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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.

Confidence in the evidence

Moderate-High
  • Multiple double-blind RCTs (e.g., two-site trial with N=73, phase 3 with N=227) consistently show rapid antidepressant effects versus active placebo (midazolam) or standard care.
  • A large phase 3 withdrawal study (N=297) demonstrated relapse prevention over 16 weeks, supporting sustained efficacy.
  • Evidence is limited by short follow-up durations, open-label extensions, and lack of long-term safety data beyond 4 weeks in most trials.
  • Consistency across studies is high for acute response, but heterogeneity in dosing, route (IV vs. intranasal), and patient populations (TRD vs. suicidal ideation) tempers confidence.
How we rate confidence

Confidence reflects the strength of the underlying evidence, not whether the result is favorable. It weighs the number and size of studies, their design (randomized trials count for more than observational or single-case work), how consistently they point the same way, and their risk of bias.

Tiers run from Insufficient to High. High is rare in this field: small, early, or open-label studies land lower even when their direction is encouraging.

Evidence by study

Direction is each study's finding relative to your question: Supports, Opposes, No effect, Mixed, or Unclear.

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

3,152 articles · 1,824 from the last two years · 4,295,200 participants across 1,451 studies reporting sample size

Common study designs

review 551 systematic review 176 experimental study 173 observational cohort 162 randomized controlled trial 402

Research

Synthesize the evidence → Search all →

Treatment of Chronic Fatigue Syndrome (CFS) in Post-SARS-CoV-2 Infection through combined outpatient Neuromodulation Therapy with Repetitive Transcranial Magnetic Stimulation (rTMS) and Ketamine IV Therapy - A Case Series

Chiara Rolle, Mario H W Scheib, Anja Frank et al. • 1 citation preprint

Four patients with post-COVID syndrome and chronic fatigue syndrome were treated with a combination of low-frequency repetitive transcranial magnetic stimulation and ketamine intravenous infusion over two to three weeks. Three patients experienced significant improvement. The authors indicate further research is needed.

DOI: 10.31219/osf.io/qzgc9

Assessing the Impact of Ketamine-Assisted Multimodal Therapy on Depressive Symptoms: A Longitudinal Pre-Post BDI-II Study with Exploratory Follow-Up Analysis

Anja Frank, Mario H W Scheib preprint

A multimodal therapy combining ketamine-assisted psychotherapy, repetitive transcranial magnetic stimulation, neurofeedback, and additional psychotherapy sessions substantially reduced depressive symptoms in a Spanish clinic. Among 67 patients with various diagnoses who were screened for depression, Beck Depression Inventory-II scores dropped significantly from before to after treatment, with a large effect size. Exploratory follow-up of 28 patients indicated that improvements could be sustained for months or even years. The findings suggest that integrating multiple biological and psychological interventions may offer an effective approach for treating depression in a clinical setting.

DOI: 10.31219/osf.io/4smjr_v1

Psychedelic Therapy: A Primer for Primary Care Clinicians – Part VII. Ketamine

Viviana D. Evans, Alejandro Arenas, Kenneth Shinozuka et al. preprint

Ketamine, originally a dissociative anesthetic, is now used for treatment-resistant depression and major depressive disorder with suicidal ideation. A single intravenous infusion shows antidepressant effects within hours, with a large effect size on depression scores. It also reduces PTSD symptom severity and suicidal ideation in emergency settings. However, therapeutic effects often subside within weeks, requiring repeated doses. Risks include temporary or persistent memory impairment, cardiovascular issues, liver toxicity, and bladder inflammation. Ketamine's opioid-sparing effect improves postoperative pain management.

DOI: 10.31234/osf.io/dtb6a

Concurrent Changes in Self-Reported Sleep Disturbance During At-Home Ketamine-Assisted Therapy for Depression: A Retrospective Analysis of 13,963 Adults

Research Square • Jack Swain, Davis Carter, Leonardo Vando et al.

Among 13,963 adults with moderate-to-severe sleep disturbances who received at-home ketamine-assisted therapy for depression, 67.4% showed at least a 1-point improvement on a single sleep-related item from a depression screening tool after two sessions. By session six, 76.8% of completers met that threshold, and the average score dropped 48.8% from baseline. However, the study could not separate sleep changes from mood improvement because all participants were treated for depression and no control group was included. Side effects were reported by 3.7% to 5.0% of participants across sessions.

DOI: 10.21203/rs.3.rs-9553669/v1

Too big to fail? Comparing effect sizes of MDMA assisted therapy to unmasking bias

Balazs Szigeti, Ellen Bradley, Joshua Woolley preprint

Unmasking bias—where participants or researchers can guess who received a treatment due to its noticeable effects—may account for the reported benefits of MDMA-assisted therapy for PTSD. Analyzing data from trials of ketamine and escitalopram, the authors found that the magnitude of unmasking bias is larger than the treatment-versus-control effect size observed for MDMA. This indicates that MDMA-AT's effect sizes are not too large to be explained by unmasking alone, though the findings do not prove that the effects are entirely or partially due to this bias.

DOI: 10.31219/osf.io/ujtpf

Ketamine-induced pleasant but not unpleasant dissociation is linked to the functional connectivity profile of the posteromedial cortex

Zumrut Duygu Sen, Nitin Sharma, Lena Vera Danyeli et al. preprint

Ketamine causes temporary dissociative experiences alongside its rapid therapeutic effects. This study examined whether pleasant and unpleasant dissociations can be predicted by functional connectivity of the posteromedial cortex (PMC) in 35 male participants during ultrahigh-field MRI. Pleasant dissociation (oceanic boundlessness) was predicted by PMC connections with control network regions at baseline and during infusion, and additionally with default mode network regions during infusion. Unpleasant dissociation (anxious ego dissolution) could not be predicted by PMC connectivity. The findings suggest distinct brain mechanisms for pleasant versus unpleasant dissociations, and that PMC connectivity changes may be a shared neural feature of dissociation from both ketamine and psychedelics.

DOI: 10.31234/osf.io/eadr2

Brain State Dynamics in Ketamine-Induced Dissociation Resemble Those in PTSD

Noam Goldway, Taly Markovits, Naomi Fine et al. preprint

Dissociation—feeling detached from one's body, surroundings, or self—is common in PTSD but its neural basis is poorly understood. Using network control theory, researchers examined brain dynamics during dissociative states in two contexts: ketamine-induced dissociation in 30 healthy volunteers and therapeutic interventions in 78 PTSD patients. Ketamine produced brain dynamics similar to those seen in PTSD patients before treatment, with increased dominance of a default mode network meta-state and decreased dominance of a somatomotor meta-state. Ketamine did not significantly alter the brain's energetic landscape, but transition energies increased after PTSD treatment, suggesting more organized, less entropic brain dynamics.

DOI: 10.31234/osf.io/v52qb

Intron retention, a novel method for evaluating the response to ketamine in patients with treatment-resistant depression

Research Square • Norihiro Okada, Kenshiro Oshima, Akiko Maruko et al.

Non-responders to ketamine treatment for depression show elevated viral infection markers based on intron retention (IR) gene analysis of RNA-seq data. Several IR genes associated with viral infection returned to healthy levels after ketamine regardless of responder status, suggesting non-responders are not resistant to ketamine but rather have an extremely high inflammatory state that the drug's effects cannot overcome. Excluding one transcriptomic outlier with extreme viral infection did not change IR gene conclusions but did alter differentially expressed gene (DEG) results, supporting the authors' claim that IR genes may be more useful markers of depression than DEGs.

DOI: 10.21203/rs.3.rs-5823020/v1

Ketamine treatment safety and tolerability in treatment-resistant depression with somatic comorbidities: focus on dissociation and psychotic symptomatology.

Research Square (Research Square) • Adam Włodarczyk, Wiesław J. Cubała, Maria Węgielnik-gałuszko et al.

In hospitalized patients with treatment-resistant depression (major depressive or bipolar disorder), intravenous ketamine treatment was associated with changes in psychotic symptoms over time among those with epilepsy, but not among those with other somatic conditions. The study, which included 49 participants and was limited by a small, unblinded, single-site design, suggests that careful monitoring for psychotic symptoms is needed when using ketamine in patients with epilepsy, and that somatic comorbidities may influence dissociative side effects.

DOI: 10.21203/rs.3.rs-42473/v1

Can we change depressive beliefs? Modulation of belief updating by ketamine in treatment resistant depression

Hugo Bottemanne, Orphée Morlaàs, Anne Claret et al. • 4 citations preprint

Ketamine infusion makes people with treatment-resistant depression more optimistic about the future by changing how they learn from good and bad news. After a single infusion, patients updated their beliefs more after favorable information and less after unfavorable information, compared to healthy controls. This shift toward optimism was driven by learning more from positive surprises than negative ones. This change in belief-updating predicted early clinical improvement at one week, seen in 19% of patients. The findings suggest ketamine's antidepressant effects involve altering cognitive biases, which could enhance psychotherapy for depression.

DOI: 10.31234/osf.io/zx5vr

Clinical trials

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