What is Ketamine Therapy? How Does it Change the Way We Treat Depression?
Depression is a complex mental health condition, with symptoms and treatment responses varying widely between individuals. Traditional psychiatric care is not a one-size-fits-all solution, leaving some people struggling to find relief. Although several antidepressant treatments are available, they often take weeks to produce noticeable effects, and some individuals do not achieve remission after trying multiple medications. When depression does not respond adequately to at least two appropriate antidepressant treatments, it is commonly described as treatment-resistant depression (Rizvi et al., 2014).
Ketamine has emerged as a potential alternative for some people with treatment-resistant depression. Research suggests that carefully administered doses can produce antidepressant effects more rapidly than conventional medications, partly through their effects on the brain's glutamate system. However, its benefits, limitations and safety requirements remain important considerations.
What Exactly is Ketamine?
Ketamine is a medication developed in the 1960s and widely used as an anesthetic, including during the Vietnam War. It produces a dissociative state, reduces pain perception and can cause sedation and amnesia. Its effects on breathing differ from those of many other anesthetic agents, although respiratory complications remain possible (Savic Vujovic et al., 2023).
While ketamine was initially developed for anesthesia and pain management, researchers later began investigating its potential psychiatric applications. A clinical trial published in 2000 demonstrated that ketamine could produce rapid antidepressant effects, drawing attention to the role of the glutamate system in depression treatment.
Unlike conventional antidepressants, which primarily influence neurotransmitters such as serotonin and norepinephrine, ketamine acts on a different signalling pathway. This distinction has made it an important subject of research into treatments for people who have not responded to existing options.
The Difference Between Traditional Antidepressants and Ketamine
To understand why ketamine may work differently, it is useful to examine how conventional antidepressants affect the brain.
Many commonly prescribed antidepressants influence neurotransmitters such as serotonin and norepinephrine, which are involved in regulating mood and other functions. Although these medications can begin affecting neurotransmitter activity relatively quickly, meaningful improvements in depressive symptoms often take several weeks to emerge (Bottaccioli et al., 2025).
Researchers continue to investigate why this delay occurs. One explanation involves neuroplasticity, the brain's ability to adapt and reorganize connections between nerve cells. Depression has been associated with changes in neural circuits involved in mood regulation, and some antidepressant treatments may gradually influence these processes.
Ketamine works differently. Research by Abdallah et al. (2016) examined its effects on N-methyl-D-aspartate (NMDA) receptors, which are involved in glutamate signalling. By blocking these receptors, ketamine can trigger changes in glutamate activity and other cellular processes associated with synaptic plasticity.
Glutamate is a major excitatory neurotransmitter involved in communication between nerve cells. Research suggests that ketamine's effects on glutamate signalling may help strengthen or restore connections in brain circuits affected by depression and chronic stress. However, the precise mechanisms responsible for its antidepressant effects are still being investigated.
One of ketamine's most significant characteristics is the speed at which it can act. Some patients experience improvements in depressive symptoms within hours of treatment, compared with the several weeks often required for conventional antidepressants (Antos et al., 2024; van Zanten et al., 2025).
These effects are not necessarily permanent. Improvements following a single treatment may diminish over subsequent days, and some patients require repeated sessions or additional treatment to maintain their response. The duration and effectiveness of treatment vary between individuals.
How is Ketamine Administered?
Ketamine can be administered through several routes, although the evidence supporting their effectiveness for depression differs (Walsh et al., 2022).
Intravenous (IV) ketamine is administered directly into the bloodstream, allowing clinicians to control the dose and monitor the patient's response. IV ketamine has been extensively studied for treatment-resistant depression, but its psychiatric use remains off-label in Canada.
Intranasal esketamine, a medication derived from one of the two molecular forms of ketamine, is administered through a nasal spray. Marketed as Spravato, it is approved by Health Canada for specified uses involving major depressive disorder, including treatment-resistant depression. Unlike off-label ketamine formulations, Spravato has undergone regulatory review for these psychiatric indications and must be administered under medical supervision.
Intramuscular (IM) ketamine is injected into a muscle and is sometimes used in ketamine-assisted psychotherapy (KAP). In these settings, medication administration may be combined with psychological support or psychotherapy. However, evidence supporting this approach remains more limited than the evidence for IV ketamine and intranasal esketamine.
Oral ketamine is taken by mouth, while sublingual ketamine is placed under the tongue and absorbed through the tissues of the mouth. These methods are sometimes used in clinical or psychotherapy settings, but their absorption and effects can be less predictable, and the evidence supporting their use for depression is less established.
Research has examined the relative effectiveness of IV ketamine and intranasal esketamine. Both have demonstrated antidepressant benefits in people with treatment-resistant depression, although studies differ in their methods, treatment schedules and patient populations. Current evidence does not establish that one approach is consistently more effective for every patient (Yavi et al., 2022).
How to Access Ketamine-Assisted Psychotherapy and Ketamine Infusions in Canada
Access to ketamine-based treatment in Canada depends on the medication, the patient's circumstances and the services available in their province.
Some hospital-based psychiatric programs and specialized clinics provide IV ketamine for treatment-resistant depression. Because ketamine itself is approved primarily for anesthetic purposes, its use for psychiatric conditions is generally considered off-label. This means a clinician may prescribe it for a condition outside its authorized indications when they determine that doing so is clinically appropriate.
Intranasal esketamine is different because Spravato has specific Health Canada approvals for depression treatment. It is provided through a controlled distribution program with requirements for patient assessment, administration and monitoring.
Ketamine-assisted psychotherapy is also offered by some specialized clinics. These programs combine ketamine administration with psychological support, although the structure, qualifications of providers and available evidence may differ between services.
Patients considering these treatments generally undergo a medical and psychiatric assessment to determine whether the approach is appropriate. Clinicians may review previous treatments, current medications, physical health conditions and potential risks before recommending a treatment plan.
Cost can be another barrier. Coverage for ketamine-based treatment varies depending on the province, treatment setting, medication and insurance plan. Some patients may face substantial out-of-pocket expenses, particularly when accessing treatment through private clinics.
These differences can make access uneven across Canada, even as interest in ketamine-based mental health treatment continues to grow.
What to Expect During a Session
The experience of ketamine treatment varies depending on the medication, method of administration and clinical setting.
For IV ketamine, patients generally receive treatment in a supervised medical environment where healthcare professionals monitor vital signs, including blood pressure and heart rate. Some clinics provide a quiet room and may offer headphones or an eye mask to make the experience more comfortable.
Ketamine can produce dissociation, a temporary feeling of separation from one's surroundings, body or usual sense of awareness. Some patients also experience changes in perception, dizziness or sedation. These effects are monitored by clinical staff and generally diminish as the medication wears off.
In ketamine-assisted psychotherapy, psychological support may be provided before, during or after medication administration. Some programs include follow-up sessions intended to help patients reflect on their experiences and incorporate relevant insights into ongoing treatment.
However, the role of psychotherapy in enhancing ketamine's antidepressant effects remains an area of ongoing research. Not all ketamine treatments involve psychotherapy, and not all patients experience meaningful psychological insights during a session.
Intranasal esketamine follows a different protocol. Spravato is administered in a supervised healthcare setting, with patients monitored for at least two hours afterward because of risks including sedation, dissociation and changes in blood pressure.
Patients are generally advised not to drive or perform activities requiring full alertness until they have recovered in accordance with their clinician's instructions. Depending on the treatment, they may need someone to accompany them home.
Side Effects and Considerations
Although ketamine and esketamine have demonstrated potential benefits for depression, they also carry important risks.
Common short-term side effects can include nausea, dizziness, dissociation, sedation, changes in perception and temporary increases in blood pressure. The intensity and duration of these effects depend on the dose, route of administration and individual patient factors.
More serious concerns include respiratory complications, misuse and dependence, particularly when ketamine is used outside appropriate medical supervision. Repeated or prolonged exposure may also be associated with urinary tract and bladder problems, as well as possible cognitive effects.
Medical supervision is therefore an important part of treatment. Clinicians must assess whether patients have conditions or risk factors that could make ketamine inappropriate or require additional precautions.
People with certain cardiovascular conditions, uncontrolled high blood pressure, a history of psychosis or particular substance use concerns may require more careful assessment. Pregnancy and other medical circumstances can also affect treatment decisions.
A 2024 study examining at-home ketamine treatment identified several factors relevant to patient selection and safety, including psychiatric history, cardiovascular health and the potential for adverse effects (Mathai et al., 2024). However, eligibility cannot be determined through a single list of exclusions, and decisions should be made through an individualized clinical assessment.
The growing availability of remote prescribing and at-home ketamine services has also raised concerns about monitoring and patient safety. Unlike treatment administered in a supervised clinical setting, at-home use may involve fewer opportunities for immediate medical intervention if complications occur.
Patients considering ketamine-based treatment should therefore understand the differences between approved medications, off-label prescribing and the levels of supervision available through different providers.
Another important limitation is the uncertainty surrounding long-term outcomes. While research supports ketamine's rapid antidepressant effects in some patients, questions remain about the effectiveness and safety of repeated treatment over extended periods.
What Does The Future Hold For Ketamine Treatment In Canada?
Ketamine represents an important development in the treatment of depression, particularly for people who have not experienced sufficient improvement with conventional antidepressants.
Its rapid effects have challenged traditional approaches to understanding antidepressant treatment and encouraged further research into glutamate signalling, neuroplasticity and the biological mechanisms associated with depression.
However, ketamine is not a universal solution. Some patients experience substantial improvements, while others respond only partially or not at all. Questions about long-term safety, treatment frequency, cost and accessibility remain unresolved.
In Canada, differences in provincial healthcare coverage and access to specialized services may create additional barriers for people considering these treatments.
Further research is needed to establish which patients are most likely to benefit, how treatment responses can be maintained and whether combining ketamine with psychotherapy provides additional long-term advantages.
Ketamine has opened another avenue for understanding and treating depression. Its future role in Canadian mental healthcare will depend on continued research, appropriate clinical oversight and efforts to ensure that emerging treatments are both safe and accessible.