Cannabigerol is a cannabinoid compound synthesized by Cannabis sativa, which in its acid form acts as the substrate for both Δ9-tetraydrocannabinol and cannabidiol formation. Given its lack of psychoactive effects, emerging research has focused on cannabigerol as a potential therapeutic for health conditions including algesia, epilepsy, anxiety, and cancer. While cannabigerol can bind to classical cannabinoid receptors, it is also an agonist at α2-adrenoreceptors (α2AR) which, when activated, inhibit presynaptic norepinephrine release. This raises the possibility that cannabigerol could activate α2AR to reduce norepinephrine release to cardiovascular end organs to lower blood pressure. Despite this possibility, there are no reports examining cannabigerol cardiovascular effects. In this study, we tested the hypothesis that acute cannabigerol administration lowers blood pressure. Blood pressure was assessed via radiotelemetry at baseline and following intraperitoneal injection of cannabigerol (3.3 and 10 mg/kg) or vehicle administered in a randomized crossover design in male C57BL/6J mice. Acute cannabigerol significantly lowered mean blood pressure (−28 ± 2 mmHg with 10 mg/kg versus −12 ± 5 mmHg vehicle, respectively; p = 0.018), with no apparent dose responsiveness (−22 ± 2 mmHg with 3.3 mg/kg). The depressor effect of cannabigerol was lower in magnitude than the α2AR agonist guanfacine and was prevented by pretreatment with the α2AR antagonist atipamezole. These findings suggest that acute cannabigerol lowers blood pressure in phenotypically normal mice likely via an α2AR mechanism, which may be an important consideration for therapeutic cannabigerol administration.

Cannabigerol (CBG) is a cannabinoid compound that is synthesized from Cannabis sativa L. and acts as a substrate for both Δ9‐tetraydrocannabinol (Δ9‐THC) and cannabidiol (CBD) formation. Given that it does not exhibit psychoactive effects, emerging research has focused on CBG as a potential therapeutic for health conditions including algesia, epilepsy, anxiety, and cancer. While CBG can bind to cannabinoid receptors CB1 and CB2, it has also been described as an agonist at α2‐adrenoreceptors (A2‐AR), which when activated inhibit the release of norepinephrine from α‐adrenergic neurons. This raises the concern that CBG could act at A2‐AR to reduce norepinephrine release to cardiovascular end organs, such as the heart and kidneys, causing a reduction in blood pressure. Despite this possibility, there are no reports examining cardiovascular effects of CBG. In this study, we tested the hypothesis that acute CBG administration can lower blood pressure. To test this, six male C57BL/6J mice underwent surgery at 8‐10 weeks of age to implant a radiotelemetry probe, which allows for continuous measurement of blood pressure, heart rate and locomotor activity in conscious, freely moving mice. Following 10 days of recovery, baseline measurements were obtained and then mice were randomized to receive intraperitoneal injections of CBG (3.3, 5.6, and 10 mg/kg) and vehicle in a crossover design, with at least one‐week washout between treatments. Changes in blood pressure, heart rate, and locomotor activity were measured for two hours post‐injection. We found that acute CBG significantly lowered blood pressure compared with vehicle (‐12±5 mmHg vehicle vs. ‐28±2 mmHg at 10 mg/kg CBG; p=0.018), with no apparent dose responsiveness at the doses used in this study (‐22±2 mmHg at 3.3 mg/kg CBG; ‐28±4 at 5.6 mg/kg CBG). The greatest blood pressure reduction was seen at 90‐minutes post‐CBG administration, which is consistent with reports for peak plasma concentrations of this compound in rodents. The blood pressure lowering effects of CBG occurred in the absence of changes in heart rate or locomotor activity. These overall findings suggest acute CBG may lower blood pressure in phenotypically normal young adult male mice, which may provide caution for the potential of hypotension as an adverse effect of CBG administration. Additional studies are needed to determine if the blood pressure lowering effects of CBG are via an A2‐AR mechanism.

Cannabigerol (CBG), the precursor of the major cannabinoid compounds synthesized from Cannabis sativa L., has emerged as a novel potential therapeutic target due to its lack of psychoactive effects and efficacy at reducing pain and inflammation in animal models. Despite this, little is known about the safety of CBG, including its impact on cardiovascular function. Our laboratory recently showed that acute CBG administration lowers blood pressure, by over 20 mmHg, in phenotypically normal male mice via an α2-adrenoreceptor mechanism, which could suggest the need for caution in using this compound in healthy individuals. In this study, we tested the hypothesis that CBG can also lower blood pressure in mice when administered chronically. To test this hypothesis, four male C57BL/6J mice were implanted with radiotelemetry probes at 8-10 weeks of age and allowed to recover for 10 days. This approach allows for continuous measurement of blood pressure, heart rate, and locomotor activity in conscious animals. Baseline blood pressure and heart rate were recorded for 24-hours prior to drug treatment. Mice were then administered CBG at a dose previously found to acutely lower blood pressure (10 mg/kg, intraperitoneal) for 14 days, with vital signs recorded for 24-hours at the end of treatment. We found that chronic CBG reduced 24-hour systolic blood pressure by ~5 mmHg (129±3 mmHg baseline vs. 124±2 mmHg post-CBG; p=0.040 via paired t-test), with similar trends for diastolic and mean blood pressure. This depressor effect was accompanied by a significant decrease in heart rate (581±15 bpm baseline vs. 502±19 bpm post-CBG; p=0.003), with no effect on locomotor activity. These overall findings suggest that chronic CBG may produce a small, but significant, decrease in blood pressure in phenotypically normal male mice. The magnitude of chronic CBG depressor effects was smaller than previously observed for acute administration. This could reflect multiple mechanisms including a2-adrenoreceptor desensitization or baroreflex buffering, but this remains to be tested. Regardless, these findings may provide caution for potential hypotensive effects of CBG under normotensive conditions. Funding sources: PA Options for Wellness and Penn State Medical Marijuana Academic Clinical Research Center This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.