Neuroimaging research in human MDMA users: a review

Abstract

Rationale Determining whether, under what circumstances, and to what extent 3,4-methylenedioxymethamphetamine (MDMA) exposure produces chronic changes in human brain function is a critical public health issue. MDMA is a widely used recreational drug commonly sold as "Ecstasy". Because findings from the animal literature have indicated that specific dosage regimens of MDMA can produce longlasting alterations in serotonergic function, existing studies of MDMA effects in humans have examined brain serotonin (5-HT) transporters (5-HTT) and receptors or have examined brain structures or functions potentially affected by MDMA. Objectives The objectives of this review are to provide a background for interpreting human MDMA neuroimaging research, to examine existing neuroimaging data regarding the rationale for and limitations to human MDMA research, and to provide suggestions for improving the design and interpretation of future neuroimaging approaches. Results Of the existing neuroimaging studies in human MDMA users, few experimental designs have been replicated across different research groups. Only investigations employing nuclear imaging methods to assay brain 5-HTT levels have been replicated across methods and research laboratories. These studies have found reduced levels of the 5-HTT in recently abstinent MDMA users with some evidence for normalization of 5-HTT levels with prolonged abstinence. However, the sensitivity of these methods is unknown.Conclusions The current state of neuroimaging in human MDMA users does not permit conclusions regarding the long-term effects of MDMA exposure. Future study designs might benefit from improved sample homogeneity, increased length of MDMA abstinence, longitudinal study design, test-retest measures, serotonergic specificity, and multimodal approaches.

Dissociation of the Neurochemical and Behavioral Toxicology of MDMA (‘Ecstasy’) by Citalopram

“…We further argue that such a conclusion has potential clinical relevance for the treatment of Ecstasy users who are suffering from cognitive, mood, or anxiety disorders that may be related to their substance use. Although the overall single-day dose of 40 mg/kg of MDMA used in the present study is clearly much greater than recreational human doses, SERT imaging studies of users raise the possibility that cumulative exposure involving many smaller Ecstasy doses could, over time, produce the kind of serotonergic neurotoxicity seen in animal binge studies (Cowan, 2007). Finally, some websites aimed at the general public suggest that taking an SSRI with Ecstasy can prevent the adverse side effects of MDMA, which may be a fallacious assumption based in part on the present results.…”

Human Ecstasy Use is Associated with Increased Cortical Excitability: An fMRI Study

“…As reviewed previously (Cowan, 2007;Cowan et al, 2008a), previous studies employing more complex cognitive paradigms found a range of activation patterns following chronic MDMA exposure (Daumann et al, 2003(Daumann et al, , 2004(Daumann et al, , 2005Jager et al, 2008a, b;Jacobsen et al, 2004;Moeller et al, 2004). Subsequent studies have revealed a similarly mixed picture when using fMRI to examine brain activation during cognitive paradigms (Roberts et al, 2009).…”

“…However, matching average use across groups does not account fully for individual patterns in drug exposure and also controls only for the most commonly used substances (e.g., cannabis). Third, most studies investigating MDMA effects on human neurophysiology have employed paradigms that involve the performance of complex cognitive tasks during functional neuroimaging (reviewed by Cowan, 2007). However, interpreting functional neuroimaging findings arising from complex cognitive tasks in terms of underlying brain neurophysiology is challenging.…”

“…Despite this evidence for long-lasting brain effects, functional neuroimaging studies of human MDMA users have not found a consistent pattern of altered brain neurophysiology in association with MDMA exposure (Cowan, 2007;Cowan et al, 2008a;Daumann et al, 2003Daumann et al, , 2004Daumann et al, , 2005Jager et al, 2008a, b;Jacobsen et al, 2004;Moeller et al, 2004;Roberts et al, 2009;Raj et al, 2009). Several factors, including dose-response effects, polydrug effects, and task design, may account for the absence of a consistent neurophysiological effect of MDMA exposure in extant functional neuroimaging studies.…”

“…Third, 5-HT influences visual cortical excitatory and inhibitory tone (Moreau et al, 2010), suggesting that MDMA-induced loss or reduction in 5-HT signaling would be expected to alter visual cortical excitability. Fourth, human MDMA use is associated with reduced occipital cortex 5-HT reuptake transporter (eg, McCann et al, 1998(eg, McCann et al, , 2005Semple et al, 1999;Kish et al, 2010), increased 5-HT2A receptor binding (Reneman et al, 2002; reviewed by Cowan, 2007), and altered visual activation (Cowan et al, 2006). Fifth, MDMA users have altered visual perception (Brown et al, 2007;Oliveri and Calvo, 2003).…”