A systematic review by the Canadian Network for Mood and Anxiety Treatments evaluated evidence for racemic ketamine in treatment-resistant depression. Single intravenous infusions have Level 1 evidence for efficacy in adults, while multiple or maintenance infusions have only Level 3 evidence. Adverse events include dissociative symptoms and hypertension. Non-IV formulations have Level 3 or 4 evidence. Single-dose IV racemic ketamine is a third-line recommendation; repeated use requires careful case-by-case risk-benefit assessment. Oral and other formulations should be limited to specialists with ketamine expertise at tertiary centers due to limited evidence and risk of misuse.
A biopsychosocial approach to ketamine for treatment-resistant depression, called the Montreal model, pairs ketamine infusions with structured psychiatric care and psychotherapy. Developed over six years in public healthcare settings, the model conceptualizes ketamine as a brief intervention that creates windows of opportunity for enhanced care and psychological growth. It combines six ketamine infusions with psychedelic-inspired nonpharmacological adjuncts, including preparative and integrative psychological support. The model aims to bridge biomedical and psychedelic perspectives, offering a standardized yet flexible approach for severe, real-world patients. Further research is needed to assess its effectiveness and hypothesized psychological mechanisms.
Past environmental exposures can significantly shape psychedelic drug experiences and their therapeutic outcomes, a concept the authors call 'imprinting.' In a clinical trial of ketamine for treatment-resistant depression, two patients' subjective experiences were altered by the type and amount of digital media they consumed in the days before treatment: higher media exposure reduced mystical and emotional qualities of the ketamine experience, overriding standard intention-setting practices and changing therapeutic results. Eight additional patients spontaneously reported past environmental exposures manifesting as visual hallucinations during ketamine sessions. Similar imprinting effects appear in historical reports of other psychedelic drugs and in dreaming. The authors propose expanding the contextual model of psychedelic action to include imprinting, which may help clinicians and researchers better understand these drug effects.