Although 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a known serotonergic neurotoxin in different animal species, there is to date no conclusive evidence of its neurotoxicity in humans. MDMA use was associated with impairments of psychological well-being, verbal memory and altered serotonergic functioning in a number of crosssectional studies. Due to inherent methodological limitations, such as the notorious polydrug use of ecstasy users and lack of control of possible pre-existing differences between ecstasy users and control participants, researchers have called for well-controlled, prospective longitudinal studies to shed more light on the issue of MDMA neurotoxicity to the human brain.
This longitudinal study investigated whether mood, cognition and central serotonin transporters (SERT) would deteriorate with continued MDMA use and whether or not they would recover over increasing periods of MDMA abstinence.
In a repeated-measures design, 11 current and ten ex-ecstasy users, and 11 polydrug (but not MDMA) and 15 drug-naive controls participated three times within approximately two years. Both ecstasy user groups reported a polydrug use pattern besides heavy ecstasy use. Subjective reports of ecstasy use or abstinence were veri.ed by toxicological analyses. On each trial, the participants underwent a cognitive test battery and .lled in the Symptom Check List. The availability of central SERT was assessed with positron emission tomography using the McN5652 ligand for all groups at t1, and only for the ecstasy user groups on follow-ups.
The factor Group yielded signi.cant results in the SCL-90 scales Global Severity Index, Anxiety, Obsessive/compulsive and Interpersonal sensitivity, with the ex-ecstasy users reporting the highest symptom scores. There were signi.cant Group effects in all measures of verbal memory, with the lowest performance in the group of ex-ecstasy users. The repeated-measures analyses yielded no signi.cant Group × Time interactions in any SCL-90 scales or measures of memory performance, with the exception of AVLT 1 immediate recall. Thus the ex-ecstasy users' psychopathological symptoms and memory performance failed to improve, and the current ecstasy users' failed to deteriorate, over time relative to the other groups. While there was a signi.cant effect of Group in all brain regions examined (except the control region white matter), the current users' SERT availability seems to have recovered in the mesencephalon, as indicated by a signi.cant Group × Time interaction.
Reduced SERT availability might be a transient effect of heavy ecstasy use, since it partially recovered as the current users reduced their MDMA use. However, this measure may not necessarily be a valid indicator of the number or integrity of serotonergic neurons. Ex-ecstasy users' verbal memory showed no sign of improvement even after over 2.5 years of abstinence and thus may represent persistent functional consequences of MDMA neurotoxicity. However, alternative causes such as pre-existing group differences cannot be completely ruled out in spite of the longitudinal design.
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