Psychopharmacology (2004) 173:383–390 DOI 10.1007/s00213-003-1679-4 ORIGINAL INVESTIGATION Leslie K. Jacobsen · W. Einar Mencl · Kenneth R. Pugh · Pawel Skudlarski · John H. Krystal Preliminary evidence of hippocampal dysfunction in adolescent MDMA (“ecstasy”) users: possible relationship to neurotoxic effects Received: 11 September 2003 / Accepted: 14 October 2003 / Published online: 28 November 2003  Springer-Verlag 2003 Abstract Rationale: 3,4-Methylenedioxymethamphet- amine (MDMA or ecstasy) is a potent and selective serotonin neurotoxin whose use is growing among adolescents. Although cognitive deficits among adult MDMA users are well documented, little is known of the cognitive and brain functional sequelae of MDMA use during adolescence. Objective: We tested for evidence of cognitive deficits and changes in brain function in a pilot sample of adolescent MDMA users, who were compared with adolescent non-users of MDMA. Methods: Selective and divided attention and verbal working memory were examined in six adolescent MDMA users and six non- users of MDMA who were similar in age, gender, IQ, and other substance use. Brain function was assessed during performance of the working memory task using functional magnetic resonance imaging (fMRI). Results: MDMA users had significantly prolonged reaction times during tests of selective and divided attention, and failed to deactivate the left hippocampus normally during high verbal working memory load. Conclusions: MDMA use in adolescence may be associated with cognitive impair- ments and dysfunction of inhibitory circuits within the hippocampus. Further work is urgently needed to delin- eate the developmental impact and long-term functional and clinical significance of MDMA use during adoles- cence. Keywords MDMA · Ecstasy · Adolescent · Selective attention · Divided attention · Working memory Introduction MDMA is a ring-substituted amphetamine derivative with structural similarities to mescaline (Anderson et al. 1978). In light of increasing recreational use, together with growing evidence of its neurotoxicity, MDMA was designated as a schedule I controlled substance by the US Drug Enforcement Agency in 1986 (Steele et al. 1994). In spite of this, recreational use has continued to grow, and age at initiation of use has continued to decline (Parrott 2002; von Sydow et al. 2002). Recent surveys of college students have demonstrated persistent and grow- ing use of MDMA despite declining use of other drugs (Peroutka 1987; Pope et al. 2001; Schuster et al. 1998), and the 2002 Monitoring the Future Survey observed a lifetime prevalence of MDMA use of 4.3% among 8th graders, 6.6% among 10th graders, and 10.5% among 12th graders in the United States (http://monitoringthefu- ture.org/data/02data.html). Neurotoxicity A consistent profile of long-lasting serotonergic damage has been demonstrated in a variety of rodent species and in New and Old World monkeys (Steele et al. 1994; Hegadoren et al. 1999; Parrott 2002; Taffe et al. 2002). MDMA produces dose-related reductions in brain con- centrations of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), in the density of 5-HT uptake sites, and in L. K. Jacobsen · J. H. Krystal Department of Psychiatry, Yale University School of Medicine, New Haven, Conn., USA L. K. Jacobsen · K. R. Pugh Department of Pediatrics, Yale University School of Medicine, New Haven, Conn., USA W. E. Mencl · K. R. Pugh Haskins Laboratory, Yale University, New Haven, Conn., USA P. Skudlarski Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Conn., USA L. K. Jacobsen ( ) ) Yale University School of Medicine, 100 York Street 2B, New Haven, CT 06511, USA e-mail: leslie.jacobsen@yale.edu