Safety and Tolerability of Low-Dose Full-Spectrum Cannabidiol in Long-Term Virally Suppressed Adults with HIV: A Randomized Double-Blind Placebo-Controlled Trial

Introduction: People with long-term virologically suppressed HIV (PWH) experience chronic inflammation. Beneficial effects such as lower levels of inflammation were reported for cannabis-based medicine but data on the safety of standardized low-dose full-spectrum cannabidiol (CBD) are limited. Methods: This double-blind randomized placebo-controlled trial (NCT05306249) included 80 ART-treated PWH with undetectable viremia (median time on efficient ART 14 years, median age 54 years), encompassing 30% women. Participants received 1 mg/kg CBD oil twice daily (full-spectrum, THC <0.3%) or placebo for 12 weeks plus a 4 week follow-up. Primary trial endpoint (autophagy gene expression) will be described elsewhere; here we evaluate the treatment impact on prespecified safety outcomes such as hemodynamic with electrocardiograms, HIV immunovirological parameters and comprehensive assessments of liver and kidney functions, performed using standard blood tests. Mixed-effects models adjusted for baseline age, sex, BMI, CD4 count and duration of viral suppression assessed longitudinal changes. Results: Of 80 randomized participants, 35 PWH in CBD and 37 in placebo groups completed week 12. No clinically meaningful differences emerged in creatinine, aminotransferases (ALT, AST), or conjugated bilirubin. Total bilirubin decreased in the CBD arm vs placebo (mixed effect model considering time, group and time*group, adjusted for covariates p=0.046). In exploratory sex-stratified analysis, a significant difference starting at week 12 (-8.0 bpm [95% CI -15.6; -0.4], p=0.0425) and persisting at week 16 (-7.9 bpm [95% CI -14.6; -1.3], p=0.0191) evidences a lower heart rate in men belonging to the CBD group compared to the placebo group; no change in females. There was no change in plasma viral load, cell-associated HIV-DNA levels and CD4/CD8 ratio. Discussion: Low-dose full-spectrum GMP-certified CBD was well tolerated over 12 weeks in virally suppressed people with HIV. Observed reductions in total bilirubin and male heart rate are exploratory and warrant confirmation in adequately powered trials incorporating inflammatory biomarkers and pharmacokinetics.