Ketamine is an anesthetic that has been used in medicine since the 1960s. Over the past two decades it has become the first widely available fast-acting treatment for severe depression. It is also a drug with a history of misuse, which makes the story complicated.

How it differs from standard antidepressants

Conventional antidepressants such as SSRIs typically take weeks to work. Ketamine, given at low, controlled doses, can reduce depressive symptoms within hours to days in some people. Researchers think it acts through the glutamate system, which is different from the serotonin pathways targeted by most antidepressants. That is why it can help people who have not responded to other treatments.

Two forms

Racemic ketamine is a mix of two mirror-image molecules and is generic, inexpensive, and used off-label for depression in many clinics. It is usually given as an intravenous infusion or by other routes under supervision.

Esketamine (brand name Spravato) is one of the two mirror-image molecules, developed as a nasal spray. The U.S. FDA approved it in 2019 for treatment-resistant depression, to be used in combination with an oral antidepressant and administered under supervision at a certified site, with monitoring after each dose. It has also been approved in many other countries.

The evidence

Early small studies in the 2000s found rapid antidepressant effects after a single infusion. Later trials of esketamine showed benefit compared with placebo when added to an antidepressant, with some trials producing stronger evidence than others.

A notable head-to-head trial, ELEKT-D, published in the New England Journal of Medicine in 2023, compared intravenous ketamine with electroconvulsive therapy (ECT) in treatment-resistant depression. It found ketamine was non-inferior to ECT for response, with response rates around 55% for ketamine and around 41% for ECT in the paper’s analysis (check the original for exact figures). ECT remains highly effective, so the result was seen as showing ketamine to be a reasonable alternative, not a replacement.

Risks and limitations

Short-term side effects. These include dissociation, dizziness, blood pressure increases, nausea, and sedation. For this reason, treatment occurs in clinic settings with monitoring, and patients cannot drive after sessions.

Durability. The effect often fades after days to weeks, so maintenance treatment is common. The long-term safety of repeated dosing is less well studied.

Misuse and bladder effects. Chronic, high-dose recreational ketamine use is associated with bladder damage and other harms. Clinical use differs in dose and frequency, but monitoring is still advised.

Suicidality. Ketamine can reduce suicidal thoughts in the short term for some patients, but evidence is mixed on long-term outcomes and it is not a stand-alone suicide-prevention measure.

Unregulated clinics. The explosion of private ketamine clinics and telehealth services has raised concerns about oversight, quality of screening, and compounded products whose strength may vary. Patients should check clinician credentials and ask about screening and follow-up.

Who is a poor candidate

People with uncontrolled hypertension, certain cardiovascular conditions, a history of psychosis, or active substance use disorders may be advised against ketamine. A clinician should make that call.

Access in Canada

Esketamine is approved in Canada for treatment-resistant depression under specific conditions, and ketamine is used off-label in some clinics and hospital programs. Coverage and wait times vary by province.

If you are struggling

Treatment-resistant depression is serious. If you are thinking about suicide, contact local emergency services or a crisis line in your region. In Canada, you can call or text 9-8-8.

The takeaway

Ketamine is the best-established member of the new wave of rapid-acting psychiatric treatments. It is effective for many people who’ve exhausted other options, but it has real limits and is best delivered in supervised, regulated settings.

Sources: FDA approval of esketamine (2019); ELEKT-D (Anand et al., NEJM 2023). Verify exact response rates against the original paper.