Major depressive disorder (MDD) is a world-leading cause of disability, hence there is a large need for new treatment options. Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy (MAP) is a novel integrative approach for treatment of mental disorders. Studies show substantial and long lasting improvement in post-traumatic stress disorder (PTSD), paving the way for phase 3-trials. MAP have also shown promise for other indications, but has never been investigated for MDD. Here we present the rationale for conducting a trial of MDMA-assisted psychotherapy for MDD: Significant antidepressant effects of MAP have been demonstrated in two of the PTSD trials. A large proportion of depressed patients report traumatic experiences, suggesting that the effect seen in PTSD trials may also apply to depression trials. Qualitative studies indicate broad therapeutic effects in the PTSD-trials, far beyond reduction of PTSD-symptoms. In MAP studies, participants report improved mentalization skills, emotion regulation, and cognitive insights, all factors that are associated with improvement of MDD. The published data on emotion processing and MAP support the application in depression, as well as indications of effect on attachment insecurities, also seen in depression. MDMA affects neuroplasticity and increases oxytocin levels, leading to prosocial behavior and strengthening of the therapeutic alliance thus increasing effects of psychotherapy. Moreover, several uncontrolled reports from early clinical use suggests a therapeutic potential for MAP in the treatment of depression. There is an increasing amount of data justifying MAP for MDD, and clinical trials are warranted.