Source / Quelle: https://jintb.org/index.php/jintb/article/view/30
Abstract
Inflammation and oxidative stress contribute to numerous human diseases. Conventional therapies provide symptomatic relief but fail to address molecular dysfunction. Cannabinoids emerge as promising modulators of these processes, influencing CB1/2 receptor signaling, regulating NF-κB and Nrf2 pathways, and reactive oxygen species production. Preclinical studies demonstrate them to reduce cytokine release, limit oxidative damage, and protect tissue integrity across multiple systems. Early clinical investigations suggest potential benefits in pain management, neurodegeneration, and metabolic conditions. Future research focusing on minor and synthetic cannabinoids, biomarker-guided dosing, and combination therapies can enhance translational success, but regulatory and safety considerations remain critical. By bridging mechanistic insights with clinical application, cannabinoids hold significant potential to address diseases driven by inflammation and oxidative stress and to expand therapeutic landscape.
1.Inflammation
Inflammation and oxidative stress are contributors to the development and progression of numerous diseases (1,2). Chronic or dysregulated inflammatory responses can damage tissues and disrupt homeostasis, whereas oxidative stress leads to cell injury through excessive reactive oxygen species (ROS) production (3-5). These processes create a self-perpetuating cycle that underlies disease pathology; highlights urgent need for effective modulators. Despite advances in anti-inflammatory and antioxidant therapies, current treatments exhibit limited efficacy, off-target effects, or toxicity in chronic conditions. Nonsteroidal anti-inflammatory drugs, corticosteroids, and conventional antioxidants can alleviate symptoms but rarely address underlying molecular drivers (6,7). This therapeutic gap underscores the importance of identifying novel strategies that target pathways linking inflammation and oxidative stress. Cannabinoids emerged as promising modulators of these processes. Endocannabinoids maintain physiological balance by interacting with cannabinoid receptors throughout body, and phytocannabinoids such as cannabidiol and tetrahydrocannabinol (THC) exhibit diverse immunomodulatory and redox-regulating effects (8,9). Synthetic cannabinoids offer opportunities to fine-tune receptor specificity and pharmacokinetics, expanding potential for targeted interventions (10,11).
This review aims to integrate mechanistic insights with translational perspectives and highlight how cannabinoids influence inflammatory signaling and oxidative pathways in both experimental and clinical contexts. By bridging molecular evidence with therapeutic potential, we provide a comprehensive framework to understand the role of cannabinoids in managing diseases where inflammation and oxidative stress are key players. Such approach is essential to guide future research, informing clinical strategies, and translating basic discoveries into meaningful patient outcomes. The integrated role of cannabinoids in modulating inflammation and oxidative stress and their translational relevance is summarized (Figure 1).Figure 1: Cannabidiol modulates inflammation and oxidative stress. Cannabidiol reduces pro-inflammatory cytokine production, oxidative stress and enhances antioxidant responses. The combined modulation contributes to improved outcomes in neurodegenerative disorders, autoimmune diseases, and pain management.
2. Endocannabinoid System
Endocannabinoid system (ECS) is complex signaling network that plays pivotal role in maintaining physiological homeostasis and modulating inflammation and oxidative stress (8,12,13). CB1 receptors are highly abundant in central nervous system, where they influence neurotransmission, neuroinflammation, and neuronal survival (14,15). In contrast, CB2 receptors are also expressed in immune cells, macrophages, microglia, and lymphocytes, where they regulate immune activation, cytokine release, and oxidative responses (16-19). The differential localization of these receptors allows ECS to coordinate tissue-specific responses to physiological and/or pathological stimuli. Endogenous ligands anandamide and 2-arachidonoylglycerol serve as intrinsic modulators of CB1 and CB2 receptor activity. These molecules are synthesized on demand from membrane phospholipids and rapidly degraded by enzymes like fatty acid amide hydrolase and monoacylglycerol lipase (8,20).
Anandamide engages CB1 receptors but can also interact with CB2 and non-cannabinoid targets, whereas 2-arachidonoylglycerol exhibits potent agonism at both receptor types (21-23). Through these ligands, ECS finely tunes cellular responses to stress and balances pro-and anti-inflammatory signals and influencing oxidative pathways.Activationof cannabinoid receptors initiates multiple intracellular signaling cascades relevant to inflammation and oxidative stress. CB1/2 signaling involves inhibition of adenylate cyclase, modulation of cyclic AMP levels, and regulation of mitogen-activated protein kinases (MAPKs). These pathways can suppress the transcription of pro-inflammatory mediators, enhance antioxidant defenses, and modulate apoptosis. In immune cells, CB2 reduces ROS production, limits inflammatory cytokine release, and promotes a shift toward anti-inflammatory phenotypes, underscoring its role in maintaining immune and redox balance (17,24-26).ECS exhibits extensive cross-talk with other physiological systems. In immune system, cannabinoid signaling interconnects Toll-like receptors and NF-κB pathways (27,28). In metabolic tissues, ECS interacts with insulin and adipokine signaling (29). In nervous system, endocannabinoid signaling modulates neurotransmitter release, glial activation, and neuroinflammatory cascades (30,31). This highlights ECS as a hub integrating multiple pathways that converge on inflammation and oxidative stress, making it a compelling target for therapeutic intervention. By mapping expression, signaling, and systemic interactions of CB1/2 receptors, along with endogenous ligands, a clearer understanding emerges of how ECS can be harnessed to modulate disease-relevant pathways. Control of inflammation and oxidative stress by ECS provides a foundation for exploring cannabinoid-based therapies with precision and specificity.
3. Cannabinoids and Inflammation
Cannabinoids have been studied to modulate inflammatory processes, providing convincing evidence of their immunoregulatory potential. In vitro studies demonstrate that both endocannabinoids and phytocannabinoids can attenuate the production of pro-inflammatory cytokines, chemokines, and ROS (32,33). Similarly, animal models of inflammatory disease show reduced tissue damage and improved functional outcomes following cannabinoid administration (34,35). These findingsunderscore a consistent pattern, i.e., cannabinoids act as modulators, rather than immune response suppressors. At molecular level, cannabinoids influence key signaling pathways that govern inflammation. One central mechanism involves NF-κB pathway. CB2 receptor activation in immune cells inhibits NF-κB translocation to nucleus, reducing pro-inflammatory cytokines transcription (36-40). Additionally, cannabinoids modulate MAPK and PI3K/Akt pathways, affecting cell survival, proliferation, and inflammatory mediators production (41). These effects enable finely tuned suppression of excessive inflammation while preserving essential immune functions. Disease-specific investigations highlight therapeutic relevance of cannabinoids. In neuroinflammation models, e.g., multiple sclerosis or Alzheimer’s disease, cannabinoids reduce microglial activation, limit oxidative stress, and preserve neuronal integrity (42,43). Autoimmune disease models, including rheumatoid arthritis and inflammatory bowel disease, demonstrate decreased leukocyte infiltration, cytokine release, and tissue injury following cannabinoid treatment (44,45). In metabolic disorders, chronic low-grade inflammation drives insulin resistance and cardiovascular risk; cannabinoids have improved inflammatory profilesand mitigate organ damage (46,47). Collectively, these studies suggest that cannabinoids exert multi-level control over both acute and chronic inflammatory responses. Importantly, anti-inflammatory effects of cannabinoids are context-dependent, influenced by receptor subtype expression, ligand concentration, and tissue microenvironment (48,49). For example, CB2 receptor activation tends to dominate in peripheral immune tissues, whereas CB1-mediated modulation can impact neuroimmune interactions (26,41). This spatial and functional specificity underscores need for targeted approaches when considering therapeutic applications. By linking cellular mechanisms to disease-relevant outcomes, preclinical research provides robust foundation to explorecannabinoids as inflammation modulators. Evidence suggests not only alleviating pathological immune activation but also a potential to restore homeostatic balance across multiple organ systems. The integrated role of cannabinoids in modulating inflammation and oxidative stress, including CB1/CB2 receptor signaling, NF-κB inhibition, Nrf2 activation, and ROS regulation is illustrated (Figure 2).
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