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Official websites use. Share sensitive information only on official, secure websites. Correspondence: Boris B. For commercial re-use, please contact journals. Previous studies in chronic MDMA users demonstrated selective adaptations in the serotonin system, which were assumed to be associated with cognitive deficits. Here, we applied both sequences to assess their agreement and potential confounders underlying the diverging results. These insights may offer new mechanistic explanations for cognitive deficits e. However, a clear mechanistic link is missing. These findings indicate that chronic MDMA use is related to changes in the principal excitatory and inhibitory neurotransmitter systems, and thus cognitive deficits commonly observed in MDMA users might stem from glutamatergic and GABAergic changes, particularly in the striatum. In addition, their interaction is modulated by monoaminergic neurotransmitters i. Specifically, 5-HT modulates excitatory and inhibitory activity via adaptation of presynaptic glutamate and GABA release or postsynaptic excitability of glutamatergic and GABAergic neurons Ciranna, Chronic use of MDMA has been repeatedly associated with cognitive deficits, such as impaired memory and impulse control Morgan et al. Thus, although some impact of repeated MDMA use on the 5-HT system is evident, precisely how the major excitatory and inhibitory neurotransmitter systems are altered by MDMA use in humans remains elusive. In rats, repeated administration of MDMA permanently attenuated 5-HT—mediated inhibition of glutamate-evoked cell firing in the striatum Obradovic et al. Thus, although there is evidence from animal models that repeated MDMA-induced 5-HT release indirectly alters glutamatergic and GABAergic neurotransmission in the long term, this has not yet been demonstrated in humans. So far only two studies have reported glutamate concentrations measured via proton magnetic resonance spectroscopy MRS in chronic MDMA users, and neither study observed an effect in the occipital or midfrontal cortex nor in the striatum Chang et al. Because MDMA users tend to display a widespread pattern of polysubstance use Gouzoulis-Mayfrank and Daumann, and self-reports generally underestimate substance use Steinhoff et al. Moreover, Chang et al. MRS is, to date, the only available non-invasive method to measure glutamate and GABA concentrations in the human brain in vivo. Glutamate is frequently measured using a conventional point resolved spectroscopy sequence PRESS; Bottomley, with a short echo time TE of 30—35 milliseconds, but due to strong overlap of their resonance at clinical magnetic field strength, glutamate and glutamine are often reported as a composite signal glutamate-glutamine complex \[GLX\] Bell et al. The mechanisms responsible for this divergence are still poorly understood van Veenendaal et al. The region of interests chosen in this study are similar to the previous studies assessing effects of MDMA use on brain metabolites in humans Chang et al. However, none of these studies have measured GABA levels in these regions. We adopted a conventional volume of interest VOI approach to measure brain neurotransmitters because there are strong a priori hypotheses about the relevance of the selected regions to our study. Several studies have shown that GABA and glutamate play a critical role in impulsive behavior related to substance use Goodman, ; Kalivas and Volkow, ; McCullumsmith and Sanacora, ; Naaijen et al. It has also been shown that striatal GABAergic and glutamatergic concentrations highly modulate the behavioral performance during inhibitory control Dharmadhikari et al. MDMA use has been constantly associated with increased impulsive behavior and impaired inhibitory control in several studies Morgan et al. However, clear mechanistic evidence in humans is lacking to date, and potential adaptations in glutamate and GABA levels might hint at a distinct mechanistic explanation. Additionally, the striatum and ACC are key loci for the initiation and maintenance of substance use, specifically linked to glutamatergic and GABAergic signaling, respectively Kalivas, ; Koob and Volkow, Previously, MDMA use-related molecular changes in humans that persist for months after last use have been attributed exclusively to the 5-HT system, and with this study we aimed to assess whether long-term changes also occur in the main excitatory and inhibitory systems. The raphe nuclei provide substantial afferent input to the striatum as well as ACC, and 5-HT has profound inhibitory effects in these regions Finch et al. Accordingly, known long-term 5-HT adaptations in MDMA users are likely to affect major inhibitory and excitatory neurotransmitters in these regions as well. MDMA users were included if they had used MDMA on more than 25 occasions and their last consumption was no longer than 4 months ago, which was verified by forensic hair toxicology see below. Control participants were excluded if they had used illicit substances other than cannabis on more than 15 occasions during their lifetime. Further, general exclusion criteria included past or current Axis I DSM-IV psychiatric disorder with the exception of substance use disorders for the MDMA user group ; current or previous neurological disorders; severe somatic diseases or head injury; current use of medications that affect the central nervous system; previous or current intravenous heroin use; daily cannabis consumption; a DSM-IV diagnosis of schizophrenia, bipolar disorder, or obsessive-compulsive disorder in first-degree relatives; and any MRI contraindications. Participants were instructed to abstain from psychotropic substances for at least 3 days tested via urine toxicology, see below and from alcohol for 24 hours before attending the study. Five control participants had to be excluded due to the detection of MDMA traces in hair analysis. Diffusion tensor imaging data of the this sample have already been published in Zimmermann et al. The remaining participants in both groups were matched for age, sex, verbal intelligence, years of education, and nicotine use. After quality control of MRS data see below , the data of participants with clear artefacts in the MRS spectrum were discarded from analysis. Forensic hair toxicological analyses were performed using liquid chromatography-tandem mass spectrometry as described in Scholz et al. Additionally, to assess acute drug intoxication, urine samples were analyzed using liquid chromatography-tandem mass spectrometry. Both sequences used a spectral width of Hz and spectral points, VAPOR water suppression, and second-order automatic pencil-beam shim. Metabolite concentrations for both sequences were extracted from fitting an LCModel version 6. Brain tissue within VOI was segmented into grey matter, white matter, and cerebrospinal fluid using SPM12 Ashburner and Friston, to perform appropriate tissue correction. Metabolite concentrations are reported as the ratio to the unsuppressed water peak and reflect an estimation of metabolite concentration in moles per kilogram of brain water excluding water within CSF. Data quality of spectra was assessed for artefacts via visual inspection by an experienced MR physicist, and, in accordance with Kreis, , participants with inadequate data quality were excluded. An overview of quality measures per sequence, metabolite, region, and participant group is reported in Table 2. Complete and detailed MRS parameter specifications are listed supplementary Table 1. The VOI was rotated towards midline in axial plane and in anterior direction in sagittal plane, to cover as much as possible of the caudate nucleus and the putamen, while avoiding any parts of the ventricles. The VOI was positioned on top of the corpus callosum, centered at midline, and translated as well as rotated in the anterior direction of the sagittal plane, such that the anterior edge of the VOI was above the most anterior part of the corpus callosum genu. Hence, including most parts of the dorsal ACC. The smooth black lines represent the baseline model determined by LCModel. The signal of GABA displays three coupled resonances 3. Thus, two different scans are necessary to reveal the GABA peak at 3. In the so-called ON scan, an editing pulse is applied at a frequency of 1. In the OFF scan, the editing pulse is chosen such that it does not affect the 3. Covariates for the regression models included age, sex, and co-use of substances other than MDMA alcohol use \[estimated use within 6 months prior to testing according to self-reports\], cannabis, and stimulant use \[i. These covariates were included based on the evidence that age Sailasuta et al. Although we rigorously excluded participants whose MRS spectra showed prominent artefacts, the GLX and GABA concentrations still contained outlier data points, and therefore robust regression models as implemented in the function lmrob from the R-package robustbase Maechler et al. Robust regression is a form of weighted linear regression minimizing the influence of outlier data points, and here the estimation of robust regression coefficients was achieved using an MM-type estimator as described in Koller and Stahel All correlation coefficients reflect robust estimates based on the approach described above. Statistical analysis and data visualization were performed in R version 4. MDMA users co-used other substances, such as cannabis and stimulants, even though to a lesser extent, so that MDMA was clearly the most frequently used illicit substance. Values reflect mean and SD, except that for hair residuals the median and median absolute deviation are shown due to a highly right-skewed distribution. Independent t tests were used for quantitative data and chi-squared tests for frequency data; significant P values are displayed in bold. To assess whether observed group differences regarding GLX in the left striatum resulted from subacute effects rather than chronic long-term adaptations, we tested the association between GLX concentration and days since last MDMA use occasion range 5— days within the user group. Complete standard and robust linear regression outcomes for the left striatum and ACC are listed in supplementary Tables 2—5. The P value reflects the estimated group difference using linear regression on z-scored GLX concentrations including covariates for age, sex and co-use of other substances. Due to outlier data points, this effect was confirmed by robust regression. The correlation coefficient reflects a robust correlation estimate. In an exploratory follow-up analysis, to potentially disentangle effects of MDMA use on either glutamate or glutamine in the striatum, linear regression models including the same covariates as above were computed for the two metabolites separately. Quality metrics of MRS acquisition as well as analyzed and excluded participants per sequence, region, and group are listed in Table 2. All correlation coefficients reflect robust correlation estimates. However, complete outcomes of both sequences are reported in the Supplement Tables 2—4. However, this finding should be interpreted with caution in the absence of a significant group difference. Furthermore, our results may indicate that the alterations in GLX reflect long-term neuroplastic adaptations rather than subacute effects of MDMA use, given the absence of a relation between GLX concentration and the abstinence duration of MDMA use range, 5— days , although this hypothesis cannot be entirely confirmed in an observational study. The interpretation of GLX in terms of neurotransmitter alterations is complicated because the glutamate—glutamine cycle is tightly linked to the energy metabolism of the brain Massucci et al. However, our exploratory follow-up analysis suggested that the increase in GLX is due to glutamate rather than glutamine, and accordingly, MDMA use may actually affect glutamate at the neurotransmitter level. The serotonergic projections from the raphe nuclei to the striatum, together with the nigrostriatal dopaminergic and corticostriatal glutamatergic projections, form the main afferents of the striatum Guerra et al. The striatum consists mainly of GABAergic neurons Kreitzer, , and, accordingly, striatal glutamate release derives only from afferent projections of the cortex, thalamus, and hippocampus Pittenger et al. The effect of 5-HT in the striatum is mainly inhibitory Miguelez et al. This hypothesis is supported by findings in rats that after repeated MDMA administration, the inhibitory effect of 5-HT on glutamate release in the ventral striatum is attenuated Obradovic et al. Accordingly, glutamate might be released more strongly and facilitate long-term potentiation at glutamatergic synapses in the striatum. This could explain the observed elevated GLX levels in MDMA users, as a sustained increase in extracellular glutamate was observed after long-term potentiation at glutamatergic synapses in rats Richter-Levin et al. However, they solely used the PRESS sequence to quantify GLX in the striatum, which we have shown in this study may be more strongly distorted by confounding signal, especially in structures near large ventricles. On the other hand, the lack of an effect in the ACC in our study is consistent with the observations from Chang et al. Thus, our study raises the possibility that 5-HT adaptations may not solely be responsible for the impulse control deficits commonly observed in chronic MDMA users, as previously assumed Morgan et al. The increased striatal GLX levels in MDMA users might point to an imbalance in the fronto-striatal pathways commonly associated with impulsive behavior Dalley and Robbins, It has been shown that increased striatal glutamate levels are associated with elevated dopamine concentrations and might enhance dopamine release Rogeau et al. Moreover, previous studies proposed that highly impulsive individuals exhibit potentiated striatal dopamine release in response to novel, salient, or rewarding stimuli Buckholtz et al. According to these results, we speculate that elevated GLX levels in MDMA users might promote increased salience-related striatal dopamine release and thus enhance impulsive behavior. This hypothesis would also match previous neurobiological models of compulsory substance use suggesting dopamine-dependent excessive attribution of salience to drug-related cues and inadequate inhibitory control over these reinforcing circuits Goldstein and Volkow, ; Kozak et al. Thus, it could be argued that elevated GLX levels in the striatum might rather reflect a general feature of, or even a risk factor for, substance use. However, this is rather unlikely given that studies on stimulant users have reported the opposite, that is, reduced glutamate levels in the nucleus accumbens Engeli et al. Moreover, higher cocaine use was associated with lower glutamine levels in the pregenual anterior cingulate cortex Hulka et al. Accordingly, regions with inherently lower measurement quality e. A longer TE may reduce the susceptibility to confounding signals, because lipids and macromolecules contribute less to the spectra at longer TEs due to their short relaxation time Behar et al. We encourage future clinical studies applying both sequences to report the agreement between them to improve our understanding of the diverging results, which is critical for the advancement of clinical MRS studies. Our results are limited by the fact that glutamate represents a precursor for the synthesis of GABA, making it difficult to fully decipher the interpretation of the measured GLX concentration in terms of glutamate or GABA. Another potential limitation is that only one side of the striatum was measured; however, we did not expect any lateralization effects. Furthermore, this study has not been pre-registered. Nevertheless, we are confident that the transparent reporting in this manuscript and making data as well as analysis code publicly available ensure the credibility of our results. In conclusion, we have provided evidence that MDMA use not only affects the 5-HT system, as previously thought, but is in addition associated with long-term alterations in striatal GLX levels. These adaptations appear to be region specific, as an effect was only observed in the left striatum but not in the ACC. Future studies should address the functional consequences of these striatal adaptations, in particular their potential relation to impulsivity and cognitive control. Georg Oeltzschner, Russell H. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Int J Neuropsychopharmacol. Find articles by Josua Zimmermann. Find articles by Rebecca Coray. Find articles by Francesco Bavato. Find articles by Nicole Friedli. Find articles by Markus R Baumgartner. Find articles by Andrea E Steuer. Find articles by Antje Opitz. Find articles by Annett Werner. Georg Oeltzschner 14 Russell H. Find articles by Georg Oeltzschner. Find articles by Erich Seifritz. Find articles by Ann-Kathrin Stock. Find articles by Christian Beste. Find articles by David M Cole. Find articles by Boris B Quednow. Open in a new tab. Click here for additional data file. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. FWHM Hz a. Dose per week, mg a. Occasions per week a. Cumulative dose lifetime tablets b. Days since last consumption c. Dose per week, g a.

Buying Ecstasy Wenendaal