ArticleAnesthesiology2014
(R,S)-Ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin function.
Article in Anesthesiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
65 citing papers in PubMed, 1 synthesis or guideline pooled it, 113 citations in OpenAlex.
- Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review.European journal of clinical pharmacology · 2021Pooled it
- Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial.Nature medicine · 2024Trial
- Ketamine metabolites, clinical response, and gamma power in a randomized, placebo-controlled, crossover trial for treatment-resistant major depression.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2020Trial
- Ketamine metabolite pilot study in a suicidal depression trial.Journal of psychiatric research · 2019Trial
- d-Serine is a potential biomarker for clinical response in treatment of post-traumatic stress disorder using (R,S)-ketamine infusion and TIMBER psychotherapy: A pilot study.Biochimica et biophysica acta. Proteins and proteomics · 2018Trial
- D-serine plasma concentration is a potential biomarker of (R,S)-ketamine antidepressant response in subjects with treatment-resistant depression.Psychopharmacology · 2015Trial
- The effects of low-dose ketamine and (2R,6R)-Hydroxynorketamine on affective behaviors associated with protracted oxycodone withdrawal.Psychopharmacology · 2026Article
- Mechanism-guided identification of antidepressant G protein-coupled receptor drug targets.Cell · 2026Article
- Cortical Mechanisms Contributing to Ketamine-Induced Dissociation.The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry · 2026Review
- A single S-ketamine injection enhances mTOR signaling in rat skeletal muscle.Journal of muscle research and cell motility · 2026Article
- A Novel Tertiary Carbamate Prodrug Strategy to Overcome Metabolic Barriers in Oral Ketamine Delivery.ChemMedChem · 2026Article
- Ketamine enantiomers and the gut microbiota: mechanisms, clinical implications, and future directions.Molecular biology reports · 2025Review
- Ketamine-From an Anesthetic to a Psychiatric Drug: Mechanisms of Action, Clinical Applications and Potential Risks.Molecules (Basel, Switzerland) · 2025Review
- Personalized use of ketamine and esketamine for treatment-resistant depression.Translational psychiatry · 2024Review
- The ketamine metabolite (2R,6R)-hydroxynorketamine rescues hippocampal mRNA translation, synaptic plasticity and memory in mouse models of Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- Pathology of pain and its implications for therapeutic interventions.Signal transduction and targeted therapy · 2024Review
- Ketamine in Substance Use Disorder Treatment: A Narrative Review.Alpha psychiatry · 2024Review
- Antidepressants enter cells, organelles, and membranes.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Review
- Article
- Narrative Review: Low-Dose Ketamine for Pain Management.Journal of clinical medicine · 2023Review
5 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors at 1 institution in 3 countries.
Funding
Abstract
backgroundSubanesthetic doses of (R,S)-ketamine are used in the treatment of neuropathic pain and depression. In the rat, the antidepressant effects of (R,S)-ketamine are associated with increased activity and function of mammalian target of rapamycin (mTOR); however, (R,S)-ketamine is extensively metabolized and the contribution of its metabolites to increased mTOR signaling is unknown.
methodsRats (n = 3 per time point) were given (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine and their effect on the mTOR pathway determined after 20, 30, and 60 min. PC-12 pheochromocytoma cells (n = 3 per experiment) were treated with escalating concentrations of each compound and the impact on the mTOR pathway was determined.
resultsThe phosphorylation of mTOR and its downstream targets was significantly increased in rat prefrontal cortex tissue by more than ~2.5-, ~25-, and ~2-fold, respectively, in response to a 60-min postadministration of (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine (P < 0.05, ANOVA analysis). In PC-12 pheochromocytoma cells, the test compounds activated the mTOR pathway in a concentration-dependent manner, which resulted in a significantly higher expression of serine racemase with ~2-fold increases at 0.05 nM (2S,6S)-hydroxynorketamine, 10 nM (R,S)-norketamine, and 1,000 nM (R,S)-ketamine. The potency of the effect reflected antagonistic activity of the test compounds at the α7-nicotinic acetylcholine receptor.
conclusionsThe data demonstrate that (R,S)-norketamine and (2S,6S)-hydroxynorketamine have potent pharmacological activity both in vitro and in vivo and contribute to the molecular effects produced by subanesthetic doses of (R,S)-ketamine. The results suggest that the determination of the mechanisms underlying the antidepressant and analgesic effects of (R,S)-ketamine requires a full study of the parent compound and its metabolites.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.