oa Editorial [Hot topic: MDMA (Ecstasy) Toxicity: Pharmacokinetic, Metabolism, Cell Response and Pathological Consequences (Guest Editor: Vittorio Fineschi)]

This special issue of Current Pharmaceutical Biotechnology contains in depth reviews on latest and most important research developments about 3,4-Methylenedioxy-N-methylamphetamine (MDMA), a semisynthetic entactogen of the phenethylamine family. MDMA is considered a recreational drug and has long had a strong association with the rave culture. The use of ecstasy became widespread among young people, finally providing clear evidence that the drug is not harmless. MDMA is listed by the US Drug Enforcement Administration as a highly addictive and therapeutically risky drug. The increasing recreational use of MDMA led to a number of cases of intoxication, but these were still insufficient (partly due to the superficiality of case reports) to draw a clear picture of the pathological effects. Studying the problem is difficult because different experimental animals respond differently both from other models and from humans. In general, the acute effects of MDMA seem to be more or less the same in most animal models, but the models diverge widely when it comes to their ability to produce the changes induced by chronic exposure. Taken together, these studies show a close relationship between MDMA abuse and multiple organs' injury both in humans and in animals. Turillazzi and co-workers focus about the evidence that MDMA produces acute and long-lasting toxic effects in animals and humans. The conditions under which ecstasy is taken play a role in determining the pathological effects it provokes. This review of existing evidences on MDMA - related pathological findings both in humans and animals may aid in understanding the effects of MDMA on different organs. Together, the use of advanced animal models, in particular genetically modified mice, has significantly contributed to our understanding of the mechanisms underlying the (toxic) effects of MDMA. Stove and collaborators stress the role of these models, together with models under development; advanced animal models, in particular genetically modified mice may help to answer remaining questions and may assist in the development of therapies, aimed at ameliorating potential neuronal damage and cognitive impairment following abuse of MDMA and related substances. The aim of the review introduced by Byoung-Joon Song and his research group, is to present an update of the mechanistic studies on MDMA-mediated organ damage partly caused by increased oxidative/nitrosative stress. They briefly describe a method to systematically identify oxidatively-modified mitochondrial proteins in control and MDMA-exposed rats by using biotin-N-maleimide (biotin-NM) as a sensitive probe for oxidized proteins. Furthermore, some of the potential targets (including Bcl-2 family proteins involved in apoptosis) of these stress-activated protein kinases need to be experimentally demonstrated in the future. Again, results in an increase in both ROS and RNS that produces oxidative stress, mitochondrial dysfunction, and inflammatory responses in various tissue of the body are described by Cerretani & Fiaschi. Whatever is need to considerate that the oxidative stress is one of the possible mechanisms of MDMA-induced toxicity and most of reports in literature concern “in vitro” experiments and “in vivo” animal models that presents it own limitations that make extrapolation from animals to human difficult, particularly when the process being studied incorporate many components. De Letter and co-workers review the current knowledge of possible interference by the post-mortem phenomena when interpreting a post-mortem 3,4-methylenedioxymethamphetamine (MDMA) blood level. Post-mortem distribution and redistribution of MDMA is of major interest, in order to evaluate which fluid and/or tissue sample after death most closely represents the ante-mortem concentration. To that aim, animal experimental and human data were closely considered and compared. The molecular mechanisms involved in the genesis of the neurotoxic effects are not yet fully clarified, but the oxidative stress, exitotoxicity, and mitochondrial dysfunction appear to be causal events that converge to mediate MDMA-induced neurotoxicity, as measured by loss of various markers of dopaminergic and serotonergic terminals. Sarkar & Schmued cover the following topics: pharmacological mechanisms, metabolic pathways and acute effects in laboratory animals, as well as in humans, with special attention on the mechanism of MDMA induced neurotoxicity. Although the studies on MDMA induced neurotoxicity started over two decades ago, the underlying mechanism of neurotoxicity has not yet been fully elucidated. In this review, they give an overview of the factors and mechanisms that might explain MDMA induced neurotoxicity....