We commend Kvam and colleagues for their article ‘MDMA-assisted therapy (MDMA-AT) as a treatment for major depressive disorder: proof of principle study’, which represents a timely and bold exploration into novel approaches for treating major depressive disorder (MDD). ^{Reference Kvam, Goksøyr, Rog, van de Vooren, Stewart and Autran1} Their findings provide early signals of feasibility and safety in a population that has long awaited more effective and durable interventions. However, as clinicians working closely with patients experiencing treatment-resistant depression, we would like to highlight three clinically relevant concerns that warrant further investigation before MDMA-AT can be meaningfully integrated into standard psychiatric practice.

First, although the study reports a high rate of clinical response (75% remitters), the generalisability of this outcome to broader clinical populations is uncertain due to the recruitment strategy. Eleven of 12 participants were self-referred and had extensive prior psychotherapy exposure, averaging over 200 sessions, far exceeding typical clinical experience. These individuals may represent a distinct subset – motivated, psychologically minded and unusually familiar with introspective work – which could amplify MDMA’s psychotherapeutic catalysis. In standard out-patient settings, patients with limited insight, personality pathology or low distress tolerance are often less able to meaningfully engage in inner-directed therapy, especially under the disinhibitory effects of MDMA. This raises concerns about the scalability of outcomes and whether the intervention’s apparent efficacy is contingent on an atypically primed subgroup. To understand MDMA-AT’s true scope, future trials should intentionally recruit through public psychiatric services, include individuals with limited prior therapy exposure and assess readiness for introspective work using structured psychological screening tools. This could help delineate which patient profiles are most likely to benefit and whether additional preparatory work is required for those with lower baseline insight or affect tolerance.

Second, while the study focuses on depressive symptom reduction and functional improvement at 8 weeks, it does not explore the temporal dynamics of response or risk of relapse beyond that window. In clinical settings, relapse is a critical outcome, particularly for therapies delivered episodically rather than continuously. MDMA-AT’s appeal lies partly in its departure from daily pharmacotherapy; however, without data on durability, it remains unclear whether symptom reductions are transient emotional breakthroughs or sustainable cognitive shifts. Notably, the high rate of early termination before dosing (3 of 15) contrasts with the full retention post-dosing, suggesting that for those who proceed, immediate engagement is high – but long-term trajectories remain unknown. In clinical implementation, a therapy that requires resource-intensive dosing and integration sessions must demonstrate durable benefit to justify its cost and complexity. We suggest that subsequent trials include long-term follow-up extending at least 6 to 12 months, with relapse rates, functional reintegration and quality of life as key outcomes. Additionally, structured booster integration sessions at predefined intervals could be studied as a strategy to maintain therapeutic gains without repeated MDMA administration. Such data would be invaluable in determining whether MDMA-AT should be conceptualised as a one-time intervention, a cyclical treatment or part of a stepped-care model.

Third, the protocol’s allowance for substantial psychotropic medication tapering raises concerns about withdrawal confounds. Sixty-seven percent of participants discontinued medications before dosing, including antidepressants, quetiapine and other ongoing psychotropic medications. While discontinuation reduces pharmacological confounds, it also introduces potential withdrawal effects that may affect symptom baselines and trajectories. In future trials, a stratified design comparing patients who continue versus taper antidepressants could clarify whether MDMA-AT exerts differential effects based on medication status. Moreover, gradual cross-tapering protocols with longer washout periods and systematic withdrawal symptom monitoring (e.g. using the DESS or FINISH checklist) would help isolate true treatment effects from discontinuation artefacts. ^{Reference Vollebregt, Goh, Chan, Dudding, Furlong and Hamdy2,Reference Kozyra, Lau, Fenn, Hategan and Bourgeois3} From a practical standpoint, clarifying whether MDMA-AT can safely and effectively augment ongoing pharmacotherapy would greatly expand its clinical applicability.

In summary, while this pioneering study offers a hopeful signal for MDMA-AT in MDD, future trials must address whether these results extend beyond highly selected, motivated participants; whether effects persist over time; and whether symptom improvements can be disentangled from medication withdrawal effects. Clarifying these issues will be crucial for determining whether MDMA-AT represents a scalable, durable and clinically meaningful advance in the treatment of depression.