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1.  Disrupted ‘reflection’ impulsivity in cannabis users but not current or former ecstasy users 
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 questionnaire, 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 sampled 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.
doi:10.1177/0269881108089587
PMCID: PMC2637477  PMID: 18515464
addiction; cannabis; decision-making; inhibition; MDMA
2.  The effect of polymorphism at the serotonin transporter gene on decision-making, memory and executive function in ecstasy users and controls 
Psychopharmacology  2006;188(2):213-227.
Rationale
3, 4-Methylenedioxymethamphetamine (MDMA or “ecstasy”) is a popular drug of abuse known to result in depletions of the serotonin (5-HT) system. A number of studies have reported that ecstasy users differ from controls on a variety of measures of cognitive function. However, the literature is not consistent and many negative findings were also reported. One reason for such inconsistency might be interindividual variance in vulnerability to the deleterious effects of ecstasy due to a number of factors, both genetic and environmental.
Objectives
To investigate the hypothesis that carriers of the s allele at the 5-HT transporter gene-linked polymorphic region (5-HTTLPR), which was associated with reduced serotonergic neurotransmission relative to the l allele, would be most vulnerable to the effects of ecstasy on cognitive function.
Methods
We assessed memory, decision-making, and executive function in ecstasy users and controls, stratifying by genotype at the 5-HTTLPR.
Results
We observed that the 5-HTTLPR genotype groups differed on a number of measures in both the ecstasy users and the controls. While performing a risky decision-making task, ss and ls controls attended to differences in the probability of winning chosen gambles to a greater extent than the ll controls. However, this difference was dramatically attenuated in the ss ecstasy users. Furthermore, independent of ecstasy use, volunteers of the ss genotype outperformed the ll genotype on a visual planning task.
Conclusions
The results are consistent with the hypothesis that cognitive impairment in ecstasy users may depend on genetic variation at the 5-HTTLPR.
doi:10.1007/s00213-006-0495-z
PMCID: PMC2585286  PMID: 16941121
Ecstasy (MDMA); Decision-making; Serotonin transporter-linked polymorphic region (5-HTTLPR); Neuropsychology; Memory; Executive function
3.  Ecstasy Exposure & Gender: Examining Components of Verbal Memory Functioning 
PLoS ONE  2014;9(12):e115645.
Objective
Studies have demonstrated verbal memory deficits associated with past year ecstasy use, although specific underlying components of these deficits are less understood. Further, prior research suggests potential gender differences in ecstasy-induced serotonergic changes. Therefore, the current study investigated whether gender moderated the relationship between ecstasy exposure and components of verbal memory after controlling for polydrug use and confounding variables.
Method
Data were collected from 65 polydrug users with a wide range of ecstasy exposure (ages 18–35; 48 ecstasy and 17 marijuana users; 0–2310 ecstasy tablets). Participants completed a verbal learning and memory task, psychological questionnaires, and a drug use interview.
Results
Increased past year ecstasy exposure predicted poorer short and long delayed free and cued recalls, retention, and recall discrimination. Male ecstasy users were more susceptible to dose-dependent deficits in retention than female users.
Conclusion
Past year ecstasy consumption was associated with verbal memory retrieval, retention, and discrimination deficits in a dose-dependent manner in a sample of healthy young adult polydrug users. Male ecstasy users were at particular risk for deficits in retention following a long delay. Gender difference may be reflective of different patterns of polydrug use as well as increased hippocampal sensitivity. Future research examining neuronal correlates of verbal memory deficits in ecstasy users are needed.
doi:10.1371/journal.pone.0115645
PMCID: PMC4278706  PMID: 25545890
4.  Reward-Related Decision-Making Deficits and Elevated Impulsivity Among MDMA and Other Drug Users 
Drug and alcohol dependence  2008;96(1-2):99-110.
Background
The recreational drug, MDMA (3,4-methylenedioxymethamphetamine; ‘Ecstasy’), is a synthetic amphetamine derivative and a serotonin neurotoxin. MDMA use is associated with cognitive dysfunction and impulsivity, but since polydrug abuse is common among users it is difficult to attribute these problems specifically to MDMA. Moreover, few studies have examined reward-related cognitive processes. Our aim was to examine reward-related decision-making and impulsivity among MDMA users while controlling for polydrug use via appropriate comparison groups.
Methods
We examined decision-making (Iowa Gambling Task; IGT; Bechara et al., 1994), self-reported impulsivity (Multidimensional Personality Questionnaire – Brief Form [Constraint subscale]; Barratt Impulsiveness Scale; Zuckerman Sensation Seeking Scale), and drug use among 22 abstinent MDMA users, 30 other drug users, and 29 healthy non-drug controls.
Results
MDMA and other drug users showed comparable patterns of decision-making and impulsivity. However, both drug groups demonstrated poorer IGT performance and elevated self-reported impulsivity relative to controls. Poorer decision-making was related to heavier drug use in the past year, heavier weekly alcohol use, and meeting lifetime substance use disorder (SUD) criteria for more drug classes. Elevated impulsivity was associated with heavier drug use, heavier weekly alcohol use, more lifetime SUDs, and higher self-reported depression levels.
Conclusions
These findings contradict the idea that MDMA is specifically associated with deficient decision-making. Drug users, in general, may be at risk for decision-making deficits and elevated impulsivity. Such behaviors may represent trait factors that lead to the initiation of drug and alcohol use, and/or they may represent behavior patterns that are exacerbated by extensive use.
doi:10.1016/j.drugalcdep.2008.02.003
PMCID: PMC2492887  PMID: 18384979
MDMA; drug use; alcohol use; executive functions; decision-making; impulsivity
5.  3,4-methylenedioxymethamphetamine (MDMA): current perspectives 
Ecstasy is a widely used recreational drug that usually consists primarily of 3,4-methylenedioxymethamphetamine (MDMA). Most ecstasy users consume other substances as well, which complicates the interpretation of research in this field. The positively rated effects of MDMA consumption include euphoria, arousal, enhanced mood, increased sociability, and heightened perceptions; some common adverse reactions are nausea, headache, tachycardia, bruxism, and trismus. Lowering of mood is an aftereffect that is sometimes reported from 2 to 5 days after a session of ecstasy use. The acute effects of MDMA in ecstasy users have been attributed primarily to increased release and inhibited reuptake of serotonin (5-HT) and norepinephrine, along with possible release of the neuropeptide oxytocin. Repeated or high-dose MDMA/ecstasy use has been associated with tolerance, depressive symptomatology, and persisting cognitive deficits, particularly in memory tests. Animal studies have demonstrated that high doses of MDMA can lead to long-term decreases in forebrain 5-HT concentrations, tryptophan hydroxylase activity, serotonin transporter (SERT) expression, and visualization of axons immunoreactive for 5-HT or SERT. These neurotoxic effects may reflect either a drug-induced degeneration of serotonergic fibers or a long-lasting downregulation in 5-HT and SERT biosynthesis. Possible neurotoxicity in heavy ecstasy users has been revealed by neuroimaging studies showing reduced SERT binding and increased 5-HT2A receptor binding in several cortical and/or subcortical areas. MDMA overdose or use with certain other drugs can also cause severe morbidity and even death. Repeated use of MDMA may lead to dose escalation and the development of dependence, although such dependence is usually not as profound as is seen with many other drugs of abuse. MDMA/ecstasy-dependent patients are treated with standard addiction programs, since there are no specific programs for this substance and no proven medications. Finally, even though MDMA is listed as a Schedule I compound by the Drug Enforcement Agency, MDMA-assisted psychotherapy for patients with chronic, treatment-resistant posttraumatic stress disorder is currently under investigation. Initial results show efficacy for this treatment approach, although considerably more research must be performed to confirm such efficacy and to ensure that the benefits of MDMA-assisted therapy outweigh the risks to the patients.
doi:10.2147/SAR.S37258
PMCID: PMC3931692  PMID: 24648791
MDMA; ecstasy; mood; cognition; neurotoxicity; dependence; PTSD
6.  Impaired cognitive performance in drug free users of recreational ecstasy (MDMA) 
OBJECTIVES—Ecstasy (3,4-methylenedioxymethamphetamine (MDMA) and related congerers: MDA, MDEA) is the name given to a group of popular recreational drugs. Animal data raise concern about neurotoxic effects of high doses of ecstasy on central serotonergic systems. The threshold dose for neurotoxicity in humans is not clear and serotonin is involved in several functions including cognition. The purpose of this study was to investigate cognitive performance in a group of typical recreational ecstasy users.
METHODS—A comprehensive cognitive test battery was administered to 28 abstinent ecstasy users with concomitant use of cannabis only and to two equally sized matched groups of cannabis users and non-users. The sample consisted of ecstasy users with a typical recreational use pattern and did not include very heavy users.
RESULTS—Ecstasy users were unimpaired in simple tests of attention (alertness). However, they performed worse than one or both control groups in the more complex tests of attention, in memory and learning tasks, and in tasks reflecting aspects of general intelligence. Heavier ecstasy and heavier cannabis use were associated with poorer performance in the group of ecstasy users. By contrast, the cannabis users did not differ significantly in their performance from the non-users.
CONCLUSIONS—The present data raise concern that use of ecstasy possibly in conjunction with cannabis may lead to cognitive decline in otherwise healthy young people. Although the nature of the emerging cognitive disturbance is not yet clear, an impairment of working memory might be the common denominator underlying or contributing to declines of performance in various tasks. The cognitive disturbance is likely to be related to the well recognised neurotoxic potential of ecstasy. The data suggest that even typical recreational doses of ecstasy are sufficient to cause neurotoxicity in humans.


doi:10.1136/jnnp.68.6.719
PMCID: PMC1736948  PMID: 10811694
7.  Modifiable risk factors of ecstasy use: risk perception, current dependence, perceived control, and depression 
Addictive behaviors  2009;35(3):201.
Risk perception, perceived behavioral control of obtaining ecstasy (PBC-obtaining), current ecstasy dependence, and recent depression have been associated with past ecstasy use, however, their utility in predicting ecstasy use has not been demonstrated. This study aimed to determine whether these four modifiable risk factors could predict ecstasy use after controlling for socio-demographic covariates and recent polydrug use. Data from 601 ecstasy users in the National Institute on Drug Abuse funded TriCity Study of Club Drug Use, Abuse and Dependence were analyzed using multivariate logistic regression. Participants were interviewed twice within a 2-week period using standardized instruments. Thirteen percent (n=80) of the participants reported using ecstasy between the two interviews. Low risk perception, high PBC-obtaining (an estimated ecstasy procurement time < 24 hours), and current ecstasy dependence were statistically associated with ecstasy use between the two interviews. Recent depression was not a significant predictor. Despite not being a target predictor, recent polydrug use was also statistically associated with ecstasy use. The present findings may inform the development of interventions targeting ecstasy users.
doi:10.1016/j.addbeh.2009.10.003
PMCID: PMC2815072  PMID: 19880258
Ecstasy; MDMA; “Risk perception”; dependence; “perceived control”; depression
8.  Prospective Memory Deficits in Ecstasy Users: Effects of Longer Ongoing Task Delay Interval 
Ecstasy use has been associated with neurotoxicity and neurocognitive impairment in a variety of domains, including prospective memory (ProM), which involves the delayed execution of a previously encoded intention in response to a specific cue. The present study adopted the multiprocess theory of ProM to evaluate the hypothesis that ecstasy users would evidence differentially impaired ProM on longer versus shorter ongoing task delays. Ecstasy (n = 31) users, high-risk alcohol users (n = 21) and healthy nonusers (n = 31) completed the short (2-min) and long (15-min) delay ProM scales of the Memory for Intentions Screening Test. Results showed a significant group by ProM delay interaction, such that ecstasy users performed comparably to the comparison groups on short-delay trials, but were impaired on long-delay ProM, particularly for time-based cues. Among the ecstasy users, long-delay ProM was positively associated with risky decision-making, but not with retrospective memory or other aspects of executive functions. These findings suggest that ecstasy users may be particularly susceptible to deficits in strategic target monitoring and maintenance of cue-intention pairings over longer ProM delays. Findings are discussed in the context of their potential everyday functioning (e.g., academic, vocational) and treatment implications for ecstasy users.
doi:10.1080/13803395.2011.614595
PMCID: PMC3229681  PMID: 22047194
Prospective memory; ecstasy; substance abuse; episodic memory; executive functions; time perception; cognition
9.  Decreased cerebral cortical serotonin transporter binding in ecstasy users: a positron emission tomography/[11C]DASB and structural brain imaging study 
Brain  2010;133(6):1779-1797.
Animal data indicate that the recreational drug ecstasy (3,4-methylenedioxymethamphetamine) can damage brain serotonin neurons. However, human neuroimaging measurements of serotonin transporter binding, a serotonin neuron marker, remain contradictory, especially regarding brain areas affected; and the possibility that structural brain differences might account for serotonin transporter binding changes has not been explored. We measured brain serotonin transporter binding using [11C] N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine in 50 control subjects and in 49 chronic (mean 4 years) ecstasy users (typically one to two tablets bi-monthly) withdrawn from the drug (mean 45 days). A magnetic resonance image for positron emission tomography image co-registration and structural analyses was acquired. Hair toxicology confirmed group allocation but also indicated use of other psychoactive drugs in most users. Serotonin transporter binding in ecstasy users was significantly decreased throughout all cerebral cortices (range –19 to –46%) and hippocampus (–21%) and related to the extent of drug use (years, maximum dose), but was normal in basal ganglia and midbrain. Substantial overlap was observed between control and user values except for insular cortex, in which 51% of ecstasy user values fell below the lower limit of the control range. Voxel-based analyses confirmed a caudorostral gradient of cortical serotonin transporter binding loss with occipital cortex most severely affected. Magnetic resonance image measurement revealed no overall regional volume differences between groups; however, a slight left-hemispheric biased cortical thinning was detected in methamphetamine-using ecstasy users. The serotonin transporter binding loss was not related to structural changes or partial volume effect, use of other stimulant drugs, blood testosterone or oestradiol levels, major serotonin transporter gene promoter polymorphisms, gender, psychiatric status, or self-reported hyperthermia or tolerance. The ecstasy group, although ‘grossly behaviourally normal’, reported subnormal mood and demonstrated generally modest deficits on some tests of attention, executive function and memory, with the latter associated with serotonin transporter decrease. Our findings suggest that the ‘typical’/low dose (one to two tablets/session) chronic ecstasy-polydrug user might display a highly selective mild to marked loss of serotonin transporter in cerebral cortex/hippocampus in the range of that observed in Parkinson’s disease, which is not gender-specific or completely accounted for by structural brain changes, recent use of other drugs (as assessed by hair analyses) or other potential confounds that we could address. The striking sparing of serotonin transporter-rich striatum (although possibly affected in ‘heavier’ users) suggests that serotonergic neurons innervating cerebral cortex are more susceptible, for unknown reasons, to ecstasy than those innervating subcortical regions and that behavioural problems in some ecstasy users during abstinence might be related to serotonin transporter changes limited to cortical regions.
doi:10.1093/brain/awq103
PMCID: PMC2912692  PMID: 20483717
MDMA; ecstasy; PET; serotonin transporter; methamphetamine; cortical thickness
10.  Neuropsychological function in ecstasy users: a study controlling for polydrug use 
Psychopharmacology  2005;189(4):505-516.
Rationale
A number of studies have compared ecstasy users to control groups on various measures of neuropsychological function in order to determine whether ecstasy use results in lasting cognitive deficits. However, few of those studies controlled adequately for non-ecstasy illicit drug use.
Objective
The aim of this study was to investigate neuropsychological function in chronic ecstasy users while controlling for polydrug use.
Methods
Neuropsychological function was assessed in four groups—30 current 3,4-methylenedioxymethamphetamine (MDMA) users with a little history of illicit drug use other than ecstasy and cannabis, 30 polydrug controls, 30 drug-naïve controls and 20 ex-MDMA users—using a battery of well-validated, computerized neuropsychological tests. The battery focused on memory, executive function, impulsivity and risk-taking.
Results
Few differences were apparent between the groups, and on no measure were the current MDMA users impaired significantly relative to the polydrug controls. However, within the current MDMA users, questionnaire-measured impulsivity correlated with performance on a number of tests—a relationship that was not apparent in the controls.
Conclusions
These data highlight the complexity in understanding the current ecstasy literature and suggest that some individuals may be particularly vulnerable to cognitive impairment following chronic use. Although no differences were identified between the current MDMA users and the controls, trait impulsiveness was significantly correlated with impairment on a number of neuropsychological outcome measures in the MDMA users, but not in the controls. These data suggest that impulsive individuals may be those most at risk for the development of cognitive impairment following chronic ecstasy use.
doi:10.1007/s00213-005-0101-9
PMCID: PMC2653936  PMID: 16163532
3,4-Methylenedioxymethamphetamine (MDMA); Ecstasy; Neuropsychology; Polydrug use; Executive function; Memory; Decision-making; Risk-taking; Impulsivity
11.  Persistent Nigrostriatal Dopaminergic Abnormalities in Ex-Users of MDMA (‘Ecstasy'): An 18F-Dopa PET Study 
Neuropsychopharmacology  2010;36(4):735-743.
Ecstasy (±3,4-methylenedioxymethamphetamine, MDMA) is a popular recreational drug with known serotonergic neurotoxicity. Its long-term effects on dopaminergic function are less certain. Studying the long-term effects of ecstasy is often confounded by concomitant polydrug use and the short duration of abstinence. We used 18F-dopa positron emission tomography (PET) to investigate the long-term effects of ecstasy on nigrostriatal dopaminergic function in a group of male ex-recreational users of ecstasy who had been abstinent for a mean of 3.22 years. We studied 14 ex-ecstasy users (EEs), 14 polydrug-using controls (PCs) (matched to the ex-users for other recreational drug use), and 12 drug-naive controls (DCs). Each participant underwent one 18F-dopa PET, cognitive assessments, and hair and urinary analyses to corroborate drug-use history. The putamen 18F-dopa uptake of EEs was 9% higher than that of DCs (p=0.021). The putamen uptake rate of PCs fell between the other two groups, suggesting that the hyperdopaminergic state in EEs may be due to the combined effects of ecstasy and polydrug use. There was no relationship between the amount of ecstasy used and striatal 18F-dopa uptake. Increased putaminal 18F-dopa uptake in EEs after an abstinence of >3 years (mean) suggests that the effects are long lasting. Our findings suggest potential long-term effects of ecstasy use, in conjunction with other recreational drugs, on nigrostriatal dopaminergic functions. Further longitudinal studies are required to elucidate the significance of these findings as they may have important public health implications.
doi:10.1038/npp.2010.201
PMCID: PMC3037848  PMID: 21160467
MDMA; ecstasy; addiction; dopamine; F-dopa; PET; addiction & substance abuse; dopamine; imaging, clinical or preclinical; psychopharmacology; ecstasy
12.  Residual Neurocognitive Features of Long-Term Ecstasy Users With Minimal Exposure to Other Drugs 
Addiction (Abingdon, England)  2011;106(4):777-786.
Aims
In field studies assessing cognitive function in illicit ecstasy users, there are several frequent confounding factors that might plausibly bias the findings toward an overestimate of ecstasy-induced neurocognitive toxicity. We designed an investigation seeking to minimize these possible sources of bias.
Design
We compared illicit ecstasy users and non-users while 1) excluding individuals with significant lifetime exposure to other illicit drugs or alcohol; 2) requiring that all participants be members of the “rave” subculture; and 3) testing all participants with breath, urine, and hair samples at the time of evaluation to exclude possible surreptitious substance use. We compared groups with adjustment for age, gender, race/ethnicity, family-of-origin variables, and childhood history of conduct disorder and attention deficit hyperactivity disorder. We provide significance levels without correction for multiple comparisons.
Setting
Field study.
Participants
Fifty-two illicit ecstasy users and 59 non-users, age 18-45.
Measurements
Battery of 15 neuropsychological tests tapping a range of cognitive functions.
Findings
We found little evidence of decreased cognitive performance in ecstasy users, save for poorer strategic-self-regulation, possibly reflecting increased impulsivity. However this finding might have reflected a premorbid attribute of ecstasy users, rather than a residual neurotoxic effect of the drug.
Conclusions
In a study designed to minimize limitations found in many prior investigations, we failed to demonstrate marked residual cognitive effects in ecstasy users. This finding contrasts with many previous findings—including our own—and emphasizes the need for continued caution in interpreting field studies of cognitive function in illicit ecstasy users.
doi:10.1111/j.1360-0443.2010.03252.x
PMCID: PMC3053129  PMID: 21205042
ecstasy; MDMA; substance abuse; cognitive function; neurotoxicity
13.  Understanding recreational ecstasy use in the United States: A qualitative inquiry 
Background
Ecstasy use has increasingly become popular among young adults, many of whom view it as a safe drug with no or limited negative social and health consequences. In this paper, we explore the perceptions of ecstasy users about its recreational use as well as regarding the normalization of use.
Methods
The study participants were recruited using targeted and theoretical sampling. To be eligible, they had to be between 18 and 25 years and have used ecstasy at least four times within the past 90 days. In-depth interviews were conducted with 112 individuals. Data analysis included the constant comparison method commonly used in modified grounded theory.
Results
The study participants associated their recreational ecstasy use with control, shaping both the timing and setting of their use. In addition, they supported that easy access/availability and social accommodations of use contributed to their acceptance of ecstasy use as a normal part of life. Moreover, low risk perceptions of the social and health consequences of ecstasy used were identified as resulting in normalization.
Conclusion
The study findings reveal the importance of considering recreational ecstasy use from the perspective of the users themselves for prevention efforts and when providing social and health services, including intervention strategies. In addition, the potential normalization of ecstasy use must be considered.
doi:10.1016/j.drugpo.2007.10.003
PMCID: PMC2630386  PMID: 18068967
ecstasy; young adults; recreational drug use
14.  Association of a Functional Polymorphism in the Serotonin Transporter Gene With Abnormal Emotional Processing in Ecstasy Users 
The American journal of psychiatry  2005;162(3):609-612.
Objective
The long-term effects of the use of 3,4-methylenedioxymethamphetamine (MDMA, or Ecstasy) in humans are controversial and unclear. The authors’ goal was to assess the contribution of a functional polymorphism in the gene encoding serotonin transporter to changes in emotional processing following chronic Ecstasy use.
Method
They investigated Beck Depression Inventory scores and performance on the Affective Go/No-Go test, a computerized neuropsychological test sensitive to emotional processing, in Ecstasy users and comparison subjects, stratifying the results by serotonin transporter genotype.
Results
Ecstasy use was associated with higher Beck Depression Inventory score and abnormalities in the Affective Go/No-Go test in individuals with the ss and ls genotype but not those with the ll genotype.
Conclusions
Ecstasy users carrying the s allele, but not comparison subjects carrying the s allele, showed abnormal emotional processing. On the basis of a comparison with acute tryptophan depletion, the authors hypothesize that chronic Ecstasy use may cause long-term changes to the serotonin system, and that Ecstasy users carrying the s allele may be at particular risk for emotional dysfunction.
doi:10.1176/appi.ajp.162.3.609
PMCID: PMC2631647  PMID: 15741482
15.  Tri-city Study of Ecstasy Use Problems: A Latent Class Analysis 
Drug and alcohol dependence  2008;98(3):249-263.
This study used latent class analysis to examine distinctive subtypes of Ecstasy users based on 24 abuse and dependence symptoms underlying standard DSM-IV criteria. Data came from a three-site, population-based, epidemiological study to examine diagnostic nosology for Ecstasy use. Subject inclusion criteria included lifetime Ecstasy use exceeding five times and once in the past year, with participants ranging in age between 16 to 47 years of age from St. Louis, Miami, U.S. and Sydney, Australia. A satisfactory model typified four latent classes representing clearly differentiated diagnostic clusters including: (1) A group of sub-threshold users endorsing few abuse and dependence symptom (negatives), (2) A group of ‘diagnostic orphans’ who had characteristic features of dependence for a select group of symptoms (mild dependent), (3) a ‘transitional group’ mimicking the orphans with regard to their profile of dependence also but reporting some abuse symptoms (moderate dependent), and (4) a ‘severe dependent’ group with a distinct profile of abuse and dependence symptoms. A multinomial logistic regression model indicated that certain latent classes showed unique associations with external non-diagnostic markers. Controlling for demographic characteristics and lifetime quantity of Ecstasy pill use, criminal behavior and motivational cues for Ecstasy use were the most efficient predictors of cluster membership. This study reinforces the heuristic utility of DSM-IV criteria applied to Ecstasy but with a different collage of symptoms that produced four distinct classes of Ecstasy users.
doi:10.1016/j.drugalcdep.2008.06.008
PMCID: PMC2630416  PMID: 18674872
Ecstasy; substance use disorders; abuse; dependence; latent class analysis
16.  An In-Depth Qualitative Examination of the Ecstasy Experience: Results of a Focus Group with Ecstasy-Using College Students 
Substance use & misuse  2005;40(9-10):1427-1441.
This study examined ecstasy use in 30 college students who participated in one of four 60-minute focus groups with other participants who also had a history of ecstasy use. Ten topics emerged in the sessions: 1) pill ingredients, 2) mechanism of MDMA effects, 3) reasons for initiating ecstasy use, 4) risky behaviors and ecstasy use, 5) sexual activity and ecstasy, 6) positive effects from ecstasy use, 7) negative effects related to ecstasy use, 8) ecstasy and polysubstance use, 9) perceived risks of ecstasy use, and 10) motivational factors related to quitting ecstasy use. Most participants had a basic understanding of the contents of ecstasy pills, and the effects that ecstasy has on the brain and bodily functions. Participants reported positive effects on mood, social pressure, curiosity, availability, boredom, desire for an altered state of mind, desire to escape, self-medication, desire to have fun, and the ease of use of ecstasy in comparison to other drugs as reasons for initiating ecstasy use. They were divided regarding whether ecstasy increased the likelihood of engaging in risky behaviors, including risky sexual behavior. Participants described their experiences of both the positive and negative effects (physical and psychological) that they attributed to their use of ecstasy. All participants were polysubstance users, consuming a number of other substances simultaneously and concurrently with ecstasy. The majority was unaware of specific types of problems ecstasy could potentially cause and discounted its potential harm. Participants varied in their motivation for quitting ecstasy use, including negative personal experiences while using ecstasy, health concerns, and addiction/tolerance. Implications for prevention and intervention are discussed.
doi:10.1081/JA-200066810
PMCID: PMC2948966  PMID: 16048826
ecstasy; X; club drugs; raves; college students
17.  Ecstasy-induced recurrent toxic hepatitis in a young adult 
BACKGROUND: The drug 3,4-methylenedioxymethamphetamine (MDMA), otherwise known as “ecstasy,” is a synthetic amphetamine that produces euphoria, increases sociability and energy, and is often used as a “weekend” recreational drug by young adults.
CASE SUMMARY: A 23-year-old male (height, 184 cm; weight, 68 kg) presented to the emergency department of Marmara University Hospital, Istanbul, Turkey, with jaundice and nausea lasting for 6 days. The patient reported that he had been a chronic user of MDMA for 2 years. He also reported that 1 week before presenting, he had ingested twice (2 tablets) the usual amount (1 tablet) of the drug at the same time. Blood tests were performed and hematologic findings were as follows: aspartate aminotransferase (AST), 1423 U/L (reference range, 10–37 U/L); alanine aminotransferase (ALT), 2748 U/L (10–40 U/L); alkaline phosphatase, 271 U/L (0–270 U/L); γ-glutamyl transpeptidase, 124 U/L (7–49 U/L); total bilirubin, 13.23 mg/dL (0.2–1 mg/dL); direct bilirubin, 8.75 mg/dL (0–0.3 mg/dL); amylase, 80 U/L (0–220 U/L); prothrombin time, 21.2 sec; activated partial thromboplastin time, 37.3 sec; and international normalized ratio, 1.66. Liver enzymes and bilirubin levels were found to be extremely high (AST = 40x normal, ALT = 70x normal, and bilirubin = 13x normal). Viral, autoimmune, and metabolic causes were excluded. Serologic tests for hepatitis A, B, and C viruses, mononucleosis, cytomegalovirus, and HIV infection were all negative. A diagnosis of ecstasy-induced toxic hepatitis was made. The patient's medical history further revealed that the current incident was actually his second occurrence of jaundice and acute hepatitis associated with the ingestion of higher amounts (twice the usual amount of MDMA he ingested at the same time). Supportive therapy (IV saline and vital sign monitoring) was initiated and liver enzymes, bilirubin levels, and prothrombin times were monitored daily. All had returned to normal values in 2 weeks.
CONCLUSIONS: MDMA, or the recreational drug ecstasy, might be responsible for acute hepatitis and/or acute liver failure, particularly in young people. Physicians might need to be alert to the possibility of ecstasy-induced liver damage occurring in younger patients, although the presence of other hepatotoxins and alternative diagnoses requires exclusion. The use of this drug should be investigated in young patients with severe hepatitis of unknown origin.
doi:10.1016/j.curtheres.2008.06.001
PMCID: PMC3969910  PMID: 24692804
3,4-methylenedioxymethamphetamine; MDMA; ecstasy; recurrent acute hepatitis
18.  Ecstasy and Gateway Drugs: Initiating the Use of Ecstasy and Other Drugs 
Annals of epidemiology  2006;17(1):74-80.
Purpose
The main purposes of this study are to examine if, and to what extent, ecstasy use serves as a gateway to the use of hard drugs such as cocaine, heroin, and methamphetamine and to compare the age of onset of alcohol and marijuana use and subsequent use of cocaine, heroin, and methamphetamine among young adult ecstasy users.
Methods
Face-to-face surveys were conducted with 268 young adult ecstasy users in Atlanta, Georgia. Subjects were solicited using the community identification process, including targeted sampling and guided recruitment. Data analysis involved discrete-time, event history analysis.
Results
Results suggest that the age of onset of ecstasy use influences the initiation of cocaine and methamphetamine for our sample of active ecstasy users. In addition, alcohol and marijuana use precedes the initiation of cocaine and methamphetamine, but only marijuana influences the initiation of heroin.
Conclusions
The sequential progression of drug use proposed in the gateway literature is not immutable. Researchers must take into account the changing popularity of drugs over time, such as the emergence of ecstasy use, when identifying patterns of drug use onset.
doi:10.1016/j.annepidem.2006.07.013
PMCID: PMC1851690  PMID: 17140814
MDMA; Ecstasy (Drug); 3,4-Methylenedioxymethamphetamine; street drugs
19.  Sleep Deprivation Differentially Impairs Cognitive Performance in Abstinent Methylenedioxymethamphetamine (“Ecstasy”) Users 
Methylenedioxymethamphetamine (MDMA; “Ecstasy”) is a popular recreational drug and brain serotonin (5-HT) neurotoxin. Neuroimaging data indicate that some human MDMA users develop persistent deficits in brain 5-HT neuronal markers. Although the consequences of MDMA-induced 5-HT neurotoxicity are not fully understood, abstinent MDMA users have been found to have subtle cognitive deficits and altered sleep architecture. The present study sought to test the hypothesis that sleep disturbance plays a role in cognitive deficits in MDMA users. Nineteen abstinent MDMA users and 21 control subjects participated in a 5 d inpatient study in a clinical research unit. Baseline sleep quality was measured using the Pittsburgh Sleep Quality Inventory. Cognitive performance was tested three times daily using a computerized cognitive battery. On the third day of admission, subjects began a 40 h sleep deprivation period and continued cognitive testing using the same daily schedule. At baseline, MDMA users performed less accurately than controls on a task of working memory and more impulsively on four of the seven computerized tests. During sleep deprivation, MDMA users, but not controls, became increasingly impulsive, performing more rapidly at the expense of accuracy on tasks of working and short-term memory. Tests of mediation implicated baseline sleep disturbance in the cognitive decline seen during sleep deprivation. These findings are the first to demonstrate that memory problems in MDMA users may be related, at least in part, to sleep disturbance and suggest that cognitive deficits in MDMA users may become more prominent in situations associated with sleep deprivation.
doi:10.1523/JNEUROSCI.4654-09.2009
PMCID: PMC3047479  PMID: 19890014
20.  Human ecstasy (MDMA) polydrug users have altered brain activation during semantic processing 
Psychopharmacology  2012;227(1):41-54.
Rationale
Ecstasy (MDMA) polydrug users have verbal memory performance that is statistically significantly lower than comparison control subjects. Studies have correlated long-term MDMA use with altered brain activation in regions that play a role in verbal memory.
Objectives
The aim of our study was to examine the association of lifetime ecstasy use with semantic memory performance and brain activation in ecstasy polydrug users.
Methods
23 abstinent ecstasy polydrug users (age=24.57) and 11 controls (age=22.36) performed a two-part fMRI semantic encoding and recognition task. To isolate brain regions activated during each semantic task, we created statistical activation maps in which brain activation was greater for word stimuli than for non-word stimuli (corrected p<0.05).
Results
During the encoding phase, ecstasy polydrug users had greater activation during semantic encoding bilaterally in language processing regions, including Brodmann Areas 7, 39, and 40. Of this bilateral activation, signal intensity with a peak T in the right superior parietal lobe was correlated with lifetime ecstasy use (rs=0.43, p=0.042). Behavioral performance did not differ between groups.
Conclusions
These findings demonstrate that ecstasy polydrug users have increased brain activation during semantic processing. This increase in brain activation in the absence of behavioral deficits suggests that ecstasy polydrug users have reduced cortical efficiency during semantic encoding, possibly secondary to MDMA-induced 5-HT neurotoxicity. Although pre-existing differences cannot be ruled out, this suggests the possibility of a compensatory mechanism allowing ecstasy polydrug users to perform equivalently to controls, providing additional support for an association of altered cerebral neurophysiology with MDMA exposure.
doi:10.1007/s00213-012-2936-1
PMCID: PMC3615064  PMID: 23241648
21.  Cortisol and 3,4-Methylenedioxymethamphetamine: Neurohormonal Aspects of Bioenergetic Stress in Ecstasy Users 
Neuropsychobiology  2009;60(3-4):148-158.
Aims
3,4-Methylenedioxymethamphetamine (MDMA) can affect both neurotransmitter and neurohormonal activity. This review will debate the role of the metabolic activation hormone cortisol for the psychobiological effects of ecstasy/MDMA.
Methods
The empirical literature on cortisol release following acute MDMA administration and cortisol functioning in drug-free recreational ecstasy/MDMA users will be reviewed. This will be followed by an overview of cortisol as a bioenergetic stress neurohormone, and a debate on how it could be modulating the acute and chronic psychobiological effects of MDMA.
Results
Cortisol release is increased by stimulatory factors, including physical activity, thermal stress and stimulant drugs. In laboratory studies MDMA leads to an acute cortisol increase of around 150% in sedentary humans. In MDMA-using dance clubbers, the cortisol levels are increased by around 800%, possibly due to the combined factors of stimulant drug, physical exertion and psychosocial stimulation. Regular ecstasy/MDMA users also demonstrate changes in baseline cortisol levels and cortisol reactivity, with compromised hypothalamic-pituitary-adrenal activity. Nonpharmacological research has shown how cortisol is important for psychological aspects such as memory, cognition, sleep, impulsivity, depression and neuronal damage. These same functions are often impaired in recreational ecstasy/MDMA users, and cortisol may be an important modulatory co-factor.
Conclusions
The energizing hormone cortisol is involved in the psychobiology of MDMA, probably via its effects on energy metabolism. Acute cortisol release may potentiate the stimulating effects of MDMA in dance clubbers. Chronically, cortisol may contribute to the variance in functional and structural consequences of repeated ecstasy usage.
doi:10.1159/000253551
PMCID: PMC2826870  PMID: 19893332
3,4-Methylenedioxymethamphetamine; Ecstasy; Cortisol; Hormone; Stress; Energy; Cognition
22.  Procedural and declarative memory performance, and the memory consolidation function of sleep, in recent and abstinent Ecstasy/MDMA users 
This study assessed the effects of ecstasy/MDMA on declarative memory (Rivermead Behavioral Memory task - RBMT), on procedural learning (Finger Tapping Task - FTT), and on the memory consolidation function of sleep for these two tasks. Testing occurred in 2 afternoon testing sessions, 24 hours apart so that a full period of sleep was allowed between them. Groups were: Non-drug taking Controls (n=24); Recent Ecstasy/MDMA users, who had taken ecstasy and/or MDMA 2–3 days before the first testing session (n=25), and Abstinent Ecstasy/MDMA users, who had not taken ecstasy/MDMA for at least 8 days before the first session (n=17). The recent ecstasy/MDMA users performed significantly worse than controls on the RBMT (mean recall 76.1% of control group recall), but did not differ from controls on FTT performance. Correspondingly there was a significant regression between the continuous variable of recency of ecstasy/MDMA use and RBMT performance. However, there was an interaction between ecstasy/MDMA use and subsequent other drug use. Controls had similar RBMT scores to recent ecstasy/MDMA users who did not take other drugs 48 – 24 hours before testing, but scored significantly better than recent ecstasy/MDMA users who took various other drugs (mainly cannabis) 48 – 24 hours before testing. For both tasks the control, recent ecstasy/MDMA and abstinent ecstasy/MDMA users did not differ in their change of performance across 24 hours; there was thus no evidence that ecstasy/MDMA impairs the memory consolidation function of sleep for either declarative or procedural memory. For participants in the two ecstasy/MDMA groups greater lifetime consumption of ecstasy tablets was associated with significantly more deficits in procedural memory. Furthermore, greater lifetime consumption of ecstasy tablets and of cocaine, were also associated with significantly more deficits in declarative memory.
doi:10.1177/0269881110372545
PMCID: PMC3604193  PMID: 20615932
MDMA; ecstasy (drug); sleep; learning; memory; declarative memory; procedural learning; memory consolidation
23.  Maximising the Highs and Minimising the Lows: Harm Reduction Guidance within Ecstasy Distribution Networks 
Background
Little is known about how users build and share knowledge concerning the highs and lows of Ecstasy and the role that Ecstasy sellers play in the exchange of this information.
Methods
These findings are based on a National Institute on Drug Abuse-funded project, “An Exploratory Study of Ecstasy Distribution,” conducted between 2003 and 2006. We completed in-depth interviews with 120 men and women in the San Francisco Bay Area who had sold 5 or more doses 5 or more times in the 6 months prior to the interview. The research focused on buyer-seller relationships and the influence of these relationships on users’ health.
Results
Users constructed harm reduction strategies in attempts to maximise the Ecstasy high and minimise the risks. The social context of Ecstasy use allowed for the exchange of harm reduction information and advice on how to maximise the pleasurable aspects of Ecstasy. Some participants served as “guides” to ensure that their customers had safe and enjoyable experiences while using Ecstasy.
Conclusion
These findings suggest that Ecstasy sellers are important points of intervention for the dissemination of harm reduction information as friendship networks were the primary link in creating awareness of safer Ecstasy use.
doi:10.1016/j.drugpo.2007.09.003
PMCID: PMC2606146  PMID: 17964771
Ecstasy; Harm Reduction; Pleasure; Ecstasy sellers
24.  Dance Clubbing on MDMA and during Abstinence from Ecstasy/MDMA: Prospective Neuroendocrine and Psychobiological Changes 
Neuropsychobiology  2008;57(4):165-180.
Background/Aims
The present study is the first to prospectively compare a group of recreational Ecstasy users when dance clubbing on 3,4-methylenedioxymethamphetamine (MDMA) and when clubbing during abstinence from Ecstasy/MDMA.
Methods
Twelve normal healthy volunteers (mean age = 23.2 years) were assessed at a Saturday night dance club under self-administered MDMA. On the other weekend they went to the same dance club without taking MDMA (order counterbalanced). Both conditions involved 5 test sessions conducted at similar times: pre-drug baseline, 1 h post-drug clubbing, 2.5 h post-drug clubbing, and 2 and 4 days later. The assessments included body and ambient temperature, physical activity (pedometer), as well as self-ratings for mood state, physical activity, thermal comfort and thirst. Saliva samples were analyzed for MDMA, cortisol and testosterone.
Results
The cortisol levels increased significantly by 800% when dance clubbing on MDMA, while testosterone increased significantly by 75%; neither neuroendocrine measure was altered during abstinence. Saliva analyses confirmed the presence of MDMA when dancing on Ecstasy and its absence when dancing off Ecstasy. The pedometer values and self-rated levels of dancing were similar at both weekends. Hot and cold flushes and feeling hot increased significantly under MDMA. The mean body temperature did not change significantly, although there was a borderline trend for increased values after MDMA. Feelings of happiness and excitement increased under MDMA, although they were not significantly greater than when clubbing during abstinence.
Conclusions
Neurohormonal release may be an important part of the acute MDMA experience. The large cortisol increase provides further data on the bioenergetic stress model of recreational Ecstasy/MDMA.
doi:10.1159/000147470
PMCID: PMC3575116  PMID: 18654086
3,4-Methylenedioxymethamphetamine (MDMA); Ecstasy; Cortisol; Testosterone; Neuroendocrine; Temperature; Energy; Stress; Serotonin
25.  Evidence of Neurotoxicity of Ecstasy: Sustained Effects on Electroencephalographic Activity in Polydrug Users 
PLoS ONE  2010;5(11):e14097.
Objective
According to previous EEG reports of indicative disturbances in Alpha and Beta activities, a systematic search for distinct EEG abnormalities in a broader population of Ecstasy users may especially corroborate the presumed specific neurotoxicity of Ecstasy in humans.
Methods
105 poly-drug consumers with former Ecstasy use and 41 persons with comparable drug history without Ecstasy use, and 11 drug naives were investigated for EEG features. Conventional EEG derivations of 19 electrodes according to the 10-20-system were conducted. Besides standard EEG bands, quantitative EEG analyses of 1-Hz-subdivided power ranges of Alpha, Theta and Beta bands have been considered.
Results
Ecstasy users with medium and high cumulative Ecstasy doses revealed an increase in Theta and lower Alpha activities, significant increases in Beta activities, and a reduction of background activity. Ecstasy users with low cumulative Ecstasy doses showed a significant Alpha activity at 11 Hz. Interestingly, the spectral power of low frequencies in medium and high Ecstasy users was already significantly increased in the early phase of EEG recording. Statistical analyses suggested the main effect of Ecstasy to EEG results.
Conclusions
Our data from a major sample of Ecstasy users support previous data revealing alterations of EEG frequency spectrum due rather to neurotoxic effects of Ecstasy on serotonergic systems in more detail. Accordingly, our data may be in line with the observation of attentional and memory impairments in Ecstasy users with moderate to high misuse. Despite the methodological problem of polydrug use also in our approach, our EEG results may be indicative of the neuropathophysiological background of the reported memory and attentional deficits in Ecstasy abusers. Overall, our findings may suggest the usefulness of EEG in diagnostic approaches in assessing neurotoxic sequela of this common drug abuse.
doi:10.1371/journal.pone.0014097
PMCID: PMC2990767  PMID: 21124854

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