International Journal of Drug Delivery Technology
June 30, 2026
Angelin Grace Thomas, Dhivyaprasath Palaniappan, Sagar Guruswamy et al.
Esketamine nasal spray reduces depressive symptoms more effectively than a placebo or other treatments like quetiapine for people with treatment-resistant depression. Many patients felt better within days, and some benefits lasted weeks or months after stopping treatment. Most side effects, such as dizziness, nausea, and blood pressure changes, were mild to moderate and resolved within two hours. No serious side effects or deaths were reported. Gathering patient feedback during treatment helped doctors create better care plans. Some studies had small sample sizes, and long-term effects beyond 12 months are not well documented. Ongoing phase 3 studies aim to clarify optimal dosages and long-term outcomes.
Preprints.org
June 30, 2026
preprint
Ketamine shows antidepressant effects by blocking NMDA receptors and promoting neuroplasticity. Combining it with psychotherapy may enhance treatment for depression, trauma, addiction, and other serious conditions by temporarily disrupting rigid thought patterns and enabling new cognitive and emotional connections. This approach remains experimental and is recommended only after standard treatments fail. The article outlines the neurobiological basis of altered states of consciousness and presents initial clinical experience with ketamine-augmented hypnotherapy (KAHT) as one specific method of ketamine-assisted psychotherapy.
Current neuropharmacology
June 30, 2026
Jiaying Wang, Rui Zhang, Yuanyuan Ma et al.
Prenatal exposure to ketamine or its analog 2-fluorodeschloroketamine disrupts mitochondrial energy production in developing brain cells, increasing the risk of neurological damage. Using human cerebral organoids and single-cell RNA sequencing of 83,436 cells, the study found that both substances altered gene networks controlling mitochondrial oxidative phosphorylation in cortical cells. Experiments in fetal mouse neurons confirmed that exposure increased mitochondrial fragmentation and oxidative stress while reducing ATP production capacity. These energy disruptions during rapid brain development can make offspring more vulnerable to neurological issues. The results provide direct evidence of neurodevelopmental toxicity from these substances and identify mitochondrial dysfunction as a probable primary molecular mechanism.
Neuropsychiatrie : Klinik, Diagnostik, Therapie und Rehabilitation : Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater
June 30, 2026
Cielo A Estela-Fernandez, Reem Mohamed Yousif Elsheikh, Dal Bianco Beatrice et al.
Psychedelics show significant potential for treatment-resistant depression (TRD) by promoting neuroplasticity, corticolimbic function, and epigenetic changes beyond serotonergic agonism. Psilocybin-assisted therapy induces short-term symptom improvement lasting weeks to months. Ketamine, in intravenous, subcutaneous, and oral forms, produces rapid and robust reductions in depressive symptoms and relapses without impairing cognitive function. Esketamine yields early, clinically meaningful improvements in function and productivity. Ayahuasca demonstrates fast and sustained effects with higher remission rates and good safety. Despite encouraging findings, large, well-designed studies are needed before psychedelics become standard recommendations for TRD.
Asian Journal of Medical Sciences
June 30, 2026
Raja Suhail Shounthoo, Ajaiz Rasool, Athar Un Nisa Quraishi et al.
Ketamine, a dissociative anesthetic developed in the 1960s, is experiencing a resurgence as a treatment for depression and pain. Unlike standard antidepressants that target monoamine systems, ketamine works by modulating glutamate, a key neurotransmitter, and enhancing synaptic plasticity. It shows rapid antidepressant effects in treatment-resistant depression and effectiveness for both acute and chronic pain. However, significant concerns remain about long-term safety, lack of standardized protocols, and potential for misuse. This review examines ketamine's expanding roles in anesthesia, psychiatry, and pain medicine, highlighting its mechanisms, clinical uses, safety issues, and gaps in current evidence.
Journal of affective disorders
June 29, 2026
Yao Ge, Lijuan Chen, Yu Shen et al.
In people with major depressive disorder, the balance between excitation and inhibition across the brain's cortex is disrupted, particularly in the parietal and prefrontal-cingulate regions. Using resting-state functional magnetic resonance imaging data from 254 patients and 451 healthy controls, the Hurst exponent—a proxy for excitation-inhibition balance—was found to be significantly reduced in patients. This imbalance was linked to specific gene expression related to neuronal structure, metabolism, and mitochondrial function, as well as to neurotransmitter systems including GABA, opioid, serotonin, and synaptic density. In a separate trial of 32 patients with treatment-resistant depression, ketamine increased the Hurst exponent in the anterior cingulate and medial prefrontal cortices, suggesting that restoring excitation-inhibition balance may underlie ketamine's antidepressant effects.
Asian J Psychiatr
June 28, 2026
A single adolescent with treatment-resistant depression, severe obesity, and pseudo-Cushing syndrome showed rapid improvement in depressive symptoms after a single intravenous infusion of ketamine. The patient's depression scores dropped substantially within 24 hours, and the improvement persisted for at least one week. This case suggests that ketamine may be a rapid-acting option for adolescents with complex, treatment-resistant depression, even when accompanied by significant medical comorbidities.
Behavioral and brain functions : BBF
June 28, 2026
Godson Emeka Anyanwu, Victoria Onyemachi Chukwu, Nto Johnson Nto et al.
Ketamine, an NMDA receptor antagonist, induces cognitive impairments and neurotransmitter imbalances that resemble schizophrenia. In male Wistar rats, mangiferin—a potent antioxidant—was tested for its ability to reverse these effects. Mangiferin dose-dependently improved spatial learning, working memory, and recognition memory, and normalized locomotor activity. It restored cortical GABA and glutamate levels, reduced dopamine and acetylcholinesterase activity, preserved brain cell structure, and reversed ketamine-induced astrogliosis while increasing Nrf2 expression, indicating activation of antioxidant defenses. Mangiferin shows potential for treating neuropsychiatric conditions involving oxidative stress and glial dysfunction.
Anatolian Journal of Emergency Medicine
June 28, 2026
Sergey Motov
Ketamine, while essential in emergency medicine, can cause four specific adverse effects that clinicians must recognize. Acute psycho-perceptual effects occur in up to 92% of patients receiving sub-dissociative ketamine by intravenous push but can be reduced by about 40% with slow infusion. Ketamine-induced cystitis affects 25–27% of chronic users and is progressive but partially reversible with early cessation. Ketamine-induced cholangiopathy occurs in roughly 10% of chronic users and mimics primary sclerosing cholangitis. Recreational ketamine use has surged globally, with US seizures increasing over 1,100% between 2017 and 2022 and UK treatment admissions rising fivefold since 2015. Across all chronic toxicity syndromes, ketamine cessation is the single most important intervention.
Clinical Neuropsychopharmacology and Addiction
June 25, 2026
Luca Persico, Giacomo D’andrea, Clara Cavallotto et al.
Intranasal esketamine substantially reduced depression severity in 210 patients with treatment-resistant depression treated in routine clinical practice. Depression scores improved markedly over three months, and men showed a modest advantage over women by the end of treatment, with lower depression ratings and higher rates of response and remission. Among patients under 65 years, sex differences were small and not statistically significant; among those 65 and older, men appeared to benefit more numerically, but this difference did not hold up after statistical correction and remains uncertain. Discontinuation rates and safety outcomes were similar between sexes. The authors call for future studies to examine hormonal, vascular, inflammatory, and other factors that might explain the observed sex differences.
Journal of psychopharmacology (Oxford, England)
June 25, 2026
Joost C Van Mechelen, Tobias A Wieles, Laura G J M Borghans et al.
Oral S-ketamine (S-KETPO) has poor bioavailability (9-12%) and produces much lower peak concentrations of S-ketamine but higher levels of its active metabolites norketamine and hydroxynorketamine compared to intravenous S-ketamine (S-KETIV). In 16 healthy participants, S-KETIV caused sedative, psychomotor, and psychotomimetic effects along with reductions in brain electrical activity, while the higher oral dose (0.45 mg/kg) showed limited psychotomimetic effects and smaller brain activity reductions, and the lower oral dose (0.20 mg/kg) had no effects. Safety was similar across treatments. These pharmacokinetic and pharmacodynamic differences may affect dose selection and therapeutic outcomes in treatment-resistant depression.
British journal of clinical pharmacology
June 24, 2026
Catherine M K E De Cuba, Annika A De Goede, Joost C Van Mechelen et al.
A single intravenous dose of S-ketamine produced acute and delayed effects on brain activity and motor cortex excitability that lasted up to seven days in 16 healthy adults. Intravenous S-ketamine reduced motor-evoked potential amplitude acutely and caused a sustained weakening of long-interval intracortical inhibition, which followed a linear relationship with drug concentration. Transcranial magnetic stimulation combined with electroencephalography showed acute changes in brain electrical activity across all treatments, but delayed changes only after intravenous and high-dose oral S-ketamine. Electroencephalography revealed acute decreases in alpha, beta, and delta power with eyes closed, and sustained increases in delta power with eyes open, the latter also showing a linear concentration-effect relationship. These delayed pharmacodynamic effects are distinct from acute effects and may help explain S-ketamine's antidepressant action.
Frontiers in Psychiatry
June 24, 2026
Kathryn Fletcher, Nadine Ezard, Krista J. Siefried et al.
People with methamphetamine use disorder who underwent ketamine-assisted psychotherapy described the treatment as a multi-stage process rather than a simple drug effect. Participants reported that ketamine created a temporary state of reduced emotional and cognitive reactivity, which they called 'psychological space,' making them more receptive to psychotherapy. However, behavioral changes—including reduced methamphetamine use—were variable and depended on ongoing therapeutic engagement, personal motivation, and life context. Participants were uncertain whether improvements came from the ketamine, the therapy, or the supportive environment. Acceptability was generally high when treatment occurred in a structured clinical setting.
International Journal of Innovative Technologies in Social Science
June 24, 2026
Irmina Grygutis, Oskar Mikołajczyk, Kornelia Julia Fimiarz et al.
Ketamine and its derivative esketamine are rapid-acting treatments for treatment-resistant depression, but the best way to give them depends on balancing effectiveness, safety, cost, and available healthcare resources. Intravenous (IV) ketamine works fastest and most strongly but requires infusion equipment and monitoring for temporary high blood pressure and dissociation. FDA-approved intranasal esketamine has strong long-term data but needs supervised in-clinic administration and blood pressure checks. Oral and sublingual forms are easier and cheaper but less effective and carry higher risk of misuse. Subcutaneous and intramuscular injections offer high absorption with minimal setup but have little supporting evidence. The choice of route should be tailored to each patient's situation.
Journal of psychopharmacology (Oxford, England)
June 24, 2026
Shreya Vasudeva, Gabrielle F M Lovell, Sabrina Wong et al.
Ketamine and its enantiomer esketamine show low risk of abuse, dependence, or misuse when administered under controlled clinical supervision, based on a systematic review of 30 studies (25 clinical and 5 preclinical). Clinical studies found minimal evidence of craving, dose escalation, or illicit use in monitored settings. Preclinical work indicated that (S)-ketamine produces reward-related behaviors, racemic ketamine shows reinforcing effects at higher doses, and (R)-ketamine has minimal reinforcing effects. Abuse risk was identified mainly in case reports lacking proper monitoring. The findings support safe incorporation of ketamine into mood disorder treatment protocols with structured administration and ongoing monitoring.
Nature Structural & Molecular Biology
June 22, 2026
Qianru Jiang, Jianming Han, Eve Fine et al.
Ketamine, used for treatment-resistant depression and severe pain, acts primarily by blocking the N-methyl-D-aspartate receptor, but its therapeutic and abuse-related effects may involve additional targets. Structural evidence shows that ketamine and its analog phencyclidine (PCP) can directly bind to and activate human opioid receptors. The study identifies key molecular motifs involved in this binding and efficacy modulation, and also reveals the structure of the ligand-free state of the κ opioid receptor. Ketamine exhibits more dynamic binding than PCP at the orthosteric site, which may explain its distinct pharmacology. These findings indicate that opioid receptors are important for understanding ketamine's clinical versatility.
Journal of Education Health and Sport
June 22, 2026
Urszula Szuleta, Wiktoria Zawada, Krystian Kaczmarek et al.
Major depressive disorder often resists current treatments; a reanalysis of the STAR*D study found a cumulative remission rate of about 41% after up to four treatment steps. Ketamine and its derivatives have attracted attention for their rapid antidepressant effects, especially in treatment-resistant depression. This review summarizes evidence on their efficacy, safety, and clinical use. Ketamine appears promising due to its fast onset of action, and some evidence suggests it may reduce suicidal ideation in high-risk patients. However, the authors emphasize the need for further large-scale, long-term studies to clarify the durability of benefit and long-term safety.
UNC Libraries
June 21, 2026
Verina Guirguis
Esketamine is an effective treatment for individuals with treatment-resistant depression, showing significant mood improvements shortly after administration. In a study of five participants with major depressive disorder, subjective feelings of 'Highness' increased by 31.73% and 'Happiness' by 22.75% within 15 minutes. A notable reduction in alpha power was observed, peaking at a decrease of 46.36% at 35 minutes post-administration. These changes correlate with mood fluctuations, suggesting dynamic brain network alterations during treatment.
Progress in neuro-psychopharmacology & biological psychiatry
June 20, 2026
Aline Freyssin, Reina Benabou, Hanna Zoe Müller et al.
A novel compound, RST-01, a fluoroalkyl derivative of amantadine, shows promise as a treatment for early PTSD in preclinical rat models, producing efficacy without the dissociative side effects or neurotoxic Olney's lesions associated with R,S-ketamine and memantine. In vitro electrophysiological assays measuring IC₅₀ values for human GluN1/GluN2A-D receptors revealed that RST-01 has a more differentiated selectivity profile across the four GluN2 subunits compared to ketamine or memantine. This distinct subunit-specific pharmacological signature offers a mechanistic explanation for the improved safety margins observed, supporting development of safer NMDAR-targeting therapies.