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.
Journal of psychopharmacology (Oxford, England) – June 20, 2025
Source: PubMed
Summary
An oral ketamine capsule shows promise! Initial findings reveal its **safety** and **tolerability** in healthy volunteers. This investigation explored how different doses of **ketamine** are processed by the body (**pharmacokinetics**) and their effects (**pharmacodynamics**). Results showed dose-proportional **pharmacokinetics**, meaning the body handled higher doses predictably. While some mild, temporary effects like dissociation occurred, they were expected and resolved quickly. Overall, the capsule demonstrated a favorable profile, suggesting its potential for future use.
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).