Category Archives: Endocannabinoid System

Unravelling a novel role for cannabidivarin in the modulation of subventricular zone postnatal neurogenesis

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“Postnatal neurogenesis has been shown to rely on the endocannabinoid system. Here we aimed at unravelling the role of Cannabidivarin (CBDV), a non-psychoactive cannabinoid, with high affinity for the non-classical cannabinoid receptor TRPV1, on subventricular zone (SVZ) postnatal neurogenesis.

Using the neurosphere assay, SVZ-derived neural stem/progenitor cells (NSPCs) were incubated with CBDV and/or 5′-Iodoresinferotoxin (TRPV1 antagonist), and their role on cell viability, proliferation, and differentiation were dissected. CBDV was able to promote, through a TRPV1-dependent mechanism, cell survival, cell proliferation and neuronal differentiation. Furthermore, pulse-chase experiments revealed that CBDV-induced neuronal differentiation was a result of cell cycle exit of NSPCs. Regarding oligodendrocyte differentiation, CBDV inhibited oligodendrocyte differentiation and maturation. Since our data suggested that the CBDV-induced modulation of NSPCs acted via TRPV1, a sodium-calcium channel, and that intracellular calcium levels are known regulators of NSPCs fate and neuronal maturation, single cell calcium imaging was performed to evaluate the functional response of SVZ-derived cells. We observed that CBDV-responsive cells displayed a two-phase calcium influx profile, being the initial phase dependent on TRPV1 activation.

Taken together, this work unveiled a novel and untapped neurogenic potential of CBDV via TRPV1 modulation. These findings pave the way to future neural stem cell biological studies and repair strategies by repurposing this non-psychoactive cannabinoid as a valuable therapeutic target.”

https://pubmed.ncbi.nlm.nih.gov/37802277/

“These findings suggest the potential of CBDV as a novel therapeutic target for neural stem cell repair strategies.”

https://www.sciencedirect.com/science/article/abs/pii/S0014299923005915?via%3Dihub

The Effect of Orally Administered Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) on Obesity Parameters in Mice

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“Prolonged cannabis users show a lower prevalence of obesity and associated comorbidities. In rodent models, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) from the plant Cannabis sativa L. have shown anti-obesity properties, suggesting a link between the endocannabinoid system (ECS) and obesity. However, the oral administration route has rarely been studied in this context. The aim of this study was to investigate the effect of prolonged oral administration of pure THC and CBD on obesity-related parameters and peripheral endocannabinoids. C57BL/6 male mice were fed with either a high-fat or standard diet and then received oral treatment in ramping doses, namely 10 mg/kg of THC or CBD for 5 weeks followed by 30 mg/kg for an additional 5 weeks. Mice treated with THC had attenuated weight gain and improved glucose tolerance, followed by improvement in steatosis markers and decreased hypertrophic cells in adipose epididymal tissue. Mice treated with CBD had improved glucose tolerance and increased markers of lipid metabolism in adipose and liver tissues, but in contrast to THC, CBD had no effect on weight gain and steatosis markers. CBD exclusively decreased the level of the endocannabinoid 2-arachidonoylglycerol in the liver. These data suggest that the prolonged oral consumption of THC, but not of CBD, ameliorates diet-induced obesity and metabolic parameters, possibly through a mechanism of adipose tissue adaptation.”

https://pubmed.ncbi.nlm.nih.gov/37762099/

“In conclusion, the present findings provide evidence for the ability of THC to improve obesity-related metabolic complications when administered orally in ramping doses. The limited effect of CBD demonstrated in our study suggests that the low prevalence of obesity and metabolic diseases seen in cannabis users is mainly attributed to the presence of THC.”

https://www.mdpi.com/1422-0067/24/18/13797

Anti-Inflammatory Effects of Minor Cannabinoids CBC, THCV, and CBN in Human Macrophages

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“Inflammation is a natural response of the body to signals of tissue damage or infection caused by pathogens. However, when it becomes imbalanced, it can lead to various disorders such as cancer, obesity, cardiovascular problems, neurological conditions, and diabetes. The endocannabinoid system, which is present throughout the body, plays a regulatory role in different organs and influences functions such as food intake, pain perception, stress response, glucose tolerance, inflammation, cell growth and specialization, and metabolism. Phytocannabinoids derived from Cannabis sativa can interact with this system and affect its functioning. In this study, we investigate the mechanisms underlying the anti-inflammatory effects of three minor phytocannabinoids including tetrahydrocannabivarin (THCV), cannabichromene (CBC), and cannabinol (CBN) using an in vitro system. We pre-treated THP-1 macrophages with different doses of phytocannabinoids or vehicle for one hour, followed by treating the cells with 500 ng/mL of LPS or leaving them untreated for three hours. To induce the second phase of NLRP3 inflammasome activation, LPS-treated cells were further treated with 5 mM ATP for 30 min. Our findings suggest that the mitigation of the PANX1/P2X7 axis plays a significant role in the anti-inflammatory effects of THCV and CBC on NLRP3 inflammasome activation. Additionally, we observed that CBC and THCV could also downregulate the IL-6/TYK-2/STAT-3 pathway. Furthermore, we discovered that CBN may exert its inhibitory impact on the assembly of the NLRP3 inflammasome by reducing PANX1 cleavage. Interestingly, we also found that the elevated ADAR1 transcript responded negatively to THCV and CBC in LPS-macrophages, indicating a potential involvement of ADAR1 in the anti-inflammatory effects of these two phytocannabinoids. THCV and CBN inhibit P-NF-κB, downregulating proinflammatory gene transcription. In summary, THCV, CBC, and CBN exert anti-inflammatory effects by influencing different stages of gene expression: transcription, post-transcriptional regulation, translation, and post-translational regulation.”

https://pubmed.ncbi.nlm.nih.gov/37764262/

https://www.mdpi.com/1420-3049/28/18/6487

Phytocannabinoids Reduce Seizures in Larval Zebrafish and Affect Endocannabinoid Gene Expression

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“Cannabis has demonstrated anticonvulsant properties, and about thirty percent of epileptic patients do not have satisfactory seizure management with standard treatment and could potentially benefit from cannabis-based intervention. Here, we report the use of cannabinoids to treat pentylenetetrazol (PTZ)-induced convulsions in a zebrafish model, their effect on gene expression, and a simple assay for assessing their uptake in zebrafish tissues. Using an optimized behavioral assay, we show that cannabidiol (CBD) and cannabichromene (CBC) and cannabinol (CBN) are effective at reducing seizures at low doses, with little evidence of sedation, and our novel HPLC assay indicates that CBC is effective with the lowest accumulation in larval tissues. All cannabinoids tested were effective at higher concentrations. Pharmacological manipulation of potential receptors demonstrates that Gpr55 partially mediates the anticonvulsant effects of CBD. Treatment of zebrafish larvae with endocannabinoids, such as 2-arachidonoylglycerol (2-AG) and anandamide (AEA), altered larvae movement, and the expression of genes that regulate their metabolism was affected by phytocannabinoid treatment, highlighting the possibility that changes to endocannabinoid levels may represent one facet of the anticonvulsant effect of phytocannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/37759798/

https://www.mdpi.com/2218-273X/13/9/1398

Cannabinoids and the GI Tract

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“The synthesis and degradation of endocannabinoids, location of cannabinoid (CB) receptors, and cannabinoid mechanisms of action on immune/inflammatory, neuromuscular, and sensory functions in digestive organs are well documented. CB2 mechanisms are particularly relevant in immune and sensory functions. Increasing use of cannabinoids in the USA is impacted by social determinants of health including racial discrimination which is associated with tobacco and cannabis co-use, and combined use disorders. Several conditions associated with emesis are related to cannabinoid use, including cannabinoid hyperemesis or withdrawal, cyclic vomiting syndrome, nausea and vomiting of pregnancy. Cannabinoids generally inhibit gastrointestinal motor function; yet they relieve symptoms in patients with gastroparesis and diverse nausea syndromes. Cannabinoid effects on inflammatory mechanisms have shown promise in relatively small placebo-controlled studies in reducing disease activity and abdominal pain in patients with inflammatory bowel disease (IBD). Cannabinoids have been studied in disorders of motility, pain, and disorders of gut brain interaction. The CB2 receptor agonist, cannabidiol, reduced total Gastroparesis Cardinal Symptom Index and increased ability to tolerate a meal in patients with gastroparesis appraised over 4 weeks of treatment. In contrast, predominant-pain endpoints in functional dyspepsia with normal gastric emptying were not significantly improved with cannabidiol. The CB2 agonist, olorinab, reduced abdominal pain in IBD in an open-label trial and in constipation-predominant irritable bowel syndrome in a placebo-controlled trial. Cannabinoid mechanisms alter inflammation in pancreatic and liver diseases. In conclusion, cannabinoids, particularly agents affecting CB2 mechanisms, have potential for inflammatory, gastroparesis, and pain disorders; however, the trials require replication and further understanding of risk-benefit to enhance use of cannabinoids in gastrointestinal diseases.”

https://pubmed.ncbi.nlm.nih.gov/37678488/

The endocannabinoid system as a putative target for the development of novel drugs for the treatment of psychiatric illnesses

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“Cannabis is well established to impact affective states, emotion and perceptual processing, primarily through its interactions with the endocannabinoid system. While cannabis use is quite prevalent in many individuals afflicted with psychiatric illnesses, there is considerable controversy as to whether cannabis may worsen these conditions or provide some form of therapeutic benefit. The development of pharmacological agents which interact with components of the endocannabinoid system in more localized and discrete ways then via phytocannabinoids found in cannabis, has allowed the investigation if direct targeting of the endocannabinoid system itself may represent a novel approach to treat psychiatric illness without the potential untoward side effects associated with cannabis. Herein we review the current body of literature regarding the various pharmacological tools that have been developed to target the endocannabinoid system, their impact in preclinical models of psychiatric illness and the recent data emerging of their utilization in clinical trials for psychiatric illnesses, with a specific focus on substance use disorders, trauma-related disorders, and autism. We highlight several candidate drugs which target endocannabinoid function, particularly inhibitors of endocannabinoid metabolism or modulators of cannabinoid receptor signaling, which have emerged as potential candidates for the treatment of psychiatric conditions, particularly substance use disorder, anxiety and trauma-related disorders and autism spectrum disorders. Although there needs to be ongoing clinical work to establish the potential utility of endocannabinoid-based drugs for the treatment of psychiatric illnesses, the current data available is quite promising and shows indications of several potential candidate diseases which may benefit from this approach.”

https://pubmed.ncbi.nlm.nih.gov/37671673/

https://www.cambridge.org/core/journals/psychological-medicine/article/endocannabinoid-system-as-a-putative-target-for-the-development-of-novel-drugs-for-the-treatment-of-psychiatric-illnesses/52BFF0428246735E980829CFE8F03C67

Can cannabidiol have an analgesic effect?

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“Background: Cannabis, more commonly known as marijuana or hemp, has been used for centuries to treat various conditions. Cannabis contains two main components cannabidiol (CBD) and tetrahydrocannabinol (THC). CBD, unlike THC, is devoid of psychoactive effects and is well tolerated by the human body but has no direct effect on the receptors of the endocannabid system, despite the lack of action on the receptors of the endocannabid system.

Objectives and methods: We have prepared a literature review based on the latest available literature regarding the analgesic effects of CBD. CBD has a wide range of effects on the human body. In this study, we will present the potential mechanisms responsible for the analgesic effect of CBD. To the best of our knowledge, this is the first review to explore the analgesic mechanisms of CBD.

Results and conclusion: The analgesic effect of CBD is complex and still being researched. CBD models the perception of pain by acting on G protein-coupled receptors. Another group of receptors that CBD acts on are serotonergic receptors. The effect of CBD on an enzyme of potential importance in the production of inflammatory factors such as cyclooxygenases and lipoxygenases has also been confirmed. The presented potential mechanisms of CBD’s analgesic effect are currently being extensively studied.”

https://pubmed.ncbi.nlm.nih.gov/37584368/

https://onlinelibrary.wiley.com/doi/10.1111/fcp.12947

β-Caryophyllene, a Dietary Phytocannabinoid, Alleviates Diabetic Cardiomyopathy in Mice by Inhibiting Oxidative Stress and Inflammation Activating Cannabinoid Type-2 Receptors

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“Diabetes mellitus (DM) and its associated complications are considered one of the major health risks globally. Among numerous complications, diabetic cardiomyopathy (DCM) is characterized by increased accumulation of lipids and reduced glucose utilization following abnormal lipid metabolism in the myocardium along with oxidative stress, myocardial fibrosis, and inflammation that eventually result in cardiac dysfunction. The abnormal metabolism of lipids plays a fundamental role in cardiac lipotoxicity following the occurrence and development of DCM. Recently, it has been revealed that cannabinoid type-2 (CB2) receptors, an essential component of the endocannabinoid system, play a crucial role in the pathogenesis of obesity, hyperlipidemia, and DM. Provided the role of CB2R in regulating the glucolipid metabolic dysfunction and its antioxidant as well as anti-inflammatory activities, we carried out the current study to investigate the protective effects of a selective CB2R agonist, β-caryophyllene (BCP), a natural dietary cannabinoid in the murine model of DCM and elucidated the underlying pharmacological and molecular mechanisms. Mice were fed a high-fat diet for 4 weeks followed by a single intraperitoneal injection of streptozotocin (100 mg/kg) to induce the model of DCM. BCP (50 mg/kg body weight) was given orally for 12 weeks. AM630, a CB2R antagonist, was given 30 min before BCP treatment to demonstrate the CB2R-dependent mechanism of BCP. DCM mice exhibited hyperglycemia, increased serum lactate dehydrogenase, impaired cardiac function, and hypertrophy. In addition, DCM mice showed alternations in serum lipids and increased oxidative stress concomitant to reduced antioxidant defenses and enhanced cardiac lipid accumulation in the diabetic heart. DCM mice also exhibited activation of TLR4/NF-κB/MAPK signaling and triggered the production of inflammatory cytokines and inflammatory enzyme mediators. However, treatment with BCP exerted remarkable protective effects by favorable modulation of the biochemical and molecular parameters, which were altered in DCM mice. Interestingly, pretreatment with AM630 abrogated the protective effects of BCP in DCM mice. Taken together, the findings of the present study demonstrate that BCP possesses the capability to mitigate the progression of DCM by inhibition of lipotoxicity-mediated cardiac oxidative stress and inflammation and favorable modulation of TLR4/NF-κB/MAPK signaling pathways mediating the CB2R-dependent mechanism.”

https://pubmed.ncbi.nlm.nih.gov/37588762/

https://pubs.acs.org/doi/10.1021/acsptsci.3c00027?cookieSet=1

Hippocampal differential expression underlying the neuroprotective effect of delta-9-tetrahydrocannabinol microdose on old mice

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“Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive compound of the cannabis plant and an exogenous ligand of the endocannabinoid system. In previous studies, we demonstrated that a single microdose of THC (0.002 mg/kg, 3-4 orders of magnitude lower than the standard dose for rodents) exerts distinct, long-term neuroprotection in model mice subjected to acute neurological insults. When administered to old, healthy mice, the THC microdose induced remarkable long-lasting (weeks) improvement in a wide range of cognitive functions, including significant morphological and biochemical brain alterations. To elucidate the mechanisms underlying these effects, we analyzed the gene expression of hippocampal samples from the model mice. Samples taken 5 days after THC treatment showed significant differential expression of genes associated with neurogenesis and brain development. In samples taken 5 weeks after treatment, the transcriptional signature was shifted to that of neuronal differentiation and survival. This study demonstrated the use of hippocampal transcriptome profiling in uncovering the molecular basis of the atypical, anti-aging effects of THC microdose treatment in old mice.”

https://pubmed.ncbi.nlm.nih.gov/37534036/

“Our findings imply that the THC microdose treatment alleviates age-dependent cognitive deficits by modulating multiple hallmarks of brain aging, supporting past hypotheses regarding the relation between aging and the endocannabinoid system.”

https://www.frontiersin.org/articles/10.3389/fnins.2023.1182932/full

A RANDOMIZED, CONTROLLED TRIAL OF EFFICACY AND SAFETY OF CANNABIDIOL IN IDIOPATHIC AND DIABETIC GASTROPARESIS

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“Background: Cannabis (Δ9THC), a non-selective cannabinoid receptor (CBR) agonist relieves nausea and pain. Cannabidiol (CBD), a CBR2 inverse agonist with central effects, also reduces gut sensation and inflammation.

Aims: To compare effects of 4 weeks’ treatment with pharmaceutical CBD vs. placebo in patients with idiopathic (IG) or diabetic (DM) gastroparesis.

Methods: We performed a randomized, double-blinded, placebo-controlled study of CBD b.i.d. (Epidiolex® escalated to 20mg/kg/day) in patients with nonsurgical gastroparesis with delayed gastric emptying of solids (GES). Symptoms were assessed by Gastroparesis Cardinal Symptom Index Daily Diary (GCSI-DD). After 4 weeks’ treatment, we measured GES, gastric volumes, and Ensure® satiation test (1kcal/mL, 30mL/min) to assess volume to comfortable fullness (VTF) and maximum tolerance (MTV). Patients underwent specific FAAH and CNR1 genotyping. Statistical analysis compared 2 treatments using ANOVA including baseline measurements and BMI as covariates.

Results: Among 44 patients (32 IG, 6 DM1, and 6 DM2), 5 patients did not tolerate full dose escalation; 3 withdrew before completing 4 weeks’ treatment (2 placebo, 1 CBD); 95% completed 4 weeks’ treatment and diaries. Compared to placebo, CBD reduced total GCSI score (P=0.008), inability to finish a normal-sized meal (P=0.029), number of vomiting episodes/24 hours (P=0.006), and overall symptom severity (P=0.034). Patients treated with CBD had higher VTF and MTV and slower GES. FAAH rs34420 genotype significantly impacted nutrient drink ingestion. The most common adverse events reported were diarrhea (14), fatigue (8), headache (8), and nausea (7).

Conclusions: CBD provides symptom relief in patients with gastroparesis and improves the tolerance of liquid nutrient intake, despite slowing of GES.”

https://pubmed.ncbi.nlm.nih.gov/37482172/

https://www.cghjournal.org/article/S1542-3565(23)00543-8/pdf