Post-Traumatic Stress Disorder (PTSD) is a severe psychiatric condition that develops after exposure to trauma such as combat, natural disasters, or assault. It is characterized by re-experiencing trauma, avoidance, hyperarousal, and negative alterations in cognition and mood. Since its formal inclusion in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-III in 1980, PTSD has been extensively researched. Current guideline-recommended treatments include trauma-focused psychotherapies and medications. However, a significant proportion of patients show limited response to these treatments. Psychedelic-assisted therapies, particularly 3,4-Methylenedioxymethamphetamine (MDMA)-assisted therapy, offer an innovative approach for treating PTSD. Over the past two decades, MDMA-assisted therapy has emerged as one of the most promising psychedelic treatments, especially for patients resistant to conventional therapies. MDMA can enhance the processing of traumatic memories during psychotherapy and holds potential for other psychiatric disorders. Recent clinical trials highlight the effectiveness of MDMA-assisted therapy, demonstrating substantial and sustained reductions in PTSD symptoms. The FDA has designated MDMA-assisted therapy as a "breakthrough therapy" for PTSD in 2017. However, due to methodological concerns such as unblinding and potential expectancy effects, the FDA decided in 2024 not to approve MDMA- assisted therapy for clinical use, requiring additional research to address these issues. This chapter explores the clinical research on psychedelic-assisted therapies for PTSD, with a particular focus on MDMA-assisted therapy. It will examine the potential psychological and neurobiological mechanisms of action, as well as the methodological challenges and future directions in the field. The growing body of evidence supporting MDMA-assisted therapy for PTSD is promising, especially for individuals who have not responded to traditional treatments.
