MDMA-assisted therapy for posttraumatic stress disorder: A pooled analysis of ethnoracial differences in efficacy and safety from two Phase 2 open-label lead-in trials and a Phase 3 randomized, blinded placebo-controlled trial

This study (2022) analysed data from two Phase II and one Phase III trials from MAPS where MDMA-assisted therapy (MDMA-AT) was used to treat PTSD in order to compare the efficacy and safety of MDMA-AT between Black, Indigenous, and People of Color (BIPOC) and non-Hispanic White participants. No significant ethnoracial difference in CAPS-5 scores was observed while BIPOC participants trended toward greater reductions following MDMA-AT.

Abstract

“Background: Limited ethnoracial diversity in previous ±3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) trials for posttraumatic stress disorder (PTSD) has prompted questions concerning whether Black, Indigenous, and People of Color (BIPOC) also benefit from this treatment.

Methods: Secondary analysis was conducted using a modified intent-to-treat sample pooled from two Phase 2 open-label trials and a Phase 3 randomized, blinded placebo-controlled trial to compare the efficacy and safety of MDMA-AT for PTSD between BIPOC and non-Hispanic White participants. Four subgroups were of interest: MDMA-AT, BIPOC (n = 20); MDMA-AT, non-Hispanic White (n = 63); Placebo-assisted therapy (Placebo-AT), BIPOC (n = 17); and Placebo-AT, non-Hispanic White (n = 27). Planned comparisons tested subgroup differences in changes in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) scores from baseline to primary endpoint, controlling for study type and baseline scores. Adverse events (AEs) on the day of (day 0) to 2 days post-dosing were reported for each subgroup.

Results: In the MDMA-AT group, no significant ethnoracial difference in CAPS-5 change scores was observed. In the Placebo-AT group, BIPOC participants trended toward greater reductions in CAPS-5 scores than non-Hispanic Whites. Among non-Hispanic Whites, MDMA-AT was accompanied by significantly greater reductions in CAPS-5 scores than Placebo-AT. No treatment difference emerged among BIPOC participants. AEs were mostly rated as mild or moderate across subgroups.

Conclusions: These findings provide preliminary support for the efficacy and safety of MDMA-AT for treating PTSD across ethnoracial groups. There was also a trend toward greater efficacy with Placebo-AT among BIPOC participants. There was an imbalance in subgroups, highlighting the need for culturally responsive recruitment strategies to diversify future studies.

Authors: Terrence H. Ching, Monnica T. Williams, Julie B. Wang, Lisa Jerome, Berra Yazar-Klosinski, Amy Emerson & Rick Doblin

Summary

BIPOC populations have lower rates of recovery from PTSD than non-Hispanic White populations, and drop out from psychotherapy trials for PTSD at higher rates than non-Hispanic White populations. However, there is research to suggest that BIPOC participants benefit to a similar extent as non-Hispanic White participants.

A secondary analysis was conducted using data from two Phase 2 open-label trials and one Phase 3 RCT to compare efficacy and safety of MDMA-AT between BIPOC and non-Hispanic White participants. In this study, participants in the MDMA-AT group reported significantly greater reductions in PTSD symptoms than participants in the Placebo-AT group, after controlling for baseline PTSD symptoms and study type. Additionally, reliable change categories were calculated for each ethnoracial PTSD treatment subgroup.

Design and procedure

The Phase 2 open-label trials and Phase 3 RCT included participants with PTSD symptoms. They received three dosing sessions of MDMA-AT or Placebo-AT, and the CAPS-5 was administered at baseline and after each of the three dosing sessions.

Safety outcomes were assessed based on participants’ self-reported AEs and documented observations by study clinicians throughout the entire duration of the respective trials. AEs were coded based on an established taxonomy.

Data analytical plan

Five BIPOC participants and four non-Hispanic White participants terminated prematurely from the MDMA-AT trial. The last observation carried forward (LOCF) method was used to impute minimal missing data on the CAPS-5.

Four subgroups were examined for change in CAPS-5 scores: MDMA-AT, BIPOC; MDMA-AT, non-Hispanic White; Placebo-AT, BIPOC; and Placebo-AT, non-Hispanic White. Effect sizes were calculated for these changes and RCI categories were used to describe percentages of participants in each subgroup that experienced reliable change in PTSD symptoms.

Figure 2 displays outcomes of planned subgroup comparisons on CAPS-5 change scores, controlling for study type and baseline PTSD symptom severity. Non-Hispanic White participants in the MDMA-AT group reported significantly greater mean improvement in PTSD symptoms than non-Hispanic White participants in the Placebo-AT group.

The RCI for pre-post CAPS-5 difference scores for the pooled sample was 10.77, and 65% of BIPOC participants and 71% of non-Hispanic White participants recovered from PTSD with MDMA-AT, compared to 29% and 26% in the Placebo-AT groups, respectively.

Safety outcomes

Participants’ medical histories are shown in Supplemental Material 1. Of note, 80% of BIPOC-MDMA-AT participants reported lifetime suicidal ideation, 100% of non-Hispanic White-MDMA-AT participants reported lifetime suicide attempt, and 27% of non-Hispanic White-Placebo-AT participants reported lifetime intentional self-injury.

Tables 4(a) and 4(b) display AEs throughout study participation and on the day of dosing sessions in the MDMA-AT group. BIPOC participants had a lower prevalence of AEs than non-Hispanic White participants, except for anxiety, which was more prevalent among BIPOC participants.

One BIPOC participant in the MDMA-AT group and one non-Hispanic White participant in the Placebo-AT group reported suicide attempts, and three participants in the MDMA-AT group reported suicidal ideation, suicidal behavior, or intentional self-injury.

The present study suggests that MDMA-AT is equally effective for treating PTSD symptoms among a larger, more diverse sample than in previous Phase 2 studies, and that benefits specific to BIPOC participants may also exist. The highly supportive therapeutic approach with two co-therapists and the intentional emphasis on assessing for racial trauma may have contributed to the positive experiences of BIPOC participants in the study.

Despite disproportionate dropout rates between BIPOC and non-Hispanic White participants in this study, the retention rate was low overall, and one of the three BIPOC participants in the MDMA-AT group terminated prematurely because they reported “feeling cured” after one dosing session.

Future research should explore how participants’ different identities (e.g., race, ethnicity, gender, age, sexual orientation, etc.) interact to influence treatment response, and how well differences in participants’ and therapists’ identities are recognized and broached in an inclusive and culturally sensitive manner.

Conclusions

MDMA-AT treatment appeared to be equally efficacious among BIPOC and non-Hispanic White participants, and there was preliminary evidence of sizeable improvements in PTSD symptoms even among BIPOC participants in the Placebo-AT group.