The Endocannabinoid System as an Adaptive Hub: Beyond Canonical Cannabinoids in Neuropharmacology

The endocannabinoid system (ECS) is increasingly recognized not merely as a receptor–ligand signaling pathway, but as a dynamic integrative network that coordinates neural, immune, and metabolic responses to environmental challenges. In the central nervous system, the ECS plays a crucial role in adaptive processes related to stress resilience, neuroinflammation, immune competence, and synaptic plasticity.While early pharmacological strategies predominantly focused on direct agonism or antagonism of cannabinoid receptors, clinical translation has been hindered by safety concerns, limited specificity, and context-independent modulation. Emerging evidence now suggests that functionally tuning the ECS, rather than globally activating or blocking it, may represent a more effective and physiologically aligned therapeutic approach.This Research Topic aims to gather preclinical and clinical evidence on novel molecules capable of modulating ECS signaling beyond classical cannabinoid paradigms. Special emphasis will be placed on repurposed drugs, plant-derived bioactive compounds, and synthetic molecules originally developed for non-cannabinoid indications, which nonetheless exert meaningful effects on ECS components or tone.We particularly encourage contributions exploring compounds with established immunomodulatory, neuroactive, or stress-related indications, and addressing how their interaction with the ECS contributes to neuroprotection, immune–brain crosstalk, and adaptive homeostasis. By integrating pharmacology, neurobiology, and translational research, this topic seeks to highlight the ECS as a therapeutically actionable hub rather than a standalone target, fostering innovative strategies for neurological and neuropsychiatric disorders.We welcome original research articles, reviews, and clinical studies addressing, but not limited to:• Functional ECS ModulationIndirect, context-dependent, or tone-preserving modulation of ECS signaling as an alternative to direct receptor agonism/antagonism.• Drug Repurposing and Non-Canonical ECS ModulatorsEvidence that clinically used drugs or well-characterized bioactive molecules interact with ECS components or influence endocannabinoid tone.• Plant-Derived Compounds Beyond PhytocannabinoidsPolyphenols, terpenes, alkaloids, fatty acid derivatives, and other phytochemicals modulating ECS-related pathways, with attention to standardization and translational relevance.• Stress, Immune Competence, and NeuroinflammationECS modulation in conditions characterized by chronic stress exposure, immune suppression or dysregulation, and low-grade neuroinflammation.• Neuroadaptive and Neuroprotective MechanismsECS-mediated effects on synaptic plasticity, glial function, mitochondrial signaling, and resilience to neurodegenerative insults.• Enzymatic and Allosteric Modulation in Physiological ContextsFAAH, MAGL, and allosteric modulators studied in disease-relevant or stress-related models rather than purely pharmacodynamic settings.• Translational and Clinical PerspectivesBiomarkers, safety considerations, and clinical implications of ECS modulation by non-classical or repurposed compounds. Topic editors: Giovanna Rigillo, Marco Biagi, Anna Roszkowska Source: https://www.frontiersin.org/research-topics/73000/the-endocannabinoid-system-as-an-adaptive-hub-beyond-canonical-cannabinoids-in-neuropharmacology