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
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.
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.
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.
Psychedelics.
October 14, 2025
Mingming Zhao, Jianjun Yang, Kenji Hashimoto
MDMA (ecstasy) is a unique entactogen that increases serotonin in the brain by reversing the serotonin transporter, and also affects catecholamine and oxytocin pathways. In clinical trials, MDMA-assisted psychotherapy has led to substantial improvements in treatment-resistant PTSD, though regulatory approval has been delayed due to concerns about unblinding and protocol rigor. Early placebo-controlled studies suggest benefits for autism spectrum disorder, eating disorders with comorbid PTSD, and anxiety from life-threatening illness. Large observational studies link MDMA use with lower depression rates, reduced suicidal ideation, and improved posttrauma coping, but causal inference is limited.