Functional MRI studies in human Ecstasy and cannabis users

Abstract

Cannabis and ecstasy are among the most widely used illicit drugs in the world. However, there are substantial concerns about their neurotoxic potential for brain and brain function. Despite previous research, some crucial questions regarding the causality, course and clinical relevance have remained unanswered, mainly because of methodological limitations. These limitations include the use of cross-sectional and retrospective designs with lack of baseline data and inadequate control of potential confounders, such as poly-substance use in ecstasy users. This thesis, as part of the larger Netherlands XTC Toxicity (NeXT) study, presents four functional magnetic resonance imaging (fMRI) studies designed to overcome the limitations of previous studies and thus makes a significant contribution to the remaining questions concerning the potential neurotoxicity of ecstasy and its most commonly used co-drug cannabis. The studies presented in this thesis focused entirely on ecstasy or cannabis-induced functional consequences, in terms of sustained effects on human brain function in three cognitive domains, i.e. working memory, selective attention and episodic associative memory. In order to overcome the lack of baseline data, a prospective cohort study was performed in novice ecstasy users and persistent ecstasy-naive controls. 25 Novice users were examined before and after an episode of first ecstasy use. They were compared with 24 controls, also measured twice, and matched for gender, verbal IQ and cannabis use with the novice users. To deal with the potential confounding of poly-drug use in experienced ecstasy users, a large stratified sample with substantial variation in the amount and type of drug used was carefully composed, instead of a random recruitment among heavy ecstasy users. Subsequently, the effects of ecstasy and other drugs such as amphetamine, cocaine and cannabis could be separated with multiple regression analyses. In addition, the selective effects of frequent cannabis use were investigated in two cross-sectional fMRI studies where we compared task performance and related brain activity during working memory, attention and associative memory between groups of frequent cannabis users and cannabis-naive controls. Regarding the specific effects of ecstasy in the context of poly-substance use the results indicated that drug use was associated with reduced performance and altered brain activity for associative memory, but had little effect on working memory and attention. Importantly, memory performance was affected by amphetamine more than by ecstasy. Both drugs affected brain activity, but these effects were consistently in opposite direction, indicating separate mechanisms are at play. These findings suggest that previously reported effects of ecstasy on memory and memory-related brain function might be (partly) attributable to concomitant use of amphetamine rather than the use of ecstasy. Concerning the prospective cohort study in incident users the results showed no firm evidence for sustained effects of a low dose of ecstasy (median number of pills: 1.5) on cognitive brain function. With regard to cannabis, the results failed to show cognitive deficits or changes in cognitive brain function. It should be noted, however, that it can not be excluded that other assessment techniques measuring similar or different aspects of the brain and brain functioning could detect sustained changes in the brain or in brain functioning. Given the fact that the NeXT study is still in progress and entails an interconnected set of studies including other neuroimaging and neuropsychological assessments, a final conclusion regarding the neurotoxicity of ecstasy and cannabis is yet to be drawn.