A Phase 1 Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (2R,6R)-Hydroxynorketamine in Healthy Volunteers.
Shruti M Raja, Jeffrey T Guptill, Michelle Mack, Marni Peterson, Stephen Byard, Robert Twieg, Lynn Jordan, Natalie Rich, Richard Castledine, Samuel Bourne, Martin Wilmshurst, Sarah Oxendine, Satya G C Avula, Helen Zuleta, Paul Quigley, Sheila Lawson, Stephen J McQuaker, Reza Ahmadkhaniha, Lawrence G Appelbaum, Kevin Kowalski, Chineta T Barksdale, Brandon T Gufford, Asaad Awan, Alfredo R Sancho, Max C Moore, Karim Berrada, Gregory B Cogan, Jesse DeLaRosa, Jeanne Radcliffe, Maryland Pao, Michelle Kennedy, Quentin Lawrence, Lisa Goldfeder, Leslie Amanfo, Panos Zanos, Jessica R. Gilbert, Patrick J. Morris, Ruin Moaddel, Todd D Gould, Carlos A. Zarate, Craig J. Thomas
Clinical Pharmacology & Therapeutics November 1, 2024 DOI: 10.1002/cpt.3391 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Phase 1 clinical trial Peer reviewed |
|---|---|
| Population | Healthy volunteers |
| Interventions | (2R 6R)-Hydroxynorketamine (RR-HNK) |
| Dose | 0.1-4 mg/kg (SAD) and 1-2 mg/kg (MAD) |
| Topics | Ketamine |
| Keywords | Clinical-trials Antidepressants Ketamine-research Psychopharmacology Mental-health |
| Citations | 34 |
| Registration | NCT04711005 |
| Key findings | RR-HNK was well tolerated with minimal adverse events, no dissociative or anesthetic effects, and showed dose-proportional pharmacokinetics and central nervous system exposure, supporting progression into Phase 2 trials. |
Abstract
(R,S)-Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)-Hydroxynorketamine (RR-HNK) is a metabolite of ketamine that lacks anesthetic and dissociative activity but maintains antidepressant and analgesic activity in multiple preclinical models. To enable future assessments in selected human indications, we report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RR-HNK in a Phase 1 study in healthy volunteers (NCT04711005). A six-level single-ascending dose (SAD) (0.1-4 mg/kg) and a two-level multiple ascending dose (MAD) (1 and 2 mg/kg) study was performed using a 40-minute IV administration emulating the common practice for ketamine administration for depression. Safety assessments showed RR-HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of dissociation and sedation demonstrated that RR-HNK did not possess anesthetic or dissociative characteristics in the doses examined. RR-HNK PK parameters were measured in both the SAD and MAD studies and exhibited dose-proportional increases in exposure. Quantitative electroencephalography (EEG) measurements collected as a PD parameter based on preclinical findings and ketamine's established effect on gamma-power oscillations demonstrated increases of gamma power in some participants at the lower/mid-range doses examined. Cerebrospinal fluid examination confirmed RR-HNK exposure within the central nervous system (CNS). Collectively, these data demonstrate RR-HNK is well tolerated with an acceptable PK profile and promising PD outcomes to support the progression into Phase 2.
Comparable studies
Other non-randomized and open-label trials on ketamine, most cited first.
Citations in the library
Cited by 18
- Ketamine and Hydroxynorketamine as Novel Pharmacotherapies for the Treatment of Opioid Use Disorders. Biological Psychiatry March 15, 2025
- Rapid hippocampal synaptic potentiation induced by ketamine metabolite (2R,6R)-hydroxynorketamine persistently primes synaptic plasticity. Neuropsychopharmacology May 1, 2025
- The therapeutic potential of psilocybin beyond psychedelia through shared mechanisms with ketamine. Molecular Psychiatry July 7, 2025
- Synaptic priming: A framework for pharmacotherapy in depression. Neuron November 19, 2025
- Neural signaling mechanisms in depression: bridging classical monoamine hypotheses, animal models, and emerging antidepressant strategies Frontiers in Cell and Developmental Biology March 25, 2026
and 13 more in the library
Cites 18
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate British Journal of Pharmacology June 1, 1983
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) CNS Neuroscience & Therapeutics April 10, 2013
and 13 more in the library