Endocannabinoids and their receptors modulate endometriosis pathogenesis and immune response

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“Endometriosis (EM), characterized by the presence of endometrial-like tissue outside the uterus, is the leading cause of chronic pelvic pain and infertility in females of reproductive age. Despite its high prevalence, the molecular mechanisms underlying EM pathogenesis remain poorly understood.

The endocannabinoid system (ECS) is known to influence several cardinal features of this complex disease including pain, vascularization, and overall lesion survival, but the exact mechanisms are not known. Utilizing CNR1 knockout (k/o), CNR2 k/o, and wild-type (WT) mouse models of EM, we reveal contributions of ECS and these receptors in disease initiation, progression, and immune modulation. Particularly, we identified EM-specific T cell dysfunction in the CNR2 k/o mouse model of EM. We also demonstrate the impact of decidualization-induced changes on ECS components, and the unique disease-associated transcriptional landscape of ECS components in EM. Imaging mass cytometry (IMC) analysis revealed distinct features of the microenvironment between CNR1, CNR2, and WT genotypes in the presence or absence of decidualization.

This study, for the first time, provides an in-depth analysis of the involvement of the ECS in EM pathogenesis and lays the foundation for the development of novel therapeutic interventions to alleviate the burden of this debilitating condition.”

https://pubmed.ncbi.nlm.nih.gov/39120997/

“In conclusion, our study offers evidence for the involvement of CNR1 and CNR2 dysregulation in EM pathogenesis. Through an integrative analysis of transcriptomic profiles, immune cell dynamics, and spatial relationships within EM lesions from mice, we unveil the intricate interactions between ECS, immune responses, and cellular changes in EM. By identifying potential mechanisms through which ECS disruption could impact EM, our research provides a foundation for the development of targeted therapies addressing the ECS’s influence on EM. These findings will advance our understanding of EM and lead to innovative therapeutic strategies to manage this complex disorder.”

https://elifesciences.org/articles/96523

Cannabidiol as a possible treatment for endometriosis through suppression of inflammation and angiogenesis

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“Background: Endometriosis is associated with a wide variety of signs and symptoms and can lead to infertility, embryo death, and even miscarriage. Although the exact pathogenesis and etiology of endometriosis is still unclear, it has been shown that it has a chronic inflammatory nature and angiogenesis is also involved in it.

Objective: This review aims to explore the role of inflammation and angiogenesis in endometriosis and suggest a potential treatment targeting these pathways.

Findings: Among the pro-inflammatory cytokines, studies have shown solid roles for interleukin 1β (IL-β), IL-6, and tumor necrosis factor α (TNF-α) in the pathogenesis of this condition. Other than inflammation, angiogenesis, the formation of new blood vessels from pre-existing capillaries, is also involved in the pathogenesis of endometriosis. Among angiogenic factors, vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α), transforming growth factor β1 (TGF-β1), and matrix metalloproteinases (MMPs) are more essential in the pathogenesis of endometriosis. Interestingly, it has been shown that inflammation and angiogenesis share some similar pathways with each other that could be potentially targeted for treatment of diseases caused by these two processes. Cannabidiol (CBD) is a non-psychoactive member of cannabinoids which has well-known and notable anti-inflammatory and antiangiogenic properties. This agent has been shown to decrease IL-1β, IL-6, TNF-α, VEGF, TGFβ, and MMPs in different animal models of diseases.

Conclusion: It seems that CBD could be a possible treatment for endometriosis due to its anti-inflammatory and antiangiogenic activity, however, further studies are needed.”

https://pubmed.ncbi.nlm.nih.gov/39110084/

“So far, the exact mechanism of endometriosis is not fully understood. However, this phenomenon is known as a chronic inflammatory condition accompanied with angiogenesis. Herein, we reviewed the inflammatory aspects of this disease with an eye on angiogenesis. As we showed, the molecular pathways of angiogenesis and inflammation have a lot in common. Thus, it seems that targeting inflammation could be considered hitting two birds with one stone. Considering the potent anti-inflammatory and antiangiogenic effects of CBD under various other conditions, authors suggest in vitro and in vivo studies on CBD and endometriosis.”

https://onlinelibrary.wiley.com/doi/10.1002/iid3.1370

In Silico Approach for Assessment of the Anti-tumor Potential of Cannabinoid Compounds by Targeting Glucose-6-phosphate Dehydrogenase Enzyme

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“Glucose-6-phosphate dehydrogenase (G6PD) is a pentose phosphate pathway (PPP) enzyme that generates NADPH, which is required for cellular redox equilibrium and reductive biosynthesis.

It has been demonstrated that abnormal G6PD activation promotes cancer cell proliferation and metastasis. To date, no G6PD inhibitor has passed clinical testing successfully enough to be launched as a medicine. As a result, in this investigation, cannabinoids were chosen to evaluate their anticancer potential by targeting G6PD.

Molecular docking indicated that three molecules, Tetrahydrocannabinolic acid (THCA), Cannabichromenic acid (CBCA), and tetrahydrocannabivarin (THCV), have the highest binding affinities for G6PD of -8.61, – 8.39, and 8.01 Kcal/mol. ADMET analysis found that all of them were safe prospective drug candidates. Molecular dynamics (MD) simulation and MM-PBSA analysis confirm the structural compactness and lower conformational variation of protein-ligand complexes, thereby maintaining structural stability and rigidity.

Thus, our in silico investigation exhibited all three cannabinoids as potential competitive inhibitors of G6PD.”

https://pubmed.ncbi.nlm.nih.gov/39109709/

https://onlinelibrary.wiley.com/doi/10.1002/cbdv.202401338

Effects of ∆-9 tetrahydrocannabinol on the small intestine altered by high fructose diet: A Histopathological study

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“The consumption of fructose is increasing day by day. Understanding the impact of increasing fructose consumption on the small intestine is crucial since the small intestine processes fructose into glucose.

∆9-Tetrahydrocannabinol (THC), a key cannabinoid, interacts with CB1 and CB2 receptors in the gastrointestinal tract, potentially mitigating inflammation. Therefore, this study aimed to investigate the effects of the high-fructose diet (HFD) on the jejunum of rats and the role of THC consumption in reversing these effects.

Experiments were conducted on Sprague-Dawley rats, with the experimental groups as follows: control (C), HFD, THC, and HFD + THC. The HFD group received a 10% fructose solution in drinking water for 12 weeks. THC groups were administered 1.5 mg/kg/day of THC intraperitoneally for the last four weeks. Following sacrification, the jejunum was evaluated for mucus secretion capacity. IL-6, JNK, CB2 and PCNA expressions were assessed through immunohistochemical analysis and the ultrastructural alterations via transmission electron microscopy.

The results showed that fructose consumption did not cause weight gain but triggered inflammation in the jejunum, disrupted the cell proliferation balance, and increased mucus secretion in rats. Conversely, THC treatment displayed suppressed inflammation and improved cell proliferation balance caused by HFD. Ultrastructural examinations showed that the zonula occludens structures deteriorated in the HFD group, along with desmosome shrinkage. Mitochondria were found to be increased due to THC application following HFD.

In conclusion, the findings of this research reveal the therapeutic potential of THC in reversing HFD-related alterations and provide valuable insights for clinical application.”

https://pubmed.ncbi.nlm.nih.gov/39110194/

“Plant-derived cannabinoids and their synthetic analogs could be used medically. It is thought that THC could be used to prevent or reverse the effects of possible ultrastructural epithelial barrier damage caused by an HFD. In conclusion, our results show that high fructose consumption causes inflammation in the jejunum, increases mucus production, and disrupts the balance of cell proliferation. It has been determined that THC application is efficient in reversing these effects. In this context, new findings have been presented that THC can be a candidate as a therapeutic agent.”

https://link.springer.com/article/10.1007/s00418-024-02311-y

Regulation of cannabinoid and opioid receptor levels by endogenous and pharmacological chaperones

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“Cannabinoid and opioid receptor activities can be modulated by a variety of posttranslational mechanisms including the formation of interacting complexes.

This study examines the involvement of endogenous and exogenous chaperones in modulating the abundance and activity of cannabinoid CB1 receptor (CB1R), delta opioid receptor (DOR), and CB1R-DOR interacting complexes.

Focussing on endogenous protein chaperones namely receptor transporter proteins (RTPs), we examined relative mRNA expression in the mouse spinal cord and found RTP4 to be expressed at higher levels compared to other RTPs. Next, we assessed the effect of RTP4 on receptor abundance by manipulating RTP4 expression in cell lines. Overexpression of RTP4 causes an increase and knock-down causes a decrease in the levels of CB1R, DOR, and CB1R-DOR interacting complexes; this is accompanied by parallel changes in signaling. The ability of small molecule lipophilic ligands to function as exogenous chaperones was examined using receptor-selective antagonists. Long term treatment leads to increases in receptor abundance and activity with no changes in mRNA supporting a role as pharmacological chaperones.

Finally, the effect of cannabidiol (CBD), a small molecule ligand and a major active component of Cannabis, on receptor abundance and activity in mice was examined. We find that CBD administration leads to increases in receptor abundance and activity in mouse spinal cord.

Together, these results highlight a role for chaperones (proteins and small molecules) in modulating levels and activity of CB1R, DOR, and their interacting complexes potentially through mechanisms including receptor maturation and trafficking. 

Significance Statement This study highlights a role for chaperones (endogenous and small membrane-permeable molecules) in modulating levels of CB1R, DOR, and their interacting complexes. These chaperones could be developed as therapeutics for pathologies involving these receptors.”

https://pubmed.ncbi.nlm.nih.gov/39103231/

https://jpet.aspetjournals.org/content/early/2024/08/05/jpet.124.002187

Clinical Benefits and Safety of Medical Cannabis Products: A Narrative Review on Natural Extracts

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“Interest in medical cannabis and cannabis-based medicinal products (CBMPs) has increased greatly in recent years. Two cannabinoids are of principal importance; delta-9-tetrahydrocannabinol (∆9-THC), the primary psychoactive component, and also cannabidiol (CBD), considered non-intoxicating. Each has distinct mechanisms of action and different therapeutic potentials. CBMPs differ in their ∆9-THC and CBD components; predominantly ∆9-THC, balanced formulations with equivalent ∆9-THC and CBD elements, and CBD-predominant products.

In this narrative review, we evaluate the published evidence for the clinical benefits of CBMPs and overall benefits in well-being. We also review the overall safety profile and discuss the potential for dependence with CBMPs. Evidence can be drawn from a wide range of randomized and other controlled studies and from observational real-world studies.

Most data from observational registry studies are supportive of ∆9-THC-based products (∆9-THC-predominant or balanced CBMPs) in the management of chronic neuropathic pain. Balanced products are also effective in reducing spasticity in multiple sclerosis. Most CBMPs show benefit in providing symptomatic benefits in reducing anxiety, nausea, and in improving sleep, but the place of specific products is more subtle, and choice guided by specific circumstances. Symptomatic improvements are accompanied by improved quality of life and well-being. Safety data indicate that CBMPs are generally well tolerated in most patients without specific contraindications. The majority of adverse effects are non-serious, and transient; most are principally associated with ∆9-THC and are dose-dependent. In contrast to recreational cannabis use, there is little evidence from clinical studies that CBMPs have any potential for dependence.”

https://pubmed.ncbi.nlm.nih.gov/39096481/

https://link.springer.com/article/10.1007/s40122-024-00643-0

Cannabis sativa essential oils orally administered to CD1 mice: Tissue distribution of main constituents

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“The essential oil (EO) obtained from hemp (Cannabis sativa L.) biomass is rich of bioactive constituents and its oral administration can be valuable.

In this paper two different hemp EOs were orally administered to CD1 mice. One EO, obtained from the fresh plant material resulted rich in monoterpenes (monoterpene rich oil, MRO) and the other, obtained from the dried biomass, contained mainly sesquiterpenes and CBD (sesquiterpene rich oil, SRO). The blood levels of the most abundant constituents were evaluated in the animals 30 and 90 min after oral administration of hemp EOs. Furthermore, compounds were also measured in brain, liver, kidney, spleen, and cecum content to evaluate their tissue distribution at the same times.

Results showed the easy absorption and the ability of the major hemp EOs constituents to reach brain, liver, and kidney. Oral administration of MRO resulted in blood levels of monoterpenes in the range 45-115 ng/g at 30 min and significant tissue distribution with the detection of monoterpenes in brain, liver, and kidney. Oral administration of SRO resulted in blood levels, at 30 min, in the range 70-80 ng/g of sesquiterpenes and 139 ng/g of CBD. The compounds are still detectable in blood and brain 90 min after oral administration and significant concentrations of terpenoids are observed in liver and kidney.

MRO and SRO can be considered as valuable sources of these bioactive compounds and further investigations are needed to evaluate the potential uses of hemp EO as constituent of innovative drug formulations.”

https://pubmed.ncbi.nlm.nih.gov/39094699/

https://www.sciencedirect.com/science/article/abs/pii/S0367326X24003307?via%3Dihub

Analgesic properties of next generation modulators of endocannabinoid signaling: leveraging modern tools for the development of novel therapeutics

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“Targeting the endocannabinoid (eCB) signaling system for pain relief is an important treatment option that is only now beginning to be mechanistically explored.

In this review, we focus on two recently appreciated cannabinoid-based targeting strategies, treatments with cannabidiol (CBD) and a/b-hydrolase domain containing 6 (ABHD6) inhibitors, which have the exciting potential to produce pain relief through distinct mechanisms of action (MOA) and without intoxication.

We review evidence on plant-derived cannabinoids for pain, with an emphasis on CBD and its multiple molecular targets expressed in pain pathways. We also discuss the function of eCB signaling in regulating pain responses and the therapeutic promises of inhibitors targeting ABHD6, a 2-arachidonoylglycerol (2-AG) hydrolyzing enzyme. Finally, we discuss how the novel cannabinoid biosensor, GRABeCB2.0, may be leveraged to enable the discovery of targets modulated by cannabinoids at a circuit-specific level. 

Significance Statement Cannabis has been used by humans as an effective medicine for millennia, including for pain management. Recent evidence emphasizes the therapeutic potential of compounds that modulate endocannabinoid signaling. Specifically, cannabidiol and inhibitors of the enzyme ABHD6 represent promising strategies to achieve pain relief by modulating endocannabinoid signaling in pain pathways via distinct, non-intoxicating, mechanisms of action.”

https://pubmed.ncbi.nlm.nih.gov/39060165/

https://jpet.aspetjournals.org/content/early/2024/07/26/jpet.124.002119

Examining the moderating role of cannabis use on the relationship between alcohol consumption and inflammation in individuals with alcohol use disorder

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“Inflammation appears to be a critical mechanism in the development of alcohol use disorder (AUD) and a consequence of chronic alcohol use.

The potential anti-inflammatory properties of cannabis may modulate the proinflammatory effects of alcohol.

This study sought to extend previous work investigating the relationship between alcohol consumption, cannabis use and circulating interleukin (IL)-6 levels in a sample with AUD. One hundred and thirty-three individuals with an AUD provided blood samples to assess IL-6 and answered questions regarding alcohol and cannabis use. An ordinary least squares multiple regression analysis was conducted to assess the effect of alcohol and cannabis use on IL-6. A moderation analysis examined cannabis use as a potential moderator of the relationship between alcohol use and circulating IL-6 levels.

Alcohol use was predictive of higher log IL-6 levels (standardized β = 0.16, p = 0.03), while cannabis use was not predictive of log IL-6 levels (p = 0.36). Days of cannabis use moderated the relationship between alcohol use and IL-6 levels, such that the relationship between alcohol use and IL-6 levels was only significant in individuals with AUD without recent cannabis use. This study extends previous work to a clinical sample with an AUD and underscores the importance of considering cannabis use in studies on alcohol use and inflammation. This study also indicates the need for in-depth analyses on cannabinoids and inflammation and the interaction between cannabinoids and alcohol use on inflammation.”

https://pubmed.ncbi.nlm.nih.gov/39091190/

https://onlinelibrary.wiley.com/doi/10.1111/adb.13431

Long-term efficacy and safety of cannabidiol in patients with tuberous sclerosis complex: 3-year results from the cannabidiol expanded access program

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“Objective: The cannabidiol (CBD) Expanded Access Program provided compassionate access to CBD for patients with treatment-resistant epilepsy, including tuberous sclerosis complex (TSC), at 35 US epilepsy centers. Here, we present the long-term efficacy and safety outcomes for add-on CBD treatment in patients with TSC.

Methods: Patients received plant-derived, highly purified CBD (Epidiolex® 100 mg/mL, oral solution), increasing from 2 to 10 mg/kg/d to tolerance or maximum of 25-50 mg/kg/d. Efficacy endpoints were percentage change from baseline in median monthly convulsive, focal, and total seizure frequency and ≥ 50%, ≥75%, and 100% responder rates across 12-week visit windows through 144 weeks. Adverse events (AEs) are reported through 233 weeks.

Results: Thirty-four patients with confirmed TSC were included. Mean age was 12.4 years (range, 1.8-31.2), and patients were receiving a median of 3 (range, 1-7) antiseizure medications (ASMs) at baseline. Median CBD dose was 25-28 mg/kg/d for 36 weeks and then 20-50 mg/kg/d through 228 weeks. Dose reduction from baseline occurred for most ASMs, except topiramate. Median reduction in the frequency of convulsive, focal, and total seizures was 44%-81%, 51%-87%, and 44%-87%, respectively, through 144 weeks. Responder rates (≥50%, ≥75%, and 100% reduction) were 43%-71%, 14%-58%, and 0%-25% for convulsive seizures; 52%-75%, 35%-60%, and 7%-32% for focal seizures; and 46%-79%, 26%-65%, and 0%-13% for total seizures. A total of 94% of patients experienced ≥1 AE; 47% had serious AEs, considered treatment unrelated by the investigator. Treatment-related AEs (TRAEs) occurred in 71% of patients. The most frequently reported TRAEs were somnolence, diarrhea, and ataxia. Two patients experienced AEs leading to discontinuation. There were no deaths.

Significance: Long-term add-on CBD use was associated with reduced seizure frequency through 144 weeks. The safety profile was consistent with previous reports.

Plain language summary: In this study, we evaluated efficacy and safety of cannabidiol (CBD) treatment in patients with tuberous sclerosis complex receiving CBD in addition to other antiseizure treatments in an Expanded Access Program. After starting CBD, 46%-79% of patients had at least 50% reduction and 26%-65% had at least 75% reduction in the number of seizures per month; up to 13% had no seizures through 144 weeks. Safety results were similar to prior studies; sleepiness and diarrhea were common treatment-related side effects. These results show that long-term CBD treatment was associated with fewer seizures and mild/moderate side effects.”

https://pubmed.ncbi.nlm.nih.gov/39088193/

“The results of this pooled analysis of data from a cohort of patients with TSC in the CBD EAP show that add-on CBD treatment was associated with a reduction in the frequency of seizures through 144 weeks of treatment, and its safety profile was similar to that observed in previously reported EAP analyses and clinical trials, supporting the long-term use of CBD for patients with TSC.”

https://onlinelibrary.wiley.com/doi/10.1002/epi4.13013