Background. The neuropathology of anxiety disorders, including specific phobias, social phobias, and generalized anxiety disorders (GAD), has been believed to be rooted in a reduced inhibition of limbic areas by the dorsolateral prefrontal cortex (DLPFC). Trait anxiety has been linked to insufficient recruitment of DLPFC mechanisms for attentional control. Despite limited research on individuals with anxiety disorders, our study utilized transcranial magnetic stimulation to assess DLPFC cortical activity and emotional states using the N100 as an indicator of GABA-B-mediated cortical inhibition. Additionally, we aimed to correlate trait anxiety scores with cortical activity. Methods. A total of 20 subjects with social phobia and GAD and 21 subjects with specific phobia were compared to 24 control subjects regarding their inhibitory N100 in the DLPFC. Therefore, TMS was applied on the left and right DLPFC during an emotional task with fearful, angry, and neutral faces and a rest condition. Results. Smaller N100 amplitudes after DLPFC stimulation were found in subjects with social phobia, GAD, and social phobias compared to the control group. Furthermore, a correlation between trait anxiety scores and smaller N100 amplitudes, independent of group effects, was found. Conclusion. There appears to be a decrease in GABA-B-mediated cortical inhibition in the DLPFC in subjects with anxiety disorders. The correlation between trait anxiety and N100 amplitudes suggests a trait-related modulation of cortical inhibition.

Background Amphetamine-type stimulants (ATS) have become a critical public health issue. Animal models have indicated a clear neurotoxic potential of ATSs. In humans, chronic use has been associated with cognitive deficits and structural brain abnormalities. However, cross-sectional retrospective designs in chronic users cannot truly determine the causal direction of the effects. Objective To prospectively determine effects of occasional ATS use on cognitive functioning and brain structure. Methods In a prospective longitudinal study design, cognitive functioning and brain structure were assessed at baseline and at 12-month follow-up in occasional ATS users (cumulative lifetime use <10 units at baseline). Results Examination of change scores between the initial examination and follow-up revealed declined verbal memory performance and putamen volume in users with high relative to low interim ATS exposure. In the entire sample, interim ATS use, memory decline, and putamen volume reductions were strongly associated. Conclusions The present findings support the hypothesis that ATS use is associated with deficient dorsal striatal morphology that might reflect alterations in dopaminergic pathways. More importantly, these findings strongly suggest that even occasional, low-dose ATS use disrupts striatal integrity and cognitive functioning.

Research on potential long-term consequences of ecstasy use suggests alterations in psychological well-being and cognitive performance. Due to methodological difficulties, it is still unclear whether this effect may be attributed to ecstasy itself or to other confounding factors, such as negative expectations. This study is aimed at discerning the effect of identifying with a negative stereotype upon performance on a battery of cognitive tests. Ecstasy users with self-reported decline were categorized by their subjective deterioration, attributed either to ecstasy use or to other reasons. Subjects were compared by their performance on frontal/executive functioning, episodic memory and information and processing speed. No effect has been observed for frontal/executive functioning and information and processing speed. However, the groups differed on total acquisition and recognition performance of the AuditivVerbale Lerntest (AVLT). Verbal memory tasks seem to be susceptible to worries and fears generated by negative expectations in ecstasy users. This aspect should be taken into account while measuring cognitive decline in ecstasy users.

Background: It is still unknown whether psychopathological symptoms found in ecstasy and amphetamine users were apparent before the first use or developed subsequent to its use. Objectives: The present study presents the third follow-up evaluation of a longitudinal study to assess the nature of the relationship between ecstasy, amphetamine (AMPH) and psychopathology. Methods: In this sample, 69 beginning ecstasy andAMPHuserswere followed over a period of 4 years. To explore different psychopathological dimensions, the Symptom Checklist-90-Revised was applied. Use of ecstasy, AMPH, cannabis and was gathered by structured interviews and use of cigarettes by a questionnaire. First, linear mixed models for repeated measures (unstructured covariance matrix) on the nine primary symptoms of the SCL-90-R with a separate model for each symptom category were performed. Second, linear regression analyses with the nine primary symptom categories of the baseline assessment (T-0) as predictors and with ecstasy and AMPH use as dependent variables were fitted. Results: No significant associations between ecstasy, AMPH, and psychopathology were evident. However, a significant two-way interaction between ecstasy and cigarette use at the baseline assessment, as well as a three-way interaction effect between ecstasy, cigarette use, and time on obsessive-compulsive symptoms, were found. Conclusions: This study suggests that nicotine may moderate the effect of ecstasy on obsessive-compulsive symptoms. However, no associations between ecstasy, AMPH, and psychopathology have been found. This is one of the few studies, which highlights the role of nicotine in the study of psychopathology in beginning ecstasy and AMPH users.

The aim of the present study was to investigate the relevance of different parameters of 3,4-methylenedioxymethamphetamine (MDMA) use, including age of first use, cumulative lifetime dose and highest daily dose for predicting cognitive performance and self-reported psychopathology. Moreover, interactions between those parameters were examined. Ninety-six new MDMA users were interviewed to assess their drug use, and they completed a battery of cognitive tests concerning attention and information processing speed, episodic memory and executive functioning and self-reported psychopathology. Subjects participated again after 1 year to provide follow-up data. Significant associations between age of first use and cumulative lifetime dose have been found for attention and information processing speed. Furthermore, the results showed a significant effect of age of first use on the recognition performance of the episodic memory. The findings of the current study provide a first estimation of the interactions between different MDMA use parameters. Future research should focus upon additional parameters of drug use and concentrate on consequent follow-up effects.

It still remains unclear whether psychopathological abnormalities described in human 3,4-methylenedioxymethamphetamine users (MDMA users) and d-amphetamine users (AMPH users) existed before the beginning of regular use or if they develop with ongoing use.

3,4-Methylenedioxymethamphetamine (MDMA) is associated with changes in neurocognitive performance. Recent studies in laboratory animals have provided additional support for the neurodegeneration hypothesis. However, results from animal research need to be applied to humans with caution. Moreover, several of the studies that examine MDMA users suffer from methodological shortcomings. Therefore, a prospective cohort study was designed in order to overcome these previous methodological shortcomings and to assess the relationship between the continuing use of MDMA and cognitive performance in incipient MDMA users. It was hypothesized that, depending on the amount of MDMA taken, the continued use of MDMA over a 2-year period would lead to further decreases in cognitive performance, especially in visual paired association learning tasks. Ninety-six subjects were assessed, at the second follow-up assessment: 31 of these were non-users, 55 moderate-users, and 10 heavy-users. Separate repeated measures analyses of variance were conducted for each cognitive domain, including attention and information processing speed, episodic memory, and executive functioning. Furthermore, possible confounders including age, general intelligence, cannabis use, alcohol use, use of other concomitant substances, recent medical treatment, participation in sports, level of nutrition, sleep patterns, and subjective well-being were assessed. The Repeated measures analysis of variance (rANOVA) revealed that a marginally significant change in immediate and delayed recall test performances of visual paired associates learning had taken place within the follow-up period of 2 years. No further deterioration in continuing MDMA-users was observed in the second follow-up period. No significant differences with the other neuropsychological tests were noted. It seems that MDMA use can impair visual paired associates learning in new users. However, the groups differed in their use of concomitant use of illicit drugs. Therefore, performance differences between the groups cannot completely ascribed to the use of MDMA.

Drug addiction is a chronic, relapsing brain disorder. The identification of biomarkers that render individuals vulnerable for the transition from occasional drug use to addiction is of key importance to develop early intervention strategies. The aim of the present study was to prospectively assess brain structural markers for escalating drug use in two independent samples of occasional amphetamine-type stimulant users. At baseline occasional users of amphetamine and 3,4-methylenedioxymethamphetamine (cumulative lifetime use ≤10 units) underwent structural brain imaging and were followed up at 12 months and 24 months (Study 1, n = 38; Study 2, n = 28). Structural vulnerability markers for escalating amphetamine-type drug use were examined by comparing baseline grey matter volumes of participants who increased use with those who maintained or reduced use during the follow-up period. Participants in both samples who subsequently increased amphetamine-type drugs use displayed smaller medial prefrontal cortex volumes and, additionally, in the basolateral amygdala (Study 1) and dorsal striatum (Study 2). In both samples the baseline volumes were significantly negatively correlated with stimulant use during the subsequent 12 and 24 months. Additional multiple regression analyses on the pooled data sets revealed some evidence of a compound-specific association between the baseline volume of the left basolateral amygdala and the subsequent use of amphetamine. These findings indicate that smaller brain volumes in fronto-striato-limbic regions implicated in impulsivity and decision-making might render an individual vulnerable for the transition from occasional to escalating amphetamine-type stimulant use.

Qualitative poor decision-making and associated altered neuronal activation patterns have been described for the users of several drugs, amongst others for stimulants like amphetamine and MDMA. Deficits in decision-making might be caused by an augmented attraction to short-term rewarding properties despite negative long-term consequences, leading to rigid stimulus-response patterns. In the present imaging study, we investigated decision-making and associated neuronal activation in three groups differing in their exposure to amphetamine and MDMA. An established paradigm on risky choices was used to evaluate decision-making performance and corresponding functional magnet resonance imaging (fMRI) activation. Subjects could choose between a low-risk control gamble and an experimental gamble, which always differed in the probability of winning or losing, as well as the magnitudes of monetary gain or loss. Experienced users (EU), users with low exposure to stimulants and drug-naive controls, did not differ from each other in behavioral performance. In accordance with our hypotheses, the anticipation of reward led to an activation of primarily the frontal cortex and the striatum in low-exposure users and drug-naive controls. In contrast, frontal and parietal activation was observed in all groups when the actual outcome of an experimental gamble was presented. EU displayed more activation compared to both control groups when there was a high probability of winning. The study at hand supports the hypothesis that neuronal activation patterns might even differ between drug users and healthy controls when no behavioral deficits are apparent. In EU, the probability of the occurrence of an event has more influence on neuronal activation than on the actual magnitude of reinforcing properties of this event.

AIMS: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.DESIGN:A prospective cohort study in new MDMA users between 2006 and 2009 with a follow-up duration of 12 months.SETTING AND PARTICIPANTS: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.MEASUREMENTS: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.FINDINGS: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.CONCLUSIONS:MDMA appears to impair visual paired associates learning in new users, suggesting serotonergic dysfunction in hippocampal regions as a consequence of MDMA use.

Recreational use of ecstasy (3,4-methylenedioxymethamphetamine [MDMA]) has been associated with memory impairments. Functional neuroimaging studies with cross-sectional designs reported altered memory-related hippocampal functioning in ecstasy-polydrug users. However, differences might be pre-existing or related to the concomitant use of amphetamine.

Amphetamine-type stimulants (ATS) refer to a group of drugs whose principal members include amphetamine, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Worldwide, ATS are among the most common illicit drugs. Therefore, understanding whether and to what extent ATS exposure affects brain structure and functioning in recreational users has become a critical public health issue. We studied gray and white matter densities in 20 experienced users of ATS (more than 100units MDMA and/or 50g of amphetamine lifetime dose), 42 low exposure users with very limited ATS experience (less than 5units lifetime dose) and 16 drug-naive controls. A tract-based spatial statistics (TBSS) analysis of fractional anisotropy images was applied to diffusion magnetic resonance imaging (MRI) data. Furthermore, alignment invariant white matter tract representations acquired from the TBSS analysis were used as a reference for inter-subject brain registrations in a voxel-based morphometry (VBM) analysis of gray matter volume, reducing characteristic alignment inaccuracies associated with this voxel-wise gray matter investigation approach. Between-group white matter comparison revealed no significant results. However, compared to low exposure users, experienced users showed several regions of lower gray matter volume in medial frontal regions, in particular the orbital and medial frontal cortex. Differences are likely to reflect effects of repeated ATS exposure even in recreational users. However, differences in pre-existing or confounding factors might also account for between-group differences.

Article history: Received 21 December 2009 Received in revised form 18 March 2010 Accepted 25 March 2010 Available online xxxx

Converging lines of evidence suggest an association between cannabis use and impaired episodic memory as well as related associative learning. These deficits have been associated with the duration, frequency, and age of onset of cannabis use. However, it remains unclear whether these parameters of use differently impact memory-related hippocampal functioning.

Recently, the impact of different parameters of cannabis use, including the age of first use, the average frequency of use, the cumulative lifetime dose, the average dose per occasion, and the duration of regular use upon cognitive functions has been discussed. However, to date no study has systematically investigated the interactions of these parameters with regard to cognitive performance. To determine whether these interactions exist, 142 healthy young adult cannabis users participated in a neuropsychological assessment study with a German version of the Rey Auditory Verbal Learning Test (RAVLT). In line with previous studies on cannabis use and verbal memory, significant associations between certain components of verbal memory and frequency of use, cumulative lifetime dose and duration of regular use respectively were found. Remarkably, a multivariate analysis solely revealed a significant main effect of the duration of cannabis use with regard to immediate recall and recall after interference. Moreover, the findings suggest that age of first use, duration of use and frequency of cannabis use interact with regard to their impact on different measures of verbal memory. The findings of the present study provide first evidence that particular parameters of cannabis use interact with regard to their impact on cognitive functions in unintoxicated cannabis users. This finding might deliver more insight into the complex mechanisms underlying the impaired memory functions observed in cannabis users.

Cannabis is the most commonly used illicit drug. Prevalence rates are particularly high among adolescents. Neuropsychological studies have identified cannabis-associated memory deficits, particularly linked to an early onset of use. However, it remains unclear, whether the age of onset accounts for altered cortical activation patterns usually observed in cannabis users. Functional magnetic resonance imaging was used to examine cortical activation during verbal working memory challenge in (1) early-onset (onset before the age of sixteen; n=26) and (2) late-onset cannabis users (age at onset at least sixteen; n=17). Early-onset users showed increased activation in the left superior parietal lobe. Correlational analyses confirmed the association between an earlier start of use and increased activity. Contrariwise neither cumulative dose, frequency nor time since last use was significantly associated with cortical activity. Our findings suggest that an early start of cannabis use is associated with increased cortical activation in adult cannabis users, possibly reflecting suboptimal cortical efficiency during cognitive challenge. The maturing brain might be more vulnerable to the harmful effects of cannabis use. However, due to a lack of a non-using control group we cannot exclude alternative interpretations.