The Effects of Ecstasy (MDMA) on Brain Serotonin Transporters Are Dependent on Age-of-First Exposure in Recreational Users and Animals

RATIONALE AND OBJECTIVE: Little is known on the effects of ecstasy (MDMA, a potent 5-HT-releaser and neurotoxin) exposure on brain development in teenagers. The objective of this study was to investigate whether in humans, like previous observations made in animals, the effects of MDMA on the 5-HT system are dependent on age-of-first exposure. METHODS: 5-HT transporter (SERT) densities in the frontal cortex and midbrain were assessed with [(123)I]β-CIT single photon emission computed tomography in 33 users of ecstasy. Subjects were stratified for early-exposed users (age-at-first exposure 14–18 years; developing brain), and late-exposed users (age-at-first exposure 18–36 years; mature brain). In parallel, we investigated the effects of age experimentally with MDMA in early-exposed (adolescent) rats and late-exposed (adult) rats using the same radioligand. RESULTS: On average, five years after first exposure, we found a strong inverse relationship, wherein age-at-first exposure predicted 79% of the midbrain SERT variability in early (developing brain) exposed ecstasy users, whereas this was only 0.3% in late (mature brain) exposed users (p = 0.007). No such effect was observed in the frontal cortex. In rats, a significant age-BY-treatment effect (p<0.01) was observed as well, however only in the frontal cortex. CONCLUSIONS: These age-related effects most likely reflect differences in the maturational stage of the 5-HT projection fields at age-at-first exposure and enhanced outgrowth of the 5-HT system due to 5-HT’s neurotrophic effects. Ultimately, our findings stress the need for more knowledge on the effects of pharmacotherapies that alter brain 5-HT levels in the pediatric population.