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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, esketamine, arketamine, then ranked by relevance.

Ketamine and its enantiomer esketamine produce rapid (within hours to days) and clinically meaningful antidepressant effects in treatment-resistant depression, with response rates of 64% at 24 hours in one large RCT and sustained benefits in relapse prevention over weeks. The evidence is strongest for short-term efficacy, but durability beyond a few weeks is less established, and concerns remain about dissociative side effects, abuse potential, and the need for controlled administration settings.

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
Unclear

Ketamine produced schizophrenia-like symptoms, perceptual changes, and cognitive impairments in healthy subjects, establishing its psychotomimetic profile.

RCT 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 density in prefrontal cortex, and these effects were necessary for antidepressant-like behavior in rats.

preclinical

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 prefrontal cortex via AMPA/kainate receptors, and blocking these receptors prevented ketamine-induced cognitive impairment.

preclinical

NMDAR inhibition-independent antidepressant actions of ketamine metabolites 2016
Supports

The ketamine metabolite (2R,6R)-HNK produced antidepressant-like effects in mice independent of NMDA receptor inhibition but dependent on AMPA receptor activation, and lacked ketamine's side effects.

preclinical

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

Ketamine selectively blocked NMDA receptor-mediated excitation of spinal neurons, suggesting this mechanism contributes to its anesthetic/analgesic properties.

preclinical

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

Ketamine has analgesic, anti-inflammatory, and antidepressant actions; its metabolites, especially HNK, may have broader clinical relevance than previously thought.

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 at 24 hours than midazolam (MADRS difference 7.95 points), with response rates of 64% vs. 28%.

RCT Sample size: 73

Mechanisms of Ketamine Action as an Antidepressant 2018
Supports

Multiple mechanisms are proposed for ketamine's antidepressant action, including NMDA receptor inhibition, AMPA receptor activation, and downstream synaptic plasticity via BDNF, mTOR, and eEF2.

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 new antidepressant was superior to antidepressant plus placebo at day 28 (MADRS difference -4.0 points) in treatment-resistant depression.

RCT Sample size: 227

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

Continued esketamine nasal spray plus oral antidepressant delayed relapse of depressive symptoms compared to switching to placebo nasal spray in patients with treatment-resistant depression.

RCT Sample size: 297

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

Intranasal esketamine (28, 56, or 84 mg) adjunctive to oral antidepressant showed dose-related antidepressant effects over 2 weeks in treatment-resistant depression.

RCT 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

International experts concluded that ketamine and esketamine are effective rapid-onset treatments for treatment-resistant depression, but concerns about safety, tolerability, and implementation remain.

review

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

Ketamine is a safe anesthetic with analgesic and antidepressant properties, but chronic use is associated with cognitive disturbances and frontal white matter abnormalities.

review

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

A single dose of ketamine rapidly reduced suicidal ideation within one day, with moderate-to-large effect sizes (Cohen's d=0.51-0.85), and effects remained significant after adjusting for depression severity.

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
Supports

Intranasal esketamine (84 mg) plus standard care improved depression and suicidal ideation at 4 and 24 hours compared to placebo, but not at day 25.

RCT 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 occurred during esketamine sessions in 22 patients; in 72.7% episodes resolved with continued treatment, but 27.3% discontinued due to these episodes.

observational 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 Clinician-Administered Dissociative States Scale was developed and validated using nitrous oxide-induced dissociation, showing strong correlation with the full scale.

observational Sample size: 229

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

Ketamine treatment increased morning cortisol awakening response at 24 hours, and this increase showed a small, nonsignificant correlation with reduction in suicidal ideation.

RCT Sample size: 61

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

Esketamine users had higher risks of comorbid substance use disorders compared to antidepressant-only or rTMS patients, and comorbid SUD was associated with higher risks of self-harm, suicide attempt, and hospitalization.

observational Sample size: 30670

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

Esketamine showed faster time to response (median 36 vs. 49 days) and earlier improvement in suicidal ideation (median 9 vs. 26 days) compared to rTMS, but cumulative response rates were similar by 90 days.

observational Sample size: 372

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

Ketamine was 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
Unclear

Ketamine enhanced high-frequency oscillations (130-180 Hz) in olfactory bulb via kainate and GABA-A receptor mechanisms, which propagated to ventral striatum and prefrontal cortex.

preclinical

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 were well tolerated and may reduce risk of postpartum depression, but the quality of evidence was low to very low.

systematic review and network meta-analysis Sample size: 36

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

Ketamine-related neural changes were frequently reported in subcortical regions and default-mode, ventral attention, and visual networks, but results were heterogeneous across imaging modalities and task contexts.

systematic review

Clinical correlates of anhedonia non-response to ketamine in treatment-resistant depression. 2026
Mixed

47.1% of patients were anhedonia non-responders to ketamine; non-responders had lower prior substance use disorder, fewer depressive episodes, and were more likely to be single.

observational Sample size: 34

Points of agreement

  • Ketamine and esketamine produce rapid (within hours to days) antidepressant effects in treatment-resistant depression.
  • The antidepressant mechanism involves NMDA receptor antagonism, AMPA receptor activation, and downstream synaptic plasticity (e.g., mTOR, BDNF).
  • Ketamine rapidly reduces suicidal ideation, with effects evident within 24 hours.
  • Esketamine nasal spray is effective for relapse prevention in treatment-resistant depression over weeks to months.
  • Dissociative and psychotomimetic side effects are common but generally transient.

Conflicts

  • One study found that ketamine's antidepressant effects may be mediated by its metabolite (2R,6R)-HNK independent of NMDA receptor inhibition, while other studies emphasize NMDA receptor blockade as the primary mechanism.
  • Trauma re-experiencing during esketamine treatment resolved with continued use in most patients but led to discontinuation in a minority, indicating variable tolerability in PTSD-comorbid populations.
  • Esketamine users had higher rates of comorbid substance use disorders compared to other treatments, but this may reflect prescribing bias rather than a causal effect.

Gaps

  • Long-term safety and efficacy data beyond 4-16 weeks are limited.
  • Comparative effectiveness against other treatments (e.g., rTMS, ECT) is understudied.
  • Predictors of response (e.g., anhedonia, sleep disturbances, cortisol levels) require replication in larger samples.
  • Mechanisms of action in humans remain incompletely understood, especially the role of metabolites and circuit-level changes.
  • Data on ketamine use in special populations (e.g., postpartum depression, bipolar disorder, PTSD) are preliminary and low quality.
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: June 2026 →

3,195 articles · 1,466 from the last two years · 4,016,130 participants across 1,267 studies reporting sample size

Common study designs

review 670 systematic review 185 experimental study 226 observational cohort 161 randomized controlled trial 235

Research

Synthesize the evidence → Search all →

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

Journal of Affective Disorders November 1, 2026 Tse-Hwei Choo, Hanga C Galfalvy, John G Keilp et al.

A midazolam-controlled trial of intravenous ketamine for suicidal depressed patients found that ketamine rapidly reduced suicidal ideation within 24 hours. An exploratory analysis measured saliva cortisol awakening response at baseline and 24 hours after infusion. Waking cortisol significantly increased 24 hours after ketamine treatment. The increase in waking cortisol from baseline to post-infusion showed a small to medium, nonsignificant correlation with decreased suicidal ideation. These preliminary results, pending replication, align with evidence that moderate cortisol increases may enhance stress-resilience.

DOI: 10.1016/j.jad.2026.122175 (opens in new tab) Full text (opens in new tab) Depression Ketamine Cortisol Resilience +2

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

Journal of Affective Disorders September 15, 2026 Rutger Boesjes, Claudia Oosterveld, Jeanine Kamphuis et al. 1 citation

Ketamine and its enantiomers show rapid antidepressant effects for major depressive disorder and bipolar disorder, but responses vary widely. This systematic review of 26 studies (1694 participants) found that ketamine treatment is linked to improved subjective sleep quality. Preliminary evidence suggests that baseline sleep disturbances and early sleep improvements may predict antidepressant response. Some studies also indicate beneficial effects on objective sleep and circadian rhythmicity, but this finding is tentative due to few published articles. The authors call for more research on objective circadian measures and potential synergy with chronotherapies.

DOI: 10.1016/j.jad.2026.121915 (opens in new tab) Full text (opens in new tab) Depression Ketamine Major depressive disorder Bipolar disorder +3

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

Neuropharmacology September 15, 2026 Taisiia Prosvirova, Wiktoria Podolecka, Jacek Wróbel et al.

Ketamine rapidly reorganizes fast brain rhythms differently across cortical networks. In freely moving rats, neocortical gamma power increased broadly, while the olfactory bulb showed suppressed gamma alongside robust high-frequency oscillations (HFO; 130-180 Hz). Local blockade of non-NMDA glutamate receptors in the olfactory bulb suppressed ketamine-enhanced HFO in the bulb, ventral striatum, and prefrontal cortex without affecting neocortical gamma, indicating separate circuit mechanisms. Within the bulb, a kainate receptor antagonist markedly reduced HFO, while AMPA receptor blockade had minimal effect. Blocking GABA-A receptors reduced HFO power while increasing gamma power, showing that fast inhibition is necessary for HFO expression. The findings suggest that tonic kainate-dependent depolarization recruits interneurons to generate an inhibitory network rhythm that drives HFO propagation through olfactory-limbic circuits.

DOI: 10.1016/j.neuropharm.2026.111012 (opens in new tab) Full text (opens in new tab) Ketamine Gaba-a receptor Gamma oscillations High-frequency oscillations hfo +3

Simultaneous LC-MS/MS determination of the emerging ketamine analogue 2F-2-oxo-PCPr and related compounds in human hair and application to forensic casework.

Forensic Science International September 1, 2026 Byungsuk Cho, Seonghoon Yeon, Sanghee Woo et al.

A white powder submitted to South Korea's National Forensic Service in early 2025 was identified as 2F-2-oxo-PCPr, a new ketamine analogue with fluorine replacing chlorine and a propyl group replacing the amine methyl group. Because ketamine produces hallucinogenic and dissociative effects by blocking NMDA receptors, this analogue may act similarly. To detect such substances in biological samples, researchers developed and validated a liquid chromatography-tandem mass spectrometry method for simultaneously measuring 2F-2-oxo-PCPr, 2F-2-oxo-PCE, 2F-deschloroketamine, ketamine, and their metabolites in human hair. The method met all validation criteria and was applied to hair from eight individuals suspected of using ketamine-related drugs. This is the first reported single hair-based workflow covering ketamine alongside three fluorinated analogues and their metabolites.

DOI: 10.1016/j.forsciint.2026.113011 (opens in new tab) Full text (opens in new tab) 2f-2-oxo-pcpr Hair analysis Ketamine analogues Lc-ms/ms

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

Journal of Affective Disorders September 1, 2026 Nesreen Sedeek, Carley Rivers, Lucas Williamson et al.

Ketamine's rapid antidepressant effects in treatment-resistant depression are linked to changes in brain activity, but previous studies have been hard to compare due to differences in imaging techniques, analysis methods, and timing. A review combining fMRI and PET studies found that ketamine-related effects commonly appear in subcortical brain regions, with more variable effects in cortical areas like the prefrontal and anterior cingulate cortices. Network-level patterns suggest involvement of the default-mode, ventral attention, and visual systems. These findings are hypothesis-generating and highlight the need for future studies that harmonize methods to directly connect circuit changes to molecular mechanisms and clinical outcomes.

DOI: 10.1016/j.jad.2026.121891 (opens in new tab) Full text (opens in new tab) Ketamine Brain networks Multimodal synthesis PET +2

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

Psychiatry Research September 1, 2026 Isis Lunsky, Gilmar Gutierrez, Xena Wang et al.

Postpartum depression (PPD) is common and harmful if untreated, with few effective prevention strategies. Ketamine and esketamine are rapid-acting antidepressants showing promise for PPD. This review searched five databases for peer-reviewed randomized controlled trials, pilot studies, and observational studies examining ketamine or esketamine for PPD prevention during pregnancy or postpartum, for both cesarean and vaginal deliveries. A network meta-analysis and narrative synthesis were used. Thirty-six studies were identified; five included vaginal delivery, thirty included cesarean section, and one did not specify delivery mode. Results suggested that ketamine and esketamine were well tolerated and may reduce PPD risk. However, data quality was low to very low, so results should be interpreted cautiously. More high-quality studies are needed.

DOI: 10.1016/j.psychres.2026.117221 (opens in new tab) Full text (opens in new tab) Esketamine Perinatal mental health Postpartum depression Psychopharmacology

Clinical correlates of anhedonia non-response to ketamine in treatment-resistant depression.

Journal of Affective Disorders August 15, 2026 Michał Walaszek, Wiesław Jerzy Cubała, Zofia Kachlik et al.

Anhedonia, a core symptom of major depressive disorder linked to poor outcomes, may be reduced by ketamine. In a retrospective analysis of 34 inpatients with treatment-resistant depression receiving short-term ketamine as an add-on to standard care, 16 patients (47.1%) did not respond to treatment, defined as less than a 50% reduction on the Snaith-Hamilton Pleasure Scale. Non-responders were more likely to be single, had fewer lifetime depressive episodes, and lower rates of prior substance use disorder. These factors suggest that psychosocial and demographic characteristics influence anhedonia treatment outcomes, supporting a personalized approach to mood disorder treatment.

DOI: 10.1016/j.jad.2026.121762 (opens in new tab) Full text (opens in new tab) Ketamine Treatment-resistant depression Anhedonia Psychopharmacology

Comparative effectiveness and safety of esketamine versus injectable racemic ketamine and oral antidepressants for major depressive disorder: A population-based target trial emulation.

Journal of Affective Disorders August 1, 2026 Ching-Hua Julie Lee, Yunzhe Qian, Weiqun Yu et al.

Compared with injectable ketamine, esketamine was linked to higher risks of suicidal ideation (24% increase), generalized anxiety disorder (55% increase), insomnia (25% increase), and cardiac arrest (57% increase). Compared with oral antidepressants in treatment-resistant depression, esketamine was associated with lower risks of suicidal ideation (11% decrease), suicide attempt (29% decrease), and generalized anxiety disorder (18% decrease), but a higher risk of cardiac arrest (109% increase). Injectable ketamine showed a more favorable safety and effectiveness profile than esketamine. Head-to-head clinical trials are needed to validate these findings.

DOI: 10.1016/j.jad.2026.121487 (opens in new tab) Full text (opens in new tab) Esketamine Major depressive disorder Treatment-resistant depression Outcomes +1

Role of concomitant benzodiazepines, lithium, and lamotrigine in modulating the antidepressant effects of subcutaneous esketamine in patients with treatment-resistant depressive episodes: A retrospective naturalistic study.

Journal of Affective Disorders August 1, 2026 João Paulo Atidio, Rodrigo Simonini Delfino, Igor Saque Garios et al.

In patients with treatment-resistant depression receiving subcutaneous esketamine over six weeks, depressive symptoms improved significantly, with MADRS scores dropping by an average of 2.82 points per week. Those also taking benzodiazepines had higher depression scores throughout treatment, while lamotrigine and lithium showed no significant effect on outcomes. No medication altered the rate of improvement over time. The findings suggest benzodiazepine use may blunt the antidepressant response to esketamine, but further prospective research is needed.

DOI: 10.1016/j.jad.2026.121721 (opens in new tab) Full text (opens in new tab) Esketamine Treatment-resistant depression Benzodiazepine Lamotrigine +3

Ketamine for Depression in Serious Illness: Evidence, Safety, and Practical Approaches.

Journal of Pain and Symptom Management August 1, 2026 Paul Noufi, Joshua B Borris, Danielle Chammas et al.

Ketamine and esketamine offer rapid antidepressant effects, with intravenous ketamine producing moderate-to-large improvements within 1–24 hours that last one to two weeks, and a number needed to treat of three in the first week. Esketamine nasal spray shows similar early efficacy and is FDA-approved for treatment-resistant depression and major depression with suicidal ideation. Evidence specific to people with serious illnesses is limited to perioperative cancer trials and small open-label studies, showing short-term reductions in depressive symptoms and suicidal ideation but not addressing long-term management. Safety is generally favorable, with transient dissociation, hypertension, and somnolence as common adverse effects. Rigorous psychiatric trials in serious illness are lacking.

DOI: 10.1016/j.jpainsymman.2026.04.604 (opens in new tab) Full text (opens in new tab) Depression Ketamine Palliative care Psychopharmacology +1

Clinical trials

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