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

J Psychopharmacol. 2025 Jun;39(6):545-558. doi: 10.1177/02698811251340925. Epub 2025 Jun 20.

Abstract

Background: 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.

Aims: 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.

Methods: 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.

Results: 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.

Conclusions: 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).

Keywords: Pharmacokinetics; ketamine; pharmacodynamics; safety; tolerability.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Capsules
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Excitatory Amino Acid Antagonists* / administration & dosage
  • Excitatory Amino Acid Antagonists* / adverse effects
  • Excitatory Amino Acid Antagonists* / pharmacokinetics
  • Excitatory Amino Acid Antagonists* / pharmacology
  • Female
  • Healthy Volunteers
  • Humans
  • Ketamine* / administration & dosage
  • Ketamine* / adverse effects
  • Ketamine* / pharmacokinetics
  • Ketamine* / pharmacology
  • Male
  • Middle Aged
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Young Adult

Substances

  • Ketamine
  • Capsules
  • Receptors, N-Methyl-D-Aspartate
  • Excitatory Amino Acid Antagonists