“The incidence of type 2 diabetes (T2D) is rising, and finding new treatments is important. C. sativa is a plant suggested as a potential treatment for T2D, but how it works needs to be clarified. This study explored the pharmacological mechanism of C. sativa in treating T2D. We identified the active compounds in C. sativa and their targets. From there, we examined the genes associated with T2D and found overlapping genes. We conducted an enrichment analysis and created a protein-protein and target-compound interactions network. We confirmed the binding activities of the hub proteins and compounds with molecular docking. We identified thirteen active compounds from C. sativa, which have 150 therapeutic targets in T2D. The enrichment analysis showed that these proteins are involved in the hormone, lipid, and stress responses. They bind transcription factors and metals and participate in the insulin, PI3K/Akt, HIF-1, and FoxO signaling pathways. We found four hub proteins (EGFR, ESR1, HSP90AA1, and SRC) that bind to the thirteen bioactive compounds. This was verified using molecular docking. Our findings suggest that C. sativa‘s antidiabetic action is carried out through the insulin signaling pathway, with the participation of HIF-1 and FoxO.”
Category Archives: Diabetes
β-Caryophyllene, a Dietary Phytocannabinoid, Alleviates Diabetic Cardiomyopathy in Mice by Inhibiting Oxidative Stress and Inflammation Activating Cannabinoid Type-2 Receptors
“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
Association between cannabis use and risk of diabetes mellitus type 2: A systematic review and meta-analysis
“Background: Cannabis consumption exerts multiple effects on metabolism via various pathways, including glucose regulation and insulin secretion. Studies concerning the association between cannabis use and diabetes mellitus type 2 are discrepant.
Objective: This study was conducted to evaluate the association between cannabis use and type 2 diabetes mellitus (T2DM).
Search methods: We searched PubMed, Scopus, Embase, Proquest, Web of Science, and Cochrane Library with no time, language or study types restriction until July 1, 2022, using various forms of “cannabis” and “diabetes mellitus” search terms.
Selection criteria: Randomized control trials, cohort, and case-control studies investigating the relationship between cannabis consumption and diabetes mellitus type 2 were included.
Data collection and analysis: The Newcastle-Ottawa scale was used to assess the quality of studies. We pooled odds ratio (OR) with 95% confidence interval (CI) using the random-effects model, generic inverse variance method, DerSimonian and Laird approach.
Main results: A meta-analysis of seven studies, containing 11 surveys and 4 cohorts, revealed that the odds of developing T2DM in individuals exposed to cannabis was 0.48 times (95% CI: 0.39 to 0.59) lower than in those without cannabis exposure.
Conclusions: A protective effect of cannabis consumption on the odds of diabetes mellitus type 2 development has been suggested. Yet given the considerable interstudy heterogeneity, the upward trend of cannabis consumption and cannabis legalization is recommended to conduct studies with higher levels of evidence.”
Cannabidiol ameliorates inflammatory response partly by AGE-RAGE pathway in diabetic mice
“Cannabidiol (CBD), the most abundant nonpsychoactive constituent of Cannabis sativa plant, is a promising potential pharmacotherapy for the treatment of diabetes and associated comorbidities. Previous studies have shown the potential of CBD to prevent diabetes in mice, the precise mechanisms of action remain unclear. The purpose of this study was to explore the mechanism of CBD alleviating hyperglycemia. The results demonstrated that CBD reduced blood glucose of STZ-induced diabetic mice without causing hypoglycemia. To elucidate the possible mechanisms of CBD effect, RNA-seq analysis was performed on high glucose-induced human mesangial cells (HMCs). By cluster analysis of differential genes, the results showed that advanced glycation end products-receptor of advanced glycation endproducts (AGE-RAGE) pathway-related genes CCL2 and interleukin-1β (IL-1β) play an important role in the biological of CBD. The expression of CCL2 and IL-1β were significantly increased in HMCs. Whereas, treatment with CBD decreased the expression of CCL2 and IL-1β. In addition, CBD significantly reduced AGE-RAGE levels in high glucose-induced HMCs. Similar results were confirmed in diabetic mice. In conclusion, we discovered for the first time that CBD ameliorates hyperglycemia partly through AGE-RAGE mediated CCL2/IL-1β pathway.”
A RANDOMIZED, CONTROLLED TRIAL OF EFFICACY AND SAFETY OF CANNABIDIOL IN IDIOPATHIC AND DIABETIC GASTROPARESIS
“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
Protective Effects of Hemp ( Cannabis sativa) Root Extracts against Insulin-Deficient Diabetes Mellitus In Mice

“The pharmacological potential of industrial hemp (Cannabis sativa) has been widely studied. However, the majority of studies have focused on cannabidiol, isolated from the inflorescence and leaf of the plant. In the present study, we evaluated the anti-diabetic potential of hemp root water (HWE) and ethanol extracts (HEE) in streptozotocin (STZ)-induced insulin-deficient diabetic mice. The administration of HWE and HEE ameliorated hyperglycemia and improved glucose homeostasis and islet function in STZ-treated mice (p < 0.05). HWE and HEE suppressed β-cell apoptosis and cytokine-induced inflammatory signaling in the pancreas (p < 0.05). Moreover, HWE and HEE normalized insulin-signaling defects in skeletal muscles and apoptotic response in the liver and kidney induced by STZ (p < 0.05). Gas chromatography-mass spectrometry analysis of HWE and HEE showed possible active compounds which might be responsible for the observed anti-diabetic potential. These findings indicate the possible mechanisms by which hemp root extracts protect mice against insulin-deficient diabetes, and support the need for further studies geared towards the application of hemp root as a novel bioactive material.”
https://pubmed.ncbi.nlm.nih.gov/37175224/
“These findings provide novel scientific evidence for the pharmaceutical application of hemp root, which has been considered a minor part of the plant in Cannabis-based medicinal and functional food studies.”
Tetrahydrocannabivarin (THCV) Protects Adipose-Derived Mesenchymal Stem Cells (ASC) against Endoplasmic Reticulum Stress Development and Reduces Inflammation during Adipogenesis

“The endoplasmic reticulum (ER) fulfills essential duties in cell physiology, and impairment of this organelle’s functions is associated with a wide number of metabolic diseases. When ER stress is generated in the adipose tissue, it is observed that the metabolism and energy homeostasis of the adipocytes are altered, leading to obesity-associated metabolic disorders such as type 2 diabetes (T2D).
In the present work, we aimed to evaluate the protective effects of Δ9-tetrahydrocannabivarin (THCV, a cannabinoid compound isolated from Cannabis sativa L.) against ER stress in adipose-derived mesenchymal stem cells.
Our results show that pre-treatment with THCV prevents the subcellular alteration of cell components such as nuclei, F-actin, or mitochondria distribution, and restores cell migration, cell proliferation and colony-forming capacity upon ER stress. In addition, THCV partially reverts the effects that ER stress induces regarding the activation of apoptosis and the altered anti- and pro-inflammatory cytokine profile.
This indicates the protective characteristics of this cannabinoid compound in the adipose tissue. Most importantly, our data demonstrate that THCV decreases the expression of genes involved in the unfolded protein response (UPR) pathway, which were upregulated upon induction of ER stress.
Altogether, our study shows that the cannabinoid THCV is a promising compound that counters the harmful effects triggered by ER stress in the adipose tissue. This work paves the way for the development of new therapeutic means based on THCV and its regenerative properties to create a favorable environment for the development of healthy mature adipocyte tissue and to reduce the incidence and clinical outcome of metabolic diseases such as diabetes.”
https://pubmed.ncbi.nlm.nih.gov/37108282/
“Considering that nowadays there is still a need for metabolic disorder (including obesity) prevention and the enhancement of regenerative outcomes of autologous stem cells, the potential use of the natural plant compound THCV, which is non-psychotropic, could be an effective and economical way to cope with those obstacles.”
A Phase I Randomized, Double-blind, Placebo-controlled Study on Efficacy and Safety Profile of a Sublingually Administered Cannabidiol /Delta 9-tetrahydrocannabidiol (10: 1) Regimen in Diabetes Type 2 Patients

“The current study aimed to evaluate the safety profile and efficacy of a cannabis-based sublingual spray, CBDEX10® (containing 100 µg cannabidiol and 10 µg Δ9-tetrahydrocannabinol per puff; CBD/Δ9-THC 10:1), in improving lipid profile and glycemic state of the diabetic patients.
Fifty diabetic patients were randomly allocated to the treatment (n = 25; receiving two puffs of CBDEX10® twice daily) or the control groups (n = 25; receiving two puffs of placebo). The primary endpoint of the study was to evaluate the efficacy of the CBDEX10® adjunctive therapy in improving the lipid profile and glycemic state of diabetic patients; the secondary endpoint was to assess the safety profile and tolerability of the spray.
A statistically significant decline in total cholesterol [estimated treatment difference (ETD) = −19.73 mg/dL; P < 0.05], triglyceride (ETD = −27.84 mg/dL; P < 0.01), LDL-C (ETD = −5.37 mg/dL; P < 0.01), FBS (ETD = −12 mg/dL; P < 0.01), Hb A1C (ETD = −0.21 mg/dL; P < 0.01) and insulin secretion (ETD = -5.21 mIU/L; P < 0.01) was observable in the patients treated with CBDEX10® at the end of the 8-week treatment period. Regarding safety, the mentioned adjunctive regimen was well, and there were no serious or severe adverse effects.
Overall, CBDEX1® sublingual spray could be a new therapeutic agent for lipid and glycemic control in diabetic patients.”
“Based on these observations, the combination of CBD/Δ9-THC regimen could be a new therapeutic regimen for controlling the lipid profile and glycemic state of DM patients.”
Blockade of CB1 or Activation of CB2 Cannabinoid Receptors Is Differentially Efficacious in the Treatment of the Early Pathological Events in Streptozotocin-Induced Diabetic Rats

“Oxidative stress, neurodegeneration, neuroinflammation, and vascular leakage are believed to play a key role in the early stage of diabetic retinopathy (ESDR). The aim of this study was to investigate the blockade of cannabinoid receptor 1 (CB1R) and activation of cannabinoid receptor 2 (CB2R) as putative therapeutics for the treatment of the early toxic events in DR. Diabetic rats [streptozotocin (STZ)-induced] were treated topically (20 μL, 10 mg/mL), once daily for fourteen days (early stage DR model), with SR141716 (CB1R antagonist), AM1710 (CB2R agonist), and the dual treatment SR141716/AM1710. Immunohistochemical-histological, ELISA, and Evans-Blue analyses were performed to assess the neuroprotective and vasculoprotective properties of the pharmacological treatments on diabetes-induced retinal toxicity. Activation of CB2R or blockade of CB1R, as well as the dual treatment, attenuated the nitrative stress induced by diabetes. Both single treatments protected neural elements (e.g., RGC axons) and reduced vascular leakage. AM1710 alone reversed all toxic insults. These findings provide new knowledge regarding the differential efficacies of the cannabinoids, when administered topically, in the treatment of ESDR. Cannabinoid neuroprotection of the diabetic retina in ESDR may prove therapeutic in delaying the development of the advanced stage of the disease.”
https://pubmed.ncbi.nlm.nih.gov/36613692/
“In closing, our findings suggest that topical administration of the three cannabinoid treatments, such as eye drops, provides protection to the diabetic retina in a differential manner against the four pathologies of ESDR. The actions of both CB2R activation and CB1R blockade in restoring ganglion cell axons (NFL-IR) in ESDR suggest that both agents may be effective in retarding RGC death. AM1710 is efficacious as an antioxidant, anti-inflammatory, neuroprotective and vasculoprotective agent and, thus, a promising new therapeutic for ESDR. Further advancement of retinal imaging to screen and identify the early events in DR, such as neurodegeneration in diabetic patients, is crucial for selecting neuroprotective drugs and implementing personalized treatments. As our findings clearly implicate the endocannabinoid system, the therapeutic benefits of this class of compounds should also extend to patients with diabetic nephropathy and cardiopathy/stroke since DR has been associated with the development of these diseases.”
The function of the endocannabinoid system in the pancreatic islet and its implications on metabolic syndrome and diabetes
“The following review focuses on the scientific studies related to the role of endocannabinoid system (ECS) in pancreatic islet physiology and dysfunction. Different natural or synthetic agonists and antagonists have been suggested as an alternative treatment for diabetes, obesity and metabolic syndrome. Therapeutic use of Cannabis led to the discovery and characterization of the ECS, a signaling complex involved in regulation of various physiological processes, including food intake and metabolism. After the development of different agonists and antagonists, evidence have demonstrated the presence and activity of cannabinoid receptors in several organs and tissues, including pancreatic islets. Insulin and glucagon expression, stimulated secretion, and the development of diabetes and other metabolic disorders have been associated with the activity and modulation of ECS in pancreatic islets. However, according to the animal model and experimental design, either endogenous or pharmacological ligands of cannabinoid receptors have guided to contradictory and paradoxical results that suggest a complex physiological interaction. In consensus, ECS activity modulates insulin and glucagon secretions according to glucose in media; over-stimulation of cannabinoid receptors affects islets negatively, leading to glucose intolerance, meanwhile the treatment with antagonists in diabetic models and humans suggests an improvement in islets function.”
https://pubmed.ncbi.nlm.nih.gov/36598083/
https://www.tandfonline.com/doi/full/10.1080/19382014.2022.2163826