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 eVects 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 diVer 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 suYcient to cause neurotoxicity in humans.

The present study suggests that the NMDA antagonist model of psychosis is not overall superior to the serotonin 5-HT2A agonist model. Rather, the two classes of drugs tend to model different aspects or types of schizophrenia. The NMDA antagonist state may be an appropriate model for psychoses with prominent negative and possibly also catatonic features, while the 5-HT2A agonist state may be a better model for psychoses of the paranoid type.

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 findings associate subtle cognitive, particularly memory, deficits 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 findings in user populations to one specific 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 well-recognized 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.

No abstract

The neurometabolic effects of the hallucinogen psilocybin (PSI; 0.2 mg/kg), the entactogen 3,4-methylenedioxyethylamphetamine (MDE; 2 mg/kg) and the stimulant d-methamphetamine (METH; 0.2-0.4 mg/kg) and the drugs' interactions with a prefrontal activation taskwere investigated in a double-blind, placebo-controlled human [F-18]fluorodeoxyglucoseFDG-positron emission tomographicPET study (each group: n ϭ 8 Experimental studies of cerebral blood flow and metabolism with psychoactive drugs in humans aim to explore the interaction of these drugs with human brain function. Recent studies with hallucinogenic, "mind-expanding" drugs in healthy subjects provided evidence in favor of an altered functional interhemispheric balance From the Department of Psychiatry and Psychotherapy (EG-M, BT, HS), University of Technology (RWTH), Aachen, Germany; Department of Nuclear Medicine (MS, OS, CA, UB), University of Technology (RWTH), Aachen, Germany; Department of Psychiatry (MS), University of Ulm, Ulm, Germany; Pharmaceutical Institute (K-AK), University of Tübingen, Tübingen, Germany; Psychiatric and Neurological Hospital Christophsbad (LH), Göppingen, Germany.Address correspondence to: E. Gouzoulis-Mayfrank, M.D., Department of Psychiatry and Psychotherapy, University of Technology (RWTH), Pauwelsstrasse 30, D-52074 Aachen, Germany.Received March 14, 1998, accepted July 20, 1998 566 E. Gouzoulis-Mayfrank et al. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 20 , NO . 6 with right hemispheric dominance and an increased activity in frontocortical regions after acute administration of mescaline, psilocybin, or ketamine (Hermle et al. 1992; Vollenweider et al. 1997a, b). The most profound increase in metabolism was found in the anterior cingulate (Vollenweider et al. 1997a(Vollenweider et al. , 1997b, which is linked to both emotional and attentional functions (Vogt et al. 1992;Devinsky et al. 1995;Murtha et al. 1996). These functions are, in turn, tightly connected to both the effects of hallucinogens and the symptoms of schizophrenic and schizophrenia-spectrum psychoses.Hallucinogenic drug-induced states can be used as models for acute endogenous psychotic states in psychiatric research (Hermle et al. 1992; Vollenweider et al. 1997a, b;Gouzoulis-Mayfrank et al. 1998). Within the framework of this model psychosis paradigm neurometabolic data from the above-mentioned studies can be interpreted in the sense that acute psychotic states with prominent positive symptoms are linked to increased activity in frontal neocortical, and limbic areas. This is in contrast to the majority of functional neuroimaging studies with schizophrenic patients, which demostrate hypofrontality both in resting states (Buchsbaum et al. 1982;Farkas et al. 1984;Wolkin et al. 1988;Siegel et al. 1993) and under cognitive tasks believed to employ frontal brain areas (Cohen et al. 1987;Weinberger et al. 1988;Buchsbaum et al. 1990;Andreasen et al. 1992). However, most of these studies were performed with chronically ill patients on various neuroleptic medications, a...

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.

Although 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.

The aim of this study was to contribute to the characterization of the entactogen (ecstasy) substance group. The psychopathological, neuroendocrine and autonomic effects of common recreational doses of the entactogen 3,4-methylenedioxyethylamphetamine (MDE), the hallucinogen psilocybin, the stimulant d-methamphetamine and placebo were investigated in a double-blind study with healthy volunteers (n = 32). Psychological effects of the drugs were assessed by means of standardized rating scales, self assessment inventories and free descriptions. The most characteristic effects of MDE were pleasant emotional experiences of relaxation, peacefulness, content and closeness to others. However, significant stimulant and hallucinogen-like effects were also present, although the latter were weaker than the effects of psilocybin. MDE elicited the strongest endocrine and autonomic effects among the three drugs, including robust rises of serum cortisol and prolactin, elevations of blood pressure and heart rate, and a moderate, but significant rise of body temperature. The apparent contrast between psychological and autonomic effects (subjective relaxation versus physical activation) was a unique feature of the MDE state. Our findings are in line with both users' reports and results from previous experimental studies, and support the view that entactogens constitute a distinct psychoactive substance class taking an intermediate position between hallucinogens and stimulants.