Ketamine Dose and Duration Effects in Internalizing Disorders
Neil McNaughton, Ben Beaglehole, Paul Glue
The Journal of Clinical Pharmacology September 1, 2026 DOI: 10.1002/jcph.70299 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Secondary analysis of a three-way within-subject double-blind active-controlled cross-over trial Peer reviewed |
|---|---|
| Population | Patients with treatment-resistant depression, post-traumatic stress disorder, generalized and/or social anxiety, or obsessive-compulsive disorder |
| Interventions | Racemic ketamine psychoactive control |
| Dose | 0.5 and 1.0 mg/kg |
| Duration | Assessments at 24 h and 168 h after dosing |
| Topics | Esketamine Ketamine |
| Key findings | Single intramuscular racemic ketamine doses of 0.5 and 1.0 mg/kg produced robust improvements on diagnosis-appropriate outcome scales across all studied internalizing disorders compared with psychoactive controls, with effects largest at 24 hours and noticeably smaller at 168 hours. The 1 mg/kg dose did not differ significantly from 0.5 mg/kg at either time point, and responses did not differ significantly between disorders at 24 hours. The authors propose that ketamine may have a narrow inverted-U dose-response profile peaking around 0.5-1.0 mg/kg in these patients. |
Abstract
The dose-response profile of racemic ketamine in internalizing disorders is poorly characterized. This was a secondary analysis of outcome responses in patients with treatment-resistant depression, post-traumatic stress disorder, generalized and/or social anxiety, or obsessive-compulsive disorder. For each disorder, they received single intramuscular doses of racemic ketamine (0.5 and 1.0 mg/kg) and a psychoactive control, using a three-way within-subject double-blind active-controlled cross-over design. Intramuscular racemic ketamine doses of 0.5 and 1.0 mg/kg produced robust effects on diagnosis-appropriate outcome scales for all these internalizing disorders, compared with psychoactive controls. These effects were most obvious at 24 h after dosing and noticeably smaller at 168 h. The magnitude of change after 1 mg/kg did not differ significantly from 0.5 mg/kg at either time point, and did not differ significantly between the internalizing disorders at 24 h. When combined with other ketamine dose-response data, we propose that ketamine may have a narrow inverted-U dose-response profile (peaking in the regions of 0.5-1.0 mg/kg) in patients with internalizing disorders.
Comparable studies
Other randomized controlled trials on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Healthy human subjects recruited from the community | 1994 | Randomized controlled trial | n = 19 |
| Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode | 2013 | Randomized controlled trial | n = 73 |
| Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine Patients undergoing major abdominal surgery | 2005 | Randomized controlled trial | n = 75 |
| Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder Patients with chronic PTSD related to a range of trauma exposures | 2014 | Randomized controlled trial | n = 41 |
| Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Healthy volunteers | 2000 | Single-blind placebo-controlled study | n = 20 |
Citations in the library
Cites 10
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- Double-Blind, Placebo-Controlled, Dose-Ranging Trial of Intravenous Ketamine as Adjunctive Therapy in Treatment-Resistant Depression (TRD) Molecular Psychiatry October 3, 2018
- Ketamine for the treatment of major depression: a systematic review and meta-analysis EClinicalMedicine August 1, 2023
- NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine Journal of Neuroscience January 3, 2023
- Effects of ketamine in patients with treatment-refractory generalized anxiety and social anxiety disorders: Exploratory double-blind psychoactive-controlled replication study Journal of Psychopharmacology March 1, 2020
and 5 more in the library