In a recent study published in the journal Nature Medicine, a group of researchers assessed the efficacy, safety, and tolerability of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) in comparison to placebo with therapy in treating participants with moderate to severe post-traumatic stress disorder (PTSD).
Study: MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Image Credit: eldar nurkovic / Shutterstock
Background
Approximately 5% of the United States (U.S.) population is affected by PTSD annually. The challenges in treating it arise from factors like the dissociative subtype and recurrent trauma. Traditional trauma-focused therapies, coupled with Food and Drug Administration (FDA)-approved serotonin reuptake inhibitors (SSRIs) such as sertraline and paroxetine, often have high dropout rates and limited efficacy. MDMA-AT, which influences fear memory and encourages prosocial behavior, recently emerged as a promising treatment option.
Given the widespread nature and intricacies of PTSD, along with existing treatment limitations, there is an urgent need for new therapeutic approaches. Although MDMA-AT offers potential, there is a need for further research to assess its effectiveness across diverse groups that have traditionally been underrepresented in clinical studies, ensuring its broad relevance.
About the study
Conducted across thirteen sites, eleven in the U.S. and two in Israel, the present study adhered to international ethical and clinical guidelines while an independent committee supervised to ensure participant safety and adequate sample size.
Adult participants aged 18 and above with a Clinician-Administered PTSD Scale (CAPS-5) severity score of 28 or higher, indicating a moderate or more severe PTSD condition, were required to cease all psychiatric medications before starting to avoid potential interactions. These individuals were then randomized equally, either receiving MDMA-AT or a placebo, with assignments kept secret. Independent assessors, blinded to the study's specifics, gaged PTSD severity using the CAPS-5 assessment. Each participant was assessed by a different assessor each time to avoid bias, and assessors underwent thorough training and oversight to ensure consistency.
The trial involved three preparation sessions, after which participants received either MDMA-AT or the placebo in conjunction with therapy over three months. During three 8-hour dosing sessions, spaced a month apart, participants were administered doses of MDMA or placebo, with the exact amount varying between sessions. After each session, participants engaged in three 90-minute integration sessions to help process their experiences.
Study results
From August 2020 to May 2022, 324 individuals were screened for the present study, leading to 121 being enrolled; however, only 104 participants proceeded to randomization after 17 did not progress past the initial stages. These participants were either assigned to a therapy involving the drug MDMA-AT or a placebo. Ultimately, 94 participants completed the study, representing a diverse mix of gender and ethnicity, with a notable 71.2% identified as female at birth. Furthermore, 33.7% identified as non-White, and 26.9% as Hispanic or Latino. On average, participants had been living with PTSD for 16.2 years.
After 18 weeks, results showed that MDMA-AT significantly reduced PTSD symptoms in participants. Secondary outcomes highlighted its positive effect on functional impairment, especially concerning family, social, and professional aspects. Further exploratory outcomes revealed that 86.5% of those in the MDMA-AT group displayed clinically significant improvement, showcasing optimistic results.
By the end of the study, 71.2% of participants in the MDMA-AT group no longer matched the criteria for PTSD, compared to 47.6% in the placebo group. Additionally, other factors such as alcohol or substance abuse risk, childhood trauma, and the subtype of PTSD did not significantly impact these results. However, a history of SSRI use did correlate with improved results from MDMA-AT treatment. Notably, female participants and those with a certain baseline depression score were more likely to see improved outcomes, regardless of the treatment type.
In the MDMA-AT group, most participants believed they had received the drug due to the positive emotional and physical effects they experienced, highlighting their perceptions. In contrast, the majority in the placebo group believed they had received the placebo due to a lack of noticeable effects.
Nearly all participants experienced at least one side effect during the study, with most being mild or moderate in nature; a few participants had cardiac-related side effects, likely stemming from MDMA's effects on heart rate and blood pressure. There were also psychiatric side effects, including suicidal thoughts, anxiety, and insomnia. However, the majority of these were also mild to moderate. A small percentage of participants from both groups reported severe suicidal ideation at some point, though this was not necessarily linked directly to the treatment.
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