CANNABIDIOL IS EFFICACIOUS AND SAFE IN ADULT GASTROPARESIS: A RANDOMIZED, PLACEBO-CONTROL TRIAL INCLUDING PHARMACODYNAMICS

Background: Idiopathic gastroparesis (IG) is an increasingly prevalent subtype of gastroparesis and causes significant morbidity and decreased quality of life. Prior studies have shown loss of Interstitial Cells of Cajal (ICC), key regulators of gastrointestinal motility, as well as anti-inflammatory macrophages in gastroparesis. Our aim was to determine druggable molecules and signaling for human IG using a deep multiomics approach through untargeted transcriptomics and proteomics on gastric muscle tissue.

Methods: We enrolled 13 IG patients (43±2 yrs, 10 F) and 18 non-diabetic controls (NDC; 46±10 yrs, 14 F) patients from Gastroparesis Clinical Research Consortium sites and Mayo Clinic, respectively. Bulk RNA-seq and Gel-based Liquid Chromatography/Mass-Spectrometry (LC-MS) were performed on mucosa-free gastric muscle. Differentially expressed genes and proteins were determined. Gene Set Enrichment Analysis and Search Tool for Retrieval of Interacting Genes and Proteins (STRING) were used to generate signalling pathways. Next, transcriptomic, and proteomic datasets were integrated. EnrichmentMap (EM) analysis in Cytoscape was used to determine networks of integrated STRING pathways. Finally, CiberSort was used to determine distribution of immune cell markers.

Results: RNA-seq detected 16755 genes, of which, 2569 (1338 up, 1231 down in IG compared to NDC) were significantly different (FDR<0.05, FC≥|1.5|). Mitochondrial genes involved in oxidative phosphorylation (OXPHOS; COX6C, SDHA, SDHB) and apoptosis (AIFM1, GHITM, HTRA2), as well as OXPHOS pathways (KEGG, Hallmark, FDR<0.001) were increased in IG. Using CiberSort, a significant increase in memory B-cell, and CD8+ T-cell, and a decrease in M2-associated (anti-inflammatory) macrophage markers were found in IG. Proteomics analysis detected 6444 named proteins, of which, ~50% were significantly different (FDR<0.05, FC≥|1.5|; 1485 up, 1541 down in IG). Top pathways (Hallmark: “Oxidative Phosphorylation”; Reactome: “Electron Transport Chain”, FDR<0.001), and proteins (TRAP1, WASL, SDHA) were noted. Overlap of the 2 datasets revealed 1241 significantly different gene-protein pairs (574 up, 667 down in IG). EM analysis showed that network joining “Signaling by SCF-Kit”, “Kit receptor Signaling”, and “PDGFR-beta signaling” pathways as the largest downregulated network, whereas “OXPHOS system in mitochondria” and “Metabolism” was the primary upregulated network in IG (Figure 1).

Conclusions: Our deep multiomics profiling of gastric muscularis propria in IG has uncovered oxidative phosphorylation and mitochondrial dysfunction, as well as confirmed Kit-signaling to be important in pathophysiology of IG. Loss of genes associated with anti-inflammatory macrophages, and upregulation of memory B-cell, and cytotoxic CD8+ T-cells further makes a case for determining immunobiology of idiopathic gastroparesis.

Background: Medical cannabis (^Δ9THC) is used to relieve nausea and pain, and the non-selective cannabinoid receptor (CBR) agonist dronabinol delays gastric emptying (GE) and enhances gastric accommodation (GA). Cannabidiol (CBD), a selective CBR2 agonist with limited effects in the central nervous system, may modulate effects of endocannabinoids on CBR1. CBD also affects sensation as inverse agonist of G protein-coupled receptors 3, 6, and 12, desensitization of TRPV1, TRPV2 and TRPA1 receptors and anti-inflammatory effects (via CBR2). We studied an FDA-approved oral formulation of purified CBD (100mg/mL). Aim: To compare pharmacodynamics and clinical effects of 4 weeks’ treatment with pharmaceutical grade CBD and placebo on GE of solids, fasting gastric volume (FGV), GA, satiation, and symptom response endpoints in patients with non-surgical gastroparesis. Methods: We performed a randomized, double-blind, placebo-control (1:1 ratio) 4-week study of oral CBD b.i.d. (up to 10mg/kg/day using FDA dose escalation guidance) in patients with non-surgical gastroparesis and delayed GE (postprandial GE ≤25% emptied at 2 hours, or ≤75% at 4 hours). Symptoms were assessed by the validated Gastroparesis Cardinal Symptom Index Daily Diary (GCSI). At baseline and after 4 weeks’ treatment, all patients underwent measurements of GE of solids, gastric volumes (FGV, GA), and maximum tolerated volume (MTV) during Ensure^® (1kcal/mL) satiation test ingested 30mL/min. All data collected in participants were analyzed. Statistical analysis compared 2 treatments for all endpoints, using baseline measurements and BMI as co-variates (expressed as least square means). Results: Table 1 shows demographics and baseline variables of gastroparesis (29 idiopathic, 6 type 1 diabetes, and 6 type 2 diabetes). Four patients did not tolerate full dose escalation; 3 withdrew before completing 4 weeks’ treatment (2 on placebo, 1 on CBD). However, 95% completed at least 2 weeks of treatment and diaries. Table 2 summarizes the effects of cannabidiol and placebo treatment in gastroparesis. CBD reduced the total GCSI score compared to placebo and improved symptoms of inability to finish a normal-sized meal, number of vomiting episodes in 24 hours, and overall gastroparesis symptom severity. Patients treated with CBD had higher MTV during satiation test. CBD group had longer GE lag time, which was also observed at baseline. CBD delayed GE at 2 hours, but there were no differences in GE T_1/2, proportion emptied at 4 hours, or GA. The most common adverse events reported were diarrhea (13), fatigue (8), headache (8), and nausea (7). Conclusions: Pharmaceutical grade CBD provides symptom relief in patients with non-surgical gastroparesis by improving the tolerance of nutrient intake and reducing the number of emesis, without deleterious effects on GA or overall GE.