BACKGROUND: 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) is currently being evaluated for treatment of patients with moderate or higher severity post-traumatic stress disorder (PTSD). OBJECTIVE: To provide a comprehensive summary of investigational MDMA-AT and current treatments for PTSD. METHODS: A search was conducted in PubMed and Embase (December 20, 2023). Populations included adults with chronic, treatment-resistant, moderate or higher severity PTSD. Interventions were MDMA-AT and comparators based on PTSD treatment guidelines. The primary outcome of interest was the Clinician-Administered PTSD Scale (CAPS) score. Other outcomes observed were Beck Depression Inventory (BDI), and loss of diagnosis (LOD). Studies observing chronic, moderate or higher severity treatment-resistant PTSD in adults were included. Only randomized controlled trials published in English were considered. The NICE quality appraisal checklist was used to assess risk of bias in included studies. We provided qualitative synthesis of evidence presented in extraction tables. RESULTS: Overall, 77 studies were included. Phase II/III trials consistently reported significantly greater CAPS improvement with MDMA-AT vs. placebo with therapy (PT) after two or three interventional sessions. Durability was observed in a long-term follow-up trial (mean duration, 45.4 months) with a 0.9-point CAPS decrease from post-treatment. FDA-approved and off-label medications used for PTSD treatment did not yield a consistently greater CAPS decrease vs. control arms across trials. Significant CAPS improvement was consistently observed in venlafaxine ER, olanzapine, propranolol (with traumatic memory reactivation), nefazodone, and nabilone placebo-controlled trials. Most psychotherapy trials lacked between-group statistical assessments. Significant CAPS decrease compared to the waitlist was reported for cognitive therapy (CT), cognitive behavioral therapy (CBT), cognitive processing therapy (CPT), prolonged exposure (PE), and group cognitive exposure therapy. CAPS improvement was persistent for CPT and PE in long-term follow up (mean duration 6.2 years). MDMA-AT demonstrated significant improvement in BDI-II score compared to PT (19.7-point vs. 10.8-point decrease, respectively; p = 0.003). The percentage of participants with LOD after two or three active-dose MDMA-AT sessions ranged from 41.7-83.3%. CONCLUSION: This systematic review suggests current treatments for PTSD are associated with heterogeneous evidence and the majority do not demonstrate sustained effects. Results from MDMA-AT showed consistent improvements in CAPS, BDI and LOD.