Abstract
Background and purpose
Emerging data indicates that cannabidiol (CBD), a non-intoxicating constituent of cannabis, exhibits significant cardiovascular effects. In light of the presumed blood pressure (BP) reducing effect, the primary aim of the HYPER-H21-4 trial was to explore the influence of chronic CBD supplementation on 24h ambulatory BP in hypertensive patients. Secondary aims included measurement of multiple cardiovascular parameters including heart-rate variability (HRV), arterial stiffness and multiple biomarkers, all with the goal of elucidating the mechanisms by which CBD affects cardiovascular system.

Methods
The trial was designed as a triple-blind randomized crossover trial. A total of 70 patients with primary hypertension were included. Exclusion criteria included the presence of significant comorbidities, smoking (tobacco and CBD), pregnancy, and BMI ≥ 35 kg/m2. Patients were randomly assigned to receive either oral CBD or placebo-matched capsules for the period of 5 weeks. After a 2-week washout, patients were crossed over to alternate therapy (CBD or placebo). There were 6 visit in total (at the start, middle and end of each dosing period). At each visit, venous blood samples were obtained from each patient. Furthermore, patients were instructed with ambulatory BP and ECG Holter monitors. Biomarkers of interest included catestatin, urotensin-II and multiple inflammatory biomarkers (interleukin 1β (IL-1β), IL-8, IL-6, IL-10, IL-18, Plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor alpha (TNF-α) and lectin-type oxidized LDL receptor 1 (LOX-1) were measured. Safety and tolerability of the CBD formulation was monitored throughout the whole course of the study.

Results
After 5 weeks of CBD supplementation, 24h systolic and diastolic BP dropped for ~4 mmHg and ~3 mmHg, respectively. No such change was observed following 5-week course of placebo. The reduction in BP was accompanied by reduction in serum catestatin and urotensin-II levels. Serum IL-8, IL-10 and IL-18 followed similar pattern as the latter. Moreover, the extent of change in BP moderately correlated with the extent of change in serum levels of the aforementioned biomarkers. On the other hand, no significant changes in other serum cytokines, HRV, or indices of vascular stiffness were noted after CBD or placebo dosing. No significant adverse events were noted during the whole course of the study.

Conlusions: The results of the HYPER-H21-4 trial indicate that chronic CBD supplementation leads to BP reduction. Sub-studies of the trial seem to intricate changes in sympathetic nervous system, endothelia and inflammation as mediators of the observed reduction. Yet, considering the multitude of CBD molecular targets, the relative contribution of these mechanisms remains elusive.