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.
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.
Mueller and colleagues frame the review around ongoing uncertainty over whether MDMA ("ecstasy") produces neurotoxic effects in humans. Much of the prior neuroimaging literature sampled heavy or long‑term users, with cumulative lifetime exposure in the hundreds or thousands of tablets and frequent polydrug use, whereas most MDMA consumers use the drug transiently and at much lower cumulative doses. The authors note additional relevance given renewed interest in MDMA as an adjunct in psychotherapy, where administration is limited to a few controlled sessions, and argue that evidence specific to moderate patterns of use is required to inform both public health debates and clinical considerations. This systematic review therefore set out to identify and synthesise human neuroimaging studies that examined non‑acute brain structure, function or neurochemistry in groups with moderate MDMA exposure. Moderate use was pre‑defined as an average of <50 lifetime episodes of ecstasy use or a lifetime consumption of <100 ecstasy tablets. The review aims to assess whether neuroimaging findings in such cohorts provide convincing evidence of MDMA‑related brain alterations and to characterise methodological limitations that affect interpretation.
Papers cited by this study that are also in Blossom
Liechti, M. E., Gamma, A., Vollenweider, F. X. · Psychopharmacology (2001)
Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T. et al. · Journal of Psychopharmacology (2010)
Nichols, D. E. · Journal of Psychoactive Drugs (1986)
Oehen, P., Traber, R., Widmer, V. et al. · Journal of Psychopharmacology (2012)
The investigators performed a systematic review following PRISMA guidance. They searched PubMed through July 2015 using the search string (mdma OR ecstasy OR 3,4methylenedioxymethamphetamine) AND (mri OR fmri OR pet OR spect OR imaging OR neuroimaging), with no language restriction, and screened reference lists of included articles. Inclusion criteria required original, peer‑reviewed human studies (observational or interventional) that used structural, functional or neurochemical neuroimaging to evaluate non‑acute MDMA effects and that included at least one group with mean lifetime use below the predefined moderate thresholds (<50 episodes or <100 tablets). Titles and abstracts were screened and full texts reviewed independently by two reviewers (FM, MS), with a third reviewer (CL) resolving disagreements when necessary. For each included study the reviewers extracted centre, year, design, imaging modality, sample sizes (including overlaps between studies where reported), demographics, detailed exposure metrics (tablets, episodes, estimated mg), usual and maximum dose per occasion where available, age at onset, time since last use, duration of use, matching of control groups (including matching for other drug use), abstinence verification, domains and regions tested, statistical thresholds and principal findings. Where necessary they converted heterogeneous exposure metrics into common units: a supplementary search of tablet content studies yielded a weighted mean MDMA content of 76 mg per tablet, and a weighted mean of 1.3 tablets per occasion was used to convert session‑based reports into tablet estimates. The reviewers included studies published up to July 2015. If subject overlap between publications was suspected but not reported, the authors contacted original investigators to clarify and incorporated that information when available. When key data could be computed from a report, the reviewers derived and included those values.
The search identified 250 PubMed records plus one additional article from reference screening; after screening and application of the moderate‑use inclusion criteria, 19 articles were included (publications dated 2001–2014). Nineteen studies comprised a mixture of modalities: ten used task‑based fMRI, four were neurochemical imaging studies (primarily PET and SPECT), and the remainder used structural MRI, voxel‑based morphometry (VBM), diffusion metrics (DTI) or other MR techniques; some centres contributed multiple papers with partially overlapping samples. Most studies (15/19) were retrospective observational designs; four were prospective. Control groups were present in all but two studies, but few studies matched controls for other drug use. Abstinence was usually checked, commonly by urine screening. Across modalities the overall pattern reported by the authors was a lack of consistent, replicated MDMA‑related alterations in cohorts with moderate lifetime exposure. In the fMRI literature (10 studies) task domains included working memory, associative memory, attention, decision‑making, motor function, visual stimulation and semantic memory. Behavioural task performance differences between users and controls were generally absent (all but two studies reporting no significant performance differences). Specific neuroimaging findings were heterogeneous. Daumann and colleagues reported, using both liberal and conservative thresholds, mixed regional BOLD differences in parietal, temporal and premotor areas when comparing user groups (including polydrug and ‘‘pure’’ MDMA users) with drug‑naïve controls. Jacobsen et al. observed less deactivation in the left hippocampus during an attention‑demanding condition in adolescent MDMA users and reported a small negative correlation between left hippocampal activation and abstinence (reported r = -0.05), but no correlation with cumulative dose. Jager et al., in a prospective cohort with minimal exposure at baseline, found no significant group differences across working memory, associative memory and selective attention paradigms. Becker et al. reported decreased encoding‑related activity in the left parahippocampal gyrus that correlated negatively with interim MDMA use in a sample with limited amphetamine‑type stimulant exposure, but noted baseline differences and possible recovery effects during abstinence. Watkins et al. reported greater activation in left precuneus and right superior parietal lobule during semantic encoding, with a positive correlation between right superior parietal activation and lifetime ecstasy use (Spearman's rho rS = 0.43, p = 0.042). Karageorgiou et al. found increased activation in the right supplementary motor area during a motor tapping task and within‑group correlations between MDMA amount and BOLD in basal ganglia and precentral regions; Salomon et al. reanalysed that dataset and reported reduced intraregional thalamic coherence and altered functional connectivity related to lifetime MDMA use. Bauernfeind and colleagues reported within‑group positive correlations between cumulative MDMA use and stimulus‑evoked activation in the lateral geniculate nucleus (rS = 0.59), BA17 (rS = 0.50) and BA18 (rS = 0.48), with some effects reduced after adjustment for scanner and stimulus method. Structural MRI and other MR techniques produced mixed results. Several VBM and cortical thickness studies that included modest lifetime MDMA exposure reported either no global differences or small, spatially limited volume reductions (for example in left orbitofrontal and right occipital regions). Mackey et al., studying a sample with higher use of prescription stimulants and cocaine than MDMA, reported regional increases and decreases in subcortical and cortical volumes but noted that including MDMA in analyses did not materially change results. Two consecutive prospective studies by De Win et al. assessed diffusion metrics (fractional anisotropy, apparent diffusion coefficient) and regional perfusion: with liberal thresholds they reported various increases/decreases in FA, ADC and regional blood flow, but after correction for multiple comparisons only a decrease in dorsolateral frontal grey matter perfusion remained significant in the earlier cohort; later findings were inconsistent and potentially confounded by interim increases in use of cocaine, alcohol and cannabis. Neurochemical imaging studies were also inconsistent. Three investigations of serotonin transporter binding reported no clear alterations across a range of lifetime doses. Two studies examined 5‑HT2A receptor binding with divergent outcomes: Di Iorio et al. reported increased estimated 5‑HT2A receptor densities in several cortical regions with positive correlations to cumulative MDMA dose (duration of abstinence did not affect binding), whereas Erritzoe et al. found no increased receptor densities in a sample with higher cumulative dose and shorter abstinence. A PET study of glucose metabolism in a polydrug inpatient sample showed negative correlations between duration of MDMA use and metabolism in left postcentral/inferior parietal gyrus, right inferior frontal/dorsolateral prefrontal cortex and right superior temporal pole, but lacked a non‑using control group and was confounded by other substance use. Overall, where studies reported significant associations these were often unreplicated, based on small samples, used liberal statistical thresholds or were potentially driven by co‑consumption of other substances. The reviewers emphasised pervasive methodological limitations across the literature: polydrug confounding, variable and often incomplete exposure metrics, reliance on self‑report for dose and drug identity, self‑selection of participants, small samples, retrospective designs and inconsistent control for legal drugs such as alcohol and nicotine. The reviewers also reported their data‑standardisation steps (weighted mean tablet MDMA content 76 mg; mean 1.3 tablets per occasion) used to harmonise exposure metrics across studies.
Mueller and colleagues interpret the assembled evidence as providing little, if any, convincing support that moderate lifetime exposure to MDMA produces consistent structural, functional or neurochemical changes detectable by the neuroimaging techniques used to date. Findings across studies were heterogeneous and largely non‑replicated even within similar domains. Structural MRI and VBM studies in comparable moderate‑dose samples mostly found null or divergent regional effects that could not be confidently attributed to MDMA because analyses often did not disentangle amphetamine‑type stimulant exposure, and lifetime doses in those studies were small. The authors highlight several sources of uncertainty that limit causal inference. Polydrug use is common in MDMA users and many studies either did not match controls for other substance use or provided insufficient data to adjust adequately for these confounders; alcohol, nicotine and cannabis in particular were often neglected despite potential structural and functional effects. Observational and typically retrospective recruitment strategies create risks of selection bias and confounding by pre‑existing traits such as sensation seeking. Reliance on self‑reported drug identity and dose is another limitation because tablets sold as ecstasy vary in MDMA content and may contain other psychoactive compounds. Heterogeneity in exposure reporting (tablets, episodes, mg) and sparse reporting of per‑occasion maximal doses further complicate interpretation; the reviewers note that peak dose per occasion may be important for toxicity but is infrequently reported. The discussion acknowledges specific inconsistencies within modalities: DTI measures of white matter integrity produced conflicting results across studies; PET/SPECT measures of serotonin transporters showed no clear alterations across studies, while two 5‑HT2A receptor studies produced opposing results (Di Iorio et al. reporting increased density, Erritzoe et al. not replicating this). The authors consider possible moderators such as dose and sex differences — Di Iorio's sample was exclusively female while Erritzoe's was mostly male — but also note that differences in cumulative dose and abstinence time complicate such explanations. In terms of implications, the authors state that the current neuroimaging literature does not provide clear evidence that moderate MDMA exposure produces brain changes detectable with the modalities used, and therefore does not, on the basis of these data alone, indicate that MDMA used as an adjunct in psychotherapy should be regarded as inherently dangerous. Nevertheless, they caution that absence of evidence is not evidence of absence: some alterations may be below detection limits, some studies were not designed to assess MDMA neurotoxicity specifically, and the overall quality of evidence is limited. The authors recommend future work that better accounts for co‑consumption (including alcohol and nicotine), uses appropriately matched controls, reports more complete exposure metrics (including per‑occasion dose), and applies prospective designs where feasible to reduce bias and improve causal inference.
The reviewers conclude that studies of moderate MDMA exposure are heterogeneous in design and quality and yield inconsistent neuroimaging results. Within the moderate dose range examined, there is no clear, replicated evidence from structural, functional or neurochemical imaging that MDMA induces brain alterations. However, this review does not establish that moderate MDMA use is free of neurotoxic effects, because limitations in study design, exposure characterisation, statistical power and modality sensitivity could mask true effects. The authors urge improved future studies with better matching for other substance use, clearer dosing information and prospective designs to resolve remaining uncertainties.
is the most common psychoactive component of illicit drugs sold as "ecstasy". Like other amphetamines, MDMA influences the dopamine and norepinephrine systems, but also shows strong serotonergic effects. Because of this serotonergic component, MDMA exhibits some mental effects that differ qualitatively from other amphetamine-type stimulantsand for this reason MDMA has been classified as an "entactogen". This term can be translated as "producing a touch within", which describes a state of consciousness characterised by increased openness, positive mood and calmness. MDMA was first mentioned in a patent of the German pharmaceutical company Merck in 1912, but was not widely known until its rise as a recreational drug in the 1980s. Today, MDMA is one of the most commonly used illicit drugs, especially in Oceania, North America and Europe, where prevalences of between 0.5 and 2.9% have been reported. MDMA is currently often sold as crystals of relatively high purity. For over 20 years, there has been an ongoing debate about possible neurocognitive alterations in MDMA users and concerns that MDMA may be neurotoxic -especially to serotonergic neurons. Many neuroimaging studies in MDMA consumers have been published. Most of these studies investigated samples with heavy use patterns, reflected in cumulative lifetime doses of hundreds or even thousands of consumed units and typically co-use of many other substances. However, use of MDMA is an incidental and transient phenomenon for most consumers and these studies therefore do not describe this large cohort appropriately. Only 15% of all MDMA users show considerable or heavy use patterns and approximately 80% of occasional users stop their use of MDMA and related drugs in their twenties. Moreover, there is increasing evidence that MDMA may be useful in psychotherapy, especially in the treatment of posttraumatic stress disorder. In this approach, MDMA is used as an additive in a psychotherapeutic setting and its administration is restricted to a few, typically 2-5, therapeutic sessions. Given the controversial debates surrounding MDMA, this approach, unsurprisingly, has been questioned. Therefore, results on moderate MDMA use might also be informative for this debate. In the present study, we systematically reviewed structural, functional and neurochemical brain imaging studies in moderate MDMA users, as defined by an average cumulative lifetime use of <50 lifetime episodes of ecstasy use or a lifetime consumption of <100 ecstasy tablets.
To ensure high quality reporting, we adhered to the recommendation for systematic reviews of the PRISMA statement.
Electronic search was performed using the PubMed database. The following search term was used: (mdma OR ecstasy OR 3,4methylenedioxymethamphetamine) AND (mri OR fmri OR pet OR spect OR imaging OR neuroimaging). All studies published before July 2015 were included, without any language restriction. Additionally, the reference lists of all included studies identified in the database search were manually screened for relevant studies.
Inclusion criteria were (1) original publication in a peerreviewed journal, (2) observational or interventional study design, (3) application of structural, functional or neurochemical neuroimaging techniques, (4) investigation of non-acute effects of MDMA on the human brain, (5) inclusion of at least one group with an average of <50 lifetime episodes of ecstasy use or an average lifetime consumption of <100 ecstasy tablets. After inspection for duplicates, the titles and abstracts of all records were reviewed. Publications that clearly did not meet inclusion criteria were excluded. The decision for inclusion or exclusion of the remaining publications was made on the basis of a review of the full texts. The whole process was conducted by two reviewers (FM, MS) independently. In case of disagreement, reviewers discussed their reasons for initial inclusion and exclusion. If consensus was not reached, a third reviewer (CL) was included.
The recorded variables for each article included in the review were: centre where the study was performed, authors and year of publication, study design, imaging method, number of subjects, number of subjects overlapping with other included studies, age, gender distribution, cumulative lifetime exposure to ecstasy (tablets, episodes, dosage in mg), usual MDMA dose per occasion, maximum MDMA dose per occasion, age at onset of MDMA use, time since last MDMA use, duration of MDMA use, control group matched for use of other drugs, required abstinence from alcohol, nicotine, cannabis and other (illicit) drugs, domains tested, regions analysed, statistical thresholds and principle findings (user group vs. controls and within-group results). When data were missing but computation based on the original publication was possible, the missing values were calculated and included in the review. If necessary, units were transformed. If overlaps between subjects were suspected but the original publications did not contain information on that topic, we contacted the authors and included the obtained data in the review.
The data on lifetime ecstasy use provided in the included studies were heterogeneous (tablets, episodes, dosage in mg). In order to obtain comparable results, we performed an additional search for articles providing information about the content of MDMA in ecstasy tablets. Additionally, we calculated the mean number of tablets consumed per episode, on the basis of the data provided in the studies included in this review. Three studies, with a total sample of 1149 tablets, were identified between 1991 and 2006 (Table). Tablets sold as ecstasy had a weighted mean of 76 mg per tablet. To convert data from studies which only provided lifetime use in terms of sessions of ecstasy use, we also calculated the weighted mean of tablets consumed during a single occasion. We thereby used data (n = 83) from studies included in this review, but due to overlaps, only four such studies were suitable. A weighted mean of 1.3 tablets per occasion was calculated.
Of 250 publications found in the PubMed database and one article identified in the reference lists, 19 articles were included in this review. 165 publications clearly did not meet the inclusion criteria (e.g. animal models, case reports, studies without neuroimaging, comments) and were thus excluded. Of the remaining 85 publications, 53 studies were excluded because inclusion criteria on lifetime consumption of ecstasy were not met; nine studies were excluded because only acute effects of MDMA were examined; three studies were excluded because lifetime consumption was reported as range (and not as average) and one study was excluded because neuroimaging results had already been reported in another included study. A flowchart of the selection procedure, with the included and excluded studies, is shown in Fig.. Of the total of 19 included articles, ten used fMRI during different tasks, four were neurochemical imaging studies (three PET, one SPECT), one used SPECT as well as structural MRI (sMRI; deand five used other techniques. Details are shown in Table. All studies were published between 2001 and 2014. Except for four studies, most surveys were performed by three centres (Aachen/Cologne, Amsterdam/Utrecht, Nashville) and showed some overlaps between subjects (see Table). Five studies investigated the use of amphetamine-type stimulants and thus did not focus on MDMA exclusively. Due to our limitation for the cumulative lifetime doses of MDMA, we only included subgroups in some studies. All included studies used an observational design, which was mostly retrospective (15/19). Three prospective studies from the Amsterdam/Utrecht centre investigated a population with no use of ecstasy at baseline but a high probability of starting to use ecstasy in the future. Another study prospectively investigated a sample with "first but limited experience" with amphetamine-type stimulants. All but two studiesincluded control groups, that were matched for age, with one exception, and gender, also with one exceptioncase; user and control groups were matched for education or IQ in all three cases; two studies reported no data on level of education. Most studies did not provide a control group that was matched for use of other drugs (see Table). All but one studyreported some kind of control of abstinence from drugs, mostly by urine drug screening. We have appended summary tables of all included studies to assist the reader to form an independent view of the core results (Tables).
Ten studies used fMRI during different tasks (four working memory, two associative memory, one decision making, two selective attention, two motor function, one visual stimulation, one semantic memory). For details see Table. Of the studies reporting results of task performance, allbut tworeported no significant differences between users and controls. Daumann et al. performed two fMRI studies investigating working memory via n-back tasks with three levels of difficulty (0-, 1-, 2-back task). The control group was drug-naïve, while the MDMA user group showed use of cannabis and amphetamine as well, but no clear data was provided about the extent of use of these drugs. No significant differences were reported for a restrictive statistical threshold in terms of the BOLD signal. For a liberal threshold, increases in activation in the right parietal cortex (1-back, 2-back) and the left parietal cortex (2-back) were observed. In order to address the limitations from the use of other drugs in the MDMA group, the authors compared a polydrug user and a drug-naïve control group using the same task in their second study. "Pure use" of MDMA was defined as no use of other substances more than "once per month or more frequently over 6 months within the last two years". The duration of abstinence was considerably shorter than in the first study. Polydrug users showed no significant differences compared with controls in the fMRI results. Compared with controls, pure MDMA users showed decreased activation in the inferior temporal region (1-back) and angular gyrus (1-back, 2-back) and, compared with the polydrug user group, decreased activation in the striate cortex (1-back) and the angular gyrus (2-back) and increased activation in the premotor cortex (1-back). Jacobsen et al. used an auditory n-back task (1-, 2-back) to examine working memory, and a selective, divided attention paradigm (binaural and dichotic verbal stimuli) in adolescents during fMRI. The study focused exclusively on the hippocampus. An additional binaural 3-back task was tested in three controls and all MDMA users. Groups were matched for use of nicotine and alcohol, but only a few details were reported of illicit drug use histories. One MDMA user was reported to have consumed cocaine as well and all but one participant in the control group had a history of cannabis use of unclear extent. Compared with controls, the MDMA user group showed less deactivation in the left hippocampus during the dichotic 2-back condition and this was still significant after removal of two subjects with a positive urine screen for cannabis (one MDMA user, one control). The binaural 3-back task was used for correlation with parameters of MDMA use. A negative correlation was observed between activation of the left hippocampus and time of abstinence, which was most pronounced during the binaural 3-back task (r = -0.05); no correlation was found for cumulative lifetime dose or onset of use. Jager et al. tested three paradigms during fMRI acquisition. In this prospective design, none of the participants had used MDMA at baseline and they only exhibited a small exposure at follow-up. Subjects were tested for working memory (item-recognition task), associative memory (pictorial associative memory task) and selective attention (visuo-auditory selective attention). The control group was matched for use of all drugs that were taken into account (alcohol, nicotine, cannabis, other amphetamines, cocaine). The whole brain as well as the ROI analysis showed no significant differences between the user and the control group for any of the paradigms. Becker et al. prospectively investigated associative memory in a sample of amphetamine-type stimulants users with limited experience of MDMA and/or other amphetamines. At the whole brain level, no significant differences were reported. An ROI analysis of the hippocampus and the parahippocampus yielded decreased encoding-related activity in the left parahippocampal gyrus, which was negatively correlated with interim use of MDMA, but not cannabis or other amphetamines. The authors noted that differences in hippocampal activity between interim abstinent subjects and subjects who continued use of amphetamine-type stimulants were already present at baseline. They discuss different durations of abstinence as an explanation for this finding and notice that the observed results in the parahippocampal gyrus were also driven by a relative increase in activity in the interim abstinent users, which might be due to recovery during this time of abstinence. Koester et al. examined decision-making in amphetamine-type stimulants users. The control group had no experience with any illicit drugs, including cannabis. No attempt was made to disentangle use of MDMA and other amphetamines. Subjects had to choose between control gambles with a 50% chance of losing or winning a small amount of money and experimental gambles with a low or a high chance of losing or winning. Drug-naïve controls chose fewer experimental gambles than the amphetamine-type stimulants group. With the FMRIB's Local Analysis of Mixed Effects, no significant differences were observed; however, with ordinary least squares, 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 that consisted mostly 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 (cannabis, cocaine, opium, sedatives, LSD, psilocybin). During semantic encoding, the user group showed greater activation in the left precuneus and the right superior parietal lobule, whereas no differences were observed during semantic recognition. Activation in the right superior parietal lobe was positively correlated with lifetime ecstasy use (Spearman's rho, r S = 0.43, p = 0.042). No significant correlation was found between lifetime use of other drugs and activation in the right superior parietal lobule or the left precuneus. Karageorgiou et al. tested motor function with fMRI using a motor tapping task (1-, 2-, 4-tap task). The user group showed a significantly higher use of cocaine than controls. The ROI analysis yielded an increased BOLD signal and an increase in percent activated voxels in the right supplementary motor area during the tap-4 condition in the MDMA user group compared with controls. No dose dependent effect was observed. For the within-group comparison, a positive correlation was described between the amount of MDMA use and the BOLD signal increase in the right putamen and the right pallidum, as well as with the spatial extent of activation in the right precentral cortex and the left thalamus. No differences in the right supplementary motor area were observed in the withingroup comparison and no correlation was found between lifetime episodes of alcohol, cannabis, cocaine and methamphetamine use and BOLD signal. For the tap-4 condition, a significant association was seen between alcohol use and percentage of activated voxels in the left postcentral and left precentral cortex. No association was found for other drugs (cannabis, cocaine, methamphetamine). Salomon et al. reanalysed the data set from Karageorgiou et al. for intraregional coherence and functional connectivity. Reduction in intraregional thalamic coherence and weaker interregional functional connectivity in different regionpairs were reported. The functional connectivity within-group analysis showed relationships between lifetime use of MDMA and various region-pairs. This was not accounted for by the significantly higher use of cocaine in the MDMA user group.an ROI analysis of visual stimulation during fMRI. Control subjects were included but no clear data about drug use patterns in this group were provided. For the within-group analysis, a positive correlation (Spearman's Rank correlations) was reported between cumulative lifetime use and the stimulus-evoked activation in the lateral geniculate nucleus (r S = 0.59), BA 17 (r S = 0.50) and 18 (r S = 0.48), as well as with the spatial extent of activation in BA 17 (r S = 0.59) and 18 (r S = 0.55). After adjusting for two different scanners and stimulus delivery methods, only the activation in the lateral geniculate nucleus remained significant. After inclusion of lifetime use of other drugs, some effects were seen for use of MDMA combined with methamphetamine, but not for other drugs (alcohol, cannabis, cocaine, codeine, LSD, opium, psilocybin, sedatives). For the between-group comparison, no differences were seen in signal intensity or spatial extent. After splitting the MDMA group into low and high exposure groups, a significantly greater spatial extent of activation was reported in BA 17 and 18 (heavy user group), with decreased signal intensity in the lateral geniculate nucleus (low exposure group).
Five studies applied other MR Imaging techniques. For details see Table.andinvestigated the same cohort using a VBM approach and focused on grey matter, cortical thickness/volume and subcortical structures, respectively. Use of MDMA and other amphetamines was not differentiated in the analysis, but summarised under "use of amphetamine-type stimulants". No significant differences were reported, except for reductions in the volumes of the small left orbitofrontal and right occipital regions. Mackey et al. conducted a VBM whole brain analysis in a population with a substantially higher use of (prescription) amphetamine-type stimulants, and of cocaine rather than MDMA (mean 24.5/21.4 episodes vs. 3.1 episodes). The control group was not matched for nicotine, alcohol and cannabis use and, due to the design, showed no use of prescription stimulants and cocaine. The authors reported increased volume of the left ventral anterior putamen and decreased volume of the right dorsolateral cerebellum and the right inferior parietal cortex. They noted that including or excluding the use of MDMA in the analysis did not have any substantial effect on their results. They also found correlations between the use of other amphetamine type stimulant/cocaine and various areas. In two prospective studies in subjects with no use of MDMA at baseline, De Win et al. investigated brain metabolites by 1 H-MRS, regional relative blood flow by PWI, as well as apparent diffusion coefficient and fractional anisotropy by. The 2007 study examined a cohort soon after their first use of ecstasy. No control group was included and subjects showed a significant interim increase in cocaine use. With a liberal statistical criterion (p < 0.05, uncorrected for multiple comparisons), an increase in fractional anisotropy in the centrum semiovale, a decrease in apparent diffusion in the thalamus and a decrease in regional relative blood flow in the thalamus, dorsolateral frontal and superior parietal grey matter were reported. After correction for multiple comparisons, only the decrease in blood flow in the dorsolateral frontal grey matter remained significant. The authors corrected for the parallel increase in cocaine use by excluding these subjects in a second analysis. Except for the increase in fractional anisotropy in the centrum semiovale, all results with the liberal criterion remained unchanged, as did the result with the conservative criterion. In their 2008 study, a larger cohort with increased use of MDMA was examined. With a threshold of p < 0.05 (uncorrected), they reported a decrease in fractional anisotropy in the thalamus and the frontoparietal white matter, an increase of fractional anisotropy in the globus pallidus, an increase in apparent diffusion in the thalamus and a decrease in regional relative blood flow in the globus pallidus and putamen. The user group showed a significant interim increase in the use of alcohol, cannabis, amphetamine and cocaine. However, all results remained significant after correction for these confounders. White matter tract integrity has been assessed by fractional anisotropy; see above). No significant differences were reported.
Four included studies investigated serotonin transporter and serotonin 5-HT 2A receptor densities in moderate MDMA users via SPECT and PET, respectively, and one study applied FDG-PET in a sample of polydrug users. For details and principal findings see Table. Two studies investigated densities of serotonin transporters by measuring radioligand binding via. Reneman et al. retrospectively investigated One study used PET to measure binding to serotonin 5-HT 2A receptorsand one study examined binding to serotonin transporters and 5-HT 2A receptors by. Di Iorio et al. reported an increase in estimated 5-HT 2A receptor densities in several regions. The cumulative lifetime dose of MDMA was positively correlated with receptor binding in the frontoparietal, occipitotemporal, frontolimbic and frontal regions. Duration of abstinence had no effect on receptor binding. The within-group analysis yielded no association to use of other drugs, including nicotine. Erritzoe et al. found no increased receptor densities in their sample; the doses were considerably higher and time of abstinence shorter than with Di Iorio et al. Differences between controls and users in the use of other drugs were not clearly specified (the control group was drug-naïve expect for <15 episodes of cannabis use, the user group had exposure to cannabis, amphetamines, cocaine, gamma-hydroxybutyrate, and ketamine, but lifetime doses were not given). Moreno-López et al. investigated a sample of polydrug users (heroin, cocaine, cannabis, alcohol, and MDMA) recruited from an inpatient treatment centre using FDG-PET. No control group was used. The aim of the study was to identify specific alterations in brain metabolism induced by individual substances using correlation analysis. No correlation was reported for the amount of MDMA use, but 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.
We have conducted a systematic review to examine the effects of moderate exposure to MDMA in humans using neuroimaging methods. In summary, the included studies provide little, if any, evidence for alterations induced by MDMA. Findings could not be replicated in studies on similar domains. Three studies applying structural techniques in samples with comparable lifetime doses of MDMA found either no significant results or divergent changes; either these were not due to MDMA or causation by MDMA remains unclear, as amphetamine-type stimulants were not further differentiated. However, lifetime doses of MDMA were small in all three studies, and structural changes might become apparent at higher doses. The same holds true for fractional anisotropy deduced from DTI measurements, where one study found no alterations and two consecutive studies, which also investigated apparent diffusion and relative regional blood flow, reported no consistent results. Three studies investigated serotonin transporter binding at several lifetime doses of MDMA and found no significant alterations. Two studies examined densities of serotonin 5-HT 2A receptors but reported divergent results. In a sample that exclusively included women, Di Iorio et al. observed increased receptor density in various cortical areas, which was interpreted as compensatory upregulation due to serotonergic neurotoxicity. However, these findings were not reproduced by another study. It seems unlikely that the described increase in receptor density is due to the use of other drugs as, in the study of Di Iorio et al., the user group only showed significantly higher use of psilocybin, which, as a serotonin agonist, would presumably cause receptor downregulation, if anything. As there is evidence that the effects of MDMA are more pronounced in womenand the population in Erritzoe et al. consisted mostly of men, it can be speculated that women might also be more vulnerable to neurotoxic effects. However, cumulative lifetime dose was more than three times higher in the sample used by Erritzoe et al. and it is thus questionable whether gender might fully explain these differences. Four studies investigated working memory by fMRI. With a small cumulative lifetime dose of MDMA and a conservative statistical threshold, Jager et al. found no significant alterations.reported several divergent results in their studies with considerably higher doses and liberal thresholds. These divergent results might thus be due to different doses or different statistical thresholds and resulting type I or II errors. Additionally, except for Jager et al., the studies are imprecise about the use of other drugs in their populations and none fully accounts for the use of illicit and legal drugs, which makes interpretation of these results even more difficult. Associative memory was investigated in two fMRI studies by. While Jager et al. reported no significant findings and Becker et al. found decreased activity in the left parahippocampal gyrus at a higher lifetime dose of MDMA in their population, the reason for these findings remains unclear, as some differences between user groups and controls were present at baseline. Five studies examined decision-making, different aspects of motor function, visual stimulation and brain metabolism. One of these studies focused on amphetamine-type stimulants in general and did not differentiate MDMA. Another study did not account for the significant consumption of cocaine in the MDMA user group. So once again, causation by MDMA remains unclear in these reports. After adjusting for different scanners and stimulus delivery methods, Bauernfeind et al. reported a positive correlation between lifetime use of MDMA and the BOLD signal in the lateral geniculate nucleus in their within-group analysis but no differences were found in the between-group analysis. Results of these studies should thus be replicated by (ROI) analysis using more conservative thresholds.
MDMA users are typically polydrug users, with alcohol, tobacco, cannabis and other stimulants being the most common substances. Alcohol and nicotine are often neglected in the analyses and the use of cannabis is not excluded for pragmatic reasons. These confounders might have a considerable influence on the results, as all of these substances may cause both structural and functional changesand subacute effects of cannabis can bias functional results. Co-consumption of other substances may increase adverse effects caused by MDMA, as the use of other drugs, such as nicotine, alcohol, cocaine and other amphetamines, may lead to pharmacological interactions and additive effects. These effects can also be protective, as cannabis may antagonisethe hyperthermic effects of MDMA, which are supposed to increase MDMA's neurotoxicity. In general, there is considerable uncertainty about the extent of use and potential influence of other drugs in the studies discussed in this review. Three studies explicitly investigated effects of amphetamine-type stimulants and not of MDMA. We included these studies because they provided data about lifetime use of MDMA but, due to the design, no attempt was made to disentangle the effects of different amphetamines. Therefore the results of these studies provide only limited information about the specific focus of this review. A fourth study investigated the use of amphetamine-type substances and cocaine in a population with very moderate use of MDMA and the authors noted that MDMA was probably not the cause of the observed effects. Of the remaining studies, only two studies provided a control group that was matched for use of illicit or legal drugs (Table). Seven studies found significant differences between user groups and controls in co-consumptions of illicit drugs and two studies reported significant differences in the use of legal drugs. All but one of those studies tried to account for these confounders in some way. Eight studies provided no clear data about differences in the use of illicit drugs between controls and user groups and seven provided no clear data about the use of legal drugs. We tried to calculate these missing values and found significant use of cannabis in three of those studies, while the others did not provide enough data for calculation. Of the 15 studies which reported any significant result, seven failed to provide any clear identification of differences in the use of illicit or legal drugs, nor did they account for these confounders in their analysis, which leaves some uncertainty regarding interpretation.
All included studies use observational designs and therefore suffer from a high risk for bias and confounding. Participants were recruited by advertisements or by word of mouth and were thus self-selected, not randomised members of a particular subpopulation, and may have exhibited a variety of possible pre-existing differences, such as a tendency for sensation seeking and a special "life style". Consequently, these pre-existing factors may be reflected in neuroimaging as has already been shown for structural alterations in users of amphetamine-type stimulants with escalating consumption patterns. This is also well illustrated in one of the studies included in this review on decision-making in amphetamine-type stimulants users. As the authors note, it is hard to tell whether risky decision-making should be regarded as a cause or a consequence of stimulant use. Prospective studies can overcome some of these problems; however, only four studies included in the review used a prospective design. Furthermore, there is inherent uncertainty about the substances actually ingested as "MDMA" as well as the dose, as researchers have to rely on self-reported histories of drug use and the true doses are unknown in a naturalistic environment. Drugs that are sold as MDMA or "ecstasy" contain varying amounts of MDMA, may contain precursors or intermediates, and may additionally or exclusively contain other psychoactive compounds with (unkown) neurotoxic effects, such as other amphetamines or novel psychoactive substances. By default, studies in this field report dosages as a cumulative lifetime dose. With respect to toxicity, dosages taken per occasion may be even more importantthan lifetime dose. As Cole et al. remark, "if MDMA-induced neurotoxicity relied simply upon such a 'cumulative dose' then all patients prescribed the neurotoxic amphetamine fenfluramine on a daily basis should be exhibiting serotonergic neurotoxicity". MDMA users often ingest more than one tablet per occasion. However, only three studies reported data about maximal doses per occasion and this information is usually not taken into account. As heavy users are more likely to show excessive use patterns, this might also explain some findings on neurotoxicity obtained in neuroimaging studies in this group. Additionally, heavy users are also more likely to show higher use of other drugs and several environmental and lifestyle factors might be accentuated. Use of higher doses of MDMA per occasion, effects of and interactions with other drugs, as well as other factors might lead to increased hyperthermia and oxidative stress, factors that are thought to cause neurotoxicity associated with MDMA.
In summary, studies in this field exhibit a variety of differences and report highly heterogeneous results. Additionally, they suffer from problems that are inherent to the observational designs or due to other reasons. While some problems, like imprecise data on actual consumed doses, are unlikely to be solved, others should be carefully accounted for, for example appropriately matched control groups, including the consumption of the legal drugs nicotine and alcohol; moreover, such controls might be difficult to recruit. In the moderate dose range investigated in this review, we found no clear evidence from neuroimaging techniques that MDMA induces changes in the human brain. This also implies that there is currently no clear evidence from neuroimaging that the use of MDMA as an additive in psychotherapy should be regarded as dangerous per se. On the other hand, our systematic review does not allow the conclusion that MDMA is not neurotoxic in moderate use, as possible alterations caused by MDMA might not be detectable with the techniques used, some of the included studies were not specifically designed to investigate neurotoxic effects of MDMA in moderate users and several studies were of rather poor quality.
Create a free account to open full-text PDFs.
Parrott, A. C. · Journal of Psychoactive Drugs (2014)
Schmid, Y., Enzler, F., Gasser, P. et al. · Biological Psychiatry (2015)
Papers in Blossom that reference this study
Kloft, L., Otgaar, H., Blokland, A. et al. · European Neuropsychopharmacology (2022)
van Dongen, R. M., Alderliefste, G. J., Onderwater, G. L. J. et al. · European Journal of Neurology (2021)
Müller, F., Brändle, R., Liechti, M. E. et al. · Neuroscience and Biobehavioral Reviews (2019)
Dunlap, L. E., Andrews, A. M. · ACS Chemical Neuroscience (2018)
Bouso, J. C., Dos Santos, R. G., Hallak, J. E. · Neuroscience and Biobehavioral Reviews (2018)
Curry, D. W., Young, M. B., Tran, A. N. et al. · Neuropharmacology (2017)
Roberts, C. A., Quednow, B. B., Montgomery, C. et al. · Neuroscience and Biobehavioral Reviews (2017)
Dos Santos, R. G., Hallak, J. E., Bouso, J. C. · Therapeutic Advances in Psychopharmacology (2017)
Vizeli, P., Liechti, M. E. · Journal of Psychopharmacology (2017)
Dos Santos, R. G., Osório, F. L., Crippa, J. A. et al. · Neuroscience and Biobehavioral Reviews (2016)