Purpose: Neuropsychological, neuroendocrine; To investigate plasma concentrations of monoamine neurotransmitters in ecstasy users, abstinent ecstasy users and non-ecstasy using controls.

Design: Retrospective (non-experimental) between-subjects study design, with drug use (ecstasy user, abstinent ecstasy user or polydrug-no ecstasy user) serving as between subjects factor, with all participants undergoing periodic collection of blood samples in order to test for plasma monoamine and metabolite content.

Subjects: 107 ecstasy users, 11 abstinent ecstasy users and 41 drug users reporting no ecstasy use, apparently residing in the Hamburg (Germany) area. Ecstasy users divided into "light to medium" ("E1", n = 34), "medium to heavy" ("E2", n = 42) and "heavy" (E3, n = 30) users. No information is provided concerning nature of recruitment or matched variables; apparently findings using the same or an overlapping sample appeared in a German-language publication (Weiner Z Suchtforsung). In papers previously published by one researcher listed here (Obrocki et al. 2002) report recruiting participants from local discotheques and matching users and non-users for age and gender.

Criteria for Inclusion - Ecstasy Users - Abstinence from ecstasy for at least 3 days prior to study day, with compliance verified through urinary analysis. Abstinent ecstasy users - Reporting abstinence from ecstasy for an unspecified amount of time, possibly longer than 30 days (see information on abstinence for all 3 "ecstasy user groups."). Non-ecstasy users - Reported never having used ecstasy, with verification within limited time period obtained via hair analysis. All Groups - No other inclusionary or exclusionary criteria are described; presumably taking medication that might alter blood monoamine levels was prohibited, and participants were healthy enough to provide blood samples. A previously published study by this team included only subjects aged 30 or younger.

Drug Use Parameters - Group "E1" - Participants in this group reported a lifetime dose less than 100 tablets. Group "E2" - Participants in this group reported a lifetime ecstasy dose of between 100 and 499 tablets. Group "E3" - Participants in this group reported a lifetime ecstasy dose of 500 to 2500 tablets. Duration of use is given for all 3 groups combined as an average of 5.3 months (range = 0.13-96 months). Time since last use, in days, is listed as less than 30 days (1 month). Abstinent Users - No information is provided on lifetime dose of abstinent ecstasy users. No information is provided on frequency of dose, per month or on average dose per use. Other Drugs - Use of other drugs permitted for all participants, but no information provided about the amount or types of drugs used by any of the ecstasy using groups, the abstinent ecstasy users or the non-user controls.

Group Demographics and Matched Variables - No information is provided on matched variables. Gender, as M/F ratio - (For overall sample only) 91/68. Age - No information is given on participant age, either overall or within each drug use group. Education - No information is provided about level of education obtained by participants overall or within any of the user groups.

Measures: Plasma monoamine neurotransmitters were measured via HPLC, with blood collected while participants were lying down for 5 h.

Analyses: Plasma Monoamines - Differences in plasma monoamine or metabolite values were analyzed via separate 1-way analyses of variance (ANOVAs), with drug use group (Light-medium (E1), medium-heavy (E2), heavy (E3) ecstasy user, abstinent ecstasy user or no ecstasy use) serving as a between-subjects factor. Analyses were conducted on plasma 5-HT,. 5-HIAA, epinephrine (E), norepinephrine (NE) and DA values. Post-hoc comparisons were made between means, and p. was set at 0.05.

Drug use parameters and plasma monoamine values - Spearman's rank coefficient was used to examine association between plasma monoamine values and cumulative ecstasy use (lifetime dose), amount of ecstasy used in 30 days prior to study day, and amount of ecstasy use in year prior to study day. P value was set at 0.05.

Results-Significant Differences: Plasma Monoamines - "Light to medium" ecstasy users had significantly higher plasma epinephrine values than the no-ecstasy use group. Light to medium ecstasy users also had higher epinephrine values than did abstinent ecstasy users. Plasma NE was significantly higher in "light to medium" (E1) ecstasy users than in abstinent ecstasy users, and plasma NE in "light to medium" (E1) ecstasy users was also significantly higher than plasma NE in non-users. Plasma NE in "medium to heavy" (E2) ecstasy users was significantly higher than plasma NE values for abstinent ecstasy users or in non-users. Plasma DA values were significantly higher in "medium to heavy" ecstasy users (E2) when compared with polydrug user controls.

Drug Use Parameters and Plasma Monoamines - Plasma NE values were associated with cumulative ecstasy dose (lifetime dose), amount of ecstasy used in 30 days prior to study and amount of ecstasy used in the past year; plasma NE values increased as amount of ecstasy taken in given time period increased. (Relationship is not specifically stated). Plasma DA values were only correlated with amount of ecstasy used in prior year. Plasma catecholamines (E, NE and DA) were all correlated with each other.

Results - No Significant Differences Found: Plasma Monoamines - There were no significant variations in plasma 5-HT value across groups (though examination of means finds it highest in "heavy" users (E2) and lowest in non-users and abstinent users. All 3 groups of ecstasy users, abstinent users and non-users did not have significantly different plasma 5-HIAA values (examination of means shows no evidence of linear relationship between overall amount of ecstasy used or time since last use and plasma 5-HIAA).

Drug Use Parameters and Plasma Monoamines - Plasma 5-HT values were not significantly associated with cumulative (lifetime) ecstasy dose, amount used 30 days prior to the study day, or amount used in last year. Plasma 5-HIAA values were not associated with any of the drug use variables examined (cumulative (lifetime) dose, amount of ecstasy used either in the last 30 days or in the last year. Plasma E (epinephrine) was not significantly associated with cumulative (lifetime) ecstasy use, amount of ecstasy used in the last 30 days or in the last year prior to study day. Plasma 5-HT and 5-HIAA were not significantly associated with plasma values for E, NE or DA.

Overall Effects: Resting plasma NE values were significantly higher in "light to medium" and "medium to heavy" (<100 tablets - 499 tablets) ecstasy users than in abstinent ecstasy users (cumulative dose not reported) or in polydrug users reporting no use of ecstasy. Resting plasma epinephrine was significantly higher in "light to medium" users than in non-users, but similar epinephrine values were detected in "light to medium" users and abstinent ecstasy users. Resting plasma DA was higher in "medium to heavy" ecstasy users than in non-users. Somewhat surprisingly, there were no significant differences in plasma 5-HT or plasma 5-HIAA across any of the groups, though at least in the case of 5-HT, an informal examination of means suggests that "heavy" ecstasy users had greater plasma 5-HT than all other groups, and abstinent users and non-users had the lowest plasma 5-HT values. When individual plasma monoamine values were plotted against drug use parameters, it was found that plasma NE was associated with cumulative (overall) ecstasy consumption, amount used in the last month before the study and amount used in the last year before the study, with greater ecstasy indicating higher plasma NE. While plasma DA values were not associated with overall ecstasy use or with amount used in the month prior to the study, DA values were related to amount used in the year before the study. The authors describe these findings as indicating higher sympathetic tone in (mostly current) ecstasy users, as compared with people who have either never used ecstasy or who have ceased using it for an unspecified amount of time.

Comments: This is the first report of differences in peripheral monoamine concentrations in current ecstasy users, as compared with abstinent users and non-using controls. However, information on group demographics and drug use parameters are insufficiently reported and often absent, making it difficult to ascertain whether study findings are solely the result of ecstasy use or some other variables. The authors do not comment upon the apparent lack of association between plasma 5-HT and 5-HIAA values across groups (with 5-HT values increasing linearly with cumulative ecstasy exposure, but with no such relationship for 5-HIAA levels). One possible explanation for the lack of significant difference (and linear trend) in 5-HT is an inverse relationship between centrally versus peripherally synthesized 5-HT. However, even this explanation fails to account for the lack of any linear trend between ecstasy use and 5-HIAA values. It is also difficult to relate study findings presented here with other comparisons of ecstasy users, as these largely focus on brain function rather than peripheral monoamine concentration. However, study findings may be comparable with reported changes in cardiovascular response to the Valsalva maneuver (measures sympathetic and parasympathetic activation) in ecstasy users described by Brody and colleagues )Brody et al. 1998). The cardiovascular response to the Valsalva maneuver is reported as being indicative of reduced parasympathetic tone. Despite an impressively large sample size, conclusions are hard to draw from this study due to lack of information on participant demographics, drug use parameters and the presence or absence of matched variables. There are far fewer abstinent users than ecstasy users or non-users, making findings in this group less certain than findings in other groups. At least one member of this research team has already published imaging studies comparing ecstasy users with cancer patients who had not used ecstasy. Some overlap may exist between the sample of ecstasy users examined in this study and the sample described in earlier papers, though an examination of sample demographics and drug use parameters also suggests that at least half of the ecstasy users appearing in this study did not participate in previous studies.