{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:49:48Z","timestamp":1793040588138,"version":"4.5.0"},"reference-count":239,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The endocannabinoid system (ECS) is a primary regulatory system in human physiology that serves to help maintain homeostasis throughout the nervous system, immune system, and gastrointestinal system. This review has the goal of evaluating the unique opportunity for the ECS to provide a regulatory axis within the microbiota\u2013gut\u2013brain axis, particularly with regard to neurodevelopment, immune tolerance, and gut health. Cannabinoid receptors CB1 and CB2 and endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG have the ability to provide a variety of signaling pathways that can regulate cognitive resilience, emotional tuning, and immune regulation. Because the ECS has the ability to regulate multiple neurochemicals, alter immune cell functions, and maintain gut barriers, the ECS exists at the crossroads of many physiological systems, which also have a predictive role in neurodegenerative disease, chronic inflammation, and mental illness. Our goal is to present the latest and best recent advances in the ECS literature and establish evidence that there exists some modest potential for the therapeutic modulation of the ECS to improve pathological manifestations of cross-system dysregulation. In addition to cellular signaling pathways, the ECS affects other homeostatic processes, such as synaptic plasticity and the level of neuroprotection in the CNS, immune-related homeostasis, and coordinating the composition of gut microbiota. We argue that the ECS represents a suitable new therapeutic target that could modulate dysregulation across these systems more inclusively. This paper aims to emphasize the proposed potential of the ECS\u2019s position in this axis and propose advanced cannabinoid-based interventions as a novel mechanism for developing personalized medicine and health systems through multi-system integration.<\/jats:p>","DOI":"10.3390\/ijms262211132","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T09:58:42Z","timestamp":1763459922000},"page":"11132","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["The Endocannabinoid System in Human Disease: Molecular Signaling, Receptor Pharmacology, and Therapeutic Innovation"],"prefix":"10.3390","volume":"26","author":[{"given":"Matei","family":"\u0218erban","sequence":"first","affiliation":[{"name":"Puls Med Association, 051885 Bucharest, Romania"},{"name":"Department of Neurosurgery, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Vascular Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 077160 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corneliu","family":"Toader","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Vascular Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 077160 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u0103zvan-Adrian","family":"Covache-Busuioc","sequence":"additional","affiliation":[{"name":"Puls Med Association, 051885 Bucharest, Romania"},{"name":"Department of Neurosurgery, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Vascular Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 077160 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1530\/EC-19-0548","article-title":"The Endocrine Disruptor DEHP and the ECS: Analysis of a Possible Crosstalk","volume":"9","author":"Ernst","year":"2020","journal-title":"Endocr. 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