MDMA-assisted psychotherapy for treatment of anxiety and other psychological distress related to life-threatening illnesses: a randomized pilot study

A significant population faces anxiety, depression, and existential distress due to life-threatening illnesses (LTIs), even after remission or cure. These psychological burdens are substantial, impacting not only the individual but also their families and caregivers. Existing treatment options often fall short in addressing the unique challenges of LTI-related distress. Early research with psychedelics like LSD showed promise in alleviating anxiety and pain in LTI patients. More recent studies with psilocybin and LSD have demonstrated efficacy in reducing anxiety and depression in this population. MDMA, another psychedelic compound, is being explored as an adjunct to psychotherapy for various anxiety disorders. Promising results from Phase 2 trials for posttraumatic stress disorder (PTSD) led to a Breakthrough Therapy designation by the FDA. MDMA's mechanism of action, including the release of monoamines and oxytocin, reduction in amygdala activity, and increased frontal cortex activity, suggests potential benefits in reducing anxiety and improving emotional processing. Given the parallels between LTI-related anxiety and PTSD symptoms, and the success of MDMA in treating PTSD and social anxiety, this study aimed to assess the safety and efficacy of MDMA-assisted psychotherapy for individuals with LTI-related anxiety.

The literature review highlights the significant unmet need for effective treatments addressing the psychological distress experienced by individuals with life-threatening illnesses (LTIs). Early research on psychedelics, particularly LSD, indicated potential benefits in managing pain and anxiety in this context. More recent, rigorous studies have focused on psilocybin and LSD, reporting significant reductions in anxiety and depression symptoms among LTI patients compared to control groups. These studies provide evidence supporting the efficacy of psychedelic-assisted psychotherapy for this population. The review then transitions to discussing the current research and promising results using MDMA assisted psychotherapy for PTSD, highlighting its potential mechanisms of action. The literature review ultimately positions MDMA-assisted psychotherapy as a potentially promising approach for LTI-related anxiety, given its effectiveness for similar conditions and its neurobiological effects.

This Phase 2 clinical trial employed a double-blind, randomized, placebo-controlled design with an open-label crossover. Eighteen participants (18 years or older) diagnosed with life-threatening cancer or non-dementing neurological illness (with at least a nine-month life expectancy) and moderate-to-severe anxiety (STAI-Trait score ≥ 45) were enrolled. Participants were randomized in a 1:3 ratio to receive either 125 mg MDMA or placebo (125 mg lactose) across two experimental sessions, two to four weeks apart. Each session included 8 hours of MDMA or placebo administration combined with psychotherapy, followed by overnight observation. Nine 60–90-minute non-drug psychotherapy sessions were also provided, three before the first experimental session and six post-sessions. The blinding was broken after the primary outcome assessment (one month post-second session). The MDMA group received an additional open-label MDMA session, while the placebo group crossed over to receive three open-label MDMA sessions. Assessments included the STAI-Trait (primary outcome), STAI-State, BDI-II, PSQI, PTGI, MADRS, GAF, FFMQ, DAP, SCS, and FACIT scales. Physiological data (blood pressure, heart rate, temperature) were also collected during sessions. Independent-samples t-tests were used for primary and secondary outcome comparisons between groups during the blinded phase. A repeated-measures ANOVA was conducted to analyze the combined data (MDMA and placebo/MDMA groups) from the open-label phase, assessing changes across baseline, treatment exit, 6-month, and 12-month follow-up.

Eighteen participants were enrolled, with 13 in the MDMA group and 5 in the placebo group. The primary outcome, change in STAI-Trait scores from baseline to one month after the second blinded session, showed a larger mean reduction in the MDMA group (-23.5) than in the placebo group (-8.8). However, this difference was not statistically significant (p = 0.056). Excluding a potential outlier in the placebo group yielded statistical significance (p = 0.0066). Secondary outcomes revealed significant improvements in the MDMA group compared to placebo for posttraumatic growth (PTGI) and mindfulness (FFMQ) (p = 0.04 for both). Other secondary outcomes, such as STAI-State, depression, sleep quality, and global functioning, showed trends towards improvement in the MDMA group, although statistical significance wasn’t reached. After the open-label crossover phase, all participants received three MDMA-assisted psychotherapy sessions. Analysis of the combined data showed statistically significant improvements from baseline to treatment exit and long-term follow-ups across multiple outcome measures, including anxiety (STAI-Trait, STAI-State), depression (BDI-II, MADRS), sleep quality (PSQI), global functioning (GAF), various FACIT subscales, self-compassion (SCS), mindfulness (FFMQ), and posttraumatic growth (PTGI). MDMA was well-tolerated. The most common adverse events were expected and transient.

The study's results provide preliminary evidence suggesting MDMA-assisted psychotherapy's potential as a safe and effective treatment for anxiety and other psychiatric symptoms associated with LTIs. The trend towards greater anxiety reduction in the MDMA group, although not statistically significant in the primary analysis due to a potential outlier, is encouraging. The significant improvements in posttraumatic growth and mindfulness in the MDMA group highlight the potential therapeutic benefits beyond simple anxiety reduction. The open-label crossover phase demonstrated significant improvements across various outcome measures, suggesting lasting benefits. The well-tolerated safety profile of MDMA further strengthens the case for further investigation. However, the study's small sample size and limitations of the open-label crossover analysis necessitate further research. Future larger, more diverse trials are necessary to confirm these findings and explore underlying mechanisms.

This pilot study provides preliminary evidence supporting the safety and feasibility of MDMA-assisted psychotherapy for reducing anxiety and alleviating other psychiatric symptoms associated with LTIs. The results, while not statistically significant in the primary analysis due to study limitations, demonstrate trends of substantial improvement and warrant further investigation in larger, more diverse clinical trials. Future research should focus on confirming these findings, examining the long-term effects, and exploring the underlying mechanisms of action.

The small sample size of this pilot study is a major limitation, impacting statistical power and the generalizability of findings. The presence of a potential outlier in the placebo group influenced the primary outcome analysis. The open-label crossover design limits the ability to draw strong conclusions about long-term effects, as it lacks a control group after the crossover. The predominantly female and White/Caucasian sample limits the generalizability to other populations. Future research should address these limitations by employing larger, more diverse samples and improved study designs.