Translational Psychiatry
September 1, 2015
Chun Yang, Yukihiko Shirayama, J-C Zhang et al.
600 citations
R-ketamine, a stereoisomer of the anesthetic ketamine, produces a more potent and longer-lasting antidepressant effect than S-ketamine (esketamine) in mouse models of depression, without causing psychotomimetic side effects or abuse liability. In the social defeat stress and learned helplessness models, R-ketamine more effectively restored decreased dendritic spine density, brain-derived neurotrophic factor (BDNF)-TrkB signaling, and synaptogenesis in the prefrontal cortex, CA3, and dentate gyrus of the hippocampus. Neither isomer affected these measures in the nucleus accumbens. S-ketamine, but not R-ketamine, caused hyperlocomotion, prepulse inhibition deficits, rewarding effects, and loss of parvalbumin-positive cells in the medial prefrontal cortex and dentate gyrus. R-ketamine appears to be a safe, long-lasting antidepressant.
Psychiatry and Clinical Neurosciences
June 19, 2019
Kenji Hashimoto
325 citations
Ketamine, particularly its enantiomers (R)-ketamine and (S)-ketamine, shows rapid and sustained antidepressant effects in patients with treatment-resistant major depressive disorder (MDD) or bipolar disorder (BD). While (S)-ketamine (esketamine) was FDA-approved as a nasal spray in 2019 due to its higher affinity for the NMDA receptor, preclinical data suggest (R)-ketamine may have greater potency, longer-lasting effects, and fewer side effects. The author reviews the historical development of ketamine enantiomers and their metabolites, compares other rapid-acting antidepressant candidates, and discusses the molecular and cellular mechanisms underlying ketamine's effects.
Molecular Psychiatry
May 7, 2021
Wei Yan, Lijia Chang, Kenji Hashimoto
242 citations
The antidepressant effects of the drug (R,S)-ketamine, a mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), are not primarily due to blocking the N-methyl-D-aspartate receptor (NMDAR), despite initial assumptions. Preclinical studies in rodents show arketamine has more potent and longer-lasting antidepressant-like effects than esketamine, even though arketamine binds less strongly to NMDAR. Clinical trials with other NMDAR-blocking compounds failed to produce robust antidepressant effects in humans, indicating rodent findings do not always translate. The exact molecular mechanisms remain unclear. This review covers recent findings on these mechanisms, the possible roles of the brain-gut-microbiota and brain-spleen axes, and arketamine's potential for treating cognitive impairment, Parkinson's disease, osteoporosis, inflammatory bowel diseases, and stroke.
Biochemical pharmacology
July 1, 2020
Kenji Hashimoto
232 citations
Ketamine, developed as an anesthetic in the 1960s, is also abused recreationally for its dissociative effects. It shows strong antidepressant effects in treatment-resistant depression. The racemic mixture contains (R)-ketamine and (S)-ketamine; (S)-ketamine nasal spray was approved by the US FDA in 2019 and in Europe later that year. Although (R)-ketamine has lower affinity for the NMDAR, it produces more potent and longer-lasting antidepressant-like effects in animal models with fewer side effects than (R,S)-ketamine or (S)-ketamine. BDNF and TrkB receptor involvement is suggested, and RNA-sequencing points to TGF-β1 in (R)-ketamine's effects. A pilot study showed rapid, sustained antidepressant effects of (R)-ketamine in treatment-resistant patients. This review covers mechanisms of ketamine enantiomers and metabolites and discusses the brain-gut-microbiota and brain-spleen axes in stress-related disorders.
European Archives of Psychiatry and Clinical Neuroscience
April 18, 2016
Kenji Hashimoto, Takeharu Kakiuchi, Hiroyuki Ohba et al.
125 citations
Esketamine, but not R-ketamine, reduces dopamine D2/3 receptor binding availability in the monkey striatum, indicating that esketamine triggers dopamine release in this brain region. This dopamine release may underlie the psychotomimetic side effects of esketamine. R-ketamine, in contrast, does not affect striatal dopamine D2/3 binding, consistent with its proposed safer profile as a rapid antidepressant. The findings suggest a neurochemical difference between the two ketamine enantiomers that could explain their distinct side-effect profiles.
Progress in Neuro-Psychopharmacology and Biological Psychiatry
July 30, 2006
Eiji Shimizu, Hiroyuki Watanabe, Takashi Kojima et al.
103 citations
No Summary
European Archives of Psychiatry and Clinical Neuroscience
February 27, 2024
Kenji Hashimoto
51 citations
The relationship between mystical experiences and antidepressant effects of ketamine and classic psychedelics like psilocybin is debated. Ketamine can cause dissociative symptoms such as out-of-body experiences, while psychedelics often produce hallucinogenic experiences like a sense of unity. Clinical studies indicate that dissociative symptoms from ketamine or esketamine are not directly linked to their antidepressant properties. The antidepressant potential of arketamine, which lacks dissociative side effects, remains unproven in large-scale trials. Activation of the serotonin 5-HT2A receptor is crucial for psychedelics' hallucinogenic effects, but its role in antidepressant action is unclear. This article examines whether mystical experiences enhance antidepressant outcomes.
Pharmacology, Biochemistry and Behavior
April 22, 2020
J. Witkin, J. Kranzler, K. Kaniecki et al.
33 citations
The (R)-ketamine enantiomer may offer a safer treatment for substance abuse disorder by reducing withdrawal symptoms and drug-seeking behavior without causing negative mood or anhedonia. In experiments with morphine-dependent rats, (R)-ketamine alleviated withdrawal signs and blocked morphine-induced place preference in mice without producing place preference itself. Unlike S-ketamine, (R)-ketamine did not induce anhedonia in rats. These findings suggest (R)-ketamine could dampen withdrawal and drug liking without the dissociative or mood-related side effects that limit current therapies, supporting further preclinical and clinical investigation.
Neurobiology of disease
December 1, 2023
Youge Qu, Akifumi Eguchi, Li Ma et al.
26 citations
Pretreatment with MDMA for 14 days blocked anhedonia-like behavior and reduced synaptic proteins and brain-derived neurotrophic factor in the prefrontal cortex of mice exposed to chronic restraint stress. Cutting the subdiaphragmatic vagus nerve (vagotomy) blocked these beneficial effects. The gut microbiome showed differences in α-diversity between groups, and specific microbes varied between vehicle- and MDMA-treated stressed mice. Vagotomy prevented increases in three plasma compounds seen in MDMA-treated stressed mice, and two of those compounds correlated positively with several microbes. The data suggest that the gut-brain axis via the subdiaphragmatic vagus nerve may contribute to MDMA-induced stress resilience.
Neurobiology of disease
September 1, 2024
Lijia Chang, Yan Wei, Youge Qu et al.
22 citations
In mice susceptible to chronic social defeat stress, removing the spleen reduces arketamine's antidepressant-like effects. RNA sequencing of the prefrontal cortex revealed that the oxidative phosphorylation (OXPHOS) pathway mediates this effect. Inhibiting OXPHOS with oligomycin A reversed the spleen removal's suppressive effect. Specific OXPHOS genes—COX11, UQCR11, and ATP5e—may be involved. Transforming growth factor β1 (TGF-β1) and COX11 appear to modulate the suppression; activating the TGF-β1 receptor with SRI-01138 alleviated it. Cutting the subdiaphragmatic vagus nerve also counteracted the inhibitory effect of splenectomy. These results suggest that arketamine's antidepressant-like effects involve the OXPHOS pathway and TGF-β1 in the prefrontal cortex, communicated through a spleen-brain axis via the vagus nerve.
Journal of affective disorders
December 15, 2024
Dan Xu, Guilin Liu, Mingming Zhao et al.
21 citations
A single dose of arketamine (10 mg/kg) improved both depression-like behaviors and demyelination in the corpus callosum of mice exposed to chronic restraint stress. Correlations linked depression-like behaviors with demyelination in that brain region. Blocking the transforming growth factor β1 (TGF-β1) receptor with RepSox prevented arketamine's beneficial effects, while a single intranasal dose of TGF-β1 alone also ameliorated both depression-like behaviors and demyelination. The precise mechanisms remain unclear, but the findings suggest that stress-induced demyelination in the corpus callosum may contribute to depression-like behaviors, and arketamine may act through a TGF-β1-dependent pathway.
Pharmacology, biochemistry, and behavior
December 1, 2023
Guilin Liu, Li Ma, Youge Qu et al.
16 citations
Arketamine, but not the psychedelic drugs DOI or lisuride, produced long-lasting prophylactic effects in mouse models of depression. Male mice pretreated with arketamine six days before an immune challenge (lipopolysaccharide, LPS) showed reduced body weight loss, less spleen enlargement, less immobility in a forced swim test, and higher levels of the synaptic protein PSD-95 in the prefrontal cortex compared to mice pretreated with DOI or lisuride. Similarly, arketamine given one day before seven days of chronic restraint stress prevented increased immobility, restored sucrose preference, and protected PSD-95 expression. DOI and lisuride did not show these protective effects.
European journal of pharmacology
December 15, 2024
Ming-Ming Zhao, Ting-Ting Zhu, Dan Xu et al.
14 citations
Arketamine, the (R)-enantiomer of ketamine, reduces damage to the myelin sheath and promotes its repair in the brains of mice treated with cuprizone, a chemical that induces demyelination. The beneficial effects occur through a mechanism dependent on transforming growth factor β1 (TGF-β1). Blocking the TGF-β1 receptor with RepSox prevented arketamine's protective effects. Directly administering TGF-β1 intranasally also reduced demyelination and enhanced remyelination in the corpus callosum. These findings suggest that arketamine's effects on myelin repair rely on TGF-β1 signaling, pointing to potential therapeutic targets for demyelinating diseases like multiple sclerosis.
Pharmacology, biochemistry, and behavior
May 1, 2024
Li Ma, Akifumi Eguchi, Guilin Liu et al.
11 citations
Pretreatment with the antidepressant arketamine prevented stress-induced body weight loss, increased behavioral despair, decreased sucrose preference, and reduced synaptic protein expression in the prefrontal cortex of male mice exposed to chronic restraint stress. Gut microbiota analysis indicated that arketamine may restore stress-related changes in microbial abundance. Metabolomics identified four blood metabolites altered between stress-exposed and arketamine-pretreated mice. Network analysis linked synaptic proteins in the prefrontal cortex with specific gut microbes and blood metabolites. These findings suggest that the gut-brain axis, including microbial metabolites, may partly underlie the sustained prophylactic effects of arketamine.
European archives of psychiatry and clinical neuroscience
April 25, 2024
Li-Yuan Zhao, Guang-Fen Zhang, Xue-Jie Lou et al.
11 citations
Over the past two decades, research on the antidepressant effects of ketamine and its enantiomers has grown substantially, culminating in the approval of esketamine nasal spray for treatment-resistant depression. A bibliometric analysis of 4,274 publications from 2000 to 2023, using visualization tools, reveals two main research foci: the efficacy and safety of these compounds in treating depression, and the mechanisms underlying their rapid antidepressant effects. The rapid onset of ketamine's effects has spurred further investigation into its mechanisms and the search for new antidepressants with fewer side effects.
Science (New York, N.Y.)
May 8, 2025
Kenji Hashimoto
9 citations
Ketamine's rapid antidepressant effects are limited in duration. Boosting a specific intracellular signaling pathway, the mammalian target of rapamycin (mTOR) pathway, can preserve the antidepressant response to ketamine in animal models. Activating this pathway extends the duration of ketamine's effects, suggesting a potential strategy for prolonging therapeutic benefits in depression treatment.
Science advances
July 11, 2025
Lujuan He, Xuenan Wang, Shilin Luo et al.
8 citations
Arketamine, the (R)-enantiomer of ketamine, produces faster and longer-lasting antidepressant-like effects than esketamine in mice subjected to chronic social defeat stress. Activating the proteins CREB and MeCP2 drives the production of brain-derived neurotrophic factor (BDNF) in microglia, the brain's immune cells. This microglia-derived BDNF strengthens excitatory synaptic transmission in the infralimbic region of the medial prefrontal cortex (mPFC). It also activates mPFC neurons that project to the nucleus accumbens (NAc) shell, a brain area involved in reward and mood. These mechanisms together underlie arketamine's antidepressant-like effects, highlighting the essential role of microglial BDNF in modulating this neural pathway.
European journal of pharmacology
March 15, 2025
Mingming Zhao, Akifumi Eguchi, Rumi Murayama et al.
6 citations
Intermittent MDMA administration (10 mg/kg, three times weekly for 6 weeks) reduced demyelination in the corpus callosum of mice treated with cuprizone, a chemical that induces myelin loss. The effect appears linked to changes in gut bacteria and metabolites, including β-D-allose, L-sorbose, and carnitine, which correlated negatively with specific microbes such as Romboutsia. These findings suggest MDMA may influence brain demyelination through the gut-brain axis, though further research is needed to clarify the roles of gut microbiota and metabolites.
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
Intermittent doses of MDMA (10 mg/kg three times per week for six weeks) increased whole-body and femoral bone mineral density in ovariectomized mice, compared with vehicle. The treatment shifted bone-remodeling markers toward an antiresorptive profile—lower RANKL and higher osteoprotegerin. Gut microbiota profiling showed reduced Clostridia and enriched Bacilli, and untargeted metabolomics revealed a marked decrease in plasma β-D-allose, a metabolite linked to Lactobacillus johnsonii. These findings suggest that intermittent MDMA may mitigate bone density loss after ovariectomy, potentially through remodeling of a gut microbiota–bone axis. Causal microbial and metabolic mediators remain to be defined.
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) involves declines in memory, attention, and executive abilities after surgery, with no effective drugs available. In a mouse model of POCD, a single injection of arketamine (10 mg/kg) improved cognitive function and reduced demyelination in the corpus callosum. Blocking TGF-β receptor 1 with RepSox (10 mg/kg) prevented these benefits, while intranasal TGF-β1 (3.0 μg/kg) alone alleviated cognitive impairments and demyelination. The findings indicate arketamine acts through a TGF-β1-dependent mechanism, suggesting it as a potential treatment for POCD.
Translational psychiatry
November 9, 2024
Tianwen Huang, Yangyang He, Ruijuan Cheng et al.
5 citations
In mice with cisplatin-induced acute kidney injury (AKI), a single dose of ketamine reduced kidney damage, pathological changes in other organs, and depression-like behaviors. The beneficial effects were reversed by blocking the TrkB receptor, and analysis implicated the TrkB and ERK-CREB signaling pathways and blood metabolites like C16-ceramide. The findings suggest ketamine may alleviate both kidney injury and associated depressive symptoms, though the role of the kidney-brain axis remains unclear.
Progress in neuro-psychopharmacology & biological psychiatry
March 20, 2025
Yong Yue, Xiayun Wan, Guilin Liu et al.
4 citations
The gut-brain axis, specifically the subdiaphragmatic vagus nerve, is critical for MDMA's effects on the oxytocin system in rats. Cutting this nerve (subdiaphragmatic vagotomy) lowered baseline oxytocin levels in the blood and reduced oxytocin expression in the paraventricular and supraoptic nuclei of the hypothalamus. It also dampened MDMA-induced increases in blood oxytocin and the expression of oxytocin and c-Fos in those brain regions. The findings suggest the vagus nerve mediates brain-body communication that underlies MDMA's pharmacological actions on oxytocin.
Current neuropharmacology
January 16, 2025
Sen Wang, Chaoli Huang, Mengyu Wang et al.
4 citations
Depression affects about 300 million people worldwide, and its underlying mechanisms remain unclear. Changes in oligodendrocytes and myelin are implicated in depression pathology. Conventional antidepressants take weeks to work and fail for about one-third of patients. Ketamine provides rapid, sustained antidepressant effects in treatment-resistant patients. Reduced myelination is linked to depression, so repairing myelin damage may be a key mechanism behind ketamine's prolonged effects. This review summarizes the relationship between demyelination and depression and discusses how ketamine might exert antidepressant effects by repairing myelin, offering new insights into the role of myelination in antidepressant mechanisms.
Progress in neuro-psychopharmacology & biological psychiatry
January 10, 2025
Dan Xu, Akifumi Eguchi, Rumi Murayama et al.
4 citations
Repeated oral administration of MDMA (10 mg/kg/day for 14 days) to male rats significantly altered gut microbiota composition in the small intestine, cecum, and colon, with distinct effects in each region. Analysis of microbial functional capabilities indicated shifts in several metabolic pathways. Untargeted metabolomics showed that MDMA changed levels of two metabolites in the colon—ferulic acid and methylmalonic acid—without affecting levels in blood, small intestine, or cecum. Methylmalonic acid levels in the colon positively correlated with the bacteria Lawsonibacter and Oscillibacter. These results suggest that repeated MDMA treatment can modify gut microbiota across intestinal regions, which may contribute to its pharmacological effects.
Pharmacology, biochemistry, and behavior
December 1, 2024
Guilin Liu, Li Ma, Akemi Sakamoto et al.
4 citations
A single dose of arketamine, the (R)-enantiomer of ketamine, reduced depression-like behavior and inflammation in mice given lipopolysaccharide (LPS), a bacterial toxin that triggers an immune response. Arketamine also prevented these effects when given six days before LPS. LPS lowered the proportion of γδ T cells in the spleen, and arketamine reversed this change and reduced spleen enlargement and interleukin-6 levels. Blocking γδ T cells with an antibody eliminated arketamine's benefits, suggesting these immune cells are essential for its effects. The findings indicate splenic γδ T cells may be a new target for treating inflammation-related depression.