Anti-inflammatory effects of cannabidiol in the treatment of type 1 diabetes: A mini review

Table 1 Anti-inflammatory and immunomodulatory effects of cannabidiol in type 1 diabetes models

Ref.	Experimental model	Dose/route of administration	Treatment duration	Inflammatory markers evaluated	Main findings	Quality assessment
Li et al[13]	Male C57BL/6 mice (6-8 weeks old) with STZ-induced T1D	Cannabidiol at doses of 5 mg/kg and 10 mg/kg, administered intraperitoneally	Once daily for 28 consecutive days	CCL2 (monocyte chemoattractant protein-1), IL-1β, AGEs, RAGE	Significantly reduced immunomodulator levels in the liver and spleen, and decreased expression of AGEs and RAGE in mouse tissues	High
González-Mariscal et al[18]	NOD and C57BL/6J mice with STZ-induced diabetes (150 mg/kg)	Abn-CBD (abnormal cannabidiol); intraperitoneal injection at doses of 0.1 mg/kg and 1 mg/kg	NOD mice: Once daily for 12 weeks; STZ-induced mice: 7 consecutive days	Inflammatory cytokines (IL-6, TNF-α), NF-κB and TXNIP activation, CD4+ and CD8+ T cell infiltration in pancreatic islets	Reduction in insulitis and β-cell apoptosis, decreased pancreatic inflammation, and improved glucose tolerance	High
Lehmann et al[19]	Female NOD mice (6 weeks old)	5 mg/kg, intraperitoneally	10 weeks (5 times per week)	Leukocyte rolling and adhesion (intravital microscopy); functional capillary density; plasma cytokines; ICAM-1 and 1P-selectin	CBD delayed the onset of T1DM, reduced leukocyte activation, and increased pancreatic capillary perfusion	High
Weiss et al[30]	Female NOD mice (6-12 weeks old)	5 mg/kg, intraperitoneally	2 to 4 weeks (10-20 applications)	IFN-γ, TNF-α, IL-12, IL-10, IL-4 (in plasma, splenocytes, and macrophages); pancreatic histology (insulitis)	Reduction in T1DM incidence (from 86% to 30%), delayed disease onset, reduced insulitis, suppression of Th1 cytokines, and increased IL-10 and IL-4	High
Weiss et al[31]	Female NOD mice (11-14 weeks old)	5 mg/kg, intraperitoneally	4 weeks (5 times per week)	IL-6, IL-12, TNF-α, IL-10, IL-4 (from splenocyte and macrophage cultures); islet infiltration (pancreatic histology)	Significant reduction in T1DM incidence [32% vs (86%-100%)], decreased insulitis, increased Th2 cytokines (IL-10, IL-4), and reduced IL-6 and IL-12 Levels	High
González-Mariscal et al[36]	Male C57BL/6J mice with T1D mellitus induced by streptozotocin (150mg/kg)	Synthetic cannabidiol derivative: (+)-CBD-HPE, 10 mg/kg, administered intraperitoneally	7 consecutive days, starting before diabetes induction	Phospho-NF-κB, cleaved caspase-3, CD3+ (T lymphocyte infiltration), plasma cytokines (interferon-gamma, IL-5, TNF-α, IL-18)	Inhibited NF-κB transcription factor activation, reduced T-cell infiltration in pancreatic islets and kidneys, prevented β-cell apoptosis, and lowered interferon-gamma levels	High
Aseer et al[37]	Female NOD mice with β-cell-specific genetic deletion of the CB1	Genetic deletion (β-cell-specific knockout); JD-5037 (CB1 inverse agonist) also tested separately	26-week follow-up; JD-5037 administered for 4 weeks	Inflammatory cytokines: Interferon-gamma, IL-1β, IL-12p70, TNF-α; chemokines: CXCL9, CXCL10, CCL5; adhesion molecules	Reduced islet inflammation, with lower expression of proinflammatory cytokines, increased frequency of regulatory T cells, and reduced insulitis score	High

¹P-selectin: A cell adhesion molecule involved in leukocyte interactions.

Abn-CBD: Abnormal cannabidiol; AGEs: Advanced glycation end products; CB1: Cannabinoid receptor type 1; CBD: Cannabidiol; (+)-CBD-HPE: Synthetic cannabidiol derivative; CCL: C-C motif chemokine ligand; CXCL: C-X-C motif chemokine ligand; ICAM-1: Intercellular adhesion molecule-1; IFN: Interferon; IL: Interleukin; JD-5037: Cannabinoid receptor type 1 inverse agonist; NF-κB: Nuclear factor kappa B; NOD: Non-obese diabetic; RAGE: Receptor for advanced glycation end product; STZ: Streptozotocin; T1D: Type 1 diabetes; T1DM: Type 1 diabetes mellitus; TXNIP: Thioredoxin-interacting protein.

Table 2 Metabolic, behavioral, and complication-related effects of cannabidiol in type 1 diabetes models

Ref.	Experimental model	Dose/route of administration	Treatment duration	Evaluated parameters	Main findings	Quality assessment
Rajesh et al[24]	C57BL/6J mice with STZ-induced T1D	Cannabidiol administered intraperitoneally at doses of 1 mg/kg to 20 mg/kg	Once daily for 11 weeks	Cardiac function, inflammation, oxidative stress, fibrosis, apoptosis	Cannabidiol improved cardiac function and reduced inflammation, oxidative stress, fibrosis, and cell death, with effects observed even in advanced stages of the disease	High
Toth et al[25]	Mice with STZ-induced T1DM	CBD (CB2 agonist): 0.1-2 mg/kg intranasally or 1-20 mg/kg intraperitoneally	3 months, administered once per week	Tactile and thermal pain sensitivity, microglial density and activation (Iba-1, p-p38), nerve conduction	CBD reduced the development of neuropathic pain and microglial activation when administered early, but had no effect once pain was already established	High
Chaves et al[26]	Adult male Wistar rats (weighing 180-220 g) with STZ-induced T1DM	Cannabidiol at doses of 3 mg/kg, 10 mg/kg, and 30 mg/kg, administered intraperitoneally once daily	14 consecutive days, starting two weeks after diabetes induction	Blood glucose, plasma insulin levels, body weight gain, anxiety-like and depressive-like behaviors, serotonin, norepinephrine, and dopamine levels in the prefrontal cortex and hippocampus	Promoted weight gain, improved glycemic and behavioral profile, with partial normalization of serotonin and norepinephrine levels in the analyzed brain regions	High
Carmona-Hidalgo et al[27]	C57BL/6J mice with STZ-induced T1D	10 mg/kg of CBD, administered intraperitoneally	Once daily for 14 days	Blood glucose, glucose tolerance, renal histology (glomerular, tubular, and interstitial), fibrosis, creatinine, and urea levels	CBD did not prevent diabetes, worsened β-cell loss, and significantly aggravated diabetic nephropathy, although it slightly reduced CD3+ T cell infiltration	High
Chaves et al[28]	Wistar rats with STZ-induced T1D	30 mg/kg of CBD, administered intraperitoneally	Daily for 14 days, with pretreatment using specific antagonists of 5-HT1A, CB1, and CB2 receptors	Anxiolytic behavior, antidepressant behavior, blood glucose levels	Antidepressant and anxiolytic effects mediated by 5-HT1A and CB1 receptors; blood glucose reduction mediated by CB2 receptor	High
Spyridakos et al[29]	Wistar rats with STZ-induced T1DM	CB1 antagonist and CB2 agonist, both administered as eye drops (20 μL, 10 mg/mL)	Once daily for 14 consecutive days	Retinal thickness, number of amacrine cells, apoptosis, and vascular integrity	Restored retinal thickness, reduced apoptosis, and increased amacrine cell density. Both treatments reduced vascular leakage
Chaves et al[34]	Wistar rats with STZ-induced T1D	60 mg/kg of CBD, administered intraperitoneally	Single dose, immediately after contextual fear conditioning	Contextual fear behavior, Arc protein expression in the dorsal hippocampus, anxiety-related behavior	Impaired consolidation and generalization of contextual fear memory; anxiolytic effect observed in the elevated plus maze
McKillop et al[35]	NIH Swiss mice with T1DM induced by five consecutive doses of STZ	Abn-CBD: 0.1 micromole per kilogram, administered orally	Once daily for 28 consecutive days	Pancreatic insulin secretion and content, glucose tolerance, insulin sensitivity, plasma glucagon levels, lipid profile, pancreatic β-cell proliferation, islet morphology	Reduced blood glucose and glucagon levels, increased insulin secretion and pancreatic content, improved glucose tolerance and insulin sensitivity, decreased triglycerides and total cholesterol, and stimulated β-cell proliferation	High
Zheng et al[38]	Clinical trial with patients diagnosed with idiopathic gastroparesis or gastroparesis associated with T1DM/T2DM (6 patients with T1D)	Epidiolex® (CBD), oral dose titrated up to 20 mg/kg/day	Twice daily for 4 weeks	Gastroparesis symptoms, gastric emptying, and gastric volumes	Reduction in gastroparesis symptoms, increased tolerance to liquids, and positive effects even with delayed gastric emptying	High

5-HT1A: 5-hydroxytryptamine 1A receptor; Abn-CBD: Abnormal cannabidiol; Arc: Activity-regulated cytoskeleton-associated protein; CB1: Cannabinoid receptor type 1; CB2: Cannabinoid receptor type 2; CBD: Cannabidiol; Epidiolex^®: Pharmaceutical-grade cannabidiol oral solution; Iba-1: Ionized calcium-binding adapter molecule 1; NIH: National Institutes of Health; P-p38: Phosphorylated p38 mitogen-activated protein kinase; STZ: Streptozotocin; T1D: Type 1 diabetes; T1DM: Type 1 diabetes mellitus.