Ketamine-assisted therapy
Ketamine-assisted therapy (KAT), also called ketamine-assisted psychotherapy (KAP), is a form of psychiatric treatment that combines the administration of ketamine — a dissociative anesthetic — with structured psychotherapy to treat mental health conditions. It is most commonly used for treatment-resistant depression, and has also been studied for post-traumatic stress disorder (PTSD), bipolar disorder, obsessive–compulsive disorder (OCD), substance use disorder, and suicidality.[1]
Background
Ketamine was first synthesized in 1962 and approved by the U.S. Food and Drug Administration (FDA) as a surgical anesthetic in 1970.[2] Its antidepressant properties were observed incidentally and became the subject of formal research beginning in the 2000s. Unlike traditional antidepressants that act on the serotonin system, ketamine acts primarily on NMDA receptor antagonism in the glutamate system, producing rapid antidepressant effects within hours rather than weeks.[3]
Mechanism of action
The primary antidepressant mechanism of ketamine involves NMDA receptor antagonism, which leads to a rapid increase in AMPA receptor activity and downstream release of brain-derived neurotrophic factor (BDNF), promoting synaptogenesis — the growth of new synaptic connections in the prefrontal cortex and hippocampus. This neuroplasticity effect is thought to underlie both the rapid onset and the persistence of antidepressant effects.[4]
The dissociative state induced by ketamine is also theorized to enhance the effectiveness of concurrent psychotherapy by creating a state of increased cognitive flexibility, reduced psychological defenses, and heightened neuroplasticity — a therapeutic window sometimes referred to as the "ketamine window."[5]
Esketamine (Spravato) FDA approval
In March 2019, the FDA approved esketamine (brand name Spravato), an S-enantiomer of ketamine administered as a nasal spray, for treatment-resistant depression in adults who have failed at least two oral antidepressant treatments.[6] In August 2020, the FDA expanded the indication to include major depressive disorder with acute suicidal ideation or behavior.[7]
Esketamine must be administered in a certified healthcare setting under medical supervision due to the risk of sedation and dissociation, and patients must be monitored for at least two hours after each dose.
Clinical evidence
Treatment-resistant depression
Multiple randomized controlled trials have demonstrated rapid antidepressant effects from ketamine in patients with treatment-resistant depression. A landmark 2006 randomized, placebo-controlled, double-blind crossover trial by Zarate et al. found that a single intravenous infusion of ketamine produced significant antidepressant effects within two hours, with effects persisting for up to one week in some patients.[8]
A 2019 meta-analysis of 83 trials found robust evidence for rapid antidepressant effects of ketamine across multiple routes of administration (IV, intranasal, oral, intramuscular), with response rates significantly exceeding placebo.[9]
PTSD
Early clinical trials have investigated ketamine for post-traumatic stress disorder, with evidence suggesting rapid reduction in PTSD symptom severity. A 2021 randomized controlled trial found that repeated intravenous ketamine infusions produced significant, rapid PTSD symptom reduction compared to midazolam control.[10]
Administration formats
Ketamine-assisted therapy is typically administered in one of the following formats:
- Intravenous (IV) infusion: The most studied and consistently effective route; typically given as a series of six infusions over two to three weeks. Not FDA-approved specifically for depression (off-label use of generic ketamine).
- Intranasal esketamine (Spravato): FDA-approved for treatment-resistant depression and MDD with acute suicidality; administered in certified clinical settings twice weekly initially.
- Intramuscular (IM) injection: Used at some specialized ketamine clinics; produces a similar but somewhat different dissociative experience than IV.
- Oral/sublingual lozenges: Lower bioavailability; sometimes used as maintenance between IV sessions; off-label.
Psychotherapy integration
Ketamine-assisted psychotherapy (KAP) specifically refers to protocols that integrate psychotherapy — typically cognitive behavioral therapy (CBT), internal family systems (IFS), or somatic therapy — before, during, and after ketamine administration. Proponents argue that the neuroplastic window created by ketamine enhances therapeutic processing, and that psychological integration sessions help consolidate insights from the ketamine experience into lasting behavioral change.[11]
The three-phase KAP protocol includes: (1) Preparation — building therapeutic alliance and setting intentions; (2) Ketamine session — administration with therapist present or immediately available; (3) Integration — processing the experience in subsequent sessions.
Safety and contraindications
Ketamine carries risks of dissociation, sedation, and transient blood pressure elevation. Absolute contraindications include:
- Personal or family history of psychosis or schizophrenia
- Uncontrolled hypertension
- Active substance use disorder (particularly stimulant or dissociative use)
- Increased intracranial pressure
Relative contraindications include:
- History of mania or bipolar I disorder (risk of manic switch)
- Hyperthyroidism
- Severe cardiovascular disease
Long-term repeated use carries a risk of ketamine bladder syndrome (cystitis), documented primarily in recreational high-dose users rather than clinical patients receiving low-dose therapeutic protocols.[12]
Access and regulatory status
As of 2026, ketamine infusion therapy (IV generic ketamine) is widely available at specialized clinics in the United States as an off-label psychiatric treatment. Esketamine (Spravato) is available at FDA-certified healthcare facilities. Neither IV ketamine nor oral/IM ketamine are covered by most insurance plans; costs range from $400–$800 per infusion session.
Access disparities exist: the treatment is disproportionately available to patients with commercial insurance or ability to pay out-of-pocket, limiting equitable access for lower-income and publicly insured patients.[13]
See also
- Esketamine
- Ketamine
- Treatment-resistant depression
- Psychedelic-assisted therapy
- MDMA-assisted therapy
References
- ↑ Dore, Jennifer (2019). "Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy". Journal of Psychoactive Drugs. 51 (2): 189–198. doi:10.1080/02791072.2019.1587556. PMID 30916005.
- ↑ Mion, Georges (2017). "History of anaesthesia: The ketamine story — past, present and future". European Journal of Anaesthesiology. 34 (9): 571–575. doi:10.1097/EJA.0000000000000638. PMID 28700386.
- ↑ Berman, Robert M. (2000). "Antidepressant effects of ketamine in depressed patients". Biological Psychiatry. 47 (4): 351–354. doi:10.1016/s0006-3223(99)00230-9. PMID 10686270.
- ↑ Castrén, Eero (2021). "Antidepressant effects of ketamine: Mechanisms behind rapid-onset antidepressant action". Molecular Psychiatry. 26: 7147–7162. doi:10.1038/s41380-021-01234-3. PMID 34385703 Check
|pmid=value (help). - ↑ Dore, Jennifer (2019). "Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy". Journal of Psychoactive Drugs. 51 (2): 189–198. doi:10.1080/02791072.2019.1587556. PMID 30916005.
- ↑ "FDA approves new nasal spray medication for treatment-resistant depression". U.S. Food and Drug Administration. March 5, 2019. Retrieved 2026-03-28.
- ↑ "FDA approves new indication for antidepressant Spravato to treat major depressive disorder with acute suicidal ideation or behavior". U.S. Food and Drug Administration. August 3, 2020. Retrieved 2026-03-28.
- ↑ Zarate, Carlos A. (2006). "A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression". Archives of General Psychiatry. 63 (8): 856–864. doi:10.1001/archpsyc.63.8.856. PMID 16894061.
- ↑ Fond, Guillaume (2019). "Ketamine administration in depressive disorders: A systematic review and meta-analysis". Psychopharmacology. 232: 3509–3520. doi:10.1007/s00213-015-4017-x. PMID 26199132.
- ↑ Feder, Adriana (2021). "A randomized controlled trial of repeated ketamine administration for chronic posttraumatic stress disorder". Nature Medicine. 27: 1025–1033. doi:10.1038/s41591-021-01352-3. PMID 34031605 Check
|pmid=value (help). - ↑ Dore, Jennifer (2019). "Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy". Journal of Psychoactive Drugs. 51 (2): 189–198. doi:10.1080/02791072.2019.1587556. PMID 30916005.
- ↑ Chu, Peggy S. (2008). "The destruction of the lower urinary tract by ketamine abuse: a new syndrome". BJU International. 102 (11): 1616–1622. doi:10.1111/j.1464-410X.2008.07920.x. PMID 18564368.
- ↑ Rhoads, Savannah (2023). "Access to ketamine treatment for depression: An analysis of barriers and facilitators". Psychiatric Services. doi:10.1176/appi.ps.20220454. PMID 37226462 Check
|pmid=value (help).
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