Kenji Hashimoto - The Consciousness Library

Comparative network pharmacology analysis of ketamine and xanomeline in major depressive disorder: Shared and distinct molecular mechanisms.

Progress in neuro-psychopharmacology & biological psychiatry June 20, 2026 Xin Ding, Kenji Hashimoto, Jian-Jun Yang

Major depressive disorder (MDD) is a leading cause of disability worldwide, and currently available antidepressants remain limited by delayed onset of action, incomplete response, and adverse effects. Ketamine is a rapid-acting antidepressant, whereas xanomeline, an M1/M4 muscarinic receptor agonist, may represent a mechanistically distinct non-monoaminergic strategy. However, the molecular...

DOI: 10.1016/j.pnpbp.2026.111727 Full text Ketamine Major depressive disorder Molecular docking Network pharmacology +1

Antibiotic-induced Microbiome Depletion Selectively Reduces Baseline Hypothalamic Oxytocin Signaling without Affecting MDMA-induced Oxytocin Response in Rats.

Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology May 31, 2026 Yong Yue, Yi Cai, Rumi Murayama et al.

To determine whether antibiotic-induced microbiome depletion influences baseline or 3,4-methylenedioxymethamphetamine (MDMA)-induced oxytocin signaling in rats. Male Wistar rats received broad-spectrum antibiotics (ABX) or water for 7 days, followed by a single oral administration of MDMA (30 mg/kg). Plasma oxytocin levels were measured by ELISA, and oxytocin-immunoreactivity in the...

DOI: 10.9758/cpn.25.1381 Full text Anti-bacterial agents Gut-brain axis N-methyl-3,4-methylenedioxyamphetamine Oxytocin

Xanomeline-trospium reverses phencyclidine-induced cognitive deficits through modulation of the gut microbiota-brain axis in mice

Translational Psychiatry May 20, 2026 Xin Ding, Rumi Murayama, Yi Cai et al. 1 citation

), a combination of the muscarinic M1/M4 receptor agonist xanomeline and the peripherally restricted antagonist trospium, effectively reduces psychosis but is associated with gastrointestinal adverse effects. Here, we tested whether KarXT reverses phencyclidine (PCP)-induced cognitive deficits through microbiota-associated mechanisms in adult male mice. Mice received saline or PCP (10...

DOI: 10.1038/s41398-026-04097-0 Full text Cognition Schizophrenia object-oriented programming Modulation music Central nervous system +2

Pleiotropic modulation of the gut-brain-lung axis by ketamine and its enantiomers.

Molecular Psychiatry April 13, 2026 Xin Zhao, Xinyu Zhang, Shiying Yuan et al.

Ketamine, a potent N-methyl-D-aspartate receptor (NMDAR) antagonist, is widely used for anesthesia and analgesia and, because of its rapid antidepressant effects, in psychiatry. Increasing evidence suggests that ketamine and its enantiomers-(R)-ketamine (arketamine) and (S)-ketamine (esketamine)-also modulate systemic immunity and provide organ protection, partly through interactions with the...

DOI: 10.1038/s41380-026-03590-8 Full text

Therapeutic Potential of Classical Psychedelics and NonHallucinogenic Psychoplastogens in Psychiatric Disorders

Psychiatry and Clinical Psychopharmacology March 30, 2026 Kenji Hashimoto, Feyza Arıcıoğlu, Mesut Çetin

Major depressive disorder remains a leading cause of disability worldwide, and current antidepressants are limited by delayed onset and incomplete response. Building on advances driven by ketamine research, renewed interest has focused on classical serotonergic psychedelics—particularly psilocybin, N,N-dimethyltryptamine (DMT), 5-methoxy-DMT, and lysergic acid diethylamide (LSD)—which, under...

DOI: 10.65801/pcp.3512 Serotonergic Addiction Blinding Expectancy theory +6

Rethinking the Treatment-Resistant Depression.

Advances in experimental medicine and biology 2026 Yunfei Tan, Kenji Hashimoto 1 citation

Treatment-resistant depression (TRD) affects about one-third of people with major depression and leads to higher suicide rates, impaired functioning, and increased healthcare use. Originally defined as nonresponse to tricyclic antidepressants, TRD now encompasses inadequate response to multiple antidepressant classes, psychotherapy, and neuromodulation. Inconsistent criteria-varying by agency,...

DOI: 10.1007/978-981-95-6872-7_5 Full text Ketamine Biomarkers Individualized treatment Inflammation +2

Intestinal γδ T17-IL-17A signaling disrupts hippocampal mitophagy in stress-induced depression and is restored by arketamine.

Journal of Neuroinflammation December 18, 2025 Mengqi Han, Bing Xie, Yuan Yu et al.

Chronic stress precipitates depression, yet how gut-immune-brain interactions translate stress into mood pathology remains unclear. We tested the hypothesis that stress-primed small intestinal γδ T cells drive hippocampal mitochondrial dysfunction and depression-like behavior via interleukin-17A (IL-1A). In mice exposed to chronic restraint stress (CRS), we combined behavioral assays...

DOI: 10.1186/s12974-025-03656-4 Full text Depression Ketamine Chronic restraint stress Gut-brain axis +2

Intermittent MDMA Attenuates Ovariectomy-induced Bone Loss via a Gut Microbiota-Bone Axis.

Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology November 30, 2025 Xiayun Wan, Akifumi Eguchi, Rumi Murayama et al. 5 citations

3,4-Methylenedioxymethamphetamine (MDMA) is widely used recreationally but also modulates serotonergic signaling in the gut, potentially influencing the microbiota. Because low bone mineral density (BMD) is common in depression and other psychiatric disorders, we tested whether repeated, intermittent MDMA attenuates BMD loss in ovariectomized (OVX) mice. OVX mice received MDMA (10 mg/kg) three...

DOI: 10.9758/cpn.25.1309 Full text MDMA Bone mineral density Gut microbiota Metabolites

Esketamine prevents postoperative sleep disturbance in patients with preoperative sleep disorders: a role for oral microbiota.

Translational Psychiatry November 24, 2025 Xin-Yu Li, Di Qiu, Ni Du et al. 1 citation

Patients with preexisting sleep disorders face a significantly increased risk of postoperative sleep disturbance (PSD) due to heightened sensitivity to surgical stress, anesthesia, and hospital-related environmental factors. There is a critical unmet need for effective prophylactic medications to prevent PSD, as current treatment options are limited and often inadequate. This study investigated...

DOI: 10.1038/s41398-025-03705-9 Full text Esketamine Ketamine derivative Anesthetic Analgesic +20

MDMA in Psychiatry: From PTSD to emerging indications, safety, and future directions

Psychedelics. October 14, 2025 Mingming Zhao, Jianjun Yang, Kenji Hashimoto

MDMA, 3,4-methylenedioxymethamphetamine (“ecstasy,” “molly”), is a distinctive entactogen that reverses the serotonin (5-HT) transporter to increase synaptic 5-HT, while also engaging catecholaminergic and oxytocinergic pathways. In clinical trials, MDMA-assisted psychotherapy has yielded substantial improvements in treatment-resistant posttraumatic stress disorder (PTSD), although regulatory...

DOI: 10.61373/pp025i.0035 MDMA Anxiety Neuroplasticity Cognition +5

Microglial BDNF modulates arketamine's antidepressant-like effects through cortico-accumbal pathways.

Science Advances July 11, 2025 Lujuan He, Xuenan Wang, Shilin Luo et al. 8 citations

Arketamine, the (R)-enantiomer of (R,S)-ketamine, shows even greater rapid and sustained antidepressant-like effects in rodent models compared to esketamine, yet the underlying mechanisms remain unclear. In this study, we used the chronic social defeat stress (CSDS) model to investigate how arketamine exerts its antidepressant-like effects. We found that activating cAMP response element-binding...

DOI: 10.1126/sciadv.adv5986 Full text Arketamine Neuroplasticity Depression Microglia +15

Demyelination in psychiatric and neurological disorders: Mechanisms, clinical impact, and novel therapeutic strategies.

Neuroscience and Biobehavioral Reviews July 1, 2025 Rumi Murayama, Yi Cai, Hiroyuki Nakamura et al.

Demyelination, defined as the loss of myelin sheaths around neuronal axons, is increasingly recognized as a key factor in a broad range of psychiatric and neurological disorders, including schizophrenia, major depressive disorder, bipolar disorder, post-traumatic stress disorder, autism spectrum disorder, substance use disorders, Alzheimer's disease, Parkinson's disease, and multiple sclerosis....

DOI: 10.1016/j.neubiorev.2025.106209 Full text Ketamine Demyelination Gut-brain axis Oligodendrocyte +3

Extending ketamine's antidepressant effects.

Science (New York, N.Y.) May 8, 2025 Kenji Hashimoto 9 citations

Boosting an intracellular signaling pathway preserves the antidepressant response to ketamine.

DOI: 10.1126/science.adx4559 Full text Ketamine Depression Mental health Pharmacology

Subdiaphragmatic vagotomy reduces hypothalamic oxytocin expression and blood levels after oral MDMA administration in male rats.

Progress in neuro-psychopharmacology & biological psychiatry March 20, 2025 Yong Yue, Xiayun Wan, Guilin Liu et al. 4 citations

3,4-Methylenedioxymethamphetamine (MDMA) is a widely recognized entactogen frequently used recreationally. It is known for its interaction with the serotonin and oxytocin systems, which underlie its entactogenic effects in humans. Recently, we demonstrated that the gut-brain axis, mediated by the subdiaphragmatic vagus nerve, contributes to MDMA-induced resilience enhancement in rodents. This...

DOI: 10.1016/j.pnpbp.2025.111260 Full text Gut-brain axis Oxytocin Paraventricular nucleus Supraoptic nucleus +4

Repeated intermittent administration of 3,4-methylenedioxymethamphetamine mitigates demyelination in the brain from cuprizone-treated mice.

European Journal of Pharmacology March 15, 2025 Mingming Zhao, Akifumi Eguchi, Rumi Murayama et al. 6 citations

3,4-Methylenedioxymethamphetamine (MDMA), commonly known as a recreational drug, may also offer therapeutic benefits for mental health. Population-based studies suggest that MDMA users have a lower risk of demyelinating diseases, such as depression. Given the role of the gut microbiota in mediating MDMA's effects, we hypothesized that MDMA might confer mental health benefits via the gut-brain...

DOI: 10.1016/j.ejphar.2025.177345 Full text MDMA Demyelination Gut microbiota Metabolites +4

Myelin Repair as a Novel Mechanism for Ketamine's Sustained Antidepressant Effects.

Current Neuropharmacology January 16, 2025 Sen Wang, Chaoli Huang, Mengyu Wang et al. 4 citations

Depression is a prevalent mental disorder, affecting approximately 300 million people worldwide. Despite decades of research into the underlying mechanisms of depression, a consensus remains elusive. Recent studies have implicated changes in oligodendrocytes and myelin in the pathogenesis of depression. Conventional antidepressants may alleviate symptoms within weeks of use, but approximately...

DOI: 10.2174/011570159X349856241213144902 Full text Arketamine Depression Esketamine Enantiomer +6

Arketamine alleviates cognitive impairments and demyelination in mice with postoperative cognitive dysfunction via TGF-β1 activation.

Progress in neuro-psychopharmacology & biological psychiatry January 10, 2025 Ting-Ting Zhu, Ming-Ming Zhao, Dan Xu et al. 5 citations

Postoperative cognitive dysfunction (POCD) is characterized by a decline in cognitive functions, including memory, attention, and executive abilities, following surgery, with no effective therapeutic drugs currently available. Arketamine, the (R)-enantiomer of ketamine, has shown promise in mitigating cognitive deficits in animal models. In this study, we investigated whether arketamine could...

DOI: 10.1016/j.pnpbp.2024.111228 Full text Arketamine Demyelination Postoperative cognitive dysfunction Surgery +5

Effects of 3,4-methylenedioxymethamphetamine on the gut microbiota and metabolites in the small intestine, cecum, and colon of male rats.

Progress in neuro-psychopharmacology & biological psychiatry January 10, 2025 Dan Xu, Akifumi Eguchi, Rumi Murayama et al. 4 citations

3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy) is a widely abused recreational drug that has also gained interest for potential clinical applications in mental health. With the growing recognition of gut microbiota's role in mental health, this study examined whether repeated oral MDMA administration could affect gut microbiota in the small intestine, cecum, and colon of male rats. Repeated...

DOI: 10.1016/j.pnpbp.2024.111223 Full text Molly Entactogen Gastrointestinal tract Gut microbiota +6

Effects of arketamine on depression-like behaviors and demyelination in mice exposed to chronic restrain stress: A role of transforming growth factor-β1.

Journal of Affective Disorders December 15, 2024 Dan Xu, Guilin Liu, Mingming Zhao et al. 21 citations

Chronic restrain stress (CRS) induces depression-like behaviors and demyelination in the brain; however, the relationship between these depression-like behaviors and demyelination remains unclear. Arketamine, the (R)-enantiomer of ketamine, has shown rapid antidepressant-like effects in CRS-exposed mice. We examined whether arketamine can improve both depression-like behaviors and demyelination...

DOI: 10.1016/j.jad.2024.08.222 Full text Arketamine Depression Antidepressant Chronic stress +6

Transforming growth factor-β1 mediates the beneficial effects of arketamine on demyelination and remyelination in the brains of cuprizone-treated mice.

European Journal of Pharmacology December 15, 2024 Ming-Ming Zhao, Ting-Ting Zhu, Dan Xu et al. 14 citations

The novel antidepressant arketamine, the (R)-enantiomer of ketamine, has been shown to ameliorate demyelination and facilitate remyelination in the brains of cuprizone (CPZ)-treated mice. However, the mechanisms behind its effects remain unclear. Given the role of transforming growth factor β1 (TGF-β1) in arketamine's antidepressant-like effects, we examined whether TGF-β1 also plays a role in...

DOI: 10.1016/j.ejphar.2024.177096 Full text Arketamine Cuprizone Demyelination Remyelination +5

Splenic γδ T cells mediate antidepressant and prophylactic actions of arketamine in lipopolysaccharide-induced depression in mice.

Pharmacology, biochemistry, and behavior December 1, 2024 Guilin Liu, Li Ma, Akemi Sakamoto et al. 4 citations

Arketamine, the (R)-enantiomer of ketamine, exhibits both therapeutic and sustained prophylactic effects in an inflammation-driven model of depression, although the precise mechanisms remain elusive. Given the involvement of γδ T cells in inflammatory processes, this study explored their role in the effects of arketamine. To assess therapeutic outcomes, mice received lipopolysaccharide (LPS:1.0...

DOI: 10.1016/j.pbb.2024.173906 Full text Arketamine Prophylactic Spleen Antidepressants antidepressant medication +8

Ketamine attenuates kidney damage and depression-like behaviors in mice with cisplatin-induced acute kidney injury.

Translational Psychiatry November 9, 2024 Tianwen Huang, Yangyang He, Ruijuan Cheng et al. 5 citations

Acute kidney injury (AKI) is a serious condition characterized by decreased urine output, often accompanied by psychiatric symptoms like depression. However, there are limited pharmacological treatments available for AKI and its associated depressive symptoms. In this study, we investigated whether cisplatin-induced AKI in mice leads to depression-like behaviors and whether ketamine could...

DOI: 10.1038/s41398-024-03176-4 Full text Ketamine therapy Mental health treatment Nephrology research Psychopharmacology +1

Role of oxidative phosphorylation in the antidepressant effects of arketamine via the vagus nerve-dependent spleen-brain axis.

Neurobiology of Disease September 1, 2024 Lijia Chang, Yan Wei, Youge Qu et al. 22 citations

Arketamine, the (R)-enantiomer of ketamine, exhibits antidepressant-like effects in mice, though the precise molecular mechanisms remain elusive. It has been shown to reduce splenomegaly and depression-like behaviors in the chronic social defeat stress (CSDS) model of depression. This study investigated whether the spleen contributes to the antidepressant-like effects of arketamine in the CSDS...

DOI: 10.1016/j.nbd.2024.106573 Full text Arketamine Oxidative phosphorylation Spleen-brain axis Vagus nerve +5

Ketamine and its two enantiomers in anesthesiology and psychiatry: A historical review and future directions

Journal of Anesthesia and Translational Medicine July 11, 2024 Kenji Hashimoto, Mingming Zhao, Tingting Zhu et al. 32 citations

Ketamine, a dissociative anesthetic, is widely utilized in both human and veterinary anesthesia. Its (S)-enantiomer, esketamine, is similarly employed for anesthesia and analgesia. The anesthetic effects of both ketamine and esketamine arise from their antagonism of the N-methyl-D-aspartate receptor (NMDAR). In field of psychiatry, the rapid-acting antidepressant properties of ketamine for...

DOI: 10.1016/j.jatmed.2024.07.001 Ketamine Treatment-resistant depression Major depressive disorder Anxiety +10

A role of gut-brain axis on prophylactic actions of arketamine in male mice exposed to chronic restrain stress.

Pharmacology, biochemistry, and behavior May 1, 2024 Li Ma, Akifumi Eguchi, Guilin Liu et al. 11 citations

The gut-brain axis, which includes gut microbiota and microbiome-derived metabolites, might be implicated in depression. We reported the sustained prophylactic effects of a new antidepressant arketamine in chronic restrain stress (CRS) model of depression. In this study, we investigated the role of gut-brain axis on the prophylactic effects of arketamine in the CRS (7 days) model. Pretreatment...

DOI: 10.1016/j.pbb.2024.173736 Full text Chronic restrain stress Gut microbiota Metabolites Prophylactic effect: resilience +5

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