Reply

We thank Ai et al for their thoughtful commentary on our trial of MDMA-assisted therapy (MDMA-AT) for major depressive disorder (MDD). ^{Reference Ai, Xie and Hou1} They raise relevant questions regarding trial populations, long-term outcomes and the impact of tapering and preparatory psychotherapy.

We agree with Ai et al that future trials should aim to include more representative MDD populations, including individuals with less prior psychotherapeutic experience. It should be emphasised that this trial was conceived as a proof-of-principle study. In early-phase clinical research, restricting the sample to a more narrowly defined population is often warranted to reduce variability, safeguard participant safety and increase the likelihood of giving an initial impression of efficacy. ² Our trial was pre-registered with a protocol specifying eligibility criteria in advance. ^{Reference Kvam, Goksøyr, Stewart, Repantis, Røssberg and Andreassen3} To meet these requirements, recruitment was conducted through both self-referrals and referrals from general practitioners, psychiatrists and psychotherapists. ^{Reference Kvam, Goksoyr, Rog, van de Vooren, Stewart and Autran4} Nonetheless, the eligibility criteria limited recruitment from clinical units, resulting in a sample that represents a subgroup of the MDD population. Broader inclusion criteria would have improved the representativeness of the study sample. However, it is worth noting that MDMA-AT is unlikely to become a first-line treatment for MDD in the foreseeable future. In this context, prior psychotherapy may be advantageous, or even necessary for safety reasons, to help ensure that the introspective work catalysed by MDMA is not overwhelming. Establishing trust and a strong therapeutic alliance is essential for the safe delivery of psychedelic-assisted therapies, ^{Reference Johnson, Richards and Griffiths5} and limited prior psychotherapy may impede the development of such an alliance. Furthermore, although the extensive psychotherapeutic experience in the sample limits generalisability, it reflects a certain level of therapy resistance, thereby highlighting an unmet need in treatment-resistant depression. Future studies could benefit from stratifying participants by baseline characteristics such as psychotherapy history or treatment readiness, while incorporating additional preparatory work for those with less prior psychotherapeutic exposure. We also agree with Ai et al regarding the need for long-term follow-up data and the necessity of demonstrating sustained effects to justify potential integration into standard clinical practice. In line with the study protocol, we conducted a 7-month, post-baseline follow-up study (6 months after the final MDMA dosing session). ^{Reference Kvam, Goksøyr, Stewart, Repantis, Røssberg and Andreassen3} The report from this study is currently under review and will be published subsequently. As in our initial publication, ^{Reference Kvam, Goksoyr, Rog, van de Vooren, Stewart and Autran4} we assessed retention rates, suicidal ideation and behaviour and repeated post-treatment measures, including depression severity (Montgomery–Åsberg Depression Rating Scale) and functional impairment (Sheehan Disability Scale), as well as the exploratory outcome measures. In response to Ai et al’s suggestion, we have also collected data on relapse rates and quality of life, the latter to be reported separately. We concur on the potential value of booster integration sessions. In our study, three participants received additional visits to manage adverse events and we recommend a flexible protocol that allows for extra on-site or telephone visits when needed. As noted in our original article, future research should explore the optimal number of MDMA dosing sessions and the potential benefit of additional dosing sessions when indicated. ^{Reference Kvam, Goksoyr, Rog, van de Vooren, Stewart and Autran4} Such flexibility may also help address concerns regarding generalisability to broader MDD populations, by allowing supplementary psychotherapy or dosing sessions for participants without extensive prior therapy.

Finally, the authors discuss the potential for withdrawal confounds following the tapering of psychotropic medications. The mean Beck Depression Inventory scores declined from 37.3 (s.d. 9.5) at screening (prior to enrolment and tapering) to 33.5 (s.d. 9.6) at visit 4 (post-enrolment, after tapering and during the third preparatory psychotherapy session). This reduction was non-significant both in the overall sample (P = 0.089) and when analysed separately for participants who tapered (n = 8, P = 0.313) and those who did not (n = 4, P = 0.250). A transient symptom exacerbation related to tapering cannot be excluded, because tapering overlapped with preparatory sessions, which may have contributed to the non-significant symptom reduction.

Taken together, these comments underscore both the promise and challenges of developing MDMA-AT for MDD. Although the most important next step is to carry out a randomised clinical trial, future trials should consider broader inclusion criteria, more flexibility in dosing and psychotherapy and careful control of withdrawal-related confounds. Such measures will be critical to balancing safety, feasibility and generalisability, and to determining the potential role of MDMA-AT in the treatment of depression.