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3,4-Methylenedioxymethamphetamine (MDMA), commonly referred to as ‘ecstasy’, is a psychostimulant drug which is popular among young adults. In Europe, the life-time prevalence of MDMA use is 5.6% in the 15–34-year-old population, with highest prevalence estimates in the United Kingdom (12.7%) . For North America the life-time prevalence rates are generally estimated higher than in Europe . MDMA is used illegally as a recreational drug, in particular by visitors of techno clubs and rave parties .
MDMA and related substances act primarily upon indirect serotonergic and dopaminergic mechanisms in the central nervous systems (CNS). Since the mid-1980s, repeated administrations of MDMA to experimental animals have suggested neurotoxic degeneration of serotonergic axon terminals followed by a decrease of 5-HT (5-hydroxytryptamine; serotonin) concentration in brain tissue . This effect persists even after several years [4, 5]. Studies investigating different markers of 5-HT [main metabolite in cerebral spinal fluid (5-hydroxyindoleacetic acid), 5-HT transporter density, postsynaptic 5-HT receptors] in human users, support the hypothesis that the suggested neurotoxic potential of MDMA which was reported in laboratory animal research could be relevant to humans [5-10]. With this it is to be considered that, in contrast to the neurodegeneration hypotheses, neuroregulatory mechanisms are suggested to underlie MDMA-induced serotonergic dysfunction . 5-HT is involved in many functional systems, including psychopathology, neuroendocrine and sleep regulation as well as regulation of vegetative functions. Additionally, a number of impairments in cognition and stimulus processing are conceivable as a consequence of MDMA-induced serotonergic dysfunction.
With regard to cognitive performance, a large number of cross-sectional studies and a handful of longitudinal investigations indicate that the most consistent findings have been decrements in memory and learning performance . However, deficits in working memory, planning ability and central executive control, as well as high cognitive impulsivity, have also been reported [3, 13, 14].
In general, most studies on the cognitive effects of MDMA suffer from several methodological problems (e.g. pre-existing differences, polydrug use, differences in life-style). Therefore, a prospective methodological approach was applied in order to assess cognitive performance. In the present study, a comprehensive neuropsychological test battery was applied to assess cognitive performance over the course of 1 year in new MDMA users. In addition, a comprehensive number of possibly confounding variables including age, general intelligence, cannabis use, alcohol use, cigarette use, medical treatment, participation in sports, nutrition, sleep patterns and subjective wellbeing were explored and controlled for with regard to the statistical analyses. The goal was to address the following questions.
- Does the use of MDMA over a period of 1 year lead to a cognitive performance decrease?
- Which cognitive domains are most vulnerable to be affected by initial/incipient use of MDMA over a period of 1 year?
- Are the potential effects of initial/incipient MDMA use on cognitive impairments confounded by age, general intelligence, cannabis use, alcohol use, cigarette use, medical treatment, participation in sports, nutrition, sleep patterns and/or subjective wellbeing?
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The aim of the present investigation was to examine the nature of cognitive deficits in new ecstasy users over the course of a 1-year-period. A neuropsychological test battery including tests of learning, memory, working memory and executive functions was administered to 149 subjects, of whom 109 participated in the second assessment after 1 year. In addition, there were no statistically significant differences on a comprehensive number of possibly relevant confounders including age, general intelligence, cannabis use, alcohol use, cigarette use, medical treatment, participation in sports, nutrition, sleep patterns and subjective wellbeing. Significant effects of immediate and delayed recall of a paired associates learning task between subjects who used 10 or more ecstasy pills and subjects who did not use any illicit substance apart from cannabis during the course of the year (non-users) were found. No significant differences were found on any of the other neuropsychological tests.
Deficits in visual and associative learning among ecstasy users have been described previously [9, 30-33]. Due to the cross-sectional design of available studies, it was not possible to determine whether the found alterations existed before initiation of use or whether concomitant health behaviour variables were responsible for a percentage of the deficits. In addition, the role of concomitant use of cannabis in this context was not fully understood. In the present study, these methodological concerns were dispelled and a comparably large sample was investigated. Most intriguingly, although pre-existing group differences were ruled out and a comprehensive number of possible confounders were controlled for, the effects of ecstasy on paired associates learning remained significant despite the relatively short time-period (1 year) and the amounts of MDMA used (10–60 pills MDMA, mean: 32.44). Keeping in mind that no significant effect of MDMA on any other cognitive variable was found in the present study, the results indicate a specific effect of relative small amounts of MDMA on paired associates learning. This finding is consistent with the findings of Brown and colleagues , who also found significant deficits on an associate learning task in the absence of deficits on other memory tasks. Whether or not the influence of MDMA on other cognitive variables becomes significant with increasing time-periods and amount of use remains unclear, and is a promising hypothesis for future longitudinal investigations. In this respect, our results are inconsistent with the conclusions made by Halpern and colleagues . They suggested that their findings ‘might instead reflect correctly that illicit ecstasy use, by itself, does not generally produce lasting residual neurotoxicity’. Potential reasons for the discrepant results could be found in the nature of the samples and the choice of measures that were administered. Because these issues have been already discussed extensively, we refer to the corresponding publications [36-38].
With regard to the intercorrelation between MDMA and amphetamine use in our MDMA users sample, it is unclear if the decrements in visual relational memory can be ascribed to the use of MDMA alone or to the polydrug use of MDMA and amphetamine. However, Gouzoulis-Mayfrank and colleagues  reported a significant influence of MDMA use on the immediate and delayed recall score in the same test that was used in the present study. Interestingly, in their sample it was possible to ascribe the effects to MDMA use by means of linear stepwise regression analysis. Therefore, it seems most likely that the decrements in visual relational memory can be ascribed to the use of MDMA rather than to the polydrug use of MDMA and amphetamine. Furthermore, after taking into account the potential effect of the use of other illicit drugs by means of multiple regression analyses, Schilt and colleagues  reported that ecstasy use was dose-related to verbal memory impairments, and there was still a significant association thereof.
Given that the hippocampus plays a fundamental role in relational memory , the findings of the present study support the hypothesis that the neural basis for the detrimental effects of MDMA on neurocognition appears to be a hippocampal dysfunction. Studies using animal models have shown that MDMA causes selective and persistent lesions of central serotonergic nerve terminals [4, 5, 40-42]. In addition, Kish and colleagues reported serotonin transporter changes in human MDMA users . In particular, the hippocampus and parahippocampus display relatively high rates of serotonergic denervation after MDMA exposure . Moreover, serotonin plays a central role in hippocampal neurogenesis inherent to learning and memory processes . As a result, Gouzoulis-Mayfrank and colleagues  proposed that this may explain why hippocampal systems might be more sensitive to serotonin depletion than neocortical brain regions. Furthermore, it possibly accounts for the pattern of cognitive performance in ecstasy users with more consistent decrements in memory and learning performance compared to other cognitive domains that are dependent only on neocortical function. As mentioned previously, Brown and colleagues  also found significant deficits on an associate learning task in the absence of deficits on other memory tasks. However, they also found no deficits in ecstasy users on tests which have been shown to be more specific to the hippocampus and therefore interpreted their findings to complex interactions between multiple brain regions including the prefrontal cortex rather than to the hippocampus alone. The contributory role of other brain areas has also been illustrated by Burgess and colleagues who found reduced left parietal lobe activity during word recognition in abstinent MDMA users .
The underlying molecular mechanisms of these long-term effects have yet to be elucidated. Studies in laboratory animals have supported the involvement of oxidative stress in MDMA neurotoxicity by decreasing the levels of antioxidants in serotonergic terminals [46, 47]. Additionally, mitochondrial dysfunction and hyperthermia have been associated with administration of MDMA and subsequent toxicity to serotonergic terminals. Moreover, inflammatory cytokines, the ubiquitin proteasome system, environmental stress, neurotrophic factors and apoptotic proteins have been reported recently as potential mediators of MDMA toxicity that may also explain the terminal as the somatic degeneration . In addition, by affecting basal synaptic transmission and long-term potentiation (LTP; an activity-induced increase in synaptic efficacy) via activation of serotonin receptors systems in the hippocampus, decreases in memory performance seem likely. Deciphering these molecular mechanisms is a promising task for further research. Moreover, neuroregulatory mechanisms are suggested to underlie MDMA-induced serotonergic dysfunction rather than neurodegeneration . Similarly, this issue is an important target for future studies.
There are some methodological limitations which are inherent to open-trial studies and are outlined below. First of all, although we chose a prospective approach, the design was not experimental and therefore a causal relationship between MDMA use and decline in paired associates learning may not be presumed as a matter of course. Additionally, for reasons of practicability the minimal abstinence period from cannabis in the present study was 12 hours. Therefore, we cannot rule out an impure distinction between subacute and long-term effects of cannabis use. However, the mean time since last cannabis use did not differ between MDMA users and controls. Furthermore, the quantity of use was reported by the participants themselves. Nevertheless, studies validating self-reported voluntary substance use found a high reliability of the reported drug quantity [48-50]. Additionally, hair samples taken randomly by the Institute of Legal Medicine of the University of Cologne confirmed the self-reported substance use in all cases but one (which was excluded from the analyses). Another limitation concerns the concentration and purity of illicit drugs and their mode of consumption. However, evidence from German police seizures suggest that 99.65% of the confiscated ecstasy pills in 2008 contained only one psychoactive ingredient. MDMA was found in 96.8% of the confiscated ecstasy pills. The remaining share of 3.2% of the confiscated ecstasy pills consisted of 1-(3-chlorphenyl)-piperazine (m-CPP), amphetamines, methamphetamine or MDA . Cannabis is a natural product, inherently variable in its strength and composition. Therefore, estimates of the life-time cumulative exposure of illicit drugs represent only crude approximations of actual exposure [3, 52]. Furthermore, subjects were aware that their drug use was critical to the research design, and this awareness may have caused selection bias or created expectation effects, and subjects who took ecstasy may have experienced anxiety about confirming . However, the significant differences were found specifically in paired associates learning, and not in other domains of cognitive functioning.
In conclusion, a significant effect of MDMA use on visual paired associates learning was found, suggesting specific deterioration of hippocampal functioning. Given the fact that memory impairments remained significant after controlling for a large variety of confounders, our findings may raise concerns with regard to MDMA use, even in recreational amounts over a relatively short time-period.
Declarations of interest
This work was supported by a grant to E. Gouzoulis-Mayfrank and J. Daumann from the German Research Foundation (Deutsche Forschungsgemeinschaft DFG, Go 717/6-1/2). Furthermore, the authors declare that, except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 36 months for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. This pertains to all the authors of the study, their spouses or partners and their children (aged under 18).