ArticleMolecular psychiatry2021
Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability.
Article in Molecular psychiatry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 135 papers, 5 of them syntheses 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.
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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.
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Who cites it
135 citing papers in PubMed, 5 syntheses or guidelines pooled it, 251 citations in OpenAlex.
- Is the antidepressant efficacy of ketamine and esketamine mediated via opioid mechanisms?European psychiatry : the journal of the Association of European Psychiatrists · 2026Pooled it
- Efficacy and safety of esketamine for sedation during colonoscopy: A systematic review and Meta-analysis of randomized controlled trials.European journal of clinical pharmacology · 2026Pooled it
- Clinical trials since 2020 of rapid anti-suicidal ideation effects of ketamine and its enantiomers: a systematic review.Translational psychiatry · 2025Pooled it
- Efficacy and safety of racemic ketamine and esketamine for depression: a systematic review and meta-analysis.Expert opinion on drug safety · 2022Pooled it
- Ketamine and other glutamate receptor modulators for depression in adults with bipolar disorder.The Cochrane database of systematic reviews · 2021Pooled it
- Effect of naltrexone pretreatment on ketamine-induced glutamatergic activity and symptoms of depression: a randomized crossover study.Nature medicine · 2025Trial
- Effect of intraoperative low-dose esketamine infusion on postoperative sleep disturbance after laparoscopic cholecystectomy: a randomized clinical trial.BMC anesthesiology · 2025Trial
- Compare the Effects of 0 mg/kg, 0.1 mg/kg, 0.3 mg/kg and 0.5 mg/kg Esketamine on Emergence Agitation After Tonsillectomy and Adenoidectomy in Children: A Randomized Control Trial.Drug design, development and therapy · 2025Trial
- Effect of Esketamine on Perioperative Inflammatory Factors and Postoperative Analgesic Outcomes in Patients with Obstructive Sleep Apnea Syndrome: A Randomized Controlled Trial.Drug design, development and therapy · 2025Trial
- Feasibility of Closed-Loop TCI Based on New EEG Baseline in the Presence of Low Dose of Esketamine: A Randomized Controlled Equivalence Trial.Drug design, development and therapy · 2025Trial
- Efficacy and safety of esketamine combined with propofol for curative endoscopic resection in colorectum: a prospective, randomized controlled trial.BMC anesthesiology · 2024Trial
- Perioperative Adjunctive Esketamine for Postpartum Depression Among Women Undergoing Elective Cesarean Delivery: A Randomized Clinical Trial.JAMA network open · 2024Trial
- The effect of esketamine combined with propofol-induced general anesthesia on cerebral blood flow velocity: a randomized clinical trial.BMC anesthesiology · 2024Trial
- Effect of Continuous Infusion of Different Doses of Esketamine on the Bispectral Index During Sevoflurane Anesthesia: A Randomized Controlled Trial.Drug design, development and therapy · 2024Trial
- Effect of Low-Dose Esketamine on Postoperative Delirium in Elderly Patients Undergoing Total Hip or Knee Arthroplasty: A Randomized Controlled Trial.Drug design, development and therapy · 2024Trial
- Effect of Intraoperative Esketamine Infusion on Postoperative Sleep Disturbance After Gynecological Laparoscopy: A Randomized Clinical Trial.JAMA network open · 2022Trial
- κ-Opioid Receptor Plasma Levels Are Associated With Sex and Diagnosis of Major Depressive Disorder But Not Response to Ketamine.Journal of clinical psychopharmacologyTrial
- Is (S)-norketamine an active mediator of esketamine's antidepressant effects?Molecular psychiatry · 2026Article
- Molecular snapshots confirm ketamine's opioid nature.Nature structural & molecular biology · 2026Article
- Structural basis of opioid receptor activation by PCP and ketamine.Nature structural & molecular biology · 2026Article
75 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
Abstract
Ketamine, a racemic mixture of (S)-ketamine and (R)-ketamine enantiomers, has been used as an anesthetic, analgesic and more recently, as an antidepressant. However, ketamine has known abuse liability (the tendency of a drug to be used in non-medical situations due to its psychoactive effects), which raises concerns for its therapeutic use. (S)-ketamine was recently approved by the United States' FDA for treatment-resistant depression. Recent studies showed that (R)-ketamine has greater efficacy than (S)-ketamine in preclinical models of depression, but its clinical antidepressant efficacy has not been established. The behavioral effects of racemic ketamine have been studied extensively in preclinical models predictive of abuse liability in humans (self-administration and conditioned place preference [CPP]). In contrast, the behavioral effects of each enantiomer in these models are unknown. We show here that in the intravenous drug self-administration model, the gold standard procedure to assess potential abuse liability of drugs in humans, rats self-administered (S)-ketamine but not (R)-ketamine. Subanesthetic, antidepressant-like doses of (S)-ketamine, but not of (R)-ketamine, induced locomotor activity (in an opioid receptor-dependent manner), induced psychomotor sensitization, induced CPP in mice, and selectively increased metabolic activity and dopamine tone in medial prefrontal cortex (mPFC) of rats. Pharmacological screening across thousands of human proteins and at biological targets known to interact with ketamine yielded divergent binding and functional enantiomer profiles, including selective mu and kappa opioid receptor activation by (S)-ketamine in mPFC. Our results demonstrate divergence in the pharmacological, functional, and behavioral effects of ketamine enantiomers, and suggest that racemic ketamine's abuse liability in humans is primarily due to the pharmacological effects of its (S)-enantiomer.
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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.