MDMA Users Research Articles

The role of adenosine receptor agonist and antagonist on Hippocampal MDMA detrimental effects; a structural and behavioral study

There is abundant evidence showing that repeated use of MDMA (3, 4-Methylenedioxymethamphetamine, ecstasy) has been associated with depression, anxiety and deficits in learning and memory, suggesting detrimental effects on hippocampus. Adenosine is an endogenous purine nucleoside that has a neuromodulatory role in the central nervous system. In the present study, we investigated the role of A2a adenosine receptors agonist (CGS) and antagonist (SCH) on the body temperature, learning deficits, and hippocampal cell death induced by MDMA administration. In this study, 63 adult, male, Sprague - Dawley rats were subjected to MDMA (10 and 20mg/kg) followed by intraperitoneal CGS (0.03mg/kg) or SCH (0.03mg/kg) injection. The animals were tested for spatial learning in the Morris water maze (MWM) task performance, accompanied by a recording of body temperature, electron microscopy and stereological study. Our results showed that MDMA treatment increased body temperature significantly, and impaired the ability of rats to locate the hidden platform(P < 0.05). The number of hippocampal dark neurons also increased especially in CA1. These impairments were aggravated by co-administration of A2a antagonist (SCH) with MDMA. Furthermore, the administration of the A2a receptor agonist (CGS) provided partial protection against MWM deficits and hippocampal cell death(P < 0.05). This study provides for the first time evidence that, in contrast to A2a antagonist (SCH) effects, co-administration of A2a agonist (CGS) with MDMA can protect against MDMA hippocampal neurotoxic effects; providing a potential value in the prevention of learning deficits observed in MDMA users. However, the exact mechanism of these interactions requires further studies.

One-year outcomes of prenatal exposure to MDMA and other recreational drugs.

A widely used illicit recreational drug among young adults, 3,4-methylenedioxymethamphetamine (MDMA) or ecstasy, is an indirect monoaminergic agonist/reuptake inhibitor affecting the serotonin system. Preclinical studies found prenatal exposure related to long-term learning and memory impairments. There are no studies of sequelae of prenatal MDMA exposure in humans, despite potential harmful effects to the fetus. A total of 96 women in the United Kingdom (28 MDMA users; 68 non-MDMA) were interviewed about recreational drug use during pregnancy. Their infants were seen at 12 months using standardized assessments of cognitive, language, and motor development (Preschool Language Scale, Bayley Mental and Motor Development and Behavior Rating Scales [Mental Development Index, Psychomotor Development Index, Behavioral Rating Scale]). Mothers completed the Child Domain Scale of the Parenting Stress Index, The Home Observation of the Environment Scale (in interview), the Brief Symptom Inventory, and the Drug Abuse Screening Test. Women were primarily middle class with some university education, in stable partner relationships, and polydrug users. MDMA and other drug effects were assessed through multiple regression analyses controlling for confounding variables, and analysis of covariance comparing heavier versus lighter and nonexposed groups. Amount of prenatal MDMA exposure predicted poorer infant mental and motor development at 12 months in a dose-dependent manner. Heavily exposed infants were delayed in motor development. Lighter-exposed infants were comparable to nonexposed infants. There were no effects on language, emotional regulation, or parenting stress. Findings document persistent neurotoxic effects of heavier prenatal MDMA exposure on motor development through the first year of life.

A prospective study of learning, memory, and executive function in new MDMA users

It is still unclear if cognitive abnormalities in human 3,4-methylenedioxymeth-amphetamine (MDMA) users existed before the beginning of use or if other confounders could explain the deficits. The present study was conducted in order to assess the relationship between beginning MDMA use and subsequent cognitive performance and to overcome previous methodological shortcomings. A prospective cohort study in new MDMA users between 2006 and 2009 with a follow-up duration of 12 months. Of the 149 almost MDMA-naive subjects examined at the initial assessment, 109 subjects participated again after 1 year. During this period, 43 subjects did not use any other illicit substance apart from cannabis; 23 subjects used more than 10 pills MDMA (mean = 33.6). These groups then were compared by means of multivariate analyses of variance. Change scores between the initial examination and follow-up on a neuropsychological test battery including measures of learning, memory, and frontal executive functions [Auditiv-Verbaler Lerntest (AVLT), Lern- und Gedächtnistest (LGT) 3, digit span test, digit symbol test, Stroop task, Trail-making test]. In addition, a comprehensive number of possibly relevant confounders including age, general intelligence, cannabis use, alcohol use, cigarette use, medical treatment, participation in sports, nutrition, sleep patterns and subjective wellbeing was assessed. Groups did not differ in any of the potential confounders. However, significant effects of immediate and delayed recall of a visual paired associates learning task between MDMA users and controls were found (respectively, F ((1,64)) = 11.43, P = 0.001, η(2) = 0.136 and F ((1,64)) = 11.08, P = 0.002, η(2) = 0.144). No significant differences on the other neuropsychological tests were found. MDMA appears to impair visual paired associates learning in new users, suggesting serotonergic dysfunction in hippocampal regions as a consequence of MDMA use.

Differential alteration of the effects of MDMA (ecstasy) on locomotor activity and cocaine conditioned place preference in male adolescent rats by social and environmental enrichment

Ecstasy (MDMA) is used predominately by adolescents and young adults. Young MDMA users are more likely than non-users to use other drugs, including cocaine. The response to stimulant drugs can be affected by environmental factors; however, little information exists about the role that housing plays in mediating effects of MDMA in adolescence. The present experiment examined whether social and environmental factors alter effects of MDMA on activity and cocaine reward. Male adolescent rats were housed on PND 23. Isolated rats were housed alone (1 rat/cage) in an impoverished environment with no toys (II) or enriched with toys (IE). Social rats were housed three/cage with (SE3) or without (SI3) toys. Starting on PND 29, 5 mg/kg MDMA or saline was injected and activity was measured for 60 min once daily for five consecutive days. On PND 36-40, cocaine CPP was conducted. Saline vehicle-induced activity of II rats was higher than other groups, and all groups became sensitized to the locomotor-stimulant effects of MDMA. In II rats, maximal CPP was increased after MDMA pre-exposure compared to vehicle. Environmental enrichment blocked this; however, dose-effect curves for cocaine CPP shifted to the left in both IE and SE3 rats. In rats with just social enrichment, there were no effects of MDMA on cocaine CPP. Drug prevention and treatment strategies should take into account different environments in which adolescents live. These findings show that MDMA increases cocaine reward in male adolescents, and social enrichment diminishes, while environmental enrichment enhances this.

Simultaneous polysubstance use among Danish 3,4‐methylenedioxymethamphetamine and hallucinogen users: combination patterns and proposed biological bases

To describe patterns of simultaneous polysubstance use (SPU) among Danish 3,4-methylenedioxymethamphetamine (MDMA) ("Ecstasy") and hallucinogen users. A cross-sectional survey of 98 active MDMA and/or hallucinogen users recruited through homepage advertisements, flyers, and word of mouth in Denmark. Lifetime and recent substance use and SPU at last recalled use was described by structured interviews. Hair samples from a subset of participants were analyzed for MDMA. The participants had used an average of 12.6 (95% confidence interval: 11.7-13.4) psychoactive substances during their lifetime. SPU was prevalent among MDMA, d-lysergic acid diethylamide (LSD), and psilocybin users, in particular with alcohol and cannabis. Among MDMA users, 69% had combined MDMA with amphetamines, 56% with hallucinogens, and 47% with cocaine. At last recalled use, MDMA was taken with 2.1 ± 1.2 substances in 32 different combinations. The participants preferred specific drug combinations and named several, which in their experience enhanced or counteracted each other. Alcohol and cannabis were typically used before, during, and after MDMA, LSD, and psilocybin, whereas amphetamines were predominantly taken before these substances. When LSD was combined with MDMA, the majority took MDMA after LSD. Simultaneous polysubstance use was common among Danish MDMA and hallucinogen users, and patterns of preferred substance combinations were evident.

The effects of multitasking on psychological stress reactivity in recreational users of cannabis and MDMA

Cannabis and 3,4-methylenedioxymethamphetamine (MDMA) use is associated with psychobiological and neurocognitive deficits. Assessments of the latter typically include tests of memory and everyday cognitive functioning. However, to date, little attention has been paid to effects of drug use on psychological stress reactivity. We report three studies examining the effects of recreational use of cannabis and MDMA on mood and psychological responses to multitasking using a cognitively demanding laboratory stressor that provides an analogue for everyday situations involving responses to multiple stimuli. The effects of the multitasking framework on mood and perceived workload were assessed in cannabis (N=25), younger (N=18) and older (N=20) MDMA users and compared with non-target drug controls. Compared with respective control groups, cannabis users became less alert and content, and both MDMA groups became less calm following acute stress. Unexpectedly, the stressor increased ratings of calm in cannabis users. Users also scored higher than their controls with respect to ratings of resources needed to complete the multitasking framework. These findings show, for the first time, that recreational use of cannabis and MDMA, beyond the period of intoxication, can negatively influence psychological responses to a multitasking stressor, and this may have implications for real-life situations which place high demands on cognitive resources.

Sustained Recreational Use of Ecstasy Is Associated with Altered Pre and Postsynaptic Markers of Serotonin Transmission in Neocortical Areas: A PET Study with [11C]DASB and [11C]MDL 100907

3,4-Methylenedioxymethamphetamine (MDMA), the main psychoactive component of the recreational drug ecstasy, is a potent serotonin (5-HT) releaser. In animals, MDMA induces 5-HT depletion and toxicity in 5-HT neurons. The aim of this study was to investigate both presynaptic (5-HT transporter, SERT) and postsynaptic (5-HT(2A) receptor) markers of 5-HT transmission in recently abstinent chronic MDMA users compared with matched healthy controls. We hypothesized that MDMA use is associated with lower SERT density and concomitant upregulation of 5-HT(2A) receptors. Positron emission tomography studies using the SERT ligand [¹¹C]DASB and the 5-HT(2A) receptor ligand [¹¹C]MDL 100907 were evaluated in 13 current and recently detoxified MDMA users and 13 matched healthy controls. MDMA users reported a mean duration of ecstasy use of 8 years, regular exposure, and at least 2 weeks of abstinence before the scans. SERT and 5-HT(2A) receptor availability (binding potential, BP(ND)) were analyzed with a two-tissue compartment model with arterial input function. Current recreational MDMA use was significantly associated with lower SERT BP(ND) and higher 5-HT(2A) receptor BP(ND) in cortical, but not subcortical regions. Decreased SERT BP(ND) was regionally associated with upregulated 5-HT(2A) receptor BP(ND). In light of the animal literature, the most parsimonious interpretation is that repeated exposure to MDMA in humans, even in moderate amounts, leads to damage in 5-HT neuron terminals innervating the cortex. Alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain MDMA use. The reversibility of these changes upon abstinence remains to be firmly established.

Changes in CYP1A2 Activity in Humans after 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) Administration Using Caffeine as a Probe Drug

3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is a ring-substituted amphetamine widely used for recreational purposes. MDMA is predominantly O-demethylenated in humans by cytochrome P450 (CYP) 2D6, and is also a potent mechanism-based inhibitor of the enzyme. After assessing the inhibition and recovery of CYP2D6 in a previous study, the aim of this work was to study in humans the activity of CYP1A2 in vivo after CYP2D6 had been inhibited by MDMA, using caffeine as a probe drug. Twelve male and nine female recreational MDMA users were included. In session 1, 100 mg of caffeine was given at 0 h. In session 2, a 1.5 mg/kg MDMA dose (range 75-100 mg) was given at 0 h followed by a 100 mg dose of caffeine 4 h later. Aliquots of plasma were assayed for caffeine (137X) and paraxanthine (17X) and statistically significant differences were assessed with a one-way ANOVA. There were significant gender differences at basal condition, which persisted after MDMA administration. CYP1A2 activity was higher in both genders after drug administration, with an increase in 40% in females and 20% in males. Results show an increase in CYP1A2 activity when CYP2D6 is inhibited by MDMA in both genders, being more pronounced in females.

Mapping serotonergic dysfunction in MDMA (ecstasy) users using pharmacological MRI

3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is a popular recreational drug that has been shown to induce loss of brain serotonin (5-HT) neurons. The purpose of this study was to determine the usefulness of pharmacological magnetic resonance imaging (phMRI) in assessing 5-HT dysfunction by examining the hemodynamic response evoked by infusion with the selective 5-HT reuptake inhibitor citalopram. We studied the effects of MDMA on brain hemodynamics using arterial spin labeling (ASL) based phMRI following a citalopram challenge (7.5mg/kg, i.v.), combined with [123I]β-CIT SPECT imaging in ten male MDMA users and seven healthy non-users. Single photon emission computed tomography (SPECT) imaging was used to assess the availability of 5-HT transporters (SERT). Imaging results were compared with the results of behavioral measures and mood changes following drug administration, in both groups (using the Beck Depression Inventory, Barratt Impulsiveness Scale and a visual analog scale). Reductions in SERT binding were observed in the occipital cortex of MDMA users. In line with this, citalopram induced decreases in cerebral blood flow (CBF) in the occipital cortex of MDMA users. ASL based phMRI also detected a CBF decrease in the thalamus of MDMA users. In concordance with imaging findings, behavioral measures differed significantly between MDMA users and controls. MDMA users had higher impulsivity scores and felt more uncomfortable after citalopram infusion, compared with control subjects. Our findings indicate that phMRI is very well suited for in-vivo assessment of 5-HT dysfunction.

Evidence for Chronically Altered Serotonin Function in the Cerebral Cortex of Female 3,4-Methylenedioxymethamphetamine Polydrug Users

MDMA (3,4-methylenedioxymethamphetamine, also popularly known as "ecstasy") is a popular recreational drug that produces loss of serotonin axons in animal models. Whether MDMA produces chronic reductions in serotonin signaling in humans remains controversial. To determine whether MDMA use is associated with chronic reductions in serotonin signaling in the cerebral cortex of women as reflected by increased serotonin(2A) receptor levels. Cross-sectional case-control study comparing serotonin(2A) receptor levels in abstinent female MDMA polydrug users with those in women who did not use MDMA (within-group design assessing the association of lifetime MDMA use and serotonin(2A) receptors). Case participants were abstinent from MDMA use for at least 90 days as verified by analysis of hair samples. The serotonin(2A) receptor levels in the cerebral cortex were determined using serotonin(2A)-specific positron emission tomography with radioligand fluorine 18-labeled setoperone as the tracer. Academic medical center research laboratory. A total of 14 female MDMA users and 10 women who did not use MDMA (controls). The main exclusion criteria were nondrug-related DSM-IV Axis I psychiatric disorders and general medical illness. Cortical serotonin(2A) receptor nondisplaceable binding potential (serotonin(2A)BP(ND)). MDMA users had increased serotonin(2A)BP(ND) in occipital-parietal (19.7%), temporal (20.5%), occipitotemporal-parietal (18.3%), frontal (16.6%), and frontoparietal (18.5%) regions (corrected P < .05). Lifetime MDMA use was positively associated with serotonin(2A)BP(ND) in frontoparietal (β = 0.665; P = .007), occipitotemporal (β = 0.798; P = .002), frontolimbic (β = 0.634; P = .02), and frontal (β = 0.691; P = .008) regions. In contrast, there were no regions in which MDMA use was inversely associated with receptor levels. There were no statistically significant effects of the duration of MDMA abstinence on serotonin(2A)BP(ND). The recreational use of MDMA is associated with long-lasting increases in serotonin(2A) receptor density. Serotonin(2A) receptor levels correlate positively with lifetime MDMA use and do not decrease with abstinence. These results suggest that MDMA use produces chronic serotonin neurotoxicity in humans. Given the broad role of serotonin in human brain function, the possibility for therapeutic MDMA use, and the widespread recreational popularity of this drug, these results have critical public health implications.

The Influence of Genetic and Environmental Factors among MDMA Users in Cognitive Performance

This study is aimed to clarify the association between MDMA cumulative use and cognitive dysfunction, and the potential role of candidate genetic polymorphisms in explaining individual differences in the cognitive effects of MDMA. Gene polymorphisms related to reduced serotonin function, poor competency of executive control and memory consolidation systems, and high enzymatic activity linked to bioactivation of MDMA to neurotoxic metabolites may contribute to explain variations in the cognitive impact of MDMA across regular users of this drug. Sixty ecstasy polydrug users, 110 cannabis users and 93 non-drug users were assessed using cognitive measures of Verbal Memory (California Verbal Learning Test, CVLT), Visual Memory (Rey-Osterrieth Complex Figure Test, ROCFT), Semantic Fluency, and Perceptual Attention (Symbol Digit Modalities Test, SDMT). Participants were also genotyped for polymorphisms within the 5HTT, 5HTR2A, COMT, CYP2D6, BDNF, and GRIN2B genes using polymerase chain reaction and TaqMan polymerase assays. Lifetime cumulative MDMA use was significantly associated with poorer performance on visuospatial memory and perceptual attention. Heavy MDMA users (>100 tablets lifetime use) interacted with candidate gene polymorphisms in explaining individual differences in cognitive performance between MDMA users and controls. MDMA users carrying COMT val/val and SERT s/s had poorer performance than paired controls on visuospatial attention and memory, and MDMA users with CYP2D6 ultra-rapid metabolizers performed worse than controls on semantic fluency. Both MDMA lifetime use and gene-related individual differences influence cognitive dysfunction in ecstasy users.

The most frequent psychopathology related to the use of 3,4-methylenedioxymethamphetamine (MDMA) of medical help seekers: causality or coincidence?

Background: 3,4-methylendioxymethamphetamine (MDMA) represents the most popular recreational synthetic drug. The increasing popularity of MDMA, health consequences due to its recreational use and possibility of neurodegeneration of brain serotonin neurons are the reasons for increasing concern. Numerous studies suggest a link between exposure to MDMA and the consequent psychopathology. The literature indicates the incidence of various psychiatric disorders associated with single or multiple use of MDMA. The most frequent psychiatric disorders for which MDMA users search medical assistance are psychotic states, depression and panic attacks. However, it is not easy to conclude that there is a causal link between exposure to MDMA and psychopathology. This paper describes current knowledge of some aspects of this phenomenon, which represents the starting point for further challenges to various researchers and experts.

MDMA (ecstasy) effects on actual driving performance before and after sleep deprivation, as function of dose and concentration in blood and oral fluid

RationaleExperimental research has shown that 3,4-methylenedioxymethamphetamine (MDMA) can improve some psychomotor driving skills when administered during the day. In real life, however, MDMA is taken during the night, and driving may likely occur early in the morning after a night of “raving” and sleep loss.ObjectivesThe present study assessed the effects of MDMA on road-tracking and car-following performance in on-the-road driving tests in normal traffic.MethodsSixteen recreational MDMA users participated in a randomized double-blind placebo-controlled four-way cross-over design. They received single, evening doses of 0, 25, 50, and 100 mg MDMA on separate occasions. Actual driving tests were conducted in the evening when MDMA serum concentrations were maximal and in the morning after a night of sleep loss.ResultsThe primary measure of driving, i.e., standard deviation of lateral position (SDLP, a measure of weaving) was significantly increased during driving tests in the morning in all treatment conditions, irrespective of MDMA dose and concentration. The increments in SDLP were of high clinical relevance and comparable to those observed for alcohol at blood alcohol concentrations >0.8 mg/mL. These impairments were primarily caused by sleep loss.ConclusionsIn general, MDMA did not affect driving performance nor did it change the impairing effects of sleep loss. It is concluded that MDMA cannot compensate for the impairing effects of sleep loss and that drivers who are under the influence of MDMA and sleep deprived are unfit to drive.

Modulatory effects of low-dose MDMA on cocaine-induced locomotor activity and place conditioning in rats

Methylenedioxymethamphetamine (MDMA; “Ecstasy”) is commonly abused by humans in environments such as nightclubs and rave parties where other drugs of abuse are readily available. Despite the popularity of polysubstance abuse among recreational MDMA users, relatively few controlled experimental studies have documented the neurobehavioral effects of MDMA in combination with other abused substances. This study employed conditioned place preference procedures (CPP) to assess the locomotor activating and place conditioning effects of acute concurrent administration of MDMA (1.5 or 3.0mg/kg) and cocaine (10 or 20mg/kg) in rats. Results indicate that low dose MDMA can enhance the locomotor and conditioned rewarding effects of cocaine. These findings may have important implications for understanding the contribution of serotonergic–dopaminergic interactions in the abuse liability of MDMA when used in combination with cocaine or other psychostimulant drugs.

Implications of MDMA use for prospective memory function and substance use patterns in an Australian sample: A web‐based pilot study

The use of amphetamine type stimulants, particularly MDMA, is a global concern. Little research has been conducted on the association between MDMA use and everyday memory function—prospective memory. Twenty‐five MDMA users, 37 cannabis users, and 43 illicit substance‐naïve controls were assessed on their substance use history and reported prospective memory performance as measured by the Prospective Memory Questionnaire (PMQ) using a web‐based survey. There were significant differences between MDMA users and controls and cannabis users and controls on long‐term episodic subscale of the PMQ. However, given the high prevalence of cannabis co‐use by MDMA users, it was not possible to determine if MDMA use alone is associated with prospective memory performance. The substance use patterns of the sample were evaluated. Alcohol was the most used substance followed by tobacco, cannabis, and MDMA. The incidence of polydrug use was high, with all illicit substance use reporting having used at least two substances in their lifetime. The present study supports previous research into prospective memory deficits associated with substance use, and provides a basis for future research, particularly for elucidation of prospective memory deficits specific to MDMA use and further evaluation of substance use patterns.

Potential Long-term Effects of MDMA on the Basal Ganglia–Thalamocortical Circuit: A Proton MR Spectroscopy and Diffusion-Tensor Imaging Study

To investigate the effects of 3,4-methylenedioxymethamphetamine (MDMA, commonly known as "ecstasy") on the alterations of brain metabolites and anatomic tissue integrity related to the function of the basal ganglia-thalamocortical circuit by using proton magnetic resonance (MR) spectroscopy and diffusion-tensor MR imaging. This study was approved by a local institutional review board, and written informed consent was obtained from all subjects. Thirty-one long-term (>1 year) MDMA users and 33 healthy subjects were enrolled. Proton MR spectroscopy from the middle frontal cortex and bilateral basal ganglia and whole-brain diffusion-tensor MR imaging were performed with a 3.0-T system. Absolute concentrations of metabolites were computed, and diffusion-tensor data were registered to the International Consortium for Brain Mapping template to facilitate voxel-based group comparison. The mean myo-inositol level in the basal ganglia of MDMA users (left: 4.55 mmol/L ± 2.01 [standard deviation], right: 4.48 mmol/L ± 1.33) was significantly higher than that in control subjects (left: 3.25 mmol/L ± 1.30, right: 3.31 mmol/L ± 1.19) (P < .001). Cumulative lifetime MDMA dose showed a positive correlation with the levels of choline-containing compounds (Cho) in the right basal ganglia (r = 0.47, P = .02). MDMA users also showed a significant increase in fractional anisotropy (FA) in the bilateral thalami and significant changes in water diffusion in several regions related to the basal ganglia-thalamocortical circuit as compared with control subjects (P < .05; cluster size, >50 voxels). Increased myo-inositol and Cho concentrations in the basal ganglia of MDMA users are suggestive of glial response to degenerating serotonergic functions. The abnormal metabolic changes in the basal ganglia may consequently affect the inhibitory effect of the basal ganglia to the thalamus, as suggested by the increased FA in the thalamus and abnormal changes in water diffusion in the corresponding basal ganglia-thalamocortical circuit.

MDMA (Ecstasy) association with impaired fMRI BOLD thalamic coherence and functional connectivity

Background MDMA exposure is associated with chronic serotonergic dysfunction in preclinical and clinical studies. A recent functional magnetic resonance imaging (fMRI) comparison of past MDMA users to non-MDMA-using controls revealed increased spatial extent and amplitude of activation in the supplementary motor area during motor tasks ( Karageorgiou et al., 2009). Blood oxygenation level dependent (BOLD) data from that study were reanalyzed for intraregional coherence and for inter-regional temporal correlations between time series, as functional connectivity. Methods Fourteen MDMA users and ten controls reporting similar non-MDMA abuse performed finger taps during fMRI. Fourteen motor pathway regions plus a pontine raphé region were examined. Coherence was expressed as percent of voxels positively correlated with an intraregional index voxel. Functional connectivity was determined using wavelet correlations. Results Intraregional thalamic coherence was significantly diminished at low frequencies in MDMA users compared to controls ( p = 0.009). Inter-regional functional connectivity was significantly weaker for right thalamo – left caudate ( p = 0.002), right thalamo – left thalamus ( p = 0.007), right caudate – right postcentral ( p = 0.007) and right supplementary motor area – right precentral gyrus ( p = 0.011) region pairs compared to controls. When stratified by lifetime exposure, significant negative associations were observed between cumulative MDMA use and functional connectivity in seven other region-pairs, while only one region-pair showed a positive association. Conclusions Reported prior MDMA use was associated with deficits in BOLD intraregional coherence and inter-regional functional connectivity, even among functionally robust pathways involving motor regions. This suggests that MDMA use is associated with long-lasting effects on brain neurophysiology beyond the cognitive domain.

In Vivo Imaging of Cerebral Serotonin Transporter and Serotonin2A Receptor Binding in 3,4-Methylenedioxymethamphetamine (MDMA or “Ecstasy”) and Hallucinogen Users

Both hallucinogens and 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") have direct agonistic effects on postsynaptic serotonin(2A) receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin. To assess the differential effects of MDMA and hallucinogen use on cerebral serotonin transporter (SERT) and serotonin(2A) receptor binding. A positron emission tomography study of 24 young adult drug users and 21 nonusing control participants performed with carbon 11 ((11)C)-labeled 3-amino-4-[2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile (DASB) and fluorine 18 ((18)F)-labeled altanserin, respectively. Scans were performed in the user group after a minimum drug abstinence period of 11 days, and the group was subdivided into hallucinogen-preferring users (n = 10) and MDMA-preferring users (n = 14). Twenty-four young adult users of MDMA and/or hallucinogenic drugs and 21 nonusing controls. In vivo cerebral SERT and serotonin(2A) receptor binding. Compared with nonusers, MDMA-preferring users showed significant decreases in SERT nondisplaceable binding potential (neocortex, -56%; pallidostriatum, -19%; and amygdala, -32%); no significant changes were seen in hallucinogen-preferring users. Both cortical and pallidostriatal SERT nondisplaceable binding potential was negatively correlated with the number of lifetime MDMA exposures, and the time of abstinence from MDMA was positively correlated with subcortical, but not cortical, SERT binding. A small decrease in neocortical serotonin(2A) receptor binding in the serotonin(2A) receptor agonist users (both user groups) was also detected. We found evidence that MDMA but not hallucinogen use is associated with changes in the cerebral presynaptic serotonergic transmitter system. Because hallucinogenic drugs primarily have serotonin(2A) receptor agonistic actions, we conclude that the negative association between MDMA use and cerebral SERT binding is mediated through a direct presynaptic MDMA effect rather than by the serotonin(2A) agonistic effects of MDMA. Our cross-sectional data suggest that subcortical, but not cortical, recovery of SERT binding might take place after several months of MDMA abstinence.

MDMA &amp; Cannabis: A Mini-Review of Cognitive, Behavioral, and Neurobiological Effects of Co-Consumption

Although the prevalence of co-use of cannabis and 3,4 methylenedioxymethamphetamine (MDMA) is very common among polydrug users in western societies, few studies have tested the consequences on behavior, cognition or neurobiology. This review examines 23 articles published between 2002 and 2010 with an explicit focus on the combination, or administration, of MDMA and cannabis or cannabinoid agents. The aim was to provide a short overview on the latest human research concerning cognitive effects of co-consumption of MDMA and cannabis, and a more elaborate picture of the state of knowledge about the interaction of cannabinoid agents and MDMA from animal studies. It was found that recent retrospective studies on cognitive functions in long-term drug abusers point to an additive negative effect on different types of memory, as well as a cannabis-independent decrease in learning and decision-making in MDMA users. Behavioral experiments in rodents and in vitro studies investigating the combined effect of MDMA and cannabinoid agents demonstrate modulator effects of acute co-administration on measures like body temperature, conditioned reinforcement, and presumed neurotoxicity. As neural mechanism underlying these changes, an interaction between the cannabinoid system, especially cannabinoid receptor 1, and the serotonergic and dopaminergic system in the prefrontal cortex, nucleus accumbens, and hippocampus is suggested. In conclusion, there are few and somewhat contradictory studies examining the effects of co-use of these drugs on cognitive measures like impulsivity, memory and executive functions or underlying neurobiological alterations, and a shortage of animal studies examining long-term effects of chronic co-administration.

Altered pain responses in abstinent (±)3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) users

(±)3,4-Methylenedioxymethamphetamine (MDMA) is a popular recreational drug that has potential to damage brain serotonin (5-HT) neurons in humans. Brain 5-HT neurons play a role in pain modulation, yet little is known about long-term effects of MDMA on pain function. Notably, MDMA users have been shown to have altered sleep, a phenomenon that can lead to altered pain modulation. This study sought to assess pain processing in MDMA users using objective methods, and explore potential relationships between pain processing and sleep indices. Forty-two abstinent MDMA users and 43 age-matched controls participated in a 5-day inpatient study. Outcome measures included standardized measures of pain, sleep polysomnograms, and power spectral measures of the sleep EEG. When differences in psychophysiological measures of pain were found, the relationship between pain and sleep measures was explored. MDMA users demonstrated lower pressure pain thresholds, increased cold pain ratings, increased pain ratings during testing of diffuse noxious inhibitory control, and decreased Stage 2 sleep. Numerous significant relationships between sleep and pain measures were identified, but differences in sleep between the two groups were not found to mediate altered pain perception in MDMA users. Abstinent MDMA users have altered pain perception and sleep architecture. Although pain and sleep outcomes were related, differences in sleep architecture in MDMA users did not mediate altered pain responses. It remains to be determined whether alterations in pain perception in MDMA users are secondary to neurotoxicity of 5-HT-mediated pain pathways or alterations in other brain processes that modulate pain perception.