Carl A. Roberts

Electrophysiological indices of response inhibition in human polydrug users.

Previous research in ecstasy users suggests impairment of various executive functions. In general, the executive function of response inhibition appears unaffected by ecstasy use. Nonetheless, it remains a possibility that cognitive tasks alone are not sensitive enough to pick up subtle changes in function. The current study sought to investigate behavioural measures of response inhibition and their electrophysiological correlates in drug users. Twenty ecstasy polydrug users, 20 non-ecstasy polydrug users and 20 drug naïve controls were recruited. Participants completed questionnaires about their background drug use, sleep quality, fluid intelligence and mood state. Each individual also completed a Go/NoGo response inhibition task whilst electroencephalography (EEG) measures were recorded. Analysis of variance (ANOVA) revealed that there were no between-group differences on the behavioural measure of response inhibition. Multivariate analysis of variance (MANOVA) revealed no main effect of group across midline electrodes for the P3, N2 and P2 components. Univariate ANOVA revealed significant between-group differences in the P2 component with the ecstasy user group having a significantly higher mean amplitude than drug naïve controls at two midline frontal electrodes: at Fz and significantly higher mean amplitude than both control groups at FCz. The present study provides evidence of atypical early processing in ecstasy users that is suggestive of compensatory mechanisms ameliorating any behavioural differences.

Meta-analysis of molecular imaging of serotonin transporters in ecstasy/polydrug users.

We conducted a meta-analysis on the available data from studies investigating SERTs in ecstasy users and polydrug using controls. From 7 studies we compared data from 157 ecstasy users and 148 controls across 14 brain regions. The main effect suggested ecstasy/MDMA related SERT reductions (SMD=0.52, 95% CIs [0.40, 0.65]; Z=8.36, p<.01, I(2)=89%). A significant effect of subgroups (X(2)=37.41, df=13, p<.01, I(2)=65.3%) suggested differential effects across brain ROIs. Ecstasy users showed significant SERT reductions in 11 out of the 14 regions, including every neocortical and limbic region analysed. Greatest effects were observed in the occipital cortex (SMD=1.09, 95% CIs [0.70, 1.48]). No group effects were observed in subcortical areas of the caudate, putamen and midbrain. Literature on Postsynaptic 5HT2A receptor imaging was synthesised with these results. We conclude that, in line with preclinical data, serotonin axons with the longest projections from the raphe nuclei appear to be most affected by ecstasy/MDMA use.

Meta-analysis of executive functioning in ecstasy/polydrug users

Ecstasy/3,4-methylenedioxymethamphetamine (MDMA) use is proposed to cause damage to serotonergic (5-HT) axons in humans. Therefore, users should show deficits in cognitive processes that rely on serotonin-rich, prefrontal areas of the brain. However, there is inconsistency in findings to support this hypothesis. The aim of the current study was to examine deficits in executive functioning in ecstasy users compared with controls using meta-analysis. We identified k = 39 studies, contributing 89 effect sizes, investigating executive functioning in ecstasy users and polydrug-using controls. We compared function-specific task performance in 1221 current ecstasy users and 1242 drug-using controls, from tasks tapping the executive functions – updating, switching, inhibition and access to long-term memory. The significant main effect demonstrated overall executive dysfunction in ecstasy users [standardized mean difference (SMD) = −0.18, 95% confidence interval (CI) −0.26 to −0.11, Z = 5.05, p < 0.001, I2 = 82%], with a significant subgroup effect (χ2 = 22.06, degrees of freedom = 3, p < 0.001, I2 = 86.4%) demonstrating differential effects across executive functions. Ecstasy users showed significant performance deficits in access (SMD = −0.33, 95% CI −0.46 to −0.19, Z = 4.72, p < 0.001, I2 = 74%), switching (SMD = −0.19, 95% CI −0.36 to −0.02, Z = 2.16, p < 0.05, I2 = 85%) and updating (SMD = −0.26, 95% CI −0.37 to −0.15, Z = 4.49, p < 0.001, I2 = 82%). No differences were observed in inhibitory control. We conclude that this is the most comprehensive analysis of executive function in ecstasy users to date and provides a behavioural correlate of potential serotonergic neurotoxicity.

ERP evidence suggests executive dysfunction in ecstasy polydrug users

BackgroundDeficits in executive functions such as access to semantic/long-term memory have been shown in ecstasy users in previous research. Equally, there have been many reports of equivocal findings in this area. The current study sought to further investigate behavioural and electro-physiological measures of this executive function in ecstasy users.MethodTwenty ecstasy–polydrug users, 20 non-ecstasy–polydrug users and 20 drug-naïve controls were recruited. Participants completed background questionnaires about their drug use, sleep quality, fluid intelligence and mood state. Each individual also completed a semantic retrieval task whilst 64 channel Electroencephalography (EEG) measures were recorded.ResultsAnalysis of Variance (ANOVA) revealed no between-group differences in behavioural performance on the task. Mixed ANOVA on event-related potential (ERP) components P2, N2 and P3 revealed significant between-group differences in the N2 component. Subsequent exploratory univariate ANOVAs on the N2 component revealed marginally significant between-group differences, generally showing greater negativity at occipito-parietal electrodes in ecstasy users compared to drug-naïve controls. Despite absence of behavioural differences, differences in N2 magnitude are evidence of abnormal executive functioning in ecstasy–polydrug users.

Differences in prefrontal blood oxygenation during an acute multitasking stressor in ecstasy polydrug users

BACKGROUND Cognitive deficits are well documented in ecstasy (3,4-methylenedioxymethamphetamine; MDMA) users, with such deficits being taken as evidence of dysregulation of the serotonin (5-hydroxytryptamine; 5-HT) system. More recently neuroimaging has been used to corroborate these deficits. The present study aimed to assess multitasking performance in ecstasy polydrug users, polydrug users and drug-naive individuals. It was predicted that ecstasy polydrug users would perform worse than non-users on the behavioural measure and this would be supported by differences in cortical blood oxygenation. METHOD In the study, 20 ecstasy-polydrug users, 17 polydrug users and 19 drug-naive individuals took part. On day 1, drug use history was taken and questionnaire measures were completed. On day 2, participants completed a 20-min multitasking stressor while brain blood oxygenation was measured using functional near infrared spectroscopy (fNIRS). RESULTS There were no significant differences between the three groups on the subscales of the multitasking stressor. In addition, there were no significant differences on self-report measures of perceived workload (NASA Task Load Index). In terms of mood, ecstasy users were significantly less calm and less relaxed compared with drug-naive controls. There were also significant differences at three voxels on the fNIRS, indicating decreased blood oxygenation in ecstasy users compared with drug-naive controls at voxel 2 (left dorsolateral prefrontal cortex), voxel 14 and voxel 16 (right dorsolateral prefrontal cortex), and compared with polydrug controls at V14. CONCLUSIONS The results of the present study provide support for changes in brain activation during performance of demanding tasks in ecstasy polydrug users, which could be related to cerebral vasoconstriction.

Compensatory changes in energy balance during dapagliflozin treatment in type 2 diabetes mellitus: a randomised double-blind, placebo-controlled, cross-over trial (ENERGIZE)-study protocol.

Introduction Sodium glucose cotransporter 2 (SGLT2) inhibitors are effective blood-glucose-lowering medications with beneficial effects on body weight in patients with type 2 diabetes mellitus (T2DM). However, observed weight loss is less than that predicted from quantified glycosuria, suggesting a compensatory increase in energy intake or a decrease in energy expenditure. Studies using dual-energy X-ray absorptiometry (DEXA) have suggested most body weight change is due to loss of adipose tissue, but organ-specific changes in fat content (eg, liver, skeletal muscle) have not been determined. In this randomised, double-blind, placebo-controlled crossover study, we aim to study the compensatory changes in energy intake, eating behaviour and energy expenditure accompanying use of the SGLT2 inhibitor, dapagliflozin. Additionally, we aim to quantify changes in fat distribution using MRI, in liver fat using proton magnetic resonance spectroscopy (1H-MRS) and in central nervous system (CNS) responses to food images using blood oxygen level dependent (BOLD) functional MRI (fMRI). Methods and analysis This outpatient study will evaluate the effect of dapagliflozin (10 mg), compared with placebo, on food intake and energy expenditure at 7 days and 12 weeks. 52 patients with T2DM will be randomised to dapagliflozin or placebo for short-term and long-term trial interventions in a within participants, crossover design. The primary outcome is the difference in energy intake during a test meal between dapagliflozin and placebo. Intake data are collected automatically using a customised programme operating a universal eating monitor (UEM). Secondary outcomes include (1) measures of appetite regulation including rate of eating, satiety quotient, appetite ratings (between and within meals), changes in CNS responses to food images measured using BOLD-fMRI, (2) measures of energy expenditure and (3) changes in body composition including changes in liver fat and abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). Ethical approval This study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/0340) and is conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice (GCP). Trial registration number ISRCTN14818531. EUDRACT number 2013-004264-60.

Cortical oxygenation suggests increased effort during cognitive inhibition in ecstasy polydrug users.

Background: It is understood that 3,4-methylenedioxymethamphetamine (ecstasy) causes serotonin dysfunction and deficits in executive functioning. When investigating executive function, functional neuroimaging allows the physiological changes underlying these deficits to be investigated. The present study investigated behavioural and brain indices of inhibition in ecstasy-polydrug users. Methods: Twenty ecstasy-polydrug users and 20 drug-naïve participants completed an inhibitory control task (Random Letter Generation (RLG)) while prefrontal haemodynamic response was assessed using functional near infrared spectroscopy (fNIRS). Results: There were no group differences on background measures including sleep quality and mood state. There were also no behavioural differences between the two groups. However, ecstasy-polydrug users displayed significant increases in oxygenated haemoglobin (oxy-Hb) from baseline compared to controls at several voxels relating to areas of the inferior right medial prefrontal cortex, as well the right and left dorsolateral prefrontal cortex. Regression analysis revealed that recency of ecstasy use was a significant predictor of oxy-Hb increase at two voxels over the right hemisphere after controlling for alcohol and cannabis use indices. Conclusion: Ecstasy-polydrug users show increased neuronal activation in the prefrontal cortex compared to non-users. This is taken to be compensatory activation/recruitment of additional resources to attain similar performance levels on the task, which may be reversible with prolonged abstinence.

Recreational 3,4-methylenedioxymethamphetamine or ‘ecstasy’: Current perspective and future research prospects

Aims: The purpose of this article is to debate current understandings about the psychobiological effects of recreational 3,4-methylenedioxymethamphetamine (MDMA or ‘ecstasy’), and recommend theoretically-driven topics for future research. Methods: Recent empirical findings, especially those from novel topic areas were reviewed. Potential causes for the high variance often found in group findings were also examined. Results and conclusions: The first empirical reports into psychobiological and psychiatric aspects from the early 1990s concluded that regular users demonstrated some selective psychobiological deficits, for instance worse declarative memory, or heightened depression. More recent research has covered a far wider range of psychobiological functions, and deficits have emerged in aspects of vision, higher cognitive skill, neurohormonal functioning, and foetal developmental outcomes. However, variance levels are often high, indicating that while some recreational users develop problems, others are less affected. Potential reasons for this high variance are debated. An explanatory model based on multi-factorial causation is then proposed. Future directions: A number of theoretically driven research topics are suggested, in order to empirically investigate the potential causes for these diverse psychobiological deficits. Future neuroimaging studies should study the practical implications of any serotonergic and/or neurohormonal changes, using a wide range of functional measures.

Electrophysiological evidence of atypical processing underlying mental set shifting in ecstasy polydrug and polydrug users.

Executive functioning deficits are reported in ecstasy users. However research into mental set switching has been equivocal, with behavioral studies suggesting the function is preserved. The current study sought to address the issue of switching deficits in ecstasy users by combining behavioral performance with electrophysiological correlates (electroencephalography; EEG). Twenty ecstasy polydrug users, 20 nonecstasy polydrug users, and 20 drug naive controls were recruited. Participants completed questionnaires about their drug use, sleep quality, fluid intelligence, and current mood state. Each participant completed a mental set switching task (the number-letter task) while EEG measures were recorded. Analysis of variance (ANOVA) revealed no between-group differences on performance of the task; however a regression suggested that ecstasy use was a significant predictor for performance, after controlling for cannabis use. Mixed ANOVA revealed a significant effect of group on the P3, with significant differences between both drug groups and naives. There was also an interaction between electrode and group on the P2 component, with ecstasy users differing from both other groups. On the P3 component the results suggest a reduction in positivity at parieto-occipital electrodes for drug users compared to controls. Furthermore a significant increase in negativity in ecstasy users compared to control groups could be observed in several occipito-parietal electrodes at an N2 component as well as observable atypicalities in early processing (P2) displayed by ecstasy users and polydrug controls. The present study provides evidence of atypical processing of attentional shifting in ecstasy and polydrug users. Deficits in this executive function could reflect cognitive inflexibility and paucity of rapid behavioral adjustment, which may be problematic in real world situations.

Tailoring pharmacotherapy to specific eating behaviours in obesity: Can recommendations for personalised therapy be made from the current data?

Abstract Pharmacotherapy provides an adjunct to behaviour modification in the management of obesity. There are a number of new drug therapies purportedly targeting appetite; liraglutide, and bupropion/naltrexone, which are European Medicines Agency and US Food and Drug Administration (FDA) approved, and lorcaserin and phentermine/topiramate, which have FDA approval only. Each of the six drugs, used singly or in combination, has distinct pharmacological, and presumably distinct behavioural, mechanisms of action, thus the potential to provide defined therapeutic options to personalise the management of obesity. Yet, with regard to pharmacotherapy for obesity, we are far from true personalised medicine. We review the limited mechanistic data with four mono and combination pharmacotherapies, to assess the potential for tailoring their use to target specific obesogenic behaviours. Potential treatment options are considered, but in the absence of adequate research in respect to effects of these drugs on eating behaviour, neural activity and psychological substrates that underlie poorly controlled eating, we are far from definitive therapeutic recommendations. Specific mechanistic studies and broader behavioural phenotyping, possibly in conjunction with pharmacogenetic research, are required to characterise responders for distinct pharmacotherapeutic options.