MDMA's prosocial effects can be separated from its addictive properties by using fenfluramine, a selective serotonin-releasing compound. This finding reveals a conserved neuronal pathway that could be targeted to develop new therapeutics with limited abuse liability, offering a potential strategy for creating safer treatments that promote social connection without the risks of addiction.
MDMA releases both dopamine and serotonin in the brain's reward center, the nucleus accumbens, but its strong serotonin release limits dopamine release and abuse potential. Using conditional knockout mice and direct brain infusions, the authors show that MDMA's serotonin release, acting through the serotonin transporter and 5-HT2C receptors, reduces the drug's reinforcing effects and conditioned place preference, while its prosocial effects are mediated by separate mechanisms. This platform predicts that (R)-MDMA, a novel entactogen, will have prosocial effects and low abuse potential.