The Music for Subanesthetic Infusions of Ketamine randomised clinical trial: ketamine as a psychedelic treatment for highly refractory depression

In a clinical trial of ketamine combined with psychotherapy for severe treatment-resistant depression, 32 participants received six ketamine infusions with psychological support, either with or without music. Both groups showed large and sustained reductions in depression, anxiety, and suicidality at four weeks, fully maintained at eight-week follow-up. The ketamine experiences were highly emotional and mystical, comparable to those seen with psilocybin. Converging analyses suggested that mystical-like experiences contributed to the immediate and lasting antidepressant effects. Music did not enhance outcomes or psychedelic experiences.

Study at a glance

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.