the drug was administered cumulatively, vs when it was given as a single bolus dose.…”

Nonlinear Pharmacokinetics of (±)3,4-Methylenedioxymethamphetamine (MDMA) and Its Pharmacodynamic Consequences in the Rat

“…There are discrepancies in whether MDMA follows nonlinear pharmacokinetics in rats, as documented in humans, monkeys, and mice (de la Torre et al, 2000;Kolbrich et al, 2008b;Mueller et al, 2008;Scheidweiler et al, 2011). Green et al (2009Green et al ( , 2012 compared literature values for plasma MDMA concentrations following highdose MDMA administration in rats (i.e., 5-20 mg/kg via i.p., s.c., or po routes) to those produced by low-dose administration in humans (i.e., 0.5-2 mg/kg po).…”

Pharmacodynamic interactions between MDMA and concomitants in MDMA tablets on extracellular dopamine and serotonin in the rat brain

“…Several studies suggest a non-linear pharmacokinetic response to MDMA in human, monkey and rat (Kolbrich et al, 2008;de la Torre et al, 2000;Chu et al, 1996;Mueller et al, 2008). There have been a few reports regarding the physical or pharmacological effects resulting from interactions caused by MDMA tablet intake or multi-drug abuse.…”