Verbal memory impairment in polydrug ecstasy users: a clinical perspective

This meta-analysis of four placebo-controlled studies (n=130; 2016) investigated the effects of MDMA (75 mg) and history of poly-drug use on verbal memory impairment. Although verbal memory was impaired during acute MDMA intoxication, there was no evidence of memory impairment in relation to either post-acute abstinence or long-term ecstasy use.

Abstract

“Background: Ecstasy use has been associated with short-term and long-term memory deficits on a standard Word Learning Task (WLT). The clinical relevance of this has been debated and is currently unknown. The present study aimed at evaluating the clinical relevance of verbal memory impairment in Ecstasy users. To that end, clinical memory impairment was defined as decrement in memory performance that exceeded the cut-off value of 1.5 times the standard deviation of the average score in the healthy control sample. The primary question was whether being an Ecstasy user (E-user) was predictive of having clinically deficient memory performance compared to a healthy control group.

Methods: WLT data were pooled from four experimental MDMA studies that compared memory performance during placebo and MDMA intoxication. Control data were taken from healthy volunteers with no drug use history who completed the WLT as part of a placebo-controlled clinical trial. This resulted in a sample size of 65 E-users and 65 age- and gender-matched healthy drug-naïve controls. All participants were recruited by similar means and were tested at the same testing facilities using identical standard operating procedures. Data were analyzed using linear mixed-effects models, Bayes factor, and logistic regressions.

Results: Findings were that verbal memory performance of placebo-treated E-users did not differ from that of controls, and there was substantial evidence in favor of the null hypothesis. History of use was not predictive of memory impairment. During MDMA intoxication of E-users, verbal memory was impaired.

Conclusion: The combination of the acute and long-term findings demonstrates that, while clinically relevant memory impairment is present during intoxication, it is absent during abstinence. This suggests that use of Ecstasy/MDMA does not lead to clinically deficient memory performance in the long term. Additionally, it has to be investigated whether the current findings apply to more complex cognitive measures in diverse ‘user categories’ using a combination of genetics, imaging techniques and neuropsychological assessments.”

Authors: Kim P. C. Kuypers, Eef L. Theunissen, Janelle H. P. van Wel, Elizabeth B. de Sousa Fernandes Perna, Anke Linssen, Anke Sambeth, Benjamin G. Schultz & Johannes G. Ramaekers

Summary

Introduction

Ecstasy was highly popular in the 1980’s and 1990’s and peaked in mid-2000, after which it declined. Recent data has shown that the scenery has changed again with a higher availability of pills with a high dose of MDMA.

Ecstasy use stabilized in 2015 and is still used by a substantial proportion of the population in Europe, the US, and Australia. Young adult Ecstasy use is relatively transient and declines before reaching their mid-twenties.

Researchers have tried to uncover the long lasting negative effects of Ecstasy on mental health and cognition. They have found that a single dose of MDMA (75 mg) can temporarily distort verbal memory in light E-users, but that this impairment is transient in nature.

Ecstasy users have worse short-term memory performance compared to drug-nave and polydrug controls, and this impairment might become chronic after long term use.

Retrospective studies encounter a number of methodological issues that can be circumvented by prospective studies in which a group of drug-naive persons is followed in time and tested several times before and after onset of MDMA use. In the ‘NeXT’ study, persons with a high probability to start using Ecstasy were included. The study showed that novice Ecstasy users had lower verbal memory scores than persistent Ecstasy-nave persons, but the findings were overstated as all test scores were within the normal range. In a prospective study, no effects of Ecstasy use on verbal memory were shown. However, the group was split based on the continuation of Ecstasy/MDMA use.

Despite methodological differences between prospective studies and between prospective versus retrospective studies, the results seem to point in the same direction, that is, that verbal memory performance of E-users differs from that of control subjects, but the differences tend to fall within normal ranges.

In this study, researchers pooled data from studies that used identical standard operating procedures at identical test locations, same study design, and used the same assessment of memory performance. The results indicated that light polydrug users demonstrated a great frequency of clinically relevant memory impairment.

Patients with MCI, performing 1.5 SD below the norm, do have functional impairments compared to a healthy control group.

Based on previous studies on E-users, it was hypothesized that E-users show lower memory scores than a healthy control group. However, it was expected that the clinical significance of these findings was low.

Participants

Two groups were included in the present study: polydrug E-users from four placebo-controlled experimental MDMA studies and drug-naive participants from six placebo-controlled experimental studies.

The sample size from the MDMA studies was 70; five participants participated in multiple studies and were excluded, while 65 participants were matched by age and gender. The drug use history of the participants was checked with a medical questionnaire and an interview with a medical doctor.

Procedure

Participants were screened for alcohol and drug use at the start of the test day, did a training session, were given their ‘treatments’ (either active substance or placebo), and completed a mood questionnaire. After a light breakfast and 30 minutes of tasks, the cognitive tests started.

Word Learning Task

All studies included in this analysis used the same adapted version and procedure of the Word Learning Task (WLT). The dependent variables used in these analyses were the Total Immediate Recall and the Delayed Recall scores.

Verbal Memory Impairment Criterion

A criterion for verbal memory impairment was calculated based on the control sample. The E-users group was classified into two categories: impaired or not.

Statistical analysis

A Linear Mixed-Effects Model was used to examine differences in verbal memory ability between MDMA users and controls. The LMEM was fit to the data using the lme function of the nlme library for the R package of statistical computing.

LMEM and Bayes factor analyses were performed using R statistical software, and regression analyses were conducted to determine relationships between drug use and verbal memory performance. The odds ratio (OR) together with 95% Confidence Intervals (CI) are reported for each analysis.

Missing data

We had 65 complete sets for the IR-Score and 48 complete sets for the DR-Score, but missing data for life time Ecstasy use and MDMA concentrations were included in specific analyses.

Long-term or chronic effects of Ecstasy use

Long-term MDMA use does not impair verbal memory ability. The LMEM yielded no significant differences between Eusers and healthy controls on measures of immediate recall and delayed recall.

Ecstasy use did not significantly contribute to clinically relevant memory impairment.

Ecstasy exposure and memory impairment. Time used did not significantly contribute to the odds of having clinically deficient immediate recall (IR) and delayed recall (DR) memory impairment.

Short-term or acute effects of MDMA

MDMA intoxication caused significant impairment in immediate and delayed memory. Logistic regression revealed that MDMA intoxication contributed to the chance of having clinically deficient memory performance during immediate recall and delayed recall.

MDMA disposition and memory: LMEM analyses showed no significant effect of clinical impairment, and Bayes factor t-tests revealed only anecdotal evidence for the null hypothesis that MDMA concentrations are not associated with memory impairment.

Discussion

Results showed that light E-users had normal memory performance and that lifetime E-use did not increase the chance of having clinically relevant verbal memory impairment.

The absence of a persistent long-term effect of Ecstasy on memory performance might be attributed to the fact that participants in the present study were drawn from comparable groups and that they had a low lifetime use history. The interaction between Ecstasy/MDMA and other co-consumed substances may lead to increased toxicity and/or higher chance at compulsive use, but light E-users probably haven’t been subject to ‘aggregation toxicity’ to such an extent as heavy users have.

A study by Brown and colleagues showed that moderate E-users had memory deficits in higher complexity tasks, but this study did not test this assumption or establish whether low-use E-users were impaired in tasks of higher complexity.

In this study, MDMA intoxication leads to statistically and clinically significant memory impairment. However, MDMA blood concentrations during intoxication did not contribute to the chance of having clinically significant memory impairment, and light Ecstasy use does not lead to clinically deficient memory performance in simple explicit memory tasks.

The present study only included light (polydrug) E-users and therefore results only pertain to this particular group. Additionally, information on premorbid intelligence levels was not systematically gathered in the pooled studies and therefore participants in the pooled studies could be regarded as similar in terms of cognitive abilities. The present study only used the Word Learning Test and did not consider baseline levels of performance or the impact of subtle deficits on daily life activities.

Future studies should gather additional genetic information on the long-term effects of Ecstasy use, including genes determining metabolism rate and neurotoxicological potential of MDMA. Furthermore, epigenetics might provide additional information on the mechanisms underlying potential impairment observed in E-users. Besides genetics, it would be interesting to include data on environmental circumstances linked to drug use history to investigate the contribution of these factors to cognitive performance. Furthermore, inclusion of tasks of different complexity and brain imaging measures could provide a more detailed picture on the potential impairing effect of chronic Ecstasy use. Light use of Ecstasy/ MDMA does not lead to clinically deficient memory performance on the long-term, after 1 – 12 years of use.