Can Endocannabinoids Explain CBD-Mediated Reduction in Blood Pressure? Insights from a Randomized, Placebo-Controlled, Crossover Trial

<b>Background:</b> HYPER-H21-4 trial, a randomized, placebo-controlled, crossover trial, showed that chronic cannabidiol (CBD) supplementation reduces blood pressure (BP) in patients with primary hypertension. Given the association between the endocannabinoid (EC) system and hypertension, we aimed to determine whether changes in circulating ECs, signaling molecules of the EC system, could explain CBD-mediated cardiovascular effects. <b>Methods:</b> For this purpose, anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured in 66 patients with hypertension. Patients were assigned to receive CBD for 5 weeks (225-300 mg/day for the first 2.5 weeks, increasing to 375-450 mg/day for the subsequent 2.5 weeks), followed by 5 weeks of placebo, or 5 weeks of placebo followed by 5 weeks of CBD. <b>Results:</b> Administration of the CBD formulation for 5 weeks resulted in a significant increase in plasma AEA levels, whereas no such increase was observed during the placebo period (Placebo: 37.0 ± 18.0 ng/mL vs. 38.9 ± 20.8 ng/mL, CBD: 36.7 ± 18.0 ng/mL vs. 47.9 ± 24.6 ng/mL, <i>F</i> = 3.592, <i>p</i> = 0.042; Δ_CBDAEA 11.1 ± 3.7 ng/mL, <i>p</i> = 0.025). Change in AEA levels following CBD administration (Δ_CBDAEA) did not correlate with change in systolic BP following CBD administration (Δ_CBDSBP) (<i>r</i> = -0.106, <i>p</i> = 0.428). Multivariate analysis showed that body mass index, current antihypertensive treatment, and fasting plasma glucose at baseline emerged as significant predictors of AEA increase, while BP reduction did not demonstrate a significant association. No significant association was found between chronic CBD administration and 2-AG plasma concentrations (placebo: 28.8 ± 4.3 ng/mL vs. 38.9 ± 20.8 ng/mL; CBD: 36.7 ± 18.0 ng/mL vs. 47.9 ± 24.6 ng/mL; <i>F</i> = 0.513, <i>p</i> = 0.478). <b>Conclusions:</b> Collectively, these findings suggest that although chronic CBD administration appears to increase AEA, but not 2-AG plasma levels, this study provides no conclusive evidence that such alterations explain CBD-mediated BP reduction.