97-98 This interpretation is in line with the animal experimental data, which demonstrated particularly strong and long-lasting neurotoxic

effects of MDMA in the hippocampus,11 and a stimulatory role of 5-HT for neurogenesis in the hippocampus.49 Interestingly, three studies in current and former MDMA users with an abstinence period Inhibitors,research,lifescience,medical of several months or even years reported similar or even poorer memory performance in the former MDMA users,68,70,99 although SERT availability was only reduced in current users.68-70 Two longitudinal studies yielded conflicting results: a small study in 15 ecstasy users reported memory decline after continued use and improvement after abstinence Inhibitors,research,lifescience,medical over 36 months,100-101 but a larger study in 38 ecstasy users reported no further deterioration of memory performance after continued use and no improvement after abstinence over 18 months.102 Although these results may be interpreted as evidence against neurotoxicity-related memory decline,

it is still possible that memory deficits in ecstasy users persist even after 18 months of abstinence because, as shown in primate studies,11 regeneration of serotonergic axons may take Inhibitors,research,lifescience,medical a long time and may remain incomplete. In addition, the functional consequences of neurotoxic lesions observed following a threshold use of ecstasy may manifest themselves in binary (yes/no) manner. Compensatory neural mechanisms that might develop could possibly explain the absence of functional deterioration despite subsequent “enlargement” of the neurotoxic Inhibitors,research,lifescience,medical lesions. This view would be in line both with findings of a dose-dependent memory deficit in cross-sectional studies comparing ecstasy users with control Inhibitors,research,lifescience,medical samples, and with the finding

of stable performance in the larger within-subject longitudinal study.102 Finally, findings from the only prospective study to date do support this view (part of the Netherlands XTC Toxicity [NeXT] study). A large number of young subjects who socialized in the drug scene, but had not yet used amphetamines or ecstasy, were followed up and CH5424802 reexamined after a mean period of 3 years’ follow-up.103 Although the 58 novice MDMA users reported only very sporadic and low-dose use of MDMA in the followup period (mean 3.2, median 1.5 tablets) they failed to demonstrate check retest improvements in verbal memory shown by the persistent MDMA-naive group of 60 subjects.103 This finding suggests that even very low MDMA doses may be associated with persisting alterations in memory and learning functions. Although the clinical relevance of this subtle finding is clearly limited, longterm negative consequences are conceivable. In conclusion, the linkage between ecstasy use and memorydecline is considered probable at this stage.