The Influence of Genetic and Environmental Factors among MDMA Users in Cognitive Performance Elisabet Cuya `s 1,2 , Antonio Verdejo-Garcı´a 1,3 , Ana Beatriz Fagundo 1,2 , Olha Khymenets 1,4 , Joan Rodrı´guez 1 , Aida Cuenca 5 , Susana de Sola Llopis 1 , Klaus Langohr 1,6 , Jordi Pen ˜ a-Casanova 2,7 , Marta Torrens 2,8 , Rocı´o Martı ´n-Santos 1,9 , Magı´ Farre ´ 1,2 , Rafael de la Torre 1,4,10 * 1 Human Pharmacology and Clinical Neurosciences Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Research Institute, Barcelona, Spain, 2 Universitat Auto ` noma de Barcelona (UAB), Barcelona, Spain, 3 Institute of Neuroscience, Universidad de Granada, Granada, Spain, 4 CIBER de Fisiopatologı ´a de la Obesidad y Nutricio ´ n (CB06/03), CIBEROBN, Hospital Clı ´nico Universitario, Santiago de Compostela, Spain, 5 Epidemiology of Drugs of Abuse Research Group, Public Health and Epidemiology Research Program, IMIM-Hospital del Mar Research Institute, Barcelona, Spain, 6 Department of Statistics and Operations Research, Universitat Polite `cnica de Catalunya (UPC), Barcelona, Spain, 7 Behavioral Neurology and Dementias Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Research Institute, Barcelona, Spain, 8 Disorders by Use of Substances Research Group, Neurosciences Research Program, IMIM-Hospital del Mar Research Institute, Barcelona, Spain, 9 Department of Psychiatry, Institute of Neurosciences, Hospital Clinic, IDIBAPS, CIBER-SAM, Barcelona, Spain, 10 Universitat Pompeu Fabra (CEXS-UPF), Barcelona, Spain Abstract This study is aimed to clarify the association between MDMA cumulative use and cognitive dysfunction, and the potential role of candidate genetic polymorphisms in explaining individual differences in the cognitive effects of MDMA. Gene polymorphisms related to reduced serotonin function, poor competency of executive control and memory consolidation systems, and high enzymatic activity linked to bioactivation of MDMA to neurotoxic metabolites may contribute to explain variations in the cognitive impact of MDMA across regular users of this drug. Sixty ecstasy polydrug users, 110 cannabis users and 93 non-drug users were assessed using cognitive measures of Verbal Memory (California Verbal Learning Test, CVLT), Visual Memory (Rey-Osterrieth Complex Figure Test, ROCFT), Semantic Fluency, and Perceptual Attention (Symbol Digit Modalities Test, SDMT). Participants were also genotyped for polymorphisms within the 5HTT, 5HTR2A, COMT, CYP2D6, BDNF, and GRIN2B genes using polymerase chain reaction and TaqMan polymerase assays. Lifetime cumulative MDMA use was significantly associated with poorer performance on visuospatial memory and perceptual attention. Heavy MDMA users (.100 tablets lifetime use) interacted with candidate gene polymorphisms in explaining individual differences in cognitive performance between MDMA users and controls. MDMA users carrying COMT val/val and SERT s/s had poorer performance than paired controls on visuospatial attention and memory, and MDMA users with CYP2D6 ultra-rapid metabolizers performed worse than controls on semantic fluency. Both MDMA lifetime use and gene-related individual differences influence cognitive dysfunction in ecstasy users. Citation: Cuya `s E, Verdejo-Garcı ´a A, Fagundo AB, Khymenets O, Rodrı ´guez J, et al. (2011) The Influence of Genetic and Environmental Factors among MDMA Users in Cognitive Performance. PLoS ONE 6(11): e27206. doi:10.1371/journal.pone.0027206 Editor: Alessandro Serretti, University of Bologna, Italy Received July 27, 2011; Accepted October 11, 2011; Published November 16, 2011 Copyright: ß 2011 Cuya `s et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by grants from the National Institutes of Health (NIH) grant no. 1 R01 DA017987, Grant 2005SGR00032, Fondo de Investigaciones Sanitarias (FIS-00/00777), Plan Nacional Sobre Drogas (INT/2012/2002) Spain, Plan Nacional Sobre Drogas: PNSD 2006/101(2007–2009) Spain. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: rtorre@imim.es Introduction 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is one of the most popular illegal psychostimulants abused among youth. There is compelling evidence that MDMA produces selective long-lasting serotonergic neuroadaptations, including regulatory changes in the expression of the serotonin transporter [1–3]. In humans, ligand-binding imaging studies have reported decreased serotonin transporter (SERT) binding throughout the cerebral cortices and the hippocampus in MDMA users compared to healthy controls [4,5]. Furthermore, these studies have shown that decreased SERT binding is associated with lower memory performance in MDMA users. Although some studies have observed MDMA abstinence-related recovery of SERT availabil- ity in the midbrain and thalamus [6,7] there is no data about SERT recovery in the cortex, and post-mortem evidence indicates that cortical SERT protein reductions can be more robust and durable than indicated by neuroimaging studies [8]. Overall these findings are suggestive of MDMA-induced neurotoxicity, which primarily affects the serotonin system and is linked to memory dysfunction. Despite these findings about serotonin neuroadaptations, there is still debate on the question if MDMA use is reliably associated with neuropsychological impairment, regardless of the effects of concomitant use of other substances (e.g., cannabis, alcohol or other stimulants). Literature on this topic is characterized by considerable heterogeneity of results, which is attributable to the large amount of confounders inherent to research on the deleterious effects of MDMA [9]. Two meta-analyses of neuropsychological studies in MDMA users have concluded that MDMA use is robustly associated with learning and memory impairments [10,11]. This conclusion is substantiated by evidence PLoS ONE | www.plosone.org 1 November 2011 | Volume 6 | Issue 11 | e27206