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This review evaluates the hypothesis that Longgu's therapeutic effects arise from a synergistic network of its constituent metal ions. We synthesized evidence from chemical analyses, pharmacological studies of Ca, Mg, Zn, Fe, Cu, and Mn, and clinical trials of Longgu\u2010containing formulations. The metal ions form an integrated network exhibiting three emergent properties. First, ionostatic balance is achieved through Ca\/Mg\u2010mediated regulation of neuronal excitability. Second, cross\u2010pathway synergy occurs where zinc concurrently modulates neurotransmission and promotes neuroplasticity via BDNF. Third, systemic integration involves zinc and manganese co\u2010regulating the gut\u2013brain axis. Clinical studies demonstrate that Longgu\u2010containing formulations improve outcomes in depression, anxiety, and insomnia, particularly for comorbid conditions, and show synergistic effects when combined with conventional antidepressants. This network pharmacology framework repositions Longgu as a model for developing multi\u2010target therapeutics, offering a strategy to overcome limitations of single\u2010target psychiatric drugs.<\/jats:p>","DOI":"10.1002\/cbdv.71623","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:20:50Z","timestamp":1788520850000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metal Ions in Longgu (Fossilized Bone) as a Natural Synergistic Network for Multi\u2010Target Therapy in Psychiatric Disorders"],"prefix":"10.1002","volume":"23","author":[{"given":"Sun","family":"Xiujia","sequence":"first","affiliation":[{"name":"School of Chinese Medicine LKS Faculty of Medicine The University of Hong Kong  Hong Kong China"},{"name":"Shanghai Mental Health Center Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2649-0832","authenticated-orcid":false,"given":"Li Zhan","family":"Hua","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine LKS Faculty of Medicine The University of Hong Kong  Hong Kong China"},{"name":"The Second Affiliated Hospital of Guangxi University of Chinese Medicine  Nanning Guangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gao","family":"Yuanze","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine LKS Faculty of Medicine The University of Hong Kong  Hong Kong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Jing","sequence":"additional","affiliation":[{"name":"Sichuan Neautus Traditional Chinese Medicine Co., Ltd.  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