3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a popular recreational drug, and clinical trials are investigating MDMA as a treatment for anxiety. Animal models suggest that MDMA causes chronic serotonin neurotoxicity, especially in neocortex. Given the role of serotonin in a broad range of brain functions, it is critical to determine whether MDMA is associated with serotonin neurotoxicity in humans. Studies examining the presynaptic serotonin reuptake transporter (SERT) as a marker of serotonin axon integrity in MDMA users have generally found reductions in SERT binding (McCann et al, 2008; Urban et al, 2012; Kish et al, 2010). Although there is some evidence for SERT recovery in subcortical regions with prolonged abstinence (Buchert et al, 2006), there is little evidence suggesting SERT recovery in neocortex.

If MDMA users actually have reduced serotonin signaling, there should be predictable effects of MDMA-induced reductions in serotonin on cortical neurophysiology. Serotonin is largely inhibitory in neocortex, therefore reductions in serotonin signaling should produce increased cortical excitability, reflected as increased activation with fMRI. In support of this hypothesis, we found that greater MDMA use was associated with greater occipital activation during visual stimulation in MDMA users, a finding consistent with increased cortical excitability and in line with the consequences of reduced serotonin signaling (Bauernfeind et al, 2011).

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