Effects Of Ecstasy On The Nervous System – Ralph Buchert, Rainer Thomasius, Bruno Nebeling, Kay Petersen, Jost Obrocki, Lars Jenicke, Florian Wilke, Lutz Wartberg, Pavlina Zapletalova and Malte Clausen

Changes in the serotonergic system due to ecstasy use have been widely documented in the recent literature. However, the reversal of these neurotoxic effects remains unclear. To address this question, PET was performed using a serotonin transporter (SERT) ligand

Effects Of Ecstasy On The Nervous System

Effects Of Ecstasy On The Nervous System

C-(+)-McN5652 was administered intravenously. Thirty-five scans were obtained according to a variable scan protocol of 90 min using a full-ring PET system. Transaxial slices were reconstructed using the iterative method. Each person’s brain is then transplanted into a pre-defined template. Diffusion volume measurements (DVRs) were obtained using the tissue regression technique. The gray matter of the cerebellum served as a reference. Brain regions rich in SERT—the mesencephalon, putamen, caudate, and thalamus—were selected to evaluate SERT availability using volumes of interest previously defined in the template. Results: Compared to drug control subjects, the DVR in real ecstasy users was significantly reduced in the mesencephalon (

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= 0.044). DVR in former ecstasy users was very close to DVR in drug control subjects in all brain regions. DVR in polydrug users was slightly higher than that in drug-naive control subjects in all SERT-rich regions (not statistically significant). Conclusion: Our results further support the hypothesis of long-lasting SERT changes induced by ecstasy. In addition, they may show altered SERT availability as measured by PET. However, this does not mean a complete reversal of neurotoxic effects.

The synthetic hallucinogen, 3,4-methylenedioxymethamphetamine (MDMA) is the psychoactive component of the popular recreational drug ecstasy. It produces pleasure, increases psychomotor drive, and improves socialization. Because of these results, excitement has increased among teenagers and young adults.

However, despite these psychological effects, there is increasing evidence of the neurotoxicity of MDMA (1). Preliminary findings in animals (in both rats and non-human primates) have shown that MDMA can cause changes in serotonergic neurons in the brain (2-5). Moreover, significantly reduced concentrations of 5-hydroxyindoleacetic acid in the cerebrospinal fluid of human ecstasy users have provided evidence that MDMA also leads to the destruction of serotonin neurons in the human brain (6).

To further explore the effect of MDMA on the serotonergic system, the characteristics of the presynaptic serotonin transporter (SERT) have been developed. Using PET, Szabo et al. (7) showed high ligand binding

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C-(+)-McN5652 binding to MDMA receptors was performed by McCann et al. (8). In 14 former users of ecstasy, a decrease in global and local binding to SERT was observed compared to that of 15 control subjects who did not use MDMA. Ecstasy users had been abstinent from psychoactive drugs for 19 wk (range, 3–147 wk) prior to the study. Semple et al. (9), using

β-CIT) SPECT, found a reduction of cerebral cortical SERT in long-term MDMA users compared to MDMA-naive but other drug-using subjects. In ecstasy users, SPECT was performed 2.6 ± 1.1 wk (range, 0.9–4.0 wk) after the last tablet. In the study of cerebral glucose metabolism using PET with

F-FDG was reduced within the striatum and amygdala in 93 ecstasy users compared to that of 27 control subjects (10, 11). The time from the last ecstasy intake to the date of PET was 28 ± 62 wk (range, 0.4–416 wk).

Effects Of Ecstasy On The Nervous System

However, it is still unclear whether MDMA leads to irreversible damage of serotonergic neurons or whether neuronal changes are reversible after withdrawal from ecstasy use. Furthermore, criticisms of previous studies refer to the possible simultaneous abuse of psychoactive agents other than ecstasy that may also cause a reduction in SERT availability.

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Therefore, the purpose of this study was to investigate the long-term effects of MDMA use on the serotonergic system.

C-(+)-McN5652 PET in a large number of subjects with specific or previous consideration of ecstasy abuse and psychoactive drug abuse other than MDMA.

C-(+)-McN5652 (12) was performed on 120 healthy subjects without psychiatric history divided into 4 different groups: actual users of ecstasy (group A), former users of ecstasy (group F), subjects without known history of illegal drugs. abuse (drug-naive, group N), and subjects of abuse of psychoactive agents other than ecstasy (polydrug users, group P). All subjects were assessed for psychopathology with the Structured Clinical Interview for DSM-IV (SKID) (13). Subjects currently suffering from an axis I disorder, other than drug-related disorders (not alcohol- or opiate-related disorders), were excluded from the study. Drug history was ascertained through a standardized questionnaire. The feasibility of self-testing of drug users has been confirmed by testing hair samples. Participants abstained from the use of psychoactive drugs for at least 3 days prior to the study. To confirm this withdrawal period, the urine of all subjects was examined for the presence of amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolites, opiates, and alcohol on the day of PET. Subjects that tested positive for any of these drug groups, other than cannabinoids, were excluded from the study. However, urine test results can be false. Therefore, in the 3 subjects that could be evaluated honestly, PET was performed despite a positive urine test. In these studies additional blood was tested for drugs. A positive urine test was confirmed by a blood test in 2 of these subjects, leading to exclusion from the study after PET scanning. In this way, the stopping time is guaranteed for all the subjects included in the study. Scanning of another subject could not be completed due to claustrophobia. Demographic data for the remaining 117 subjects are detailed in Table 1.

The study was approved by the local ethics committee and radiation protection authorities. All participants gave their written informed consent.

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Thirty ecstasy users (15 women, 15 men; mean age, 24.5 ± 4.2 y) were investigated. The inclusion criterion was regular use of ecstasy (at least once a week) at least 2 pills within 48 h each time. Drug history data are listed in detail in Tables 2 and 3.

Twenty-nine ecstasy users (14 women, 15 men; mean age, 24.2 ± 3.6 y) were investigated. The inclusion criterion was a cumulative dose of ecstasy of at least 250 tablets and 400 pills in female and male subjects, respectively. We included those subjects who had taken ecstasy for at least 36 mo and the last MDMA intake at least 20 wk before.

Twenty-nine subjects (15 women, 14 men; mean age, 23.3 ± 3.7 y) without any known history of illegal drug abuse served as a control group. Drug administration studies were not available for any psychoactive drugs. Alcohol or nicotine use that does not meet the criteria for dependence

Effects Of Ecstasy On The Nervous System

Twenty-nine subjects (14 women, 15 men; mean age, 24.4 ± 4.6 y) with the abuse of psychotropic substances other than ecstasy were investigated. Drug abuse in this group was viewed as consistent with drug abuse in groups of ecstasy consumers, without ecstasy. The last drug intake was from 3 d to a maximum of 2 weeks earlier

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The parent compound of the radiotracer, McN5652-z (6-[4-methylthiophenyl]-1, 2, 3, 5, 6, 10b-hexahydropyrrolo[2, 1-a] isoquinoline), was synthesized and fully characterized by x- Analysis X-ray structure and nuclear magnetic resonance spectroscopy (nuclear Overhauser effect measurements). The 2 diastereomers were unambiguously assigned and compared to the real sample. Since this compound has 2 centers of asymmetry, there are 4 stereoisomers (6

). Regarding the position of the hydrogen atoms at C-6 and C-10b, the 2 enantiomeric pairs were called cis and trans. The diastereoisomers were separated by preparative column chromatography, and the previously described (+)-enantiomer was separated by semipreparative chromatography on the chiral phase (amylose tris[3,5-dimethylphenyl carbamat]) and compared with the real sample of (+)-McN5652-z enantiomer (15).

C-methyliodide, the (+)-McN5652-z enantiomer was demethylated and the corresponding thiolate was isolated with a chemical purification of 98.5% using solid phase extraction methods. The precursor was separated in an amount of 200 μg and stored at −80°C.

C-(+)-McN5652-z at the end of synthesis. A 10-fold improvement in average performance was achieved when i

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The enantiomer purity, radionuclidic purity, and radiochemical purity were more than 99.5%, 99.9%, and 90.0%, respectively. Radiochemical purity was limited due to the decay of

C-(+)-McN5652-z depends on the amount of activity produced. Specific activity at the end of the integration was > 30 MBq/nmol (mean ± 1 SD, 177 ± 108 MBq/nmol; range, 30-537 MBq/nmol). The numbers given to the participants are summarized in Table 4.

PET was performed on a ring-ring, whole-body ECAT EXACT 921/47 system (Siemens/CTI, Knoxville, TN) in 2-dimensional mode. This system collects an axial field of 16.2 cm by collecting 47 transverse slices with a 3.4-mm separation.

Effects Of Ecstasy On The Nervous System

Reduction of head movement was achieved by a thermoplastic mask immobilization system (Tru-Scan Imaging, Annapolis, MD). A 15 minute transmission scan for sedation correction was obtained prior to needle tracking using a 3 round.

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C-(+)-McN5652, dissolved in 40 mL 0.9% NaCl, was injected into the left hand vein at a flow rate of 600 mL/h. Thus, the total infusion time was 4 min. At the beginning of the tracer injection a dynamic scanning process was started, including 35 frames with a total acquisition time of 90 minutes (9 × 20 s, 6 × 30 s, 4 × 60 s, 5 × 120 s.

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