Jon C. Cole

Altered states: the clinical effects of Ecstasy

Ecstasy is the second most widely abused illegal drug in Europe. Ecstasy is the colloquial name for 3,4-methylenedioxymethamphetamine (MDMA), but not all Ecstasy tablets contain MDMA. When taken in hot, crowded environments, Ecstasy/MDMA users have developed acute complications that have had fatal consequences. Epidemiological evidence indicates that adverse reactions to Ecstasy/MDMA intoxication are rare and idiosyncratic. Potential mechanisms of action are reviewed. In animal studies, MDMA damages serotonergic fibres and reduces the number of serotonin transporter sites within the CNS. Demonstration of neurotoxicity in human users of Ecstasy is hampered by a number of confounds that the majority of published studies have failed to address. These confounds are reviewed and their impact is discussed.

The pre-clinical behavioural pharmacology of 3,4-methylenedioxymethamphetamine (MDMA).

3,4-Methylenedioxymethamphetamine (MDMA) is a relatively novel drug of abuse and as such little is currently known of its behavioural pharmacology. This review aims to examine whether MDMA represents a novel class of abused drug. MDMA is known as a selective serotonergic neurotoxin in a variety of animal species but acutely it is a potent releaser and/or reuptake inhibitor of presynaptic serotonin, dopamine, noradrenaline, and acetylcholine. Interaction of these effects contributes to its behavioural pharmacology, in particular its effects on body temperature. Drug discrimination studies indicate that MDMA and related drugs produce unique interoceptive effects which have led to their classification as entactogens. This is supported by results from other behavioural paradigms although there is evidence for dose dependency of MDMA-specific effects. MDMA also produces conditioned place preference but is not a potent reinforcer in self-administration studies. These unique behavioural effects probably underlie its current popularity. MDMA is found in the street drug ecstasy but it may not be appropriate to equate the two as other drugs are routinely found in ecstasy tablets

Risk-taking but not response inhibition or delay discounting predict alcohol consumption in social drinkers

Impulsivity and risk-taking are multi-dimensional constructs that have been implicated in heavy drinking and alcohol problems. Our aim was to identify the specific component of impulsivity or risk-taking that explained the greatest variance in heavy and problem drinking among a sample of young adults recruited from a university population. Participants (N=75) completed a test battery comprising two commonly used response inhibition tasks (a Go/No-Go task and a Stop signal task), a delay discounting procedure, and the Balloon Analogue Risk Task (BART) as a measure of risk-taking. Participants also completed the Barratt Impulsivity Scales (BIS) as a measure of trait impulsivity. In a hierarchical multiple regression model, risk-taking was identified as the only behavioural measure that predicted alcohol use and problems. In a secondary analysis, we demonstrated that risk-taking predicted unique variance in alcohol use and problems over and above that explained by trait impulsivity. Results suggest that among young adults, a behavioural measure of risk-taking predicts variance in alcohol consumption and alcohol problems, even when individual differences in trait impulsivity are statistically controlled. However, behavioural measures of response inhibition and delay discounting do not predict unique variance in alcohol use in young adult social drinkers.

Multiple behavioural impulsivity tasks predict prospective alcohol involvement in adolescents

Aims We investigated reciprocal prospective relationships between multiple behavioural impulsivity tasks (assessing delay discounting, risk-taking and disinhibition) and alcohol involvement (consumption, drunkenness and problems) among adolescents. We hypothesized that performance on the tasks would predict subsequent alcohol involvement, and that alcohol involvement would lead to increases in behavioural impulsivity over time. Design Cross-lagged prospective design in which impulsivity and alcohol involvement were assessed five times over 2 years (once every 6 months, on average). Setting Classrooms in secondary schools in North West England. Participants Two hundred and eighty-seven adolescents (51.2% male) who were aged 12 or 13 years at study enrolment. Measurements Participants reported their alcohol involvement and completed computerized tasks of disinhibition, delay discounting and risk-taking at each assessment. Cross-sectional and prospective relationships between the variables of interest were investigated using cross-lagged analyses. Findings All behavioural impulsivity tasks predicted a composite index of alcohol involvement 6 months later (all Ps < 0.01), and these prospective relationships were reliable across the majority of time-points. Importantly, we did not observe the converse relationship across time: alcohol involvement did not predict performance on behavioural impulsivity tasks at any subsequent time point. Conclusions Several measures of impulsivity predict escalation in alcohol involvement in young adolescents, but alcohol use does not appear to alter impulsivity.

The varieties of ecstatic experience: an exploration of the subjective experiences of ecstasy

Previous investigations of the subjective effects of MDMA (material sold as ecstasy) have conducted interviews and surveys of various groups of ecstasy users within particular sub-populations. This study examined subjective drug effects reported by different sub-populations of ecstasy users and explored whether the function or purpose served by using ecstasy influenced the nature of the drug experience. Drawing on previous measures of alterations in consciousness, psychedelic drugs and cannabis, and informal interviews with ecstasy users and MDMA researchers, a 130-item survey assessing subjective effects of ecstasy/MDMA was developed. Principal components analysis of responses of ecstasy users revealed six components; perceptual alterations, entactogenic effects, prosocial effects, aesthetic effects, negative effects and sexual effects. The derived scale was used to predict ecstasy use behaviours, and functions and experiences of use. A variety of component scores were related to ecstasy use parameters; in particular, heavier users expected fewer negative, perceptual and aesthetic effects from taking the drug. The reasons given for using ecstasy (use function) also influenced reported drug effects. Abstainers expected greater negative, perceptual, aesthetic and sexual effects than users. These data indicate that the subjective ecstasy experience is influenced by a variety of extra-psychopharmacological factors. Drug intervention strategies may be made more effective by targeting particular user groups defined by reasons given for substance use, as it is likely that their experiences of ecstasy effects will differ. Future research into ecstasy may be improved by recognizing user diversity.

Components of behavioural impulsivity and automatic cue approach predict unique variance in hazardous drinking

RationaleHazardous drinking is associated with both increased impulsivity and automatic approach tendencies elicited by alcohol-related cues. However, impulsivity is a multi-factorial construct, and it is currently unclear if all components of impulsivity are associated with heavy drinking. Furthermore, emerging evidence suggests that the relationships between hazardous drinking and automatic alcohol cognitions may be moderated by individual differences in impulsivity.ObjectivesThe aim of this study was to investigate the independence of measures of impulsivity and their association with hazardous drinking, and to examine if the relationship between hazardous drinking and automatic alcohol approach tendencies would be moderated by individual differences in impulsivity.MethodsNinety-seven social drinkers (65 female) completed questionnaire measures of trait impulsivity, alcohol consumption and hazardous drinking. Participants also completed computerised measures of automatic alcohol approach tendencies (stimulus–response compatibility (SRC) task), and two behavioural measures of impulsivity (Go/No-go and delay discounting tasks).ResultsPrincipal component analysis revealed that the two measures of behavioural impulsivity were distinct from each other and from self-reported trait impulsivity, although self-reported non-planning impulsivity loaded on to two factors (trait impulsivity and delay discounting). Furthermore, all measures of impulsivity predicted unique variance in hazardous drinking as did automatic alcohol approach tendencies, although the latter relationship was not moderated by impulsivity.ConclusionsThese results indicate that multiple components of impulsivity and automatic alcohol approach tendencies explain unique variance in hazardous drinking.

Self-reported depressive symptomatology in community samples of polysubstance misusers who report Ecstasy use: a meta-analysis

National drugs information strategies convey the message that use of Ecstasy is associated with an increase in both the incidence and severity of major depressive disorder. However, very little primary research supports this. Unlike apparent deficits in higher cognitive functions, most published studies have found no difference in self-reported depressive symptomatology between Ecstasy users and controls. To investigate this further, we conducted a meta-analysis of studies investigating depressive symptomatology in recreational users of Ecstasy. According to selection criteria, we identified 25 relevant studies. A statistically significant effect size (ES) of 0.31 (95% confidence interval 0.17-0.37, p< 0.001) was calculated. Significance remained after examining the small number of studies that controlled for cannabis use (n = 9, p< 0.001) but, in general, drug histories were poorly reported. There was an association between ES and lifetime Ecstasy exposure (p< 0.001), but not for other use parameters or abstention (p> 0.05). These data indicate that there is an association between Ecstasy use and depressive symptomatology, but this is small and unlikely to be clinically relevant. In addition, the self-report scales used may be heavily confounded by the somatic effects of substance misuse. Public health strategies derived from psychopharmacological investigations should acknowledge the potential negative effects of substance misuse but qualify the difficulties in interpreting research studies.

Self-reported psychopathology in polydrug users

There is a large body of work investigating concurrent associations between polysubstance use and psychopathology, but much of this work has either pre-dated or failed to account for the complex and culturally specific patterns of contemporary drug use. In particular, attendees of dance music events report a greater drug history than their peers and engage in a unique lifestyle. To further investigate the consequences of this type of drug use, 100 subjects who regularly attended dance music events were administered a battery of self-report psychiatric symptom scales. This battery contained the Anxiety Sensitivity Index, the Beck Anxiety Inventory (BAI), the Center for Epidemiologic Studies Depression scale (CES-D), the Dissociative Experiences Scale, the Padua Inventory Revised and additional questions about substance use. Our study population included abstainers and drug users with a wide history of use. We demonstrated strong associations between use of many different drugs, suggesting that polydrug use is the norm in this type of population. We found weak, but statistically significant, correlations between use of alcohol (p < 0.05), amphetamine (p < 0.01) and ecstasy (p < 0.01) with self-reported score on the BAI. There were also positive associations between dissociative symptomatology and the use of amphetamine (p < 0.05) and cocaine (p < 0.05). Furthermore, weekly unit intake of alcohol positively correlated with score on the CES-D (p < 0.05). As polydrug use was the norm in this sample, we performed regression analysis to investigate the contribution of multiple drug use on self-report. This showed that weekly use of alcohol, and frequency of use of amyl nitrate and cigarettes were significant predictors of BAI score. However, the majority of subjects reported being unworried by these symptoms, which may represent a lack of self-awareness, or acceptance of them as the subacute effects of substance use. It remains to be determined at what point adverse effects of drug use begin to interfere with day-to-day life.

Social defeat increases alcohol preference of C57BL/10 strain mice; effect prevented by a CCKB antagonist

RationaleIn humans, social stress over long and short term can increase alcohol consumption, but the mechanisms involved are not understood.ObjectivesThis study was conducted to examine the effects of social defeat, using the resident/intruder paradigm, on the alcohol preference of “low alcohol drinking” individuals in a colony of C57BL/10 strain mice and the effects of two anxiolytic drugs.MethodsAlcohol preference, in a two-bottle choice (8% v/v alcohol or water), was measured, in separate experiments, after either a single experience of social defeat by a resident male mouse, five consecutive daily defeat experiences or one experience per week for 4 weeks. Comparison was made with effects of repeated social defeat on the preference for dilute sucrose. In addition, the actions of the CCKB receptor antagonist, CAM1028, and of diazepam were examined on the effects of repeated defeat experiences.ResultsFive consecutive daily defeat experiences had a slow onset effect in increasing alcohol preference and consumption, compared with five daily exposures to a novel environment. A single defeat, or one defeat per week, did not significantly alter alcohol preference or intake. There were no effects of five daily defeat experiences on sucrose preference or consumption. The effect of repeated defeats on alcohol preference was significantly decreased by administration of the CCKB receptor antagonist, CAM1028, prior to each experience, but not by corresponding administration of diazepam.ConclusionThe results show that social stress increases alcohol intake in low alcohol preference C57BL/10 mice and suggest that CCK transmission may be involved in this effect.

Acamprosate, but not naltrexone, inhibits conditioned abstinence behaviour associated with repeated ethanol administration and exposure to a plus-maze.

Abstract Rationale: Drugs that reduce relapse in alcoholics are thought to inhibit either positive reinforcement for drinking (e.g. naltrexone) or negative reinforcement (e.g. acamprosate), and may reduce the impact of conditioned stimuli associated with previous alcohol use. We have developed a model for such conditioning by repeatedly pairing ethanol administration with plus-maze exposure. Substitution of saline for ethanol greatly increased stretched-attend postures and time in the central square, conditioned to the environment. Objective: To test the hypothesis that if this behaviour indicates a negative affective state caused by the expectation of ethanol, it should be inhibited by drugs that reduce negative, but not positive, reinforcement. Methods: The effects of naltrexone and acamprosate on alcohol-conditioned abstinence behaviour were compared. Results: Acute administration of either drug alone produced no significant effects on plus-maze behaviour in naive mice. Naltrexone had no significant effect on the alcohol-conditioned abstinence behaviour, but acamprosate reduced the incidence of stretched-attend postures. Conclusions: The experiments replicated previous findings for alcohol/environment conditioned behaviour, and demonstrated, as predicted, that this was decreased by acamprosate but not by naltrexone. Effects of acamprosate on conditioned negative reinforcement may be the cause of this effect, but more work is required to establish the usefulness of this model in evaluation of anti-relapse drugs.