Cortical thinning in amphetamine-type stimulant users.

Accumulating evidence supports the hypothesis of ecstasy and amphetamine exhibiting neurotoxic properties in human recreational users. The extent and exact location of neuronal degeneration might also be associated with a specific profile of cognitive deterioration described in polydrug users. Voxel-based morphometry and cortical thickness analyses constantly gain attention for answering the question of associated neurological sequelae. We aimed to evaluate the integrity of cortical and subcortical structures in three groups that differ in the consumption of amphetamine-type stimulants. Cortical thickness, cortical grey matter volume and the shape of supposedly vulnerable subcortical structures were compared between 20 experienced users, 42 users with little exposure to these substances and 16 drug- naïve controls. Cortical thinning in experienced users compared to drug-naïve controls and low-exposure users was observed in medio-frontal regions. Effects of ecstasy and amphetamine on cortical volume were similar to those of cortical thickness, with volume reductions primarily in frontal, but also in occipital and parietal regions of low exposure and experienced users. These effects were differently lateralized for the different comparisons. The investigation of subcortical structures revealed non-significant bilateral shape differences in the hippocampi. Our data support the hypothesis that massive recreational amphetamine-type stimulant polydrug use is associated with a thinning of cortical grey matter. Disrupted neuronal integrity in frontal regions does fit well into models of addiction and the cognitive deterioration in amphetamine-type stimulant polydrug users. The exact neurotoxic mechanisms of polydrug ecstasy and amphetamine use, however, remain speculative.

Clinical effectiveness of unilateral deep brain stimulation in Tourette syndrome.

Dysfunctional basal ganglia loops are thought to underlie the clinical picture of Tourette syndrome (TS). By altering dopaminergic activity in the affected neural structures, bilateral deep brain stimulation is assumed to have a modulatory effect on dopamine transmission resulting in an amelioration of tics. While the majority of published case reports deals with the application of bilateral stimulation, the present study aims at informing about the high effectiveness of unilateral stimulation of pallidal and nigral thalamic territories in TS. Potential implications and gains of the unilateral approach are discussed.

[Prevalence of psychosis/substance abuse comorbidity. Clinical-epidemiological findings from different treatment settings in a large German city]. / Prävalenz der Komorbidität Psychose und Sucht Klinisch-epidemiologische Ergebnisse aus verschiedenen Behandlungssettings in einer deutschen Grossstadt.

Comorbid substance use disorders in schizophrenia are of high clinical relevance, because they are common and they are mostly associated with an unfavourable long-term prognosis. Whereas the clinical impression suggests a continuous increase of substance use disorders in patients with schizophrenia over the last 10-20 years, results from epidemiological studies have been inconsistent. The aim of the present investigation was to study the prevalence of substance use disorders within a large sample of patients with schizophrenia in a large German city (Cologne). The prevalence data were examined in different treatment settings (outpatient vs inpatient, university hospital vs mental health hospital). Risk factors for substance use disorders and preferences for specific substances were analysed. The lifetime prevalence of comorbid substance use disorders in the entire sample of 2,337 patients with schizophrenia was 29.4%. However, the data varied substantially depending on the setting of treatment, with the highest comorbidity rates being prevalent in the inpatient sample. Alcohol and cannabis were the most commonly used substances. Commonly recognized risk factors for substance use disorders, such as being male and unmarried and having a low education level, were replicated.

Neuronal correlates of visual and auditory alertness in the DMT and ketamine model of psychosis.

Deficits in attentional functions belong to the core cognitive symptoms in schizophrenic patients. Alertness is a nonselective attention component that refers to a state of general readiness that improves stimulus processing and response initiation. The main goal of the present study was to investigate cerebral correlates of alertness in the human 5HT(2A) agonist and N-methyl-D-aspartic acid (NMDA) antagonist model of psychosis. Fourteen healthy volunteers participated in a randomized double-blind, cross-over event-related functional magnetic resonance imaging (fMRI) study with dimethyltryptamine (DMT) and S-ketamine. A target detection task with cued and uncued trials in both the visual and the auditory modality was used. Administration of DMT led to decreased blood oxygenation level-dependent response during performance of an alertness task, particularly in extrastriate regions during visual alerting and in temporal regions during auditory alerting. In general, the effects for the visual modality were more pronounced. In contrast, administration of S-ketamine led to increased cortical activation in the left insula and precentral gyrus in the auditory modality. The results of the present study might deliver more insight into potential differences and overlapping pathomechanisms in schizophrenia. These conclusions must remain preliminary and should be explored by further fMRI studies with schizophrenic patients performing modality-specific alertness tasks.

Prepulse inhibition of the startle reflex and its attentional modulation in the human S-ketamine and N,N-dimethyltryptamine (DMT) models of psychosis.

Patients with schizophrenia exhibit diminished prepulse inhibition (PPI) of the acoustic startle reflex and deficits in the attentional modulation of PPI. Pharmacological challenges with hallucinogens are used as models for psychosis in both humans and animals. Remarkably, in contrast to the findings in schizophrenic patients and in animal hallucinogen models of psychosis, previous studies with healthy volunteers demonstrated increased levels of PPI after administration of low to moderate doses of either the antiglutamatergic hallucinogen ketamine or the serotonergic hallucinogen psilocybin. The aim of the present study was to investigate the influence of moderate and high doses of the serotonergic hallucinogen N,N-dimethyltryptamine (DMT) and the N-methyl-D-aspartate antagonist S-ketamine on PPI and its attentional modulation in humans. Fifteen healthy volunteers were included in a double-blind cross-over study with two doses of DMT and S-ketamine. Effects on PPI and its attentional modulation were investigated. Nine subjects completed both experimental days with the two doses of both drugs. S-ketamine increased PPI in both dosages, whereas DMT had no significant effects on PPI. S-ketamine decreased and DMT tended to decrease startle magnitude. There were no significant effects of either drug on the attentional modulation of PPI. In human experimental hallucinogen psychoses, and even with high, clearly psychotogenic doses of DMT or S-ketamine, healthy subjects failed to exhibit the predicted attenuation of PPI. In contrast, PPI was augmented and the startle magnitude was decreased after S-ketamine. These data point to important differences between human hallucinogen models and both animal hallucinogen models of psychosis and naturally occurring schizophrenia.

Cannabis and Ecstasy/MDMA (3,4-methylenedioxymethamphetamine): an analysis of their neuropsychobiological interactions in recreational users.

The majority of recreational Ecstasy/MDMA users (90-98%) also take cannabis. This co-drug usage is often viewed as a methodological confound, which needs to be removed statistically. Here we take a rather different approach, and debate the potential complexities of their psychobiological interactions. The ring-substituted amphetamine derivate MDMA (3,4-methylendioxymethamphetmaine, or 'Ecstasy') is a powerful CNS stimulant, whereas cannabis is a relaxant. Their co-usage may reflect opposing effects in three psychobiological areas: arousal, body temperature, and oxidative stress. Firstly MDMA is alerting whereas cannabis is sedating. Secondly MDMA is hyperthermic whereas cannabis is hypothermic. Thirdly MDMA increases oxidative stress whereas cannabinoids are antioxidant. Hence cannabis may modulate the acute and sub-acute reactions to MDMA, reduce the acute hyperthermia induced by MDMA, and ameliorate the oxidative stress caused by MDMA. The limited empirical evidence on each topic will be critically examined. In terms of chronic effects each drug is functionally damaging, so that polydrug users generally display cumulative neurobiological impairments. However in certain aspects their neuropsychobiological effects may interactive rather than additive. In particular, the combined use of cannabis and MDMA may have rather different neuropsychobiological implications, than their separate usage. In order to investigate these potential complexities, future research will need better empirical data on the exact patterns of co-drug usage.

Processing of autobiographical memory retrieval cues in borderline personality disorder.

BACKGROUND: Affective dysregulation in borderline personality disorder (BPD) in response to both external stimuli and memories has been shown to be associated with functional alterations of limbic and prefrontal brain areas. This study aimed to examine neuronal networks involved in autobiographical memory retrieval using standardized stimuli that gain autobiographical significance by illustrating marked solitary and social situations of human life. METHODS: Using event-related functional Magnetic Resonance Imaging (fMRI), we examined the processing of pictures from the Thematic Apperception Test (TAT) in 14 BPD patients and 14 controls. RESULTS: In both groups, TAT stimuli activated brain areas known to be involved in autobiographical memory retrieval. BPD subjects lacked differential amygdala, orbitofrontal and cingulate activations for TAT versus neutral stimuli. In the TAT condition, compared to controls, BPD subjects displayed increased BOLD responses in the bilateral orbitofrontal and insular regions, in the left anterior cingulate and medial prefrontal cortex, as well as in the parietal and parahippocampal areas, consistent with a more aversive and arousing experience assessed by self-reports. CONCLUSIONS: Increased BOLD responses during TAT processing in BPD subjects were in line with previously reported changes in anterior cingulate and orbitofrontal cortices, which are known to be involved in memory retrieval. However, BPD subjects displayed hyperactivation in these areas for both TAT and neutral stimuli. The deficit of selective activation of areas involved in autobiographical memory retrieval suggests a general tendency towards a self-referential mode of information processing in BPD, or a failure to switch between emotionally salient and neutral stimuli.

Neurotoxicity of methylenedioxyamphetamines (MDMA; ecstasy) in humans: how strong is the evidence for persistent brain damage?

BACKGROUND: The popular dance drug ecstasy (3,4-methylenedioxymethamphetamine: MDMA and some analogues) causes selective and persistent neurotoxic damage of central serotonergic neurones in laboratory animals. Serotonin plays a role in numerous functional systems in the central nervous system (CNS). Consequently, various abnormalities including psychiatric, vegetative, neuroendocrine and cognitive disorders could be expected in humans following MDMA-induced neurotoxic brain damage. AIMS: In recent years, the question of ecstasy-induced neurotoxicity and possible functional sequelae has been addressed in several studies with drug users. The aim of this paper was to review this literature and weigh the strength of the evidence for persistent brain damage in ecstasy users. METHODS: We used Medline to view all available publications on 'ecstasy' or 'MDMA'. All available studies dealing with ecstasy users entered this analysis. FINDINGS AND CONCLUSIONS: Despite large methodological problems the bulk of evidence suggests residual alterations of serotonergic transmission in MDMA users, although at least partial restitution may occur after long-term abstinence. However, functional sequelae may persist even after longer periods of abstinence. To date, the most consistent findings associate subtle cognitive, particularly memory, impairments with heavy ecstasy use. However, the evidence cannot be considered definite and the issues of possible pre-existing traits or the effects of polydrug use are not resolved. RECOMMENDATIONS: Questions about the neurotoxic effects of ecstasy on the brain remain highly topical in light of its popularity among young people. More longitudinal and prospective studies are clearly needed in order to obtain a better understanding of the possible long-term sequelae of ecstasy use in humans.

[Chronic neurotoxic damage in ecstasy (MDMA) users. Review of the current state of research]. / Neurotoxische Langzeitschäden bei Ecstasy (MDMA)-Konsumenten. Uberblick über den aktuellen Wissensstand.

The popular dance drug ecstasy (3,4-methylenedioxymethamphetamine, or MDMA, and some analogues) causes selective and persistent neurotoxic damage of the central serotonergic system in laboratory animals. Serotonin plays a role in numerous functional systems in the CNS. Consequently, various abnormalities including psychiatric, vegetative, neuroendocrine, and cognitive disorders might be expected in humans following damage of the central serotonergic system. In recent years, the questions of possible functional disorders following ecstasy-induced neurotoxicity were addressed in several cross-sectional studies with drug users. In this review we summarize and evaluate the quality of design of these studies. Despite large methodological problems, evidence accumulates in favor of persisting brain damage in ecstasy users resulting in subtle cognitive deterioration. Findings of relatively low memory performance associated with heavy ecstasy use are highly consistent across different studies and user populations. In addition, low performance in tests of higher executive function were reported in some but not all studies. The important questions about progression, persistence, or reversibility of damage after long periods of abstinence have to be addressed in future studies with longitudinal design.

High intensity dependence of auditory evoked dipole source activity indicates decreased serotonergic activity in abstinent ecstasy (MDMA) users.

Neurotoxic damage of central serotonergic systems has been demonstrated in numerous animal studies after exposure to methylenedioxyamphetamines (ecstasy). A high intensity dependence of auditory evoked potentials and, particularly, of the tangential N1/P2 source activity has been associated with low levels of serotonergic neurotransmission in humans. We performed an auditory evoked potentials study in 28 abstinent recreational ecstasy users and two equally sized groups of cannabis users and nonusers. The ecstasy users exhibited an increase of the amplitude of the tangential N1/P2 source activity with higher stimulus intensities; whereas, both control groups failed to exhibit this feature. These data are in line with the hypothesis that abstinent ecstasy users present with diminished central serotonergic activity. This feature of information processing is probably related to the well-recognized neurotoxic potential of ecstasy. Our data indicate that recreational ecstasy use may cause long-term alterations in the function (and possibly structure) of the human brain.

Impaired cognitive performance in drug free users of recreational ecstasy (MDMA)

OBJECTIVES: Ecstasy (3,4-methylenedioxymethamphetamine (MDMA) and related congerers: MDA, MDEA) is the name given to a group of popular recreational drugs. Animal data raise concern about neurotoxic effects of high doses of ecstasy on central serotonergic systems. The threshold dose for neurotoxicity in humans is not clear and serotonin is involved in several functions including cognition. The purpose of this study was to investigate cognitive performance in a group of typical recreational ecstasy users. METHODS: A comprehensive cognitive test battery was administered to 28 abstinent ecstasy users with concomitant use of cannabis only and to two equally sized matched groups of cannabis users and non-users. The sample consisted of ecstasy users with a typical recreational use pattern and did not include very heavy users. RESULTS: Ecstasy users were unimpaired in simple tests of attention (alertness). However, they performed worse than one or both control groups in the more complex tests of attention, in memory and learning tasks, and in tasks reflecting aspects of general intelligence. Heavier ecstasy and heavier cannabis use were associated with poorer performance in the group of ecstasy users. By contrast, the cannabis users did not differ significantly in their performance from the non-users. CONCLUSIONS: The present data raise concern that use of ecstasy possibly in conjunction with cannabis may lead to cognitive decline in otherwise healthy young people. Although the nature of the emerging cognitive disturbance is not yet clear, an impairment of working memory might be the common denominator underlying or contributing to declines of performance in various tasks. The cognitive disturbance is likely to be related to the well recognised neurotoxic potential of ecstasy. The data suggest that even typical recreational doses of ecstasy are sufficient to cause neurotoxicity in humans.