MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial.

This multi-site, randomized, double-blind, confirmatory phase 3 study evaluated the efficacy and safety of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) versus placebo with identical therapy in participants with moderate to severe post-traumatic stress disorder (PTSD). Changes in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score (primary endpoint) and Sheehan Disability Scale (SDS) functional impairment score (key secondary endpoint) were assessed by blinded independent assessors. Participants were randomized to MDMA-AT (n = 53) or placebo with therapy (n = 51). Overall, 26.9% (28/104) of participants had moderate PTSD, and 73.1% (76/104) of participants had severe PTSD. Participants were ethnoracially diverse: 28 of 104 (26.9%) identified as Hispanic/Latino, and 35 of 104 (33.7%) identified as other than White. Least squares (LS) mean change in CAPS-5 score (95% confidence interval (CI)) was -23.7 (-26.94, -20.44) for MDMA-AT versus -14.8 (-18.28, -11.28) for placebo with therapy (P < 0.001, d = 0.7). LS mean change in SDS score (95% CI) was -3.3 (-4.03, -2.60) for MDMA-AT versus -2.1 (-2.89, -1.33) for placebo with therapy (P = 0.03, d = 0.4). Seven participants had a severe treatment emergent adverse event (TEAE) (MDMA-AT, n = 5 (9.4%); placebo with therapy, n = 2 (3.9%)). There were no deaths or serious TEAEs. These data suggest that MDMA-AT reduced PTSD symptoms and functional impairment in a diverse population with moderate to severe PTSD and was generally well tolerated. ClinicalTrials.gov identifier: NCT04077437 .

MDMA-Assisted Therapy for Severe PTSD: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study.

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was -24.4 (s.d. 11.6) in the MDMA group and -13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation. Appeared originally in Nat Med 2021; 27:1025-1033.

MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study.

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was -24.4 (s.d. 11.6) in the MDMA group and -13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.

The influence of veteran race and psychometric testing on veterans affairs posttraumatic stress disorder (PTSD) disability exam outcomes.

This study examined the influence of veterans' race and examiners' use of psychometric testing during a Department of Veterans Affairs posttraumatic stress disorder (PTSD) disability examination on diagnostic and service connection status outcomes. Participants were 764 veterans enrolled in a national longitudinal registry. Current and lifetime PTSD diagnostic status was determined with the Structured Clinical Interview for DSM-IV (SCID) and was compared with PTSD diagnosis conferred upon veterans by their compensation and pension (C&P) examiners as well as with ultimate Veterans Affairs (VA) PTSD service connected status. The concordance rate between independent SCID current PTSD diagnosis and PTSD disability examination diagnosis was 70.4%, and between SCID lifetime PTSD diagnosis and PTSD disability examination diagnosis was 77.7%. Among veterans with current SCID diagnosed PTSD, Black veterans were significantly less likely than White veterans to receive a PTSD diagnosis from their C&P examiner (odds ratio [OR] = .39, p = .003, confidence interval [CI] = .20-.73). Among veterans without current SCID diagnosed PTSD, White veterans were significantly more likely than Black veterans to receive a PTSD diagnosis from their C&P examiner (OR = 4.07, p = .005, CI = 1.51-10.92). Splitting the sample by use of psychometric testing revealed that examinations that did not include psychometric testing demonstrated the same relation between veteran race and diagnostic concordance. However, for examinations in which psychometric testing was used, the racial disparity between SCID PTSD status and disability exam PTSD status was no longer significant. Results suggest that psychometric testing may reduce disparities in VA PTSD disability exam outcomes. (PsycINFO Database Record

Fidelity to the Cognitive Processing Therapy Protocol: Evaluation of Critical Elements.

The contributions of individual therapy elements to the overall efficacy of evidence-based practices for the treatment of posttraumatic stress disorder (PTSD) are not well-understood. This study first examined the extent to which theoretically important treatment components of Cognitive Processing Therapy (CPT; i.e., skill in Socratic questioning; prioritizing assimilation; attention to practice assignments; emphasis on expression of natural affect) were successfully administered across the course of therapy for 68 PTSD-positive survivors of interpersonal trauma. Therapist fidelity in the administration of these four elements was evaluated in 533 taped CPT sessions of study participants included in one of two randomized controlled CPT treatment trials. Second, we examined therapist fidelity to these components as a predictor of session-to-session PTSD and depression symptom change. Third, follow-up analyses examined the influence of high therapist competence for these four components across an entire course of therapy on symptom change from pre- to posttreatment. Results showed consistently high adherence and more variable competence for these four treatment components. There were no significant effects of therapist fidelity on session-to-session symptom change. However, results showed that overall high therapist competence for "skill in Socratic questioning" and "prioritizing assimilation before overaccommodation" were related to greater client improvement in PTSD severity, but "attention to practice assignments" and "emphasis on expression of natural affect" were not. Overall competence ratings for the four components were not significantly associated with improvement in depressive symptoms. Findings contribute to increased understanding of the relationship between the key treatment components of CPT and symptom change.

Trauma Narratives: It's What You Say, Not How You Say It.

Structural and content- related features of trauma narratives of traumatic events may help explain the development of PTSD. In a sample of 35 female assault survivors, we examined the association between the structure and content of trauma narratives and PTSD and other trauma-related reactions (i.e., depression, anxiety, anger, dissociation, and guilt). When controlling for recounting style and recounting distress, narrative structure was not strongly associated with PTSD or other trauma-related reactions. In contrast, the content of the trauma narratives (more positive and negative emotion words, higher cognitive process, and less self-focus being) was associated with lower symptomatology. Taken together, trauma narrative content rather than grammatical structure of the narrative may be more reflective of underlying emotional processing of the traumatic memory or lack thereof.

The differential diagnostic accuracy of the PTSD Checklist among men versus women in a community sample.

We evaluated the specific version of the PTSD Checklist (PCL-S) as a screening tool for the recruitment of community-residing men and women with diverse trauma experiences. We administered the PCL-S via telephone in the context of participant recruitment, as well as in a laboratory setting preceding administration of the Clinician Administered PTSD Scale (CAPS), the gold standard PTSD assessment tool. In the laboratory, the PCL-S performed reasonably well for men and women, yielding overall diagnostic efficiency (ODE) values (representing percentage of cases accurately identified) of 0.78 and 0.73, respectively, for our recommended cut-points of 42 for men and 49 for women. In contrast, as a recruitment tool, the PCL-S yielded an acceptable ODE of 0.79 for men at the recommended cut-point of 47, but only an ODE of 0.56 (representing diagnostic efficiency no greater than chance) for women at the recommended cut-point of 50. A recruitment cut-point of 57 for women yields a similarly modest ODE of 0.61, but with substantial cost to sensitivity. These findings suggest that use of the PCL-S to screen for PTSD among potential study participants may lead to gender biased study results, even when separate diagnostic cut-points for men and women are used.