mcn-5652 and Substance-Related-Disorders

Animal data suggest that the synthetic drug ecstasy may damage brain serotonin neurons. Previously we reported protracted reductions in the availability of the serotonin transporter (SERT), an index of integrity of the axon terminals of brain serotonergic neurons, in SERT-rich brain regions in current human ecstasy users. Comparison of current ecstasy users and former ecstasy users yielded some evidence that this reduction might be reversible. However, participant selection effects could not be ruled out. Therefore, follow-up examinations were performed in these subjects to test the following a priori hypothesis in a prospective longitudinal design that eliminates participant selection effects to a large extent: availability of the SERT increases towards normal levels when ecstasy use is stopped, and remains unchanged or is further decreased if use is continued.. Two follow-up positron emission tomography measurements using the SERT ligand [11C](+)McN5652 were completed by 15 current and nine former ecstasy users. All subjects used illicit drugs other than ecstasy, too. The time interval between repeated measurements was about 1 year. The time course of the availability of the SERT was analysed in the following SERT-rich regions: mesencephalon, putamen, caudate and thalamus.. Current ecstasy users showed a consistent increase in the availability of the SERT in the mesencephalon during the study (Friedman test: p = 0.010), which most likely was caused by a decrease in the intensity of ecstasy consumption (Spearman correlation coefficient -0.725, p = 0.002). Former ecstasy users showed a consistent increase in SERT availability in the thalamus (Friedman test: p = 0.006).. Ecstasy-induced protracted alterations in the availability of the SERT might be reversible.

Topics: Adolescent; Adult; Brain; Female; Follow-Up Studies; Humans; Isoquinolines; Male; N-Methyl-3,4-methylenedioxyamphetamine; Neurons; Positron-Emission Tomography; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Substance-Related Disorders

Recent functional imaging studies have reported evidence of alterations in the serotonergic system induced by 3,4-methylenedioxymethamphetamine (MDMA), or "Ecstasy." However, these studies have often been limited by small sample size, lack of tracer selectivity, unreliable assessment of MDMA doses, insufficiently matched comparison groups, or region-of-interest analysis.. Positron emission tomography (PET) using the specific serotonin transporter ligand [(11)C](+)McN5652 was performed in 117 subjects: 30 current MDMA users, 29 former MDMA users, 29 drug-naive comparison subjects, and 29 users of drugs other than MDMA (polydrug comparison subjects). Self-assessment of drug history was checked by analyzing hair samples. Local serotonin transporter availability was computed by a regularized reference tissue approach. Voxel-based comparison of serotonin transporter availability was performed using statistical parametric mapping (SPM 99).. Serotonin transporter availability in current MDMA users was significantly reduced in the mesencephalon, thalamus, left caudate, hippocampus, occipital cortex, temporal lobes, and posterior cingulate gyrus compared with all other groups. Reduction was more pronounced in female than in male subjects. There was no significant difference of serotonin transporter availability among former MDMA users and the drug-naive and polydrug comparison subjects. A negative correlation between serotonin transporter availability and mean MDMA dose was found in occipital visual areas and in the left precentral sulcus of current MDMA users. In addition, there was a significant positive correlation between the serotonin transporter availability and the MDMA abstention period in brainstem and in the basal forebrain in all MDMA users.. These findings support the hypothesis of MDMA-induced protracted alterations of the serotonergic system and indicate that the reduced availability of serotonin transporter, as measured by PET, might be reversible. Women appear to be more susceptible than men to MDMA-induced alterations of the serotonergic system.

Topics: Adult; Brain; Carbon Radioisotopes; Carrier Proteins; Dose-Response Relationship, Drug; Female; Humans; Isoquinolines; Male; Membrane Glycoproteins; Membrane Transport Proteins; N-Methyl-3,4-methylenedioxyamphetamine; Nerve Tissue Proteins; Serotonin Agents; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Sex Factors; Substance-Related Disorders; Tomography, Emission-Computed

Alterations of the serotonergic system due to ecstasy consumption have been extensively documented in recent literature. However, reversibility of these neurotoxic effects still remains unclear. To address this question, PET was performed using the serotonin transporter (SERT) ligand (11)C-(+)-McN5652 in a total of 117 subjects subdivided into 4 groups: actual ecstasy users (n = 30), former ecstasy users (n = 29), drug-naive control subjects (n = 29), and subjects with abuse of psychoactive agents other than ecstasy (n = 29).. About 500 MBq (11)C-(+)-McN5652 were injected intravenously. Thirty-five scans were acquired according to a dynamic scan protocol of 90 min using a full-ring whole-body PET system. Transaxial slices were reconstructed using an iterative method. Individual brains were transformed to a template defined earlier. Distribution volume ratios (DVRs) were derived by application of a reference tissue approach for reversible binding. Gray matter of the cerebellum served as reference. SERT-rich brain regions--mesencephalon, putamen, caudate, and thalamus--were selected for the evaluation of SERT availability using volumes of interest predefined in the template.. Compared with drug-naive control subjects, the DVR in actual ecstasy users was significantly reduced in the mesencephalon (P = 0.004) and the thalamus (P = 0.044). The DVR in former ecstasy users was very close to the DVR in drug-naive control subjects in all brain regions. The DVR in polydrug users was slightly higher than that in the drug-naive control subjects in all SERT-rich regions (not statistically significant).. Our findings further support the hypothesis of ecstasy-induced protracted alterations of the SERT. In addition, they might indicate reversibility of the availability of SERT as measured by PET. However, this does not imply full reversibility of the neurotoxic effects.

Topics: Adult; Brain; Carbon Radioisotopes; Carrier Proteins; Female; Hallucinogens; Humans; Image Processing, Computer-Assisted; Isoquinolines; Male; Membrane Glycoproteins; Membrane Transport Proteins; N-Methyl-3,4-methylenedioxyamphetamine; Nerve Tissue Proteins; Radiopharmaceuticals; Serotonin; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Substance-Related Disorders; Tomography, Emission-Computed

Chronic recreational ecstasy (MDMA) use has often been reported to be associated with psychopathology, memory impairments and serotonergic alterations. However, the findings have not been consistent.. To attempt to replicate these findings, to investigate whether such alterations would be reversible and whether they could be predicted by parameters of previous drug use.. In a cross-sectional design, 30 current and 31 ex-ecstasy users with ecstasy abstinence of at least 5 months, and 29 polydrug and 30 drug-naive controls were compared on measures of psychopathology, cognitive performance and serotonin transporter availability.. The groups did not differ significantly in age, gender distribution, education level and premorbid intelligence. The ecstasy groups did not differ significantly from polydrug controls on most of the relevant parameters of concomitant illegal drug use. Reported drug use was confirmed by hair and urine analyses. All three groups of drug users exhibited significantly elevated psychopathology compared with drug-naive controls. Only ex-ecstasy users were significantly impaired on verbal recall. Current ecstasy users showed significantly reduced distribution volume ratios of serotonin transporter availability in the mesencephalon and caudate nucleus. Regression analyses indicated that psychopathology and serotonergic alterations were best predicted by the number of ecstasy tablets taken on a typical event.. The results indicate that verbal memory impairments were possibly aggravated after prolonged ecstasy abstinence while there was tentative evidence of serotonergic recovery. On the other hand, self-reported elevated psychopathology appeared to be associated with polydrug use in general and not specifically with ecstasy use.

Topics: Adult; Affect; Brain; Carbon Radioisotopes; Carrier Proteins; Cognition; Cross-Sectional Studies; Female; Hallucinogens; Humans; Isoquinolines; Male; Membrane Glycoproteins; Membrane Transport Proteins; N-Methyl-3,4-methylenedioxyamphetamine; Nerve Tissue Proteins; Neuropsychological Tests; Serotonin; Serotonin Agents; Serotonin Plasma Membrane Transport Proteins; Substance-Related Disorders; Tomography, Emission-Computed

The popular recreational drug, 'ecstasy', mainly contains 3,4-methylenedioxymethamphetamine (MDMA) as the psychotropic agent. MDMA is suspected of causing neurotoxic lesions to the serotonergic system as demonstrated by animal studies, examinations of human cerebrospinal fluid, and the first positron emission tomography (PET) studies using the serotonin transporter ligand [11C]-McN5652. Damage of serotonergic afferents might mediate long-lasting alterations of cerebral glucose metabolism as a secondary effect. To study a relationship between ecstasy use and long-lasting alterations, PET using 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) was performed in 93 ecstasy users and 27 subjects without any known history of illicit-drug abuse. As an index of glucose metabolism, mean normalized FDG uptake was determined in both groups using a computerized brain atlas, and was compared for a selected number of brain regions. FDG uptake was normalized in each individual by dividing local FDG uptake by the maximum FDG uptake in the individual's brain. Within the group of ecstasy users we examined the relationship between FDG uptake and cumulative ecstasy dose, time since last ecstasy ingestion at the time of PET scanning, and age at first ecstasy use, respectively. Normalized FDG uptake was reduced within the striatum and amygdala of ecstasy users when compared to controls. No statistically significant correlation of the FDG uptake and the cumulative dose of ecstasy was detected. A positive correlation was found in the cingulate between FDG uptake and the time since last ecstasy ingestion. As compared to the control group, normalized FDG uptake in the cingulate was reduced in ecstasy users who took ecstasy during the last 6 months, while it was elevated in former ecstasy users who did not consume ecstasy for more than 1 year. FDG uptake was significantly more affected in ecstasy users who started to consume ecstasy before the age of 18 years. In conclusion, ecstasy abuse causes long-lasting effects on glucose metabolism in the human brain. These effects are more severe in the case of very early abuse. However, several questions still remain to be answered, i.e. the correlation of the neuronal alterations and the history of ecstasy use (cumulative dose, and time since the last dose) and its reversibility.

Topics: Adolescent; Adult; Biological Transport; Brain; Brain Neoplasms; Carbon Radioisotopes; Female; Fluorodeoxyglucose F18; Hallucinogens; Humans; Isoquinolines; Kinetics; Male; N-Methyl-3,4-methylenedioxyamphetamine; Radiopharmaceuticals; Receptors, Serotonin; Regression Analysis; Serotonin Antagonists; Substance-Related Disorders; Time Factors; Tissue Distribution; Tomography, Emission-Computed