Impact of Oral Cannabinoids on the Endocannabinoidome and Gut Microbiome in People with HIV on Antiretroviral Therapy (CTN PT028 Pilot Clinical Trial).

Background: Cannabinoid-based medicines (CBMs) have garnered attention due to their anti-inflammatory potential in people with HIV (PWH), whose comorbidities are driven by chronic inflammation. The expanded endocannabinoid system (or endocannabinoidome, eCBome) is an important target of cannabinoids that cross talks with gut microbiota and regulates many homeostatic processes and inflammation. In a prospective, pilot clinical trial, PWH on antiretroviral therapy (ART) were randomly assigned to receive cannabidiol (CBD) ± Δ9-tetrahydrocannabinol (THC) capsules for 12 weeks, titrating doses as tolerated, to examine the impact of cannabinoids on plasma eCBome mediators and gut microbiota. Methods: Ten individuals were randomized, five to the CBD+THC arm and five to the CBD-only arm. Eight individuals completed the study. Plasma was collected at each visit and measured in batches by liquid chromatography (LC)-mass spectrophotometry (MS). The eCBome mediators were measured at each visit by LC-MS-MS, whereby fecal microbiota composition was assessed by 16S rDNA sequencing at the initiation and end of treatment. Results: Plasma concentrations of THC and CBD metabolites varied throughout the course of the study. Capsule administration resulted in a significant decrease in monoacylglycerols 2-eicosapentaenoylglycerol (2-EPG) and 2-oleoylglycerol (2-OG) after treatment. No changes were observed in the levels of other mediators measured. PWH in the distinct treatment arms had different fecal bacterial taxa at baseline. These differences persisted through the course of the study and were not altered by cannabinoid administration. However, Coprobacillus and Lachnospiraceae UCG001 relative abundance was lower, while Collinsella was higher, in the THC/CBD compared with the CBD arm. Conclusion: 2-EPG and 2-OG were both reduced following cannabinoid administration. No changes in fecal bacterial taxa were observed following 12 weeks of treatment. Larger studies are needed to understand if these changes reflect adaptation of the eCBome to the beneficial effects of CBM in PWH. Trial Registration: ClinicalTrials.gov Identifier NCT0355035.