The primary goal of this application is to assess for the presence and nature of cognitive deficits in adolescents with a history of MDMA (""""""""ecstasy"""""""") use, to test for correlated changes in brain function, and to determine whether cognitive deficits improve with sustained abstinence from MDMA. In animals MDMA produces long-lasting damage to cortical and subcortical serotonergic neurons even when administered in recreational doses. Adult human MDMA users have reduced density of markers of brain serotonergic neurons, reduced cerebral spinal fluid (CSF) concentrations of the serotonin metabolite 5- hydroxyindoleacetic acid (5-HIAA), and impairments in immediate and delayed recall, executive cognitive function, and reaction time. Recreational use of MDMA remains substantial among adolescents. However, cognitive and brain functional correlates of MDMA use in adolescents remain unexplored. Further, the degree to which brain functional changes associated with MDMA use during adolescence are reversible is not known. Such information is urgently needed to guide clinicians and educators in the design of treatment and educational plans that will meet the needs of this vulnerable population. Preliminary data from a pilot study of cognition and brain function in adolescent MDMA users conducted in our laboratory suggests that adolescent MDMA users have prolonged reaction times during tests of selective and divided attention and deficits in delayed recognition memory. Functional magnetic resonance imaging (fMRI) data collected from these subjects during performance of a working memory task shows altered frontal and hippocampal function during high working memory load. The present application will employ a longitudinal design to test whether MDMA use in adolescence is associated with cognitive deficits beyond those deficits associated with cannabis or tobacco use, and whether these deficits improve with sustained abstinence from MDMA. In addition, whether MDMA use in adolescence is associated with altered function of neural circuits mediating the performance of working memory and selective and divided attention tasks will be examined. Finally, we will test whether MDMA related changes in hippocampal function predict decrements in delayed recall or recognition memory and whether MDMA-related functional changes in neurocircuits mediating selective and divided attention predict reduced speed of processing during performance of these tasks.
