“This paper presents a shared perspective from scientists and clinicians seeking to harness the therapeutic potential of cannabis while addressing Cannabis Use Disorder (CUD) through reproducible scientific findings.
Rather than blocking CNR1 receptors, which may induce hypodopaminergia, we propose a pro-dopaminergic strategy using a natural nutraceutical formulation designed to enhance dopamine release and upregulate D2 receptor mRNA, thereby increasing D2 receptor density.
Given the failure of CNR1 antagonists such as Rimonabant, we argue for an opposite approach: restoring dopamine balance through CNR1 stimulation rather than inhibition.”
“Purpose: To investigate the endocannabinoid system (ECS) and affective state responses to acute aerobic exercise in adult cancer patients versus their healthy peers.
Methods: Participants engaged in 30 min of quiet rest followed by 30 min of exercise. Exercise involved 5-min warm-up/cool-down procedures and 20 min of moderate-intensity training (64-76% of age-predicted maximal heart rate) on a treadmill or cycle. Blood samples and 10 Visual Analog Scales (VAS) were collected before and after each condition. Participants were also asked after exercise: ‘Did you experience a Runner’s high’. Blood samples were analysed for endocannabinoids: N-arachidonoylethanolamine (AEA; anandamide), 2-arachidonoylglycerol (2-AG) and 1-arachidonoylglycerol (1-AG), and endocannabinoid-like lipid mediators: palmitoylethanolamide (PEA), oleoylethanolamide (OEA) and stearoylethanolamide (SEA).
Results: Cancer patients had lower circulating AEA, OEA and log SEA versus controls across all timepoints (all p < 0.06). In the total cohort, exercise increased AEA, log 1-AG, OEA, PEA and log SEA (all p = 0.05) while log 2-AG did not change. Of 10 VAS, only Happiness increased with exercise in the total cohort (p = 0.02). There were no group x time effects or associations between ECS and VAS responses to exercise. Five patients per group (50%) reported experiencing a Runner’s high.
Conclusions: Exercise increased endocannabinoids and endocannabinoid-like lipid mediators in the total cohort. However, cancer patients exhibited lower AEA, OEA and SEA concentrations versus their peers, indicating potential ECS dysfunction.
Additional research is required to investigate the effect of various modalities and dosages of exercise on ECS markers and the clinical interpretation of these adaptations across a range of cancer populations.”
“This systematic review explores the role of the endocannabinoid system (ECS) in prodromal psychosis and its potential as a therapeutic target.
Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, 22 studies published between 2000 and 2025 were analyzed, comprising preclinical research, genetic studies, neuroimaging investigations, and clinical trials.
Converging evidence suggests that ECS alterations precede and potentially contribute to the development of psychotic symptoms, with CB1 receptor modifications and endocannabinoid levels correlating with symptom severity and transition risk to full-blown psychosis.
Neuroimaging studies revealed reduced CB1 receptor availability in key brain regions in high-risk subjects, and intervention studies, particularly with cannabidiol-though its therapeutic mechanisms likely extend beyond ECS modulation to include dopaminergic and other neurotransmitter pathways-have shown promising results.
Proposed mechanisms of action include stress response attenuation, neuroinflammatory modulation, neurodevelopmental stabilization, and normalization of the dopamine-glutamate interface.
Despite limitations of existing studies, primarily small size and short duration, this review provides a solid foundation for developing ECS-targeted interventions as a promising approach to modify disease trajectory during the prodromal phase, potentially offering safer and more effective therapeutic options for individuals at clinical high risk for psychosis.”
“Introduction: The endocannabinoid system plays a role in sleep-wake regulation. In clinical practice, people with central disorders of hypersomnolence (CDH) frequently report use of cannabis.
Methods: We compared lifetime and current use of cannabis of people with CDH to the Dutch general population. Additionally, we assessed cannabis use in relation to hypersomnolence symptoms.
Results: In total, 76 (out of 88) patients completed the online questionnaire. Lifetime cannabis use (42% vs. 23%, p < 0.001) and current use (18% vs. 4%, p < 0.001) were higher in people with CDH compared to the Dutch general population. For 57% of patients currently using cannabis, improvements of at least one CDH symptom were the motivation for use. Additionally, 79% of current cannabis users reported cannabis-related effects on a symptom, which were mostly positive (43%), some negative (7%), or mixed effects (29%). Patients that stopped using mostly started using cannabis before symptom onset and for recreational purposes. The most reported reasons to stop using were disadvantages of using or changes in the social environment.
Conclusion: This study provides a rationale for future research on the potential benefits of cannabis in CDH.”
“Cannabinoids and their G protein-coupled receptors (GPCRs) within the endocannabinoidome are pivotal regulators of neuromodulation, inflammation, and metabolic homeostasis.
Dysregulation of this system has been associated with a wide spectrum of pathological conditions, including neuropsychiatric disorders, chronic pain, and immune dysfunction.
In this review, we summarize recent structural advances in cannabinoid receptors that have deepened our understanding of receptor activation, allosteric modulation, transducer coupling selectivity, and dynamic conformational mechanisms.
These structural insights will facilitate cannabinoid receptor-targeted drug discovery, enabling the development of therapeutics with improved subtype selectivity, enhanced signaling precision, and reduced off-target effects.”
“The medicinal use of phytocannabinoids has been documented for millennia, with applications across diverse cultures in the treatment of insomnia, pain, epilepsy, headaches, and inflammation. Modern scientific investigation into cannabis began in the 1930 s, culminating in the isolation and structural characterization of its major constituents.”
“Taken together, these findings highlight cannabinoid receptors as multifaceted and dynamic therapeutic targets positioned at the intersection of neurology, immunology, and metabolism. A deeper understanding of its structural and signaling mechanisms will be critical for the rational design of next-generation cannabinoid-based therapies that harness its extensive regulatory potential with precision.”
“Background: Chronic stress is an important factor for the development of mental health impairments, such as depression and generalized anxiety disorder. Chronic social defeat (CSD) stress is an ethologically valid model of chronic stress in rodents, combining elements of psychological and physical stress. The endocannabinoid (eCB) system plays important roles in maintaining the homeostasis of biological systems through the tuning of neuronal excitability, thereby mediating a protective role after prolonged stress exposure.
Methods: In the present study, we investigated genetically modified adult male mice where the eCB signal via anandamide (AEA) was reduced (by deletion of the AEA synthesizing enzyme NAPE-PLD) or enhanced (by deletion of the AEA degradation enzyme FAAH), as well as mice lacking the cannabinoid CB1 receptor. These genetic manipulations were induced in glutamatergic neurons of the dorsal telencephalon. After the application of CSD stress, the phenotypes of these mutant mice were investigated in a battery of behavioral tests assessing sociability, anxiety, memory, shelter-seeking behavior, and despair.
Results: We could confirm a robust anxiogenic effect of CSD in the EPM test. Interestingly, we have not observed a stress effect on the sociability of any of the mouse lines as identified in the SI test. Under non-stress conditions, we observed an anxiogenic phenotype in Glu-CB1-KO and Nex-NAPE-PLD KO, and hyperlocomotion in Nex-FAAH KO mice. Additionally, we could confirm a drastic reduction of FAAH protein levels in cortical and subcortical regions of Nex-FAAH line, and a moderate reduction of NAPE-PLD protein in cortical regions of Nex-NAPE-PLD KO mice.
Conclusions: In conclusion, genetic manipulation of the endocannabinoid system in cortical glutamatergic neurons did not result in persistent effects of prolonged stress exposure. Detected differences between the genotypes in the non-stressed groups points toward baseline differences that could mask or over-power the effect of stress.”
“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-gut-brain 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’s 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.”
“In summary, the ECS presents the opportunity to appreciate how modern biology is reconstituting the definition of health—not as an absence of disease but in promoting maintenance of the homeostatic ability of the organism to interact with heterogeneous systems.”
“Collectively, the convergence of biotechnology, engineering, AI, and multi-omics is transforming ECS research and its translational potential. This convergence provides a platform for developing personalized ECS interventions that consider the interplay among the neural, immune, and microbiota systems in a unified therapeutic approach.”
“The endocannabinoid (eCB) system has been proposed as a potential target for developing new medications for opioid use disorder (OUD). However, the status of the eCB system, specifically brain cannabinoid receptor type 1 (CB1R) in OUD, is unknown.
In this study, CB1R availability was measured in males with OUD on stable opioid agonist treatment (OAT) (n = 10) versus healthy controls (HC) (n = 18), using High-Resolution Research Tomography (HRRT) and the CB1R-specific radiotracer, [ 11 C]OMAR. The average volume of distribution ( VT ) across 13 regions was compared between the OUD and HC groups. Average VT was 15% lower in OUD vs. HC subjects (p = 0.04). Lower VT in OUD compared to HC was also observed in several corticolimbic areas.
Within OUD no effects on CB1R availability were observed for treatment medication (methadone vs. buprenorphine), current stress levels, or antidepressant medication. No associations between the average VT and duration of OAT treatment or time since the last illicit opioid use were observed.
This preliminary study suggests lower CB1R availability in men with OUD. Larger studies are necessary to replicate these findings. Future research should also draw from a more heterogeneous population, particularly by incorporating females, to better assess the potential confounding and moderating clinical factors. If confirmed, the observed alterations in CB1R availability in OUD may provide a rationale for targeting the eCB system in the treatment of OUD.”
“The inflammatory response during acute lung injury and ARDS leads to an overactive immune response, causing further damage and irreparable recovery. While there are drugs to target various pathogens that cause acute lung diseases, still, the consequences of infection-induced inflammatory signaling and damage prevention are limited with available drugs.
With the rise of cannabinoids as a potential therapeutic agent in several inflammatory disease states, many studies have specifically evaluated their anti-inflammatory effects via CB2 receptors and non-cannabinoid receptors, such as GPR18, in infectious lung injury. However, the exact mechanisms behind CB2 receptor agonism in the application of acute lung injury are still not clear.
Lung macrophages are major immune cells that play a major role in checking and defending the primary and secondary consequences of lung infectious injury. The exact mechanism by which macrophages differentiate to produce anti-inflammatory effects over inflammation is still widely debated during episodes of acute lung injury or respiratory distress.
Using systematic literature evaluation and analysis of current trends and gaps in the literature, we have analyzed the mechanisms that CB2 agonists involve in dampening inflammatory signaling and redirecting the response in acute lung injuries/ARDS by modifying the nature of inflammatory macrophages to anti-inflammatory.
Our systematic review indicated that within the inflammatory macrophage response, CB2 agonists impact several signaling pathways involved in the excessive immune response, reducing the expression of inflammatory transcription factors and inflammatory cytokine storm, and redirecting the macrophages to resolve the lung injury/ARDS.”
“Various studies suggest that monocyte/macrophage adoptive transplantation reverses inflammatory injury. However, these studies showed various signaling pathways, but the question is which signaling pathway is important among those to resolve the ALI/ARDS inflammation? Thus, the full therapeutic implications of CB2 agonists are still unknown. Determining the CB2 receptor agonist signaling pathway for reducing cytokine storm and inflammation by repolarizing inflammatory macrophages into reparative macrophages will have the greatest impact in a clinical context. Studies suggested that CB2 receptor agonists, lacking central unwanted side effects, may be promising therapeutic targets in lung inflammatory diseases by modulating the pulmonary immune system and converting inflammatory macrophages to the reparative stage.”
“Epithelial-mesenchymal transition (EMT) plays a significant role in conjunctival fibrosis-related pathologies and has emerged as a promising therapeutic target for managing conjunctival fibrosis.
Cannabidiol (CBD), a predominant non-psychoactive cannabinoid derived from the cannabis plant, has demonstrated antifibrotic effects in various extraorbital tissues. However, its influence on fibrosis-associated EMT in conjunctiva remains unexplored.
Given the ubiquitous expression of cannabinoid targets in ocular tissues, including the conjunctiva, and evidence suggesting that modulation of the endocannabinoid system ameliorates ocular pathologies, this study aimed to evaluate the effects of CBD on conjunctival EMT.
Cultured human conjunctival epithelial cells were stimulated with transforming growth factor-beta 1 (TGF-β1) to induce EMT.
CBD treatment effectively mitigated EMT-related changes induced by TGF-β1, including increased cell elongation and migration, reduced epithelial markers (E-cadherin and zonula occludens-1, and elevated mesenchymal markers (alpha-smooth muscle actin and fibronectin) and EMT-associated transcription factor Snail.
Furthermore, CBD suppressed TGF-β1-mediated Smad-2/3 phosphorylation and nuclear translocation. Treatment with a specific TGF-β/Smad pathway inhibitor (SB431542) yielded comparable results, suggesting that the inhibitory effects of CBD on EMT involve disruption of TGF-β/Smad signaling. Additionally, the EMT phenotype was associated with increased interleukin-6 (IL-6) secretion, which was also attenuated by CBD treatment.
This study confirms that CBD effectively prevents EMT and EMT-associated IL-6 secretion by targeting TGF-β/Smad signaling, highlighting its therapeutic potential in mitigating conjunctival fibrosis.”
“Our study revealed the anti-EMT effects of CBD in conjunctival epithelial cells, mediated through inhibition of the TGF-β-Smad-Snail axis. “
“Overall, as a compound with diverse properties, CBD may improve ocular surface pathologies resulting from inflammation and fibrosis through regulation of EMT and the associated inflammatory secretome, while also exerting neuroprotective and antinociceptive effects.”
