medRxiv Preprint Server
May 31, 2026
Yves Martins Varela, Patrícia Cavalcanti-Ribeiro, Geovan Menezes de Sousa et al.
preprint
Ketamine rapidly reduces depression symptoms in treatment-resistant depression, but its effects may be enhanced by combining it with psychotherapy. The drug induces neuroplasticity and psychological openness, which could help patients process emotions, restructure thoughts, and maintain improvements. However, research has not yet thoroughly examined whether adding structured psychotherapy to ketamine treatment provides additional benefits.
Pharmaceuticals (Basel, Switzerland)
May 31, 2026
Wenting Zhang, Xin Guo, Jiping Zhang et al.
Combining the herbal formula Dajianzhong Decoction (DJZT) with ketamine produces synergistic antidepressant effects in a mouse model of depression. The combination restores levels of short-chain fatty acids (SCFAs), particularly acetic acid and isobutyric acid, in the gut. These SCFAs activate the FFAR2 receptor in the brain's medial prefrontal cortex, which suppresses NLRP3-IL-1β-driven neuroinflammation and reverses synaptic deficits. Blocking FFAR2 with the inhibitor GLPG0974 eliminates these benefits. The findings suggest that the SCFA-FFAR2-NLRP3-IL-1β axis mediates the prolonged antidepressant action of the combined treatment, pointing to microbiota-modulating strategies for improving ketamine therapy.
Psychiatry and Clinical Neurosciences
May 30, 2026
Nathalia Novaretti, Rebeca Mendes P Pessoa, Jaime Eduardo Cecilio Hallak et al.
Oral ketamine shows a favorable short-term safety profile across a range of uses, including depression, chronic pain, and pediatric sedation, based on a systematic review of 18 randomized controlled trials involving adults, children, and healthy volunteers. Adverse effects were predominantly mild and transient; in depression studies (427 participants), effects were mild, and pediatric premedication trials (239 participants) reported transient neurological effects without significant safety concerns. Pain and experimental studies (372 participants) showed mostly mild adverse events, with dissociative symptoms at higher doses. Dizziness, sedation, and dissociation were more common with ketamine, while serious adverse events were rare. However, the certainty of evidence is low, and long-term safety remains uncertain.
Journal of Pain & Palliative Care Pharmacotherapy
May 29, 2026
Yogendra Singhal, Pavan Gaurav R, Sreeharsh Saji et al.
Depression is common among cancer patients and harms quality of life, treatment adherence, and prognosis. Standard antidepressants take weeks to work, but ketamine may offer rapid relief. This systematic review of 14 studies (randomized trials, cohort studies, and case-control designs) found that ketamine quickly reduces depressive symptoms, often within hours to days, and also improves anxiety, pain, and quality of life. Short-term side effects include fatigue, dizziness, and dissociation; long-term safety data are limited. Ketamine appears promising as a short-term option for depression in cancer patients, especially those with treatment-resistant depression, but more research is needed on long-term outcomes and optimal dosing.
Research Square
May 27, 2026
Tychique T. Wasolua, Tanner J. Bommersbach, Roger S McIntyre et al.
Ketamine and its S-enantiomer esketamine show both neurotoxic and neuroprotective effects depending on dose, duration, and experimental model. In preclinical studies, high or repeated doses can cause neuronal damage, while lower doses may protect against injury. Human studies are limited but suggest similar potential for harm and benefit. The systematic review highlights the need for careful dosing and monitoring in clinical use, especially for depression treatment.
May 27, 2026
James Phelps
A randomized trial found that serial intravenous ketamine was not significantly more effective than the active placebo midazolam in reducing depressive symptoms or improving quality of life. The improvement in MADRS scores fell short of the minimal clinically important difference. The study had a small sample size of 63 participants and faced blinding failures, with 78% of patients and 90% of raters correctly identifying the ketamine group, suggesting results may have been influenced by unblinded expectations. Further research that controls for non-specific effects is needed.
Expert Opin Investig Drugs
May 26, 2026
Mina Takahashi, Richard C. Shelton
A review of a two-step approach for bipolar depression with acute suicidal ideation and behavior: an initial intravenous ketamine protocol for rapid symptom relief, followed by maintenance with D-cycloserine and lurasidone to prolong therapeutic effects. The strategy is mechanistically informed but uncertainties remain about which components drive efficacy, optimal dosing, and duration of benefits. Further studies are needed to refine maintenance strategies and translate insights into clinical practice.
Pharmacol Biochem Behav
May 25, 2026
Marcela Unterspann, Chrysostomos Charalambous, Martin Votava et al.
Flumazenil, midazolam, and ketamine each modulate anxiety-like behavior in rats, as measured by aversive ultrasonic vocalizations and performance on the elevated plus maze. The study provides evidence that these pharmacological agents affect anxiety-related responses, with results indicating distinct effects depending on the drug and behavioral test. No specific numerical outcomes or sample sizes are reported in the abstract.
Dijlah Journal of Medical Sciences P-ISSN 3078-3178 E-ISSN 3078-8625
May 23, 2026
Suha Adel Qasim Al-Ani
Postoperative hallucinations and other psychotropic effects are known side effects of ketamine that may be dose-dependent. In a study of 62 people (32 males, 30 females) aged 16–60 undergoing various surgeries under general anesthesia, different doses of ketamine (30, 40, 50, and 100 mg/kg) and durations of administration (10–20, 21–30, 31–40, and more than 40 minutes) were evaluated. Hallucination types (visual, auditory, or both) and severity scores (mild, moderate, severe) were monitored. Results showed significant differences between doses and durations with hallucination types and scores. The incidence and severity of postoperative hallucinations are closely tied to the dose: low doses are related to reduced risk, while moderate and high doses significantly increase risk.
Biomedicines
May 23, 2026
Dominik Jucha, Michał Klimas, Dominika Wiśniewska et al.
About 25% of people with bipolar disorder experience drug-resistant depression, where standard treatments fail. This paper reviews augmentation strategies and polypharmacotherapy for treatment-resistant bipolar depression. Atypical antipsychotics show limited efficacy and high side effects. Ketamine produces the fastest and strongest antidepressant effect with low risk of switching to mania. Pramipexole shows long-term promise but carries high risk of mania and impulse control disorders. Celecoxib, as anti-inflammatory therapy, significantly improved response and remission rates compared to escitalopram alone. Memantine showed only early, short-term benefit. The authors conclude that rational polypharmacotherapy targeting glutamatergic and inflammatory pathways is most promising, with ketamine having the greatest clinical potential.
Psychopharmacology (Berl)
May 22, 2026
Wei-Chen Lin, Li-Kai Cheng, Tung-Ping Su et al.
A single subanesthetic-dose ketamine infusion shortens the global and regional path length of brain functional connectivity in people with treatment-resistant depression and suicidal ideation, suggesting a more efficient network organization. This change in connectivity may underlie the rapid antidepressant and anti-suicidal effects of ketamine.
Ther Adv Psychopharmacol
May 22, 2026
Liliana Patarroyo-Rodriguez, Vanessa K. Pazdernik, Jennifer L. Vande Voort et al.
Among people with treatment-resistant depression, early changes in suicidal ideation after ketamine or esketamine treatment are linked to later emergency department visits for suicidality. The analysis indicates that reductions in suicidal thoughts during the first few weeks of treatment may lower the risk of subsequent emergency care for suicidality, though the relationship requires further study.
Pharmacol Rep
May 20, 2026
Aleksander Kwaśny, Alina Wilkowska, Michał Pastuszak et al.
A retrospective analysis of patient-reported outcomes found that psychiatric adverse events emerged during ketamine treatment for major depressive disorder. The text does not specify the frequency, severity, or nature of these events, nor does it provide comparative data or a control group. The analysis suggests that such events can occur, but the magnitude and clinical significance remain unclear based solely on the abstract.
Scientific Reports
May 20, 2026
Guan-Jie She, Wei-Chi Li, Chun-Hsiang Chou et al.
Ketamine infusion alters brain activity patterns in people with treatment-resistant depression, specifically in regions involved in sensory-cognitive integration, mood regulation, and cognitive control. In a study of 45 patients, those receiving ketamine showed changes in the timing and shape of hemodynamic responses in the bilateral olfactory cortex and right inferior parietal gyrus, compared to those receiving midazolam. Improvements in suicidal thoughts were linked to changes in the thalamus and superior frontal gyrus. Ketamine responders also had reduced time-to-peak in the left precuneus. These findings suggest ketamine's effects on suicidal ideation may involve neurovascular coupling dynamics.
Ther Adv Psychopharmacol
May 19, 2026
correction
No Summary
British journal of hospital medicine (London, England : 2005)
May 18, 2026
Karen L Erskine, Paul I Dargan, David M Wood
Chronic, high-dose recreational ketamine use is associated with dependence and long-term complications affecting the urinary tract, nervous system, mental health, and liver. This narrative review describes these complications and emphasizes the need for clinicians to recognize them early for proper investigation and management.
J Affect Disord
May 16, 2026
David S. Mathai, Madeleine Cluck, Amna M. Aslam et al.
1 citation
A panel of experts from the American Society of Ketamine Physicians, Psychotherapists, and Practitioners used a Delphi process to develop consensus guidelines for administering intravenous ketamine infusions to treat depressive disorders. The guidelines provide recommendations on patient selection, dosing, safety monitoring, and treatment protocols, aiming to standardize clinical practice and improve patient outcomes. The consensus reflects agreement among specialists on best practices for this off-label use of ketamine.
Asian J Psychiatr
May 16, 2026
Sonia Shenoy, Vijetha Shenoy Belle, Ravindra Neelakanthappa Munoli et al.
1 citation
A systematic review and meta-analysis of randomized controlled trials found that oral ketamine produces short-term antidepressant effects. The analysis synthesizes evidence from multiple trials, indicating that oral ketamine can reduce depressive symptoms more than placebo or control conditions over brief follow-up periods. The review notes that the evidence base is still limited and that longer-term efficacy and safety require further investigation.
J Affect Disord
May 14, 2026
Joshua Curtiss, Laya Dasari, Julianne Origlio et al.
Patients with treatment-resistant depression whose symptoms are loosely connected before ketamine therapy are more likely to respond than those with tightly linked symptoms. Among 447 patients receiving intravenous ketamine or intranasal eskatamine, non-responders had denser pre-treatment symptom networks (global strength 4.03) compared with responders (global strength 1.06). After treatment, responders' network strength increased, while non-responders' decreased. Sparse baseline symptom networks may indicate greater capacity for reorganization, making pre-treatment network density a potential marker of ketamine response.
Behavioral sciences (Basel, Switzerland)
May 14, 2026
Fabiola Raffone, Carlo Ignazio Cattaneo, Enrico Pessina et al.
Trauma-related autobiographical memories can become intrusive and distressing, contributing to post-traumatic stress disorder (PTSD) and depression, including treatment-resistant depression (TRD). Intranasal esketamine, an approved rapid-acting treatment for TRD, may create conditions that facilitate psychotherapeutic work on traumatic memories. This narrative review synthesizes evidence on ketamine and esketamine for PTSD and trauma symptoms, distinguishing intravenous ketamine studies, intranasal esketamine data, and combination approaches with psychotherapy.
Fortschr Neurol Psychiatr
May 13, 2026
Cornelius Schüle, Anna Sobieraj, Helena Rogg
1 citation
Esketamine, an NMDA receptor antagonist, is approved as a nasal spray for treatment-resistant major depression and for rapid symptom reduction in psychiatric emergencies. In the US it is also approved as a monotherapy for treatment-resistant depression. Acute treatment often causes dissociative effects, but a link between these initial symptoms and later therapeutic response is not sufficiently proven. A key methodological problem is functional unblinding, where characteristic side effects reveal group assignment. Proponents of ketamine-augmented psychotherapy suggest that ketamine-induced synaptic plasticity opens a 'therapeutic window' for psychotherapy, but current research methods cannot adequately test causal relationships due to unblinding and general limitations of psychotherapy studies.
Translational Psychiatry
May 12, 2026
Linda Bryant, Laith Alexander, Sergio Mena et al.
A machine-learning model using structural brain scans predicted which adults with treatment-resistant depression would respond to a single ketamine infusion. The model, trained on 99 participants, achieved 72% balanced accuracy in the discovery sample and 60% in two independent groups, with performance dropping to chance in a saline-treated control group. Greater gray matter volume in frontal regions predicted response, while greater cerebellar volume predicted non-response. The findings suggest that pre-treatment brain structure may help guide personalized treatment decisions for ketamine therapy.
Archives of suicide research : official journal of the International Academy for Suicide Research
May 9, 2026
Gregory Carter, Maree Hackett, Stevan Nikolin et al.
Ketamine's effect on suicidal ideation in adults with treatment-resistant depression remains uncertain. In a phase III double-blind randomized trial comparing subcutaneous racemic ketamine to midazolam over four weeks, one cohort showed no significant difference between groups on either the MADRS item 10 or the C-SSRS measure of suicidal ideation. A second cohort showed a non-significant reduction on the MADRS item 10 but a significant reduction on the C-SSRS. Baseline suicidal ideation scores were low in both cohorts. Adverse events requiring clinical review occurred in 13.8% of all treatment sessions. The authors suggest flexible-dose subcutaneous racemic ketamine may have beneficial effects on suicidal ideation scores, but future studies need to be powered for suicidal ideation as a primary outcome.
Psychological Medicine
May 8, 2026
Lou-Anne Chavigny, Véronique Desbeaumes Jodoin, Nicolas Garel et al.
A systematic review of 21 studies involving approximately 900–1,180 participants with treatment-resistant depression found that low-dose intravenous ketamine preserves and enhances certain cognitive functions. Improvements were frequently observed in processing speed and working memory, while attention remained stable or modestly improved. Results for verbal and visual memory varied across studies. Executive control, especially inhibitory performance on Stroop tasks, improved in several trials. No cognitive worsening was reported. Two studies directly examined cognition in relation to suicidal behaviors, suggesting that procognitive effects, particularly in executive control, may mediate ketamine's antisuicidal action. Standardized longitudinal studies are needed to clarify durability and clinical significance.