Cognitive performance and serotonergic function in users of ecstasy Cerebral activation in abstinent ecstasy (MDMA) users during a working memory task: a functional magnetic resonance imaging (fMRI) study. Serotonin Neurotoxicity after (±)3,4-Methylenedioxymethamphetamine (MDMA; “Ecstasy”): A Controlled Study in Humans Neural correlates of working memory in pure and polyvalent ecstasy (MDMA) users Psychological and Cardiovascular Effects and Short-Term Sequelae of MDMA (“Ecstasy”) in MDMA-Naïve Healthy Volunteers Memory impairment in abstinent MDMA (“Ecstasy”) users: A longitudinal investigation MDMA affects both error-rate dependent and independent aspects of decision-making in a two-choice prediction task 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 Mood disorders and serotonin transporter density in ecstasy users—the influence of long-term abstention, dose, and gender The safety and efficacy of ±3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study Gender differences in the subjective effects of MDMA The Netherlands XTC Toxicity (NeXT) study: objectives and methods of a study investigating causality, course, and clinical relevance. Learning, Memory, and Executive Function in New MDMA Users: A 2-Year Follow-Up Study Thermoregulatory effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans Effects of (±) 3,4-methylene–dioxymethamphetamine (ecstasy) on dopamine system function in humans
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 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 (±)3,4-Methylenedioxymethamphetamine ( MDMA ; “ Ecstasy ” ) , an increasingly popular recreational drug , is known to damage brain serotonin 5-hydroxytryptamine ( 5-HT ) neurons in experimental animals . Whether MDMA is neurotoxic in humans has not been established . Thirty MDMA users and 28 controls were admitted to a controlled inpatient setting for measurement of biologic and behavioral indexes of central 5-HT function . Outcome measures obtained after at least 2 weeks of drug abstinence included concentrations of monoamine metabolites in cerebrospinal fluid ( CSF ) , prolactin responses to L-tryptophan , nociceptive responses to ischemic pain , and personality characteristics in which 5-HT has been implicated ( i.e. , impulsivity and aggression ) . Subjects with a history of MDMA exposure had lower levels of CSF 5-hydroxyindoleacetic acid ( the major metabolite of 5-HT ) than controls ( p = .002 ) . Although they resembled controls in their prolactin response to L-tryptophan and their response to ischemic pain ,  MDMA  users had lower scores on personality measures of impulsivity ( p = . 004 ) and indirect hostility ( p = .009 ) . The CSF findings suggest that 5-HT neurotoxicity may be a potential complication of MDMA use . Further , differences in personality support the view that 5-HT systems are involved in modulating impulsive and aggressive personality traits . Additional studies of  MDMA-exposed individuals are needed to confirm and extend the present findings . Such studies could help eluci date the role of 5-HT in normal brain function as well as in neuropsychiatric disease states 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 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 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 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 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 Rationale Neurotoxic effects of 3,4-methylenedioxymethamphetamine ( MDMA , “ ecstasy ” ) on the serotonin ( 5-HT ) system have been described in animals and humans , but little is known about long-term effects of ecstasy use on mood . Objectives To investigate short-term and long-term effects of ecstasy use on mood and its association with 5-HT neurotoxicity , dose , and gender in humans . Methods Fifteen moderate ecstasy users , 23 heavy ecstasy users , 16 former heavy ecstasy users and 15 drug-using , but ecstasy-naive controls were included .  Mood was assessed using the Composite International Diagnostic Interview ( CIDI ) and the Beck Depression Inventory ( BDI ) . Outcomes were correlated with 5-HT transporter ( SERT ) density , assessed with [123I]β-CIT single photon emission computed tomography ( SPECT ) . Results The prevalence of mood disorders assessed by CIDI did not differ between all groups . The overall test for differences in BDI scores between groups was near significance ( P=0.056 ) , with BDI scores higher in former heavy ecstasy users than in ecstasy-naive controls ( P=0.045 ) . BDI scores were correlated with the total number of ecstasy tablets used ( r=0.310 ; P=0.021 ) . No associations between CIDI or BDI outcomes and SERT density or gender were observed . Conclusions These results suggest that ecstasy use is not associated with clinical depression ( CIDI ) . However , the number of ecstasy tablets taken lifetime was associated with higher BDI scores for depressive mood , and this relationship seemed to persist after ecstasy use had stopped . We did not find that depressed mood in ecstasy users was associated with decrease in SERT density . Prospect i ve studies are needed to establish the causal relationship between ecstasy use and depressed mood Case reports indicate that psychiatrists administered ±3,4-methylenedioxymethamphetamine ( MDMA ) as a catalyst to psychotherapy before recreational use of MDMA as ‘ Ecstasy ’ result ed in its criminalization in 1985 . Over two decades later , this study is the first completed clinical trial evaluating MDMA as a therapeutic adjunct . Twenty patients with chronic posttraumatic stress disorder , refractory to both psychotherapy and psychopharmacology , were r and omly assigned to psychotherapy with concomitant active drug ( n = 12 ) or inactive placebo ( n = 8) administered during two 8-h experimental psychotherapy sessions . Both groups received preparatory and follow-up non-drug psychotherapy . The primary outcome measure was the Clinician-Administered PTSD Scale , administered at baseline , 4 days after each experimental session , and 2 months after the second session . Neurocognitive testing , blood pressure , and temperature monitoring were performed . After 2-month follow-up , placebo subjects were offered the option to re-enroll in the experimental procedure with open-label MDMA .  Decrease in Clinician-Administered PTSD Scale scores from baseline was significantly greater for the group that received MDMA than for the placebo group at all three time points after baseline . The rate of clinical response was 10/12 ( 83 % ) in the active treatment group versus 2/8 ( 25 % ) in the placebo group . There were no drug-related serious adverse events , adverse neurocognitive effects or clinical ly significant blood pressure increases . MDMA-assisted psychotherapy can be administered to posttraumatic stress disorder patients without evidence of harm , and it may be useful in patients refractory to other treatments 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 This paper describes the objectives and methods of The Netherl and s XTC Toxicity ( NeXT ) study focussing on the causality , course , and clinical relevance of ecstasy neurotoxicity . Previous studies suggest that ecstasy ( 3,4 methylene-dioxymethamphetamine , MDMA , XTC ) is toxic toward brain serotonin axons , but most of these studies have serious method ological limitations . The current study is a combination of different approaches with three sub studies : ( 1 ) a crosssectional sub study among heavy ecstasy users and controls with variation in drug use , which will provide information about potential neurotoxic consequences of ecstasy in relation to other drugs ; ( 2 ) a prospect i ve cohort sub study in ecstasy-naive subjects with high risk for future ecstasy use , which will provide information on the causality and short-term course of ecstasy use and potential neurotoxicity , and ( 3 ) a retrospective cohort sub study in lifetime ecstasy users and matched controls of an existing epidemiological sample that will provide information on long-term course and outcome of ecstasy use in the general population . Neurotoxicity is studied using ( a ) different imaging techniques ( beta-CIT SPECT , 1H-MR spectroscopy , diffusion tensor imaging , perfusion weighted imaging and functional magnetic resonance imaging ) , and ( b ) neuropsychological and psychiatric assessment s of memory , depression , and personality . The combined results will lead to conclusions that can be used in prevention messages , clinical decision making , and the development of an (inter)national ecstasy policy 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 Rationale Although 3,4-methylenedioxymethamphetamine ( MDMA ; Ecstasy ) has been reported to cause fatal hyperthermia , few studies of the effects of MDMA on core body temperature in humans have been conducted demonstrating increased body temperature . In rats , MDMA causes hyperthermia at warm ambient temperatures but hypothermia at cold ones . Objectives In this study , the physiological and subjective effects of MDMA in humans were determined at cold ( 18 ° C ) and warm ( 30 ° C ) ambient temperatures in a temperature and humidity-controlled laboratory . Methods Ten healthy volunteers who were recreational users of MDMA were recruited . Four laboratory sessions were conducted in a 2 × 2 design [ i.e. , two sessions at 30 ° C and two at 18 ° C , two during MDMA ( 2 mg/kg , p.o . ) and two during placebo , in double-blind fashion ] . Core body temperature ( ingested radiotelemetry pill ) , skin temperature ( four weighted sites ) , heart rate , blood pressure , metabolic rate ( indirect calorimetry ) , shivering ( electromyogram levels ) , and sweat rate ( capacitance hygrometry ) were measured as well as subjective effects for several time periods following capsule ingestion . Results MDMA produced significant elevations in core body temperature and metabolic rate in both warm and cold conditions . MDMA also produced significant elevations in blood pressure and heart rate and significantly increased several ratings of subjective effects similar to those previously reported . There were no differences related to ambient temperature for any of the subjective effects , except that ratings of cold and warm were appropriate to the ambient temperature and were not influenced by MDMA . Conclusions Unlike findings in rats , MDMA  increased core body temperature regardless of ambient temperature in humans . These increases appeared related to increases in metabolic rate , which were substantial . These findings warrant further investigations on the role of MDMA and other stimulants in altering metabolism and thermogenesis Twelve ( + /- ) 3,4-methylenedioxymethamphetamine ( MDMA ) users , who did not show other drug dependencies or prolonged alcohol abuse ( group A ) , and 12 control subjects ( group B ) were included in the study . Prolactin ( PRL ) and growth hormone ( GH ) responses to the dopaminergic agonist bromocriptine ( BROM ) and psychometric measures were evaluated 3 weeks after MDMA discontinuation . PRL decreased both in A and B subjects after BROM suppression , without any significant difference between the two groups . PRL responses to BROM in MDMA users were in the normal range . In contrast , GH responses to BROM stimulation were found significantly reduced in ecstasy users , in comparison with control subjects ( P < 0.001 ; F = 6.26 ) .  MDMA users showed higher scores on the Novelty Seeking ( NS ) scale at the Three dimensional Personality Question naire ( TPQ ) , on direct aggressiveness subscale at Buss Durkee Hostility Inventory ( BDHI ) , on subscale D ( depression ) at Minnesota Multiphasic Personality Inventory ( MMPI 2 ) and on Hamilton Depression Rating Scale ( HDRS ) than control subjects . PRL areas under the curves ( AUCs ) showed a significant inverse correlation with NS scores both in A and B subjects . GH AUCs directly correlated with NS scores in healthy subjects , but not in MDMA users . No other psychometric measure correlated with hormonal responses . GH AUCs were inversely correlated with the measures of MDMA exposure ( r = -0.48 ; P < 0.01 ) . Lower GH response to BROM in A subjects ( MDMA users ) could reflect reduced D2 receptor sensitivity in the hypothalamus , possibly due to increased intrasynaptic dopamine concentration . Although the hypothesis of dopaminergic changes associated with a premorbid condition can not be completely excluded , the inverse correlation between DA receptors sensitivity and the extent of ecstasy exposure may suggest a direct pharmacological action of MDMA on brain dopamine function in humans
There is no convincing evidence that moderate MDMA use is associated with structural or functional brain alterations in neuroimaging measures .
MDMA ( " ecstasy " ) is widely used as a recreational drug , although there has been some debate about its neurotoxic effects in humans .
However , most studies have investigated subjects with heavy use patterns , and the effects of transient MDMA use are unclear .
In this review , we therefore focus on subjects with moderate use patterns , in order to assess the evidence for harmful effects .