Moreover, amphetamines and MDMA have been shown to be neurotoxic in animal studies, particularly when given at high and repeated doses. This neurotoxic potential of the drugs may be relevant for humans. In the following sections we review the evidence for neurotoxicity in animal studies and in human

populations. Animal studies Brain morphology and neurochemistry Several studies in different laboratories and with different species demonstrate long-term alterations in brain 5-HT systems following high and repeated doses of MDMA. In studies with primates, even single doses of MDMA were found to elicit some degree of serotonergic depletion lasting over a few weeks;4 Inhibitors,research,lifescience,medical However, the lowest MDMA dose which was shown to produce longterm neurotoxic effects that persisted over months Inhibitors,research,lifescience,medical and years has been 5 mg/kg given parenterally twice dailyover 4 days, ie, 40 mg/kg overall in 4 days.9-11 The alterations include depletion of 5-HT and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA), reduced [3H]paroxetine binding, reflecting reduced density of SERT, and reduced serotonergic axonal density in several brain regions.6-12 All but one species tested so far, including nonhuman primates, have confirmed the

pattern Inhibitors,research,lifescience,medical of selective neurotoxicity for serotonergic axons, with the sole exception of mice, which exhibit neurotoxic alterations of serotonergic and dopaminergic Inhibitors,research,lifescience,medical axons.4 The rate of recovery was shown to be region-dependent. This probably corresponds to the very different distances that must be covered in the process of reinnervation. Axons need to be regrown from their origin in the serotonergic cell bodies in the raphe nuclei of the brain stem to the different terminal areas of the brain. In rats, full

recovery was shown in most studies and most brain selleck inhibitor regions after 1 year, but some individual studies reported only Inhibitors,research,lifescience,medical partial recovery in the hippocampus and some cortical areas and hyperinnervation in the hypothalamus. In nonhuman primates, sensitivity to the neurotoxic effects of MDMA was shown to be more pronounced than in rodents, PAK6 resulting in higher rates of 5-HT depletion with smaller doses of MDMA and persisting hypoinnervation patterns in most neocortical regions and the hippocampus in the range of 20% to 40% lower SERT binding depending on the brain region examined) for as long as 7 years post-treatment.9-11 Similarly to MDMA, stimulant amphetamines, particularly METH, have also been shown to be neurotoxic in rodent and nonhuman primate studies.6,13 Typical neurotoxic METH regimens are 5 to 10 mg/kg given parenterally 4 to 10 times within 1 to 4 days. Stimulant-related neurotoxicity is not restricted to the serotonergic system.