Chronic 3,4-Methylenedioxymethamphetamine (MDMA) Use Is Related to Glutamate and GABA Concentrations in the Striatum But Not the Anterior Cingulate Cortex

Abstract

Background 3,4-Methylenedioxymethamphetamine (MDMA) is a widely used recreational substance inducing acute release of serotonin. Previous studies in chronic MDMA users demonstrated selective adaptations in the serotonin system, which were assumed to be associated with cognitive deficits. However, serotonin functions are strongly entangled with glutamate as well as γ-aminobutyric acid (GABA) neurotransmission and studies in MDMA-exposed rats show long-term adaptations in glutamatergic and GABAergic signaling. Methods We used proton magnetic resonance spectroscopy (MRS) to measure the glutamate-glutamine complex (GLX) and GABA concentrations in the left striatum and medial anterior cingulate cortex (ACC) of 44 chronic but recently abstinent MDMA users and 42 MDMA-naïve healthy controls. While the Mescher-Garwood point-resolved-spectroscopy sequence (MEGA-PRESS) is best suited to quantify GABA, recent studies reported poor agreement between conventional short-echo-time PRESS and MEGA-PRESS for GLX measures. Here, we applied both sequences to assess their agreement and potential confounders underlying the diverging results. Results Chronic MDMA users showed elevated GLX levels in the striatum, but not the ACC. Regarding GABA, we found no group difference in either region, although a negative association with MDMA use frequency was observed in the striatum. Overall, GLX measures from MEGA-PRESS, with its longer echo time, appeared to be less confounded by macromolecule signal than the short-echo-time PRESS and thus provided more robust results. Conclusion Our findings suggest that MDMA use affects not only serotonin, but also striatal GLX and GABA concentrations. These insights may offer new mechanistic explanations for cognitive deficits (e.g., impaired impulse control) observed in MDMA users.

Higher striatal glutamate in male youth with internet gaming disorder

“…However, the quantification of low concentration J-coupled metabolites such as Glx from TE 68 spectra provides reliable results and has recently been used in several studies (e.g. [ 24 , 28 , 51 ]). In future, MRS with higher field strength (7 T) and improved shimming techniques will allow to measure the ventral part of the striatum covering mainly the nucleus accumbens and the distinction of glutamate and glutamine [ 14 ].…”

New Study Reveals Long-Term Effects of MDMA on the Brain’s Glutamate-Glutamine Complex

“…It is important to note that this study focuses on the striatum and does not find significant alterations in GLX levels in the anterior cingulate cortex (ACC) ( Zimmermann et al, 2023 ). The ACC plays a critical role in various cognitive and emotional processes, including decision-making, attention, and error detection.…”

“…The study’s findings indicate that chronic MDMA use is associated with increased GLX levels in the striatum ( Zimmermann et al, 2023 ). This increase in glutamate and glutamine concentrations suggests enhanced excitatory activity in this brain region.…”

“…I am writing to discuss the significant findings presented in the study titled “Chronic 3,4-Methylenedioxymethamphetamine (MDMA) Use Is Related to Glutamate and GABA Concentrations in the Striatum But Not the Anterior Cingulate Cortex” ( Zimmermann et al, 2023 ). The research conducted by Zimmermann and colleagues provides valuable insights into the long-term effects of MDMA use on the brain, particularly in relation to the glutamate-glutamine complex (GLX) levels in the striatum.…”

“…The researchers also used a robust regression model to confirm group differences and minimize the influence of outlier data points. Additionally, the study used correlation analysis to assess the relationship between metabolite concentration and frequency of MDMA use among drug users ( Zimmermann et al, 2023 ). Conducting research on illicit substances such as MDMA poses inherent challenges due to legal and ethical considerations.…”