Ketamine-assisted psychotherapies for mental disorders: A historical overview and systematic review

Ketamine-assisted psychotherapy (KAP) is considered a promising treatment strategy in psychiatric disorders, combining psychotherapeutic interventions with the rapid-acting pharmacological effects of ketamine towards enhancing outcomes. Although KAP has been practiced for many years across different diagnoses, evidence regarding optimal treatment methods and working mechanisms remains limited and has only partly been synthesized.

This systematic review provides a historical overview of studies published up to 2025, that combined ketamine and psychotherapy for the treatment of mental disorders. Psychotherapeutic approaches were categorized into their overarching psychological paradigms: psychoanalytic and psychodynamic, behavioral, humanistic, cognitive-behavioral, integrative/holistic, and other therapeutic frameworks.

64 articles, reporting on 72 studies, were included in this review, of which only 11 were randomized controlled trials (RCTs), highlighting the limited representation of RCTs in the overall body of evidence. Diverse therapeutic approaches were found, most were classified into the 'other' category (n = 24). Results suggest transdiagnostic effectiveness for indications including major depressive disorder, posttraumatic stress disorder, obsessive-compulsive disorder, substance use disorders and eating disorders. KAP, compared to only psychotherapy, was observed to enhance treatment engagement, symptom reduction, and duration of treatment response. Only two studies randomized psychotherapy in the context of ketamine treatment, neither of which reported added effects for psychotherapy. One of those studies also randomized ketamine and did not find a significant interaction effect. This limited evidence does not support added benefit from psychotherapy nor evidence of synergy. Methodological heterogeneity and the limited number of trials that used a psychotherapy control group, restrict definitive conclusions.

Clinical effects are generally reported to be quite positive across psychiatric indications, however, there is a clear need for well-controlled trials to test for potential additive or synergistic effects of the combined use of ketamine and psychotherapy and to identify optimal therapeutic protocols.