Buchert R, Thomasius R, Nebeling B, Petersen K, Obrocki J, Jenicke L, Wilke F, Wartberg L, Zapletalova P, Clausen M (2003) Long-term effects of "Ecstasy" use on serotonin transporters of the brain investigated by PET. J Nucl Med 44: 375-84.
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Purpose: Neuroimaging; To assess the effects of long-term, heavy ecstasy use on serotonin transporter site density, as assessed through positron emission tomography (PET) with the radioligand [11C]-(+)-McN5652 in current and abstinent users. Specific hypothesis tested - That current and former ecstasy users would show reduced binding of (+)-McN5652 in serotonin-rich regions (mesencephalon, putamen, caudate and thalamus), and that there would be a difference (direction unspecified) between (+)-McN5652 binding in polydrug user controls and non-drug users.

Design: Retrospective (non-experimental) between subjects design, with drug use (current ecstasy use, previous ecstasy use, polydrug use or no drug use) serving as a between-subjects factor, and with all participants undergoing PET scans with (+)-McN5652.

Subjects: [Some details drawn from Thomasius et al. 2003] 30 current ecstasy users, 29 former ecstasy users, 29 polydrug user controls and 29 non-drug user controls probably residing in or near Hamburg (Germany). All participants were recruited through advertisements in local newspapers and magazines and leaflets distributed at dance events and educational institutions in the Hamburg area. Matching - Groups were matched on age, gender, pre-morbid IQ, and (in drug users) use of drugs other than ecstasy. Groups were approximately matched on education. (Data on cognitive function and self-reported psychological problems in the same sample are reported in a separate publication (Thomasius et al. 2003).

Criteria for Inclusion, Current Ecstasy Users - Having used ecstasy for at least 20 weeks at a self-reported frequency of at least weekly use of 2 or more tablets in a 48-h period. Former Ecstasy Users - Self-reported lifetime consumption of at least 250 tablets in women and at least 400 tablets in men, having used ecstasy for at least 3 years (36 months) but having ceased ecstasy use for at least 20 weeks prior to the study date. Polydrug Users - No reported use of ecstasy, but use of other substances in amounts similar to those reported by ecstasy users. Non-drug Users - Never having used any illicit substance, but matching the other groups in demographic variables. All groups - Ages 18-30, absence of major acute medical or psychiatric illness, no signs of epilepsy, not pregnant, and abstinence from use of any illicit substances for six days prior to study days, with abstinence verified through urinary analyses. Drug histories were also verified through hair analyses.

Drug Use Parameters - [Average dose per use and maximum dose per use parameters drawn from the sample of 31 former ecstasy users assessed in Thomasius et al. 2003. Minor errors in reporting of drug use parameters appeared in this paper, and were subsequently corrected in Buchert et al. 2004, see also a summary of the 2004 paper.] Current ecstasy users reported an average lifetime consumption of 827 +/- 1268 tablets (range = 13-6873), with an average dose per use of 3.95 +/- 2.53 tablets, and a maximum dose per use of 8.51 +/- 11.81 tablets. Current ecstasy users reported an average duration of use, in months, as 54 +/- 32 mo (range = 5-120 mo). Average time since last ecstasy use in current ecstasy users, in days, was 24 +/- 16 days (range = 4-60). Age of onset of ecstasy use was 20 +/- 3.8 (range = 14-30). Former ecstasy users reported lifetime consumption of 793 +/- 679 tablets (range = 78-3122), with an average dose per use of 4.06 +/- 3.87 tablets per use, and a maximum dose per use of 8.28 +/- 3.53 tablets. Former ecstasy users reported average duration of use, in months, as 55 +/- 27 mo (range = 18-116 mo). Time elapsed from last ecstasy use to study day, in days in former ecstasy users was, on average, 514 +/- 472 days (range = 90-1500 days; note that 90 days = approximately 13 weeks, and not 20, weeks of abstinence). Former ecstasy users reported age of onset for ecstasy use as 18.3 +/- 3 years (range = 18-28). Use of Other Drugs (Information in parentheses collected from Thomasius et al. 2003, in a sample of 31 former ecstasy users versus 29 in this paper). Cannabis: Current ecstasy user reporting a lifetime consumption of 567 +/- 1188 joints, former ecstasy users reported an average lifetime consumption of 2133 +/- 2200 joints and polydrug users had an average lifetime consumption of 1232 +/- 1303 joints. (Cannabis was used by 29/30 current ecstasy users, 31/31 former ecstasy users and 28/29 polydrug users. Monthly cannabis consumption, in grams, was 7.76 +/- 18.29 g, in former ecstasy users was 18.46 +/- 28.57 g). Amphetamine: Current ecstasy users had an average lifetime consumption of 68 +/- 106 g, former ecstasy users had an average lifetime consumption of 77 +/- 115 g and polydrug users had an average lifetime consumption of 4 +/- 9 g. (Amphetamine was used by 27/30 current ecstasy users, 27/31 former ecstasy users and 12/29 polydrug users. Monthly amphetamine consumption was 2.65 +/- 1046 g in current ecstasy users, none listed for former ecstasy users and 0.07 +/- 0.37 g for polydrug users.) LSD: Current ecstasy users had an average lifetime consumption of 1.6 +/- 5.2 g, former ecstasy users had an average lifetime consumption of 2.4 +/- 5.1 g and polydrug users had an average lifetime consumption of 0.2 +/-0.4 g. (LSD was used by 22/30 current ecstasy users, 27/31 former ecstasy users and 11/29 polydrug users. Monthly LSD consumption was (in mcg) 17.92 mcg in current ecstasy users, not used in former ecstasy users or in polydrug users.) Psilocybin: Current ecstasy users had an average lifetime consumption of 0.9 +/- 3.2 g, former ecstasy users had an average lifetime consumption of 2.1 +/- 15.6 g, and polydrug users had an average lifetime consumption of 14.4 +/- 32.5 g. (Psilocybin, was used by 3 current ecstasy users, 6 former ecstasy users and 10 polydrug users. Monthly psilocybin consumption was 0.067 g in current ecstasy users, 0.31 +/- 1.23 g in former ecstasy users and 0.069 +/- 0.37 in polydrug users). Cocaine: Current ecstasy users had an average lifetime consumption of 38 +/- 75 g, former ecstasy users had an average lifetime consumption of 101 +/- 219 g, and polydrug users had an average lifetime consumption of 255 +/- 708 g. (Current was used by 28/30 current ecstasy users, 30/31 former ecstasy users and 22/29 polydrug users. Monthly cocaine consumption was 0.39 +/- 0.88 g in current ecstasy users, 0.27 +/- 1.01 g in former ecstasy users and 1.85 +/- 5.49 g in polydrug users). Alcohol: Current users had an average weekly use of 94 +/- 97 g, former ecstasy users had an average weekly use of 152 +/- 198 g, polydrug users had an average weekly use of 197 +/- 195 g, and non-drug users had a weekly use of 71 +/- 71g. Tobacco: Current ecstasy users had a weekly use of 53 +/- 58 cigarettes, former ecstasy users had a weekly consumption of 101 +/- 71 cigarettes, polydrug users had a weekly consumption of 135 +/- 80 cigarettes and non-drug users had a weekly use of 66 +/- 65 cigarettes. Demographics and Matched Variables - The authors matched groups for gender, age, premorbid IQ, use of other drugs (in all drug-using groups), and approximately matched groups for education. Current and former ecstasy users were enrolled first, and controls were selected on the basis of their similarity to ecstasy users on matched variables. Gender - as M/F ratio: Current ecstasy users = 15/15, former ecstasy users = 15/14, polydrug users = 14/15, non-drug users = 15/14. Age - Average age of current ecstasy users was 24.5 +/- 4.2 (range = 19-34), of former ecstasy users was 24.2 +/- 3.6 (range = 19-36), of polydrug users was 23.3 +/- 3.7 (range = 18.33) and of non-drug users was 24.4 +/- 4.6 (range = 18-35). Education - [Educational attainment presented in Thomasius et al. 2003 only and coded as either basic (9 years), intermediate (10 years), or college admission level (13 years); estimated years of education and original coding provided. On average, current ecstasy users attained 10.93 years of education (8 basic/10 intermediate/12 college admission), former ecstasy users attained 10.9 years (8 basic, 11 intermediate, 12 college), polydrug users attained 10.96 years (5 basic, 13 intermediate, 11 college), and non-drug users attained 11.06 years of education (7 basic, 10 intermediate, 13 college admission). Pre-morbid IQ - [From Thomasius et al. 2003]. Current ecstasy users had an average IQ of 102.5 +/- 9.64, former ecstasy users had an IQ of 106.48 +/- 13.94, polydrug users had an IQ of 104.28 +/- 9.9 and non-drug users had an IQ of 104.97 +/- 13.47.

Measures: All participants underwent a full-body PET scan with 466 +/- 76 MBq [11-C]-(+)-McN5652 with an infusion time of 4 minutes, and with a scan time of 90 minutes. Mesencephalon, putamen, caudate and thalamus were selected as volumes of interest (VOIs) in order to test hypotheses concerning serotonin transporter availability. White matter served as control region (where no ecstasy-related effects were expected because of absence of serotonin transporter sites there) and cerebellar gray matter was used as a reference site for kinetic modeling. Distribution volume ratios for (+)-McN5652 were calculated to reflect receptor density. Standardized uptake volumes (SUVs) were also calculated by summing frames (images) taken from 50 to 90 minutes after (+)-McN5652 injection and considered the ratio of tracer uptake to injected dose per body weight of McN5652.

Analyses: DVRs were compared across groups with a one-way, between-subjects analysis of variance (ANOVA), with drug use (current ecstasy user, former ecstasy user, polydrug user or non-drug user) serving as the between-subjects factor. Post-hoc comparisons were made through Scheffe test, with p value unstated but apparently set at p. = 0.05. SUVs were compared across groups via one-way between-subjects ANOVA, with drug use (current ecstasy user, former ecstasy user, polydrug user or non-drug user) serving as a between-subjects factor. Post-hoc tests were performed via Scheffe test, with p (apparently) set at 0.05.

Results - Significant Differences Found: DVRs for (+)-McN5652 binding in mesencephalon were lowest in current ecstasy users compared to all other groups (Current ecstasy users < former ecstasy users = polydrug users = non-drug user controls). Thalamus (+)-McN5652 DVRs were lower in current ecstasy users than in either polydrug users or non-drug user controls (Current ecstasy users < polydrug users = non-drug users). Caudate (+)-McN5652 values were lower in current ecstasy users than in polydrug user controls (Current ecstasy users < polydrug users). (Initial analysis found significant differences in white matter SUVs, with white matter SUV highest in drug-naïve controls, but significance was not confirmed after Scheffe test).

Results - No Significant Differences: All four groups did not significantly differ in putamen or white matter (+)-McN5652 DVRs. Former ecstasy users' (+)-McN5652 DVRs for mesencephalon, caudate or thalamus were not significantly different from those of polydrug users or non-drug users. None of the four groups had significantly different SUVs for mesencephalon, putamen, caudate or thalamus. (There was a trend only for higher mesencephalon SUV in non-drug users than in current ecstasy users, former ecstasy users or non-drug user controls. (+)-McN5652 DVRs were not significantly different between polydrug users, former ecstasy users and non-drug users for all regions (mesencephalon, putamen, caudate, thalamus and white matter). Polydrug users' SUVs for all regions (mesencephalon, putamen, caudate and thalamus) were not significantly different from those in all other groups (current and former ecstasy users, non-drug users).

Overall Effects: Analysis of PET scans performed with [11-C]-(+)-McN5652 on current ecstasy users, former ecstasy users, polydrug users and non-drug users controls matched for a number of demographic variables found lower ligand binding in current, but not former, ecstasy users when compared to non-drug user and polydrug user controls. This was true in mesencephalon, caudate and thalamus. Though not stated by the authors, current ecstasy users had only a 4% to 6% reduction in estimated serotonin transporter binding. A comparison of standardized uptake volumes (SUVs) for (+)-McN5652 failed to find any significant differences between groups in serotonin-rich areas. While polydrug users tended to have higher (+)-McN5652 binding than all other groups, this difference never reached significance. If ligand binding DVRs serve as accurate measures of serotonin transporter site density, then study findings indicate that continued regular, heavy ecstasy use lowered serotonin transporter availability, but that formerly regular, heavy ecstasy users no longer had lower serotonin transporter availability. Specific hypotheses were only partially confirmed; current, but not former, ecstasy users showed lower DVRs in mesencephalon, caudate and thalamus, and the differences between polydrug users and non-drug users did not reach significance.

Comments: This is the second published report of an imaging study using the radioligand McN5652. The first publication (McCann et al. 1998) employed methods that others considered questionable. Other researchers have employed a different radioligand for measuring serotonin transporter availability (e.g. Semple et al. 1999; Reneman et al. 2002; 2001). Like Semple and colleagues (1999), these researchers attempted to verify drug use history through hair analysis and verified abstinence via urinary analysis rather than through self-report. Compared with other imaging studies, the samples appearing in this report were well-matched, with drug user groups matched on all but perhaps amphetamine and cannabis use. Unlike the previous paper with McN5652, this report found reduced ligand binding only in current ecstasy users, and not former users. These study findings suggest that repeated, heavy ecstasy use (along with regular use of other substances) is associated with a temporary reduction in brain serotonin transporter availability. Changes in serotonin transporter availability may arise from downregulation of serotonin function, harm to serotonin axons or both causes, but effects are not permanent. However, effects on cortical areas cannot be measured with (+)-McN5652, and at least one study in non-human primates has found reduced brain serotonin 7 years after a repeated-dose regimen (Hatzidimitriou et al. 1999). Like nearly all other studies, this study is retrospective, and while samples are significantly larger than those appearing in other studies, the sample size is still relatively small. http://www.maps.org/w3pb/new/2003/2003_buchert_6041_1.pdf

 
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