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Background: Posttraumatic stress disorder (PTSD) is a severe condition often complicated by co-occurring disorders, such as major depression, alcohol use disorder, and substance use disorders. A well-powered phase 3 randomized, placebo-controlled trial has shown that MDMA-assisted therapy (MDMA-AT) may be an effective treatment for severe PTSD. However, the psychological mechanisms driving the therapeutic effects of MDMA-AT remain unclear. One potential mechanism is self-compassion, which is commonly conceptualized as a balance between compassionate self-responding (CS) - encompassing self-kindness, common humanity, and mindfulness - and uncompassionate self-responding (UCS) - encompassing self-judgment, isolation, and over-identification.Objective: This secondary analysis aimed to explore whether MDMA-AT enhances aspects of self-compassion and if changes in self-compassion mediate the therapy's effectiveness in reducing PTSD severity, depressive, and alcohol and substance use symptoms.Method: Eighty-two adults diagnosed with severe PTSD participated in a double-blind trial comparing three sessions of either MDMA-AT or placebo combined with therapy. Measures of PTSD severity, depressive symptoms, alcohol and substance use, and self-compassion were collected at baseline and 18 weeks later.Results: MDMA-AT led to statistically significant improvements in both UCS and CS. Significant improvements were also observed across all six subscales of the Self-Compassion Scale, including self-kindness, self-judgment, common humanity, isolation, mindfulness, and over-identification, most with large effect sizes. Changes in UCS and CS significantly and fully mediated the effects of MDMA-AT compared to placebo plus therapy in reducing PTSD severity and depressive symptoms. Findings were not significant for alcohol and substance use outcomes.Conclusions: These findings suggest that self-compassion may play a critical role in the therapeutic effects of MDMA-AT. Further research is needed to investigate the role of self-compassion in MDMA-AT to refine and develop more targeted, effective interventions for individuals with PTSD and co-occurring depression. MDMA-assisted therapy significantly improves self-compassion in individuals with severe posttraumatic stress disorder, showing large effect sizes across various aspects, including self-kindness and mindfulness.Changes in self-compassion play a key role in reducing posttraumatic stress and depressive symptoms, mediating the therapeutic effects of MDMA-assisted therapy.These findings highlight self-compassion as a potential target for developing more effective treatments for individuals with posttraumatic stress disorder and co-occurring depression. Antecedentes: El trastorno de estr s postraum tico (TEPT) es una condici n grave que a menudo se complica por trastornos concurrentes, como la depresi n mayor, el trastorno por consumo de alcohol y los trastornos por consumo de sustancias. Un ensayo aleatorizado y controlado con placebo de fase 3 bien potenciado ha demostrado que la terapia asistida con MDMA (MDMA-AT) puede ser un tratamiento eficaz para el TEPT grave. Sin embargo, los mecanismos psicol gicos que impulsan los efectos terap uticos de la MDMA-AT siguen sin estar claros. Un mecanismo potencial es la autocompasi n, que se conceptualiza com nmente como un equilibrio entre la autorrespuesta compasiva (CS, por sus siglas en ingl s) que abarca la autocompasi n, la humanidad compartida y la atenci n plena y la autorrespuesta no compasiva (UCS, por sus siglas en ingl s) que abarca el auto-juicio, el aislamiento y la sobreidentificaci n-. Objetivo: Este an lisis secundario pretend a explorar si la MDMA-AT mejora aspectos de la autocompasi n y si los cambios en la autocompasi n median en la eficacia de la terapia para reducir la gravedad del TEPT, los s ntomas depresivos y de consumo de alcohol y sustancias. M todo: Ochenta y dos adultos diagnosticados con TEPT grave participaron en un ensayo doble ciego en el que se compararon tres sesiones de MDMA-AT o placebo combinadas con terapia. Se recogieron medidas de la gravedad del TEPT, s ntomas depresivos, consumo de alcohol y sustancias, y autocompasi n al inicio y 18 semanas despu s. Resultados: MDMA-AT condujo a mejoras estad sticamente significativas tanto en UCS como en CS. Tambi n se observaron mejoras significativas en las seis subescalas de la Escala de Autocompasi n, incluyendo la autocompasi n, el auto-juicio, la humanidad compartida, el aislamiento, la atenci n plena y la sobreidentificaci n, la mayor a con grandes tama os de efecto. Los cambios en UCS y CS mediaron de forma significativa y completa los efectos de MDMA-AT en comparaci n con placebo m s terapia en la reducci n de la gravedad del TEPT y los s ntomas depresivos. Los hallazgos no fueron significativos para los resultados de consumo de alcohol y sustancias. Conclusiones: Estos hallazgos sugieren que la autocompasi n puede desempe ar un papel cr tico en los efectos terap uticos de la MDMA-AT. Es necesario seguir investigando el papel de la autocompasi n en la MDMA-AT para perfeccionar y desarrollar intervenciones m s espec ficas y eficaces para las personas con TEPT y depresi n concurrente.