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Ketamine

A dissociative anesthetic with rapid-acting antidepressant effects, now an approved treatment for treatment-resistant depression.

State of the evidence

Synthesized

Synthesized from 25 studies in the library · AI-generated, grounded in the abstracts below

Found by searching the library for Ketamine, racemic ketamine, arketamine, R-ketamine, then ranked by relevance.

Research indicates that ketamine and its enantiomer esketamine produce rapid antidepressant effects, including reductions in suicidal ideation, with response rates around 64% versus 28% for midazolam at 24 hours in treatment-resistant depression. Effects are consistent across multiple RCTs and meta-analyses, though durability varies and long-term safety, especially in comorbid substance use, remains a concern. The main caveat is that many studies are short-term, and evidence for some populations (e.g., postpartum depression) is low quality.

Evidence by study

Direction is which way each study's own result points, not our rating of the study.

What the directions mean
Supports:
the study found the intervention worked, or its hypothesis held.
Opposes:
it found the opposite, no benefit or a harm.
No effect:
no significant difference either way.
Mixed:
effects in both directions within the same study.
Unclear:
the abstract does not report a direction.
Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans 1994
Supports

Ketamine produced schizophrenia-like and dissociative symptoms and cognitive deficits in healthy subjects, supporting its role as a model for psychosis.

randomized controlled trial Sample size: 19

mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists 2010
Supports

Ketamine rapidly activated mTOR signaling, increased synaptic proteins and spine synapses in the prefrontal cortex, and blocking mTOR prevented its antidepressant-like effects in rats.

observational study

Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex 1997
Supports

Low-dose ketamine increased glutamate and dopamine release in the rat prefrontal cortex via non-NMDA receptors, contributing to cognitive impairment.

dose-response study with microdialysis and behavioral testing

NMDAR inhibition-independent antidepressant actions of ketamine metabolites 2016
Supports

The (2R,6R)-HNK metabolite of ketamine exerted antidepressant-related actions in mice independently of NMDAR inhibition but through AMPAR activation, and lacked ketamine-related side effects.

preclinical study

The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate 1983
Supports

Ketamine and phencyclidine selectively blocked N-methyl-aspartate-induced excitation of spinal neurons, suggesting this mechanism contributes to their anesthetic and analgesic properties.

experimental study

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms 2018
Supports

Ketamine's therapeutic effects involve multiple pharmacological targets beyond NMDA receptors, and its metabolites, especially hydroxynorketamine, may have antidepressant efficacy in preclinical studies.

review

Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial 2013
Supports

Ketamine produced greater improvement in depression severity than midazolam 24 hours after a single infusion, with a 7.95-point lower MADRS score and a 64% response rate versus 28%.

randomized controlled trial Sample size: 73

Mechanisms of Ketamine Action as an Antidepressant 2018
Supports

Ketamine's antidepressant actions likely involve multiple complementary molecular mechanisms that converge on sustained strengthening of excitatory synapses.

review

Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study 2019
Supports

Esketamine nasal spray plus a newly initiated antidepressant produced a significantly greater reduction in depression severity at day 28 compared with antidepressant plus placebo nasal spray.

phase 3, double-blind, active-controlled, multicenter randomized controlled trial Sample size: 227

Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression 2019
Supports

Continuing esketamine nasal spray plus an oral antidepressant reduced the risk of relapse by 51% among stable remitters and by 70% among stable responders, compared with switching to placebo.

phase 3, multicenter, double-blind, randomized withdrawal study Sample size: 297

Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression 2017
Supports

Intranasal esketamine produced a rapid, dose-related antidepressant effect in treatment-resistant depression, with response appearing to persist for more than 2 months at a lower dosing frequency.

phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study Sample size: 67

Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation 2021
Supports

Ketamine and esketamine are effective rapid-onset treatments for treatment-resistant depression, but safety, tolerability, and implementation guidance remain key considerations.

review

Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) 2013
Supports

Ketamine is a safe anesthetic with potent analgesic and antidepressive effects, acting primarily through NMDA receptor antagonism, though chronic use is linked to cognitive disturbances and potential long-term risks.

review

The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis 2017
Supports

Ketamine rapidly reduced suicidal ideation for up to one week, with moderate-to-large effect sizes, and effects were partially independent of mood improvement.

systematic review and individual participant data meta-analysis Sample size: 167

Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study 2018
Mixed

Intranasal esketamine plus standard care led to significantly greater improvement in depressive symptoms at 4 and 24 hours compared with placebo, but not at day 25, and did not reduce clinician-rated suicide risk.

randomized controlled trial Sample size: 68

Trauma re-experiencing episodes during esketamine treatment in patients with treatment-resistant depression and comorbid PTSD: a retrospective case series. 2026
Mixed

Trauma re-experiencing episodes during esketamine treatment resolved in most patients as sessions continued, but in 27.3% treatment was stopped; when continued, favorable outcomes for depression and PTSD were observed.

retrospective observational study Sample size: 22

Development and validation of a short-form (6-item) version of the clinician-administered dissociative states scale (CADSS-SF). 2026
Unclear

A 6-item short form of the CADSS, consisting of derealization and depersonalization items, showed excellent psychometric properties for rapid assessment of drug-induced dissociation.

scale development and validation Sample size: 309

Effects of sub-anesthetic doses of esketamine on immune function and postoperative negative emotions in acoustic neuroma patients: a randomized clinical trial. 2026
Supports

Perioperative sub-anesthetic esketamine reduced postoperative depression, anxiety, and sleep disturbances after acoustic neuroma surgery, but did not significantly affect early immune function or acute postoperative analgesia.

randomized controlled trial Sample size: 77

Increased morning cortisol after ketamine treatment for suicidal depression: Exploratory report from a randomized trial. 2026
Mixed

Ketamine treatment produced a significant increase in waking cortisol 24 hours after infusion, but the correlation between this cortisol increase and reduction in suicidal ideation was small to medium and not statistically significant.

randomized controlled trial Sample size: 61

Prescribing bias and adverse outcomes of esketamine in major depression comorbid substance. 2026
Opposes

Esketamine users with comorbid substance use disorder had higher risks of self-harm, suicide attempt, emergency visits, hospitalization, and mortality compared to esketamine users without substance use disorder.

retrospective cohort study Sample size: 30670

Comparing transcranial magnetic stimulation and esketamine treatment response trajectories in resistant depression. 2026
Supports

Intranasal esketamine was associated with faster antidepressant and anti-suicidal response than rTMS, but overall efficacy at 90 days was similar.

retrospective analysis Sample size: 372

Effects of ketamine on sleep and circadian rhythmicity in major depressive disorder and bipolar disorder: A systematic review. 2026
Supports

Ketamine treatment is associated with favorable effects on subjective sleep quality, and baseline sleep disturbances and early sleep improvements may predict antidepressant response.

systematic review Sample size: 1694

Olfactory bulb circuits drive ketamine-enhanced high-frequency oscillations via kainate and GABAergic mechanisms. 2026
Supports

Ketamine reorganizes fast oscillations across cortical networks by differentially affecting gamma and high-frequency oscillations through dissociable circuit mechanisms involving kainate and GABA-A receptors in the olfactory bulb.

experimental study with simultaneous multiregion recordings

Ketamine and esketamine for the prevention of postpartum depression: A systematic review and network meta-analysis, with an integrated evidence synthesis. 2026
Supports

Ketamine and esketamine treatment may be associated with a reduced risk of developing postpartum depression, but the quality of the data was low to very low.

systematic review with network meta-analysis and narrative synthesis Sample size: 36

Ketamine-related neural changes in treatment-resistant depression: A multimodal synthesis of fMRI and PET studies. 2026
Supports

Ketamine-related effects were frequently reported in subcortical regions, with distributed and context-dependent effects across cortical systems, and network-level summaries suggested involvement of default-mode, ventral attention, and visual systems.

systematic review with multimodal synthesis

Points of agreement

  • Ketamine and esketamine produce rapid antidepressant effects, often within hours to days, in treatment-resistant depression.
  • Ketamine reduces suicidal ideation rapidly, with effects lasting up to one week.
  • Ketamine's antidepressant mechanisms involve NMDA receptor antagonism and downstream synaptic plasticity pathways, including mTOR and AMPA receptors.
  • Esketamine nasal spray plus an oral antidepressant is more effective than antidepressant alone for treatment-resistant depression.
  • Ketamine is associated with dissociative and psychotomimetic side effects.

Conflicts

  • One RCT found esketamine did not reduce clinician-rated suicide risk despite improving depressive symptoms, while a meta-analysis found significant effects on suicidal ideation.
  • A retrospective cohort found esketamine users with comorbid substance use disorder had worse outcomes, whereas other studies did not report such risks.
  • Some studies suggest ketamine's antidepressant effects are independent of NMDA receptor inhibition, while others emphasize NMDA receptor antagonism as the primary mechanism.

Gaps

  • Long-term durability of antidepressant effects beyond a few weeks is not well established.
  • Safety and efficacy in special populations (e.g., postpartum women, comorbid PTSD, substance use disorder) require more research.
  • Optimal dosing, route of administration, and treatment frequency are not fully standardized.
  • Objective biomarkers predicting response (e.g., sleep, cortisol, neuroimaging) are preliminary and need replication.
  • Comparative effectiveness against other treatments (e.g., rTMS) is based on limited retrospective data.
Browse these studies in the library
How we analyze this

This synthesis reads the 15 most-cited and 10 most recent studies whose primary subject is Ketamine, up to 25 in all. The most-cited set anchors the established evidence, and the recent set surfaces work that is too new to have gathered citations yet.

A study qualifies only when Ketamine or a known alias appears in its title or keywords, so broad reviews that mention it only in passing are left out. Each study is read from its abstract, strongest evidence first, and the summary reports the direction of the results along with any conflicts and gaps.

Ask your own question in the Research Synthesis Tool

Latest monthly recap: August 2026 →

3,492 articles · 1,534 from the last two years · 4,112,686 participants across 1,363 studies reporting sample size

Common study designs

review 709 systematic review 196 experimental study 232 observational cohort 176 randomized controlled trial 245

Research

Synthesize the evidence → Search all →

Correlation of Ketamine and Classic Psychedelics with Pain-Related Neural Connectivity: A Scoping Review of Clinical Experiments on a Potential Therapeutic Target Concerning Ketamine and Classical Psychedelics Administration for Pain Relief

Psychedelic Medicine September 14, 2026 Vasileios Chytas, Georgios Tsimploulis, Dimitrios Chytas

Purpose: Ketamine and classic psychedelics have recently gained increased scientific interest regarding their role in pain management, while there is evidence that pain induces neural connectivity changes. We performed a scoping review to investigate the correlation of ketamine and classic psychedelics with pain-related neural connectivity, aiming to find potential therapeutic targets for these...

DOI: 10.1177/28314425261489067 (opens in new tab)

EFFECTS OF KETAMINE AND ESKETAMINE ON SUICIDAL IDEATION WITHIN THE FIRST 24 HOURS IN ADULTS WITH DEPRESSIVE DISORDERS: VARIABILITY IN CLINICAL FINDINGS AND INTERPRETATIVE CHALLENGES - A NARRATIVE REVIEW

International Journal of Innovative Technologies in Social Science September 11, 2026 Marta Borkowska, Małgorzata Witaszczyk, Alicja Sołtan et al.

Background: Ketamine and esketamine have been studied as rapid-acting interventions in adults with depressive disorders and suicidal ideation, but findings vary across populations, settings, comparators, routes, and outcome measures. Aim: To examine their effects on suicidal ideation within the first 24 hours and to identify factors contributing to variability across studies. Methods: This...

DOI: 10.31435/ijitss.3(51).2026.6636 (opens in new tab)

Chronic sensing during subcallosal cingulate deep brain stimulation captures ketamine-associated changes in major depressive disorder

medRxiv September 11, 2026 Srdjan Sumarac, Tristan Lawson, Leonardo Favi Bocca et al. preprint

Ketamine and subcallosal cingulate (SCC) deep brain stimulation (DBS) have each shown antidepressant effects in treatment-resistant depression, yet how ketamine modulates SCC physiology during chronic stimulation remains poorly understood. We analyzed 5,907 hours of bilateral SCC sensing, 485 participant-triggered recordings across 193 days, 47 ketamine dosing episodes, and an in-clinic...

DOI: 10.64898/2026.09.08.26362080 (opens in new tab)

716. A randomised-controlled feasibility study of ketamine for the treatment of depression with anorexia nervosa

International Journal of Neuropsychopharmacology September 9, 2026 J Keeler, H Himmerich, J Treasure et al.

Abstract Background Approximately a third of people with anorexia nervosa (AN) develop a severe and enduring form of the illness, which is often accompanied by depression. This can be a key barrier to recovery. Anti-depressant medications are less effective in treating depression in patients with acute AN, thus new pharmacological treatment options are needed. Ketamine is currently used for...

DOI: 10.1093/ijnp/pyag040.488 (opens in new tab)

301. Multimodal MRI signatures predict ketamine antidepressant response in treatment-resistant depression: a machine-learning analysis of independent clinical trials

International Journal of Neuropsychopharmacology September 9, 2026 P-C Wu, T-P Su, C-T Li et al.

Abstract Background While ketamine produces rapid antidepressant effects in treatment-resistant depression (TRD), response heterogeneity necessitates robust biomarkers to optimize clinical decision-making. Aims & Objectives To validate a machine-learning (ML) framework for predicting ketamine antidepressant response from pre-treatment multimodal neuroimaging features across independent...

DOI: 10.1093/ijnp/pyag040.042 (opens in new tab)

286. Restoration by ketamine metabolites of cognitive and affective prosocial behaviors in a mouse model of depression

International Journal of Neuropsychopharmacology September 9, 2026 R Yokoyama, M Matsumi, S Asano et al.

Abstract Background The execution of prosocial behaviors requires the ability to accurately understand and infer others’ affective states. Impairments in prosocial functioning have been shown to be associated with the pathology of several psychiatric disorders. In particular, individuals with depression exhibit reduced cognitive and affective responses to others’ emotions. These impairments may...

DOI: 10.1093/ijnp/pyag040.230 (opens in new tab)

507. Ketamine use disorder following intranasal esketamine for treatment-resistant depression: a case report and literature review

International Journal of Neuropsychopharmacology September 9, 2026 Y-H Chan, H-M Chang

Abstract Background Esketamine, the S-enantiomer of ketamine, is an NMDA receptor antagonist approved for treatment-resistant depression (TRD). Although regulated clinical trials suggest a low risk of misuse, concerns remain that esketamine exposure may facilitate transition to ketamine dependence, particularly in East Asia where illicit ketamine is widely available. Aims & Objectives To...

DOI: 10.1093/ijnp/pyag040.332 (opens in new tab)

Ketamine-Induced Dissociation as an Ethical Signal, Not a Side Effect: Context as the Determinant of Clinical Duties Under Beneficence and Non-maleficence

HEC Forum September 9, 2026 Gun Moon, Jack Noto, Zachary Shuler et al.

Ketamine has emerged as an important intervention in contemporary psychiatry, yet its acute dissociative effects remain ethically under-theorized. Clinical approaches often frame dissociation as either a liability to minimize or a therapeutic feature to promote, but both views oversimplify a context-dependent phenomenon. We propose that ketamine-induced dissociation is better understood as an...

DOI: 10.1007/s10730-026-09611-x (opens in new tab) Full text (opens in new tab)

47. Early improvement predicts subsequent antidepressant response to intravenous ketamine

International Journal of Neuropsychopharmacology September 9, 2026 Omer A. Syed, Fahad Alam, Peter Giacobbe

Abstract Background Major depressive disorder (MDD) is a debilitating medical condition that places a significant psychological, social, and financial burden on the individuals and families of those affected. However, a third of individuals with MDD do not respond to standard treatments – diagnosed with treatment-resistant depression (TRD). Repeated dosing of intravenous (IV) ketamine has...

DOI: 10.1093/ijnp/pyag040.176 (opens in new tab)

669. Imaging reward circuitry to guide precision ketamine treatment in treatment-resistant depression

International Journal of Neuropsychopharmacology September 9, 2026 C Zarate

Abstract Background Ketamine produces rapid antidepressant and anti-anhedonic effects in treatment-resistant depression, but response is heterogeneous and mechanisms at the circuit level remain incompletely defined. Convergent imaging work implicates anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), and reward-related networks as key loci for ketamine’s therapeutic and...

DOI: 10.1093/ijnp/pyag040.451 (opens in new tab)

Clinical trials

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