January 2026
Ketamine
What January 2026's 25 new studies found, synthesized from the papers below. All Ketamine research →
The synthesis
Synthesized from 18 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 in January 2026 indicates that ketamine and esketamine generally show rapid antidepressant effects, particularly for treatment-resistant depression (TRD), postpartum depression, and bipolar depression, with some evidence for long-term effectiveness and use in complex cases like opioid tapering and trauma. However, one randomized trial found no significant benefit of serial ketamine infusions over a psychoactive placebo for inpatient depression, and a small trial found no statistically significant anti-fatigue effect. Potential adverse effects include neurotoxicity in animal models, postoperative delirium in a case report, and urinary symptoms with long-term esketamine use.
Confidence in the evidence
Moderate- Multiple studies (n=18 relevant) across various designs (RCT, meta-analysis, retrospective, case series, animal studies, reviews) were published.
- One RCT (n=322) supports esketamine for postpartum depression, and one meta-analysis (9 studies) supports real-world esketamine efficacy for TRD.
- One randomized trial found no effect for serial ketamine in inpatient depression, conflicting with other positive findings.
- Animal studies and case reports raise concerns about ketamine neurotoxicity and adverse events like delirium and urinary symptoms.
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 |
|---|---|---|---|---|
| Multimodal rapid anti-depression: Esketamine combined with dexmedetomidine patient-controlled sleep for treatment-resistant depression - A retrospective study. 2026 | retrospective study | 233 | Supports | Multimodal treatment combining esketamine with dexmedetomidine was associated with sustained reductions in depressive symptoms and improved sleep quality in TRD patients over 6 months. |
| α-tocopherol alleviates ketamine toxicity in rat brain neurons. 2026 | in vitro study | Opposes | Ketamine significantly reduced rat neuron viability, increased ROS production, and damaged mitochondrial and lysosomal membranes, indicating neurotoxicity. | |
| Repeated 7-day exposure to ketamine induces anxiety-like behaviors and neuronal apoptosis in mice via DRD1-medicated inhibition of Akt/Gsk-3β phosphorylation. 2026 | animal study | Opposes | Repeated ketamine exposure induced anxiety-like and depressive-like behavior, cognitive dysfunction, and neuronal apoptosis in mice, mediated by DRD1-dependent inhibition of Akt/Gsk3β phosphorylation. | |
| Prophylactic esketamine to reduce postpartum depression in primiparae: A multicentre, double-blind, randomised clinical trial. 2026 | RCT | 322 | Supports | Prophylactic esketamine significantly reduced the total incidence of postpartum depression (PPD) within 3 months postpartum (11.59% vs. 20.89%) and at 7 days postpartum. |
| Combining Intranasal Esketamine and Electroconvulsive Therapy in Severe Treatment‑Resistant Depression: A Case Series. 2026 | case series | 4 | Supports | Combined ECT and intranasal esketamine was feasible and associated with sustained symptom improvement (mean 58% reduction in MADRS) in 4 severe TRD patients over 24 weeks, with mild and transient adverse events. |
| Systematic review and meta-analysis of intranasal esketamine for treatment-resistant depression: Evidence from real-world studies. 2026 | systematic review and meta-analysis | 9 | Supports | Intranasal esketamine demonstrated substantial effectiveness in real-world TRD patients (Hedges' g = -1.98), with patients about five times more likely to achieve remission at three months, and a pooled prevalence of any adverse event of 82%. |
| Brief report: Ketamine-assisted "bridge therapy" for opioid tapering in complex cases. 2026 | case report | 1 | Supports | Intravenous ketamine infusions as an adjunct to opioid tapering in a complex case of OUD, chronic pain, and MDD led to a 50% methadone reduction, improved pain/craving control, reduced withdrawal, and increased psychotherapy engagement. |
| Modulating tonic NMDA receptor currents: mechanistic insights into ketamine, esketamine, and dextromethorphan for major depressive disorder and implications for the discovery and development of investigational agents. 2026 | review | Supports | This review proposes that selective dampening of NR2C/D-mediated tonic NMDA receptor currents underlies the rapid and sustained antidepressant effects of ketamine, esketamine, and dextromethorphan in TRD. | |
| Atypical Manifestation of Postoperative Delirium After an Opioid-free Prostatectomy: A Case Study Report. 2026 | case report | Opposes | A case report described an unusual occurrence of postoperative delirium in a patient who received intraoperative ketamine as part of an opioid-free anesthesia protocol for prostatectomy. | |
| Ketamine in the treatment of bipolar depression 2026 | review | 6 | Supports | A review of six clinical trials suggests that ketamine appears to be an alternative treatment for bipolar depression when first and second-line medications are ineffective, though more studies are needed. |
| Serial ketamine infusions not effective as adjunctive care for depression 2026 | randomized trial | No effect | A randomized trial found that up to eight serial ketamine infusions were not more effective than a psychoactive placebo (midazolam) in reducing depressive symptoms or improving cognition and quality of life in inpatient depression treatment. | |
| Long-term effectiveness and side-effects of intranasal esketamine in treatment-resistant depression: real-world, single-arm study of over 100 sessions. 2026 | retrospective, single-arm, pre-post study | 20 | Supports | Long-term intranasal esketamine (average 129 sessions over 2.5 years) was associated with significant reductions in depression and anxiety symptoms in 20 TRD patients, with 25% achieving remission for depression, and mild, transient side effects, though 20% experienced urinary symptoms. |
| Symptom trajectories and clinical outcomes of intravenous ketamine in treatment-resistant depression: A real-world study using group-based trajectory modeling. 2026 | retrospective chart review | 209 | Supports | Intravenous ketamine treatment (4 or 6 infusions) in 209 TRD adults led to significant reductions in MADRS and GAD-7 scores, with numerically higher response and remission rates in the six-infusion group, though not statistically significant. |
| Beyond first-line antidepressants: lithium, quetiapine, or esketamine? Integrating meta-analyses and preliminary head-to-head evidence 2026 | systematic review | 4 | Supports | A review found that esketamine, lithium, and quetiapine are all effective for TRD, with a descriptive superiority of esketamine over quetiapine and quetiapine over lithium, suggesting a re-evaluation of treatment algorithms. |
| Ketamine-assisted group psychotherapy integrating cognitive processing therapy to address identity-based trauma: a pilot study 2026 | mixed-methods pilot study | 8 | Supports | A pilot study found that a 9-week ketamine-assisted group psychotherapy program integrating CPT was feasible, highly acceptable, and associated with significant reductions in depression, anxiety, and cognitive fusion scores in transgender and gender-expansive adults. |
| Efficacy of Oral Ketamine in Patients with Depression and Suicidality: A Retrospective Study. 2026 | retrospective cross-sectional study | 41 | Supports | Oral ketamine therapy in 41 patients with depression and suicidality led to significant reductions in HAMD and MSSI scores after the third session, with common side effects including dizziness, nausea, and hypertension. |
| A preliminary proof-of-concept trial on the effects of ketamine on fatigue: a randomized crossover trial. 2026 | randomized, double-blind, crossover trial | 10 | No effect | A small randomized crossover trial (n=10) found no statistically significant difference in anti-fatigue effects between ketamine (0.5 mg/kg) and midazolam, though a reduction exceeding the 20% efficacy threshold was observed in the ketamine arm at 1 day post-infusion. |
| Progress, potential and pitfalls of ketamine as a treatment for depression 2026 | review | Supports | This review states that evidence for intravenous ketamine and intranasal esketamine for depression has dramatically increased, supporting antidepressant effects and an adequate safety profile, with promising preliminary data for other conditions, but challenges remain. |
Multimodal treatment combining esketamine with dexmedetomidine was associated with sustained reductions in depressive symptoms and improved sleep quality in TRD patients over 6 months.
retrospective study Sample size: 233
Ketamine significantly reduced rat neuron viability, increased ROS production, and damaged mitochondrial and lysosomal membranes, indicating neurotoxicity.
in vitro study
Repeated ketamine exposure induced anxiety-like and depressive-like behavior, cognitive dysfunction, and neuronal apoptosis in mice, mediated by DRD1-dependent inhibition of Akt/Gsk3β phosphorylation.
animal study
Prophylactic esketamine significantly reduced the total incidence of postpartum depression (PPD) within 3 months postpartum (11.59% vs. 20.89%) and at 7 days postpartum.
RCT Sample size: 322
Combined ECT and intranasal esketamine was feasible and associated with sustained symptom improvement (mean 58% reduction in MADRS) in 4 severe TRD patients over 24 weeks, with mild and transient adverse events.
case series Sample size: 4
Intranasal esketamine demonstrated substantial effectiveness in real-world TRD patients (Hedges' g = -1.98), with patients about five times more likely to achieve remission at three months, and a pooled prevalence of any adverse event of 82%.
systematic review and meta-analysis Sample size: 9
Intravenous ketamine infusions as an adjunct to opioid tapering in a complex case of OUD, chronic pain, and MDD led to a 50% methadone reduction, improved pain/craving control, reduced withdrawal, and increased psychotherapy engagement.
case report Sample size: 1
This review proposes that selective dampening of NR2C/D-mediated tonic NMDA receptor currents underlies the rapid and sustained antidepressant effects of ketamine, esketamine, and dextromethorphan in TRD.
review
A case report described an unusual occurrence of postoperative delirium in a patient who received intraoperative ketamine as part of an opioid-free anesthesia protocol for prostatectomy.
case report
A review of six clinical trials suggests that ketamine appears to be an alternative treatment for bipolar depression when first and second-line medications are ineffective, though more studies are needed.
review Sample size: 6
A randomized trial found that up to eight serial ketamine infusions were not more effective than a psychoactive placebo (midazolam) in reducing depressive symptoms or improving cognition and quality of life in inpatient depression treatment.
randomized trial
Long-term intranasal esketamine (average 129 sessions over 2.5 years) was associated with significant reductions in depression and anxiety symptoms in 20 TRD patients, with 25% achieving remission for depression, and mild, transient side effects, though 20% experienced urinary symptoms.
retrospective, single-arm, pre-post study Sample size: 20
Intravenous ketamine treatment (4 or 6 infusions) in 209 TRD adults led to significant reductions in MADRS and GAD-7 scores, with numerically higher response and remission rates in the six-infusion group, though not statistically significant.
retrospective chart review Sample size: 209
A review found that esketamine, lithium, and quetiapine are all effective for TRD, with a descriptive superiority of esketamine over quetiapine and quetiapine over lithium, suggesting a re-evaluation of treatment algorithms.
systematic review Sample size: 4
A pilot study found that a 9-week ketamine-assisted group psychotherapy program integrating CPT was feasible, highly acceptable, and associated with significant reductions in depression, anxiety, and cognitive fusion scores in transgender and gender-expansive adults.
mixed-methods pilot study Sample size: 8
Oral ketamine therapy in 41 patients with depression and suicidality led to significant reductions in HAMD and MSSI scores after the third session, with common side effects including dizziness, nausea, and hypertension.
retrospective cross-sectional study Sample size: 41
A small randomized crossover trial (n=10) found no statistically significant difference in anti-fatigue effects between ketamine (0.5 mg/kg) and midazolam, though a reduction exceeding the 20% efficacy threshold was observed in the ketamine arm at 1 day post-infusion.
randomized, double-blind, crossover trial Sample size: 10
This review states that evidence for intravenous ketamine and intranasal esketamine for depression has dramatically increased, supporting antidepressant effects and an adequate safety profile, with promising preliminary data for other conditions, but challenges remain.
review
Points of agreement
- Ketamine and esketamine generally show rapid antidepressant effects in various depressive disorders, including TRD, MDD, bipolar depression, and PPD.
- Ketamine/esketamine can be effective as an adjunct or in treatment-resistant cases.
- Common side effects like dissociation, nausea, dizziness, and hypertension are generally transient.
- Ketamine has potential for use in complex cases beyond depression, such as opioid tapering and trauma-related distress.
- Long-term use of esketamine may be associated with urinary symptoms.
Conflicts
- One randomized trial (article_id: 25219) found serial ketamine infusions no more effective than a psychoactive placebo for inpatient depression, contrasting with other studies showing antidepressant efficacy.
- Animal studies (article_id: 18928, 18929) indicate ketamine neurotoxicity and induction of anxiety-like behaviors, while clinical studies focus on therapeutic benefits.
Gaps
- Durability of effects beyond 6 months in larger, well-controlled studies.
- Optimal number and frequency of ketamine/esketamine infusions for different conditions.
- Efficacy of alternative routes of administration compared to intravenous ketamine.
- Long-term safety, especially regarding neurotoxicity and urinary issues, in larger and more diverse populations.
- Identification of predictors of response and non-response to ketamine/esketamine treatment.
- More large-scale, double-blind RCTs comparing ketamine to active comparators for various conditions.