MDMA’s Path to Approval: Insights on PTSD Treatment

Overview: Recent phase 3 trials confirm the efficacy and safety of MDMA-assisted therapy (MDMA-AT) for PTSD treatment, offering hope for those resistant to traditional approaches. Participant screening ensured study integrity, with both groups showing similar baseline characteristics. The therapy protocol involved preparatory sessions followed by three MDMA-AT sessions spaced a month apart, resulting in significant reductions in PTSD symptoms and functional impairment. MDMA-AT may soon be available as a treatment option, pending FDA approval, following the recent acceptance of a New Drug Application

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MDMA-Assisted Therapy: A Beacon of Hope for PTSD Recovery

Post-traumatic stress disorder (PTSD) is a severe psychiatric condition that casts a shadow over the lives of millions worldwide. In the United States alone, approximately 15 million people grapple with its debilitating effects each year.

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For those diagnosed with the dissociative subtype of PTSD, along with individuals facing recurring exposure to trauma and battling comorbidities like depression and substance use disorders, the road to recovery is often fraught with challenges.

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Despite the availability of first-line treatments such as trauma-focused psychotherapies and selective serotonin reuptake inhibitors (SSRIs) like sertraline and paroxetine, up to half of patients find little solace in these options, highlighting the urgent need for more effective interventions.

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Mounting evidence suggests that MDMA-assisted therapy (MDMA-AT) holds promise as a potentially transformative treatment for PTSD. Research indicates that MDMA (also called “ecstasy” or “Molly”) promotes empathy, openness, and prosocial behavior, while also facilitating the reconsolidation of traumatic memories, offering a ray of hope for those ensnared in the grip of PTSD.

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Following several successful phase 2 trials demonstrating the safety and efficacy of MDMA-AT in individuals with PTSD, the results of the first phase 3 study provided further validation. This study revealed that MDMA-AT was not only well-tolerated but also instrumental in reducing the severity of PTSD symptoms and alleviating functional impairment.

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Now, with the publication of a second, confirmatory phase 3 study, the journey towards effective PTSD treatment takes another significant stride forward. This latest study extends the findings of its predecessor, offering renewed hope to individuals grappling with moderate to severe PTSD.

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Understanding MDMA-Assisted Therapy Trials

Clinical trials document participant characteristics and establish inclusion and exclusion criteria to ensure the study’s integrity and safety. These criteria often encompass various factors such as medical history, psychiatric conditions, and substance use patterns.

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Participant Selection and Criteria

In the study, 104 participants were randomly assigned to receive either MDMA-assisted therapy or placebo with therapy, with 53 participants allocated to the MDMA-AT group and 51 to the placebo group. Of these, 94 participants completed the study, while nine discontinued, including one from the MDMA-AT group and eight from the placebo group.

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Baseline characteristics such as gender, age, and ethnicity were generally similar between the two groups. On average, participants had been living with PTSD for approximately 16.2 years. Among the participants, 28 had moderate PTSD, and 76 had severe PTSD, with 24 of them presenting with the dissociative subtype of PTSD. 

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To ensure eligibility, participants underwent a thorough screening process after providing written informed consent. They were required to be adults aged 18 years or older and meet the full criteria for current PTSD according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), as assessed by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). Specifically, participants must have had a CAPS-5 total severity score of 28 or higher, indicating moderate or higher severity, with a symptom duration of at least 6 months.

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Exclusion criteria were carefully established to ensure the safety and integrity of the study. These included:

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• History of or current primary psychotic disorder
• Bipolar I disorder
• Dissociative identity disorder
• Eating disorder with active purging
• Major depressive disorder with psychotic features
• Personality disorders
• Any substance use disorder within 12 months prior to enrollment
• Use of ecstasy (material represented as containing MDMA) more than 10 times within the last 10 years or at least once within 6 months of the first experimental session
• Serious imminent suicide risk
• Any medical condition that could make receiving MDMA harmful due to increased blood pressure and heart rate, including uncontrolled hypertension, history of arrhythmia, or marked baseline prolongation of QT and/or QTc interval
• Weighing 48 kg or less
• Pregnant or nursing
• Engaged in electroconvulsive therapy or ketamine-assisted therapy, or had used ketamine within 12 weeks of enrollment.

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Additionally, as part of the screening process, participants were tapered off all psychiatric medications before the MDMA or placebo treatment sessions. This precaution was taken to avoid potentially dangerous drug interactions and ensure the safety of participants during the study.

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A Closer Look at the Therapeutic Protocol

The methods section of a study provides a detailed account of the procedures followed throughout the trial, outlining the specific actions undertaken by both researchers and participants. This section elucidates the study design, intervention protocols, outcome measures, and other details essential for understanding how the study was conducted.

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In this study, participants underwent a comprehensive therapeutic protocol consisting of preparatory sessions and MDMA-AT sessions. The preparation phase involved three 90-minute sessions with a two-person therapy team, which included at least one licensed therapist. These sessions were crucial for establishing rapport, setting intentions, and preparing participants for the therapeutic process.

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Participants randomized to the MDMA-AT group underwent three 8-hour MDMA-AT sessions spaced approximately one month apart. Therapy during these sessions was conducted by trained personnel following the guidelines outlined in the Multidisciplinary Association for Psychedelic Studies' (MAPS) MDMA-AT treatment manual and trial protocol. 

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During MDMA sessions, participants received a split dose of MDMA ranging from 120-180 milligrams (mg). This dosage protocol included an initial dose of 80 mg, followed by a supplemental half-dose of 40 mg administered 1.5-2 hours after the initial dose. In subsequent sessions, the initial dose was increased to 120 mg, followed by a supplemental half-dose of 60 mg. This dosage protocol was determined to be the most effective based on previous research findings.

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Following each MDMA session, participants engaged in three 90-minute integration sessions aimed at supporting them in processing and understanding their MDMA experiences. The first integration session took place the morning immediately after the MDMA session, with the remaining sessions occurring over the following 3-4 weeks.

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These integration sessions are thought to be crucial for integrating insights gained during the MDMA experience into daily life and promoting long-term therapeutic benefits.

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MDMA Therapy Success: Positive Findings in PTSD Treatment

In the study, MDMA-AT demonstrated significant reductions in PTSD symptoms compared to placebo with therapy. This improvement was measured by a reduction in the CAPS-5 total severity score from baseline to 18 weeks. The analysis revealed a change of -23.7 for the MDMA-AT group compared to -14.8 for the placebo with the therapy group.

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Moreover, MDMA-AT significantly alleviated clinician-rated functional impairment, as assessed by the Sheehan Disability Scale (SDS) from baseline. Notably, improvements were observed across all domains, including family life, social life, and work life.

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Of the participants in the MDMA-AT group, 86.5% were considered responders with a clinically meaningful improvement at 18 weeks after baseline, defined as a reduction of at least 10 points in the CAPS-5 total severity score, compared to 69.0% in the placebo with therapy group.

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By the end of the study, 71.2% of participants in the MDMA-AT group no longer met the DSM-5 criteria for PTSD, whereas 47.6% of participants in the placebo with therapy group achieved this outcome. Furthermore, 46.2% of participants in the MDMA-AT group and 21.4% in the placebo with therapy group met the criteria for remission (where the symptoms have significantly reduced). 

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It's worth noting that similar responses to treatment were observed regardless of the severity of PTSD, substance use disorder, severe adverse childhood experiences, or dissociative subtype PTSD. 

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“I’m happy again for the first time in years, and I have no doubt that it saved my life.” - Ed Thompson, former firefighter after MDMA-assisted therapy for PTSD. 

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Recapping MDMA’s Potential in PTSD Care

In conclusion, MDMA-AT demonstrated significant improvements in PTSD symptoms and functional impairment compared to placebo with therapy over 18 weeks.

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The high proportion of participants achieving clinically meaningful benefits and no longer meeting PTSD criteria by the end of the study underscores the potential of MDMA-AT as a treatment option. Importantly, these findings align with and build upon those observed in previous studies.

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Safety remains a paramount concern, and fortunately, no major safety issues were reported in this study. Common adverse events were consistent with previous research and manageable, and the low rates of cardiac adverse events and transient cardiovascular effects further support the safety profile of MDMA-AT.

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The sustained improvement in PTSD symptoms observed in previous phase 2 trials suggests the potential for long-term benefits with MDMA-AT. However, while MDMA-AT appears promising compared to SSRIs for PTSD treatment, direct comparisons are needed to establish whether or not it may be superior. The authors of this study argue that future research should explore this.

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Following the successful completion of the confirmatory phase 3 trial discussed here, Lykos Therapeutics (formerly MAPS Public Benefit Corporation) has taken a decisive step by applying for a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for MDMA-assisted therapy. This application, recently accepted by the FDA, signals progress toward making MDMA-assisted therapy a viable treatment option for individuals grappling with PTSD.

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With this development, MDMA-assisted therapy could potentially become available as early as 2024, offering hope for improved outcomes and quality of life for those affected by this debilitating condition. This follows the recent approval of MDMA for PTSD treatment in Australia, marking a significant milestone in the recognition of its therapeutic potential.