Summary: A randomized clinical trial led by researchers at McGill University demonstrates that ketamine treatment for severe, treatment‑resistant depression is substantially more effective when combined with structured psychotherapy and a supportive treatment environment. Participants receiving this integrated care reported about a 30% reduction in depressive symptoms, with notable decreases in anxiety and suicidal thoughts that lasted at least eight weeks after the intervention.
The trial found that participants who experienced intense emotional or mystical‑type states during ketamine sessions showed the largest clinical improvements, suggesting these experiential elements may play an important role in recovery. The study presents the Montreal Model, a patient‑centered approach that integrates psychiatric care with principles from psychedelic therapy in routine clinical settings.
Key facts:
- Extended benefit: Improvements from ketamine plus psychotherapy persisted for at least eight weeks, longer than the brief effects typically reported with standard ketamine treatments.
- Experiential correlation: Strong emotional or mystical experiences during sessions were associated with better antidepressant outcomes.
- Montreal Model: A structured therapeutic framework combining psychiatry and psychedelic‑informed practices appeared to amplify ketamine’s antidepressant effects within real‑world clinical settings.
Source: McGill University
Trial participants and clinical context
The study enrolled 32 adults with chronic, treatment‑resistant depression (TRD). Many participants had complex clinical histories, including comorbid mental health conditions and active suicidal thoughts. The intervention combined six subanesthetic ketamine infusions delivered across four weeks with psychological support and weekly psychotherapy sessions, implemented within a therapeutic setting designed to promote safety and emotional exploration.
Therapeutic outcomes and durability
Across the sample, clinician‑rated depression scores fell by roughly 30% on average. Self‑reported symptoms, anxiety measures, and suicidality also improved significantly by the end of the four‑week course. Unlike common reports that ketamine’s antidepressant effects dissipate within days, participants in this trial maintained their gains through an eight‑week follow‑up assessment.
Role of emotional and mystical experiences
Ketamine can produce altered perceptions, time distortions, out‑of‑body sensations and other profound subjective effects. In this study, participants who rated their ketamine sessions as particularly emotional or mystical experienced the greatest clinical benefit. While these phenomena are sometimes described merely as side effects, the investigators argue the experiences may be a central mechanism contributing to recovery.
Lead author Dr. Kyle Greenway, Assistant Professor in McGill’s Division of Social and Transcultural Psychiatry, noted that the trial is the first to strongly link specific aspects of ketamine‑induced experiences with antidepressant effects in severe TRD. Co‑lead Dr. Nicolas Garel emphasized the need for standardized clinical models as ketamine therapy becomes more widely available.
Trial design: music, mindfulness and setting
The randomized, single‑blind, two‑center trial compared ketamine‑psychotherapy sessions delivered with either carefully curated music or matched non‑music support (e.g., guided mindfulness) during infusions. All participants received the same dose schedule and weekly psychotherapy. The therapeutic rooms were intentionally designed with calming elements—soft lighting, plants and music or mindfulness—to create a safe space for psychological exploration.
Analyses found no significant differences in clinical outcomes between the music and non‑music groups. Both conditions produced large and clinically meaningful reductions in depression and anxiety, with effect sizes indicating robust improvement that was maintained at follow‑up.
The Montreal Model: integrating psychiatry and psychedelic principles
The Montreal Model was developed by Drs. Greenway and Garel during their psychiatry training at McGill, with supervision and collaboration from colleagues including Dr. Stephane Richard‑Devantoy. The model applies core practices from traditional psychiatry together with techniques adapted from psychedelic therapy—such as preparation, set and setting optimization, and psychotherapeutic integration—to support patients receiving ketamine.
According to the investigators, the Montreal Model can be delivered safely and effectively in public and resource‑limited healthcare settings, and it may help standardize care as ketamine programs expand in hospitals and private clinics. The research team also offered training on the model to clinicians from around the world.
Study details, funding and publication
This two‑center randomized clinical trial was conducted in Montreal between January 2021 and August 2022 (ClinicalTrials.gov identifier NCT04701866). Participants received six subanesthetic ketamine infusions over four weeks, along with psychological support and weekly psychotherapy. Primary outcomes were assessed with the Montgomery–Åsberg Depression Rating Scale by blinded raters. Subjective experiences were measured using validated instruments, including the Mystical Experience Questionnaire and the Emotional Breakthrough Inventory.
The trial included 32 participants who together received 181 ketamine infusions. Both clinician‑rated and self‑reported measures showed large, statistically significant reductions in depression and anxiety at four weeks that were sustained through eight‑week follow‑up. The study was funded by the Réseau québécois sur le suicide, les troubles de l’humeur et les troubles associés and supported by the Jewish General Hospital Foundation.
Author and research notes
Author: Keila DePape
Source: McGill University
Contact: Keila DePape – McGill University
Image credit: Neuroscience News
Original research: “The Music for Subanesthetic Infusions of Ketamine randomised clinical trial: ketamine as a psychedelic treatment for highly refractory depression” by Kyle Greenway et al., published in the British Journal of Psychiatry. The study is open access.
Abstract summary
Ketamine produces rapid but often short‑lived antidepressant effects in treatment‑resistant depression. This randomized clinical trial evaluated a psychedelic‑informed ketamine‑psychotherapy protocol (the Montreal Model), delivered with or without music during infusions. The trial examined both clinical outcomes and the role of subjective psychedelic‑like experiences as potential mechanisms of benefit.
Results showed large, sustained reductions in depression, anxiety and suicidality in a severely ill, comorbid sample. Participants reported highly emotional and mystical experiences of an intensity comparable to those observed with classic psychedelics such as psilocybin. Analyses indicated that mystical‑like experiences were associated with ketamine’s antidepressant effects, supporting the idea that these subjective states may contribute to both immediate and enduring therapeutic gains.