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.
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.