A randomized, double-blind, placebo-controlled, Phase 1 study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of an immediate-release oral ketamine capsule in healthy volunteers.
Mutahira Qureshi, Daniel Silman, Romayne Gadelrab, Hans-Christian Stein, Pietro Carmellini, Graeme Duncan, Mitul A. Mehta, Allan H. Young, Carmel Reilly, Mario F Juruena
Journal of Psychopharmacology June 20, 2025 DOI: 10.1177/02698811251340925 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized, double-blind, placebo-controlled, Phase 1 study Peer reviewed |
|---|---|
| Sample size | 19 |
| Population | Healthy volunteers aged 18–55 years |
| Intervention | Oral ketamine |
| Dose | 40-240 mg |
| Duration | Up to 24 h after dosing |
| Topics | Ketamine Esketamine |
| Keywords | Pharmacokinetics Pharmacodynamics Tolerability Drug safety Clinical trials |
| Citations | 3 |
| Key points | Oral ketamine (40–240 mg) was safe and well-tolerated in healthy adults, with dose-proportional pharmacokinetics and transient, reversible dissociation and mood effects. |
Abstract
Ketamine, a rapid-acting N-methyl-D-aspartate receptor antagonist used as a therapeutic for treatment-resistant depression (TRD), is usually administered intravenously or intranasally. This randomized, double-blind, placebo-controlled, Phase 1 study investigated safety and tolerability (primary endpoint), pharmacokinetics (PK) and pharmacodynamics (PD) of an immediate-release oral ketamine. Healthy volunteers (18-55 years) were randomized to each receive two single doses of oral ketamine (40-240 mg) and one oral placebo dose. Treatment-emergent adverse events (TEAEs) and PK and PD assessments (e.g., Bond and Lader visual analogue scale, Modified Observer's Assessment of Alertness/Sedation Scale) were assessed up to 24 h after dosing. Descriptive statistics were used. Nineteen participants were randomized (mean age: 31 years; male, 68%); 18 completed the study. Eighty mild or moderate TEAEs were reported following oral ketamine (40-240 mg) and five following placebo. There were no TEAE-related discontinuations. Most TEAEs (86%) were considered probably related to study drug. The most common TEAEs with oral ketamine were dissociation (26 events), dizziness (nine events) and headache (nine events). A positive relationship between increasing ketamine doses and dissociation events was observed. PK parameters (Cmax, AUCinf) of oral ketamine and its primary metabolites (2S,6S;2R,6R-hydroxynorketamine, R/S-norketamine) were dose proportional. Transient changes in mood and dissociation were detected 1 h postdose with a return to predose values after ~4 h. There were no unexpected safety signals with oral ketamine. PK properties were consistent with those reported for other rapid-acting formulations. These findings warrant further investigation of oral ketamine capsules in TRD (EudraCT No. 2019-001019-22).
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
Cited by 3
- Esketamine/Ketamine: Dual‐Action Mechanisms and Clinical Prospects beyond Anesthesia in Psychiatry, Immunology, and Oncology Advanced Science December 14, 2025
- Pharmacokinetics and pharmacodynamics of orally administered S-ketamine in healthy participants. Journal of Psychopharmacology June 25, 2026
- Safety and tolerance of oral ketamine: A systematic review. Psychiatry and Clinical Neurosciences May 30, 2026
Cites 25
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Measurement of dissociative states with the Clinician‐Administered Dissociative States Scale (CADSS) Journal of Traumatic Stress 1998
- A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression American Journal of Psychiatry April 8, 2016
- Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism American Journal of Psychiatry August 29, 2018
and 20 more in the library