MDMA-assisted therapy as a treatment for major depressive disorder: proof of principle study

Major depressive disorder (MDD) is highly prevalent and a leading cause of disability, with many people deriving limited benefit from existing treatments and experiencing high relapse rates. 3,4-methylenedioxymethamphetamine (MDMA) has monoamine-releasing and reuptake inhibitor properties and may promote neuroplasticity; when combined with psychotherapy (MDMA-assisted therapy, MDMA-AT) it is hypothesised to facilitate therapeutic processes by reducing anxiety and enhancing trust, insight and emotion regulation. Clinical research to date has focused primarily on post-traumatic stress disorder (PTSD), where randomised phase 3 trials have shown safety and efficacy; MDMA-AT has not previously been studied for a primary diagnosis of MDD. This study aimed to provide a proof-of-principle assessment of MDMA-AT for people with moderate to severe MDD, focusing on feasibility and safety and providing preliminary efficacy data. Kvam and colleagues set out an open-label design to explore whether MDMA-AT can be safely delivered to this population and whether changes in depressive symptoms and functioning warrant further randomised controlled trials. The study therefore serves as an initial, exploratory investigation rather than a definitive test of efficacy.

An open-label proof-of-concept trial design was used as this was the first study of MDMA-AT for a primary diagnosis of MDD; the protocol is referenced for further procedural detail. Twelve participants were enrolled between January 2023 and May 2024; recruitment was by self-referral or referral from primary care or mental health professionals. Inclusion criteria required DSM-5 MDD (single or recurrent episode) of duration >12 weeks and <2 years, age ≥18 years, and at least moderate depression (Montgomery-Åsberg Depression Rating Scale, MADRS ≥20). Key exclusions included psychotic disorders, mania, certain personality and eating disorders, substance use disorder, serious suicide risk, pregnancy, recent ECT or ketamine, and medical conditions creating cardiovascular risk. Participants reported gender assigned at birth and gender identity separately. The intervention comprised preparatory psychotherapy (three 90-minute sessions and a baseline visit), two MDMA dosing sessions spaced approximately 4 weeks apart with integrative psychotherapy afterwards, and scheduled follow-up telephone calls. At the first dosing session the initial MDMA dose was 80 mg; at the second session participants were offered an increased initial dose of 120 mg. A supplemental half-dose was offered 90–120 minutes after the initial dose to prolong effects; all but one participant accepted the supplemental dose at both sessions. Sessions lasted about 8 hours and participants stayed overnight at the study site with optional night-time support. Psychotherapists were licensed clinicians (three psychologists and one psychiatrist), three of whom had prior training in MDMA-AT from a sponsored PTSD trial. Raters for the primary outcome were relatively independent from the therapy team but not fully blinded. Primary and secondary outcomes were pre-specified. The primary outcome was change in clinician-rated MADRS from baseline to the primary outcome visit approximately 8 weeks after the second MDMA session (about 12 weeks post baseline). The secondary outcome was change in functional impairment measured by the Sheehan Disability Scale (SDS) over the same interval. Exploratory measures included Beck Depression Inventory II (BDI-II), Bergen Insomnia Scale (BIS), PTSD Checklist for DSM-5 (PCL-5), Generalised Anxiety Disorder 7 (GAD-7), AUDIT and DUDIT. Safety monitoring included recording adverse events (AEs) and treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs) related to cardiac function, suicidality measured with the Columbia–Suicide Severity Rating Scale (C-SSRS), vitals during dosing, concomitant psychotropic use, and any hospitalisations or discontinuations. Psychotropic medications were tapered following enrollment according to protocol. Statistical analyses combined descriptive statistics with non-parametric testing: two-tailed Wilcoxon signed-rank tests compared baseline and outcome scores, and 4,000 bootstrap resamples of mean change were used to estimate 95% confidence intervals. Mixed-effects modelling was applied to repeated BDI-II measures. Ethical approvals were obtained from the Norwegian Medicines Agency and the regional ethics committee, and written informed consent was secured from all participants.

Feasibility and retention were good: recruitment ran from January 2023 to May 2024, 11 participants self-referred and one was therapist-referred, and no post-dosing early terminations, drop-outs or losses to follow-up occurred. Demographically, the sample comprised 12 participants (7 women), mean age 44.1 years (s.d. 9.2); nearly all were Caucasian. Most had recurrent MDD with a mean time since first episode of 16.1 years (s.d. 10.4). Baseline MADRS averaged 29.6 (s.d. 4.9), with 10 participants meeting the moderate range (MADRS 20–34) and 2 meeting severe range (MADRS ≥35). Prior psychotherapeutic experience was common and varied widely. Primary outcome: at the primary outcome visit (V13, about 8 weeks after the second MDMA session) mean MADRS was 9.7 (s.d. 10.0), representing a mean change of −19.3 (s.d. 8.3). Bootstrap 95% CI for the mean change was −14.9 to −23.7. The reduction in MADRS was statistically significant (Wilcoxon z = −3.1, P < 0.001). Among the nine participants without comorbid PTSD, mean MADRS change was −18.1 (s.d. 8.8), similar to the full sample. Secondary outcome: mean SDS total at outcome was 9.7 (s.d. 9.2), yielding a mean change of −11.7 (s.d. 7.6). Bootstrap 95% CI for SDS change was 7.6–15.8, and the reduction was statistically significant (z = −3.0, P = 0.001). Exploratory outcomes and responder status: 9 of 12 participants (75%) met the study's responder criterion (≥50% reduction in MADRS) and 9 of 12 (75%) met the remission criterion (MADRS ≤12). Significant improvements were reported on BDI-II, BIS, GAD-7 and PCL-5. A mixed-effects model on BDI-II estimated a slope of −0.19 points per day (95% CI −0.24 to −0.15, z = −8.32, P < 0.0001), indicating a linear decline across the trial period after accounting for variable visit timing; visual data suggested nonlinearity but the model found a linear trend. Safety: ten participants experienced at least one adverse event, with 46 AEs in total; 31 were mild and 15 moderate. One AE classified as suicidal ideation deterioration occurred prior to study drug administration; otherwise AEs were treatment-emergent. There were no serious or severe AEs, no AESIs, no hospitalisations and no discontinuations of MDMA-AT. The most common TEAEs were headache, increased suicidal ideation and jaw muscle tightness. TEAEs were typically transient: median duration 1 day, while mean duration was inflated by outliers (mean 7.3 days, s.d. 17.6). Non-responders experienced more and longer AEs than responders. Two participants received benzodiazepines and zopiclone within 2 days of dosing to manage anxiety and insomnia; additional psychotropic or symptomatic medications were used for several participants for clinical indications during the treatment period. Suicidality at the group level did not exceed baseline levels; no instances of serious suicidal ideation (C-SSRS score 4–5) or suicidal behaviour occurred during the study. Vital signs showed transient elevations in blood pressure, heart rate and body temperature during dosing sessions, but there were no cardiovascular AEs or arrhythmias. Measures of hazardous alcohol or substance use (AUDIT and DUDIT) did not change significantly.

Kvam and colleagues interpret these open-label findings as indicating that MDMA-AT can be delivered to people with MDD with acceptable feasibility and an encouraging safety profile when careful screening, monitoring and psychotherapeutic support are provided. The investigators observed statistically and clinically significant reductions in depressive symptoms and functional impairment at the primary outcome timepoint, and a high proportion of responders and remitters (75%). Improvements were also seen on secondary and exploratory measures including anxiety, insomnia and PTSD symptom scales. The authors situate the results alongside prior MDMA-AT research in PTSD, noting similar patterns of symptom reduction and comparable responder/remitter proportions to those observed in phase 3 PTSD trials. They highlight that many participants processed traumatic and relational material even where they did not meet formal PTSD criteria, which may have contributed to improvements. The psychotherapy team reported that an inner-directed therapeutic approach aided processing of spontaneously emerging material, and several participants suggested a potential benefit from a third MDMA session, consistent with findings from PTSD trials. Key limitations are acknowledged: the trial's open-label, uncontrolled design precludes attribution of observed changes specifically to MDMA-AT rather than expectancy effects or natural symptom fluctuation. Outcome raters were not fully blinded, introducing the potential for rater bias, and adverse events were reported to the therapy team which may have led to underreporting. The small, self-referred and predominantly White sample limits generalisability, and the study did not formally assess adherence to the therapy manual. Variable timing of visits complicated trajectory analyses. Given these limitations, the authors emphasise that efficacy cannot be concluded from this study alone. For future research the investigators recommend randomised controlled trials with blinded independent raters, exploration of optimal session number and flexible dosing, and further evaluation of safety and generalisability across more diverse populations. They also suggest that integrative sessions, follow-up contacts and flexibility to provide extra support may enhance both safety and therapeutic benefit. Overall, the findings are presented as preliminary evidence supporting further RCTs to establish whether MDMA-AT is an effective and safe treatment option for MDD.