June 2026
Ketamine
What June 2026's 25 new studies found, synthesized from the papers below. All Ketamine research →
The synthesis
Synthesized from 19 studies in the library · AI-generated, grounded in the abstracts below
Found by searching the library for Ketamine, esketamine, arketamine, then ranked by relevance.
Research on ketamine in June 2026 continued to support its rapid antidepressant effects in treatment-resistant depression, particularly via intravenous and intranasal routes, with emerging evidence of sex differences in response and low abuse liability in controlled settings. However, significant concerns remain regarding neurodevelopmental toxicity, adverse effects like cystitis and cholangiopathy, and the need for long-term safety data. The evidence is largely consistent but limited by small sample sizes, open-label designs, and a predominance of reviews over new clinical trials.
Confidence in the evidence
Moderate- Multiple reviews and a systematic review consistently report rapid antidepressant efficacy and low abuse liability in controlled settings.
- One secondary analysis of a real-world study (n=210) provides initial evidence of sex differences, but this is a single study.
- Preclinical studies raise neurodevelopmental toxicity concerns, but human data are lacking.
- Many studies are narrative reviews or case reports, with few new large-scale RCTs published in this specific month.
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.
| Study | Design | Sample size | Direction | Finding |
|---|---|---|---|---|
| Exposure to Ketamine and 2-Fluorodeschloroketamine Impairs Mitochondrial Oxidative Phosphorylation in Human Cerebral Organoids: Implications for Neurodevelopmental Toxicity. 2026 | preclinical | — | Opposes | Ketamine exposure impaired mitochondrial oxidative phosphorylation, increased oxidative stress, and reduced ATP production in human cerebral organoids, suggesting neurodevelopmental toxicity. |
| Psychedelics in treatment-resistant depression: a comprehensive review of mechanisms, clinical evidence, and recommendations. 2026 | review | — | Supports | Ketamine in intravenous, subcutaneous, and oral forms had rapid and robust effects in reducing depressive symptoms and relapses without decreasing cognitive function. |
| Ketamine-Augmented Hypnotherapy 2026 | theoretical | — | Supports | Ketamine-augmented hypnotherapy is described as a promising augmentation strategy for treatment-resistant depression and other conditions, though still experimental. |
| Comprehensive Systematic Review of Esketamine Nasal Spray as a Standalone Rapid-Acting Treatment for Treatment-Resistant Depression: Integrating Clinical Trial Data and Emerging Real-World Evidence on Efficacy, Safety, And Relapse Prevention 2026 | review | — | Supports | Esketamine nasal spray reduced depressive symptoms more effectively than placebo and quetiapine, with benefits appearing within days and lasting weeks to months; side effects were mild to moderate. |
| Ketamine renaissance: Expanding horizons from anesthesia to depression and pain 2026 | review | — | Supports | Ketamine shows rapid antidepressant action in treatment-resistant depression and efficacy in acute and chronic pain, but long-term safety and misuse potential remain unresolved. |
| Intrinsic excitation-inhibition imbalance in major depressive disorder. 2026 | observational | 32 | Unclear | Ketamine induced changes in cortical excitation-inhibition balance in a small clinical trial dataset, but the direction of effect relative to depression improvement was not specified in the abstract. |
| Alterations in glutamatergic and GABAergic signaling in ketamine-induced neurotoxicity: mangiferin mitigates neurochemical, oxidative, and astrocytic dysregulation in the rat temporal-frontal cortex. 2026 | preclinical | — | Opposes | Ketamine induced cognitive deficits, hyperlocomotion, and excitatory-inhibitory imbalance in rats, confirming neurochemical disruption. |
| The Dark Side of Ketamine: Brain, Bladder, and Beyond: a Focused Clinical Review for Emergency Medicine Clinicians 2026 | review | — | Opposes | Ketamine is associated with psycho-perceptual adverse effects (up to 92% with IV push), ketamine-induced cystitis (25-27% of chronic users), cholangiopathy (~10% of chronic users), and ketamine use disorder. |
| Rapid clinical improvement after intravenous ketamine in an adolescent with treatment-resistant depression, severe obesity, and pseudo-Cushing syndrome: A case report. 2026 | case report | 1 | Supports | Intravenous ketamine led to rapid clinical improvement in an adolescent with treatment-resistant depression and complex comorbidities. |
| Sex- and Age-Stratified Differences in Antidepressant Response to Intranasal Esketamine in Treatment-Resistant Depression: A Secondary Analysis of the REAL-ESK Study 2026 | observational | 210 | Mixed | Intranasal esketamine was associated with substantial antidepressant improvement, with a modest overall male advantage in response and remission at three months, but sex differences were small and non-significant in those under 65. |
| Pharmacokinetics and pharmacodynamics of orally administered S-ketamine in healthy participants. 2026 | RCT | 16 | Unclear | Oral S-ketamine had poor bioavailability (9-12%) and produced different metabolite profiles compared to intravenous S-ketamine, raising safety and efficacy concerns for oral use in TRD. |
| COMPARING ROUTES OF KETAMINE ADMINISTRATION IN TREATMENT-RESISTANT DEPRESSION: EFFICACY, SAFETY, AND OPTIMIZATION OF DOSING STRATEGIES 2026 | review | — | Supports | Intravenous racemic ketamine shows the strongest and fastest antidepressant effect, while FDA-approved intranasal esketamine offers robust long-term data; both are best-supported for rapid response. |
| Navigating ‘k-land’: a qualitative exploration of participants’ experiences of ketamine-assisted psychotherapy for methamphetamine use disorder 2026 | qualitative | 14 | Supports | Participants reported reduced emotional and cognitive reactivity and sustained behavioral changes after ketamine-assisted psychotherapy for methamphetamine use disorder. |
| Evaluating the abuse liability of ketamine in the treatment of mood disorders: A systematic review. 2026 | systematic review | — | Supports | Ketamine and esketamine carry low abuse liability when delivered in monitored clinical settings, with minimal evidence of craving, dose escalation, or misuse in clinical studies. |
| Sustained pharmacodynamic effects of S-ketamine on cortical excitability and resting-state brain activity: A randomized, placebo-controlled trial. 2026 | RCT | 16 | Unclear | Intravenous S-ketamine induced acute and sustained changes in cortical excitability and resting-state brain activity, with some effects lasting up to 7 days, but the clinical relevance for depression was not directly assessed. |
| Ketamine and Esketamine in Depression: Current Evidence on Mechanisms, Efficacy, Safety and Clinical Use – A Review 2026 | review | — | Supports | Current data indicate that ketamine and its derivatives show rapid antidepressant effects, but limitations in existing data and the need for further research are emphasized. |
| Structural basis of opioid receptor activation by PCP and ketamine 2026 | preclinical | — | Unclear | Ketamine can directly bind and activate opioid receptors, suggesting its therapeutic effects may extend beyond NMDA receptor inhibition, but the clinical implications are not specified. |
| Effects of Esketamine on EEG temporal dynamics in patients with depression 2026 | observational | 5 | Supports | Esketamine administration was associated with increased subjective 'Happiness' and reduced alpha power in EEG, peaking 15-35 minutes post-dose, paralleling mood improvements. |
| NMDA receptor subtype differential affinity as a key enabler for precision neuropsychiatry. 2026 | preclinical | — | Opposes | Ketamine's use is limited by dissociative side effects and potential long-term cognitive impairment, and it is linked to neuropathological alterations such as Olney's lesions in preclinical studies. |
Ketamine exposure impaired mitochondrial oxidative phosphorylation, increased oxidative stress, and reduced ATP production in human cerebral organoids, suggesting neurodevelopmental toxicity.
preclinical
Ketamine in intravenous, subcutaneous, and oral forms had rapid and robust effects in reducing depressive symptoms and relapses without decreasing cognitive function.
review
Ketamine-augmented hypnotherapy is described as a promising augmentation strategy for treatment-resistant depression and other conditions, though still experimental.
theoretical
Esketamine nasal spray reduced depressive symptoms more effectively than placebo and quetiapine, with benefits appearing within days and lasting weeks to months; side effects were mild to moderate.
review
Ketamine shows rapid antidepressant action in treatment-resistant depression and efficacy in acute and chronic pain, but long-term safety and misuse potential remain unresolved.
review
Ketamine induced changes in cortical excitation-inhibition balance in a small clinical trial dataset, but the direction of effect relative to depression improvement was not specified in the abstract.
observational · Sample size: 32
Ketamine induced cognitive deficits, hyperlocomotion, and excitatory-inhibitory imbalance in rats, confirming neurochemical disruption.
preclinical
Ketamine is associated with psycho-perceptual adverse effects (up to 92% with IV push), ketamine-induced cystitis (25-27% of chronic users), cholangiopathy (~10% of chronic users), and ketamine use disorder.
review
Intravenous ketamine led to rapid clinical improvement in an adolescent with treatment-resistant depression and complex comorbidities.
case report · Sample size: 1
Intranasal esketamine was associated with substantial antidepressant improvement, with a modest overall male advantage in response and remission at three months, but sex differences were small and non-significant in those under 65.
observational · Sample size: 210
Oral S-ketamine had poor bioavailability (9-12%) and produced different metabolite profiles compared to intravenous S-ketamine, raising safety and efficacy concerns for oral use in TRD.
RCT · Sample size: 16
Intravenous racemic ketamine shows the strongest and fastest antidepressant effect, while FDA-approved intranasal esketamine offers robust long-term data; both are best-supported for rapid response.
review
Participants reported reduced emotional and cognitive reactivity and sustained behavioral changes after ketamine-assisted psychotherapy for methamphetamine use disorder.
qualitative · Sample size: 14
Ketamine and esketamine carry low abuse liability when delivered in monitored clinical settings, with minimal evidence of craving, dose escalation, or misuse in clinical studies.
systematic review
Intravenous S-ketamine induced acute and sustained changes in cortical excitability and resting-state brain activity, with some effects lasting up to 7 days, but the clinical relevance for depression was not directly assessed.
RCT · Sample size: 16
Current data indicate that ketamine and its derivatives show rapid antidepressant effects, but limitations in existing data and the need for further research are emphasized.
review
Ketamine can directly bind and activate opioid receptors, suggesting its therapeutic effects may extend beyond NMDA receptor inhibition, but the clinical implications are not specified.
preclinical
Esketamine administration was associated with increased subjective 'Happiness' and reduced alpha power in EEG, peaking 15-35 minutes post-dose, paralleling mood improvements.
observational · Sample size: 5
Ketamine's use is limited by dissociative side effects and potential long-term cognitive impairment, and it is linked to neuropathological alterations such as Olney's lesions in preclinical studies.
preclinical
Points of agreement
- Ketamine and esketamine demonstrate rapid antidepressant effects in treatment-resistant depression.
- Intravenous and intranasal routes are the best-supported for achieving rapid response.
- Abuse liability is low when ketamine is administered in controlled clinical settings.
- Ketamine is associated with adverse effects including psycho-perceptual effects, cystitis, and cholangiopathy, particularly with chronic or recreational use.
Conflicts
- One study found a modest male advantage in antidepressant response to esketamine, while another found no significant sex differences in younger patients.
- Preclinical studies highlight neurodevelopmental toxicity and cognitive impairment, while clinical studies emphasize rapid antidepressant benefits, creating a tension between therapeutic potential and safety concerns.
Gaps
- Long-term safety and efficacy data beyond 12 months are lacking.
- Neurodevelopmental toxicity findings are from preclinical models and need human studies.
- Optimal dosing protocols and standardization across routes remain unresolved.
- Real-world effectiveness and safety data are limited, with many studies being reviews or small trials.
- The role of ketamine in specific populations (e.g., adolescents, elderly) is understudied.