Proton magnetic resonance spectroscopy in ecstasy (MDMA) users

The popular recreational drug 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has well-recognized neurotoxic effects upon central serotonergic systems in animal studies. In humans, the use of MDMA has been linked to cognitive problems, particularly to deficits in long-term memory and learning. Recent studies with proton magnetic resonance spectroscopy (1H MRS) have reported relatively low levels of the neuronal marker N-acetylaspartate (NAA) in MDMA users, however, these results have been ambiguous. Moreover, the only available 1H MRS study of the hippocampus reported normal findings in a small sample of five MDMA users. In the present study, we compared 13 polyvalent ecstasy users with 13 matched controls. We found no differences between the NAA/creatine/phosphocreatine (Cr) ratios of users and controls in neocortical regions, and only a tendency towards lower NAA/Cr ratios in the left hippocampus of MDMA users. Thus, compared with cognitive deficits, 1H MRS appears to be a less sensitive marker of potential neurotoxic damage in ecstasy users.     

Chronic neurotoxic damage in ecstasy (MDMA) users. Review of the current state of research

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.     

Neural correlates of working memory in pure and polyvalent ecstasy (MDMA) users

Poor cognitive performance in ecstasy (3,4-methylenedioxymethamphetamine; MDMA) users has been related to the well-recognized neurotoxic effects of the drug upon central serotonergic and possibly also dopaminergic systems. However, concomitant use of other drugs has been a critical confound in most investigations. In this study we used an n-back task and fMRI to investigate working memory performance and related cerebral activation in eight, currently abstinent pure MDMA users and two matched groups of polyvalent MDMA users and non-users. Pure MDMA users presented lower activations than controls and/or polyvalent users, most notably in inferior temporal regions, the angular gyrus and the striate cortex, whereas polyvalent users did not differ from controls. Our results suggest that altered brain activation patterns during cognitive processing in ecstasy users may be mainly associated with prior MDMA use. Concomitant use of other drugs may modify this effect.     

Neurotoxicity of drugs of abuse - the case of methylenedioxy amphetamines (MDMA,ecstasy ), and amphetamines

Ecstasy (MDMA, 3,4-methylendioxymethamphetamine) and the stimulants methamphetamine (METH, speed) and amphetamine are popular drugs among young people, particularly in the dance scene. When given in high doses both MDMA and the stimulant amphetamines are clearly neurotoxic in laboratory animals. MDMA causes selective and persistent lesions of central serotonergic nerve terminals, whereas amphetamines damage both the serotonergic and dopaminergic systems. In recent years, the question of ecstasy-induced neurotoxicity and possible functional sequelae has been addressed in several studies in drug users. Despite large methodological problems, the bulk of evidence suggests residual alterations of serotonergic transmission in MDMA users, although at least partial recovery 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 impairments with ecstasy use, particularly with memory. In contrast, studies on possible long-term neurotoxic effects of stimulant use have been relatively scarce. Preliminary evidence suggests that alterations of the dopaminergic system may persist even after years of abstinence from METH, and may be associated with deficits in motor and cognitive performance. In this paper, we will review the literature focusing on human studies.     

Comorbidity of substance use and other psychiatric disorders--theoretical foundation and evidence based therapy

The coincidence of two or more psychiatric disorders in the same person (comorbidity or dual diagnosis) is no rare exception. It is rather common and therapeutically highly relevant. Comorbid patients exhibit frequently severe manifestations of the disorder(s) and they require intensive treatment to meet their special needs and the interdependencies of their disorders. The present overview deals with the theoretical foundations of comorbidity of substance use and other psychiatric disorders. We present data on the prevalence of different comorbidities and discuss the models, which have been proposed to explain how substance use and other disorders relate with each other. Furthermore, we describe the clinical characteristics and long-term course of comorbid patients, as well as some general therapeutic principles including the advantages of integrated therapeutic programmes. In addition, we carried out a systematic literature search on specific pharmaco- and psychotherapies for common comorbidities using the databases MEDLINE, EMBASE and PsycInfo (up to December 2007), and assessed the methodological quality of the identified trials. Based on this search we present the empirical evidence for the effectiveness of specific treatments and make therapeutic recommendations which are graded according to the strength of existing evidence. In conclusion, integrated treatment programs are more effective, provided they take into account the multiple deficits of comorbid patients, adjust and adapt the different therapeutic components to each other, and set realistic goals. The next step should be a broader application of integrated treatment programs and their adoption as standard treatment within the national health systems.     

Cerebral interregional correlations of associative language processing: a positron emission tomography activation study using fluorine-18 fluorodeoxyglucose

Even though there have been numerous positron emission tomography (PET) activation studies on the perfusional and metabolic bases of language processing, little is known about the intracerebral functional network of language and cognitive processes. It was the aim of this study to investigate the cerebral interregional correlations during voluntary word association versus word repetition in healthy subjects to gain insight into the functional connectivity of associative speech processing. Due to individual variability in functional anatomy, the study protocol was designed as an averaged single-subject study. Eight healthy volunteers performed a verbal association task during fluorine-18 fluorodeoxyglucose (¹⁸F-FDG) PET scanning. Two different tasks were performed in randomized order: (a) word repetition (after auditory presentation of nouns) as a control condition, and (b) word association (after auditory presentation of nouns) as a specific semantic activation. The regional metabolic rate of glucose (rMRGlu) was calculated after brain regionalization [112 regions of interest on individual 3D flash magnetic resonance imaging (MRI)] and PET/MRI realignment. Statistical analysis was performed for comparison of association and repetition and for calculation of interregional correlation coefficients during both tasks. Compared with word repetition, word association was associated with significant increases in rMRGlu in the left prefrontal cortex, the left frontal operculum (Broca’s area) and the left insula, indicating involvement of these areas in associative language processing. Decreased rMRGlu was found in the left posterior cingulum during word association. During word repetition, highly significant negative correlations were found between the left prefrontal cortex, the contralateral cortex areas and the ipsilateral posterior cingulum. These negative correlations were almost completely eliminated during the association task, suggesting a functional decoupling of the strict intercorrelation pattern. Received 16 March and in revised form 9 July 1998     

Neurotoxische Langzeitsch?den bei Ecstasy (MDMA)-Konsumenten überblick über den aktuellen Wissensstand überblick über den aktuellen Wissensstand

Ecstasy (3,4-Methylendioxymethamphetamin=MDMA und einige chemische Analoga) sch?digt im Tierexperiment selektiv und langanhaltend das zentrale serotonerge System. Aufgrund der Beteiligung von Serotonin an vielen funktionellen Systemen w?ren als Konsequenzen einer zentralen serotonergen Sch?digung beim Menschen psychiatrische, vegetative und neuroendokrine St?rungen sowie Ver?nderungen kognitiver Funktionen denkbar. In den letzten Jahren wurden mehrere Studien zu m?glichen funktionellen Auswirkungen einer serotonergen Sch?digung bei Ecstasy-Konsumenten durchgeführt. Diese werden in der vorliegenden übersicht referiert und entsprechend der Qualit?t ihres Studiendesigns in ihrer Aussagekraft gewichtet. Zusammenfassend verdichten sich trotz forschungsimmanenter methodischer Probleme die Verdachtsmomente in Richtung langfristiger ZNS-Sch?den mit Auswirkungen insbesondere im kognitiven Bereich. In mehreren Studien konnten bei Ecstasy-Konsumenten mit hoher Konsistenz relative Beeintr?chtigungen mnestischer Funktionen in Abh?ngigkeit vom Ausma? des Ecstasy-Konsums nachgewiesen werden. Weniger konsistent wurden auch St?rungen zentraler exekutiver Funktionen berichtet. Wesentliche Fragen nach der Progredienz, Persistenz oder (Teil-)Reversibilit?t der Ver?nderungen nach langen Abstinenzperioden sind noch offen und werden in zukünftigen L?ngsschnittstudien gekl?rt werden müssen.     

Memory performance in polyvalent MDMA (ecstasy) users who continue or discontinue MDMA use

Background:The popular dance drug ecstasy (3,4-methylenedioxymethamphetamine = MDMA) is a serotonergic neurotoxin in animal studies. Several cross-sectional investigations reported low memory and learning performance in ecstasy users, particularly in those reporting heavy patterns of drug use. Since, serotonin has a recognized role in memory processes, these findings were mostly interpreted as evidence for ecstasy-related neurotoxicity in humans. However, studies with user populations and controls suffer from many inherent methodological problems. Moreover, longitudinal data on memory performance after continued or discontinued ecstasy use are scarce.Methods:In the present longitudinal study, we examined memory performance in 38 MDMA users over the course of 18 months.Results:Subjects who stopped MDMA use after the baseline examination (n = 17) did not improve, and subjects who continued MDMA use (n = 21) did not deteriorate in terms of test performance.Conclusions:Our data do not support, but they also do not rule out memory decline following use of the serotonergic neurotoxin MDMA. In light of the popularity of ecstasy among young people, further investigations are needed. In our view, research strategies should now move to prospective designs in order to shed more light on the course of possible adverse cognitive effects of ecstasy use.     

Pharmacological modulation of the neural basis underlying inhibition of return (IOR) in the human 5-HT2A agonist and NMDA antagonist model of psychosis

Rationale  Attentional deficits are common symptoms in schizophrenia. Recent evidence suggests that schizophrenic patients show abnormalities in spatial orienting of attention, particularly a deficit of inhibition of return (IOR). IOR is mostly thought to reflect an automatic, inhibitory mechanism protecting the organism from redirecting attention to previously scanned, insignificant locations. Pharmacologic challenges with hallucinogens have been used as models for psychosis. Objectives  The aim of this study was to investigate the neural correlates underlying orienting of attention in the human N-methyl-d-aspartic acid antagonist and 5-HT_2A agonist models of psychosis. Materials and methods  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. We administered a covert orienting of attention task with nonpredictive peripheral cues, and we scanned the subjects on two separate days at least 14 days apart with a placebo and a verum condition on each day. Results  DMT, but not S-ketamine, slowed down reaction times significantly. IOR was blunted after DMT, but not after S-ketamine. Relative to placebo, S-ketamine increased activation in the IOR condition in the right superior frontal gyrus, left superior temporal gyrus, and right midfrontal frontal gyrus. Conclusions  The discrepancy between the behavioral and functional imaging outcome indicates that pharmacological fMRI might be a sensitive tool to detect drug-modulated blood oxygenation level-dependent signal changes in the absence of behavioral abnormalities. Our findings might help to further clarify the contradictory findings of IOR in schizophrenic patients and might, thus, shed more light on possible differential pathomechanisms of schizophrenic symptoms.