Nature
April 24, 2016
P. Zanos, R. Moaddel, Patrick J. Morris et al.
1,602 citations
A metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), produces rapid and sustained antidepressant-like effects in mice without the side effects associated with ketamine itself. These effects do not rely on blocking NMDA receptors but instead involve early and ongoing activation of AMPA receptors. This finding points to a new mechanism for developing faster-acting antidepressants with fewer unwanted effects.
Pharmacological Reviews
June 26, 2018
P. Zanos, R. Moaddel, Patrick J. Morris et al.
1,272 citations
Ketamine, in clinical use since 1970, is best known as a dissociative anesthetic but also has analgesic, anti-inflammatory, and antidepressant effects. This review covers its therapeutic uses by dose, route, and time course, along with side effects from short-term or prolonged exposure and recreational use. Ketamine is rapidly metabolized into norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK). While anesthetic and analgesic actions stem from inhibition of N-methyl-D-aspartate receptors, other targets include GABA, dopamine, serotonin, sigma, opioid, and cholinergic receptors, plus ion channels. HNK metabolites show antidepressant efficacy in preclinical studies, suggesting broader clinical relevance. Understanding these targets may help develop new drugs with ketamine's benefits but fewer side effects.
Molecular Psychiatry
April 15, 2021
J. Bonaventura, Sherry Lam, Meghan L. Carlton et al.
266 citations
Ketamine, a mixture of two mirror-image molecules called (S)-ketamine and (R)-ketamine, is used as an anesthetic and, more recently, as an antidepressant, but it carries a risk of abuse. The (S)-form is FDA-approved for treatment-resistant depression, while the (R)-form shows promise in animal models but has not been tested in people. In rats and mice, (S)-ketamine, but not (R)-ketamine, produced behaviors linked to abuse potential, such as self-administration, increased movement, and preference for places where the drug was given. (S)-ketamine also boosted activity and dopamine levels in a brain region called the medial prefrontal cortex, partly by activating opioid receptors. These findings indicate that the abuse liability of racemic ketamine stems mainly from its (S)-enantiomer.
Proceedings of the National Academy of Sciences of the United States of America
February 22, 2019
E. Lumsden, Timothy A. Troppoli, S. J. Myers et al.
159 citations
A single low dose of the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) produces rapid antidepressant-like effects in mice without blocking NMDA glutamate receptors (NMDARs), unlike ketamine itself. At a dose of 10 mg/kg, which triggers antidepressant-related behavioral and cellular responses, (2R,6R)-HNK reaches hippocampal concentrations of about 8 µM—far below the levels needed to inhibit NMDARs in vitro. The dose required to prevent NMDA-induced lethality was 228 mg/kg for (2R,6R)-HNK versus 6.4 mg/kg for ketamine, indicating weak NMDAR inhibition. These findings suggest that (2R,6R)-HNK's antidepressant effects occur through alternative molecular targets, potentially avoiding ketamine's adverse effects such as dissociation and abuse potential.
Proceedings of the National Academy of Sciences
March 13, 2019
Panos Zanos, Jaclyn N. Highland, Brent W. Stewart et al.
153 citations
A single subanesthetic dose of ketamine produces rapid (within hours) and sustained antidepressant effects, unlike standard antidepressants that take months and fail in about 30% of patients. The ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a rapid-acting antidepressant candidate with fewer adverse effects. Using behavioral, genetic, pharmacological approaches and EEG measurements, the study found that antidepressant-relevant actions of (2R,6R)-HNK involve metabotropic glutamate receptor subtype 2 (mGlu2) signaling and identified high-frequency EEG oscillations as a marker of rapid antidepressant responses. The findings suggest clinical trials combining subtherapeutic doses of mGlu2 receptor inhibitors with ketamine or (2R,6R)-HNK for depression treatment.
Clinical pharmacology and therapeutics
November 1, 2024
Shruti M Raja, Jeffrey T Guptill, Michelle Mack et al.
34 citations
A metabolite of ketamine, (2R,6R)-hydroxynorketamine (RR-HNK), was tested in a Phase 1 study in healthy volunteers for safety and tolerability. RR-HNK lacks anesthetic and dissociative effects but retains antidepressant and analgesic activity in preclinical models. In single doses from 0.1 to 4 mg/kg and multiple doses of 1 and 2 mg/kg given intravenously over 40 minutes, RR-HNK showed minimal adverse events and no serious adverse events. It did not cause dissociation or sedation. Drug levels in the body increased proportionally with dose, and cerebrospinal fluid analysis confirmed it reached the central nervous system. Some participants showed increases in gamma brain wave activity at lower to mid doses. These results support moving to Phase 2 trials.
Translational Psychiatry
May 2, 2022
Ruin Moaddel, Panos Zanos, Cristan A Farmer et al.
32 citations
Subanesthetic-dose ketamine produces rapid antidepressant effects, but its mechanism remains unclear. A targeted metabolomic analysis of plasma and cerebrospinal fluid from nine healthy volunteers receiving a 40-minute ketamine infusion (0.5 mg/kg), along with parallel analysis in mice given ketamine, (2R,6R)-hydroxynorketamine (HNK), or saline, found that both ketamine and HNK affect multiple inflammatory pathways. Some changes were unique to humans or mice, suggesting species differences. Consistently implicated mechanisms across both species and sample types include LAT1, IDO1, NAD+, nitric oxide signaling, and the sphingolipid rheostat.
The Journal of neuroscience : the official journal of the Society for Neuroscience
February 3, 2026
Kyle A Brown, Patrick J. Morris, Craig J. Thomas et al.
The antidepressant effects of ketamine arise from its metabolite (2R,6R)-hydroxynorketamine (2R6R), not from ketamine itself. In mouse hippocampal slices, 2R6R rapidly strengthens synapses and induces long-lasting metaplasticity—a form of plasticity that primes synapses for future change—whereas ketamine alone does not. This rapid and sustained plasticity requires mTOR signaling and can be mimicked by activating mTOR. The sustained phase also depends on IP3 receptors, L-type calcium channels, and delayed BDNF/TrkB signaling, but not on new protein synthesis. The findings outline a sequence of molecular events underlying 2R6R's synaptic actions, with implications for developing rapid-acting antidepressants and understanding activity-dependent plasticity.
British Journal of Pharmacology
July 1, 2019
Panos Zanos, Jaclyn N. Highland, Xin Liu et al.
In mice, (R)-ketamine's metabolism to (2R,6R)-hydroxynorketamine (HNK) enhances its antidepressant-relevant actions. A deuterated form of (R)-ketamine that blocks this metabolism had less potency in antidepressant-sensitive behavioral tests, while (2R,6R)-HNK itself produced dose-dependent sustained antidepressant effects. However, (R)-ketamine also caused NMDA receptor-mediated adverse effects—including locomotor stimulation, conditioned-place preference, prepulse inhibition deficits, and motor incoordination—at sub-anaesthetic doses, with about half the potency of racemic ketamine. These findings indicate that while antidepressant-relevant effects occur at lower doses, there is a potential risk for sensory dissociation and abuse liability at higher doses.