Ketamine-Assisted Therapy: What the Evidence Shows
Ketamine has emerged as a rapid-acting treatment option for treatment-resistant mental health conditions, with the strongest and most well-established evidence supporting its use in treatment-resistant depression (TRD). Unlike traditional antidepressants, which may take weeks to show benefit, ketamine has demonstrated the ability to reduce depressive symptoms within hours to days, making it an area of growing clinical and research interest.¹²
In Canada, ketamine is used within regulated medical settings, often as an off-label treatment for psychiatric conditions. Off-label prescribing is a common and accepted medical practice when supported by scientific evidence and clinical judgment.
This article summarizes what current research tells us about ketamine-assisted therapy, where the evidence is strongest, and where further study is still needed.
What Is Ketamine?
Ketamine is a medication that has been used safely for decades as an anesthetic and pain-control agent. At much lower doses than those used in surgery, ketamine has been found to have rapid antidepressant and anti-suicidal effects.
Ketamine works differently from traditional antidepressants. While most antidepressants target serotonin, norepinephrine, or dopamine, ketamine primarily affects the glutamate system, the brain’s most abundant excitatory neurotransmitter network. This mechanism is thought to enhance neuroplasticity—the brain’s ability to form and reorganize connections—which may help individuals move out of rigid or repetitive thought patterns seen in depression and other mental health conditions.³⁴
Ketamine can be administered through several medical routes depending on clinical context and patient needs, including intravenous (IV), intramuscular (IM), and intranasal (IN) delivery.
Ketamine as Part of an Integrated Treatment Approach
One of the central challenges in ketamine research is durability—how long benefits last after treatment. Studies consistently show that improvements from a single ketamine dose or a short treatment course often diminish over time without additional support.²⁵
This has led to increasing emphasis on structured psychotherapy during and after ketamine treatment. These approaches are based on the hypothesis that ketamine’s temporary effects on brain plasticity may create a therapeutic window during which psychotherapy is more effective. During this period, individuals may be better able to process emotions, challenge entrenched thought patterns, and consolidate insight compared to medication or therapy alone.⁶⁷
For this reason, many expert consensus statements and clinical programs emphasize that ketamine is most appropriately delivered within a comprehensive treatment framework, rather than as a standalone medical intervention.
Depression and Treatment-Resistant Depression
Treatment-resistant depression is generally defined as depression that has not improved despite trials of at least two adequate antidepressant treatments.¹² TRD affects a substantial proportion of individuals with major depressive disorder and is associated with increased disability, medical comorbidity, and suicide risk.
Ketamine demonstrates significant antidepressant efficacy in treatment-resistant depression. Meta-analyses of randomized controlled trials show substantial reductions in depressive symptoms compared with placebo within 24 hours, with effects comparable to or greater than many conventional antidepressant trials.⁴
While ketamine’s antidepressant effects are rapid, they are often transient, typically lasting several days to two weeks following a single administration.²⁵ Evidence from clinical trials and real-world protocols suggests that an induction course of 6–8 treatments, administered every 2–4 days, may help prolong and consolidate therapeutic response in a subset of patients.² Given its rapid onset, ketamine may be considered when timely symptom relief is clinically important, within a comprehensive treatment framework.
Other Mental Health Conditions
Beyond depression, ketamine has shown promise for several other psychiatric conditions:
Post-Traumatic Stress Disorder (PTSD): Randomized trials demonstrate significant reductions in PTSD symptom severity following ketamine treatment.⁷
Obsessive-Compulsive Disorder (OCD): Short-term reductions in obsessive-compulsive symptoms have been observed, though effects may be transient.⁷
Anxiety Disorders: Ketamine may reduce anxiety symptoms, though findings are more variable and further research is needed.⁸
Alcohol Use Disorder: Emerging evidence suggests ketamine, when paired with psychotherapy, may reduce cravings, increase abstinence rates, and prolong time to relapse.⁷
Safety and Limitations
When administered in medical settings, ketamine is generally well tolerated. Common side effects are usually mild and temporary and may include transient increases in blood pressure or heart rate, dissociation, and perceptual changes. These effects typically resolve within hours.²³
Durability of benefit and specific dosing protocols continue to be investigated. Racemic ketamine (IV or IM) does not have formal psychiatric approval in Canada and is used off-label based on available evidence and expert consensus. Professional organizations emphasize careful patient selection, informed consent, and ongoing monitoring.⁹
Summary
Ketamine-assisted therapy represents a meaningful advance in the treatment of treatment-resistant depression, offering rapid symptom relief when other treatments have failed. While evidence is strongest for TRD, growing research suggests potential benefits for PTSD, OCD, anxiety disorders, and alcohol use disorder.
Ketamine is not a cure and appears most effective when integrated into a patient-centred, psychotherapy-informed treatment plan that supports both short-term relief and longer-term psychological change.
References
Sanacora G, Frye MA, McDonald W, et al. A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA Psychiatry. 2017.
Andrade C. Ketamine for Depression: Clinical Summary of Efficacy and Adverse Effects. J Clin Psychiatry. 2017.
Naughton M, Clarke G, O’Leary OF, Cryan JF, Dinan TG. A Review of Ketamine in Affective Disorders. J Affect Disord. 2014.
Marwaha S, Palmer E, Suppes T, et al. Novel and Emerging Treatments for Major Depression. The Lancet. 2023.
Johnston JN, Kadriu B, Kraus C, et al. Ketamine in Neuropsychiatric Disorders: An Update. Neuropsychopharmacology. 2023.
Wilkinson ST, Rhee TG, Joormann J. Cognitive-Behavioral Therapy Following Ketamine. Am J Psychiatry. 2017.
Kwan ATH, Lakhani M, Singh G, et al. Ketamine for the Treatment of Psychiatric Disorders: A Systematic Review and Meta-Analysis. CNS Spectrums. 2024.
Marchi M, Magarini FM, Galli G, et al. Effects of Ketamine on Anxiety and Cognition. Front Neurosci. 2022.
Quintero JM, Bustos RH, Lechtig-Wassermann S, et al. Ketamine in Clinical Practice. CNS Spectrums. 2025.