The Music for Subanesthetic Infusions of Ketamine randomised clinical trial: ketamine as a psychedelic treatment for highly refractory depression
Kyle T. Greenway, Nicolas Garel, Lê-Anh Dinh-Williams, Julien Thibault Lévesque, Mendel Kaelen, Vincent Dagenais-Beaulé, Sara de la Salle, David Erritzøe, Karl Looper, Gustavo Turecki, Soham Rej, Séphane Richard-Devantoy
The British Journal of Psychiatry June 18, 2025 DOI: 10.1192/bjp.2025.102 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized clinical trial Peer reviewed |
|---|---|
| Sample size | 32 |
| Population | Adults with severe and highly comorbid treatment-resistant depression, including high rates of personality disorder and suicidality |
| Interventions | Ketamine–psychotherapy Music Non-music support |
| Dose | subanaesthetic infusions |
| Duration | 4-week intervention, 8-week follow-up |
| Topics | Depression Ketamine Esketamine |
| Keywords | Experience Psychedelics Psychotherapy Sustained relief Lasting benefits Significant Lasting reductions Potent new treatment Six ketamine infusions Psychological support |
| Citations | 8 |
| Registration | NCT04701866 |
| Key findings | Ketamine–psychotherapy produced large and sustained antidepressant effects in severe treatment-resistant depression, with mystical-like experiences contributing to the benefits. |
Abstract
Background: Ketamine exerts potent but transient antidepressant effects in treatment-resistant depression (TRD). Combinations of ketamine and psychotherapy have attracted interest, but no trial has investigated a psychedelic model of ketamine–psychotherapy for TRD to our knowledge.
Aims: This secondary analysis of a randomised clinical trial (RCT) explores the therapeutic effects and experiential mechanisms of the Montreal Model of ketamine–psychotherapy for TRD, with or without music.
Method: A two-centre, single-blinded, RCT conducted in Montreal, Canada, between January 2021 and August 2022 (NCT04701866). Participants received ketamine–psychotherapy for TRD – six subanaesthetic infusions over 4 weeks and psychological support – with either music or matched non-music support during ketamine doses, as per random group assignments. The primary therapeutic outcome was the Montgomery–Åsberg Depression Rating Scale, assessed by blinded raters. Psychedelic-like experiences, evaluated by the Mystical Experience Questionnaire and Emotional Breakthrough Inventory, and their session-by-session relationships with depression were explored with multilevel, time-lagged covariate models with autoregressive residuals.
Results: Thirty-two participants with severe and highly comorbid TRD, including high rates of personality disorder and suicidality, received 181 ketamine infusions. Therapeutic outcomes and psychedelic experiences did not differ between music ( n = 15) and non-music ( n = 17) interventions. Both groups experienced significant reductions in clinician-rated and self-reported depression ( d = 1.2 and d = 0.87, respectively; p < 0.001), anxiety ( d = 0.8, p < 0.001) and suicidality ( d = 0.4, p < 0.05) at 4 weeks, fully maintained at 8-week follow-up. Ketamine experiences were highly emotional and mystical. Converging analyses supported mystical-like ketamine experiences as mechanisms of its antidepressant effects.
Conclusions: This trial found large and notably sustained benefits of ketamine–psychotherapy for severe TRD, with or without music, and psychedelic experiences of comparable intensity to those observed with psilocybin. Mystical-like experiences may particularly contribute to ketamine’s immediate and persistent psychiatric benefits.
Comparable studies
Other randomized controlled trials on ketamine for depression, most cited first.