Memory performance in polyvalent MDMA (ecstasy) users who continue or discontinue MDMA use

Drug and Alcohol Dependence 78 (2005) 317–323

Memory performance in polyvalent MDMA (ecstasy) users who continue or discontinue MDMA use Euphrosyne Gouzoulis-Mayfrank a, ∗ , Thomas Fischermann a , Markus Rezk b , Bastian Thimm b , Gernot Hensen b , Joerg Daumann a b

a Department of Psychiatry and Psychotherapy, University of Cologne, Kerpener Strasse 62, D-50924 Cologne, Germany Department of Psychiatry and Psychotherapy, Medical Faculty of the University of Technology (RWTH), Pauwelsstrasse 30, D-52074 Aachen, Germany

Received 13 September 2004; received in revised form 8 December 2004; accepted 14 December 2004

Abstract Background: The popular dance drug ecstasy (3,4-methylenedioxymethamphetamine = MDMA) is a serotonergic neurotoxin in animal studies. Several cross-sectional investigations reported low memory and learning performance in ecstasy users, particularly in those reporting heavy patterns of drug use. Since, serotonin has a recognized role in memory processes, these findings were mostly interpreted as evidence for ecstasy-related neurotoxicity in humans. However, studies with user populations and controls suffer from many inherent methodological problems. Moreover, longitudinal data on memory performance after continued or discontinued ecstasy use are scarce. Methods: In the present longitudinal study, we examined memory performance in 38 MDMA users over the course of 18 months. Results: Subjects who stopped MDMA use after the baseline examination (n = 17) did not improve, and subjects who continued MDMA use (n = 21) did not deteriorate in terms of test performance. Conclusions: Our data do not support, but they also do not rule out memory decline following use of the serotonergic neurotoxin MDMA. In light of the popularity of ecstasy among young people, further investigations are needed. In our view, research strategies should now move to prospective designs in order to shed more light on the course of possible adverse cognitive effects of ecstasy use. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Ecstasy; MDMA; Cognition; Memory; Neurotoxicity; Serotonin

1. Introduction The popular recreational drug ecstasy (MDMA = 3,4methylenedioxymethamphetamine and other congeners) has a well recognized neurotoxic potential upon central serotonergic systems in animal studies. Repeated systemic administration of MDMA leads to widespread degeneration of presynaptic serotonergic axon terminals resulting in low levels of serotonin and its major metabolite and low densities of serotonin reuptake sites all over the brain (Ricaurte et al., 1992, 2000; review in Green et al., 2003). There is growing evidence that these toxic effects can be very long lasting or even permanent in experimental animals (Fischer et al., 1995; ∗ Corresponding author. Tel.: +49 221 478 4825/4001; fax: +49 221 478 3738. E-mail address: [email protected] (E. Gouzoulis-Mayfrank).

0376-8716/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.drugalcdep.2004.12.002

Hatzidimitriou et al., 1999), and may also occur in humans (McCann et al., 1998, 2000; Reneman et al., 2001; review in Green et al., 2003). Recent studies indicate that diminished serotonergic neurotransmission may interfere with memory and learning processes (Richter-Levin and Segal, 1996; Poulos et al., 1996; Riedel et al., 1999; Buhot et al., 2000). In line with this evidence, numerous studies reported dose-related impairments of learning and memory performance in currently abstinent ecstasy users (Krystal and Price, 1992; Bolla et al., 1998; Parrott and Lasky, 1998; Morgan, 1999; Gouzoulis-Mayfrank et al., 2000, 2003; Reneman et al., 2000; Rodgers, 2001; Bhattachary and Powell, 2001; Zakzanis and Young, 2001; Rodgers et al., 2003; Back-Madruga et al., 2003; Hanson and Luciana, 2004; McCardle et al., 2004). In addition, some studies reported deficits in short-term or working memory in the same or similar user populations (Curran and

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Travill, 1997; Morgan, 1998; McCann et al., 1999; Dafters et al., 1999; Wareing et al., 2000, 2004; Gouzoulis-Mayfrank et al., 2000; Verkes et al., 2001). Taken together, these data suggest that the relatively low memory performance of ecstasy users may be related to residual neurotoxic effects of MDMA upon central serotonergic systems. However, cross-sectional open trial studies with user populations and controls suffer from inherent methodological problems and confounding variables such as polydrug use patterns, uncertain dosage, purity and chemical composition of the illegally purchased drugs, and different motivational levels, life styles, cognitive strategies and pre-morbid performance levels (review in Curran, 2000). Although most studies did demonstrate low memory performance in ecstasy users, reports have not been entirely consistent: a minority of studies reported no differences between ecstasy users and controls (Dafters et al., 1999; Parrott, 2000; Wareing et al., 2000). Moreover, a recent study in combined users of ecstasy and cannabis reported an association between low memory performance and the extent of the concomitant use of cannabis rather than the use of ecstasy (Dafters et al., 2004). Another puzzling finding was reported in a recent crosssectional neurocognitive and positron emission tomography (PET) study with 30 current and 31 former ecstasy users with an abstinence period of at least 5 months (Thomasius et al., 2003): in this study, only the former, but not the current users showed poorer verbal memory compared to controls. At the same time, serotonin transporter (SERT) availability was reduced only in the current, but not in the former users, suggesting at least some degree of recovery of the assumed serotonergic lesion over prolonged abstinence from ecstasy. The authors argued that verbal memory impairments may have been aggravated after abstinence, but given the unimpaired performance of current users and the PET data, these results are difficult to interpret (Thomasius et al., 2003). Finally, longitudinal data on the evolution of memory functions over time under continued or discontinued ecstasy use are scarce. In fact, only one small longitudinal study with 15 ecstasy users reported memory decline after continued use over 12 months (Zakzanis and Young, 2001). Moreover, there have been no longitudinal data about changes in memory performance after prolonged abstinence. Therefore, the linkage between ecstasy use and memory decline cannot be considered proven. In the present longitudinal investigation, we followed a relatively large sample of 60 ecstasy users over a period of 18 months. Originally, this sample had been recruited for a cross-sectional investigation, which has already been published elsewhere (Gouzoulis-Mayfrank et al., 2003). In line with other reports from the literature, the major findings of this study had been: (a) lower memory performance in a subgroup of heavy ecstasy users with an estimated lifetime dose of at least 80 ecstasy pills compared to both moderate ecstasy users and non-users, and (b) statistical associations between heavier ecstasy use and lower memory and working memory performance (Gouzoulis-Mayfrank et al., 2003). Assuming a

linkage between the relatively low memory performance of ecstasy users and the neurotoxic effects of ecstasy upon central serotonergic systems, we hypothesized that continuation or discontinuation of ecstasy use during the follow-up period should affect test performance. Thus, the purpose of this longitudinal study was to evaluate whether continuation of ecstasy use results in further deterioration, and whether discontinuation of ecstasy use results in improvement of memory performance over a follow-up period of 18 months.

2. Methods 2.1. Subjects Our original sample at baseline (t1 ) consisted of 60 MDMA users (inclusion criterion: use of ecstasy on at least 20 occasions) who were recruited directly in the dance scene, via word-of-mouth and via the internet (Gouzoulis-Mayfrank et al., 2003). Because most ecstasy users tend to experiment also with other typical club drugs, subjects who reported use of amphetamines, cocaine, cannabis or LSD were not excluded. However, subjects were excluded if they reported substantial use of alcohol (defined as drunkenness occurring at a frequency of at least twice per month over 6 months or longer within the last 2 years) or regular use of other legal or illegal psychotropic drugs such as opiates and benzodiazepines (defined as use once per month or more frequently over 6 months or longer within the last 2 years). We kept in contact with the ecstasy users via telephone over a period of 18 months. Finally, we were able to examine 38 users 18 months after the initial examination (t2 ). Twenty-two participants dropped out because they either moved without giving notice of their new address (n = 15), served a sentence as a consequence of drug dealing (n = 1), simply lost interest in the study (n = 4), or developed a manifest psychiatric disorder (n = 2) and were, therefore, excluded from the follow-up. From the 22 subjects who dropped out during the follow-up period of 18 months, 16 subjects had belonged to the subgroup of heavy users (lifetime dose ≥ 80 ecstasy tablets) and only 6 subjects had belonged to the subgroup of moderate users (lifetime dose < 80 ecstasy tablets) of the original study (Gouzoulis-Mayfrank et al., 2003). For both baseline and follow-up (t1 , t2 ) all ecstasy users agreed to abstain from drug use for at least seven days prior to the study with the exception of cannabis. Because daily moderate cannabis use was part of the life style of many subjects and because cannabis screens may remain positive for several weeks after the last use (thus making it impossible to verify reported abstinence) we tolerated that most subjects agreed to abstain from cannabis only on the study days. 2.2. Procedures All subjects underwent structured interviews according to the Diagnostic and Statistical Manual of Mental Disorders-

E. Gouzoulis-Mayfrank et al. / Drug and Alcohol Dependence 78 (2005) 317–323

IV (DSM-IV). In addition, we took medical histories and detailed histories of drug use. Drug screens were performed on the study days with urine samples for stimulant amphetamines, methylenedioxyamphetamines (ecstasy), cocaine and its metabolite, marijuana, benzodiazepines, barbiturates and opiates. Exclusion criteria for all participants were: (1) a positive drug screen on the study day except for cannabis; (2) any current or previous axis I psychiatric diagnosis except for drug abuse in the two user groups; and (3) any organic brain disorder or relevant general medical condition requiring pharmacological treatment. After detailed description of the study to the subjects, written informed consent was obtained and subjects were paid for their participation. The study was in accordance with the Helsinki Declaration of 1975 and was approved by the local ethics committee at the RWTH Aachen. 2.3. Neuropsychological tests At baseline (t1 ) we administered a test battery with tests of executive control, planning ability, cognitive impulsivity, working memory and memory to 60 ecstasy users and 30 matched controls. These cross-sectional results were already published (Gouzoulis-Mayfrank et al., 2003). In summary, the entire group of ecstasy user did not differ from controls in terms of test performance. However, the subgroup of heavy ecstasy users (n = 30, lifetime dose ≥ 80 ecstasy tablets) had lower memory performance than both non-users and moderate users (n = 30, lifetime dose < 80 ecstasy tablets). In addition, poorer memory and working memory performance was associated with a heavier pattern of ecstasy use (GouzoulisMayfrank et al., 2003). Based on these cross-sectional data we administered the same working memory and memory tests to the 38 users at t2 . • Digit Span backwards (from the WAIS-R, German version (Tewes, 1991))–subjects repeat a list of orally presented digits backwards (working memory). • 2-back (from the TAP (Zimmermann and Fimm, 1995))–a task consisting of the sequential visual presentation of single digits or simple figures. Subjects have to press a button when the presented digit or figure is the same as the one presented two trials earlier (working memory). • LGT-3 (Lern- und Gedachtnistest, learning and memory test, B¨aumler, 1974); in each of the four subtests of this paper-and-pencil test the material to be learned is presented visually for one minute. Memory performance is assessed immediately after the learning phase and again after 1 h. The LGT-3 is available in two parallel versions. Thus, the material to learn was different at t1 , and t2 . - LGT-3–logos: subjects have to memorize 20 logo-like figures each consisting of a central icon and a frame. In the retrieval phase they have to identify the correct frame corresponding to each central icon out of an array of four similar frames.

319

- LGT-3–city map: subjects have to memorize a line which is drawn in the free space between small rectangles and other irregularly shaped figures. This array looks like a route on a city map. In the retrieval phase subjects are presented with the map only, and they have to draw the route in it. Deviations from the previously presented line are scored according to standardized criteria. - LGT-3–German–Turkish: subjects have to memorize 20 word pairs consisting of a Turkish word and its German translation. In the retrieval phase they have to identify the correct Turkish word corresponding to each German word out of a list consisting of five Turkish words. - LGT-3–construction of a library: subjects are given a text consisting of 10 sentences and containing information about the construction of a library (name of the architect, address, number and size of the different rooms, costs of construction, etc.). In the retrieval phase subjects have to answer a list of 21 questions on these items. 2.4. Data analysis Demographic data of the two user groups at t2 (follow-up abstinents and continuing users) were analyzed by means of unpaired Student’s t-test. Changes in test performance from t1 to t2 were analyzed separately in each group by means of paired Student’s t-test. In addition, we calculated longitudinal effects in terms of change scores (t2 − t1 ) and analyzed differences between the two groups by means of unpaired Student’s t-test. In order to obtain additional information about the impact of other drug use on test performance we also performed similar analyses with different groups of users depending on their abstinence or continued use of cannabis and stimulant amphetamines. Finally, we correlated test performance data with both the interim (between t1 and t2 ) and the lifetime drug use. All procedures were performed using SPSS version 11.0 (SPSS Inc., Chicago, III). Thresholds of p < 0.05 were considered significant and Bonferonni corrections were performed for the correlation analyses.

3. Results 3.1. Demographics and drug use Sociodemographic data of the 38 subjects with data both for the initial examination and the follow-up (t1 , t2 ) are presented in Table 1. Seventeen subjects reported complete abstinence from MDMA or very sporadic use during the follow-up period (follow-up abstinents, range: 0–5 ecstasy pills from t1 to t2 ). Twenty-one subjects reported continued ecstasy use (continuing users, range: 20–400 ecstasy pills from t1 to t2 ). The two groups were similar in terms of sex distribution (χ2 -test: (χ2 = 0.511), age (t-test: t = 1.713, df = 35, p = 0.096) and level of education (Mann–Whitney U-test: U = 167.5, p = 0.988). The patterns of drug use are presented in Table 2. Similar to our findings at t1 (Gouzoulis-Mayfrank

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Table 1 Demographic data of interim abstinent ecstasy users (n = 17) and continuing ecstasy users (n = 21) at follow-up (t2 ) Mean age in years (mean ± S.D.) Men:women Level of education 1. Basic school-leaving exam after form 9 (Hauptschulabschlulβ) 2. Intermediate school-leaving exam after form 10 (Realschule/mittlere Reife) 3. Highest school-leaving exam qualifying for admission to college/university after form 12 or 13 (Fachabitur/Abitur) 4. University degree (Hochschulabschluβ)

et al., 2003), stronger interim use of ecstasy was associated with stronger interim use of amphetamines (Pearson’s correlation coefficients: duration of regular ecstasy and duration of regular amphetamine use after t1 in months: r = 0.632, p < 0.001, cumulative ecstasy dose and duration of regular amphetamine use after t1 : r = .4431, p = 0.008). Otherwise, interim use of ecstasy was not significantly associated with interim use of other drugs. 3.2. Neuropsychological test performance Descriptive and inferential statistics of test performance are presented in Table 3. Performance remained stable over the follow-up period in the interim abstinent group. Because 10 out of the 17 interim abstinent and one out of the 21 continuing users had reported a relatively long abstinence period of 3 months or more already at t1 we performed an additional analysis after exclusion of these subjects. This analysis with n = 28 yielded similar results, i.e. there was no tendency for the subjects who stopped ecstasy use after t1 to improve their performance (data not shown). Moreover, there was no tendency for the continuing users to deteriorate in terms of test performance. To the contrary, for one memory subtest (city map, immediate recall) the performance of the continuing users was even better at t2 compared to t1 . The performance change scores of the two groups were not significantly different (analyses with and without the 11 subjects with very long abstinence period, data not shown). Similar analyses with assignments of the 38 users to different subgroups according to their interim use of or abstinence from stimulant amphetamines or cannabis yielded similarly undifferentiated results (data not shown). 3.3. Relationship between neuropsychological test performance and drug use We found a trend for an association between long periods of regular ecstasy use and low performance (correct responses) in the 2-back letters test (Pearson correlation coefficient r = −0.513, p = 0.002). However, after Bonferroni correction for multiple testing, this correlation did not pass the significance level. Also, the various other aspects of interim and lifetime use of ecstasy, amphetamines, cannabis and LSD (see Table 2) were not associated with test performance.

Interim abstinent ecstasy users

Continuing ecstasy users

27.38 ± 2.75 13:4

25.26 ± 4.30 14:7

1 6 10

1 9 10

–

1

4. Discussion The popular dance drug ecstasy (3,4-methylenedioxymethamphetamine = MDMA and some analogues) causes selective and persistent neurotoxic damage of the central serotonergic system in laboratory animals (review in Green et al., 2003). Serotonin plays a role in numerous functional systems in the brain including cognition. In recent years, the question of possible functional disorders following ecstasyinduced neurotoxicity has been addressed in several crosssectional studies with drug users. Findings of relatively low memory performance associated with heavy ecstasy use have been relatively consistent across different studies and user populations (Krystal and Price, 1992; Bolla et al., 1998; Parrott and Lasky, 1998; Morgan, 1999; Gouzoulis-Mayfrank et al., 2000; 2003; Reneman et al., 2000; Rodgers, 2001; Bhattachary and Powell, 2001; Zakzanis and Young, 2001; Rodgers et al., 2003; Back-Madruga et al., 2003; Hanson and Luciana, 2004; McCardle et al., 2004). However, there have been also some negative and puzzling reports (Dafters et al., 1999, 2004; Parrott, 2000; Wareing et al., 2000; Thomasius et al., 2003). Moreover, there has been only one small longitudinal study with 15 users which reported memory decline after continued use of ecstasy over 12 months (Zakzanis and Young, 2001). In the present study we examined memory performance in a larger sample of poly-drug ecstasy users in a longitudinal design with a follow-up period of 18 months. Twenty-two out of the original sample of 60 users (Gouzoulis-Mayfrank et al., 2003) dropped out during the follow-up period. Hence, we were able to re-examine 38 users after 18 months. Seventeen users reported continued use and 21 users reported total or almost total abstinence from ecstasy after the baseline examination. Surprisingly, follow-up abstinents did not improve in terms of memory performance after 18 months of abstinence, and continuing users did not deteriorate. Theoretically, our data may be subject to an important selection bias, since the majority of the 22 subjects who dropped out during the follow-up period had been heavy users with a lifetime dose of minimum 80 ecstasy tablets and only 6 subjects had belonged to the subgroup of moderate users of the original study with a lifetime dose of less than 80 ecstasy tablets (GouzoulisMayfrank et al., 2003). However, we do not think that this bias can fully account for our unexpected findings, because

13 19 12 6 X 93.65 ± 153.80 g 24.62 ± 38.69 g 72.73 ± 222.48 10.60 ± 8.93 25.64 ± 34.66 9.67 ± 8.82 17.18 ± 45.67 14.00 ± 14.27 5.50 ± 6.53 1.74 ± 2.15 0.73 ± 1.45 471.05 ± 684.61 mg 502.27 ± 470.17 mg 421.43 ± 695.26 mg 0.26 ± 0.53 4.80 ± 6.16 68.05 ± 157.82 41.40 ± 57.71 227.33 ± 422.39 10 positive – – –

± ± ± ± ± 1.99 g 42.94 1.64 7.50 0.23 1.22 271.95 mg 0.88 50.06 789.38 – ± ± ± ± ± 1.46 1.20 0.08 93.75 32.33 ± ± ± ± ±

61.36 g 24.52 2.76 255.93 mg 588.56

–

15 X 52.36 ± 46.44 16.05 ± 13.72 540.09 ± 507.11 2.25 ± 2.54 12 positive 85.52 pills 7.48 3.38 0.79 pills 53.66 21 53.85 12.90 2.16 1.79 58.76 –

± ± ± ± ±

1.95 pills 1.09 0.10 0.47 pills 675.24 ± ± ± ± ± 1.31 0.80 0.27 0.34 798.19 – Continuing users (n = 21)

Subjects reporting use 21 Estimated dose 357.73 ± 647.75 Duration of regular use (months) 36.55 ± 42.27 Average frequency of use (days per month) 2.95 ± 2.90 Average daily or one night dose 2.21 ± 1.74 Time since last dose in days 40.45 ± 112.10 THC-screen in urine sample –

Till t1

8 3

Between t1 and t2 Till t1

10 22.91 8.48 19.13 12.62 1.81 378.37 mg 164.58 65.92 630.00 – 11 X 11.00 ± 16.07 ± 423.33 ± 22.00 ± 9 positive

Between t1 and t2 Till t1

15 X 78.38 ± 44.87 17.47 ± 12.31 608.25 ± 460.72 mg 2.60 ± 2.90 10 positive 4

Between t1 and t2 Till t1

Subjects reporting use 17 Estimated dose 146.88 ± 212.10 pills Duration of regular use (months) 24.00 ± 20.10 Average frequency of use (days per month) 2.53 ± 2.42 Average daily or one night dose 1.60 ± 0.90 Time since last dose (days) 471.25 ± 496.03 THC-screen in urine sample –

LSD Amphetamine Cannabis Ecstasy

Interim abstinent ecstasy users (n = 17)a Pattern of use

Table 2 Patterns of drug use before t1 and in the 18-months period between t1 and t2 for interim abstinent and for continuing ecstasy users (mean values and S.D.)

a This group includes four subjects with very sporadic use of ecstasy (<5 pills) in the 18 months follow-up period. Abbreviations: THC: tetrahydrocannabinol (Cannabis); X: subjects felt that they were unable to give a reliable estimate.

24.1 trips 3.8 1.5 0.3 trips 96.0 4 6.68 ± 0.9 ± 0.4 ± 0.2 ± 97.5 ± –

– –

–

72.18 trips 15.77 2.28 1.35 trips 705.75

0

Between t1 and t2

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321

the group of continuing users took an average of about 54 ecstasy tablets in the time period between the first and second assessment (18 months) with the individual amount ranging from 20 to 400 tablets. This clearly corresponds to a regular and partly heavy use pattern. Hence, originally a high proportion of the continuing users may have been moderate users. However, during the follow-up period they developed a pattern of use that we would still have expected to cause deterioration of neuropsychological performance. Most surprisingly, continuing users not only did not deteriorate in terms of test performance, but they actually performed better in one memory subtest at follow-up. Practice effects may have contributed to this improved performance at follow-up. Theoretically, the use of parallel test versions should have minimized this possibility. However, it is possible that the materials of memory tests which consist of graphic elements such as the city map test may be particularly memorable and thus more susceptible to practice effects which would explain this unexpected finding. Nevertheless, our results challenge numerous cross-sectional findings of dose-related memory deficits in ecstasy users including our own earlier data (Krystal and Price, 1992; Bolla et al., 1998; Parrott and Lasky, 1998; Morgan, 1999; Gouzoulis-Mayfrank et al., 2000; 2003; Reneman et al., 2000; Rodgers, 2001; Bhattachary and Powell, 2001; Rodgers et al., 2003; BackMadruga et al., 2003; Hanson and Luciana, 2004; McCardle et al., 2004). Moreover, they challenge the previous small longitudinal study which reported deterioration of memory performance within a period of 12 months of continued ecstasy use (Zakzanis and Young, 2001). If memory problems in ecstasy users were neurotoxicityrelated then we would normally expect the neurotoxic effect and its functional consequences to increase with continued use. Hence, the present data may be interpreted as evidence against neurotoxicity-related memory decline in ecstasy users. Consequently, our results may imply that a factor other than ecstasy use may be responsible for the relatively low memory performance which was reported in most, but not all cross-sectional studies with ecstasy users. This factor might be loosely associated, but not causally related to ecstasy use (e.g. prolonged stress and/or disturbed sleep patterns in regular club attendants). However, in that case we would expect performance to improve after prolonged abstinence, which, in turn, will mostly be associated with changes in life style. Nevertheless, although cross-sectional studies with user populations suffer from serious methodological problems, the evidence in favor of neurotoxicity-related memory decline in ecstasy users emerging from earlier research is relatively strong (Krystal and Price, 1992; Bolla et al., 1998; Parrott and Lasky, 1998; Morgan, 1999; GouzoulisMayfrank et al., 2000; 2003; Reneman et al., 2000; Rodgers, 2001; Bhattachary and Powell, 2001; Rodgers et al., 2003; Back-Madruga et al., 2003; Hanson and Luciana, 2004; McCardle et al., 2004; Zakzanis and Young, 2001). Therefore, we should consider alternative interpretations of our present data.

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Table 3 Neuropsychological test battery scores of interim abstinent and continuing ecstasy users at baseline (t1 ) and at follow-up (t2 ) Interim abstinents (n = 17)

Continuing users (n = 21)

Scores

t-test

t1 Working memory tests DS backward 2-back letters CR 2-back figures CR LGT-3 memory test Logos City map German–Turkish Library

t2

7.75 ± 2.02 12.7 ± 1.7 9.5 ± 2.1 IM DR IM DR IM DR IM DR

12.5 11.44 17.69 17.25 11.47 10.47 13.69 12.88

± ± ± ± ± ± ± ±

2.58 3.71 4.33 5.12 4.07 3.25 4.11 3.63

Scores

T

p

8.25 ± 1.91 12.5 ± 2.2 9.2 ± 2.1

−0.889 0.372 0.511

0.388 0.716 0.618

± ± ± ± ± ± ± ±

−0.141 −0.521 −0.210 −0.176 0.499 0.549 0.433 0.832

0.889 0.610 0.837 0.862 0.626 0.592 0.671 0.419

12.63 12.06 18.0 17.56 11.0 10.07 13.19 11.94

3.01 3.32 5.77 6.83 3.38 3.33 3.51 3.84

t-test

t1 8.57 ± 1.96 12.6 ± 1.9 8.8 ± 2.42 11.8 10.33 14.48 14.14 10.65 9.05 12.62 12.33

± ± ± ± ± ± ± ±

3.25 3.10 5.0 4.14 3.56 3.94 3.73 3.99

t2

T

p

8.33 ± 1.85 13.25 ± 2.0 8.8 ± 2.28

0.576 −1.05 0.000

0.571 0.305 1.00

± ± ± ± ± ± ± ±

−.178 −1.57 −3.049 −1.661 0.056 −0.944 1.093 1.023

0.861 0.132 0.006 0.112 0.956 0.357 0.287 0.319

11.9 11.33 19.19 16.52 10.6 9.8 11.71 11.52

2.65 2.61 6.1 6.44 3.98 3.64 4.62 4.73

Abbreviations: DS = digit span score, CR = correct responses, IM = immediate recall score, DR = delayed recall score.

It is conceivable that memory deficits in ecstasy users may persist even after 18 months of abstinence because, as been shown in primate studies (Hatzidimitriou et al., 1999), regeneration of serotonergic axons may take very long and may remain incomplete. In addition, the functional consequences of neurotoxic lesions observed following a threshold use of ecstasy may manifest themselves in binary (yes/no) ways. Compensatory neural mechanisms that might develop could possibly explain the absence of deterioration of these functional consequences despite subsequent “enlargement” of the neurotoxic lesions. This view would be in line both with findings of a dose-dependent memory deficit in cross-sectional studies comparing ecstasy users with control samples and with findings of stable performance in within-subject longitudinal designs with ecstasy users. Hence, it may be premature to draw firm conclusions from our data. Moreover, we are aware of methodological limitations of our study: although we began our investigation with a relatively large sample of 60 users at baseline, the remaining samples of 21 continuing users and 17 follow-up abstinents may have been too small to detect significant changes. Furthermore, we have not been able to re-test the control group. Thus, the impact of practice effects cannot be fully evaluated and our findings must be interpreted with caution. Finally, the serious methodological limitations which are inherent to all open trial studies with user populations such as unprecise recall of the details of previous drug use, uncertain chemical composition of illegal drugs and polydrug use add to the difficulties in interpreting both our data and results from similar studies (Zakzanis and Young, 2001). Nevertheless, our findings do not support a role of the co-use of drugs other than ecstasy for cognitive performance in combined users. This may be different for other domains such as psychological well-being, since psychopathological symptoms were associated with continued cannabis rather than continued ecstasy use in the same sample (Daumann et al., 2004).

In summary, our data neither support, nor rule out memory decline due to use of the neurotoxin MDMA (ecstasy). In light of the popularity of ecstasy among young people, further investigations are needed. In our view, research strategies should now move to prospective designs in order to shed more light on the course of possible adverse cognitive effects of ecstasy use.

Acknowledgement This work was supported by a grant to the first author from the Deutsche Forschungs-gemeinschaft (DFG GO 717/4-1, 717/4-2).

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