Lost in translation: preclinical studies on 3,4‐methylenedioxymethamphetamine provide information on mechanisms of action, but do not allow accurate prediction of adverse events in humans

Abstract

Methylenedioxymethamphetamine (MDMA) induces both acute adverse effects and long-term neurotoxic loss of brain 5-HT neurones in laboratory animals. However, when choosing doses, most preclinical studies have paid little attention to the pharmacokinetics of the drug in humans or animals. The recreational use of MDMA and current clinical investigations of the drug for therapeutic purposes demand better translational pharmacology to allow accurate risk assessment of its ability to induce adverse events. Recent pharmacokinetic studies on MDMA in animals and humans are reviewed and indicate that the risks following MDMA ingestion should be re-evaluated. Acute behavioural and body temperature changes result from rapid MDMA-induced monoamine release, whereas long-term neurotoxicity is primarily caused by metabolites of the drug. Therefore acute physiological changes in humans are fairly accurately mimicked in animals by appropriate dosing, although allometric dosing calculations have little value. Long-term changes require MDMA to be metabolized in a similar manner in experimental animals and humans. However, the rate of metabolism of MDMA and its major metabolites is slower in humans than rats or monkeys, potentially allowing endogenous neuroprotective mechanisms to function in a species specific manner. Furthermore acute hyperthermia in humans probably limits the chance of recreational users ingesting sufficient MDMA to produce neurotoxicity, unlike in the rat. MDMA also inhibits the major enzyme responsible for its metabolism in humans thereby also assisting in preventing neurotoxicity. These observations question whether MDMA alone produces long-term 5-HT neurotoxicity in human brain, although when taken in combination with other recreational drugs it may induce neurotoxicity.

Studies of (±)-3,4-Methylenedioxymethamphetamine (MDMA) Metabolism and Disposition in Rats and Mice: Relationship to Neuroprotection and Neurotoxicity Profile

“…In summary, contrary to what has been recently suggested (Green et al, 2012), alterations or differences in MDMA metabolism do not account for either the neuroprotective effect of hypothermia or the different profile of MDMA neurotoxicity observed in mice and rats. Additional studies will, therefore, be needed to understand the basis for both of these phenomena.…”

“…In both rats and mice, hypothermia attenuates MDMA neurotoxicity, whereas hyperthermia exacerbates MDMA neurotoxicity O'Callaghan, 1994, 1995;Malberg and Seiden, 1998;O'Shea et al, 2006;Goni-Allo et al, 2008). It has been hypothesized that differences in MDMA metabolism underlie MDMA's different neurotoxic profile in rats and mice (Lim et al, 1992;de la Torre and Farre, 2004;Green et al, 2012). Similarly, it has been suggested that the neuroprotective effects of hypothermia on MDMA neurotoxicity are secondary to temperature influences on MDMA metabolism (Goni-Allo et al, 2008).…”

“…In mice, DA neurons are selectively damaged , whereas in rats and most other species examined to date (including nonhuman primates), 5-HT neurons are typically selectively affected (Steele et al, 1994;Green et al, 2003). The basis for the different profile of MDMA neurotoxicity in different species is unknown, but it has recently been stated that differences in MDMA disposition and metabolism play a key role (Green et al, 2012).…”

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

“…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). From this comparison, the authors concluded that MDMA doses in rats must be 4-fold higher than human doses to achieve similar peak plasma MDMA concentrations and that MDMA pharmacokinetics are linear in rats.…”

MDMA modulates spontaneous firing of subthalamic nucleus neurons in vitro

“…MDMA has a wide spectrum of psychological and physiological effects, including weak rewarding and addicting potentials in animals and humans (Green et al 2003;Reinhard and Wolffgramm 2006). Alongside a controversial discussion of the beneficial versus harmful potential of MDMA (Green et al 2012;Parrott 2012), the effects of the drug continue to be investigated, e.g. on cognition (Mithoefer et al 2013;Nelson et al 2013) and the motor system (Baumann et al 2008).…”