Meta-analysis of executive functioning in ecstasy/polydrug users

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.

Abstract

“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.”

Authors: Carl A. Roberts , A. Jones & C. Montgomery

Summary

Introduction

Ecstasy, a popular party drug, poses a major public health concern due to its potential long-term negative consequences. However, public health warnings are not being taken seriously due to mixed messages in the media and scientific literature about relative harms of drugs.

Murphy et al. (2009) suggest that ecstasy-related cognitive dysfunction is not consistently reported in the literature, and that further research is necessary to gain a coherent understanding of drug effects.

Montgomery et al. (2005a) suggested that ecstasy users are impaired on some executive functions but 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. Ecstasy use has a stronger detrimental effect on updating and access, but not on inhibitory control and mental set switching.

Several neuroimaging studies have shown that ecstasy users recruit additional resources in comparison with controls, despite not showing any performance deficits. This suggests that neurophysiological correlates of executive performance may be present before a behavioural difference manifests itself.

Participants

Studies assessing EF in human ecstasy/MDMA users aged 18 years+ were included if they did not have a history of major psychiatric or neurological problems. The mean age of ecstasy users was 23.39 years and the mean lifetime dose was 346.03 tablets.

Outcome measures

Each EF can be assessed using several tasks, and the most clear outcome measure from each task was selected for inclusion in the analysis.

Information sources and search strategy

The formal search strategy involved searching three electronic databases, and supplementary searches were conducted using the key terms ‘Ecstasy’ OR ‘MDMA’ AND ‘executive function’. Five studies were eligible for inclusion.

Article selection and extraction of data

Initial searches were carried out by one author, but supplementary searches and manual searches were carried out by two authors. Both authors assessed articles for inclusion, and decisions over article inclusion were made through discussion.

Additional handling of data

Performance scores were calculated for letter updating, spatial updating and random letter generation, and a weighted mean by number in each sample was calculated. A square root of this total was used as the S.D. in analysis.

There were many articles that used more than one task to assess an EF. The results were entered for each task, but the number of participants was divided by the number of tasks included.

In de Sola et al. (2008a, b), baseline measurements of lifetime drug use and task performance were used. Ecstasy user groups were broken down into heavy and light groups, and high/medium/low intensity users were included in the current analysis.

Data items extracted for individual studies

In the published papers, information was extracted for each group, including number of participants, gender split, age, estimated lifetime dose of ecstasy, time since last use, task used, outcome measure, and means and S.D.s for each outcome variable.

Statistical and subgroup analysis

Standardized mean differences were calculated for each executive task outcome separately in each study, and a subgroup analysis was conducted by EF. The magnitude of SMDs was interpreted as small, moderate, or large.

Analytic strategy

The direction of differences in task performance between ecstasy users and controls had to be consistent for interpretation of ecstasy-related impairment, so outcome measures were negatively coded where appropriate.

The 39 studies that assessed EF in a current ecstasy user group versus a control group that had some use of recreational drugs were included in the meta-analysis.

Study selection (Fig. 1)

After removing 76 duplicated papers, 459 articles remained, of which 88 were reviewed. Of these, 39 studies met all the inclusion criteria, but data were not available for five studies, so the final meta-analysis was conducted on data from 39 articles.

Meta-analyses (Fig. 2)

There was a significant overall executive performance deficit in ecstasy users relative to controls, albeit a small effect. There were also significant differential effects across EFs.

Access

13 studies were conducted with 483 ecstasy users and 491 controls to assess access to long-term/semantic memory. Ecstasy users performed poorly compared with controls.

Switching

Ecstasy use leads to impairment in mental set switching, as demonstrated by significant between-group differences in SMD and 95% CI.

Updating

Ecstasy users performed worse on updating tasks than controls, demonstrating an impairment with regards to updating performance.

Meta-regression

We conducted a method of moments (random-effect model) meta-regression across 64 comparisons to observe whether lifetime dose of ecstasy predicted performance differences in executive function. The results were nonsignificant.

Evidence of publication bias

The results of an Egger’s test of publication bias were significant, but should be interpreted with caution due to the high heterogeneity between studies.

Discussion

The results from this meta-analysis demonstrate that current ecstasy users have deficits in the executive functions access, switching and updating.

A meta-regression analysis using estimated lifetime dose of ecstasy to predict effect size of between-group differences was non-significant. However, there may be other ecstasy-using behaviours that have a stronger impact on behavioural measures, such as recency of use, frequency of use and higher nightly doses. There is substantial variance in the reporting of drug use histories in the literature, limiting interpretation of harmful behaviours. A unified reporting criterion should be applied to future research.

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. Several molecular imaging studies have suggested a reduction in pre-synaptic serotonin transporter availability and increased post-synaptic 5-HT2A receptor availability in ecstasy users.

Ecstasy-related impairments in switching and updating were unexpected, given that previous reviews in this area have concluded that this function is relatively stable. However, the differences in updating and access were the weakest of the three significant differences and had a small effect size.

Although not unexpected, there were no apparent group differences in inhibitory control. This could be because ecstasy users are high-functioning impulsives, or because inhibitory control impairment is associated with other psychostimulants that are primarily dopaminergic in nature.

The current analysis included studies that included ecstasy users and controls that had at least some experience with drugs other than ecstasy. However, the use of other drugs was higher in ecstasy users than in polydrug control groups, suggesting that various chronic drug effects do show independence from one another. It is possible that individuals with EF deficits are more likely to use ecstasy, though the authors think that this is unlikely. Longitudinal studies may help to determine whether recovery is possible. The current results suggest that ecstasy users may struggle with higher-level executive functioning, which may lead to difficulty performing the majority of occupational tasks.

The current meta-analysis demonstrated that EF performance in ecstasy users is significantly reduced overall compared with controls, with inhibitory control remaining unaffected.