The confounding problem of polydrug use in recreational ecstasy/MDMA users: a brief overview

The popular dance drug ecstasy (3,4-methylenedioxymethamphetamine -- MDMA) is neurotoxic upon central serotonergic neurons in laboratory animals and possibly also in humans. In recent years, several studies reported alterations of serotonergic transmission and neuropsychiatric abnormalities in ecstasy users which might be related to MDMA-induced neurotoxic brain damage. To date, the most consistent findings associate subtle cognitive, particularly memory, deficits with heavy ecstasy use. However, most studies have important inherent methodological problems. One of the most serious confounds is the widespread pattern of polydrug use which makes it dif.cult to relate the findings in user populations to one specific drug. The present paper represents a brief overview on this issue. The most commonly co-used substances are alcohol, cannabis and stimulants (amphetamines and cocaine). Stimulants are also neurotoxic upon both serotonergic and dopaminergic neurons. Hence, they may act synergistically with MDMA and enhance its long-term adverse effects. The interactions between MDMA and cannabis use may be more complex: cannabis use is a well-recognized risk factor for neuropsychiatric disorders and it was shown to contribute to psychological problems and cognitive failures in ecstasy users. However, at the cellular level, cannabinoids have neuroprotective actions and they were shown to (partially) block MDMA-induced neurotoxicity in laboratory animals. In future, longitudinal and prospective research designs should hopefully lead to a better understanding of the relation between drug use and subclinical psychological symptoms or neurocognitive failures and, also, of questions around interactions between the various substances of abuse.     

The sub-acute effects of recreational ecstasy (MDMA) use: a controlled study in humans

All previous studies of the sub-acute effects of ecstasy have failed to adequately control for group differences in psychopathology and past and concurrent substance use. The present study was designed to avoid these limitations. At an initial pre-drug baseline, a sample of 38 regular ecstasy users provided full substance histories and completed measures of personality and self-reported psychopathology. We then collected daily subjective measures of mood, cognitive impairment, restless sleep, sexual desire, craving for ecstasy and concomitant use of other substances for the next 9 days. The 20 participants who subsequently opted to take ecstasy during the 9-day assessment period reported modest sub-acute effects of ecstasy on negative mood and subjective cognitive impairment compared to those who did not after controlling for baseline group differences in psychopathology and frequency of ecstasy use. There were no significant sub-acute effects of ecstasy on interest in sexual activity or craving for ecstasy. After further controlling for co-use of alcohol with ecstasy, and the sub-acute effects of ecstasy on sleep, the sub-acute effect on mood remained marginally statistically significant but the subacute effect on cognitive impairment did not. The present findings suggest that the sub-acute effects of ecstasy in regular recreational users are relatively modest and transient but that such genuine effects may have been masked by, perhaps more clinically significant, chronic sequelae of regular ecstasy use in all previous studies of recreational ecstasy users.     

Decreased pain tolerance and mood in recreational users of MDMA

Rationale 3,4-Methylenedioxymethamphetamine (MDMA) is known to affect brain serotonin (5-HT) neurons in experimental animals. However, its effects on humans are more difficult to infer. Serotonin is implicated in the bodys ability to modulate the effects of pain and to regulate mood.Objective The aim of this research is to test nociceptive responses and mood in MDMA users as an index of central 5-HT function.Method Measurements of pain tolerance were obtained using the cold-pressor test for 15 polydrug users who regularly use MDMA, 3–4 days after the most recent usage, and ten matched polydrug users who do not use MDMA. A rating on mood was obtained for each participant using the Nowlis Mood Adjective checklist.Results Measurements of pain tolerance and mood were significantly lower in the MDMA group. A positive correlation between mood and pain tolerance was found in the MDMA group, whereas no correlation was found between these variables in the non-MDMA groupConclusion This study found an association between pain tolerance and MDMA usage and confirmed the association between MDMA and depressed mood. The current results suggest that MDMA, at least in the short term, may cause serotonin-mediated alterations in pain sensitivity.     

Cognitive performance in recreational ecstasy polydrug users: a two-year follow-up study

There is important preclinical evidence of long lasting neurotoxic and selective effects of ecstasy MDMA on serotonin systems in non-human primates. In humans long-term recreational use of ecstasy has been mainly associated with learning and memory impairments. The aim of the present study was to investigate the neuropsychological profile associated with ecstasy use within recreational polydrug users, and describe the cognitive changes related to maintained or variable ecstasy use along a two years period. We administered cognitive measures of attention, executive functions, memory and learning to three groups of participants: 37 current polydrug users with regular consumption of ecstasy and cannabis, 23 current cannabis users and 34 non-users free of illicit drugs. Four cognitive assessments were conducted during two years. At baseline, ecstasy polydrug users showed significantly poorer performance than cannabis users and non-drug using controls in a measure of semantic word fluency. When ecstasy users were classified according to lifetime use of ecstasy, the more severe users (more than 100 tablets) showed additional deficits on episodic memory. After two years ecstasy users showed persistent deficits on verbal fluency, working memory and processing speed. These findings should be interpreted with caution, since the possibility of premorbid group differences cannot be entirely excluded. Our findings support that ecstasy use, or ecstasy/cannabis synergic effects, are responsible for the sub-clinical deficits observed in ecstasy polydrug users, and provides additional evidence for long-term cognitive impairment owing to ecstasy consumption in the context of polydrug use.     

Self-reported ecstasy use: the impact of assessment method on dosage estimates in recreational users

While research has associated recreational ecstasy use with negative outcomes, there remain a number of methodological limitations of human studies. The present study examined the impact of self-report methodology on lifetime ecstasy dosage figures using three estimation methods: a single question estimation, a context-based timeline method and a quantity-frequency method. We used a repeated measures design, testing 38 participants aged over 18 years who reported using ecstasy on ten or more occasions. Methodology was found to impact on estimations made, with the timeline method producing higher figures than the single question. While single question and timeline estimations were positively correlated, there was no relationship between either of these methods and the quantity-frequency method. The present findings are in keeping with indications in the alcohol and other drug literature that the use of contextual memory cues increases accuracy of recall as indicated by higher estimations, and that quantity-frequency methods may not adequately assess variability in lifetime drug-use patterns.     

Plasticity of the acoustic startle reflex in currently abstinent ecstasy (MDMA) users

Rationale 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is neurotoxic upon central serotonin systems in experimental animals and probably also in humans. Serotonin is involved in the habituation, sensitization and prepulse inhibition (PPI) of the startle reflex.Objectives To study the plasticity of startle reflex in currently abstinent MDMA users.Methods Electromyographic responses to acoustic startle stimuli (pulse alone and prepulse-pulse trials) were recorded in 23 currently abstinent ecstasy users and 20 matched control subjects. Depending on the extent of their previous drug use ecstasy users were divided into two groups [life-time dose <90 (n=11) and 90 pills (n=12), respectively].Results There were no significant differences in habituation, sensitization or PPI of the startle reflex between the entire group of ecstasy users and controls. However, sensitization of the startle reflex was stronger in the 90 compared with either the <90 MDMA pills or the control group. Correlations between patterns of drug use and startle parameters did not reach the level of significance, although users with a younger age at the onset of MDMA (and other drug) use tended to present with higher sensitization of the startle reflex.Conclusions Heavy users of MDMA (and other recreational drugs) present with strong sensitization of the startle reflex. Nevertheless, it is unclear whether this finding is secondary to the use of MDMA and its well-recognized neurotoxic potential. Alternatively, strong sensitization might reflect a pre-existing trait predisposing to drug use. A clearer picture of the impact of ecstasy on startle plasticity may be obtained from longitudinal investigations.     

Memory deficits in abstinent MDMA (ecstasy) users: neuropsychological evidence of frontal dysfunction

Chronic administration of the common club drug 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is associated with long-term depletion of serotonin (5-HT) and loss of 5-HT axons in the brains of rodents and non-human primates, and evidence suggests that recreational MDMA consumption may also affect the human serotonergic system. Moreover, it was consistently shown that abstinent MDMA users have memory deficits. Recently, it was supposed that these deficits are an expression of a temporal or rather hippocampal dysfunction caused by the serotonergic neurotoxicity of MDMA. The aim of this study is to examine the memory deficits of MDMA users neuropsychologically in order to evaluate the role of different brain regions. Nineteen male abstinent MDMA users, 19 male abstinent cannabis users and 19 male drug-naive control subjects were examined with a German version of the Rey Auditory Verbal Learning Test (RAVLT). MDMA users showed widespread and marked verbal memory deficits, compared to drug-naive controls as well as compared to cannabis users, whereas cannabis users did not differ from control subjects in their memory performance. MDMA users revealed impairments in learning, consolidation, recall and recognition. In addition, they also showed a worse recall consistency and strong retroactive interference whereby both measures were previously associated with frontal lobe function. There was a significant correlation between memory performance and the amount of MDMA taken. These results suggest that the memory deficits of MDMA users are not only the result of a temporal or hippocampal dysfunction, but also of a dysfunction of regions within the frontal cortex.     

Drug use practices among MDMA/ecstasy users in Ohio: a latent class analysis

This study describes the drug use practices among 402 recent MDMA (3,4-methelyenedioxymethamphetamine) users recruited in Ohio using respondent-driven sampling. About 64% of the participants were men, 81.6% were white, and the mean age was 20.9 years. Latent class analysis was used to identify subgroups of MDMA users. Use of cocaine, opioids, amphetamines, tranquilizers, inhalants, marijuana, and hallucinogens during the previous 6 months, and days of "drunkenness" in the past 30, were used for classification. A three-class model was preferable and reflected "Limited range," "Moderate range," and "Wide range" drug use patterns. For example, the conditional probability of using opioids during the previous 6 months was .07 in Class 1, .59 in Class 2, and .88 in Class 3. Other substances followed similar patterns. Predictors of class membership were examined in a multinomial logit model in which the "Limited range" Class was treated as the reference group. Participants who were white, younger, and who reported more than 10 occasions of MDMA use were more likely to be in the "Wide range" drug use Class. Latent class analysis is a useful method to help describe and understand variability in polydrug use patterns.     

Gender differences in self-reported anxiety, depression, and somatization among ecstasy/MDMA polydrug users, alcohol/tobacco users, and nondrug users

Previous research has found gender differences in both psychological and physiological responses to drugs. The present investigation explores gender variability in patterns of drug use in relation to self-reported depression, anxiety, and somatization. The current study confirms that heavy illegal drug users are represented by a preponderance of males than females. However, within each drug group category, females generally reported higher psychopathology scores than males. This was significant for all three subscales in the alcohol/tobacco group, for depression scores in the alcohol/tobacco, cannabis/alcohol, and light Ecstasy users group, and for depression scores for the alcohol group. Interestingly, in the male sample, drug users reported higher symptom ratings than nondrug users, whereas women's scores remained constant across drug groups.     

Contextual profiles of young adult ecstasy users: A multisite study

These analyses assess contextual profiles of 612 young adult ecstasy users, 18-30 years of age, from St. Louis (USA), Miami (USA) and Sydney (Australia). Bivariate analyses revealed different contextual factors influencing ecstasy use. Friends were the most common sources of ecstasy at all sites and most used with friends. St. Louis and Miami use mostly occurred in residences, whereas in Sydney use was mostly at clubs, bars or restaurants. Ecstasy consumption at public places and in cars, trains or ferries was significantly higher in Miami (89% and 77%) than in St. Louis (67% and 65%) and Sydney (67% and 61%). At all sites, simultaneous use of LSD/mushroom and nitrous oxide with ecstasy was common; concurrent amphetamines predominated in Sydney and heroin/opiates in St. Louis Contextual factors influencing ecstasy use among young adults vary by geographic region. Their inclusion may help tailor effective prevention programs to reduce or ameliorate ecstasy use.     

Neurotoxicity of MDMA (ecstasy): the limitations of scaling from animals to humans

Several studies suggest that MDMA-induced acute toxicity and long-term neurotoxicity is dependent on the metabolic disposition of MDMA. Differences in MDMA metabolism among animal species might therefore account for different sensitivities to its neurotoxic effects. The kinetic parameters of enzymes that regulate the formation of neurotoxic metabolites of MDMA differ among species, as does the ability of MDMA to self-inhibit these enzymes and the degree of genetic polymorphisms exhibited by these enzymes. Such features limit allometric scaling across animal models.     

Mood,cognition and serotonin transporter availability in current and former ecstasy (MDMA) users

Rationale. Chronic recreational ecstasy (MDMA) use has often been reported to be associated with psychopathology, memory impairments and serotonergic alterations. However, the findings have not been consistent. Objectives. To attempt to replicate these findings, to investigate whether such alterations would be reversible and whether they could be predicted by parameters of previous drug use. Methods. In a cross-sectional design, 30 current and 31 ex-ecstasy users with ecstasy abstinence of at least 5 months, and 29 polydrug and 30 drug-naive controls were compared on measures of psychopathology, cognitive performance and serotonin transporter availability. Results. The groups did not differ significantly in age, gender distribution, education level and premorbid intelligence. The ecstasy groups did not differ significantly from polydrug controls on most of the relevant parameters of concomitant illegal drug use. Reported drug use was confirmed by hair and urine analyses. All three groups of drug users exhibited significantly elevated psychopathology compared with drug-naive controls. Only ex-ecstasy users were significantly impaired on verbal recall. Current ecstasy users showed significantly reduced distribution volume ratios of serotonin transporter availability in the mesencephalon and caudate nucleus. Regression analyses indicated that psychopathology and serotonergic alterations were best predicted by the number of ecstasy tablets taken on a typical event. Conclusion. The results indicate that verbal memory impairments were possibly aggravated after prolonged ecstasy abstinence while there was tentative evidence of serotonergic recovery. On the other hand, self-reported elevated psychopathology appeared to be associated with polydrug use in general and not specifically with ecstasy use. Electronic Publication     

Mood, cognition and serotonin transporter availability in current and former ecstasy (MDMA) users: the longitudinal perspective

Although 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a known serotonergic neurotoxin in different animal species, there is to date no conclusive evidence of its neurotoxicity in humans. MDMA use was associated with impairments of psychological well-being, verbal memory and altered serotonergic functioning in a number of cross-sectional studies. Due to inherent methodological limitations, such as the notorious polydrug use of ecstasy users and lack of control of possible pre-existing differences between ecstasy users and control participants, researchers have called for well-controlled, prospective longitudinal studies to shed more light on the issue of MDMA neurotoxicity to the human brain. This longitudinal study investigated whether mood, cognition and central serotonin transporters (SERT) would deteriorate with continued MDMA use and whether or not they would recover over increasing periods of MDMA abstinence. In a repeated-measures design, 11 current and ten ex-ecstasy users, and 11 polydrug (but not MDMA) and 15 drug-naive controls participated three times within approximately two years. Both ecstasy user groups reported a polydrug use pattern besides heavy ecstasy use. Subjective reports of ecstasy use or abstinence were verified by toxicological analyses. On each trial, the participants underwent a cognitive test battery and filled in the Symptom Check List. The availability of central SERT was assessed with positron emission tomography using the McN5652 ligand for all groups at t1, and only for the ecstasy user groups on follow-ups. The factor Group yielded significant results in the SCL-90 scales Global Severity Index, Anxiety, Obsessive/compulsive and Interpersonal sensitivity, with the ex-ecstasy users reporting the highest symptom scores. There were significant Group effects in all measures of verbal memory, with the lowest performance in the group of ex-ecstasy users. The repeated-measures analyses yielded no significant Group x Time interactions in any SCL-90 scales or measures of memory performance, with the exception of AVLT 1 immediate recall. Thus the ex-ecstasy users' psychopathological symptoms and memory performance failed to improve, and the current ecstasy users' failed to deteriorate, over time relative to the other groups. While there was a significant effect of Group in all brain regions examined (except the control region white matter), the current users' SERT availability seems to have recovered in the mesencephalon, as indicated by a significant Group x Time interaction. Reduced SERT availability might be a transient effect of heavy ecstasy use, since it partially recovered as the current users reduced their MDMA use. However, this measure may not necessarily be a valid indicator of the number or integrity of serotonergic neurons. Ex-ecstasy users' verbal memory showed no sign of improvement even after over 2.5 years of abstinence and thus may represent persistent functional consequences of MDMA neurotoxicity. However, alternative causes such as pre-existing group differences cannot be completely ruled out in spite of the longitudinal design.     

Self-reported psychopathological symptoms in recreational ecstasy (MDMA) users are mainly associated with regular cannabis use: further evidence from a combined cross-sectional/longitudinal investigation

Rationale 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) has become a widely used recreational drug among young people. This is of great concern, since MDMA is neurotoxic in animal studies and its use has been associated with psychological distress and a variety of self-reported psychiatric symptoms. However, exploring the origins of psychopathology in ecstasy users is hampered by the frequent polydrug use and by the cross-sectional design of all investigations, so far.Objectives The present study combines a cross-sectional with a longitudinal approach to further clarify the impact of the use of other illicit drugs on psychopathological symptoms reported by ecstasy users.Methods At baseline, we administered self-rating scales for impulsivity, sensation seeking and general psychological complaints to 60 recreational ecstasy users and 30 matched controls. From the initial sample of ecstasy users, 38 subjects were re-examined 18 months later.Results At baseline, ecstasy users reported significantly more psychological complaints than controls. However, self-reported psychopathology was mainly associated with regular cannabis use. At follow-up, subjects who had abstained from ecstasy use during the follow-up period did not differ from those reporting continued consumption. In contrast, subjects with regular concomitant cannabis use during the follow-up period reported more anxiety, interpersonal sensitivity and obsessive-compulsive behaviour than cannabis-abstinent users. Finally, higher levels of obsessive-compulsive behaviour, interpersonal sensitivity, depression, anxiety, phobic anxiety and paranoid ideation were significantly correlated with the duration of regular interim cannabis use.Conclusions The present findings suggest that self-reported psychopathology in ecstasy users is predominantly attributable to concomitant use of cannabis. Abstinence from cannabis and not ecstasy seems to be a reliable predictor for remission of psychological complaints in ecstasy users.     

Alcohol, cannabis, ecstasy and cocaine: drugs of reasoned choice amongst young adult recreational drug users in England

This paper describes the current drugs consumption patterns of a cohort of English young adults who have been tracked, longitudinally, since they were fourteen. It compares their tobacco, alcohol and illicit drugs consumption at 22 years (n=465) with when they were 18 years (n=529) using self-report questionnaires and in-depth interviews (n=86). It further explores whether, as a very drugwise/experienced sample of adolescents, this cohort are now beginning to settle down and reduce their substance use. The results suggest that any reductions in recreational drug use are likely to be delayed beyond traditional markers. The cohort have largely maintained their consumption habits with rates for current tobacco smoking (35.5%), regular drinking (82.3%), on-going drug involvement (past year, any drug, 52.1%) and more regular use (past month, any drug, 31.2%) being almost identical to their rates at 18 years. Current drug involvement is increasingly dominated by cannabis however. A minority continue to use ecstasy. LSD and amphetamine use have declined but cocaine trying (lifetime prevalence 5.9% at 18 years up to 24.6%) and use have increased dramatically. Mixing and combining substances is commonplace. Hedonistic motives for these substance use patterns remain but are now joined by the need to use psycho-active repertoires ‘sensibly’ to relax and reduce the stresses of the working week. This style of recreational drug use by generally conforming adults offers a severe challenge to current national drugs strategy.     

Contribution of cannabis and MDMA ("ecstasy") to cognitive changes in long-term polydrug users

Rationale Establishing whether cognitive changes follow long-term use of MDMA ("ecstasy") in humans has been difficult because of possible confounds with other drug use, particularly cannabis. Convincing evidence may be only obtained using experimental designs that account for such confounds.Objective In the present study, cognitive/behavioural measures were used to investigate whether long-term MDMA use or long-term cannabis use is responsible for the changes sometimes observed in recreational MDMA users.Method Tests of attention and memory were administered to subjects who used both MDMA and cannabis, cannabis only, or neither drug.Results The main finding was that cannabis users, whether or not they also used MDMA, showed significantly impaired memory function on word free-recall and on immediate and delayed story recall compared to non-users.Conclusions The findings highlight the importance of controlling for other drug use (particularly cannabis) when investigating persistent effects of MDMA in humans.