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

Abstract

The serotonergic neurotoxin, 3,4-methylenedioxymethamphetamine (MDMA/Ecstasy), is a highly popular recreational drug. Human recreational MDMA users have neurocognitive and neuropsychiatric impairments, and human neuroimaging data are consistent with animal reports of serotonin neurotoxicity. However, functional neuroimaging studies have not found consistent effects of MDMA on brain neurophysiology in human users. Several lines of evidence suggest that studying MDMA effects in visual system might reveal the general cortical and subcortical neurophysiological consequences of MDMA use. We used 3 T functional magnetic resonance imaging during visual stimulation to compare visual system lateral geniculate nucleus ( There were no between-group differences in brain activation in any region, but the heaviest MDMA users showed a significantly greater spatial extent of activation than controls in BA 17 (p ¼ 0.031) and BA 18 (p ¼ 0.049). These results suggest that human recreational MDMA use may be associated with a long-lasting increase in cortical excitability, possibly through loss of serotonin input to cortical and subcortical regions. When considered in the context of previous results, cortical hyper-excitability may be a biomarker for MDMA-induced serotonin neurotoxicity.

Critical Issues in Cross-sectional Research Studies of Human Ecstasy (MDMA) Users: A Response to Krebs and Johansen

“…As we discussed in our original manuscript (Bauernfeind et al, 2011), and in prior work in different cohorts, low-dose MDMA use tends to be associated with activation values that are somewhat lower than the control cohort mean whereas high-dose MDMA use tends to be associated with activation values greater than the control cohort mean. As we wanted to begin to address the question of the effect of low-dose MDMA on brain function, our study enrolled individuals having between 3 and 155 episodes of MDMA use and, therefore, included individuals with very-low MDMA exposure levels.…”

“…A simple average of the means or a correlation analysis that includes the control cohort, as performed by Krebs and Johansen (when the MDMA cohort includes very-low-dose MDMA users), therefore, inappropriately obscures the strong dose-response relationship between lifetime MDMA exposure and brain activation. This relationship is evident in the manuscript and in the associated correlation analyses when ranked data is used to properly account for the non-parametric distribution of lifetime MDMA use (Bauernfeind et al, 2011).Krebs and Johansen point out the possibility that psychological factors associated with cortical activation (eg, impulsivity) may predispose one to MDMA use. Although we agree with this possibility, MDMA has a well-established ability to cause serotonin neurotoxicity in non-human primates, and we are not aware of evidence to suggest that humans are less vulnerable to these effects.…”

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In a letter to the editor entitled 'Methodological weaknesses in non-randomized studies of ecstasy (MDMA) use: a cautionary note to readers and reviewers', Krebs and Johansen comment on our recent manuscript, 'Human ecstasy use is associated with increased cortical excitability: an fMRI study ' (Bauernfeind et al, 2011) and highlight important concerns inherent in the conduct of cross-sectional research in human ecstasy (MDMA) users. We are in considerable agreement with the authors regarding the need for well-controlled longitudinal studies to more precisely address the potential neurotoxic effects of recreational MDMA exposure.

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“…We are in considerable agreement with the authors regarding the need for well-controlled longitudinal studies to more precisely address the potential neurotoxic effects of recreational MDMA exposure. Although the concerns raised by Krebs and Johansen were addressed in our original report, several points merit additional consideration and clarification.In addition to commenting on our peer-reviewed manuscript (Bauernfeind et al, 2011), Krebs and Johansen note that the principal investigator (RLC) compares MDMA users to people with early Alzheimer's disease (AD) in a press release. In prior peer-reviewed publications (Karageorgiou et al, 2009;Cowan et al, 2006), we have noted the overlap between findings of increased task-evoked activation in MDMA users and in individuals at risk for AD.…”

“…In addition to commenting on our peer-reviewed manuscript (Bauernfeind et al, 2011), Krebs and Johansen note that the principal investigator (RLC) compares MDMA users to people with early Alzheimer's disease (AD) in a press release. In prior peer-reviewed publications (Karageorgiou et al, 2009;Cowan et al, 2006), we have noted the overlap between findings of increased task-evoked activation in MDMA users and in individuals at risk for AD.…”