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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

Latest monthly recap: June 2026 →

2,961 articles · 1,422 from the last two years · 4,007,129 participants across 1,192 studies reporting sample size

Common study designs

review 635 systematic review 179 experimental study 207 observational cohort 151 randomized controlled trial 217

Research

Synthesize the evidence → Search all →

Effectiveness and Experiences of Psychedelic-Based Interventions for the Treatment of Alcohol Use Disorder: A Mixed Methods Systematic Review

Baneet Gill

A mixed-methods systematic review of eight studies (four quantitative, four qualitative) examined the effectiveness and experiences of using psychedelics to treat alcohol use disorder (AUD). Quantitative studies reported an overall increase in abstinence and a decrease in drinking days after treatment, while qualitative studies reported mostly positive experiences. However, the included studies were rated mostly 'poor' or 'moderate' quality, so results should be interpreted with caution. The small number of recent studies, small sample sizes, and heterogeneity of studies limit the strength of conclusions, highlighting the need for further research.

DOI: 10.31237/osf.io/tqa8j_v1

Psychopathological descriptive model of hallucinogenic/psychedelic drugs effect in the treatment of depression and addictions

Nestor Girala

The efficacy of hallucinogenic drugs (ayahuasca, psilocybin, LSD, ketamine) in treating depression and addictions is accompanied by intense emotional states and mystical-type experiences, including feelings of oneness, transcendence, ineffability, and awe. These common psychopathological elements may mediate the drugs' therapeutic action. The paper reviews literature on subjective experiences during such treatments and compares them with other life-changing experiences, discussing the evolutionary value of these emotions for group cohesiveness and the recalibration of cognitions and emotions.

DOI: 10.14293/s2199-1006.1.sor-.ppfvg0c.v1

Binaries, Multitudes, and Beyond: A Client-Authored Case Study in Psychedelic-Assisted Therapy, Artificial Intelligence, and Narrative Agency

Mark A. Michaels

A client who is also the author documents a 10-week course of collaborative therapy that integrates EMDR, ketamine, MDMA, psilocybin, creative expression, and AI-assisted reflection and writing. Drawing on affect theory, mentalization, earned secure attachment, and Dabrowski's theory of positive disintegration, the paper analyzes how recognition of core affects, rupture-and-repair processes, and the reclamation of narrative agency contributed to rapid, positive change. Psychoeducation supported a deep exploration of these concepts. The case critiques traditional psychoanalytic framings, diagnostic overreach, and hierarchical therapeutic structures, arguing for a model emphasizing collaboration, agency, and narrative coherence. It also highlights the potential and limitations of generative AI as an adjunct in psychotherapy and narrative self-reclamation.

DOI: 10.2139/ssrn.6317678

Putative rapid-acting antidepressant nitrous oxide (“laughing gas”) evokes rebound emergence of slow EEG oscillations during which TrkB signaling is induced

Samuel Kohtala, Wiebke Theilmann, Marko Rosenholm et al. preprint

Nitrous oxide (laughing gas), a dissociative anesthetic that blocks NMDA receptors, produces rapid antidepressant effects in animals through a mechanism that emerges after the drug is withdrawn, not during its peak action. The gas induces rebound slow EEG oscillations, a brain state also seen with ketamine and electroconvulsive therapy, that is characterized by sedation and drowsiness. During this withdrawal phase, signaling changes in TrkB and GSK3β proteins gradually appear, suggesting that the antidepressant effect relies on cortical excitability triggered by the drug's offset rather than its acute presence.

DOI: 10.1101/282954

Nitrous oxide modulates cortical activity, wake–sleep oscillations, and produces antidepressant-like effects in mice

Samuel Kohtala, Puja K Parekh, Iman Baramaki et al. preprint

A single 50% nitrous oxide treatment rapidly increases neuronal calcium activity in the mouse medial prefrontal cortex, elevates c-Fos expression, and enhances wake-associated gamma oscillations and slow-wave activity during sleep, indicating cortical activation and synaptic potentiation. In a chronic corticosterone stress model, nitrous oxide produced antidepressant-like behavioral effects in several but not all domains. These actions parallel key effects of subanesthetic ketamine.

DOI: 10.1101/2025.02.13.638096

Combined Ketamine and Psychotherapy Provide No Additional Benefit Beyond Ketamine Alone in Treating Depression or PTSD: Evidence from a Help-Seeking Sample

Tyler Maxwell Moore, Kathryn Walker, Emma Tung et al. preprint

Adding psychotherapy to ketamine treatment does not significantly improve depression or PTSD symptoms more than ketamine alone over 30 days. Both approaches produced substantial, rapid symptom improvement that stabilized after 11-15 days. The study analyzed 202 help-seeking individuals (60% female, mean age 41.3 years) who received either ketamine alone or ketamine plus psychotherapy across six sessions. No significant differences in symptom trajectories emerged between the groups, though exploratory analyses suggested younger females might benefit more from combined treatment and older males from ketamine alone. The findings indicate ketamine's effects may be robust enough that concurrent psychotherapy does not enhance short-term outcomes, but longer-term and demographic-specific effects require further study.

DOI: 10.31234/osf.io/cs24j

Co-Boost: Boosting and guiding neuroplasticity by combining ketamine with neurofeedback-assisted learning – towards an individualised and integrated pharmaco-psychotherapy for cocaine addiction: study protocol for a randomised, placebo-controlled, double-blind, parallel-group, single-centre trial

Anna Stefania Trippel, Ladina Philomena Gubser, Etna Jennifer Elektra Engeli et al.

A randomized, placebo-controlled, double-blind trial will test a single ketamine infusion, three sessions of reward-imagery real-time fMRI neurofeedback training, and their combination in 120 people with cocaine use disorder. The study expects both interventions to reduce the proportion of cocaine use days, with ketamine increasing glutamate in the reward system and lowering craving, and neurofeedback re-sensitizing participants to natural rewards. This neurobiologically informed approach aims to open new treatment avenues through individualized pharmaco-psychotherapy.

DOI: 10.21203/rs.3.rs-5677691/v1

Qualitative analysis of a patient’s experience of ketamine-assisted psychotherapy for substance use disorder: Empirical synergies with twelve-step programs.

Dan Petrovitch, Jacob Spinks, Hannah B Yoo et al. preprint

A 28-year-old woman with alcohol and prescription opioid misuse underwent a collaborative treatment plan that combined ketamine-assisted psychotherapy with existing psychosocial and 12-step-based treatments. The patient attributed psychological and spiritual changes to her ketamine treatments, and her ketamine-induced experiences overlapped with the 12 steps. The report details clinical practices for managing the unique risks of ketamine interventions as substance use disorder treatments.

DOI: 10.31234/osf.io/f53wp_v1

Improvement in Depressive Symptoms in a Patient with Severe and Enduring Anorexia Nervosa and Comorbid Major Depressive Disorder Using Psychotherapy-Assisted IV Ketamine : A Case Report

Amanda Timek, Catherine Daniels-Brady, Stephen Ferrando

A 33-year-old woman with severe and enduring anorexia nervosa and major depressive disorder, who had not improved with numerous prior treatments including antidepressants, mood stabilizers, antipsychotics, electroconvulsive therapy, and various therapies, received seven sessions of intravenous ketamine combined with acceptance and commitment therapy in a hospital setting. She showed increased cognitive flexibility, disappearance of suicidal ideation, and reduction in Beck Depression Inventory scores. Her body mass index was profoundly low at 13, whereas the lowest previously documented in the literature was 16.9. Ketamine-assisted psychotherapy may be a promising treatment for patients with anorexia nervosa and comorbid depression who have failed other interventions.

DOI: 10.21203/rs.3.rs-3976846/v1

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

Clinical trials

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