Learning, Memory, and Executive Function in New MDMA Users: A 2-Year Follow-Up Study Prospective memory, everyday cognitive failure and central executive function in recreational users of Ecstasy. Neural correlates of working memory in pure and polyvalent ecstasy (MDMA) users Cerebral activation in abstinent ecstasy (MDMA) users during a working memory task: a functional magnetic resonance imaging (fMRI) study. Cognitive function and mood in MDMA/THC users, THC users and non-drug using controls A prospective study of learning, memory, and executive function in new MDMA users. Elevated Impulsivity and Impaired Decision-Making in Abstinent Ecstasy (MDMA) Users Compared to Polydrug and Drug-Naïve Controls Recreational Use of “Ecstasy” (MDMA) Is Associated with Elevated Impulsivity MDMA affects both error-rate dependent and independent aspects of decision-making in a two-choice prediction task Memory impairment in abstinent MDMA (“Ecstasy”) users: A longitudinal investigation Cognitive performance and serotonergic function in users of ecstasy Ecstasy use: cognitive deficits related to dosage rather than self-reported problematic use of the drug Incidental use of ecstasy: no evidence for harmful effects on cognitive brain function in a prospective fMRI study Psychological and Cardiovascular Effects and Short-Term Sequelae of MDMA (“Ecstasy”) in MDMA-Naïve Healthy Volunteers Memory-related hippocampal functioning in ecstasy and amphetamine users Disrupted ‘reflection’ impulsivity in cannabis users but not current or former ecstasy users Gender differences in the subjective effects of MDMA
3,4-Methylenedioxymethamphetamine ( MDMA ) is associated with changes in neurocognitive performance . Recent studies in laboratory animals have provided additional support for the neurodegeneration hypothesis . However , results from animal research need to be applied to humans with caution . Moreover , several of the studies that examine  MDMA users suffer from method ological shortcomings . Therefore , a prospect i ve cohort study was design ed in order to overcome these previous method ological shortcomings and to assess the relationship between the continuing use of MDMA and cognitive performance in incipient MDMA users . It was hypothesized that , depending on the amount of MDMA taken , the continued use of MDMA over a 2-year period would lead to further decreases in cognitive performance , especially in visual paired association learning tasks . Ninety-six subjects were assessed , at the second follow-up assessment : 31 of these were non-users , 55 moderate-users , and 10 heavy-users . Separate repeated measures analyses of variance were conducted for each cognitive domain , including attention and information processing speed , episodic memory , and executive functioning . Furthermore , possible confounders including age , general intelligence , cannabis use , alcohol use , use of other concomitant substances , recent medical treatment , participation in sports , level of nutrition , sleep patterns , and subjective well-being were assessed . The Repeated measures analysis of variance ( rANOVA ) revealed that a marginally significant change in immediate and delayed recall test performances of visual paired associates learning had taken place within the follow-up period of 2 years . No further deterioration in continuing MDMA-users  was observed in the second follow-up period . No significant differences with the other neuropsychological tests were noted . It seems that MDMA use can impair visual paired associates learning in new users . However , the groups differed in their use of concomitant use of illicit drugs . Therefore , performance differences between the groups can not completely ascribed to the use of MDMA Chronic use of MDMA ( 3,4-methylenedioxymethamphetamine ) , or Ecstasy , is believed to lead to impaired psychological performance , including well-documented decrements in laboratory and field tests of retrospective memory . Less is known about the impact of Ecstasy on aspects of ' everyday ' memory , despite obvious concerns about such effects . The three studies reported here focused on the impact of chronic Ecstasy use on prospect i ve memory ( PM ) , associated central executive function and other aspects of day-to-day cognition . In study 1 46 regular Ecstasy users were compared with 46 Ecstasy-free controls  using the  Prospect i ve Memory Question naire ( PMQ ) . Ecstasy users reported significantly more errors in PM ( remembering to do something in the future ) ; these findings persisted after controlling for other drug use and the number of strategies used to aid memory . No difference was found between representative subgroups on the Lies Scale of the Eysenck Personality Question naire . In study 2 a different group of 30 regular Ecstasy users and 37 Ecstasy-free controls was assessed on the PMQ and on a central executive task comprising verbal fluency measures . The results confirmed the significant impairments in long- and short-term PM and revealed corresponding impairments in verbal fluency . In study 3 15 Ecstasy users , 15 cannabis users and 15 non-drug users were assessed using the  Cognitive Failures Question  naire , which requires participants to provide ratings of the frequency of various day-to-day cognitive slips . The results indicate that the Ecstasy users did not perceive their general cognitive performance to be worse than that of controls . Taken together , these results suggest that Ecstasy users have impaired PM that can not be explained by an increased propensity to exaggerate cognitive failures . These may be attributable , in part , to central executive deficits that are due to frontal lobe damage associated with Ecstasy use . Copyright 2001 John Wiley & Sons , Poor cognitive performance in ecstasy ( 3,4-methylenedioxymethamphetamine ; MDMA ) users has been related to the well-recognized neurotoxic effects of the drug upon central serotonergic and possibly also dopaminergic systems . However , concomitant use of other drugs has been a critical confound in most investigations . In this study we used an n-back task and fMRI to investigate working memory performance and related cerebral activation in eight , currently abstinent pure MDMA users and two matched groups of polyvalent MDMA users and non-users . Pure MDMA users presented lower activations than controls and /or polyvalent users , most notably in inferior temporal regions , the angular gyrus and the striate cortex , whereas polyvalent users did not differ from controls . Our results suggest that altered brain activation patterns during cognitive processing in ecstasy users may be mainly associated with prior MDMA use . Concomitant use of other drugs may modify this effect The popular recreational drug ecstasy ( 3,4-methylenedioxymethamphetamine = MDMA and related congeners ) is neurotoxic upon central serotonergic systems in animal studies . So far , the most convincing evidence for neurotoxicity-related functional deficits in humans derives from neurocognitive studies demonstrating dose-related long-term learning and memory problems in ecstasy users . In our study we used functional magnetic resonance imaging ( fMRI ) and a working memory task to investigate cerebral activation in eleven heavy , but currently abstinent MDMA users and two equally sized groups of moderate users and non-users . There were no significant group differences in working memory performance and no differences in cortical activation patterns for a conservative level of significance . However , for a more liberal statistical criterion , both user groups showed stronger activations than controls in right parietal cortex . Furthermore , heavy users had a weaker blood oxygenation level-dependent ( BOLD ) response than moderate users and controls in frontal and temporal areas . Our results may indicate subtle altered brain functioning associated with prior MDMA use , although alternative interpretations of these group differences must be considered Repeated ecstasy ( MDMA ) use is reported to impair cognition and cause increased feelings of depression and anxiety . Yet , many relevant studies have failed to control for use of drugs other than MDMA , especially marijuana ( THC ) . To address these confounding effects we compared behavioural performance of 11 MDMA/THC users , 15 THC users and 15 non-drug users matched for age and intellect . We tested the hypothesis that reported feelings of depression and anxiety and cognitive impairment ( memory , executive function and decision making ) are more severe in MDMA/THC users than in THC users . MDMA/THC users reported more intense feelings of depression and anxiety than THC users and non-drug users . Memory function was impaired in both groups of drug users . MDMA/THC users showed slower psychomotor speed and less mental .exibility than non-drug users . THC users exhibited less mental .exibility and performed worse on the decision making task compared to non-drug users but these functions were similar to those in MDMA/THC users . It was concluded that MDMA use is associated with increased feelings of depression and anxiety compared to THC users and non-drug users . THC users were impaired in some cognitive abilities to the same degree as MDMA/THC users , suggesting that some cognitive impairment attributed to MDMA is more likely due to concurrent THC use AIMS It is still unclear if cognitive abnormalities in human 3,4-methylenedioxymeth-amphetamine  ( MDMA ) users existed before the beginning of use or if other confounders could explain the deficits . The present study was conducted in order to assess the relationship between beginning MDMA use and subsequent cognitive performance and to overcome previous method ological shortcomings . DESIGN A prospect i ve cohort study in new MDMA users between 2006 and 2009 with a follow-up duration of 12 months . SETTING AND PARTICIPANTS Of the 149 almost MDMA-naive subjects examined at the initial assessment , 109 subjects participated again after 1 year . During this period , 43 subjects did not use any other illicit substance apart from cannabis ; 23 subjects used more than 10 pills  MDMA ( mean = 33.6 ) . These groups then were compared by means of multivariate analyses of variance . MEASUREMENTS Change scores between the initial examination and follow-up on a neuropsychological test battery including measures of learning , memory , and frontal executive functions [ Auditiv-Verbaler Lerntest ( AVLT ) , Lern- und Gedächtnistest ( LGT ) 3 , digit span test , digit symbol test , Stroop task , Trail-making test ] . In addition , 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 was assessed . FINDINGS Groups did not differ in any of the potential confounders . However , significant effects of immediate and delayed recall of a visual paired associates learning task between MDMA users and controls were found ( respectively , F ( ( 1,64 ) ) = 11.43 , P = 0.001 , η(2 ) = 0.136 and F ( ( 1,64 ) ) = 11.08 , P = 0.002 , η(2 ) = 0.144 ) . No significant differences on the other neuropsychological tests were found . CONCLUSIONS MDMA appears to impair visual paired associates learning in new users , suggesting serotonergic dysfunction in hippocampal regions as a consequence of MDMA use Ecstasy ( MDMA ; 3,4-methylenedioxymethamphetamine ) has a well-recognized neurotoxic effect on central serotonergic ( 5-HT ) systems in animals , and there is some evidence of persistent serotonergic dysregulation in human ecstasy users . Serotonin is believed to mediate impulsive behavior and effective decision-making . Thus , the aim of the present study was to investigate impulsive behavior and decision-making in abstinent regular ecstasy users . Three groups were compared : ‘ ecstasy users ’ ( recreational ecstasy users who reported modest use of illicit drugs other than cannabis ) , ‘ polydrug controls ’ ( ecstasy naïve illicit drug users ) , and ‘ drug-naïve controls ’ .  All participants completed personal details and general drug history question naires , the National Adult Reading Test , Matching Familiar Figures Test ( MFF20 ) , a risky decision-making task ( RDMT ) , and the Card Arranging Reward Responsivity Objective Test ( CARROT ) . The groups did not differ on the CARROT measure of responsiveness to financial incentive ; however , the ecstasy group displayed significantly elevated MFF20 impulsivity , and showed reduced discrimination between magnitudes of prospect i ve gains and losses when making risky decisions , compared to the ‘ polydrug ’ and ‘ drug-naïve ’ control groups . These findings may reflect a vulnerability of 5-HT systems in the orbital prefrontal cortex and interconnected corticolimbic circuitry to the cumulative neurotoxic effects of ecstasy and have clinical significance for regular ecstasy users . The combination of elevated impulsivity and impaired use of reinforcement cues in uncertain decision-making may comprise risk factors for continued drug abuse and everyday functioning Recent pre clinical evidence suggests that repeated exposure to 3 , 4-methylenedioxy-methamphetamine ( MDMA ; “ ecstasy ” ) produces long-term reductions in serotonin ( 5-HT ) levels . 5-HT has been implicated in the regulation of mood , anxiety , aggression , impulsivity , and cognition . Accordingly , in the first of two separate studies , these variables were investigated in three groups : ( 1 ) MDMA group — recreational ecstasy users ( who also used other illicit substances ) ; ( 2 ) polydrug controls — who had never taken ecstasy , but otherwise had drug histories and personal characteristics similar to the ecstasy users ; and ( 3 ) nondrug controls — who had never used illicit drugs , but had similar personal characteristics . All participants completed mood ( Likert ) scales , personality question naires ( which included the impulsiveness , venturesomeness and empathy question naire – IVE ) , spatial span and “ Tower of London ” ( TOL ) tests , and a behavioural measure of impulsivity , the matching familiar figures test ( MFF20 ) . There were no group differences in mood , anxiety , anger/hostility , and cognitive performance , but the MDMA group committed significantly more errors in the MFF20 . Subsequently , a larger sample of participants were administered mood ( the General Health Question naire or GHQ ) and personality ( IVE ) question naires before the administration of a TOL test , followed by the MFF20 , and a second TOL test . Although there were no group differences in TOL performance , ecstasy users were again found to commit more errors in the MFF20 than polydrug users . Furthermore , the GHQ and IVE scores of the ecstasy users in the second study indicated , respectively , that they were more psychologically disturbed and impulsive than nondrug controls . The combined data from the two studies indicated that ecstasy users exhibited elevated impulsivity on both self-report and behavioral measures and that those who had taken the most ecstasy had the most elevated trait impulsiveness scores . These findings are consistent with previous evidence that elevated levels of impulsivity in humans are associated with reduced levels of serotonergic function Decision-making , i.e. selecting an action from a number of alternatives when the outcome is uncertain , is a complex process that is important for everyday life . 3,4-Methylenedioxymethamphetamine ( MDMA ) , also known as ‘ Ecstasy ’ , is a widely used recreational drug that is known to increase serotonin ( 5-HT ) and , to a lesser extent , dopamine ( DA ) in animals . This study examined whether MDMA alters decision-making in a way that depends on the degree of success and outcome . Forty-two normal , healthy volunteers were given placebo or 1.5mg/kg p.o . MDMA in a r and omized crossover design . Subjects completed the two-choice prediction task 120min after administration of the drug . Decision-making characteristics were obtained at 20 % error rate , 50 % error rate or 80 % error rate . MDMA affected decision-making via a process that is dependent on success or failure . Administration of MDMA increased the degree to which the previous response predicted the current response ( mutual information ) and the average response sequence predictability ( average dynamical entropy ) at low error rates . MDMA increased the degree to which the previous stimulus influenced the selection of the current response at 20 % , 50 % or 80 % error rate . MDMA did not significantly alter basic response characteristics such as response latency or switching . Self- assessment of the psychological state induced by MDMA did not predict the MDMA induced decision-making patterns . These results support the hypothesis that acute administration of MDMA affects success-related response selection during decision-making To examine the neurotoxic potential of continued  MDMA ( “ Ecstasy ” )  use in humans and its functional consequences over the course of 1 year , 15 MDMA users participated in a longitudinal study in which they completed a brief neuropsychological test battery composed mainly of retrospective and prospect i ve memory tasks . Subjects were abstinent for 2 weeks on initial and 1-year testing . Continued use of MDMA was associated with progressive decline in terms of immediate and delayed recall Abstract . Rationale : ( ± ) 3,4-Methylenedioxymethamphetamine ( MDMA or " ecstasy " ) has been shown to cause long term damage to serotonergic cerebral neurons in animals . The neurotoxic effects in humans are less clear and little is known about the functional consequences , although some studies suggest memory impairment . Given the widespread use of MDMA , our lack of knowledge raises concerns . Objective : We investigated , in humans , the relation between past use of ecstasy and cognitive performance as well as serotonergic function . Methods : Two groups of 21 males with moderate and heavy recreational use of MDMA , respectively , and a control group of 20 males without use of MDMA were compared . All were from the same subculture . Reaction time , direct recall , and recognition were assessed . Serotonergic function was measured by the neuro-endocrine response to a placebo-controlled , crossover challenge with dexfenfluramine . Results : Ecstasy users showed a broad pattern of statistically significant , but clinical ly small , impairment of memory and prolonged reaction times . Heavy users were affected stronger than moderate users . Release of cortisol but not of prolactin  after dexfenfluramine administration was significantly reduced in both groups of ecstasy users compared with the controls . Analyses of covariance showed that likely confounding variables including recent exposure to ecstasy , psychosocial profiles and use of other drugs did not explain the differences found between the groups . Conclusions : These results provide further evidence that use of ecstasy may be associated with impairment of memory and of serotonergic function . These findings are compatible with neurotoxicity of ecstasy as shown in animals Previous research has shown drug-free Ecstasy users to demonstrate selective cognitive impairment However , there seems to be a degree of individual variation in the occurrence of such deficits . The present study aim ed to assess whether these cognitive deficits are related to an awareness of problematic Ecstasy use , or to past drug dosage . Twenty regular Ecstasy users who reported experiencing Ecstasy-related problems were compared with 20 Ecstasy users who had not reported any previous problems . The two groups displayed similar past histories in relation to a range of illicit drugs , and were divided into low , medium and high users . The controls comprised 20 illicit recreational drug users who had never taken Ecstasy . Executive task measures comprised the  Tower of London ( TOL ) , the Wisconsin Card Sorting Task ( WCST ) and spatial working memory . Immediate and delayed word recall , matched verbal recognition and recall and simple reaction time were also included . Both Ecstasy groups performed significantly worse than controls on two executive measures : TOL planning time and spatial working memory score . There were no differences in cognitive impairment between the Ecstasy users who complained of problems and those who did not . In both groups , decrement on executive tasks was demonstrated as a function of previous drug dose . The study confirms that heavy Ecstasy polydrug use may culminate in selective executive deficits . It also demonstrates that two differently self-perceived Ecstasy groups showed similar cognitive impairment , despite only one group complaining of problems . Because all Ecstasy participants also consumed a range of other illicit drugs , the results are reflective of Ecstasy polydrug use in individuals who use Ecstasy as a drug of preference Rationale Heavy ecstasy use in humans has been associated with cognitive impairments and changes in cognitive brain function supposedly due to damage to the serotonin system . There is concern that even a single dose of 3,4-methylenedioxymethamphetamine may be neurotoxic , but very little is known about the consequences of a low dose of ecstasy for cognitive brain function . Objectives The objective of the study was to assess the effects of a low dose of ecstasy on human cognitive brain function using functional magnetic resonance imaging ( fMRI ) . Material s and method We prospect ively studied , as part of the NeXT ( Netherl and s XTC toxicity ) study , sustained effects of a low dose of ecstasy on brain function in 25 subjects before and after their first episode of ecstasy use ( mean 2.0 ± 1.4 ecstasy pills , on average 11.1 ± 12.9 weeks since last ecstasy use ) , compared to 24 persistent ecstasy-naive controls , also measured twice and matched with the novice users on age , gender , IQ , and cannabis use .  Cognitive brain function was measured in the domains of working memory , selective attention , and associative memory using fMRI . Results No significant effects were found of a low dose of ecstasy on working memory , selective attention , or associative memory neither at the behavioral level nor at the neurophysiological level . Conclusions This study yielded no firm evidence for sustained effects of a low dose of ecstasy on human cognitive brain function . The present findings are relevant for the development of prevention and harm reduction strategies . Furthermore , the study is relevant to the discussion concerning potential therapeutic use of ecstasy 3,4-methylenedioxymethamphetamine ( MDMA , “ Ecstasy ” ) is a recreational drug reported to produce a different psychological profile than that of classic hallucinogens and stimulants . It has , therefore , been tentatively classified into a novel pharmacological class termed entactogens . This double-blind placebo-controlled study examined the effects of a typical recreational dose of MDMA ( 1.7 mg/kg ) in 13 MDMA-naıuml;ve healthy volunteers .  MDMA produced an affective state of enhanced mood , well-being , and increased emotional sensitiveness , little anxiety , but no hallucinations or panic reactions . Mild depersonalization and derealization phenomena occurred together with moderate thought disorder , first signs of loss of body control , and alterations in the meaning of percepts . Subjects also displayed changes in the sense of space and time , heightened sensory awareness , and increased psychomotor drive .  MDMA did not impair selective attention as measured by the Stroop test . MDMA  increased blood pressure moderately , with the exception of one subject who showed a transient hypertensive reaction . This severe increase in blood pressure indicates that the hypertensive effects of MDMA , even at recreational doses , should not be underestimated , particularly in subjects with latent cardiovascular problems . Most frequent acute somatic complaints during the MDMA challenge were jaw clenching , lack of appetite , impaired gait , and restless legs . Adverse sequelae during the following 24 hours included lack of energy and appetite , feelings of restlessness , insomnia , jaw clenching , occasional difficulty concentrating , and brooding . The present findings are consistent with the hypothesis that MDMA produces a different psychological profile than classic hallucinogens or psychostimulants Rationale Recreational use of ecstasy ( 3,4-methylenedioxymethamphetamine [ MDMA ] ) has been associated with memory impairments . Functional neuroimaging studies with cross-sectional design s reported altered memory-related hippocampal functioning in ecstasy-polydrug users . However , differences might be pre-existing or related to the concomitant use of amphetamine . Objective To prospect ively investigate the specific effects of ecstasy on memory-related hippocampal functioning . Methods We used an associative memory task and functional magnetic resonance imaging ( fMRI ) in 40 ecstasy and /or amphetamine users at baseline ( t1 ) and after 12 months ( t2 ) . At t1 , all subjects had very limited amphetamine and /or ecstasy experience ( less than 5 units lifetime dose ) . Based on the reported drug use at t2 , subjects with continued ecstasy and /or amphetamine use ( n = 17 ) were compared to subjects who stopped use after t1 ( n = 12 ) . Results Analysis of repeated measures revealed that encoding-related activity in the left parahippocampal gyrus changed differentially between the groups . Activity in this region increased in abstinent subjects from t1 to t2 , however , decreased in subjects with continued use . Decreases within the left parahippocampal gyrus were associated with the use of ecstasy , but not amphetamine , during the follow-up period . However , there were no significant differences in memory performance . Conclusions The current findings suggest specific effects of ecstasy use on memory-related hippocampal functioning . However , alternative explanations such as (sub-)acute cannabis effects are conceivable Abstract Evidence for serotonin involvement in impulsivity has generated interest in the measurement of impulsivity in regular ecstasy users , who are thought to display serotonergic dysfunction . However , current findings are inconsistent . Here , we used a recently developed Information Sampling Test to measure ‘ reflection ’ impulsivity in 46 current ecstasy users , 14 subjects who used ecstasy in the past , 15 current cannabis users and 19 drug-naïve controls . Despite elevated scores on the Impulsivity subscale of the Eysenck Impulsiveness-Venturesomeness-Empathy question naire , the current and previous ecstasy users did not differ significantly from the drug-naive controls on the Information Sampling Test . In contrast , the cannabis users sample d significantly less information on the task , and tolerated a lower level of certainty in their decision-making , in comparison to the drug-naive controls . The effect in cannabis users extends our earlier observations in amphetamine- and opiate-dependent individuals ( Clark , et al. , 2006 , Biological Psychiatry 60 : 515–522 ) , and suggests that reduced reflection may be a common cognitive style across regular users of a variety of substances . However , the lack of effects in the two ecstasy groups suggests that the relationship between serotonin function , ecstasy use and impulsivity is more complex Abstract . Rationale : 3,4-Methylenedioxymethamphetamine ( MDMA ) mainly releases serotonin ( 5-HT ) and is contained in the recreational drug Ecstasy . 5-HT is known to play an important role in mood and anxiety disorders , for which there is a female preponderance . To date , there are no systematic data on gender differences in the subjective effects of MDMA . Objectives : The present work analyzed the pooled data from three controlled studies on the psychological and physiological effects of MDMA in healthy volunteers with no or minimal MDMA experience . A particular focus of the analyses were possible gender differences . Methods : A total of 74 subjects ( 54 male , 20 female ) participated in all three studies .  MDMA in oral doses ranging from 70–150 mg ( 1.35–1.8 mg/kg ) was administered under double-blind placebo-controlled conditions . Subjective peak changes were assessed by st and ardized psychometric rating scales . Physiological measures were blood pressure , heart rate , and peripheral body temperature . Adverse drug effects were assessed during the experimental session and after 24 h. Results : Psychoactive effects of MDMA were more intense in women than in men . Women especially had higher scores for  MDMA-induced perceptual changes , thought disturbances , and fear of loss of body control . The dose of MDMA positively correlated with the intensity of perceptual changes in women . Acute adverse effects and sequelae were also more frequent in female than in male subjects . In contrast , men showed higher increases in blood pressure than woman . Conclusions : The fact that equal doses of MDMA per kilogram body weight produce stronger responses in women compared to men is consistent with an increased susceptibility of women to the 5-HT-releasing effects of MDMA . Our results also indicate that increasing doses of MDMA produce more hallucinogen-like perceptual alterations , particularly in women
Thus , the current state of research does not allow for the conclusion that long-term use of MDMA affects decision-making behavior in general .
Different cognitive impairments have been reported as a result of long-term MDMA/ecstasy use .
Increased impulsivity and altered decision-making have been shown to be associated with the development and maintenance of addictive disorders pointing toward the necessity to underst and a potential impairment of decision-making due to MDMA use .
Thus , assessing the long-term effects of MDMA is crucial in order to evaluate its controversially discussed therapeutic use .
The aim of this systematic review was to summarize the scientific literature on potential effects of chronic MDMA use on higher order decision-making processes in humans .