Ascending‐Dose Study of Controlled‐Release Ketamine Tablets in Healthy Volunteers: Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability
Paul Glue, Natalie J. Medlicott, Peter Surman, Fred Lam, Noelyn Hung, C. Hung
The Journal of Clinical Pharmacology February 17, 2020 DOI: 10.1002/jcph.1573 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Peer reviewed |
|---|---|
| Sample size | 24 |
| Population | Healthy volunteers |
| Dose | 60, 120, or 240 mg |
| Duration | Single dose followed by every-12-hours dosing for 5 doses, with assessments up to 72 hours |
| Measures | Pharmacokinetics, pharmacodynamics (brain-derived neurotropic factor), adverse events, vital signs, dissociation ratings, ECGs, safety laboratory tests |
| Topics | Esketamine Ketamine |
| Citations | 44 |
| Key findings | Oral controlled-release ketamine tablets did not increase blood pressure or heart rate, and only at 240 mg was mild dissociation reported, indicating improved tolerability versus injected ketamine. |
Abstract
Parenteral ketamine has fast‐onset antidepressant and antianxiety effects; however, it causes dissociation, hypertension, and tachycardia shortly after dosing. Ketamine's antidepressant effects may be due to active metabolites rather than to ketamine itself. We hypothesized that oral controlled‐release ketamine tablets would improve safety and tolerability compared with injected ketamine by reducing peak ketamine exposures compared with dosing by injection. In this randomized, placebo‐controlled ascending‐dose study, ketamine doses of 60, 120, or 240 mg or matching placebo (single dose followed by every‐12‐hours dosing for 5 doses) were given to 24 healthy volunteers. Pharmacokinetics, pharmacodynamics (brain‐derived neurotropic factor), adverse events, and vital signs were assessed up to 72 hours. Drug release occurred over ∼10 hours, with most drug substance present as norketamine (∼90%). Area under the concentration‐time curve and peak concentration were dose proportional. Elimination half‐life was prolonged (7‐9 hours) compared with published data from immediate‐release oral formulations. There were no changes in blood pressure or heart rate after any dose. Mild dissociation was reported after 240 mg but not lower doses; mean dissociation ratings in this group were minimal (1‐2/76). There were no clinically significant changes in ECGs or safety laboratory tests at any time. Compared with injected ketamine, oral controlled‐release ketamine tablets did not increase blood pressure or heart rate, and only at doses of 240 mg was dissociation of mild intensity reported. Reducing and delaying ketamine peak concentration by oral dosing with controlled‐release ketamine tablets improve this drug's tolerability for patients with depression/anxiety.
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 14
- Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial. Nature Medicine July 1, 2024
- Ketamine as a therapeutic agent for depression and pain: mechanisms and evidence. Journal of Neurological Sciences 2022
- Safety and efficacy of extended release ketamine tablets in patients with treatment-resistant depression and anxiety: open label pilot study Therapeutic Advances in Psychopharmacology 2020
- Current Perspectives on the Clinical Research and Medicalization of Psychedelic Drugs for Addiction Treatments: Safety, Efficacy, Limitations and Challenges. CNS Drugs October 1, 2024
- Beyond NMDA Receptors: A Narrative Review of Ketamine's Rapid and Multifaceted Mechanisms in Depression Treatment. International Journal of Molecular Sciences December 20, 2024
and 9 more in the library
Cites 12
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- 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
- Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression The International Journal of Neuropsychopharmacology October 8, 2013
and 7 more in the library