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

Individuals diagnosed with, or recovering from, life-threatening illnesses (LTIs) frequently experience significant anxiety, depression, and existential distress that persist even after remission or cure. Survivors may fear relapse, recurrence, and death, and their families and caregivers also experience distress. Existing treatments are limited, creating a need for novel approaches. Early work with psychedelics (e.g., LSD, psilocybin) suggested reductions in distress and anxiety among LTI populations. MDMA-assisted psychotherapy, which shares features with psychedelic-assisted psychotherapy, has shown robust effects in anxiety-related conditions, notably PTSD and social anxiety in autistic adults, and may mechanistically reduce fear and facilitate emotional processing via effects on monoamines, oxytocin, and brain circuits (e.g., decreased amygdala and insular activity, increased frontal activity and amygdala-hippocampal connectivity). Given the overlap between LTI-related anxiety and PTSD-like symptoms, this pilot study tested whether MDMA-assisted psychotherapy could safely reduce anxiety and related symptoms in people with LTI.

Prior randomized, placebo-controlled trials from 2011–2016 with psilocybin and LSD in patients with LTIs demonstrated significant and sustained reductions in anxiety and depression, with some associations to subjective drug effects (e.g., mystical-type experiences). MDMA-assisted psychotherapy has obtained FDA Breakthrough Therapy designation for PTSD based on six Phase 2 trials showing significant symptom reductions with active-dose MDMA (75–125 mg) versus inactive or low-dose control, along with improvements in depression and sleep. In autistic adults with social anxiety, MDMA-assisted psychotherapy significantly improved LSAS scores relative to placebo. Neurobiological studies show MDMA increases monoamines and oxytocin, reduces amygdala and right insular responses to negative stimuli, increases superior frontal activity and amygdala–hippocampal connectivity, potentially enhancing fear extinction, self-compassion, and tolerance of emotionally challenging material. PTSD-like symptoms are common after cancer, myocardial infarction, and stroke, supporting exploration of MDMA-assisted psychotherapy for LTI-related anxiety.

Design: Phase 2, randomized, double-blind, placebo-controlled pilot trial with open-label crossover. Conducted April 2015–May 2018 at an outpatient psychiatric clinic (San Anselmo, CA). IRB-approved; conducted per the Declaration of Helsinki. Trial registration: NCT02427568. Participants: Adults ≥18 years with a diagnosis of life-threatening cancer or non-dementing neurological illness (ongoing or in remission with risk of recurrence), life expectancy ≥9 months, and moderate to severe anxiety (STAI-Trait ≥45). SCID-I/P used to confirm anxiety primarily related to LTI. Key exclusions: ongoing primary treatment for illness (e.g., initial chemotherapy), major contraindicating medical conditions (e.g., uncontrolled hypertension, significant cerebrovascular/cardiovascular disease, brain tumors, renal disease, dementing neurological disease, diabetes I/II), history of hyponatremia or hyperthermia, weight <48 kg, pregnancy/lactation, psychotic disorders, bipolar I, dissociative identity disorder, eating disorder with active purging, or inability to safely taper psychiatric medications (opiate medications allowed; SUDs allowed if in remission ≥60 days). Written informed consent required. Randomization and masking: Participants randomized ~1:3 to placebo (125 mg lactose) or MDMA (125 mg) via web-based system with unique container numbers; allocation concealed from participants, investigators, and independent rater. Capsules compounded to be visually identical. Blind broken after primary endpoint assessments (1 month post second blinded session). Intervention: Two day-long (8-h) blinded experimental sessions (MDMA 125 mg or placebo), 2–4 weeks apart, each with optional supplemental dose (62.5 mg) at 90–150 minutes. Nine 60–90 min non-drug psychotherapy sessions (3 preparatory; 1 integration the morning after each experimental session; 2 additional integration sessions after each experimental session). Non-directive, manualized therapy with a male–female co-therapy team; use of eyeshades and music encouraged; emphasis on inner-directed processing of LTI-related emotions/thoughts. Overnight stay with attendant. Vital signs (BP, HR, temperature) monitored every 30 min for 4 h, then hourly; more frequently if above cutoffs. Daily safety phone calls for 7 days post-session. Blinding assessment: participant and therapists guessed condition at session end with certainty ratings. Crossover: After primary endpoint and unblinding, MDMA group received one additional open-label MDMA session (125 mg with optional 62.5 mg). Placebo group crossed over to receive three open-label MDMA sessions (with associated integration sessions). All participants completed follow-ups at 6 and 12 months after their last experimental session. Outcomes: Primary—change in STAI-Trait (anxiety) from baseline to 1 month after second blinded session. Secondary—STAI-State; depression (MADRS via independent rater; BDI-II); sleep quality (PSQI); posttraumatic growth (PTGI, referenced to LTI); global functioning (GAF); quality of life (FACIT: physical, social/family, emotional, functional, additional concerns); mindfulness (FFMQ); self-compassion (SCS); death attitudes (DAP: fear of death, death avoidance, neutral acceptance, approach acceptance, escape acceptance). Safety—adverse events during sessions and 7 days post, vital signs, C-SSRS for suicidal ideation/behavior at each visit and select phone calls. Statistical analysis: Feasibility pilot not powered for significance. Intent-to-treat analyses with alpha=0.05 (two-tailed). Independent-samples t-tests on change scores (baseline to primary endpoint) for primary and secondary outcomes; Hedges’ g for between-group effect sizes. For open-label/crossover pooled analyses (all participants after receiving full-dose MDMA), one-way repeated-measures ANOVA across baseline, treatment exit (after three MDMA sessions), 6-month, and 12-month follow-ups; Tukey’s pairwise tests when main effects present. Peak vital signs across blinded sessions compared with t-tests. Analyses in SAS 9.4.

- Sample: 18 randomized (MDMA n=13; placebo n=5). Mean age 54.9 (SD 7.9); 77.8% female; 83.3% White/Caucasian. Most had prior diagnoses of anxiety (83.3%), major depression (77.8%), PTSD (72.2%), or insomnia (61.1). Baseline mean (SD): STAI-Trait 61.1 (7.0); STAI-State 57.4 (10.9). - Primary outcome (baseline to 1 month post 2nd blinded session): STAI-Trait change—MDMA: −23.5 (13.2); placebo: −8.8 (14.7); between-group p=0.0558; Hedges’ g=1.03 (95% CI: −5.25, 7.31). One placebo participant showed large improvement (change −35), a potential outlier; removing this outlier would yield p=0.0066 (exploratory). - Secondary outcomes (blinded segment): Significant between-group improvements favoring MDMA on PTGI (Δ=+12.9 vs −2.6; p=0.04; g=0.50) and FFMQ (Δ=+0.4 vs 0.0; p=0.04; g=0.67). Other measures (STAI-State, BDI-II, MADRS, PSQI, GAF, SCS, FACIT domains, DAP subscales) trended toward greater improvement in MDMA but were not statistically significant between groups at the primary endpoint. - Open-label/crossover and pooled within-subjects analyses (after three MDMA sessions): Significant improvements from baseline to treatment exit and sustained at 6- and 12-month follow-ups across multiple domains: • STAI-Trait: F(3,48)=51.39; p<0.0001 • STAI-State: F(3,48)=34.19; p<0.0001 • BDI-II: F(3,48)=18.74; p<0.0001 • MADRS: F(3,48)=47.30; p<0.0001 • PSQI: F(3,48)=12.29; p<0.0001 • GAF: F(3,48)=16.99; p<0.0001 • FACIT: Physical well-being F(3,45)=10.05; p<0.0001; Social/family F(3,45)=3.58; p=0.02; Emotional F(3,45)=22.71; p<0.0001; Functional F(3,45)=20.27; p<0.0001; Additional concerns F(3,45)=26.93; p<0.0001 • DAP: Fear of death F(3,48)=6.92; p=0.0006; Neutral acceptance F(3,48)=6.82; p=0.0006; Approach acceptance F(3,48)=4.03; p=0.0123; no significant changes in Death avoidance or Escape acceptance • SCS: F(3,45)=15.62; p<0.0001; FFMQ: F(3,48)=18.74; p<0.0001 - Safety/tolerability: MDMA was generally well-tolerated. Common acute reactions during MDMA sessions included thirst (84.6%), jaw clenching/tight jaw (84.6%), dry mouth (69.2%), perspiration (69.2%), headache (61.5%). In the 7 days post-session, common reactions included fatigue (92.3%), need for more sleep (92.3%), insomnia (69.2%), low mood (61.5%), jaw clenching (61.5%). Vital signs increased as expected; only peak body temperature was significantly higher with MDMA (mean 37.3°C vs 36.9°C; p<0.0001). No serious MDMA-related adverse events; no serious suicidal ideation or behavior (C-SSRS). One participant discontinued after primary endpoint due to cancer recurrence and died ~1 year later; SAEs in three participants were related to cancer progression and medical interventions, not MDMA. Blinding was often guessed correctly by investigators (88.9%) and participants (86.1%).

This pilot trial suggests MDMA-assisted psychotherapy may reduce anxiety associated with LTIs. Although the primary between-group comparison on STAI-Trait did not reach statistical significance (p=0.056), the effect favored MDMA, and an apparent outlier in the placebo group likely influenced the result in this small sample; removing the outlier yielded a significant difference (exploratory). MDMA also produced significant gains in posttraumatic growth and mindfulness at the primary endpoint. After all participants received three MDMA sessions, robust within-subject improvements were observed and sustained up to 12 months across anxiety, depression, sleep, functioning, quality of life, self-compassion, mindfulness, and attitudes about death, suggesting potential durability beyond acute drug effects. Mechanistically, MDMA’s prosocial and anxiolytic neurobiological profile (monoamine and oxytocin release; decreased amygdala and insular reactivity; increased frontal engagement and amygdala–hippocampal connectivity) may facilitate emotionally safe processing of illness-related fears and trauma-like experiences common in LTI populations, paralleling benefits seen in PTSD. The findings support further investigation in adequately powered, controlled trials to confirm efficacy, clarify moderators/mediators, and examine durability and mechanisms of change.

MDMA-assisted psychotherapy appears to be a safe and feasible intervention that may reduce anxiety and related psychiatric symptoms in people with life-threatening illnesses, with indications of sustained benefit up to one year post-treatment. These preliminary results warrant larger, adequately powered clinical trials in more diverse populations to confirm efficacy, further characterize safety, and optimize therapeutic protocols.

- Small sample size; feasibility pilot not powered for statistical significance. - Potential influence of a placebo-group outlier on primary outcome in the blinded segment. - Blinding integrity concerns: high rates of correct condition guesses; some placebo participants believed they received MDMA, potentially contributing to placebo effects. - Sample demographics skewed toward female and White/Caucasian, limiting generalizability. - Open-label crossover eliminated the control group for long-term follow-up, limiting causal inference on durability. - Single-site study; results may not generalize to other settings.