Introduction

Brazil suffers from increasing rates of violence and associated mental health problems. According to a survey of 3,744 individuals, more than 80% of the population in the metropolitan Rio de Janeiro and São Paulo have experienced traumatic events in their lifetime, with rape or sexual molestation ranging from 1.3 to 4.9%. Five percent of the general population met post-traumatic stress disorder (PTSD) diagnostic criteria in the previous year, and 10% have met PTSD diagnostic criteria in their lifetime.¹

Although various psychological and pharmacotherapeutic treatments exist for PTSD, including current first-line treatments involving combinations of pharmacology and psychotherapy,² treatment response is insufficient for a considerable proportion of patients.³ One promising alternative under development abroad is 3,4-methylenedioxymethamphetamine-assisted psychotherapy (MDMA-AP), which was granted a “breakthrough therapy” designation by the U.S. Food and Drug Administration after completing Phase 2 trials.⁴-⁶ MDMA-AP is currently under assessment in a multi-site Phase 3 trial,⁷,⁸ and thus is a strong candidate for approval as a treatment for PTSD.

Consequently, we were interested in determining whether the methods and premises of MDMA-AP would be efficacious in a Brazilian sample of PTSD patients. Given the high national prevalences of sexual abuse and molestation,¹ the high conditional risk of developing PTSD,⁹ and specific challenges in the treatment of this deleterious form of trauma,¹⁰ we conducted the first clinical trial of MDMA-AP in Brazil, following the same methodology developed abroad.¹¹

Methods

Results

Although 60 volunteers expressed interest in participation, only 24 underwent the screening process. The remaining volunteers were not screened due to distance to from the study site, scheduling conflicts, exclusionary medical histories, or non-responsiveness. Of the 24 volunteers who completed psychiatric screening, only nine met the criteria for PTSD diagnosis. Five had comorbidities or met other exclusion criteria. Four met all inclusion criteria, but one did not complete enrollment due to an untreated infection. Thus, three participants (one male and two female) were enrolled in the study. All three were victims of sexual abuse: one as an adult and two during childhood. One was Afro-Brazilian and two were Caucasian. They were 45, 35 and 41 years of age. One was married, one was divorced, and one was single.

Since all participants opted for supplemental doses in all MDMA-AP sessions, the total dosage reached 112.5 mg in the first and 187.5 mg in the second and third MDMA-AP sessions. There were clear changes in emotion, cognition, blood pressure, heart rate and temperature (Table S1, available as online-only supplementary material).

There were no serious adverse events, either related or unrelated to MDMA. In all, 54 adverse events occurred during the nine preparatory sessions, 20 during the nine total MDMA sessions, and 73 during the 27 total integrative sessions (Table 1). Somatic pain was the most frequently mentioned event during the preparatory and MDMA-AP sessions (seven and four occurrences, respectively), while anguish was the most frequently reported event during the integrative sessions (16 occurrences).

Considerable reductions in the primary outcome (CAPS-4 score) occurred for all patients. The baselines scores, 90, 78, and 72, dropped to 61, 27 and 8 at the primary endpoint, i.e. reductions of 29, 51 and 64 points, respectively (z = 1.604, r = 0.924 and p = 0.108). Secondary outcomes included improvement in PTSD symptoms according to PTSD Checklist – Civilian Version scores, post-traumatic growth according to Post-Traumatic Growth Inventory scores, reduced depressive symptoms according to Beck Depression Inventory-II scores, and improved general functioning according to Global Assessment of Functioning scores. Changes in sleep quality and dissociative symptoms were mild (Table 2).

Discussion

The three participants were all victims of sexual abuse, one of the most deleterious forms of trauma, which severely impacts mental health and psychopathology,¹⁰ and met the criteria for severe PTSD (according to baseline CAPS-4 scores). All three patients benefited from MDMA-AP treatment: one showed small but clinically significant improvement in the primary outcome (a 29-point [32%] reduction in CAPS-4 score), one showed moderate improvement (a 51-point [65%] reduction), and one showed strong improvement (a 64-point [89%] reduction). The effect size (r = 0.92) was large, but this must be interpreted with care due to small sample size. Nevertheless, two recent meta-analyses with larger samples confirmed that MDMA-AP for PTSD has large effect sizes.¹⁹,²⁰ The improved CAPS-4 scores observed in the present study were further supported by reduced PTSD symptoms according to the PTSD Checklist – Civilian Version: one patient’s scores dropped from the high severity to the little or no severity range, while the other patients’ scores dropped approximately 20 points, although they remained in the high severity range. Improvements were also seen in post-traumatic growth according to Post-Traumatic Growth Inventory scores: dramatic increases occurred in two cases (5-fold and 7-fold, for patients 1 and 3, respectively), while a considerable (2.5 fold) increase occurred in patient 2. Furthermore, considerable reductions occurred in depressive symptomatology according to Beck Depression Inventory-II scores: patient 1 dropped from severe to mild, and patients 2 and 3 dropped from severe to minimal, with final BDI scores of 10 and 2, respectively. Changes in dissociation symptoms and sleep quality were minimal according to the Dissociative Experience Scale-II and Pittsburgh Sleep Quality Index results, while Global Assessment of Functioning scores improved from serious to moderate in patient 1, from serious to mild in patient 2, and from serious to slight in patient 3 (Table 2).

Importantly, there were no serious adverse events, no cases of hyperthermia, and an acceptable level of adverse events (which were tolerable and short-lived). Nevertheless, it is important to consider this study’s limitations, including the small sample size and the open-label design, which could hinder conclusions about caregiver effect.

These results compare fairly with previous Phase 2 MDMA-AP studies, which have reported an overall success rate of about 60% in more than 100 severe PTSD cases.⁴-⁶,²¹ Although our sample size limits any definitive conclusions, it is enough to warrant further MDMA-AP studies in Brazil. These efforts are especially warranted here due to the epidemic levels of violence and high prevalence of PTSD,¹ a condition for which current treatments are ineffective for a considerable proportion of patients. Furthermore, additional studies are justified considering that a Phase 3 MDMA-AP for PTSD trial is now underway, with potential approval anticipated in a few years.⁷ To our knowledge, this is also the first scientific study in Brazil to administer a controlled psychedelic substance to a clinical population. Considering the recent surge of research on the therapeutic potential of psychedelics, especially when combined with psychotherapy,²² our results should encourage further Brazilian research about the therapeutic potential of this class of drugs.

Acknowledgements

The authors would like to acknowledge the entire MAPS staff, as well as the MAPS Public Benefit Corporation for its financial assistance and providing research-grade MDMA and training for AJ, BRC, DJ and EES. The authors would also like to thank the 407 donors from a crowdfunding campaign to support this study, as well as attorneys Emilio Nabas Figueiredo, Fernando Quintino, Lorena Otero, Roberto Jucá and Rodrigo Mesquita for services provided in the importation of MDMA for this study.