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'Ecstasy: a Human Neurotoxin?' A Novartis Foundation Meeting. Abstracts of Presentations.
Professor George Ricaurte Over the last decade, work from numerous independent research laboratories has shown that the recreational drug methylenedioxymethamphetamine (MDMA, 'ecstasy') has the potential to damage brain serotonin neurons. Neurotoxic effects of MDMA have been documented in various animal species including rats, guinea pigs, squirrel monkeys, rhesus monkeys and, most recently, baboons. In all of these animal species, MDMA produces long-term deficits in presynaptic markers of serotonin neurons, changes that are most likely secondary to a destruction or 'pruning' of serotonin nerve endings. Interestingly, the cell body or perikaryon of serotonin neurons is not affected on a long-term basis by MDMA, leaving open the possibility of axonal regrowth and recovery in MDMA-lesioned animals. Notably, the neurotoxicity of MDMA in animals occurs at doses that overlap those taken by some human MDMA users. Hence, there is growing concern that MDMA may also produce neurotoxic effects in humans. The next presenter, Professor Una McCann, who has been evaluating the neurotoxic potential of MDMA in humans, will present recent findings indicating that this concern is justified. This presentation will focus on the various lines of evidence which indicate that MDMA is a potent and selective serotonin neurotoxin in animals. It will then examine the reaction of serotonin neurons to MDMA injury in rodents and non-human primates, and draw attention to the fact that serotonin neurons in rodents (rats) recover whereas those in non-human primates (squirrel monkeys) do not). Implications of these findings to human MDMA users will be considered. Professor Una McCann A large body of pre-clinical data indicates that 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') damages brain serotonin (5-HT) axons in animals, including non-human primates. Our clinical studies have sought to determine whether human MDMA users are also susceptible to MDMA-induced 5-HT injury, and, if so, if there are measurable functional consequences. These studies have utilised the two existing validated measures of 5-HT neurotoxicity in living humans, namely, measurement of cerebrospinal fluid (CSF) 5-HIAA, the major metabolite of 5-HT and, more recently, positron emission tomography (PET) studies with a redioligand element of serotonin axon terminal. Both of these markers are decreased in MDMA users, as in experimental animals with known 5-HT injury. MDMA users, when compared to control subjects who have never used MDMA (but who may have used other recreational drugs) also have alterations in behavioural functions thought to be modulated by 5-HT. These include the neuro-endocrine and behavioural responses to drugs that act at serotonin receptors, cognitive function, impulsivity, and sleep architecture. Taken together, these studies indicate that some MDMA users develop 5-HT neurotoxic injury, and that MDMA-induced 5-HT damage may lead to long-lasting behavioural changes. Future studies will be aimed at: 1) Determining whether there are factors, such as drug dosage or extent of prior MDMA use, that are predictive of MDMA-induced 5-HT damage; 2) Better delineating the functional consequences of MDMA-induced 5-HT alterations 3) Determining whether, with advancing age, MDMA users are at a higher risk for developing neuropsychiatric illness, and; 4) Whether rational treatment strategies can be developed for alleviating MDMA-related neuropsychiatric syndromes Professor Andy Parrott Animal research has suggested that MDMA or 'ecstasy' may be neurotoxic. If MDMA damages serotonin nerve fibres in the human brain, then this may be evident in altered cognitive abilities or changed behaviours. This presentation will review those studies, which have assessed the cognitive skills and abilities of drug-free recreational ecstasy users. On most cognitive tasks, there seem to be no differences between ecstasy users and similar-aged controls who have never taken ecstasy. However, several research groups have found that ecstasy users often display poor memory scores, and this is confirmed in the self-reports of some heavy users, who feel that their memories have been adversely affected by frequent MDMA-use. Ecstasy users sometimes display poor performance on cognitive tasks involving higher executive processing, while heightened impulsivity has also been shown. Moreover, these deficits are generally seen in those who have taken large amounts of ecstasy, rather than those who have taken it on just a few occasions. However, some studies have failed to find any cognitive decrements, while one study has reported higher cognitive performance in former ecstasy users (greater verbal fluency). Before offering any neurological interpretations for these findings, some important caveats need to be raised. Firstly, there are numerous methodological problems to research in this field, which make interpretation difficult and uncertain. Thus we cannot randomly allocate naive volunteers to six months on ecstasy, or six months on placebo, then see who has developed cognitive deficits and/or neural damage. Instead, we can only monitor those who have used the drug recreationally; but there may be pre-existing differences between those who use the drug and those who don't. Regular ecstasy users also tend to take other illicit drugs (particularly amphetamine, cocaine, cannabis and LSD), and often follow poor lifestyles, with reduced nutrition and adverse patterns of rest and recuperation. All these may adversely affect Nevertheless, the patterns of cognitive deficit of some regular ecstasy users are consistent with neural damage to brain areas subserved by serotonin, particularly the frontal cortex (increased impulsivity, and executive processing difficulties), and hippocampus (memory impairments). Dr Valerie Curran This overview, following the talks of other speakers, draws together the central issues in determining whether MDMA ('ecstasy') is a human neurotoxin. Given the direct evidence of neurotoxic effects from animal studies, it then considers the more indirect evidence from human studies of two types. Type 1 studies are those which have examined neuro-pharmacological and neuroendocrine effects. Type 2 studies use changes in psychological functions (or induced psychiatric symptoms) to infer possible neurochemical effects. The degree to which such studies make causal links between use of ecstasy and subsequent neurochemical or psychological function is discussed in the context of methodological and ethical considerations. Examples from recent research are used to illustrate problems in research, including: I) polydrug use by the majority of ecstasy users ii) verifying current and previous use of psychotropic drugs iii) baseline differences in function between people who use ecstasy and those who do not Areas where our knowledge is currently very limited are outlined in terms of what research is now needed on the effects of this drug. Critically, these include first, the degree to which there is recovery of function when people stop using ecstasy and second, whether there are factors which mean that some people are more vulnerable than others to the neurotoxic and psychological effects of this drug. 4 December 1998 Novartis Meeting front page
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