MDMA-Assisted Therapy for PTSD: A Phase 3 Trial

An inside look at how MDMA-assisted therapy offers hope for PTSD treatment with symptom improvement and improved safety.

Overview: Post-traumatic stress disorder (PTSD) poses significant challenges for conventional treatments. A phase 3 clinical trial explored MDMA-assisted therapy's potential in treating PTSD. Participants receiving MDMA showed a marked reduction in symptoms compared to those on placebo. This therapy also proved effective for comorbid conditions like depression. MDMA may work by extinguishing fear-related memories and enhancing brain plasticity. The therapy's safety profile appears favorable. This study indicates that MDMA-assisted therapy could revolutionize PTSD treatment.

Challenges of PTSD Treatment

Post-traumatic stress disorder (PTSD) stands out as a particularly challenging condition. Characterized by intrusive memories, hypervigilance, and emotional numbness, PTSD can significantly impair an individual's quality of life. Unfortunately, conventional treatments often fall short of providing relief for those affected.

Despite the availability of various therapies and medications, many individuals with PTSD continue to struggle with symptoms, leading to a pressing need for more effective interventions. Recognizing this urgency, researchers have turned their attention to MDMA-assisted therapy, a therapy modality that has shown promise in early trials where MDMA (3,4-methylenedioxy-methamphetamine), commonly known as ecstasy or Molly, is used in conjunction with talk therapy to treat mental health conditions

A breakthrough phase 3 clinical trial, titled “MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study,” conducted by Mitchell and colleagues in 2023, sheds further light on the potential of this treatment modality. This study represents a critical step forward in the quest to find more efficacious treatments for PTSD, offering hope to millions of people.

A Look Inside MDMA-Assisted Therapy for PTSD

In this study, 91 participants were confirmed, with 46 randomized to receive MDMA and 44 to receive placebo. Randomization means that participants were assigned to either the MDMA group or the placebo group by chance, similar to flipping a coin.

In the first session, participants were given an initial dose of 80 milligrams (mg) of MDMA followed by a supplemental half-dose of 40 mg, whereas in the second and third sessions, they received an initial dose of 120 mg followed by a supplemental half-dose of 60 mg.

Before participating, individuals had to meet specific criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5), which defines the symptoms and diagnostic criteria for mental health conditions. Specifically, participants needed to meet the criteria for current PTSD, with symptoms lasting at least six months, and have a CAPS-5 total severity score of 35 or more at baseline. “CAPS-5” refers to the Clinician-Administered PTSD Scale for DSM-5, a structured interview considered the gold standard for assessing PTSD symptoms and severity.

Exclusion criteria (specific characteristics or conditions that disqualify individuals from participating in a research study or clinical trial) included various psychiatric disorders, substance use disorders, medical conditions that could be exacerbated by MDMA, pregnancy or lactation, and certain lifestyle factors. Participants were also required to discontinue psychiatric medications under medical supervision before baseline assessments.

During the study, participants attended preparatory therapy sessions, experimental sessions (where they received either MDMA or placebo), and integration sessions over 18 weeks. The experimental sessions involved receiving three doses of MDMA or placebo under the supervision of a trained therapy team.

The therapy provided followed a manualized approach specifically designed for MDMA-assisted therapy, aiming to facilitate healing by supporting participants in confronting and processing challenging psychological experiences, such as trauma memories, in a supportive environment that encourages introspection and healing.

Hopeful Signs: Assessing the Benefits of MDMA-assisted Therapy

Results from the study indicated a significant reduction in PTSD symptoms among participants who received MDMA-assisted therapy compared to those who received placebo with therapy. The change in CAPS-5 total severity score from baseline to 18 weeks after baseline showed a marked improvement in the MDMA-assisted therapy group.

MDMA was also found to significantly reduce functional impairment over the same period. In other words, their ability to perform daily activities or tasks was significantly improved or restored as a result of MDMA treatment.

Moreover, MDMA was effective in participants with comorbidities often associated with treatment resistance, including the dissociative subtype of PTSD. Participants with the dissociative subtype of PTSD who received MDMA-assisted therapy experienced significant symptom reduction in PTSD symptoms, comparable to those with non-dissociative PTSD.

Tracking clinically significant improvement, loss of diagnosis, and remission revealed promising outcomes. At the primary study endpoint (18 weeks after baseline), a significant proportion of participants in the MDMA group (67%) no longer met the diagnostic criteria for PTSD compared to the placebo group.

Furthermore, a notable percentage of participants in the MDMA group achieved remission, indicating significant symptom improvement.

In addition to reducing PTSD symptoms, MDMA-assisted therapy was effective in reducing depression symptoms, further highlighting the therapeutic potential of MDMA in addressing comorbid mental health conditions.

Image symbolizing the therapeutic potential of MDMA in treating PTSD and fostering emotional healing.

How Does MDMA Work?

In this study, MDMA-assisted therapy demonstrated a rapid reduction in PTSD symptoms, even among individuals with severe PTSD and comorbidities such as dissociative PTSD, depression, and substance use disorders. This is significant, given that over 80% of individuals with PTSD have at least one comorbid disorder.

Notably, participants with the dissociative subtype of PTSD, typically difficult to treat, showed significant improvement in their symptoms similar to those with non-dissociative PTSD. The authors suggest that this new therapy could greatly improve PTSD treatment outcomes, especially for those with chronic PTSD and dual diagnoses.

The therapeutic effects of MDMA may involve regulating fear-based behaviors by increasing the expression of brain-derived neurotrophic factor (BDNF) in the amygdala. BDNF is a protein that plays a crucial role in the growth, maturation, and survival of neurons, and increased levels of BDNF have been associated with improved mood and cognitive function.

Additionally, recent animal studies suggest that MDMA, through its release of oxytocin, may reopen a critical learning period in the brain, facilitating the processing and release of fear-related memories. Oxytocin is a hormone and neurotransmitter often referred to as the “love hormone” or “bonding hormone” because of its role in social bonding and trust.

Combined with therapy, these effects of MDMA on the brain could create a “window of tolerance,” allowing participants to revisit and process trauma memories without becoming overwhelmed, and with greater self-compassion and reduced PTSD-related shame and anger.

Furthermore, the prosocial and empathy-boosting effects of MDMA are thought to enhance the therapeutic relationship between the therapist and the participant, contributing positively to the therapeutic process by fostering a stronger and more trusting relationship between the two.

Wrapping Up: A New Era in PTSD Care? 

MDMA-assisted therapy appears to offer improved safety profiles compared to current first-line PTSD treatments.

The study reported no major safety issues among those who received MDMA, and adverse events of special interest such as abuse potential, cardiovascular risk, and suicidality were not induced or worsened by MDMA.

Consequently, the authors of this study suggest that MDMA-assisted therapy has the potential to transform PTSD treatment compared to current first-line therapies.

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