Dietary Cannabidiol Activates PKA/AMPK Signaling and Attenuates Chronic Inflammation and Leaky Gut in DSS-Induced Colitis Mice

Posted on January 5, 2024 by David

“Scope: Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gut, accompanied by impaired epithelial integrity, increased macrophage infiltration, and enhanced colon cancer risk.

Methods and results: Cannabidiol (CBD), a phytocannabinoid isolated from cannabis plants, is supplemented into mice diet, and its beneficial effects against dextran sulfate sodium (DSS)-induced experimental colitis is evaluated. Eight-week-old mice were fed a standard diet supplemented with or without CBD (200 mg kg^-1 ) for 5 weeks. In the 4th week of dietary treatment, mice were subjected to 2.5% DSS induction for 7 days, followed by 7 days of recovery, to induce colitis. CBD supplementation reduced body weight loss, gross bleeding, fecal consistency, and disease activity index. In addition, CBD supplementation protected the colonic structure, promoted tissue recovery, and ameliorated macrophage infiltration in the colonic tissue, which was associated with the activation of cyclic AMP-protein kinase A, extracellular signal-regulated kinase ½, and AMP-activated protein kinase signaling pathways. CBD supplementation also suppressed NLRP3 inflammasome activation and related pro-inflammatory marker secretion. Consistently, CBD feeding reduced tight junction protein claudin2 and myosin light chain kinase in DSS-treated mice.

Conclusion: Dietary CBD protects against inflammation and colitis symptoms induced by DSS, providing an alternative approach to IBD management.”

https://pubmed.ncbi.nlm.nih.gov/38175840/

https://onlinelibrary.wiley.com/doi/10.1002/mnfr.202300446

Research progress in the management of vascular disease with cannabidiol: a review

Posted on January 5, 2024 by David

“The morbidity and mortality rates associated with vascular disease (VD) have been gradually increasing. Currently, the most common treatment for VD is surgery, with the progress in drug therapy remaining slow. Cannabidiol (CBD) is a natural extract of Cannabis sativa L. with sedative, analgesic, and nonaddictive properties. CBD binds to 56 cardiovascular-related receptors and exerts extensive regulatory effects on the cardiovascular system, making it a potential pharmacological agent for the management of VD. However, most CBD studies have focused on neurological and cardiac diseases, and research on the management of VD with CBD is still rare. In this review, we summarize the currently available data on CBD in the management of VD, addressing four aspects: the major molecular targets of CBD in VD management, pharmacokinetic properties, therapeutic effects of CBD on common VDs, and side effects. The findings indicate that CBD has anti-anxiety, anti-oxidation, and anti-inflammatory properties and can inhibit abnormal proliferation and apoptosis of vascular smooth muscle and endothelial cells; these effects suggest CBD as a therapeutic agent for atherosclerosis, stress-induced hypertension, diabetes-related vasculopathy, ischemia-reperfusion injury, and vascular damage caused by smoking and alcohol abuse. This study provides a theoretical basis for further research on CBD in the management of VD.”

https://pubmed.ncbi.nlm.nih.gov/38172934/

https://cardiothoracicsurgery.biomedcentral.com/articles/10.1186/s13019-023-02476-y

Cannabidiol as a potential cessation therapeutic: Effects on intravenous nicotine self-administration and withdrawal symptoms in mice

Posted on January 5, 2024 by David

“Cigarette smoking remains a leading cause of preventable disease and death worldwide. Due to the devastating negative health effects of smoking, many users attempt to quit, but few are successful in the long-term. Thus, there is a critical need for novel therapeutic approaches. In these investigations, we sought to examine whether cannabidiol (CBD) has the potential to be repurposed as a nicotine cessation therapeutic. In the first study, male and female mice were trained to respond for intravenous nicotine infusions at either a low or moderate nicotine dose and then were pretreated with CBD prior to their drug-taking session. We found that CBD produced a significant decrease in the number of nicotine rewards earned, and this effect was evidenced across CBD doses and with both the low and moderate levels of nicotine intake. These effects on drug intake were not due to general motor-related effects, since mice self-administering food pellets did not alter their behavior with CBD administration. The potential effects of CBD in mitigating nicotine withdrawal symptoms were then investigated. We found that CBD attenuated the somatic signs of nicotine withdrawal and prevented nicotine’s hyperalgesia-inducing effects. Taken together, these results demonstrate that modulation of cannabinoid signaling may be a viable therapeutic option as a smoking cessation aid.”

https://pubmed.ncbi.nlm.nih.gov/38176534/

https://www.sciencedirect.com/science/article/abs/pii/S0028390823004239?via%3Dihub

Cannabis for medical use versus opioids for chronic non-cancer pain: a systematic review and network meta-analysis of randomised clinical trials

Posted on January 5, 2024 by David

“Objective: The objective of this study is to evaluate the comparative benefits and harms of opioids and cannabis for medical use for chronic non-cancer pain.

Design: Systematic review and network meta-analysis.

Data sources: EMBASE, MEDLINE, CINAHL, AMED, PsycINFO, PubMed, Web of Science, Cannabis-Med, Epistemonikos and the Cochrane Library (CENTRAL) from inception to March 2021.

Study selection: Randomised trials comparing any type of cannabis for medical use or opioids, against each other or placebo, with patient follow-up ≥4 weeks.

Data extraction and synthesis: Paired reviewers independently extracted data. We used Bayesian random-effects network meta-analyses to summarise the evidence and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach to evaluate the certainty of evidence and communicate our findings.

Results: Ninety trials involving 22 028 patients were eligible for review, among which the length of follow-up ranged from 28 to 180 days. Moderate certainty evidence showed that opioids provide small improvements in pain, physical functioning and sleep quality versus placebo; low to moderate certainty evidence supported similar effects for cannabis versus placebo. Neither was more effective than placebo for role, social or emotional functioning (all high to moderate certainty evidence). Moderate certainty evidence showed there is probably little to no difference between cannabis for medical use and opioids for physical functioning (weighted mean difference (WMD) 0.47 on the 100-point 36-item Short Form Survey physical component summary score, 95% credible interval (CrI) -1.97 to 2.99), and cannabis resulted in fewer discontinuations due to adverse events versus opioids (OR 0.55, 95% CrI 0.36 to 0.83). Low certainty evidence suggested little to no difference between cannabis and opioids for pain relief (WMD 0.23 cm on a 10 cm Visual Analogue Scale (VAS), 95% CrI -0.06 to 0.53) or sleep quality (WMD 0.49 mm on a 100 mm VAS, 95% CrI -4.72 to 5.59).

Conclusions: Cannabis for medical use may be similarly effective and result in fewer discontinuations than opioids for chronic non-cancer pain.”

https://pubmed.ncbi.nlm.nih.gov/38171632/

Inhibitory effects of selected cannabinoids against dipeptidyl peptidase IV, an enzyme linked to type 2 diabetes

Posted on January 5, 2024 by David

“Ethnopharmacological relevance: In recent times the decriminalisation of cannabis globally has increased its use as an alternative medication. Where it has been used in modern medicinal practises since the 1800s, there is limited scientific investigation to understand the biological activities of this plant.

Aim of the study: Dipeptidyl peptidase IV (DPP-IV) plays a key role in regulating glucose homeostasis, and inhibition of this enzyme has been used as a therapeutic approach to treat type 2 diabetes. However, some of the synthetic inhibitors for this enzyme available on the market may cause undesirable side effects. Therefore, it is important to identify new inhibitors of DPP-IV and to understand their interaction with this enzyme.

Methods: In this study, four cannabinoids (cannabidiol, cannabigerol, cannabinol and Δ⁹-tetrahydrocannabinol) were evaluated for their inhibitory effects against recombinant human DPP-IV and their potential inhibition mechanism was explored using both in vitro and in silico approaches.

Results: All four cannabinoids resulted in a dose-dependent response with IC₅₀ values of between 4.0 and 6.9 μg/mL. Kinetic analysis revealed a mixed mode of inhibition. CD spectra indicated that binding of cannabinoids results in structural and conformational changes in the secondary structure of the enzyme. These findings were supported by molecular docking studies which revealed best docking scores at both active and allosteric sites for all tested inhibitors. Furthermore, molecular dynamics simulations showed that cannabinoids formed a stable complex with DPP-IV protein via hydrogen bonds at an allosteric site, suggesting that cannabinoids act by either inducing conformational changes or blocking the active site of the enzyme.

Conclusion: These results demonstrated that cannabinoids may modulate DPP-IV activity and thereby potentially assist in improving glycaemic regulation in type 2 diabetes.”

https://pubmed.ncbi.nlm.nih.gov/38169946/

https://www.cell.com/heliyon/fulltext/S2405-8440(23)10497-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS240584402310497X%3Fshowall%3Dtrue

Cannabigerolic Acid (CBGA) Inhibits the TRPM7 Ion Channel Through its Kinase Domain

Posted on January 5, 2024 by David

“Cannabinoids are a major class of compounds produced by the plant Cannabis sativa. Previous work has demonstrated that the main cannabinoids cannabidiol (CBD) and tetrahydrocannabinol (THC) can have some beneficial effects on pain, inflammation, epilepsy, and chemotherapy-induced nausea and vomiting. While CBD and THC represent the two major plant cannabinoids, some hemp varieties with enzymatic deficiencies produce mainly cannabigerolic acid (CBGA). We recently reported that CBGA has a potent inhibitory effect on both Store-Operated Calcium Entry (SOCE) via inhibition of Calcium Release-Activated Calcium (CRAC) channels as well as currents carried by the channel-kinase TRPM7. Importantly, CBGA prevented kidney damage and suppressed mRNA expression of inflammatory cytokines through inhibition of these mechanisms in an acute nephropathic mouse model. In the present study, we investigate the most common major and minor cannabinoids to determine their potential efficacy on TRPM7 channel function. We find that approximately half of the tested cannabinoids suppress TRPM7 currents to some degree, with CBGA having the strongest inhibitory effect on TRPM7. We determined that the CBGA-mediated inhibition of TRPM7 requires a functional kinase domain, is sensitized by both intracellular Mg⋅ATP and free Mg²⁺ and reduced by increases in intracellular Ca²⁺. Finally, we demonstrate that CBGA inhibits native TRPM7 channels in a B lymphocyte cell line. In conclusion, we demonstrate that CBGA is the most potent cannabinoid in suppressing TRPM7 activity and possesses therapeutic potential for diseases in which TRPM7 is known to play an important role such as cancer, stroke, and kidney disease.”

https://pubmed.ncbi.nlm.nih.gov/38162115/

https://academic.oup.com/function/article/5/1/zqad069/7462310?login=false

Cannabis Science and Therapeutics: An Overview for Clinicians

Posted on December 28, 2023 by David

“Cannabis-based therapeutics have garnered increasing attention in recent years as patients seek alternative treatments for various medical conditions. This narrative review provides a comprehensive overview of the science behind the medical use of cannabis, focusing on the medical evidence for commonly treated conditions. In addition, the review addresses the practical considerations of using cannabis as a therapeutic agent, offering insights into dosing strategies, variations in cannabinoid formulation, and individual patient responses. Precautions, adverse consequences, and drug interactions are also discussed, with a focus on patient safety and the potential risks associated with cannabis use.”

https://pubmed.ncbi.nlm.nih.gov/38145388/

https://accp1.onlinelibrary.wiley.com/doi/10.1002/jcph.2400

Cannabidiol and Tetrahydrocannabinol Antinociceptive Activity is Mediated by Distinct Receptors in Caenorhabditis elegans

Posted on December 28, 2023 by David

“Cannabis has gained popularity in recent years as a substitute treatment for pain following the risks of typical treatments uncovered by the opioid crisis. The active ingredients frequently associated with pain-relieving effects are the phytocannabinoids Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), but their effectiveness and mechanisms of action are still under research. In this study, we used Caenorhabditis elegans, an ideal model organism for the study of nociception that expresses mammal ortholog cannabinoid (NPR-19 and NPR-32) and vanilloid (OSM-9 and OCR-2) receptors. Here, we evaluated the antinociceptive activity of THC and CBD, identifying receptor targets and several metabolic pathways activated following exposure to these molecules. The thermal avoidance index was used to phenotype each tested C. elegans experimental group. The data revealed for the first time that THC and CBD decreases the nocifensive response of C. elegans to noxious heat (32-35 °C). The effect was reversed 6 h post- CBD exposure but not for THC. Further investigations using specific mutants revealed CBD and THC are targeting different systems, namely the vanilloid and cannabinoid systems, respectively. Proteomic analysis revealed differences following Reactome pathways and gene ontology biological process database enrichment analyses between CBD or THC-treated nematodes and provided insights into potential targets for future drug development.”

https://pubmed.ncbi.nlm.nih.gov/38141130/

https://link.springer.com/article/10.1007/s11064-023-04069-6

Cannabis Use and Incident Atrial Fibrillation in a Longitudinal Cohort

Posted on December 28, 2023 by David

“Background: Cannabis use is increasing worldwide. While prior studies have reported an association between cannabis use and a higher risk of atrial fibrillation (AF), most were cross-sectional and generally relied on diagnostic coding to identify cannabis users, which may not be representative of the typical, recreational cannabis user.

Objective: To examine the association between recreational cannabis use and lifetime AF risk.

Methods: We evaluated the AF risk of participants of the UK Biobank cohort who completed the cannabis use lifestyle questionnaire. Cannabis exposure was categorized as “Occasional Use” for less than 100 times used, “Frequent Use” for more than 100 times used, and “Never” users. AF events were identified using International Classification of Diseases (ICD) codes. Cox models were used to estimate the hazard ratios (HR) between cannabis use and incident AF and were subsequently adjusted for age, sex, race, alcohol, coffee, smoking, education, and baseline cardiovascular comorbidities.

Results: A total of 150,554 participants (mean 63.4 ± 7.7 years, 57.4% female, and 22.2% using cannabis at least once) were followed for a mean 6.1 ± 0.6 years. After multivariable adjustment, there were no statistically significant differences in incident AF among occasional users (HR 0.98, 95% CI 0.89 to 1.08) nor frequent users (HR 1.03, 95% CI 0.81 to 1.32) compared to never users.

Conclusions: Among a large, prospective cohort, there was no evidence that cannabis use was associated with a higher risk of incident AF. An evaluation of cannabis ingestion methods and quantification was not possible using the current dataset.”

https://pubmed.ncbi.nlm.nih.gov/38142832/

https://www.heartrhythmjournal.com/article/S1547-5271(23)03058-8/fulltext

Impacts of delta 9-tetrahydrocannabinol against myocardial ischemia/reperfusion injury in diabetic rats: Role of PTEN/PI3K/Akt signaling pathway

Posted on December 28, 2023 by David

“Despite the current optimal therapy, patients with myocardial ischemia/reperfusion (IR) injury still experience a high mortality rate, especially when diabetes mellitus is present as a comorbidity. Investigating potential treatments aimed at improving the outcomes of myocardial IR injury in diabetic patients is necessary. Our objective was to ascertain the cardioprotective effect of delta 9-tetrahydrocannabinol (THC) against myocardial IR injury in diabetic rats and examine the role of phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway in mediating this effect. Diabetes was induced in male Wistar rats (8-10 weeks old, 200-250 g; n = 60) by a single injection of streptozotocin. The duration of the diabetic period was 10 weeks. During the last 4 weeks of diabetic period, rats were treated with THC (1.5 mg/kg/day; intraperitoneally), either alone or in combination with LY294002, and then underwent IR intervention. After 24 h of reperfusion, infarct size, cardiac function, lactate dehydrogenase (LDH) and cardiac-specific isoform of troponin-I (cTn-I) levels, myocardial apoptosis, oxidative stress markers, and expression of PTEN, PI3K, and Akt proteins were evaluated. THC pretreatment resulted in significant improvements in infarct size and cardiac function and decreases in LDH and cTn-I levels (P < 0.05). It also reduced myocardial apoptosis and oxidative stress, accompanied by the downregulation of PTEN expression and activation of the PI3K/Akt signaling pathway (P < 0.05). LY294002 pretreatment abolished the cardioprotective action of THC. This study revealed the cardioprotective effects of THC against IR-induced myocardial injury in diabetic rats and also suggested that the mechanism may be associated with enhanced activity of the PI3K/Akt signaling pathway through the reduction of PTEN phosphorylation.”

https://pubmed.ncbi.nlm.nih.gov/38149557/

“Delta 9-tetrahydrocannabinol (THC) is the main psychoactive component of cannabis and has been shown to have potential therapeutic effects in various medical conditions. THC has been shown to have anti-inflammatory and antioxidant properties, which may reduce the inflammation and oxidative stress associated with myocardial IR injury.^[ Recent studies have suggested that THC improves glucose metabolism and insulin sensitivity and reduces blood glucose concentrations, oxidative stress, and inflammation associated with diabetic cardiomyopathy.”

https://www.cjphysiology.org/article.asp?issn=0304-4920;year=2023;volume=66;issue=6;spage=446;epage=455;aulast=Zhao