The 5-HT_2A receptor and serotonin transporter in ecstasy users evaluated with [¹¹C]MDL 100907 and [¹¹C]DASB

Objectives The potent serotonin (5HT) releaser MDMA (3,4-methylenedioxy-N-methamphetamine, “ecstasy”) causes 5HT depletion with neurotoxic loss of serotonin transporters (SERT) and upregulation of 5HT_2A receptors in animal models. Some, but not all, imaging studies in human ecstasy users have observed decreased SERT binding. In vivo evidence for MDMA-induced changes in postsynaptic 5HT_2A receptors in humans has been scarce. This is the first study investigating both components of the 5HT system in the same group of users.

Methods Positron emission tomography (PET) using the specific SERT ligand [¹¹C]DASB and the selective 5HT_2A receptor ligand [¹¹C]MDL 100907 was performed in 13 detoxified and chronic moderate ecstasy users (XTC) and 13 drug naïve healthy controls (HC). Regional SERT availability and 5HT_2A receptor availability were analyzed using a two-tissue compartment model (2TCM) with arterial input function. Relationships between parameters of ecstasy use and BP_ND were analyzed using Pearson correlation coefficients.

Results Compared to HC, XTC displayed significantly increased 5HT_2A receptors availability in cortical regions (DLPFC and parietal cortex, p<0.05), and decreased SERT availability in cortical, but not subcortical, regions (medial prefrontal, temporal and occipital cortex, p<0.05). Parameters of ecstasy use (lifetime use, frequency, abstinence duration) did not significantly correlate with SERT or 5HT_2A availability in cortical regions.

Conclusions Our results support that chronic moderate ecstasy use in humans might lead to neurotoxic damage to 5HT nerve terminals in the cortex, and that this neurotoxicity might be associated with compensatory upregulation of postsynaptic 5HT_2A receptors. This study adds to the growing body of evidence suggesting the potential detrimental effects of this widely used recreational drug on the 5HT system. Reversibility of these changes upon sustained abstinence remains to be fully documented.

Research Support Funded by NIDA