Nature
November 5, 2025
Chenyu Yue, Nan Wang, Haojiang Zhai et al.
22 citations
Adenosine signaling is identified as the central mechanism underlying the rapid antidepressant effects of ketamine and electroconvulsive therapy (ECT). Experiments in mice using genetically encoded adenosine sensors and real-time optical recordings show that both therapies cause strong adenosine surges in mood-regulatory brain regions such as the medial prefrontal cortex and hippocampus. Disrupting A1 and A2A adenosine receptors genetically or pharmacologically abolishes the therapeutic effects, establishing adenosine's essential role. Ketamine increases adenosine by modulating cellular metabolism without causing neuronal hyperactivity. Newly developed ketamine derivatives that enhance adenosine signaling show improved antidepressant efficacy with fewer side effects. Acute intermittent hypoxia, a non-pharmacological intervention, also increases brain adenosine and produces antidepressant effects, paralleling ketamine and ECT.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
April 2, 2025
Cong Lin, Xiaoxuan Zhou, Mingqi Li et al.
14 citations
In a mouse model of inflammation-induced depression, S-ketamine (S-KET) reduced depressive-like behaviors and lowered pro-inflammatory factors in the medial prefrontal cortex, while R-ketamine (R-KET) did not. S-KET bound directly to the protein SIRT2 at the Q167 residue, enhancing its interaction with NF-κB subunit p65, which reduced acetylation and suppressed pro-inflammatory gene expression. Experiments using RNA interference, a SIRT2 inhibitor (AK-7), and pharmacological blockade confirmed that SIRT2 is essential for these effects. The findings indicate that SIRT2 mediates the therapeutic actions of S-KET, suggesting a target for treating inflammation-associated depression.
European journal of medicinal chemistry
January 5, 2025
Miyuan Zhang, Yuefeng Yang, Zhishuai Yang et al.
10 citations
The position of the hydroxyl group on the indole ring of psilocin analogs determines their ability to activate the 5-HT2A receptor and produce psychedelic-like effects. Analogs with the hydroxyl group at the 4th or 5th position (psilocin and bufotenine) show significantly higher agonistic activity and head-twitch responses than those with the group at the 6th or 7th position. Computer simulations reveal that the 4- and 5-position analogs form a crucial hydrogen bond with residue L229 and a stable salt bridge and hydrogen bond with residue D155, guiding them into the binding site. Analogs lacking these interactions fail to reach the orthosteric site and have poor receptor activity.
ACS Pharmacology & Translational Science
March 7, 2025
Shuai Hu, Cong Lin, Hongshuang Wang et al.
8 citations
Psychedelics such as psilocybin and MDMA show promise for treating anorexia nervosa by disrupting maladaptive neural circuits, enhancing cognitive flexibility, and facilitating emotional processing. Early studies report reductions in symptoms and improvements in psychological well-being, particularly for patients unresponsive to conventional therapies like cognitive-behavioral therapy and pharmacotherapy. However, further research is needed to establish long-term safety, efficacy, and clinical integration, and to address legal, ethical, and safety challenges.
Nature
January 28, 2026
Zheng Xu, Hongshuang Wang, Jingjing Yu et al.
5 citations
Psychedelics are being tested in over 200 clinical trials as potential treatments for psychiatric disorders, but how they work and their risks are not fully understood. The serotonin 2A receptor (5-HT2AR) is the main target of psychedelics. This study compared psychedelics with non-hallucinogenic analogues using cell and animal experiments, finding that 5-HT2AR signaling through a non-canonical Gi pathway is essential for hallucinogenic effects. Five cryo-electron microscopy structures of 5-HT2AR bound to these drugs were solved. A special contact between non-hallucinogenic analogues and the receptor biased signaling away from Gi. A derivative called DOI-NBOMe showed potent Gq-biased activity and therapeutic effects in mice without causing hallucinations. These findings reveal mechanisms of 5-HT2AR Gi signaling and guide the design of safer psychedelic-based drugs.
ACS chemical neuroscience
May 7, 2025
Hongshuang Wang, Xiaohui Wang
5 citations
Psychedelics may help treat neuropsychiatric disorders by increasing brain entropy and disrupting rigid neural patterns, which can lead to ego dissolution and profound emotional breakthroughs. This process potentially alleviates symptoms of depression, anxiety, PTSD, and addiction. However, clinical use faces challenges such as careful patient screening, managing adverse experiences, and ethical considerations, all essential for safe therapeutic integration.
ACS Pharmacology & Translational Science
May 15, 2025
Haojiang Zhai, Hongshuang Wang, Haohong Li et al.
3 citations
Psychedelics like psilocybin, LSD, and DMT may alter sleep architecture, particularly by influencing rapid eye movement (REM) sleep and vivid dreaming. This viewpoint suggests these substances could have therapeutic potential for sleep disorders, though their impact on sleep remains underexplored. The authors provide a perspective on how psychedelics might affect sleep phases and dreaming, opening an emerging area for sleep therapy.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
May 1, 2025
Yuanpeng Li, Hongyuan Li, Hongshuang Wang et al.
3 citations
Amphetamine-type stimulants (ATS) and their analogs can be rapidly evaluated using the roundworm Caenorhabditis elegans. In a swimming-induced paralysis assay, worms exposed to amphetamine, methamphetamine, MDMA, and their enantiomers showed distinct behavioral responses depending on their genetic makeup. The effects depended on dopaminergic and serotonergic pathways, specifically the DOP-3 and SER-4 receptors. The assay also distinguished between chiral forms of ATS, and meta-R amphetamines produced stronger effects than ortho-R and para-R analogs. This method offers a cost-effective, high-throughput way to assess the activity and toxicity of new psychoactive substances.
ACS Chemical Neuroscience
July 24, 2025
Anjian Yang, Xinyou Lv, Hongshuang Wang et al.
1 citation
This viewpoint proposes that mysticism and fundamentalism can be understood as brain network disorders, where rigid neural patterns underlie inflexible belief systems. Psychedelics such as psilocybin, LSD, and DMT may disrupt these patterns, potentially increasing cognitive flexibility and challenging dogmatic thinking. The authors suggest this modulation could have therapeutic applications for extremism and certain mental health conditions, though the argument remains theoretical and not empirically tested.
Current neuropharmacology
April 28, 2026
Hongshuang Wang, Xiaobing Li, Feng Yu et al.
Combining psychedelics with music in therapy may improve mental health outcomes by acting on specific brain mechanisms. Psychedelics like psilocybin activate 5-HT2A receptors and BDNF-TrkB signaling, increase neural plasticity, and desynchronize the default mode network, while music guides emotional processing and amplifies psychological insights. This synergy shows promise for treating depression, PTSD, and addiction. The review provides a mechanistic framework for understanding these interactions and identifies neurobiological targets for optimizing future therapeutic protocols.