Quantitative PET studies of the serotonin transporter in MDMA users and controls using [11C]McN5652 and [11C]DASB

Abstract

(+/-)3,4-Methylenedioxymethamphetamine (MDMA, 'Ecstasy') is a widely used illicit drug that produces toxic effects on brain serotonin axons and axon terminals in animals. The results of clinical studies addressing MDMA's serotonin neurotoxic potential in humans have been inconclusive. In the present study, 23 abstinent MDMA users and 19 non-MDMA controls underwent quantitative positron emission tomography (PET) studies using [11C]McN5652 and [11C]DASB, first- and second-generation serotonin transporter (SERT) ligands previously validated in baboons for detecting MDMA-induced brain serotonin neurotoxicity. Global and regional distribution volumes (DVs) and two additional SERT-binding parameters (DV(spec) and DVR) were compared in the two subject populations using parametric statistical analyses. Data from PET studies revealed excellent correlations between the various binding parameters of [11C]McN5652 and [11C]DASB, both in individual brain regions and individual subjects. Global SERT reductions were found in MDMA users with both PET ligands, using all three of the above-mentioned SERT-binding parameters. Preplanned comparisons in 15 regions of interest demonstrated reductions in selected cortical and subcortical structures. Exploratory correlational analyses suggested that SERT measures recover with time, and that loss of the SERT is directly associated with MDMA use intensity. These quantitative PET data, obtained using validated first- and second-generation SERT PET ligands, provide strong evidence of reduced SERT density in some recreational MDMA users.

Figure 1

Correlation between DV [¹¹C]DASB (x-axis) and DV [¹¹C]McN5652 (y-axis) binding in regions of interest in control (open circles) and MDMA subjects (closed circles).

Figure 2

Correlation between DV [¹¹C]DASB (x-axis; ml/ml) and DV [¹¹C]McN5652 (y-axis; ml/ml) binding within individual research subjects (Controls: open circles; MDMA: closed circles).

Figure 3

PET images obtained 75–95 min postinjection of [¹¹C]McN5652 and [¹¹C]DASB in a representative control subject and a representative MDMA subject, demonstrating the reductions in SERT binding in the MDMA subject with both radioligands. PET images are normalized to a common maximum.

Figure 4

Serotonin transporter-binding parameters in MDMA users and controls are shown, as measured by PET with [¹¹C]DASB and [¹¹C]McN5652 using the three binding parameters, DV (ml/ml±SD; top row), DV_spec (ml/ml±SD; middle row), and DVR±SD (bottom row). Levels of significance are designated as follows: # ≤0.05; *<0.01; **<0.001; ***<0.0001. Abbrevations of brain regions are as follows: MB, midbrain; Amyg, amygdala; HPC, hippocampus; TH, thalamus; CD, caudate; Put, putamen; DPFC, dorsolateral prefrontal cortex; OC, occipital cortex; OFC, orbitofrontal cortex; PC, parietal cortex; TC, temporal cortex; ACC, anterior cingulate cortex; PCC, posterior cingulate cortex; Dpons, dorsal pons; Vpons, ventral pons.