In an open‑label proof‑of‑principle study of 12 participants with moderate–severe major depressive disorder, two MDMA‑assisted therapy sessions plus psychotherapy were feasible, well tolerated and produced large, statistically significant reductions in depressive symptoms (mean MADRS change −19.3) and functional impairment. No unexpected or serious adverse events occurred, and the authors conclude that randomised trials are needed to confirm efficacy.
Papers cited by this study that are also in Blossom
Background 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy (MDMA-AT) has shown promising safety and efficacy in phase 3 studies of post-traumatic stress disorder, but has not been investigated for a primary diagnosis of major depressive disorder (MDD).
Aim
We aimed to explore the proof of principle and safety as a first study with MDMA-AT for MDD, and to provide preliminary efficacy data.
Method
Twelve participants (7 women, 5 men) with moderate to severe MDD received MDMA in 2 open-label sessions 1 month apart, along with psychotherapy before, during and after the MDMA sessions, between January 2023 and May 2024. The primary outcome measure was mean change in Montgomery–Asberg Depression Rating Scale (MADRS), and the secondary outcome measure was mean change in functional impairment as measured with the Sheehan Disability Scale (SDS), both from baseline to 8 weeks following the second MDMA session. We used descriptive statistics and the two-tailed Wilcoxon signed-rank test to compare baseline and outcome scores. Repeated measures were analysed by a mixed-effects model.
Results
Baseline MADRS was 29.6 (s.d. 4.9). Feasibility was demonstrated with sufficient recruitment and retention. MADRS scores were significantly reduced post treatment compared with baseline (mean difference –19.3, s.e. 2.4, CI –14.8 to –23.8, P < 0.001). SDS scores significantly decreased from baseline (mean difference –11.7, s.e. 2.2, CI –7.5 to –15.9, P = 0.001). There were no adverse events of special interest, and no unexpected or serious adverse events.
Conclusion
The study met the primary objectives of safety and feasibility, and provided indications of efficacy for MDMA-AT for MDD. Further studies with a randomised design are required to confirm these findings. Trial registration EudraCT no. 2021-000805-26.
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.
Because this is the first study to investigate MDMA-AT for MDD, an open-label proof of concept approach is justified. See the study protocol article for details.
Measures of feasibility: we collected recruitment and retention rates as indicators of feasibility. See the study protocol article for details regarding screening failures, early terminations, drop-outs and lost to follow-up.Safety outcome measures: adverse events were recorded by the study therapists in close collaboration with the sub-investigator, a psychiatrist. We tracked the outcome of adverse events, any treatments provided and any hospitalisation or discontinuation of MDMA-AT due to adverse events. We also monitored the incidence of treatment-emergent adverse events (TEAEs) and the use of psychotropic concomitant medications during the MDMA dosing sessions, and for the following 2 days, as well as throughout the entire treatment period. Suicidal ideation, the intensity of suicidal ideation and suicidal behaviour were measured with the Columbia-Suicide Severity Rating Scale (C-SSRS). Any deterioration in C-SSRS score from baseline was reported as an adverse event. Adverse events of special interest (AESIs) were related to cardiac function, serious suicide ideation or suicidal behaviour and potential for abuse, as defined in the protocol;'see also the Supplementary material. Furthermore, we evaluated mean changes in blood pressure, heart rate and body temperature before both the initial and supplemental doses, as well at the end of each MDMA dosing session.The primary outcome measure was change in MDD symptom severity, as measured by mean change in MADRS scores from baseline to outcome visit ∼8 weeks after the second MDMA session (∼12 weeks post baseline). The secondary outcome measure was change in functional impairment, as measured by mean change in Sheehan Disability Scale (SDS) score, from baseline to outcome visit. Exploratory outcome measures included changes in depression (Beck's Depression Inventory II, BDI-II), insomnia (Bergen Insomnia Scale, BIS), post-traumatic stress symptoms (the PTSD Checklist for DSM-5, PCL-5), anxiety (Generalised Anxiety Disorder 7, GAD-7), the Alcohol Use Disorders Identification Test (AUDIT) and the Drug Use Disorder Identification Test (DUDIT). These exploratory outcome measures were collected at baseline visit (visit 4), except for AUDIT and DUDIT, which were collected during screening and the study termination visit (visit 14, ∼12 weeks post baseline). Responders were defined as those having a reduction of ≥50% in MADRS score, and remitters as those with a MADRS score ≤12 post treatment.
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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.
In this small, open-label, proof-of-concept trial, we explored MDMA-AT as a potential novel treatment for MDD. With careful screening, assessment and psychotherapy throughout the study, we demonstrated that MDMA-AT can be safely administered to participants with MDD. All adverse events were expected, most being mild and transient, and no serious adverse events or AESIs were reported. To manage adverse events, two participants were given benzodiazepines and zopiclone for anxiety and insomnia while three received extra psychotherapy sessions. The frequency, severity and duration of adverse events varied according to respondent status. Recruitment and retention rates were adequate. Thus, the study successfully met its primary objectives of feasibility and safety. Furthermore, we observed statistically significant improvements in both depression and functional impairment. Consistent with previous studies of MDMA-AT for PTSD (e.g. ref.), we demonstrated both statistically and clinically significant reductions in the primary and secondary outcome measures of depression and functional impairment. Similar to PTSD studies, we observed a high proportion of both responders and remitters. In the present study on MDD, 9 out of 12 participants were classified as both responders and remitters based on MADRS scores, comparable to the loss of PTSD diagnosis in 67 and 71% of participants in the MDMA groups of the two respective phase 3 studies.Unlike previous phase 2 and 3 studies that relied on the self-reported measure BDI-II, we utilised MADRS as a clinicianrated assessment of depression. Similarly to the PTSD studies, we also observed a statistically and clinically significant reduction in PTSD symptoms, exceeding a 10-point decrease on PCL-5.Although only three participants met the criteria for PTSD diagnosis at baseline, most addressed traumatic autobiographical material, attachment injuries and/or relational trauma, which appeared to contribute to the observed reduction in depressive symptoms. Although the study was not powered to support subgroup analyses, preliminary comparisons indicate that treatment responses and safety profiles were broadly comparable between participants with and without PTSD. The most common adverse events in this study differed from those in the PTSD phase 3 trials MAPP1 and MAPP2.Generally, fewer adverse events were observed here, with dry mouth frequency similar to that in MAPP2. However, decreased appetite (16.7 v. 52.2% in MAPP1) and anxiety (25.0 v. 32.6% in MAPP1) were less frequent. Headache (58.4 v. 71.7% in MAPP1) and suicidal ideation (33.3 v. 45.7% in MAPP1) were also reported less often. These differences may reflect actual variations or factors such as underreporting. As in PTSD studies,group level of suicidality in the present study never exceeded that of baseline, although there were variations at the individual level. Jaw muscle tightness was more common in this study than jaw pain in MAPP1, possibly due to adverse event labelling differences. The current sample was predominantly well educated, with a high level of functional impairment at baseline, and primarily consisted of individuals with moderate severity MDD. The sample population was predominantly of White ethnicity, so the findings may not be generalisable to Black and minority ethnic participants. While a standardised measure of treatment-resistant depression was not used for eligibility, the level of treatment resistance, particularly to psychotherapy, was considerable. While speculative, it is possible that this level of prior psychotherapeutic experience was beneficial during the MDMA-AT sessions, potentially contributing to the positive outcome. It is worth noting that, because nearly all participants were recruited through self-referral, similar to earlier reports,this may have resulted in a sample that is less representative of the general MDD population. Additionally, the self-referred group may have had elevated expectations regarding the effectiveness of MDMA-assisted therapy, potentially exaggerating the pre-post differences in outcome measures. We implemented a comprehensive psychotherapeutic regimen in delivering MDMA-AT for MDD. Prior training and experience from a similar MDMA-AT study was important, and team discussions to manage transference, countertransference and other challenges all proved valuable. The observations of the psychotherapy team suggest that the inner-directed psychotherapeutic approach supports the processing and analysis of spontaneously emerging psychotherapeutic material during MDMA sessions for MDD, as it does for PTSD. The phase 3 trials for PTSD indicated added benefit from a third session.Several participants in the present study spontaneously expressed the opinion that a third session would have been beneficial. Future research should explore the optimal number of sessions and consider a flexible dosing approach, allowing for additional sessions when indicated. We provided psychotherapy to manage psychological distress and related TEAEs (such as increased anxiety) in scheduled and extra visits on-site or by telephone. This suggests that integrative sessions, follow-up telephone calls and a flexible protocol allowing extra visits improve the benefits but also ensure safety, in line with previous findings.Given the absence of suicidal ideation at the end of dosing sessions, the current study suggests that an overnight hospital stay may be less critical in MDMA-AT for MDD, which is also supported by recent data.The current study has some limitations. The lack of a control group prevented us from determining whether the therapeutic response was attributable to the MDMA-AT provided, expectancy effects or natural fluctuations in depression severity over time. Although we used MADRS raters who were not part of the therapy team and were unaware of participants' depression history or present condition, they were neither completely independent nor blinded. As a result, a potential rater bias may have inflated prepost difference in MADRS scores. Future studies should include blinded and independent raters, e.g. as in refs.Because adverse events were reported to the therapy team, there is a possibility of underreporting due to participants' relationship to the therapists. It would have been preferable for adverse events to be assessed by an independent adverse event assessor. We did not assess adherence to the MDMA-AT therapy manual,which may have resulted in deviations from the manual and variations in the therapeutic support provided. However, the therapists had their adherence rated in a previous MDMA trial,with supervision from an experienced MDMA-AT supervisor. Finally, in the mixed-effects model, the time intervals between visits varied considerably between patients. Although this small, uncontrolled trial cannot draw conclusions about the efficacy of MDMA-AT for MDD, the findings suggest that MDMA-AT has potential as a treatment for MDD, and supports future randomised controlled trials (RCTs). If demonstrated to be effective and safe in RCTs, MDMA-AT could represent a significant advancement in the treatment of MDD, offering an integrated approach where the drug is used several times to catalyse psychotherapy rather than being administered daily as is the case with antidepressants. In conclusion, this is the first trial of MDMA-AT for a primary diagnosis of MDD, successfully meeting the primary objectives of safety and feasibility. The statistically and clinically significant reductions in depressive symptoms and functional impairment following treatment warrant further investigation in randomised trials. the research was conducted in the absence of any commercial or financial relationships with commercial interest that could be construed as a potential conflict of interest.