Neurovascular Uncoupling: Multimodal Imaging Delineates the Acute Effects of MDMA

Psychedelic compounds have attracted increasing interest in recent years due to their therapeutic potential for psychiatric disorders. Methylenedioxymethamphetamine (MDMA) is currently being investigated in clinical trials to treat post-traumatic stress disorder. To understand the acute effects of psychedelic drugs in vivo, functional MR imaging (fMRI) has been widely used in recent years. Notably, fMRI studies have shown that MDMA leads to inhibition of brain activity, challenging earlier hypotheses indicating mainly excitatory effects. However, interpretation of hemodynamic changes induced by psychedelics is challenging because of the potent vascular effects associated with this class of substances. Therefore, this study aimed to investigate the acute effects of MDMA using simultaneous positron emission tomography (PET)/fMRI in rats. For this purpose, hemodynamic changes measured by BOLD-fMRI were related to alterations in glucose utilization and serotonin transporter (SERT) occupancy, investigated using [18F]FDG functional PET (fPET) and [11C]DASB PET. We demonstrate that MDMA induces global hemodynamic decreases accompanied by localized metabolic increases. Elevated metabolism was found primarily in limbic projection areas involved in emotion processing. Concurrent BOLD-fMRI decreases, also found in extracerebral areas, indicate that the BOLD-fMRI reductions observed in the brain are of vascular, non-neuronal origin. We further show that higher SERT occupancy strongly correlates with regional BOLD-fMRI reductions. Therefore, increased serotonin levels induced by SERT blockage may cause a neurovascular uncoupling. Correct understanding of the in vivo mechanism of MDMA not only supports ongoing research but also warrants a reassessment of previous studies on neuronal effects of psychedelics relying on neurovascular coupling.