title: Disrupted ‘reflection’ impulsivity in cannabis users but not current or former ecstasy users How could MDMA (ecstasy) help anxiety disorders? A neurobiological rationale MDMA enhances emotional empathy and prosocial behavior. Tryptophan Depletion Alters the Decision-Making of Healthy Volunteers through Altered Processing of Reward Cues Cognitive performance and serotonergic function in users of ecstasy Memory impairment in abstinent MDMA (“Ecstasy”) users: A longitudinal investigation Elevated Impulsivity and Impaired Decision-Making in Abstinent Ecstasy (MDMA) Users Compared to Polydrug and Drug-Naïve Controls Serotonin Neurotoxicity after (±)3,4-Methylenedioxymethamphetamine (MDMA; “Ecstasy”): A Controlled Study in Humans 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 Recreational Use of “Ecstasy” (MDMA) Is Associated with Elevated Impulsivity The Balloon Analogue Risk Task (BART) differentiates smokers and nonsmokers. Low-Serotonin Levels Increase Delayed Reward Discounting in Humans Behavioral and Functional Neuroimaging Evidence for Prefrontal Dysfunction in Methamphetamine-Dependent Subjects Learning, Memory, and Executive Function in New MDMA Users: A 2-Year Follow-Up Study MDMA affects both error-rate dependent and independent aspects of decision-making in a two-choice prediction task The Netherlands XTC Toxicity (NeXT) study: objectives and methods of a study investigating causality, course, and clinical relevance. Psychopathological, neuroendocrine and autonomic effects of 3,4-methylenedioxyethylamphetamine (MDE), psilocybin and d-methamphetamine in healthy volunteers
  Results of an experimental double-blind placebo-controlled study Tryptophan depletion impairs stimulus-reward learning while methylphenidate disrupts attentional control in healthy young adults: implications for the monoaminergic basis of impulsive behaviour Decision-making impairment is related to serotonin transporter promoter polymorphism in a sample of patients with obsessive–compulsive disorder Dissociable Deficits in the Decision-Making Cognition of Chronic Amphetamine Abusers, Opiate Abusers, Patients with Focal Damage to Prefrontal Cortex, and Tryptophan-Depleted Normal Volunteers: Evidence for Monoaminergic Mechanisms Cognitive function and mood in MDMA/THC users, THC users and non-drug using controls Effects of (±) 3,4-methylene–dioxymethamphetamine (ecstasy) on dopamine system function in humans Pharmacology of MDMA in humans. A prospective study of learning, memory, and executive function in new MDMA users. Mood state and brain electric activity in Ecstasy users Prospective memory, everyday cognitive failure and central executive function in recreational users of Ecstasy. Psychological and Cardiovascular Effects and Short-Term Sequelae of MDMA (“Ecstasy”) in MDMA-Naïve Healthy Volunteers A randomized, controlled pilot study of MDMA (±3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD)
abstract: 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 Exposure therapy is known to be an effective treatment for anxiety disorders . Nevertheless , exposure is not used as much as it should be , and instead patients are often given supportive medications such as serotonin reuptake inhibitors ( SSRIs ) and benzodiazepines , which may even interfere with the extinction learning that is the aim of treatment . Given that r and omized controlled trials are now investigating a few doses of ±3,4-methylenedioxymethamphetamine ( MDMA , ‘ ecstasy ’ ) in combination with psychotherapy for treatment-resistant anxiety disorders , we would like to suggest the following three mechanisms for this potentially important new approach : 1 ) MDMA  increases oxytocin levels , which may strengthen the therapeutic alliance ; 2 ) MDMA  increases ventromedial prefrontal activity and decreases amygdala activity , which may improve emotional regulation and decrease avoidance and 3 ) MDMA  increases norepinephrine release and circulating cortisol levels , which may facilitate emotional engagement and enhance extinction of learned fear associations . Thus , MDMA has a combination of pharmacological effects that , in a therapeutic setting , could provide a balance of activating emotions while feeling safe and in control , as described in case reports of MDMA-augmented psychotherapy . Further clinical and pre clinical studies of the therapeutic value of MDMA are indicated 3,4-Methylenedioxymethamphetamine ( MDMA , ' ecstasy ' ) releases serotonin and norepinephrine . MDMA is reported to produce empathogenic and prosocial feelings . It is unknown whether MDMA in fact alters empathic concern and prosocial behavior . We investigated the acute effects of MDMA using the Multifaceted Empathy Test ( MET ) , dynamic Face Emotion Recognition Task ( FERT ) and Social Value Orientation ( SVO ) test . We also assessed effects of MDMA on plasma levels of hormones involved in social behavior using a placebo-controlled , double-blind , r and om-order , cross-over design in 32 healthy volunteers ( 16 women ) .  MDMA enhanced explicit and implicit emotional empathy in the MET and increased prosocial behavior in the SVO test in men . MDMA did not alter cognitive empathy in the MET but impaired the identification of negative emotions , including fearful , angry and sad faces , in the FERT , particularly in women . MDMA increased plasma levels of cortisol and prolactin , which are markers of serotonergic and noradrenergic activity , and of oxytocin , which has been associated with prosocial behavior . In summary , MDMA sex-specifically altered the recognition of emotions , emotional empathy and prosociality . These effects likely enhance sociability when MDMA is used recreationally and may be useful when MDMA is administered in conjunction with psychotherapy in patients with social dysfunction or post-traumatic stress disorder While accumulating evidence suggests that effective real-life decision-making depends upon the functioning of the orbitofrontal cortex , much less is known about the involvement of the monoamine neurotransmitter systems and , in particular , serotonin . In the present study , we explored the impact of depleting the serotonin precursor , tryptophan , on human decision-making . Eighteen healthy volunteers consumed an amino-acid drink containing tryptophan and 18 healthy volunteers consumed an amino-acid drink without tryptophan , before choosing between simultaneously presented gambles , differing in the magnitude of expected gains ( ie reward ) , the magnitude of expected losses ( ie punishment ) , and the probabilities with which these outcomes were delivered . Volunteers also chose between gambles probing identified non-nomative biases in human decision-making , namely , risk-aversion when choosing between gains and risk-seeking when choosing between losses . Tryptophan-depleted volunteers showed reduced discrimination between magnitudes of expected gains associated with different choices . There was little evidence that tryptophan depletion was associated with altered discrimination between the magnitudes of expected losses , or altered discrimination between the relative probabilities with which these positive or negative outcomes were delivered . Risk-averse and risk-seeking biases were also unchanged . These results suggest that serotonin mediates decision-making in healthy volunteers by modulating the processing of reward cues , perhaps represented within the orbitofrontal cortex . It is possible that such a change in the cognition mediating human choice is one mechanism associated with the onset and maintenance of anhedonia and lowered mood in psychiatric illness 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 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 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 (±)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 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 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 In trying to better underst and why individuals begin and continue to smoke despite the obvious health consequences , research ers have become interested in identifying relevant personality variables , such as risk taking . In this study , the authors compared the ability of 2 behavioral measures of risk taking , the Bechara Gambling Task ( BGT ) and the Balloon Analogue Risk Task ( BART )  , to differentiate smokers and nonsmokers . Self-report measures of impulsivity and sensation seeking were taken for comparison with the 2 behavioral risk-taking tasks . Results indicate that behavior on the  BART  , and not the BGT , was related to smoking status . Further , when considered in a logistic regression analysis , only the Sensation Seeking total score and the BART score contributed uniquely to the differentiation of smokers and nonsmokers Previous animal experiments have shown that serotonin is involved in the control of impulsive choice , as characterized by high preference for small immediate rewards over larger delayed rewards . Previous human studies under serotonin manipulation , however , have been either inconclusive on the effect on impulsivity or have shown an effect in the speed of action – reward learning or the optimality of action choice . Here , we manipulated central serotonergic levels of healthy volunteers by dietary tryptophan depletion and loading . Subjects performed a “ dynamic ” delayed reward choice task that required a continuous up date of the reward value estimates to maximize total gain . By using a computational model of delayed reward choice learning , we estimated the parameters governing the subjects ' reward choices in  low- , normal , and high-serotonin conditions . We found an increase of proportion in small reward choices , together with an increase in the rate of discounting of delayed rewards in the low-serotonin condition compared with the control and high-serotonin conditions . There were no significant differences between conditions in the speed of learning of the estimated delayed reward values or in the variability of reward choice . Therefore , in line with previous animal experiments , our results show that low-serotonin levels steepen delayed reward discounting in humans . The combined results of our previous and current studies suggest that serotonin may adjust the rate of delayed reward discounting via the modulation of specific loops in parallel corticobasal ganglia circuits Stimulant-dependent subjects show dysfunctions in decision-making similar to those seen in subjects with ventromedial prefrontal cortex lesions . Studies of drug craving , reward association , and decision-making have implicated dysfunctions of the dorsolateral and orbitofrontal cortex as a key neural substrate in subjects with stimulant dependence . Here , a functional magnetic resonance imaging ( fMRI ) study was carried out to determine the relationship between decision-making dysfunction and neural activation in different prefrontal areas . This investigation tested the behavioral hypothesis that  methamphetamine-dependent subjects in early sustained remission show decision-making dysfunctions that are consistent with an increased reliance on stimulus-contingent response selection . It was hypothesized that these decision-making dysfunctions are due to differences in task-related activation in the dorsolateral and ventromedial prefrontal cortex . Ten methamphetamine-dependent subjects were compared with ten age- and education-matched controls performing a two-choice prediction task and a two-choice response task during a fMRI session .  Response bias , latency , and mutual information measures assessing the underlying strategies of the decision-making sequences were obtained . First , methamphetamine-dependent subjects were more influenced by the immediately preceding outcome during the two-choice prediction task relative to normal comparison subjects . Second , methamphetamine-dependent subjects activated less dorsolateral prefrontal cortex ( BA 9 ) and failed to activate ventromedial cortex ( BA 10,11 ) during the two-choice prediction task compared with the two-choice response task . These results support the basic hypothesis that stimulant-dependent subjects exhibit fundamental cognitive deficits during decision-making that are consistent with both orbitofrontal and dorsolateral prefrontal dysfunction 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 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 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 Abstract The aim of this study was to contribute to the characterization of the entactogen ( ecstasy ) substance group . The psychopathological , neuroendocrine and autonomic effects of common recreational doses of the entactogen 3,4-methylenedioxyethylamphetamine ( MDE ) , the hallucinogen psilocybin , the stimulant d-methamphetamine and placebo were investigated in a double-blind study with healthy volunteers ( n = 32 ) .  Psychological effects of the drugs were assessed by means of st and ardized rating scales , self assessment inventories and free descriptions . The most characteristic effects of MDE were pleasant emotional experiences of relaxation , peacefulness , content and closeness to others . However , significant stimulant and hallucinogen-like effects were also present , although the latter were weaker than the effects of psilocybin . MDE elicited the strongest endocrine and autonomic effects among the three drugs , including robust rises of serum cortisol and prolactin , elevations of blood pressure and heart rate , and a moderate , but significant rise of body temperature . The apparent contrast between psychological and autonomic effects ( subjective relaxation versus physical activation ) was a unique feature of the MDE state . Our findings are in line with both users ’ reports and results from previous experimental studies , and support the view that entactogens constitute a distinct psychoactive substance class taking an intermediate position between hallucinogens and stimulants Abstract Rationale : Altered serotonergic and dopaminergic function have been widely implicated in behavioural disorders associated with impulsivity and risk-taking . However , little research has addressed the specific cognitive consequences of changed monoaminergic function that might contribute to the production of impulsive behaviour . Objectives and methods : We compared the effects of rapid plasma tryptophan depletion , acute doses of the mixed indirect catecholamine agonist , methylpheni date ( 40 mg ) , and acute doses of the α1/α2 agonist , clonidine ( 1.5 µg/kg ) , on aspects of visual discrimination learning involving either acquisition of altered stimulus-reward associations ( i.e. updating the affective valence of exteroceptive stimuli ) or the control of attention towards relevant as opposed to irrelevant stimulus dimensions . Results : Relative to subjects who received placebo , subjects with reduced tryptophan exhibited a deficit in the ability to learn changed stimulus-reward associations , but were still able to shift an acquired attentional set away from a now-irrelevant stimulus dimension towards a newly relevant dimension . By contrast , subjects who received methylpheni date were able to learn effectively about changing stimulus-reward associations , but showed an enhanced ability to shift an attentional bias , in combination with slowed response times .  Subjects who received clonidine showed neither of these changes . Conclusions : These results suggest that reduction in central serotonin leads to altered neuromodulation of the cortical and subcortical regions ( e.g. orbitofrontal cortex , striatum and anterior temporal structures ) that mediate important aspects of associative learning whereby exteroceptive stimuli acquire altered incentive motivational value . On the other h and , facilitation of catecholamine neurotransmitters may disrupt the allocation of attention between relevant and irrelevant features of the environment , perhaps through altered modulation of the dorsolateral prefrontal cortex . The implication s of these results for underst and ing the differential neuromodulation of cognitive functions are discussed OBJECTIVE Decision-making impairment is an important feature of some psychiatric disorders , such as attention-deficit/hyperactivity disorder and substance-use disorders , and is associated with dysfunction of the fronto-subcortical circuit , mainly the orbitofrontal cortex ( OFC ) . Several data reports support significant correlations between decision-making impairment and the serotonin system . Thus , this neurotransmission system may be a major step in some cognitive features , particularly in OCD because serotonin is associated with this disorder . Therefore , the serotonin transporter promoter polymorphism ( 5-HTTLPR ) may be related to the modulation of these cognitive characteristics . In a sample of Caucasian OCD patients , we explored the link between decision-making and the 5-HTTLPR . METHOD We used the  Iowa Gambling Task ( IGT ) to measure decision-making in 49 OCD patients , according to the DSM-IV criteria . All patients were su bmi tted to Y-BOCS , BDI , BAI , the Raven Progressive Matrices , the  Continuous Performance Task  , and the Trail Making Test . We grouped S- and /or Lg-carriers in view of the fact that these act in a nearly dominant way . RESULTS On IGT , S- and /or Lg-carriers had significantly lower scores on the third , fourth , and fifth blocks . These findings were confirmed after adjusting for clinical and cognitive variables . DISCUSSION Inconclusive findings about the link between OCD and 5-HTTLPR may be better eluci date d by study ing OCD subgroups that could be more related in some genetic characteristics . Based on our study , low performance on IGT  is associated with S- and /or Lg-carriers . CONCLUSION Our results corroborate the hypothesis that the pattern of neuropsychological functioning observed in previous studies may constitute a biological marker or heritable endophenotype of OCD We used a novel computerized decision-making task to compare the decision-making behavior of chronic amphetamine abusers , chronic opiate abusers , and patients with focal lesions of orbital prefrontal cortex ( PFC ) or dorsolateral/medial PFC . We also assessed the effects of reducing central 5-hydroxytryptamine ( 5-HT ) activity using a tryptophan-depleting amino acid drink in normal volunteers . Chronic amphetamine abusers showed sub-optimal decisions ( correlated with years of abuse ) , and deliberated for significantly longer before making their choices . The opiate abusers exhibited only the second of these behavioral changes . Importantly , both sub-optimal choices and increased deliberation times were evident in the patients with damage to orbitofrontal PFC but not other sectors of PFC . Qualitatively , the performance of the subjects with lowered plasma tryptophan was similar to that associated with amphetamine abuse , consistent with recent reports of depleted 5-HT in the orbital regions of PFC of methamphetamine abusers . Overall , these data suggest that chronic amphetamine abusers show similar decision-making deficits to those seen after focal damage to orbitofrontal PFC . These deficits may reflect altered neuromodulation of the orbitofrontal PFC and interconnected limbic-striatal systems by both the ascending 5-HT and mesocortical dopamine ( DA ) projections 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 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 MDMA given at recreational doses ( range tested 50 to 150 mg ) to healthy volunteers , produced mydriasis and marked increases in systolic and diastolic blood pressure , heart rate , and pupillary diameter .  MDMA induced changes on oral temperature . The time course of this observation was biphasic , as a slight decrease at 1 h and a slight increase at 2 and 4 h were observed . MDMA induced a slight dose-dependent impairment on psychomotor performance .  MDMA produced a marked rise in plasma cortisol and prolactin concentrations . The elimination half-life of MDMA was about 8 - 9 h. Drug concentrations increased , and a parallel increase in physiologic and hormonal measures was observed . Both peak concentrations and peak effects were obtained between 1 and 2 h and decreased to baseline values 4 - 6 h after drug administration 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 Resting  EEG during open and closed eyes and subsequent mood ratings were obtained from 15 Ecstasy users and 14 Ecstasy-naive controls . Absolute spectral power on the scalp , and the three-dimensional , intracerebral distribution of neuroelectric activity using low resolution brain electromagnetic tomography ( LORETA ) were computed . LORETA revealed global increases of theta , alpha 1 and beta2/3 power during eyes open in Ecstasy users , and spectral analyses revealed a right-posterior increase of alpha2 power ( confirmed by LORETA ) and increased beta b and activity during open eyes . Ecstasy users had higher levels of state depressiveness , emotional excitability and a trend-level increase in state anxiety . The observed differences may be related to regular exposure to Ecstasy or other illicit drugs , or may be pre-existing 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 , 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 Psychiatrists and psychotherapists in the US ( 1970s to 1985 ) and Switzerl and ( 1988–1993 ) used MDMA legally as a prescription drug , to enhance the effectiveness of psychotherapy . Early reports suggest that it is useful in treating trauma-related disorders . Recently , the first completed pilot study of MDMA-assisted psychotherapy for PTSD yielded encouraging results . Design ed to test the safety and efficacy of MDMA-assisted psychotherapy in patients with treatment-resistant PTSD ; our r and omized , double-blind , active-placebo controlled trial enrolled 12 patients for treatment with either low-dose ( 25 mg , plus 12.5 mg supplemental dose ) or full-dose MDMA ( 125 mg , plus 62.5 mg supplemental dose ) .  MDMA was administered during three experimental sessions , interspersed with weekly non-drug-based psychotherapy sessions . Outcome measures used were the Clinician-Administered PTSD Scale ( CAPS ) and the Posttraumatic Diagnostic Scale ( PDS ) . Patients were assessed at baseline , three weeks after the second and third MDMA session ( end of treatment ) , and at the 2-month and 1-year follow-ups . We found that MDMA-assisted psychotherapy can be safely administered in a clinical setting . No drug-related serious adverse events occurred . We did not see statistically significant reductions in CAPS scores ( p = 0.066 ) , although there was clinical ly and statistically significant self-reported ( PDS ) improvement ( p = 0.014 ) . CAPS scores improved further at the 1-year follow-up . In addition , three MDMA sessions were more effective than two ( p = 0.016 )
target: Thus , the current state of research does not allow for the conclusion that long-term use of MDMA affects decision-making behavior in general .
background: 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 .