MDMA Research in Switzerland
Alex Gamma (author), Truls Baer and F.X. Vollenweider

Alex Gamma (author), Truls Baer and F.X. Vollenweider
Psychiatric University Hospital Research Department
P.O. Box 68
8029 Zurich
Switzerland
e-mail: alex@blisun1.unizh.ch
tel: 0041-1-384-26-32
fax: 0041-1-384-33-96

In the Autumn 1995 issue of the MAPS newsletter, Dr. Franz Vollenweider gave a brief outline of an upcoming MDMA study to be carried out at the Psychiatric University Hospital in Zurich. As this project forms the body of my thesis in neurobiology, I would like to use the opportunity to give a more detailed account of the study design and the goals we are pursuing with this investigation.

Background

Roughly a decade has passed since MDMA (Ecstasy), coming from the United States, made its first appearance in Europe. From the outset, Ecstasy has been closely tied to the nascent rave scene emerging from the Manchester area in England where the first house parties were held. Subsequently, this scene swept all over the continent and took Ecstasy along with it. In recent years, MDMA consumption has dramatically increased (with the number of doses consumed world-wide since the mid-eighties probably approaching or even exceeding one billion) and Ecstasy receives much media attention, particularly with regard to fatalities related to MDMA use at parties.

From animal studies it is known that high or repeated doses of MDMA can cause neurotoxic damage to serotonergic nerve cells. The serotonergic system is thought to be involved in processes of learning, memory and vigilance but also in mood and sleep regulation. Areas affected include the frontal cortex, hippocampus, striatum and hypothalamus. In spite of such damage, possible behavioral or functional consequences of neurotoxicity have hardly been found in animals. The important question remains whether Ecstasy use in humans leads to comparable neurotoxic damage and whether there is danger of lasting functional deficits in long-term users. The few existing studies in this field have yielded only few and dispersed results. In view of these scant findings, our project is designed to shed some more light on the acute and potential long-term effects of MDMA in humans.

Study Design

The study centers upon two basic questions. First: What are the acute physiological and psychological effects of MDMA? And second: Are there any detectable functional alterations in chronic Ecstasy users indicative of potential neurotoxicity? In order to get answers to these questions we will examine two groups of subjects: drug-naive volunteers (n=15) and chronic Ecstasy users recruited from the rave scene (n=15). Drug-naive subjects will be examined both under resting conditions and under the influence of a single dose of MDMA (~1.75mg/kg). This group (prior to MDMA administration) will function as the control. The chronic users will only be tested drug-free, because the question of most interest to us is whether heavy users have any deficits in their "normal" life, i.e. drug-free, everyday life.

All subjects will receive [15-O]-PET scans (PET = "positron emission tomography") for the measurement of cerebral metabolic activity while performing a neuropsychological task of sustained attention ("Continuous Performance Test" or CPT). 32-channel EEG and ERP ("event-related potentials") will be co-registered during the scan. In addition, standard psychometric rating scales will be used to assess MDMA-induced changes in mood, perception and ego-structure. Our main foci of interest are attentional processes based on frontal lobe circuitry. The CPT has been shown to activate particular areas in the prefrontal cortex. Since MDMA acts upon serotonergic projections, which abundantly innervate the frontal lobe, it will be very interesting to see how MDMA affects metabolic activation in the prefrontal cortex and whether it will impair or even enhance attentional processing. In chronic consumers, we hope to clarify the important question whether heavy Ecstasy use can alter brain metabolism and maybe lead to attentional deficits. We are, however, aware that potential cognitive deficits in chronic users might be very small, since studies investigating this question have not found anything consistent up to now. We believe that maybe ERP brainwave recording will be subtle enough to detect possible MDMA-induced changes in attentional processing since its temporal resolution in the millisecond range is far superior to that of PET. Moreover, in co-registering EEG brainwaves and PET metabolic activity we attempt to correlate data from these two complementary techniques. The study design is placebo-controlled and blind. Experiments are due to begin this summer and the project is planned for three years. Funding is secured for one and a half years but additional funding might be needed afterwards.

(Collaborations: Dr. A. Buck, PET department of the University Hospital, Zurich. Prof. D. Lehman, KEY Institute, Zurich, for the EEG recordings. Dr. D. Brandeis, Child and Adolescent Psychiatry Department, Zurich, for the ERP recordings.)

MDMA effects on PPI

In addition, we have a smaller project destined to start earlier. MDMA effects on pre-pulse inhibition (PPI) and selective attention (Stroop test) will be examined in 15 drug-naive subjects. PPI is based on the observation that a sharp acoustic stimulus elicits a startle reflex in a variety of species, including humans. Giving a weak pre-pulse before the actual stimulus leads to an attenuation of startle reflex amplitude. This effect can be disrupted in patients with psychiatric illness or by pharmacological stimulation in healthy subjects.

Although there is a theory of what disruption of PPI could mean, it is not well known what the PPI effect itself actually means. It could simply be a low-level property of sufficiently complex nervous systems which perhaps should not be interpreted too much in terms of higher functions. However, disruption of PPI is associated with the failure to filter irrelevant stimuli and to adequately focus on relevant information. Such an inability has been speculated in schizophrenia, too, since certain groups of schizophrenics show PPI disruption. Generally speaking, disruption of PPI suggests the disruption of "normal" attentional processing.

(Collaborations: Prof. M. Geyer, UCSD.)