medRxiv Preprint Server
March 31, 2026
Maia Mallevays, Louise Fuet, Michel Danon et al.
1 citation
preprint
In patients with treatment-resistant depression receiving esketamine, mystical experiences—similar to those induced by classic psychedelics—occurred in 58% of patients, with high variability across sessions. Higher mean and peak scores on the Mystical Experience Questionnaire (MEQ-30) were associated with greater improvement in depression severity, while dissociative or other non-mystical effects were not. Positive mood and mystical dimensions of the MEQ predicted therapeutic outcomes, and baseline spirituality predicted both treatment response and peak MEQ scores in the first week. These findings suggest that psychedelic-like mystical experiences may contribute to esketamine's therapeutic efficacy.
J Int Med Res
March 29, 2026
Hui Li, Jingjing Deng, Tao Liu et al.
Esketamine, a derivative of the anesthetic ketamine, is gaining popularity in China for surgical anesthesia, pain management, and treating mental illness due to its potent analgesic and anesthetic properties. This narrative review of literature up to June 2025 summarizes its pharmacological properties, clinical uses in surgical anesthesia, perioperative analgesia, painless procedures, intensive care, emergency care, and special populations like children and obstetric patients. It also covers organ-protective effects and adverse effects. The authors conclude that esketamine offers broader and safer applications than ketamine, particularly for psychiatric disorders.
Behavioural Brain Research
March 28, 2026
Lucas Villar Pedrosa Da Silva Pantoja, Luiza Fernanda Ramos Soares, Brenda Costa Da Conceição et al.
Adolescent female rats that received intranasal ketamine for three consecutive days, mimicking weekend recreational use, showed impairments in episodic, social, and working memory 24 hours after the last dose. The memory deficits were accompanied by reduced serotonin and norepinephrine levels in the hippocampus and prefrontal cortex. The findings indicate that early ketamine withdrawal following acute exposure disrupts cognition and monoamine signaling in the adolescent female brain.
Psychopathology
March 27, 2026
Xiaoran Ding, Yaping Wu, Juan Yang et al.
1 citation
Ketamine is a rapid-acting antidepressant, especially for treatment-resistant depression, working through multiple targets in the glutamatergic system. It blocks NMDA receptors, which disinhibits dopamine reward pathways and increases BDNF expression via eEF2K suppression, activating the mTOR pathway and enhancing synaptic plasticity. Neuroimaging shows ketamine rapidly reshapes prefrontal-limbic connectivity and normalizes brain activity. It has a fast onset and broad therapeutic window, but enantiomers and metabolites differ in effects. Long-term safety, dependence risk, and cognitive effects require monitoring. Future work should explore synergistic treatments and safer ketamine derivatives for precision psychiatry.
Medicine Advances
March 27, 2026
Thomas Edward Cutting, Richard Evans Hartman
Ketamine and its stereoisomers show efficacy for PTSD and treatment-resistant depression, with (R)-ketamine having fewer side effects. The therapeutic mechanisms involve specific brain regions: the dentate gyrus, prefrontal cortex, CA3 region of the ventral hippocampus, dorsal raphe nucleus, and the prelimbic–dorsal raphe nucleus circuit. For PTSD, ketamine attenuates serotonin signaling in the dorsal raphe nucleus and activates that circuit. When given before stress, it increases purine and pyrimidine metabolism, potentiates inhibitory neurotransmitters, and dampens excitatory ones except glutamic acid. Brain-derived neurotrophic factor activation of tropomyosin-related kinase B appears necessary for treatment effects, but N-methyl-D-aspartate receptor antagonism may not be.
Journal of Clinical Psychopharmacology
March 24, 2026
Riccardo Guglielmo, Emma Laura Facchinetti, Daniele Cioci et al.
Treatment-resistant depression, affecting up to one third of people with major depressive disorder, often involves lasting cognitive problems that hinder recovery. A systematic review of six studies found that esketamine does not appear to cause cognitive decline in adults aged 18 to 80. Improvements in attention and processing speed were the most frequent and robust findings, seen in both randomized trials and naturalistic studies. Memory remained stable in short-term studies but improved with longer follow-up. Executive functions improved mainly in participants with baseline impairments and in long-term assessments. Overall, esketamine appears cognitively safe and may offer selective cognitive benefits, particularly in attention and processing speed, potentially supporting functional recovery.
Behavioral Sciences
March 24, 2026
J. Richard Kendrick, Ghonwa Ahmad, Audrey Wood et al.
An analysis of 500 high-engagement threads (12,852 comments) from the r/TherapeuticKetamine subreddit found that people primarily use ketamine for mood-related concerns (53%). Positive effects, most often improved emotional well-being (65%), were reported alongside adverse effects that were predominantly psychological or mood-related (56%). 70% of reported doses exceeded 149 mg, indicating a trend toward higher doses. Intravenous administration (40%) and sublingual troches (23%) were the most common routes. Concurrent use of prescribed psychotropics, cannabis, and psychedelics was also reported. The findings suggest substantial heterogeneity in individual experiences and underscore the importance of clinical monitoring for addiction potential and drug interactions.
Biomolecules
March 24, 2026
Veronica Begni, Floriana de Cillis, Natascha Pfeiffer et al.
Classical and rapid-acting antidepressants alter how the brain responds to acute stress through different molecular programs. In mice exposed to swim stress, imipramine dampened stress-induced neural activation in the cortex and striatum, while ketamine preserved it. Hippocampal activation remained robust and unaffected by either drug. BDNF expression changed only in the striatum, where imipramine reduced the stress-related increase. Both drugs similarly promoted active coping behaviors, but through distinct mechanisms. The findings suggest that cortical and striatal transcriptional signatures differentiate classical from rapid-acting antidepressant action, though human studies are needed to confirm clinical relevance.
Journal of psychopharmacology (Oxford, England)
March 21, 2026
J García-jiménez, D Nuñez-arias, G Carretero Merelo et al.
In a real-world clinical setting across three Spanish centers, esketamine nasal spray produced progressive improvements in depressive symptoms and functioning in adults with treatment-resistant depression. Among 50 patients, significant reductions in depression severity and disability were observed at every assessment from week 2 through discharge, with notable gains during weeks 8–16. The median time to response was 8 weeks, and to remission 16 weeks; overall response and remission rates reached 70% and 68%. Suicidal risk shifted early toward lower categories, with no suicide attempts during treatment. Higher refractoriness, measured by the Maudsley Staging Model, independently predicted lower odds of response and remission.
Nan fang yi ke da xue xue bao = Journal of Southern Medical University
March 20, 2026
Zhuoning Zhang, Xinyu Hao, Fuyang Cao et al.
Esketamine produces antidepressant effects in mice subjected to chronic restraint stress by activating glutamatergic neurons in the medial prefrontal cortex. In a study of 150 male C57BL/6J mice, those treated with esketamine showed reduced immobility in tail suspension and forced swim tests and increased sucrose preference compared with saline-treated controls. Immunofluorescence staining indicated higher c-Fos expression in glutamatergic neurons after esketamine treatment. Chemogenetic activation of these neurons mimicked the antidepressant effects, while their inhibition blocked esketamine's benefits.
Journal of Psychoactive Drugs
March 20, 2026
Marina A. M. Portes, Leandro J Bertoglio
Endurance athletes face unique psychological and physical stressors, yet their knowledge and attitudes toward psychedelic therapies are largely unknown. A survey of 28 Brazilian endurance athletes (mean age 37) found that 64% reported a lack of mental health support in their athletic environments. Only 11% had prior psychedelic experience, while 79% were open to legal, supervised psychedelic therapies. However, 61% were unaware of evidence for psychedelics in treating mental health conditions, and 78% mistakenly believed psychedelics are addictive. Women more often reported pharmacological treatment for depression or anxiety. The findings highlight unmet mental health needs, knowledge gaps, and misconceptions, pointing to a need for targeted, evidence-based education.
BMC Psychiatry
March 17, 2026
Bernhard T Baune, Kevin Rosemann, Dimitri Hefter et al.
2 citations
In real-world clinical settings, intranasal esketamine shows effectiveness for treatment-resistant depression, with response varying based on patient characteristics. The text describes factors associated with treatment response but does not specify which factors or provide concrete numbers.
Journal of the American Academy of Child and Adolescent Psychiatry
March 17, 2026
Yunjia Liu, Qiang Wang
Adolescent major depressive disorder is a leading cause of disability and a major risk factor for suicide. For 30% to 50% of patients who do not achieve remission after multiple treatments, consequences are substantial. Selective serotonin-reuptake inhibitors, though first-line, often take weeks to work and many adolescents do not respond, leaving a critical treatment gap. Esketamine, an NMDA receptor antagonist, may provide faster relief than conventional antidepressants, including as a monotherapy for treatment-resistant depression, but its neural mechanisms in the developing brain are not fully understood. Understanding these mechanisms is needed to guide clinical use and targeted prevention.
Biological Psychiatry
March 16, 2026
Xianglian Wang, Jing Xia, Heyi Luo et al.
Ketamine produces rapid antidepressant effects but also causes hyperlocomotion, a side effect linked to increased dopamine activity in the ventral tegmental area (VTA). Cannabidiol (CBD) blocked ketamine-induced hyperlocomotion in mice when given systemically (30 mg/kg) or directly into the VTA (10 μg per mouse). Whole-brain imaging showed that ketamine increased neuronal activity in the VTA, prefrontal cortex, and nucleus accumbens, which CBD reduced. Electrophysiology revealed that ketamine suppressed glycine receptor (GlyR) function, while CBD reversed this dysfunction by antagonizing ketamine-driven delays in GlyR activation. In GlyRα1S296A mice, CBD's effect on hyperlocomotion was abolished, indicating that VTA GlyRα1 signaling, particularly the S296 residue, is essential for CBD's dissociation of ketamine's therapeutic and adverse effects.
Cureus
March 14, 2026
Suneha Shelke, Rusheeth Thummalapally
Treatment-resistant depression (TRD) affects up to a third of people with major depressive disorder who do not respond to standard antidepressants. Esketamine, a nasal spray approved for TRD in 2019, blocks NMDA receptors and may also reduce compulsive and addictive behaviors in patients whose depression and substance use disorders are linked. This review of randomized trials, cohort studies, systematic reviews, and animal research suggests that esketamine can reduce drug-seeking behavior, lessen cravings, and improve outcomes when paired with behavioral therapies like mindfulness. In rodent studies, esketamine reduced cocaine-seeking after abstinence, and clinical data hint at benefits for alcohol misuse. Esketamine may offer a dual treatment for depression and addiction, but larger studies are needed to confirm its effects and safety.
Clinics and practice
March 13, 2026
Alessandro Guffanti, Matteo Leonardi, Natascia Brondino et al.
In three young adults (ages 20–25) with mild to moderate autism spectrum disorder and treatment-resistant depression, intranasal esketamine added to standard antidepressants reduced depressive symptoms. Two patients achieved clinical remission at six months, and one showed partial response. Suicidal ideation decreased, but mentalization and social cognition improved only mildly. Subjective quality of life rose substantially for all three. No major side effects occurred. These preliminary observations require confirmation in controlled trials.
Child and Adolescent Psychiatry and Mental Health
March 13, 2026
Marc-Antoine Crocq, Philippe Auby
The recent approval of esketamine for adults has renewed interest in psychedelic compounds for psychiatric use, but their relevance for children and adolescents is unclear. This review examines the rationale for investigating classic serotonergic psychedelics (e.g., psilocybin, LSD), the entactogen MDMA, and dissociative compounds like ketamine and esketamine in young populations. Ongoing and planned trials primarily involve adolescents aged 16 years and older, driven by unmet needs in child and adolescent psychiatry, where few medications are approved and therapeutic response is often unsatisfactory. Potential targets include anorexia nervosa, autism spectrum disorder symptoms, obsessive-compulsive disorder, resistant depression, and severe PTSD. Translation to pediatric populations requires caution due to developmental vulnerabilities and limited long-term safety data.
Neurochemical Research
March 13, 2026
Lan Luo, Miao Yu, Xiaodong Li et al.
Esketamine given to mice after traumatic brain injury (TBI) improved neurological outcomes, reduced neuronal death, and lessened neuroinflammation. The drug suppressed astrocyte activation, inhibited pro-inflammatory A1 astrocyte differentiation, and promoted protective A2 astrocyte formation. These effects occurred through inhibition of the METTL5/c-Myc/PD-L1 signaling pathway. The findings suggest esketamine has significant anti-inflammatory and neuroprotective properties that could be relevant for treating TBI.
Basic & Clinical Pharmacology & Toxicology
March 11, 2026
Chendi Zhao, Yang Wang, Jinglang Wu et al.
Esketamine, the right-handed form of ketamine, blocks the NMDA receptor and is used as an anesthetic that reduces postoperative pain and opioid use. It also shows fast-acting antidepressant effects. Beyond anesthesia, esketamine has anti-inflammatory, antiapoptotic, and antioxidant properties in various diseases. This review describes esketamine's neuroprotective effects in central nervous system disorders, detailing how it influences neuronal apoptosis, microglial polarization, and astrocytic functions. The underlying molecular mechanisms involve inflammatory pathways and signaling cascades in neurological disorders.
Pharmacological Reports
March 11, 2026
Benjamin D. Brody, Dora Kanellopoulos
1 citation
People with both substance use disorders and treatment-resistant depression are more likely to respond to ketamine, which is effective for depression but also has misuse potential. The authors contrast a biological mechanism with a possible expectancy effect to explain this link, and advise weighing risks and benefits when using ketamine for these patients.
Int J Psychiatry Clin Pract
March 11, 2026
Michele Prato, Matteo Carminati, Filippo Frizzi et al.
1 citation
In a real-world clinical setting, intranasal esketamine and accelerated repetitive transcranial magnetic stimulation (rTMS) showed comparable effectiveness for treatment-resistant depression. Both treatments led to significant reductions in depressive symptoms, with no statistically significant difference between the two approaches. The findings suggest that either option can be a viable fast-acting intervention for patients who have not responded to prior treatments.
CNS Spectrums
March 10, 2026
Halima Faisal, Gia Han Le, Angela T H Kwan et al.
Ketamine rapidly alters brain reward circuitry in people with major depressive disorder, particularly in fronto-striatal and limbic networks. In a synthesis of 13 neuroimaging studies involving 623 participants (482 with depression, 141 controls), intravenous ketamine (typically 0.5 mg/kg over 40 minutes) changed resting-state connectivity in ventral striatal-prefrontal and default mode, salience, and executive networks within 2 to 48 hours, with some effects lasting up to 10 days. Task-based imaging showed altered ventral striatal responses during reward anticipation and feedback, and changes in medial prefrontal activity during emotion processing. PET scans indicated increased prefrontal-cingulate metabolism and region-specific serotonin receptor binding changes. Few studies directly measured anhedonia, suggesting the findings reflect broader antidepressant mechanisms.
bioRxiv (Cold Spring Harbor Laboratory)
March 10, 2026
Arina Nikitina, Christian Bustamante Toro, Raymond Gifford et al.
Ketamine rapidly silences population bursting in human forebrain organoids by disconnecting a subset of 'backbone' neurons that normally drive network activity, while individual neuron firing continues mostly unchanged. Acute exposure to 20 μg/mL ketamine abolished population bursts, reduced mean firing rates, and decreased functional connectivity globally, with backbone units losing their normally elevated connectivity. Re-exposure after chronic treatment no longer silenced bursting, indicating tolerance, though the network remained less active and less connected with fewer backbone units. The organoid-microelectrode array platform offers a scalable human-relevant system for studying circuit-level drug effects.
Annals of Clinical Psychiatry
March 10, 2026
Brian S. Barnett
Mental healthcare providers discussing esketamine (Spravato) online between 2019 and 2022 most frequently cited billing and reimbursement problems (65.1% of posts), billing codes (48.9%), staffing (18.3%), and pharmacy or drug procurement issues (16.7%) as implementation challenges. Sentiment about reimbursement was mostly negative (72.3%), and most posts comparing esketamine to ketamine favored using ketamine (86.7%). The findings suggest that under-reimbursement, billing difficulties, and logistical barriers may be hindering the adoption of esketamine for treatment-resistant depression.