Jörg Daumann

The confounding problem of polydrug use in recreational ecstasy/MDMA users: a brief overview.

The popular dance drug ecstasy (3,4-methylenedioxymethamphetamine -- MDMA) is neurotoxic upon central serotonergic neurons in laboratory animals and possibly also in humans. In recent years, several studies reported alterations of serotonergic transmission and neuropsychiatric abnormalities in ecstasy users which might be related to MDMA-induced neurotoxic brain damage. To date, the most consistent .ndings associate subtle cognitive, particularly memory, de.cits with heavy ecstasy use. However, most studies have important inherent methodological problems. One of the most serious confounds is the widespread pattern of polydrug use which makes it dif.cult to relate the .ndings in user populations to one speci.c drug. The present paper represents a brief overview on this issue. The most commonly co-used substances are alcohol, cannabis and stimulants (amphetamines and cocaine). Stimulants are also neurotoxic upon both serotonergic and dopaminergic neurons. Hence, they may act synergistically with MDMA and enhance its long-term adverse effects. The interactions between MDMA and cannabis use may be more complex: cannabis use is a wellrecognized risk factor for neuropsychiatric disorders and it was shown to contribute to psychological problems and cognitive failures in ecstasy users. However, at the cellular level, cannabinoids have neuroprotective actions and they were shown to (partially) block MDMA-induced neurotoxicity in laboratory animals. In future, longitudinal and prospective research designs should hopefully lead to a better understanding of the relation between drug use and subclinical psychological symptoms or neurocognitive failures and, also, of questions around interactions between the various substances of abuse.

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.

Mismatch negativity generation in the human 5HT2A agonist and NMDA antagonist model of psychosis

RationaleMany studies have reported deficits of mismatch negativity (MMN) in schizophrenic patients. Pharmacological challenges with hallucinogens in healthy humans are used as models for psychotic states. Previous studies reported a significant reduction of MMN after ketamine (N-methyl-d-aspartate acid [NMDA] antagonist model) but not after psilocybin (5HT2A agonist model).ObjectivesThe aim of the present study was to directly compare the two models of psychosis using an intraindividual crossover design.Materials and methodsFifteen healthy subjects participated in a randomized, double-blind, crossover study with a low and a high dose of the 5HT2A agonist dimethyltryptamine (DMT) and the NMDA antagonist S-ketamine. During electroencephalographic recording, the subjects were performing the AX-version of a continuous performance test (AX-CPT). A source analysis of MMN was performed on the basis of a four-source model of MMN generation.ResultsNine subjects completed both experimental days with the two doses of both drugs. Overall, we found blunted MMN and performance deficits in the AX-CPT after both drugs. However, the reduction in MMN activity was overall more pronounced after S-ketamine intake, and only S-ketamine had a significant impact on the frontal source of MMN.ConclusionsThe NDMA antagonist model and the 5HT2A agonist model of psychosis display distinct neurocognitive profiles. These findings are in line with the view of the two classes of hallucinogens modeling different aspects of psychosis.

Self-reported psychopathological symptoms in recreational ecstasy (MDMA) users are mainly associated with regular cannabis use: further evidence from a combined cross-sectional/longitudinal investigation.

Rationale3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) has become a widely used recreational drug among young people. This is of great concern, since MDMA is neurotoxic in animal studies and its use has been associated with psychological distress and a variety of self-reported psychiatric symptoms. However, exploring the origins of psychopathology in ecstasy users is hampered by the frequent polydrug use and by the cross-sectional design of all investigations, so far.ObjectivesThe present study combines a cross-sectional with a longitudinal approach to further clarify the impact of the use of other illicit drugs on psychopathological symptoms reported by ecstasy users.MethodsAt baseline, we administered self-rating scales for impulsivity, sensation seeking and general psychological complaints to 60 recreational ecstasy users and 30 matched controls. From the initial sample of ecstasy users, 38 subjects were re-examined 18 months later.ResultsAt baseline, ecstasy users reported significantly more psychological complaints than controls. However, self-reported psychopathology was mainly associated with regular cannabis use. At follow-up, subjects who had abstained from ecstasy use during the follow-up period did not differ from those reporting continued consumption. In contrast, subjects with regular concomitant cannabis use during the follow-up period reported more anxiety, interpersonal sensitivity and obsessive-compulsive behaviour than cannabis-abstinent users. Finally, higher levels of obsessive-compulsive behaviour, interpersonal sensitivity, depression, anxiety, phobic anxiety and paranoid ideation were significantly correlated with the duration of regular interim cannabis use.ConclusionsThe present findings suggest that self-reported psychopathology in ecstasy users is predominantly attributable to concomitant use of cannabis. Abstinence from cannabis and not ecstasy seems to be a reliable predictor for remission of psychological complaints in ecstasy users.

The role of cannabis in cognitive functioning of patients with schizophrenia

RationaleCognitive deficits are commonly found both in patients with schizophrenia (SCH) and in people with cannabis use disorders (CUD). Surprisingly, some small recent studies reported better cognitive performance in SCH patients with comorbid cannabis use disorders (SCH + CUD) compared to other SCH patients.ObjectivesThe aim of the present study was to investigate the residual impact of CUD and specific patterns of consumption on cognition in a larger sample of SCH + CUD patients.MethodsWe administered a cognitive test battery to 34 SCH and 35 currently abstinent SCH + CUD patients. We explored the association between patterns of cannabis consumption and cognitive performance. Potential confounds with influence on cognitive ability were assessed and controlled for.ResultsSCH + CUD patients had poorer academic achievements and lower vocabulary scores, but they performed better in tests of verbal and working memory, visuomotor speed and executive function (p < .05). More frequent cannabis use was associated with better performance in attention and working memory tasks.ConclusionsAlthough our findings might be interpreted as beneficial effect of cannabis use on cognition in patients with schizophrenia, we favorise an alternative interpretation: in our view, the better cognitive functioning of SCH + CUD patients may rather reflect a relatively lower vulnerability to psychosis compared to the SCH group. Lower vulnerability may correspond to a higher level of functioning such as cognitive ability. This conclusion is consistent with the view of cannabis playing a critical role in the manifestation of psychosis in at least some of the SCH + CUD patients.

Memory-related hippocampal dysfunction in poly-drug ecstasy (3,4-methylenedioxymethamphetamine) users

Rationale3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is neurotoxic in animal studies and its use has been associated with cognitive impairments in humans.ObjectiveTo study hippocampal activation during the retrieval from episodic memory in polyvalent users of ecstasy.MethodsTwelve polyvalent ecstasy users and twelve matched controls were examined by means of functional magnetic resonance imaging (fMRI) while they retrieved face-profession associations from episodic memory.ResultsEcstasy users had a normal structural MRI scan without focal brain lesions or anatomical abnormalities. They exhibited equal retrieval accuracy during memory retrieval to that of the matched controls. Yet, their retrieval-related activity was lower and more spatially restricted in the left anterior hippocampus than that of the controls.ConclusionsThese results provide evidence for abnormal hippocampal functioning in MDMA users even at the presence of normal memory performance. This finding may be linked to MDMA-induced neurotoxicity and suggests that diminished hippocampal activation during memory retrieval might be a more sensitive or earlier index of MDMA-related neurotoxicity than neuropsychological performance.

The impact of early-onset cannabis use on functional brain correlates of working memory.

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.

Cerebral activation in abstinent ecstasy (MDMA) users during a working memory task: a functional magnetic resonance imaging (fMRI) study

The popular recreational drug ecstasy (3,4-methylenedioxymethamphetamine=MDMA and related congeners) is neurotoxic upon central serotonergic systems in animal studies. So far, the most convincing evidence for neurotoxicity-related functional deficits in humans derives from neurocognitive studies demonstrating dose-related long-term learning and memory problems in ecstasy users. In our study we used functional magnetic resonance imaging (fMRI) and a working memory task to investigate cerebral activation in eleven heavy, but currently abstinent MDMA users and two equally sized groups of moderate users and non-users. There were no significant group differences in working memory performance and no differences in cortical activation patterns for a conservative level of significance. However, for a more liberal statistical criterion, both user groups showed stronger activations than controls in right parietal cortex. Furthermore, heavy users had a weaker blood oxygenation level-dependent (BOLD) response than moderate users and controls in frontal and temporal areas. Our results may indicate subtle altered brain functioning associated with prior MDMA use, although alternative interpretations of these group differences must be considered.

Medial prefrontal gray matter volume reductions in users of amphetamine-type stimulants revealed by combined tract-based spatial statistics and voxel-based morphometry

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 100 units MDMA and/or 50 g of amphetamine lifetime dose), 42 low exposure users with very limited ATS experience (less than 5 units 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.

Altered parahippocampal functioning in cannabis users is related to the frequency of use

RationaleConverging 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.MethodsForty-two cannabis users were examined by means of functional magnetic resonance imaging while they encoded and retrieved face–profession associations. Region of interest analysis was subsequently used to compare (para-)hippocampal functioning in users with (1) a longer and shorter duration of use, (2) a higher and lower frequency of use, and (3) an earlier and later onset. To further separate the effects of these parameters of use on performance and (para-)hippocampal activity, linear regression analysis was applied.ResultsCompared to low-frequency users, high-frequency users displayed stronger blood oxygenation level-dependent response during encoding in the left parahippocampal gyrus. No differences were obvious for the groups separated according to duration of use or an earlier and later onset of use. Linear regression analysis confirmed the association between a higher frequency of use and increased activity in the left parahippocampal gyrus.ConclusionsOur findings suggest that the frequency of use might have a particular critical impact on intact parahippocampal functioning in cannabis users. Increased activity within the encoding-related network might reflect functional compensation to maintain cognitive functioning.