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
addiction; cannabis; decision-making; inhibition; MDMA
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.
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.
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.
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.
MDMA; drug use; alcohol use; executive functions; decision-making; impulsivity
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.
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.
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.
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.
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.
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.
We assessed memory, decision-making, and executive function in ecstasy users and controls, stratifying by genotype at the 5-HTTLPR.
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.
The results are consistent with the hypothesis that cognitive impairment in ecstasy users may depend on genetic variation at the 5-HTTLPR.
Ecstasy (MDMA); Decision-making; Serotonin transporter-linked polymorphic region (5-HTTLPR); Neuropsychology; Memory; Executive function
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.
The aim of this study was to investigate neuropsychological function in chronic ecstasy users while controlling for polydrug use.
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.
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.
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.
3,4-Methylenedioxymethamphetamine (MDMA); Ecstasy; Neuropsychology; Polydrug use; Executive function; Memory; Decision-making; Risk-taking; Impulsivity
(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
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.
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.
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.
Methylenedioxymethamphetamine (MDMA, “ecstasy”) is a popular recreational drug of abuse and a selective brain serotonin neurotoxin. Functional consequences of MDMA neurotoxicity have defied ready characterization. Obstructive sleep apnea (OSA) is a common form of sleep-disordered breathing in which brain serotonin dysfunction may play a role. The present study sought to determine whether abstinent recreational MDMA users have an increased prevalence of OSA.
We studied 71 medically healthy recreational MDMA users and 62 control subjects using all-night sleep polysomnography in a controlled inpatient research setting. Rates of apneas, hypopneas, and apnea hypopnea indices were compared in the 2 groups, controlling for body mass index, age, race, and gender.
Recreational MDMA users who had been drug free for at least 2 weeks had significantly increased rates of obstructive sleep apnea and hypopnea compared with controls. The odds ratio (95% confidence interval) for sleep apnea (mild, moderate, and severe combined) in MDMA users during non-REM sleep was 8.5 (2.4–30.4), which was greater than that associated with obesity [6.9 (1.7–28.2)]. Severity of OSA was significantly related to lifetime MDMA exposure.
These findings suggest that prior recreational methylenedioxymethamphetamine use increases the risk for obstructive sleep apnea and lend support to the notion that brain serotonin neuronal dysfunction plays a role in the pathophysiology of sleep apnea.
= apnea hypopnea index;
= body mass index;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= odds ratio;
= obstructive sleep apnea;
= Scheduled Diagnostic Interview for DSM-IV;
= sleep-disordered breathing.
MDMA (3,4-methylenedioxymethamphetamine; Ecstasy) is a popular recreational drug that produces long-lasting serotonin (5-HT) neurotoxicity consisting of reductions in markers for 5-HT axons. 5-HT innervates cortical and subcortical brain regions mediating motor function, predicting that MDMA users will have altered motor system neurophysiology. We used functional magnetic resonance imaging (fMRI) to assay motor task performance-associated brain activation changes in MDMA and non-MDMA users. 24 subjects (14 MDMA users and 10 controls) performed an event-related motor tapping task (1, 2 or 4 taps) during fMRI at 3 T. Motor regions of interest were used to measure percent signal change (PSC) and percent activated voxels (PAV) in bilateral motor cortex, sensory cortex, supplementary motor area (SMA), caudate, putamen, pallidum and thalamus. We used SPM5 to measure brain activation via three methods: T-maps, PSC and PAV. There was no statistically significant difference in reaction time between the two groups. For the Tap 4 condition, MDMA users had more activation than controls in the right SMA for T-score (p = 0.02), PSC (p = 0.04) and PAV (p = 0.03). Lifetime episodes of MDMA use were positively correlated with PSC for the Tap 4 condition on the right for putamen and pallidum; with PAV in the right motor and sensory cortex and bilateral thalamus. In conclusion, we found a group difference in the right SMA and positive dose–response association between lifetime exposure to MDMA and signal magnitude and extent in several brain regions. This evidence is consistent with MDMA-induced alterations in basal ganglia–thalamocortical circuit neurophysiology and is potentially secondary to neurotoxic effects on 5-HT signaling. Further studies examining behavioral correlates and the specific neurophysiological basis of the observed findings are warranted.
Drug abuse; Neuroimaging; Serotonin; Movement; Toxicity
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.
MDMA; ecstasy; PET; serotonin transporter; methamphetamine; cortical thickness
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.
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.
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.
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.
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.
MDMA; ecstasy; addiction; dopamine; F-dopa; PET; addiction & substance abuse; dopamine; imaging, clinical or preclinical; psychopharmacology; ecstasy
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
MDMA; ecstasy (drug); sleep; learning; memory; declarative memory; procedural learning; memory consolidation
Stimulant dependence is associated with neuropsychological impairments. Here, we summarize and integrate the existing neuroimaging literature on the neural substrates of neuropsychological (dys)function in stimulant dependence, including cocaine, (meth-)amphetamine, ecstasy and nicotine dependence, and excessive caffeine use, comparing stimulant abusers (SAs) to nondrug using healthy controls (HCs). Despite some inconsistencies, most studies indicated altered brain activation in prefrontal cortex (PFC) and insula in response to reward and punishment, and higher limbic and anterior cingulate cortex (ACC)/PFC activation during craving and attentional bias paradigms in SAs compared with HCs. Impulsivity in SAs was associated with lower ACC and presupplementary motor area activity compared with HCs, and related to both ventral (amygdala, ventrolateral PFC, insula) and dorsal (dorsolateral PFC, dorsal ACC, posterior parietal cortex) systems. Decision making in SAs was associated with low dorsolateral PFC activity and high orbitofrontal activity. Finally, executive function in SAs was associated with lower activation in frontotemporal regions and higher activation in premotor cortex compared with HCs. It is concluded that the lower activations compared with HCs are likely to reflect the neural substrate of impaired neurocognitive functions, whereas higher activations in SAs compared with HCs are likely to reflect compensatory cognitive control mechanisms to keep behavioral task performance to a similar level as in HCs. However, before final conclusions can be drawn, additional research is needed using neuroimaging in SAs and HCs using larger and more homogeneous samples as well as more comparable task paradigms, study designs, and statistical analyses.
Addiction; fMRI; functional imaging; magnetic resonance imaging; stimulant dependence; stimulants
(±)3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) is a recreational drug and brain serotonin (5-HT) neurotoxin. Under certain conditions, MDMA damages brain dopamine (DA) neurons, at least in rodents. Human MDMA users have been found to have reduced brain 5-HT transporter (SERT) density and cognitive deficits, although it is not known whether these are related. We sought to determine whether MDMA users who take closely spaced sequential doses develop DA transporter (DAT) deficits, in addition to SERT deficits, and whether there is a relationship between transporter binding and cognitive performance.
Sixteen abstinent MDMA users with a history of sequential MDMA use (two or more doses over a 3-12 hour period) and sixteen age and gender- matched controls participated. Subjects underwent positron emission tomography with the DAT and SERT radioligands, [11C]WIN 35,428 and [11C]DASB, respectively. Subjects also underwent formal neuropsychiatric testing.
MDMA users had reduced SERT binding in multiple brain regions but no reductions in striatal DAT binding. Memory performance in the aggregate subject population was correlated with SERT binding in the dorsolateral prefrontal cortex, orbitofrontal cortex and parietal cortex, brain regions implicated in memory function. Prior exposure to MDMA significantly diminished the strength of this relationship.
Sequential MDMA use is associated with lasting decreases in brain SERT, but not DAT. Memory performance is associated with SERT binding in brain regions involved in memory function. Prior MDMA exposure appears to disrupt this relationship. These data are the first to directly relate memory performance to brain SERT density.
Positron emission tomography; amphetamines; pharmacokinetics; neurotoxicity; serotonin; dopamine; memory
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.
Methods: Ecstasy users and control subjects underwent single pulse transcranial magnetic stimulation (TMS) of the occipital cortex. The phosphene threshold was analysed and compared in the two groups.
Results: Phosphene thresholds were significantly lower in ecstasy users compared with control subjects, and were correlated negatively with frequency of ecstasy use. Frequency of use was positively correlated with the presence of visual hallucinations. The phosphene threshold of subjects with hallucinations was significantly lower than that of subjects without hallucinations.
Conclusions: The use of ecstasy as a recreational drug is associated with an increased excitability of the visual cortex, possibly linked with massive serotonin release, followed by serotonin depletion, in this cortical area.
The synthetic psychostimulant MDMA (±3,4-methylenedioxymethamphetamine, ecstasy) acts as an indirect serotonin, dopamine, and norepinephrine agonist and as a mechanism-based inhibitor of the cytochrome P-450 2D6 (CYP2D6). It has been suggested that women are more sensitive to MDMA effects than men but no clinical experimental studies have satisfactorily evaluated the factors contributing to such observations. There are no studies evaluating the influence of genetic polymorphism on the pharmacokinetics (CYP2D6; catechol-O-methyltransferase, COMT) and pharmacological effects of MDMA (serotonin transporter, 5-HTT; COMT). This clinical study was designed to evaluate the pharmacokinetics and physiological and subjective effects of MDMA considering gender and the genetic polymorphisms of CYP2D6, COMT, and 5-HTT. A total of 27 (12 women) healthy, recreational users of ecstasy were included (all extensive metabolizers for CYP2D6). A single oral weight-adjusted dose of MDMA was administered (1.4 mg/kg, range 75–100 mg) which was similar to recreational doses. None of the women were taking oral contraceptives and the experimental session was performed during the early follicular phase of their menstrual cycle. Principal findings show that subjects reached similar MDMA plasma concentrations, and experienced similar positive effects, irrespective of gender or CYP2D6 (not taking into consideration poor or ultra-rapid metabolizers) or COMT genotypes. However, HMMA plasma concentrations were linked to CYP2D6 genotype (higher with two functional alleles). Female subjects displayed more intense physiological (heart rate, and oral temperature) and negative effects (dizziness, sedation, depression, and psychotic symptoms). Genotypes of COMT val158met or 5-HTTLPR with high functionality (val/val or l/*) determined greater cardiovascular effects, and with low functionality (met/* or s/s) negative subjective effects (dizziness, anxiety, sedation). In conclusion, the contribution of MDMA pharmacokinetics following 1.4 mg/kg MDMA to the gender differences observed in drug effects appears to be negligible or even null. In contrast, 5-HTTLPR and COMT val158met genotypes play a major role.
Most recreational users of 3, 4-methylenedioxymethamphetamine (MDMA or “ecstasy”) also take cannabis, in part because cannabis can reduce the dysphoric symptoms of the ecstasy come-down such as agitation and insomnia. Although previous animal studies have examined the acute effects of co-administering MDMA and Δ9-tetrahydrocannabinol (THC), which is the major psychoactive ingredient in cannabis, research on chronic exposure to this drug combination is lacking. Therefore, the present study was conducted to investigate the effects of chronic adolescent administration of both THC and MDMA on behavior and on regional serotonin transporter (SERT) binding and serotonin (5-HT) concentrations as indices of serotonergic system integrity. Male Sprague-Dawley rats were divided into four drug administration groups: (1) MDMA alone, (2) THC alone, (3) MDMA plus THC, and (4) vehicle controls. MDMA (2 × 10 mg/kg × 4 h) was administered every fifth day from postnatal day (PD) 35 to 60 to simulate intermittent recreational ecstasy use, whereas THC (5 mg/kg) was given once daily over the same time period to simulate heavy cannabis use. THC unexpectedly produced a modest hyperthermic effect when administered alone, but in animals co-treated with both THC and MDMA, there was an attenuation of MDMA-induced hyperthermia on dosing days. Subsequent testing conducted after a drug washout period revealed that THC reduced MDMA-related behavioral changes in the emergence and social interaction tests of anxiety-like behavior and also blunted the MDMA-induced decrease in exploratory behavior in the hole-board test. THC additionally attenuated MDMA -induced decreases in 5-HT levels and in SERT binding in the frontal cortex, parietal cortex, and striatum, but not in the hippocampus. These results suggest that chronic co-administration of THC during adolescence can provide some protection against various adverse physiological, behavioral, and neurochemical effects produced by MDMA.
MDMA; THC; behavior; neurotoxicity
3, 4 Methylenedioxymethamphetamine (MDMA) also known as Ecstasy is a common recreational drug of abuse and reports of abuse of tricyclic antidepressants are also known. We report two cases of misuse of selective serotonin re-uptake inhibitors (SSRIs) antidepressants in combination with Ecstasy and their beneficial subjective effects experienced by misusers. We hypothesise the probable underlying pharmacological reasons and recommend its use in the treatment of neurotoxic effects of MDMA.
MDMA; antidepressant; SSRI's; treatment potential
±3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) reportedly produces unique subjective effects, including increased sociability, feelings of closeness with others, and reduced interpersonal defensiveness. Despite their apparent importance in recreational and potential psychotherapeutic use of MDMA, the defining characteristics and neurobiological mechanisms of these interpersonal effects are poorly understood.
MATERIALS AND METHODS
We investigated acute effects of MDMA on self-reported sociability, and neuronal activation in response to socially threatening (angry and fearful faces) and socially rewarding (happy faces) stimuli. Assessment of social threat response focused on amygdala activation, whereas assessment of social reward focused on ventral striatum activation. Healthy volunteers (N=9) reporting past ecstasy use completed three experimental sessions, receiving MDMA (0.75mg/kg, and 1.5mg/kg), and placebo (PBO) under double-blind conditions. During peak drug effects, participants underwent functional magnetic resonance imaging while viewing standardized images depicting emotional facial expressions including angry, fearful, happy and neutral expressions. They also completed standardized self-report measures of sociability.
MDMA (1.5mg/kg) increased self-reported sociability compared to MDMA (0.75mg/kg) and PBO. MDMA (1.5mg/kg) attenuated left amygdala response to angry facial expressions compared to PBO, but MDMA did not affect amygdala reactivity to fearful expressions. MDMA (0.75mg/kg) enhanced ventral striatum response to happy expressions relative to PBO.
These data present the first evidence that MDMA may increase sociability in humans both by diminishing responses to threatening stimuli and enhancing responses to rewarding social signals.
MDMA; ecstasy; social reward; social threat; sociability
MDMA (3,4 methylenedioxymethamphetamine) has been used by millions of people worldwide as a recreational drug. MDMA and Ecstasy are often used synonymously but it is important to note that the purity of Ecstasy sold as MDMA is not certain. MDMA use is of public health concern, not so much because MDMA produces a common or severe dependence syndrome, but rather because rodent and non-human primate studies have indicated that MDMA (when administered at certain dosages and intervals) can cause long-lasting reductions in markers of brain serotonin (5-HT) that appear specific to fine diameter axons arising largely from the dorsal raphe nucleus (DR). Given the popularity of MDMA, the potential for the drug to produce long-lasting or permanent 5-HT axon damage or loss, and the widespread role of 5-HT function in the brain, there is a great need for a better understanding of brain function in human users of this drug. To this end, neuropsychological, neuroendocrine, and neuroimaging studies have all suggested that human MDMA users may have long-lasting changes in brain function consistent with 5-HT toxicity. Data from animal models leads to testable hypotheses regarding MDMA effects on the human brain. Because neuropsychological and neuroimaging findings have focused on the neocortex, a cortical model is developed to provide context for designing and interpreting neuroimaging studies in MDMA users. Aspects of the model are supported by the available neuroimaging data but there are controversial findings in some areas and most findings have not been replicated across different laboratories and using different modalities. This paper reviews existing findings in the context of a cortical model and suggests directions for future research.
functional MRI; positron emission tomography; drug abuse; drug toxicity; magnetic resonance spectroscopy
High doses of the recreational drug 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) have been well-documented to reduce the expression of serotonergic markers in several forebrain regions of rats and nonhuman primates. Neuroimaging studies further suggest that at least one of these markers, the plasma membrane serotonin transporter (SERT), may also be reduced in heavy Ecstasy users. Such effects, particularly when observed in experimental animal models, have generally been interpreted as reflecting a loss of serotonergic fibers and terminals following MDMA exposure. This view has been challenged, however, based on the finding that MDMA usually does not elicit glial cell reactions known to occur in response to central nervous system (CNS) damage. The aim of this review is to address both sides of the MDMA-neurotoxicity controversy, including recent findings from our laboratory regarding the potential of MDMA to induce serotonergic damage in a rat binge model. Our data add to the growing literature implicating neuroregulatory mechanisms underlying MDMA-induced serotonergic dysfunction and questioning the need to invoke a degenerative response to explain such dysfunction.
MDMA; serotonin; neurodegeneration; neurotoxicity; serotonin transporter; vesicular monoamine transporter 2; gene expression; biochemical downregulation.
The goal of the current investigation was to address whether affective decision making would serve as a unique neuropsychological marker to predict drinking behaviors among adolescents. We conducted a longitudinal study of 181 Chinese adolescents in Chengdu city, China. In their 10th grade (ages 15–16), these adolescents were tested for their affective decision-making ability using the Iowa Gambling Task (IGT) and working memory capacity using the Self-Ordered Pointing Test. Self-report questionnaires were used to assess academic performance and drinking behaviors. At 1-year follow-up, questionnaires were completed to assess drinking behaviors, and the UPPS Impulsive Behavior Scale was used to examine four dimensions of impulsivity: urgency, lack of premeditation, lack of perseverance, and sensation seeking. Results indicated that those adolescents who progressed to binge drinking or exhibited consistent binge drinking not only performed poorly on the IGT but also scored significantly higher in urgency compared to those who never or occasionally drank. Moreover, better IGT scores predicted fewer drinking problems and fewer drinks 1 year later after controlling for demographic variables, the previous drinking behaviors, working memory, and impulsivity. These findings suggest that deficits in affective decision making may be important independent determinants of compulsive drinking and potentially addictive behavior in adolescents.
Executive function; Affective control; Impulsivity; Working memory; Binge drinking; Iowa Gambling Task
In Western societies, a considerable percentage of young people expose themselves to 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”). Commonly, ecstasy is used in combination with other substances, in particular alcohol (ethanol). MDMA induces both arousing as well as hallucinogenic effects, whereas ethanol is a general central nervous system depressant.
The aim of the present study is to assess the acute effects of single and co-administration of MDMA and ethanol on executive, memory, psychomotor, visuomotor, visuospatial and attention function, as well as on subjective experience.
Materials and methods
We performed a four-way, double-blind, randomised, crossover, placebo-controlled study in 16 healthy volunteers (nine male, seven female) between the ages of 18–29. MDMA was given orally (100 mg) and blood alcohol concentration was maintained at 0.6‰ by an ethanol infusion regime.
Co-administration of MDMA and ethanol was well tolerated and did not show greater impairment of performance compared to the single-drug conditions. Impaired memory function was consistently observed after all drug conditions, whereas impairment of psychomotor function and attention was less consistent across drug conditions.
Co-administration of MDMA and ethanol did not exacerbate the effects of either drug alone. Although the impairment of performance by all drug conditions was relatively moderate, all induced significant impairment of cognitive function.
MDMA; Ecstasy; Alcohol; Ethanol; Interaction; Acute; Effects; Healthy volunteers; Neuropsychologic
3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is a recreational club drug with supposed neurotoxic effects selectively on the serotonin system. MDMA users consistently exhibit memory dysfunction but there is an ongoing debate if these deficits are induced mainly by alterations in the prefrontal or mediotemporal cortex, especially the hippocampus. Thus, we investigated the relation of verbal memory deficits with alterations of regional cerebral brain glucose metabolism (rMRGlu) in recreational MDMA users.
Brain glucose metabolism in rest was assessed using 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography (18FDG PET) in 19 male recreational users of MDMA and 19 male drug-naïve controls. 18FDG PET data were correlated with memory performance assessed with a German version of the Rey Auditory Verbal Learning Test.
As previously shown, MDMA users showed significant impairment in verbal declarative memory performance. PET scans revealed significantly decreased rMRGlu in the bilateral dorsolateral prefrontal and inferior parietal cortex, bilateral thalamus, right hippocampus, right precuneus, right cerebellum, and pons (at the level of raphe nuclei) of MDMA users. Among MDMA users, learning and recall were positively correlated with rMRGlu predominantly in bilateral frontal and parietal brain regions, while recognition was additionally related to rMRGlu in the right mediotemporal and bihemispheric lateral temporal cortex. Moreover, cumulative lifetime dose of MDMA was negatively correlated with rMRGlu in the left dorsolateral and bilateral orbital and medial PFC, left inferior parietal and right lateral temporal cortex.
Verbal learning and recall deficits of recreational MDMA users are correlated with glucose hypometabolism in prefrontal and parietal cortex, while word recognition was additionally correlated with mediotemporal hypometabolism. We conclude that memory deficits of MDMA users arise from combined fronto-parieto-mediotemporal dysfunction.