MDMA-Assisted Therapy for Complex-Post-Traumatic Stress Disorder: Toward a neurocognitive account

Complex post-traumatic stress disorder (C-PTSD) is a newly recognized diagnosis that is distinguished from post-traumatic stress disorder (PTSD) through additional symptom clusters beyond re-experiencing, avoidance, and a persistent sense of threat. In addition to these core PTSD symptoms, C-PTSD is characterized by disturbances in self-organization, including affective dysregulation, negative self-concept, and interpersonal difficulties. These disruptions often result in persistent emotional instability, deep-seated feelings of worthlessness or guilt, and challenges in forming and maintaining relationships. While PTSD often arises from discrete traumatic events, C-PTSD is more commonly associated with prolonged or repeated interpersonal trauma, such as childhood maltreatment, domestic violence, or prolonged captivity. Here, we propose a novel model that explains these differences, identifies their neural substrates, and outlines the potential role of 3,4-methylenedioxymethamphetamine (MDMA) in C-PTSD treatment. Drawing on active inference theories of cognition, we apply the concept of self-modelling to elucidate the insula’s role in affective regulation and adaptation to adversity. This framework clarifies the insula’s involvement not only in C-PTSD but also in other conditions affecting self-awareness and emotional processing. By integrating insights from neuroscience and psychopharmacology, we discuss how MDMA-assisted therapy may recalibrate affective regulation and reinforce a more stable self-model, offering a promising avenue for treatment. Theoretical and clinical implications are explored, emphasizing the need for further empirical research into MDMA’s therapeutic potential for C-PTSD.