Psychopharmacology DOI 10.1007/s00213-006-0601-2 REVIEW MDMA use and neurocognition: a meta-analytic review Ari D. Kalechstein & Richard De La Garza II & James J. Mahoney III & William E. Fantegrossi & Thomas F. Newton Received: 11 August 2006 /Accepted: 21 September 2006 # Springer-Verlag 2006 Abstract associated with neurocognitive deficits in each domain. Rationale To determine the association between MDMA Small to medium effect sizes were generally observed. A misuse and neurocognition using meta-analysis. comparison of the effect sizes across the two sets of Objective Separate analyses were conducted based on two analyses did not reveal significant differences. sets of inclusion/exclusion criteria. A relatively stringent set Conclusions The findings from this review reveal that required that the subjects be matched on important MDMA use is associated with neurocognitive deficits. moderator variables, whereas the other did not. The study The implications of these findings are discussed. participants’ performance in the following neurocognitive domains was reviewed: attention/concentration, verbal and Keywords Cognition . Neuropsychology . Ecstasy. nonverbal learning and memory, psychomotor speed and Drug abuse . Drug dependence executive systems functioning. Results In the 11 studies meeting the relatively stringent inclusion/exclusion criteria for this review, MDMA use was Introduction associated with neurocognitive deficits in each domain. Similarly, in the 23 studies meeting the relatively lenient MDMA (3,4-methylenedioxymethamphetamine) is a syn- inclusion/exclusion criteria for this review, MDMA use was thetic, psychoactive drug that influences neurobiological functioning primarily, but not exclusively, via the seroto- nergic system (Nichols 1986; Rudnick and Wall 1992). These data were presented at the annual meeting of the Society for Preclinical studies showed that chronic or acute, high dose Neuroscience, San Diego, CA held last November 2004. This research MDMA administration adversely affects neurochemistry was supported in part by grants from the National Institute of Health and brain morphology. In animals exposed to chronic (DA50038, DA00388, DA07272 and P51-RR000165). MDMA, serotonin (5-HT) immunocytochemistry reveals A. D. Kalechstein : R. De La Garza II : J. J. Mahoney III : pronounced denervation throughout the neocortex, striatum T. F. Newton and thalamus, while lesser damage was observed in the Department of Psychiatry and Biobehavioral Sciences, hippocampus, hypothalamus and basal forebrain in rats David Geffen School of Medicine at the University of California, Los Angeles, CA 90024, USA (Molliver et al. 1990). The impact of acute MDMA exposure in rats includes transient inhibition of tryptophan W. E. Fantegrossi hydroxylase activity and depletion of 5-HT and its principal Yerkes National Primate Research Center, Emory University, metabolite 5-hydroxyindole acetic acid (5-HIAA); effects Atlanta GA, USA that gradually return to baseline within approximately A. D. Kalechstein (*) 2 weeks (Gibb et al. 1990). Semel Institute for Neuroscience and Human Behavior, Human studies of MDMA exposure have yielded David Geffen School of Medicine at the University of California, similar findings. For example, a number of investigators 760 Westwood Boulevard, Suite A8-148, 11 Los Angeles, CA 90024, USA using C (+)McN5652 PET (Buchert et al. 2004; McCann e-mail: [email protected] et al. 1998)or123I β-CIT SPECT (Reneman et al. 2001; Psychopharmacology Semple et al. 1999) have reported global or regional Table 1 Description of the studies included in the review reductions in 5-HT transporter binding in MDMA users as Study author(s) Year Sample size1 compared to controls. Moreover, an examination of resting published brain metabolism using 18FFlourodeoxyglucose PET, Controls MDMA revealed marked reductions in the caudate and putamen users (bilaterally) and the left amygdala in MDMA users as Back-Madruga et al. 2003 23m/5f 14m/8f compared to controls (Obrocki et al. 2002). Bhattachary and Powell 2001 11m/9f 10m/6f Based on the findings from preclinical studies, it would Daumann et al. 2003 8m/3f 8m/3f be reasonable to infer that MDMA exposure is a risk Fox et al. 2001 6m/14f 12m/8f factor for neurocognitive impairment; however, studies of Fox et al. 2003 6m/14f 12m/8f neurocognitive deficits that accompany MDMA use in Gouzoulis-Mayfrank et al. 2000 17m/11f 16m/12f humans have yielded mixed results. In particular, whereas Gouzoulis-Mayfrank et al. 2003 21m/9f 21m/9f a subset of studies reported that MDMA users demon- Halpern et al. 2004 9m/7f 8m/15f Hanson and Luciana 2004 14m/12f 14m/12f strated neurocognitive deficits relative to matched controls Heffernan et al. 2001 10m/27f 17m/13f (e.g., Bolla et al. 1998; Hanson and Luciana 2004; McCardle et al. 2004 13m/2f 13m/4f McCardle et al. 2004), others have not (Back-Madruga et Morgan 1999 19m/f 25m/f al. 2003). In those studies in which positive findings were Morgan et al. 2002 6m/9f 9m/9f reported, MDMA users showed poorer performance on Parrott et al 1998 4m/6f 8m/2f measures of attention/information processing speed, episodic Reneman et al. 2000 4m/5f 4m/1f memory (e.g., supraspan list learning task) and executive Rogers 2000 6m/9f 7m/8f systems functioning (i.e., frontal lobe functioning). Simon and Mattick 2002 37m/f 47m/f Verkes et al. 2001 20m 21m It is noteworthy that the variability in the findings across von Geusau et al. 2004 12m/21f 17m/9f studies might be related to the methodology utilized to Wareing et al. 2000 5m/5f 5m/5f study the association (Back-Madruga et al. 2003). Back- 1 Madruga et al. 2003 commented that these variations m=male/f=female included, but were not limited to, the lack of a control group and the failure to control for differences in age, education and/or IQ. The latter issue is particularly important as these factors typically moderate performance of PsycInfo and Medline. The search terms utilized in the on neurocognitive tests. computer search, MDMA, neurocognition, neuropsychology To synthesize the findings from studies that have and cognition, provided an initial bibliography of 61 examined the association between neurocognition perfor- papers. There were no restrictions with respect to the date mance and MDMA exposure, we conducted a meta-analytic of the study publication. review. This approach provides an objective review of the Based on our review of the studies, there was great association between neurocognitive profile and real-world variability in terms of the methodology used for the vocational functioning and has a number of advantages inclusion/exclusion of study participants and for the control over qualitative reviews. A primary advantage of meta- of demographic variables. To address this point, we created analytic techniques is that they provide the capacity to two sets of inclusion/exclusion criteria for the studies. One combine the results of studies utilizing different methodol- set, which was relatively lenient, required studies to meet ogies and statistical models (e.g., t test, chi-square) to the following criteria: calculate a single effect size that quantifies the magnitude 1. The study included measures of neurocognition. of the association between two variables. This technique 2. The study included matched controls. substantially increases the power of the statistical test of the association between deficits in specific neurocognitive Based on these criteria, 23 studies were included in the domains and MDMA use. Furthermore, this approach “lenient” analyses (Back-Madruga et al. 2003; Bhattachary allows us to determine whether the study design moderated and Powell 2001; Daumann et al. 2003;Fisketal.2004;Fox the results of the studies. et al. 2001; Gouzoulis-Mayfrank et al. 2000, 2003;Halpern et al. 2004; Hanson and Luciana 2004; Heffernan et al. 2001; McCann et al. 1999; McCardle et al. 2004;Montgomeryet Materials and methods al. 2005; Morgan 1999;Morganetal.2002; Parrott et al. 1998; Reneman et al. 2000; Rodgers 2000; Simon and Sample The studies included in this review are listed in Mattick 2002; Verkes et al. 2001; Vollenweider et al. 2005; Table 1 and were retrieved using an online computer search von Geusau et al. 2004; Wareing et al. 2000). Psychopharmacology An alternative set of criteria was relatively stringent. For findings that would be needed to invalidate the conclusion a study to be included in the analyses, it needed to meet the that a significant association existed between vocational following criteria: status and neurocognitive functioning in a particular domain (Rosenthal 1991). N was obtained by summing 1. The study included measures of neurocognition. fs the Z scores for the particular subgroup, dividing this sum 2. The study included matched controls. by the Z score associated with a particular probability 3. The matched controls were similar to the MDMA users value, squaring this new number, and finally, subtracting in terms of age and education or estimated level of the number of studies in that subgroup. A larger N premorbid intellectual functioning. fs indicates a more reliable association between real-world 4. The MDMA users were non-treatment seeking and vocational outcomes and neurocognitive impairment. abstinent at the time of the assessment. Based on these criteria, 11 studies were included in the Estimating the magnitude of the effect size According to meta-analysis (Back-Madruga et al. 2003; Bhattachary and Pedhazur and Schmelkin (1991), Cohen constructed the Powell 2001; Daumann et al. 2003; Gouzoulis-Mayfrank et most frequently used guidelines for the estimation of the al. 2000, 2003;HansonandLuciana2004;McCardleetal. magnitude of effect size using Cohen’s d (Cohen 1988). 2004;Morganetal.2002; Parrott et al. 1998;Thomasiuset Cohen proposed that a difference between the means of 0.2 al. 2003; Verkes et al. 2001). of a SD be characterized as small, 0.5 as medium and 0.8 as large. Effect size To determine the magnitude of the differences between the means of the comparison groups, effect size estimates were calculated using standard techniques (Rosenthal 1991).