The Netherlands XTC Toxicity (NeXT) research team has published yet one more prospective report of ecstasy users and non-users. In contrast to their earlier efforts, this report on attention and memory claims to have found differences between the two groups, with non-users performing better on verbal memory tests. However, the report contains problems both with the analysis and interpretation of the data.
Critique and Reservations
Ilsa Jerome Ph.D.
The Archives of General Psychiatry has just published the latest in a series of reports from the Netherlands XTC Toxicity (or NeXT) research team comparing cognitive function in ecstasy users and non-ecstasy using controls before and after they used ecstasy. The study is the third prospective study from this team, but it is the first to examine attention and memory beyond assessing working memory. In contrast with earlier publications, this report describes finding differences between the two groups, with ecstasy-nave controls performing better verbal memory tasks at follow-up than ecstasy users.
While these findings are notable as the first from a prospective study, there are problems in the analysis and presentation of the data that raise questions about the meaning and significance of study results. Perhaps the greatest problem with the findings relates to whether the researchers performed appropriate analyses for the comparisons they wished to make. However, other issues include retaining apparent outliers in the data, interpretation of results and overstating the significance of their conclusions.
The researchers began the study by recruiting people who planned on using ecstasy in the future, giving them tests of attention, verbal and visual memory before any of them had used any ecstasy. Up to three years after the first time, at a point when a number of people had started using ecstasy, the researchers gave participants the same tests of attention and memory. These participants included 59 people who said they had started using ecstasy and 61 who said they had not used it yet, with the controls matched on the basis of age and estimated verbal IQ. The ecstasy users reported taking an average of 3.2 tablets (range = 0.5-30 tablets, median = 1.5 tablets). Both groups performed similarly on these tests prior to anyone using ecstasy. The researchers subtracted the first score from the second score and compare the resulting change scores, finding that in most cases, ecstasy users and people who had not used ecstasy performed similarly on tests of attention and memory. However, non-ecstasy users had higher change scores on immediate and delayed recall on a list-learning task. Cumulative ecstasy dose, but not duration of use, was associated with differences in delayed recall and recognition of word lists. The researchers also found that past cocaine and amphetamine use was associated with differences in delayed list recall. After controlling for amphetamine and cocaine use, the researchers still found an association between cumulative ecstasy dose and recognition, but not delayed recall. The researchers interpreted their findings as indicating that even a relatively low dose of ecstasy can affect verbal memory.
Before going any further into these findings, it should be noted that everyone in this study attained scores within the normal range, and that in this case, relatively low use includes using 30 tablets. This being the case, the findings do not support claims that one or two doses of ecstasy impair verbal memory.
However, there are a number of reasons for not accepting the results at face value.
First of all, despite referring to detecting a decline in verbal memory, the researchers did not perform analyses comparing memory and attention before and after ecstasy use for each group as well as differences in performance over time in each group. Using change scores instead of raw scores creates a situation where improvement and impairment can look the same. And this is in fact what happened in the study; ecstasy user scores before and after their starting ecstasy use were for the most part similar. In some cases they were lower, and in others, they were higher. People who had not used ecstasy had higher verbal memory performance scores when tested again while ecstasy users scores were either the same or only slightly lower.
In an earlier report, the same team of researchers excluded a participant who had used 20 tablets from their prospective study of changes in brain activity during a working memory task (Jager et al. 2007). In that study, the researchers performed analyses with and without that participant, finding marginal effects when they included this person. Thus it is surprising that the researchers did not apply the same restrictions in this study or compare analyses with and without people who used 20 or more tablets. It is possible that removing people reporting use of 20 or more ecstasy tablets from the sample would not have found significant differences in verbal memory change scores. The researchers do not even state how many people reported used greater than ten tablets, despite using this amount as a limit in earlier studies.
The authors already address some of the other confounds and problems in their study in the Discussion section, even acknowledging that ecstasy users still reported greater use of other substances and noting that medical and neuropsychiatric history were determined on the basis of self-report only. It also remains unclear as to the degree that people who used ecstasy were unintentionally exposed to amphetamine or methamphetamine sold either alone or along with MDMA as ecstasy. The authors note that previous studies have failed to find any changes in verbal memory in low to moderate users, attributing the failure to those studies having smaller sample sizes. However, this explanation does not address studies that failed to find any effects of ecstasy use on memory, even when other effects were found (for instance Simon and Mattick. 2002; Halpern et al. 2004). They note that providing all participants with information on the risks of ecstasy may have created a self-fulfilling prophecy wherein ecstasy users did less well because of worries that they might confirm stereotypes about ecstasy users (Cole et al. 2006), but dismiss this possibility by stating that they did not see the effect in the whole sample. However, as only those who knew they had started using ecstasy would be vulnerable to the effects of stereotype threat, it remains possible that non-users performed better because they were not worried that they would do badly.
However, above and beyond the issues described above, the authors overstate and even misrepresent what their findings mean. As already noted, they describe significant differences in change scores as a decline in ecstasy users verbal memory throughout much of the paper, though at the beginning of the discussion they acknowledge that what they found was improvement in non-ecstasy users verbal memory. They suggest that the main underlying factor for their findings must be serotonin depletion in ecstasy users, yet when taken together, previous studies do not support a relationship between changes in the serotonin systems and impaired cognitive function in ecstasy users (Cowan 2006). Previous prospective reports from the same team and using a similar (but apparently not identical) sample failed to find signs of neuronal injury or damage or changes in brain activity or changes in task performance on a working memory task (de Win et al. 2006). This research team has even presented data indicating that low dose ecstasy had no effects on estimated numbers of serotonin uptake sites. It is notable that a recent study of the effects of the selective serotonin uptake inhibitor (SSRI) escitalopram alone or combined with a 5HT1A antagonist (pindolol) or a 5HT2A antagonist (ketanserin) in healthy drug-nave people found that the SSRI alone impaired verbal memory in health participants, and that the 5HT1A antagonist caused a further decline (Wingen et al. 2006). If these results are confirmed in other studies, it suggests that even when it is seen, impaired verbal memory in ecstasy users need not be the result of serotonin neurotoxicity but may occur as a result of downregulation of specific serotonin receptors. Finally, while ecstasy users in this reported considerably lower lifetime ecstasy use than seen in retrospective or longitudinal reports of ecstasy users, the inclusion of at least one person reporting use of 30 tablets means that the data man not represent the effects of low lifetime ecstasy use.
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The Second Prospective Study of Ecstasy Users: No Support for Changes in Brain Activity, Associative Memory or Selective Attention
Special Report on De Win study triggered by press reports from a conference presentation.