This meta-analysis (2016) compared cognition between current MDMA (n=1221) users and poly-drug users (n=1224) with regard to executive functions, such as updating, switching, inhibition, and access to long-term memory. Current ecstasy users exhibited significant but small-size deficits in executive functioning, with regard to access to long-term memory, task-switching, and memory updating, which was independent of their accumulated lifetime ecstasy dose.
Introduction
Ecstasy/3,4-methylenedioxymethamphetamine (MDMA) use is proposed to cause damage to serotonergic (5-HT) axons in humans. Therefore, users should show deficits in cognitive processes that rely on serotonin-rich, prefrontal areas of the brain. However, there is inconsistency in findings to support this hypothesis. The aim of the current study was to examine deficits in executive functioning in ecstasy users compared with controls using meta-analysis.
Methods
We identified k = 39 studies, contributing 89 effect sizes, investigating executive functioning in ecstasy users and polydrug-using controls. We compared function-specific task performance in 1221 current ecstasy users and 1242 drug-using controls, from tasks tapping the executive functions - updating, switching, inhibition and access to long-term memory.
Results
The significant main effect demonstrated overall executive dysfunction in ecstasy users [standardized mean difference (SMD) = −0.18, 95% confidence interval (CI) −0.26 to −0.11, Z = 5.05, p < 0.001, I 2 = 82%], with a significant subgroup effect (χ 2 = 22.06, degrees of freedom = 3, p < 0.001, I 2 = 86.4%) demonstrating differential effects across executive functions. Ecstasy users showed significant performance deficits in access (SMD = −0.33, 95% CI −0.46 to −0.19, Z = 4.72, p < 0.001, I 2 = 74%), switching (SMD = −0.19, 95% CI −0.36 to −0.02, Z = 2.16, p < 0.05, I 2 = 85%) and updating (SMD = −0.26, 95% CI −0.37 to −0.15, Z = 4.49, p < 0.001, I 2 = 82%). No differences were observed in inhibitory control.
Discussion
We conclude that this is the most comprehensive analysis of executive function in ecstasy users to date and provides a behavioural correlate of potential serotonergic neurotoxicity.
Papers cited by this study that are also in Blossom
Halpern, J. H., Sherwood, A. R., Hudson, J. I. et al. · Addiction (2011)
Papers in Blossom that reference this study
Opitz, A., Zimmermann, J., Cole, D. M. et al. · NeuroImage (2024)
Montgomery, C., Roberts, C. A. · Experimental Neurology (2021)
Roberts, C. A., Quednow, B. B., Montgomery, C. et al. · Neuroscience and Biobehavioral Reviews (2017)
Ecstasy (MDMA) use is hypothesised to damage serotonergic axons, and this has led researchers to expect deficits in cognitive processes that depend on serotonin-rich prefrontal regions. Despite animal evidence of serotonin neurotoxicity and some molecular and functional imaging findings in humans, the behavioural literature on ecstasy-related cognitive dysfunction is inconsistent. The authors note that part of this inconsistency may stem from task impurity in classic working memory and executive tasks and from treating executive function (EF) as a unitary construct rather than a set of distinct but related components. This study set out to synthesise the behavioural literature by conducting a meta-analysis of function-specific EF tasks in current ecstasy users compared with drug-using controls. Using the unity/diversity framework of executive functions, the analysis focuses on four component EFs—updating, switching, inhibition and access to long-term semantic memory—with the dual aims of testing for an overall executive deficit in ecstasy users and examining whether impairments are specific to particular EF components. The authors frame this as the most comprehensive analysis of EF in ecstasy users to date and as a means of identifying behavioural correlates of potential serotonergic neurotoxicity.
Eligible studies were human behavioural studies of executive function in ecstasy/MDMA users aged 18 years or older, excluding participants with major psychiatric or neurological conditions. Ecstasy groups were required to be current users and not intoxicated at testing; most studies enforced a minimum abstinence period of 7 days (with a few studies using shorter minima of 24–72 hours). Control groups were required to have some recreational drug experience (polydrug controls), except for three studies in which ecstasy users had minimal exposure to other drugs and drug-naive controls were included. Across included studies the mean age of ecstasy users was 23.39 years (47.72% female) and of controls 23.11 years (54.67% female); mean estimated lifetime dose of ecstasy across studies was 346.03 tablets. The meta-analysis targeted tasks mapped to four EFs: updating, inhibitory control, switching and access (semantic retrieval). For each included task the outcome measure judged to most directly index the putative EF was extracted; each task contributed a single outcome. The formal literature search (July 2015) covered PsycINFO, Scopus and Web of Science using the terms 'Ecstasy' OR 'MDMA' AND 'executive function', supplemented by searches combining drug terms with the names of specific tasks and by manual searches of references. One author performed the initial search and extraction with additional authors conducting supplementary searches and cross-checking; the authors contacted study authors when reported data were insufficient, but data requests were not met for five eligible articles. Data handling procedures included computation of composite scores when not reported, weighting and combining gender-split values, and, when a study used multiple tasks for the same EF, entering each task but dividing the group sample size across tasks to avoid double-counting participants. Where studies subdivided user groups (for example, heavy versus light users), the subgroup with the heaviest ecstasy exposure was used. Extracted variables included sample sizes, gender split, age, estimated lifetime dose, time since last use, task and outcome measure means and standard deviations. Statistical synthesis used standardized mean differences (SMDs) to account for heterogeneous outcome metrics, computed via generic inverse variance methods in RevMan 5.2. Subgroup analyses treated each EF as a subgroup; random-effects models were employed because of substantial heterogeneity. A meta-regression (method-of-moments, random-effects) examined whether estimated lifetime dose predicted SMDs, and publication bias was assessed with funnel plots and Egger's test.
The search initially returned 99 Web of Science, 79 Scopus and 386 PsycINFO records; after de-duplication and title/abstract screening, 88 articles underwent full review and 39 studies met inclusion and provided usable data. Five further eligible studies were identified via supplementary searches but five studies that otherwise met inclusion criteria lacked available data, leaving 39 articles for the final meta-analyses. The meta-analysis incorporated 39 studies contributing 89 effect sizes, with data from 1221 current ecstasy users and 1242 drug-using controls. The pooled test for overall effect indicated a small but statistically significant executive performance deficit in ecstasy users (SMD = -0.18, 95% CI -0.26 to -0.11, Z = 5.05, p < 0.001), with high heterogeneity (I2 = 82%). A formal subgroup test showed significant differences across EF components (χ2 = 22.06, df = 3, p < 0.001, I2 = 86.4%), prompting separate analyses by function. Access (semantic retrieval): 13 studies, 13 effect sizes, 483 ecstasy users versus 491 controls. Ecstasy users showed a moderate deficit (SMD = -0.33, 95% CI -0.46 to -0.19, Z = 4.72, p < 0.001, I2 = 74%). Inhibition (inhibitory control): 20 studies, 20 effect sizes, 606 ecstasy users versus 632 controls. No between-group difference was observed (SMD = 0.04, 95% CI -0.07 to 0.15, Z = 0.77, p > 0.05). Switching (mental set shifting): 18 papers, 23 effect sizes, 488 ecstasy users versus 459 controls. A small but significant deficit was found (SMD = -0.19, 95% CI -0.36 to -0.02, Z = 2.16, p < 0.05, I2 = 85%). Updating (information updating/working memory): 24 articles, 33 effect sizes, 872 ecstasy users versus 904 controls. Ecstasy users performed worse (SMD = -0.26, 95% CI -0.37 to -0.15, Z = 4.49, p < 0.001, I2 = 82%). Meta-regression using available estimates of lifetime ecstasy dose (64 comparisons) produced a non-significant association between lifetime dose and SMD (regression coefficient = -0.0001, 95% CI -0.0004 to 0.0002, Z = -0.74, p > 0.05). Separate meta-regressions for each EF were also non-significant. Examination of publication bias showed funnel-plot asymmetry and a significant Egger's test (t88 = -1.96, p = 0.05), but the authors caution interpreting this result because of the high between-study heterogeneity.
Roberts and colleagues interpret the findings as evidence of small overall executive function deficits in current ecstasy users, with clear variability by component EF. The meta-analysis found significant impairments in access, updating and switching, but not in inhibitory control; updating and access produced the more robust effects. The authors view these behavioural deficits as consistent with molecular and functional imaging evidence suggesting serotonergic alterations in prefrontal regions (for example, reduced presynaptic SERT and increased postsynaptic 5-HT2A receptor availability in frontal areas) and with imaging studies that report increased neuronal recruitment in ecstasy users despite similar behavioural performance. Several explanations for the pattern of results are offered. The absence of an association between estimated lifetime dose and effect size could reflect limitations in exposure measurement—many studies did not report lifetime dose and reporting practices vary widely—or it could indicate that other usage variables (recency of use, frequency, high single-night doses, age at onset) are more relevant to cognitive outcome. The authors note that single high doses can be neurotoxic in animal models and that haemodynamic responses have been linked to recency of use in humans. They therefore recommend more standardised and detailed reporting of drug-use histories in future research. The discussion acknowledges important limitations that temper causal inference. Polydrug confounding remains a concern: in many included studies ecstasy users had greater lifetime use, frequency and variety of other illicit drugs than controls, so the unique contribution of ecstasy cannot be fully isolated. Reverse causality—pre-existing EF deficits predisposing to heavier ecstasy use—cannot be ruled out given the cross-sectional nature of the included studies; the authors call for longitudinal designs to address directionality and to assess recovery after abstinence. High heterogeneity across studies and evidence of publication bias further limit certainty. Finally, the authors consider the potential functional implications, noting that deficits in higher-level EF may impair occupational performance and everyday functioning, and they suggest that understanding these processes could have clinical relevance. They conclude that the meta-analysis provides the most comprehensive behavioural evidence to date linking ecstasy use with selective EF impairments, consistent with putative serotonergic neurotoxicity.
Ecstasyremains popular despite reports of potential long-term negative consequences associated with repeated use (see. Furthermore, ecstasy poses a major public health concern due to an increase in recent MDMA-related deathsas well as reported increases in tablet strength, with some sources suggesting tablets may contain upwards of 200 mg of MDMA (Global Drugs Survey;. Animal literature suggests that ecstasy causes damage to serotonin axons. There is also evidence of ecstasy-related alterations in mood) and long-term changes in neuroendocrine function. However, perhaps public health warnings are not being taken seriously due to mixed messages in the media and scientific literature about relative harms of drugs (for assessment of drug-related harms, which poorly correlate with UK drug classification, see. A recent review bysuggests that ecstasy-related cognitive dysfunction is not consistently reported in the literature, thus monitoring of research is necessary to gain a coherent understanding of drug effects. Executive functions (EFs) have been defined as a set of general-purpose control processes, required for regulating thought and action. Moreover, the central executive is an integral component of working memoryand is required for coordinating and processing information. Some of the apparent inconsistency in the literature may be attributable to several of the classic working memory/'executive' tasks requiring use of multiple EFs: a problem of task impurity). An influential EF framework suggested that the central executive is not a unified construct; rather it is comprised of several correlated but distinctly separable functions. Three discrete EFs were originally identified: mental set shifting/switching ('switching'); information updating and monitoring ('updating'); and inhibition of prepotent responses ('inhibition'). A fourth component, 'access' to semantic memory, was later added by. These are the four classic EFs that have been assessed in the literature. However it is interesting to note that more recent developments in the unity/diversity frameworksuggest that inhibitory control no longer exists as an EF, as it is subsumed under the concept of working memory and EF in general.suggested that there may be a differential pattern of executive impairment based on previous drug use and type of function, whereby ecstasy-related deficits were apparent in updating and access, but not in switching or inhibition. These conclusions were arrived at by administering tasks that are understood to assess one function only. As such, it may be that ecstasy users are impaired on some EFs and not others, supporting the unity and diversity framework. There are nuances in the neuroanatomy underpinning each function, which may explain why impairment is potentially function specific. For example, the dorsolateral prefrontal cortex (DLPFC) is understood to be important for memory updating, whereas lesion studies suggest that the left DLPFC in particular is important for letter-based word fluency. Ability to switch mental set is impaired following damage to the PFC and basal ganglia, and finally response inhibition performance has long been localized to the PFC; however, of particular importance is the right inferior frontal gyrus. The conclusions reached byand the review byare that ecstasy use has a stronger detrimental effect on updating and access, and that inhibitory control and mental set switching are unaffected by use. However, there are instances of ecstasy users showing no apparent deficit in function-specific tasks that tap updating) and accessas well as instances of ecstasy-related impairments in switchingand inhibition. Several neuroimaging studies have concluded that ecstasy-related neuronal adaptations may occur neurophysiologically before they manifest functionally.suggested that ecstasy users display increased blood flow to areas of the PFC during a verbal fluency task, despite no differences in task performance. This suggests that ecstasy users work harder to achieve similar performance to controls, and that functional differences may be apparent with increased workload. Similar conclusions have been drawn from electroencephalogram studies whereby ecstasy users display evidence of recruiting additional resources in comparison with controls, whilst showing similar performance. Similarly, functional magnetic resonance imaging (fMRI) studies have shown alterations to neuronal activation consistent with ecstasy-related damage despite not showing any performance deficits. Such neuroimaging studies suggest that neurophysiological correlates of executive performance are present before a behavioural difference manifests itself. It remains plausible that many behavioural studies lack statistical power to observe subtle impairments over the entire spectrum of EFs. Therefore, the aim of this meta-analysis was to examine the evidence for overall dysfunction of executive control in ecstasy users compared with polydrug users, but also to examine any functional specific deficits.
Included studies were those assessing EF in human ecstasy/MDMA users aged 18 years+, who did not have a history of major psychiatric or neurological problems. Ecstasy user groups were eligible if they were described as current ecstasy users; control groups were eligible if they reported some use of drugs, but no ecstasy usewith the exception of studies in which the ecstasy users were recruited with the specific criteria of limited exposure to other drugs. In each case, participants were not intoxicated at the time of testing. The majority of studies included used a minimum abstinence period of 7 days, with the exception ofand, who report a minimum abstinence period of 24, 72 and 72 h, respectively. The mean age for ecstasy user group across studies was 23.39 years, with an average of 47.72% females. Mean lifetime dose across studies was 346.03 tablets. The mean age of the control group was 23.11 years, with an average of 54.67% females.
Studies comparing ecstasy users and controls in performance on behavioural tasks that are function specific were eligible for inclusion. The EFs included in this analysis were: updating; inhibitory control; switching; and access. Tasks eligible for inclusion can be seen in Table. There were no date limitations on publication.
As each EF can be assessed using several tasks, there are a number of outcome measures. The outcome measure from each task that most clearly taps its putative EF was selected for inclusion in the analysis. As such, each task contributes one outcome measure to the analysis only. Tasks included as well as the outcome measure selected can be seen in Table.
The formal search strategy involved searching three electronic databases during July 2015: PsycINFO, Scopus and Web of Science. Systematic searches used the key terms 'Ecstasy' OR 'MDMA' AND 'executive function'. Supplementary searches were also conducted using the terms 'Ecstasy' and 'MDMA' combined with the name of each task in Table. Manual searches of reference sections of initially identified studies were conducted to supplement the formal electronic search; furthermore, articles that were not identified in the initial searches that the authors knew to be eligible for inclusion were assessed for inclusion. These additional searches yielded a further five studies eligible for inclusion.
Initial searches were carried out by one author (C.A.R.). However, supplementary searches and manual searches were carried out by two authors. Both authors were responsible for the assessment of articles for inclusion, and decisions over article inclusion were made through discussion. One author (C.A.R.) extracted the relevant data and a second author (C.M.) cross-checked this. Several studies met inclusion criteria, but did not report sufficient information in the papers to compute the effect size; in each case data were requested from the corresponding author of the study. Data requests were not met for five articles:;.
Composite performance scores for letter updating, spatial updating and random letter generation were calculated from the available data, if the composite score itself was not reported in the paper. On occasions where reported values of behavioural performance were split by gender, a weighted mean by number in each sample was calculated. A weighted S.D. was also calculated by multiplying squared S.D.s by number in each group, adding these together, then dividing by total n. The square root of this total was then used as the S.D. in analysis. Data for the FAS task were provided by, with means and S.D.s given for each letter. Therefore means for performance on each letter were added up to give a total score and the S.D.s were summed and divided by 3. There were a number of cases where an article had used more than one task to assess an EF. In these cases, means and S.D.s were entered for each task; however, the number of participants in each group was divided by the number of tasks included for that function from that paper. In de, between-group comparisons were given 1 year apart. For the meta-analysis, we used baseline measurements of lifetime drug use and task performance. In cases where ecstasy user groups were broken down into further subgroups, e.g. 'heavy and 'light' users (as per, data from the heavy user group were included in the analysis. Inthe user groups were split into problem/non-problem users and low/medium/high-intensity users. The group of high-intensity users was included in the current analysis. Although the 'heavy' and 'highintensity' user group criteria were arbitrarily decided in the original papers, it seemed pertinent to include the user groups with the heaviest background ecstasy use in the current analysis, as these would be the most likely to show ecstasy-related cognitive impairment.
From each of the published papers, the following information was extracted for each group: number of participants; gender split; age; estimated lifetime dose of ecstasy; time since last use; task used (Table); outcome measure (Table); and means and S.D.s for each outcome variable. In cases where mean ecstasy abstinence duration was not reported, the minimum abstinence period required for the study was recorded. If not reported in the paper, estimates of mean lifetime dose of ecstasy were calculated from the available data. Reported ecstasy user groups could generally be defined by two categories: current users and former users. There were several categories of control groups, including: cannabis-only users; polydrug control groups (who had been recruited due to them having some degree of matching for other substances); non-users (this was a general catch-all name given to controls who were ecstasy naive but did have some other drug use); and drug-naive controls (no illicit substance use, but allowed for use of alcohol and nicotine).
Standardized mean difference (SMD) and standard error (S.E.) of the SMD between experimental conditions were calculated for each executive task outcome separately in each study. SMDs were employed due to variation in outcome measures in the behavioural Executive functioning in ecstasy/polydrug users 1583 tasks included in the analysis. SMD estimates differences between two experimental conditions on an outcome variable (SMD = mean1 -mean2/pooled S.D.). This allowed for a subgroup analysis to be conducted by EF (inhibitory control, updating, access and switching). The meta-analysis used generic inverse variance methods to synthesize individual SMDs, in the software package RevMan 5.2 (The Nordic Cochrane Centre, Copenhagen). The magnitude of SMDs can be interpreted thus: 0.2 = small, 0.5 = moderate, and 0.8 = a large effect.
The meta-analysis was conducted by separating effect sizes from tasks employed in each study into distinct EFs. The main effect and formal subgroup analysis was examined, whereby each EF was considered a subgroup. Outcome measures of the various tasks that were included in this meta-analysis had to be reviewed by the authors so that the direction of differences in task performance were consistent for interpretation of ecstasy-related impairment. For example, if ecstasy users produced fewer words on the verbal fluency tasks relative to controls, this would be indicative of ecstasy-related impairment in verbal fluency and would result in a negative SMD in the meta-analysis. However, a greater amount of perseveration errors on the Wisconsin Card Sorting Test would be indicative of impairment yet would yield a positive SMD, should ecstasy users produce more errors here. As such, a For information on previous exposure to other drugs and other groups not included in the meta-analysis, see online Supplementary Table. outcome measures were negatively coded where appropriate. The main analysis was conducted on the 39 studies that assessed one or more EF in a current ecstasy user group versus a control group that had some use of recreational drugs. Studies that employed a drug-naive control group and no-drug user control group were not included in the analysis, with the exception of three studies. These studies were included, with a drug-naive control group, as their current ecstasy user groups had minimal exposure to other drugs. The remaining studies featured a drug-using control group; as such, all between-group comparisons in this meta-analysis have at least some degree of matching for other drug use. Random-effects models were employed due to high heterogeneity in the data across studies.
Study selection (Fig.) Initial literature searches yielded 99 papers using Web of Science, 79 using Scopus and 386 papers from PsycINFO. After removing 76 duplicated papers, 459 articles remained. A brief review of the remaining Executive functioning in ecstasy/polydrug users 1589 article titles and abstracts led to exclusion of 370 irrelevant articles. Excluded papers at this stage included: review articles (23); acute administration studies (26); studies that were conducted using other substances/ did not involve ecstasy users (75); studies that were not experimental/did not include behavioural data/assess cognition (232); case studies (8); studies conducted in non-human samples (4); a study not written in English (1); and reanalyses of data (2). This left a total of 88 articles for full review. Further studies were excluded at this stage if they did not employ a function-specific task identified in Table(35), did not employ a control group or current user group, or did not conduct between-group analysis (10). Longitudinal studies using a within-groups design and prospective studies on novice users were also excluded at this stage (4). Following these data exclusion procedures, 39 studies remained. A further five studies eligible for inclusion were identified from supplementary searches. Of the 44 studies that met all the inclusion criteria, data were not available for five; as such, the final meta-analyses were conducted on data from 39 articles (Fig.).
Individual study information, including sample sizes and participant characteristics, is given in Table.
Data from 39 published studies, contributing 89 effect sizes, were included in analysis, including data from a total of 1221 current ecstasy users and 1242 controls. For descriptive information from each study, see Table. Meta-analyses (Fig.) The test for overall effects was significant [SMD = -0.18, 95% confidence interval (CI) -0.26 to -0.11, Z = 5.05, p < 0.001, I 2 = 82%], suggesting an overall executive performance deficit in ecstasy users relative to controls, albeit a small effect. However, there was also a significant subgroup effect (χ 2 = 22.06, degrees of freedom = 3, p < 0.001, I 2 = 86.4%) demonstrating differential effects across EFs. Individual analyses are reported below.
A total of 13 studies, contributing 13 effect sizes, assessed access to long-term/semantic memory, with a total of 483 ecstasy users and 491 controls. A significant difference was observed between these two comparison groups (SMD = -0.33, 95% CI -0.46 to -0.19, Z = 4.72, p < 0.001, I 2 = 74%), demonstrating that ecstasy users perform poorly compared with controls in this EF.
A total of 20 studies, contributing 20 effect sizes, investigated performance difference in inhibitory control providing a comparison between 606 ecstasy users and 632 controls. No between-group difference was observed in performance of this EF (SMD = 0.04, 95% CI -0.07 to 0.15, Z = 0.77, p > 0.05).
Switching was assessed in a total of 488 ecstasy users and 459 controls, in a total of 18 papers, contributing 23 effect sizes. There were significant between-group differences in this function (SMD = -0.19, 95% CI -0.36 to -0.02, Z = 2.16, p < 0.05, I 2 = 85%), demonstrating that ecstasy use leads to impairment in mental set switching.
A total of 872 ecstasy users and 904 controls were compared for updating performance from a total of 24 articles, contributing 33 effect sizes. Again, there was a significant between-group difference in performance of updating tasks (SMD = -0.26, 95% CI -0.37 to -0.15, Z = 4.49, p < 0.001, I 2 = 82%). This demonstrates that there is an ecstasy-related impairment with regards to updating performance.
We conducted a method of moments (random-effect model) meta-regression across the 64 comparisons included in the main meta-analysis, with the available data for estimates of lifetime dose of ecstasy. This was conducted to observe whether there was a relationship between lifetime dose of ecstasy and SMD in executive performance. The overall meta-regression was nonsignificant (regression coefficient -0.0001, 95% CI -0.0004 to 0.0002, Z = -0.74, p > 0.05), suggesting that lifetime dose did not predict performance differences. Furthermore, individual meta-regressions performed separately for each specific EF were all non-significant (p > 0.05 in each case).
Examination of a funnel plot revealed asymmetry; therefore an Egger's test of publication bias was conducted) on the 89 effect sizes included in this meta-analysis. Egger's test was significant (t 88 = -1.96, p = 0.05), suggesting evidence of publication bias. However, these results should be interpreted with caution due to the high heterogeneity between studies.
The results from this meta-analysis demonstrate EF deficits in current ecstasy users. However, the size of this overall effect was small. Subgroup analyses showed that effect sizes varied by the specific component of executive functioning. Individual analyses by function showed ecstasy-related deficits in the EFs access, switching and updating, though there was no inhibition performance deficit. Meta-regression using estimated lifetime dose of ecstasy to predict effect size of between-group differences was non-significant. This suggests that lifetime dose is not the greatest predictor in magnitude of EF deficit. However there were nine studies (providing 25 comparisons) that did not give lifetime estimates of use and so were not included in the analysis, which may have potentially given a different outcome. Nevertheless, there was high variability in effects and although estimates of lifetime use were not possible for all studies, there were 64 comparisons from 30 studies which did include estimated lifetime dose, which is far greater than the minimum of 10 required for adequate power in a meta-regression. Despite adequate power to detect an effect, it could be that the analysis is conceptually flawed, given that it is conducted on SMDs in performance between ecstasy users and controls rather than estimated lifetime dose and task performance. Alternatively, it could be that there are other ecstasy-using behaviours that have a stronger impact on behavioural measures, for example recency of use, frequency of use and higher nightly doses. Recency of use has been identified as a predictor of haemodynamic response to a cognitive task in ecstasy users. Furthermore, higher nightly doses may make an impact on cognition more than cumulative intake; indeed a single high dose of MDMA is enough to cause neurotoxicity in laboratory animals. Unfortunately, there is substantial variance in the reporting of drug use histories in the literature, limiting interpretation. Perhaps some unity on background drug use reporting would vastly improve research and our understanding of harmful behaviours. We propose that a unified reporting criterion should be applied to future research. There are also a number of variables that may contribute to the impact of cumulative doseincluding earlier onset of use, use of other drugs, and increased bioenergetic stress. Neuronal regions implicated in working memory and EF include the DLPFC and the hippocampus (depending on the nature of the task). These structures have dense innervation of serotonergic (5-HT) neurons. Therefore ecstasy-related degradation to the serotonin system, through neurotoxicity or down-regulation following chronic recent use, is understood to be a potential cause of cognitive impairment in the functions supported by these areas. If ecstasy is a serotoninspecific neurotoxin in humans as it is in animals, one would expect functional alterations following repeated use. Several molecular imaging studies in human ecstasy users suggest a reduction in pre-synaptic serotonin transporter (SERT) availability in areas including the frontal cortex) and the DLPFC. Increases in post-synaptic 5-HT 2A receptors have also been observed in ecstasy users relative to controls in the DLPFC. Decreased presynaptic SERT and increased post-synaptic 5-HT 2A receptor availability are consistent with serotonin axon damage. Moreover, functional neuroimaging studies have observed ecstasy-related adjustments to cerebral blood flow in frontal areas, with functional nearinfrared spectroscopyand fMRI. It is noteworthy that all of the functional imaging studies mentioned observe increased neuronal activity to achieve similar behavioural performance to controls. This suggests that molecular and functional neuroimaging detect changes in serotonin signalling which cause future deficits in EF. The current results support this by demonstrating behavioural correlates for the supposed neuronal degradation. Ecstasy-related impairments in switching were unexpected, given that previous reviews in this area have concluded that this function is relatively stable. However, some studies have observed significant switching differences between ecstasy users and controlsand neuroimaging studies have suggested atypical processing during switching). This highlights the necessity for larger samples to elucidate this performance deficit. However, this difference was the weakest of the three significant differences and had a small effect size; thus it should be treated with caution. The reduced performance in updating and access in ecstasy users relative to controls is more consistent with previous reports). Nevertheless, there have been previous reports of null findings in these functions. The ability to update one's memory is reflective of the concept of working memory as a whole, and Miyake and co-workers) maintain that updating is the key overarching EF which is important for daily function. Although not unexpected, it is interesting to consider why there were no apparent group differences in inhibitory control. One explanation could be that ecstasy users are high-functioning impulsives and this increased impulsivity serves to mask performance deficits on the tasks employed here. Alternatively, perhaps inhibitory control impairment is associated with other psychostimulants that are primarily dopaminergic in nature, e.g. cocaineand methamphetamine. Interestingly, in recent models of the unity and diversity of EFs,confer that inhibitory control is not necessarily a unique EF. Instead, inhibitory control is subsumed by common EF ability. With this in mind, it could be suggested that ecstasy users are therefore impaired at each level of EF. There are a number of limitations of the current analysis. Concomitant use of other drugs is often posited to contribute to the cognitive deficits displayed by ecstasy users. To try and incorporate this into the meta-analysis, comparisons were made between ecstasy users and controls that have at least some experience with drugs other than ecstasy. Nevertheless, it should be noted that in many of the studies in the analysis, the use of drugs other than ecstasy was, in fact, higher in the ecstasy user groups than the polydrug control groups (in terms of total lifetime dose, frequency of use and variety of drugs used). As such, we cannot rule out the possibility that alcohol and other drugs may also contribute to deficits in executive functioning. However, despite the increased polydrug use among ecstasy user groups, there are several instances of drug use indices predicting unique variance in EFs in regression analyses (for example,; this suggests that various chronic drug effects do show independence from one another. Increased cohesion in reporting of drug use variables would help to remove some of this uncertainty in future. Similarly, it cannot be ruled out that the direction of causality is interpreted incorrectly. It could be that individuals with EF deficits are more likely to have a stronger propensity for ecstasy use, though the authors think that this is unlikely. Future research should concentrate on longitudinal studies to obviate confusion over direction of causality. Furthermore, as the current analysis is conducted on current users and therefore cannot make any predictions about function recovery following abstention, longitudinal studies may also help to determine whether recovery is possible. The current results suggest that ecstasy users may struggle with higher-level executive functioning, and it has been suggested that such impairments would lead to difficulty in performing the majority of occupational tasks.observed ecstasy users to be impaired at a virtual reality office work task, with the suggestion that office work, as well as those occupations requiring greater executive resources, will be adversely affected by ecstasy use. Taken together, these findings suggest that prolonged ecstasy use can lead to everyday functioning problems; therefore an understanding of the processes underpinning such impairments may prove valuable to clinicians. To conclude, the current meta-analysis demonstrated that EF performance in ecstasy users is significantly reduced overall compared with controls. The three functions that show significant impairment are updating, switching and access, whilst inhibitory control is unaffected by ecstasy use. This is the most comprehensive analysis of EF in ecstasy users to date and provides a behavioural correlate of potential serotonergic neurotoxicity.
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