Neuroimaging in moderate MDMA use: A systematic review

This systematic review (2015; 19 studies) found no convincing evidence that moderate use of MDMA is associated with significant brain alterations. However, the authors point out that the included studies were very heterogeneous and often of low quality.

Abstract

“MDMA (“ecstasy”) is widely used as a recreational drug, although there has been some debate about its neurotoxic effects in humans. However, most studies have investigated subjects with heavy use patterns, and the effects of transient MDMA use are unclear. In this review, we therefore focus on subjects with moderate use patterns, in order to assess the evidence for harmful effects. We searched for studies applying neuroimaging techniques in man. Studies were included if they provided at least one group with an average of <50 lifetime episodes of ecstasy use or an average lifetime consumption of <100 ecstasy tablets. All studies published before July 2015 were included. Of the 250 studies identified in the database search, 19 were included. There is no convincing evidence that moderate MDMA use is associated with structural or functional brain alterations in neuroimaging measures. The lack of significant results was associated with high methodological heterogeneity in terms of dosages and co-consumption of other drugs, low quality of studies and small sample sizes.”

Authors: Felix Mueller, Claudia Lenz, Markus Steiner, Patrick C. Dolder, Marc Walter, Undine E. Lang, Matthias E. Liechti & Stefan Borgwardt

Summary

Mueller a , C. Lenz a , M. Steiner a , P.C. Dolder b , M. Walter a , U.E. Lang a , M.E. Liechti b ,

MDMA is a psychoactive component of illicit drugs sold as “ecstasy”, and shows strong serotonergic effects. It has been classified as an “entactogen” (producing a touch within), and is currently one of the most commonly used illicit drugs, especially in Oceania, North America and Europe.

Researchers reviewed structural, functional and neurochemical brain imaging studies in moderate MDMA users, including those who used MDMA for hundreds or even thousands of consumed units and typically co-use of many other substances.

The review included observational or interventional studies, structural, functional or neurochemical neuroimaging techniques, investigation of non-acute effects of MDMA on the human brain, and inclusion of at least one group with an average of 50 lifetime episodes of ecstasy use.

Three studies with a total sample of 1149 tablets were identified between 1991 and 2006, with a weighted mean of 76 mg per tablet. The mean number of tablets consumed per episode was calculated on the basis of the data provided in the included studies.

We reviewed 83 studies on ecstasy use and calculated the weighted average of tablets consumed during a single occasion. Of the remaining publications, 19 were included, of which ten used fMRI during different tasks, four were neurochemical imaging studies (three PET, one SPECT), and five used other techniques.

Table 2 shows that most studies were performed by three centres and showed some overlaps between subjects. Five studies investigated the use of amphetamine-type stimulants and thus did not focus on MDMA exclusively. All included studies used an observational design, were mostly retrospective (15/19), and included control groups that were matched for age, gender, and education or IQ. Two studies reported no data on studies did not provide a control group that was matched for use of other drugs.

In two fMRI studies, researchers investigated work-memory via n-back tasks with three levels of difficulty (0-, 1-, 2-, 3-).

In a study using an auditory n-back task (1-back, 2-back) and a selective, divided attention paradigm (binaural and dichotic verbal stimuli) in adolescents, fMRI showed decreased activation in the inferior temporal region (1-back) and angular gyrus (1-back, 2-back) compared with controls and increased activation in the premotor cortex (1-back).

A study focused exclusively on the hippocampus and found that MDMA users showed less deactivation in the left hippocampus during the dichotic 2-back condition compared with controls. The binaural 3-back task was used to correlate MDMA use with time of abstinence. Jager et al. tested three paradigms during fMRI acquisition and found that the left parahippocampal gyrus was negatively correlated with interim use of MDMA, but not cannabis or other amphetamines. Becker et al. investigated associative memory in a sample of amphetamine-type stimulants users with limited experi- of MDMA and/or other amphetamines. Koester et al. examined decision-making in amphetamine-type stimulants users and control groups. They observed an increased BOLD signal in the right parietal lobe during high probabilities of winning. Watkins et al. tested semantic memory in a cohort of subjects already examined in the first two fMRI studies from the same centre. The MDMA user group showed significantly more consumption of a variety of other drugs. Karageorgiou et al. tested motor function with fMRI using a motor tapping task. They found that the MDMA user group showed a significantly higher use of cocaine than controls, and that the right supplementary motor area showed an increased BOLD signal and an increased percent activated voxels during the tap-4 condition.

Bauernfeind et al. conducted an ROI analysis of visual stimulation during fMRI and found a positive correlation between cumulative lifetime use of MDMA and the stimulus-evoked activation in the lateral geniculate nucleus, BA 17 and 18, as well as with the spatial extent of activation in BA 17 and 18.

In two prospective studies, subjects with no use of MDMA at baseline were investigated for brain metabolites by 1 H-MRS, regional relative blood flow by PWI, as well as apparent diffusion coefficient and fractional anisotropy by DTI. No significant differences were reported, except for reductions in the volumes of the small left orbitofrontal and right occipital regions analysis.

In a study on the use of MDMA, fractional anisotropy was decreased in the thalamus, frontoparietal white matter, globus pallidus, apparent diffusion thalamus and regional relative blood flow in the thalamus, dorsolateral frontal and superior parietal grey matter.

Two studies investigated serotonin transporters by measuring radioligand binding via SPECT in moderate MDMA users, and one study examined serotonin transporters and 5-HT2A receptors by PET in a sample of polydrug users. No clear data were reported on alterations in the serotonin transporter in the two studies.

Moreno-López et al. investigated a sample of polydrug users using FDG-PET, and found that the duration of MDMA use was negatively correlated with metabolism in the left postcentral/inferior parietal gyrus, right inferior frontal gyrus/dorsolateral prefrontal cortex and right superior temporal pole.

The included studies provide little, if any, evidence for alterations induced by MDMA. Findings could not be replicated in studies on similar domains, and either the changes were not due to MDMA or causation by MDMA remains unclear. Three studies examined serotonin transporter binding at several lifetime doses of MDMA and found no significant alterations. Two studies examined densities of serotonin 5-HT2A receptors but reported divergent results, with the first study finding increased receptor density in women, but the second not. Four studies investigated working memory by fMRI. The results vary, possibly due to different doses or different statistical thresholds, and none fully accounts for the use of illicit and legal drugs.

Five studies examined decision-making, different aspects of motor function, visual stimulation and brain metabolism in MDMA users. While some studies reported no significant findings, others found decreased activity in the left parahippocampal gyrus at a higher lifetime dose of MDMA in their population.

The use of cannabis is not excluded for pragmatic reasons, as it may have a considerable influence on the results. Co-consumption of other substances may increase adverse effects caused by MDMA.

In general, the studies discussed in this review did not disentangle the effects of different amphetamines, and only three studies explicitly investigated effects of amphetamines and not of MDMA. Two studies provided a control group that was matched for use of illicit or legal drugs.

In 15 studies, the use of illicit drugs and legal drugs was significantly different between control and user groups. However, seven of these studies did not account for confounders, leaving some uncertainty regarding interpretation.

Studies on decision-making in amphetamine-type stimulants users have a high risk for bias and confounding, because participants were recruited by advertisements or by word of mouth and may have exhibited a variety of possible pre-existing differences.

Researchers have to rely on self-reported histories of drug use and the true doses are unknown in a naturalistic environment. The dosage taken per occasion may be even more important with respect to toxicity than the cumulative lifetime dose. MDMA users often ingest more than one tablet per occasion, and heavy users are more likely to show higher use of other drugs and several environmental and lifestyle factors might be accentuated.

We found no clear evidence from neuroimaging techniques that MDMA induces changes in the human brain in the moderate dose range investigated in this review. However, the use of MDMA as additive in psychotherapy should not be regarded as dangerous per se.