“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.”
“Pain management costs the world billions of dollars each year, and there are limited nonopioid options to treat people suffering from chronic pain. Opioids are excellent analgesics but are liable to abuse and fatal overdoses. This Microperspective summarizes challenges and opportunities pertaining to creating nonopioid drugs that could be used to treat chronic pain, substance abuse, fatty liver, or obesity by targeting the cannabinoid receptor type 1 (CB1).”
“The endocannabinoid system (ECS) is essential for energy hemostasis, obesity, and other metabolic disorders.
Cannabidiol and polyunsaturated fatty acids (PUFAs), which are found in hemp seed oil (HSO), have been found to regulate adipose tissue through the ECS. Thus, human mesenchymal stem cells (hMSCs) were differentiated into pre-adipocytes and then treated with cannabidiol (CBD), tetrahydrocannabinol (THC), 0.05% HSO, or 0.1% HSO for 3 days (72 h).
The mixture was subsequently maintained in maintenance media for 14 days, after which the condition media (CM) was collected. In addition, THP-1 cells were used to assess the inflammatory response upon exposure to CM collected from different groups of experimental cells. Quantification for lipid accumulation (Oil red O), gene expression (RT‒qPCR), and protein levels (Western blot) were performed.
We found that HSO-treated cells matured toward brown-like adipose tissue with a spindle shape and decreased intracellular lipid accumulation. HSO treatment decreased the expression of genes associated with fat accumulation and browning (BAT), with the exception of UCP-1, which leans toward brown-like adipocytes. HSO treatment upregulated the cannabinoid receptors 2 (CB2), TRPV1, and GPCR55 mRNAs and leptin mRNA found with lower expression; no alterations were observed in cannabinoid receptors 1 (CB1), FAAH, and MGL mRNAs. In THP-1 macrophage, HSO treated CM decreased the expression of IL-6, IL-8, TNF-α, and leptin mRNAs significantly when compared to CBD and THC.
The potential of HSO in promoting brown fat characteristics through the CB2 and its effect on inflammation status offers an intriguing area for future research and therapeutic interventions.”
“Overall, the availability of balanced ratios of omega 3/omega 6 PUFAs and CBD in HSO favors in maintaining optimal ECS ligands in adipocytes. Our current study revealed that HSO treatment might promote the maturation of hMSC preadipocytes toward brown-like adipose tissue, which evident morphologically. ECS might mediate this effect, as HSO treatment downregulates the CB1 receptor and increases the CB2 receptor at the mRNA and protein levels. In addition, HSO treatment decreased inflammatory marker of IL-6, IL-8, TNF-α, and leptin compared to untreated cells; however, HSO treatment resulted in a minimalized the provoking of inflammatory cytokines compared with CBD and THC treatments in THP-1 cells. In conclusion, the potential of HSO in promoting the development of brown fat characteristics through the ECS and its effect on inflammation status offers an intriguing area for future research and therapeutic interventions.”
“Although obesogenic high-fat/high-sugar diets impair memory function in humans and rodents, the underlying mechanisms remain elusive. Given that the brain endocannabinoid system and type-1 cannabinoid receptors (CB1Rs) control memory processes and are overactive under obesogenic conditions, we studied whether the effects of obesogenic diet consumption on memory function are dependent on this system.
Using an object recognition memory (ORM) task in male mice, we showed that CB1R activity is required for obesogenic-diet-induced impairment of long-term memory performance. This impairment was prevented by post-training systemic blockade of CB1R, which also normalized training-induced hippocampal cellular and synaptic overactivation.
Consistently, the obesogenic diet potentiated the increase in hippocampal endocannabinoid levels and enhanced CB1R expression induced by ORM, and genetic CB1R deletion from hippocampal glutamatergic neurons abolished diet-induced memory deficits. Strikingly, the obesogenic diet enhanced the hippocampal mechanistic target of rapamycin (mTOR) pathway in a CB1R-dependent manner, and pharmacological mTOR inhibition after training rescued diet-induced ORM consolidation deficits.
Together, these results establish how an obesogenic environment can lead to hippocampal overactivation of the endocannabinoid system and the mTOR pathway to eventually impair memory consolidation. Thus, these results shed light on the mechanisms of diet-induced cognitive alterations and may pave the way for novel therapeutic strategies.”
