THEPSYCHEDELICLIBRARY

Chapter 1

What ketamine therapy is

How ketamine is used as a treatment, the different ways it's given, and how that differs from recreational use.

ReviewedLast updated September 26, 2026

In short: ketamine is a medical anaesthetic that, in lower doses and under supervision, can relieve depression within hours. It’s the most widely available “psychedelic-adjacent” treatment today, and the one with the most clinical research behind it.

From operating room to psychiatry

Ketamine was first made in 1962 and approved as an anaesthetic in the United States in 1970. It became popular in surgery and emergency medicine because, unlike many anaesthetics, it doesn’t usually suppress breathing. It’s on the World Health Organization’s List of Essential Medicines.

Its second life began in 2000, when a small study of seven people with depression found that a single dose improved symptoms within hours.1 A larger randomized trial in 2006 confirmed the effect in treatment-resistant depression, meaning depression that hasn’t improved after at least two standard treatments.2 Most antidepressants take weeks to work, so a response measured in hours was a genuine surprise.

The different forms

Ketamine for mental health is given in several ways. They differ in how much research supports them and how they’re regulated.

  • Intravenous (IV) infusion. The most studied form. Ketamine is given slowly through a drip, usually over about 40 minutes, while staff monitor blood pressure and wellbeing. In Canada, IV ketamine for depression is prescribed “off-label”, meaning outside its approved use as an anaesthetic.
  • Esketamine nasal spray (Spravato). Ketamine is a mix of two mirror-image molecules; esketamine is one of them. The spray was approved for treatment-resistant depression in the US in 2019 and by Health Canada in 2020, alongside an oral antidepressant. It’s given in a clinic, with monitoring afterwards.3
  • Intramuscular injection. Used by some clinicians. Less studied than IV.
  • Oral and lozenge forms. Sometimes prescribed, including for use outside a clinic. These have the least research behind them, and the body absorbs them less predictably.

For a full profile of the drug itself, see our ketamine guide.

What a course of treatment looks like in research

In clinical trials, ketamine is rarely a single session. A common research pattern is a series of infusions over two to three weeks, followed by assessment. A 2023 trial of 403 people, for example, gave ketamine twice a week for three weeks and compared it with electroconvulsive therapy (ECT).4 Chapter 5, What a treatment actually involves, describes the process step by step.

Ketamine is not a classic psychedelic

Ketamine is often grouped with psychedelics, but it works differently. Classic psychedelics like psilocybin and LSD act mainly on serotonin 2A receptors. Ketamine blocks NMDA receptors in the brain’s glutamate system. At treatment doses it produces dissociation: feeling detached from your body or surroundings, with altered perception. Chapter 2, How psychedelics and ketamine work in the brain, explains the difference.

How therapeutic use differs from recreational use

The molecule is the same, but almost everything else is different:

  • Dose and frequency. Research protocols use measured doses, spaced out, for a limited course. Heavy, frequent recreational use is linked to bladder damage and dependence.
  • Setting. Treatment happens in a medical setting with screening beforehand and monitoring during and after.
  • Purpose and support. Some programs combine ketamine with psychotherapy, and researchers are studying whether that helps the benefits last.

What we still don’t know

  • How to keep the benefits going. The effect of a single dose usually fades within one to two weeks.
  • The long-term safety of repeated treatment over months or years.
  • Whether the dissociative experience itself matters, or only the chemistry.
  • How the less-studied forms (oral, lozenge, at-home) compare with IV and nasal treatment.

This chapter is educational. It isn’t medical advice. Talk to a qualified health professional about your own situation.

Sources

  1. Berman RM, et al. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry, 2000. PubMed
  2. Zarate CA Jr, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry, 2006. PubMed
  3. Popova V, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression (TRANSFORM-2). American Journal of Psychiatry, 2019. PubMed
  4. Anand A, et al. Ketamine versus ECT for nonpsychotic treatment-resistant major depression. New England Journal of Medicine, 2023. PubMed