The aim of this study was to determine the acute effects of the "Ecstasy" analogue MDE (3,4-methylene dioxyethamphetamine) on cerebral glucose metabolism (rMRGlu) of healthy volunteers and to correlate neurometabolism with acute psychopathology. In a randomized double-blind trial, 15 healthy volunteers without a history of drug abuse were examined with fluorine-18-deoxyglucose (18FDG) positron emission tomography (PET) 110-120 min after oral administration of 2 mg/kg MDE (n = 7) or placebo (n = 8). Two minutes prior to radiotracer injection, constant cognitive stimulation was started and maintained for 32 min using a word repetition paradigm to ensure constant and comparable mental conditions during cerebral glucose uptake. Individual brain anatomy was represented using Tl-weighted 3D flash magnetic resonance imaging (MRI), followed by manual regionalization into 108 regions of interest and PET/MRI overlay. After absolute quantification of rMRGlu and normalization to global metabolism, normalized rMRGlu under MDE was compared to placebo using the Mann-Whitney U-test. Acute psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) and rMRGlu was correlated to PANSS scores according to Spearman. MDE subjects showed significantly decreased rMRGlu in the bilateral frontal cortex: left frontal posterior (-7.1%, P < 0.05) and right prefrontal superior (-4.6%, P < 0.05). On the other hand, rMRGlu was significantly increased in the bilateral cerebellum (right: +10.1%, P < 0.05; left: +7.6%, P < 0.05) and in the right putamen (+6.2%, P < 0.05). There were positive correlations between rMRGlu in the middle right cingulate and grandiosity (r = 0.87, P < 0.05), both the right amygdala (r = 0.90, P < 0.01) and the left posterior cingulate (r = 0.90, P < 0.01) to difficulties in abstract thinking, and the right frontal inferior (r = 0.85, P < 0.05), right anterior cingulate (r = 0.93, P < 0.01), and left anterior cingulate (r = 0.85, P < 0.05) to attentional deficits. A negative correlation was found between the left frontal operculum (Broca's area) and attentional deficits (r = -0.85, P < 0.05). The present study revealed acute neurometabolic changes under the "Ecstasy" analogue MDE, indicating a frontostriatocerebellar imbalance paralleling other psychotropic substances or various psychiatric disorders.