Ten male subjects were recruited, but 1 withdrew for personal reasons. The mean age, weight, and height of the volunteers were 23.7 ± 3.2 years, 77.5 ± 6.4 kg, and 178.6 ± 4.5 cm (mean ± SD).

Effect of CBD on resting cardiovascular parameters. CBD treatment reduced resting systolic blood pressure (SBP) (mean difference –6 mmHg; 95% CI, –1 to –12, P < 0.05, Figure 1A). Although there was no overall difference in diastolic blood pressure (DBP) and mean arterial blood pressure (MAP) between the 2 groups, post-hoc analysis showed that both DBP and MAP were lower with CBD treatment (Figure 1, B and C, respectively; P < 0.01), particularly in the latter time points (120–160 min).

Figure 1 Changes in resting cardiovascular parameters after a single dose (600 mg) of cannabidiol (CBD) in healthy volunteers (n = 9). The effects of placebo (closed square) and CBD (open square) on systolic blood pressure (SBP) (A), diastolic blood pressure (DBP) (B), mean arterial blood pressure (MAP) (C), heart rate (HR) (D), stroke volume (SV) (E), cardiac output (CO) (F), ejection time (EJT) (G), total peripheral resistance (TPR) (H), and forearm blood flow (I), measured continuously over 2 hours after drug ingestion, except for forearm blood flow. Forearm blood was measured over a time period of 2 minutes just before the start and in between the stress tests. Dotted line denotes baseline values between the stress tests. Repeated measures 2-way ANOVA; mean ± SEM (*/+/#P < 0.05, **/++/##P < 0.01 using Bonferroni’s post-hoc analysis; + and # represent significant change in any parameter over time seen with placebo and CBD, respectively; denotes overall significant difference between 2 treatments).

CBD treatment reduced resting stroke volume (SV; mean difference –8 ml; 95% CI, –2 to –14, P < 0.05, Figure 1E) and increased heart rate (HR), with significant difference in HR between CBD and placebo from an hour after ingestion of drug (Figure 1D, P < 0.05). There was a decline in left ventricular ejection time (EJT) with both treatments (P < 0.05; Figure 1G), while cardiac output (CO) (Figure 1F) remained unchanged.

There was a trend toward reduction in total peripheral resistance (TPR, Figure 1H) with CBD in the latter half of the resting period, and a significant reduction in forearm skin blood flow before the start of the stress tests (Figure 1I; P < 0.01).

Effect of CBD on cardiovascular parameters mental stress. The individual blood pressure responses of healthy volunteers to the stresses are presented in Figure 2, showing the average baseline systolic or diastolic blood pressure in the 4 minutes preceeding the stress test, the peak response during stress, and the average recovery response in the 4 minutes after the stress test.

Figure 2 Individual systolic and diastolic blood pressure responses to all stress tests after a single dose (600 mg) of cannabidiol (CBD) or placebo in healthy volunteers (n = 9). Green color coding shows subjectS who had a reduced (compared with placebo) blood pressure response to stress after taking CBD, and red color coding shows an increased blood pressure response to stress after taking CBD.

Mental stress test. Mental stress caused a rise in HR (P < 0.05; Figure 3D) and a decline in SV (P < 0.01; Figure 3E), which was seen in both the CBD and placebo groups. There was a rise in DBP (P < 0.05; Figure 3B) and a decline in EJT (P < 0.05; Figure 3G), seen only in those who had taken CBD.

Figure 3 Cardiovascular response to mental stress after a single dose (600 mg) of cannabidiol (CBD) in healthy volunteers (n = 9). The effects of placebo (closed square) and CBD (open square) on systolic blood pressure (SBP) (A), diastolic blood pressure (DBP) (B), mean arterial blood pressure (MAP) (C), heart rate (HR) (D), stroke volume (SV) (E), cardiac output (CO) (F), ejection time (EJT) (G), total peripheral resistance (TPR) (H), and forearm blood flow (I), measured continuously just before, during, and after mental arithmetic test (dotted line denotes stress test period), except for forearm blood flow. Measurements for forearm blood flow were made over a 2-minute window just before, during, and after the stress test. Repeated measures 2-way ANOVA; mean ± SEM (+ and # denote significant change in a parameter during the stress period seen with placebo and CBD, respectively). +/#P < 0.05, ++/##P < 0.01.

Although overall, there was no difference in the cardiovascular parameters between the 2 treatments, post-hoc analysis showed that SBP (Figure 3A; P < 0.05 to < 0.0001), DBP (Figure 3B; P < 0.05 to < 0.01), and MAP (Figure 3C; P < 0.05 to < 0.0001) were significantly lower in volunteers who had taken CBD, especially immediately after the stress test. Looking at the individual response to mental stress, 6 of 9 subjects had a lower SBP before or during the mental stress test, and 9 of 9 subject had a lower SBP in the recovery period after taking CBD (Figure 2). Five of 9 subjects had a lower DBP during the mental stress test, and 6 of 9 subject had a lower DBP in the recovery period after taking CBD (Figure 2).

CBD increased HR during the latter part of mental stress and in the poststress period (Figure 3D; P < 0.05 to < 0.0001), with a corresponding decline in EJT (Figure 3G; P < 0.05 to < 0.0001). Although CBD reduced SV (Figure 3E; P < 0.05 to < 0.0001), there was no difference in CO between CBD and placebo (Figure 3F).

Compared with placebo, volunteers who had taken CBD had a lower TPR throughout and especially in the post–mental stress period (Figure 3H; P < 0.05 to < 0.0001). Volunteers who had taken CBD also reduced forearm skin blood flow before and during the latter part of mental stress (Figure 3I; P < 0.05 to < 0.01).

Exercise stress test. The isometric exercise stress caused a significant rise in the following parameters in both treatment groups; SBP (placebo P < 0.01, CBD P < 0.001; Figure 4A), DBP (placebo P < 0.01, CBD P < 0.0001; Figure 4B), MAP (placebo P < 0.01, CBD P < 0.0001; Figure 4C), and HR (placebo P < 0.05, CBD P < 0.001; Figure 4D).

Figure 4 Cardiovascular parameters in response to exercise stress after a single dose (600 mg) of cannabidiol (CBD) in healthy volunteers (n = 9). The effects of placebo (closed square) and CBD (open square) on systolic blood pressure (SBP) (A), diastolic blood pressure (DBP) (B), mean arterial blood pressure (MAP) (C), heart rate (HR) (D), stroke volume (SV) (E), cardiac output (CO) (F), ejection time (EJT) (G), total peripheral resistance (TPR) (H), and forearm blood flow (I), measured continuously just before, during, and after isometric exercise test (dotted line denotes stress test period), except for forearm blood flow. Measurements for forearm blood flow were made over a 2-minute window just before, during, and after the stress test. Repeated measures 2-way ANOVA; mean ± SEM (*/+/#P < 0.05; **/++/##P < 0.01; ***/###P < 0.001; ****/####P < 0.0001 using Bonferroni post-hoc analysis; + and # denote significant change in a parameter during the stress period seen with placebo and CBD respectively).

Overall, CBD treatment reduced SBP (mean difference –5 mmHg; 95% CI, –1 to –10, P < 0.05, Figure 4A) and MAP (mean difference –5 mmHg, 95% CI, –2 to –9, P < 0.05, Figure 4C) during the exercise stress. Looking at the individual response to exercise stress, 6 of 9 subjects had a lower SBP during isometric exercise and 8 of 9 subjects had a lower SBP in the recovery period after taking CBD (Figure 2). Five of 9 subjects had a lower DBP during exercise, and 8 of 9 subject had a lower DBP in the recovery period after taking CBD (Figure 2).

Subjects who had taken CBD had increased HR (mean difference 10 bpm; 95% CI, 5–14, P < 0.01, Figure 4D) and decreased SV (mean difference –13 ml; 95% CI, –4 to –22, P < 0.01, Figure 4E) and EJT (mean difference –0.01 sec, 95% CI, –0.001 to –0.03, P < 0.05, Figure 4G) during the exercise stress. There was no difference in CO during the exercise stress (Figure 4F).

A rise in forearm cutaneous blood flow in response to exercise (as would be expected) was only seen in volunteers who had taken placebo (P < 0.05; Figure 4I). Post-hoc analysis showed significantly lower forearm skin blood flow in those who had taken CBD (Figure 4I; P < 0.001 to < 0.0001), during the early and latter parts of the stress test. This was associated with reduced TPR (Figure 4H; P < 0.05 to < 0.001) before, after, and in the latter half of exercise stress.

Cold stress test. The cold pressor test caused a rise in SBP (placebo P < 0.01, CBD P < 0.05; Figure 5A) and MAP (placebo P < 0.001, CBD P < 0.05; Figure 5C) in both groups and a rise in DBP only with placebo (P < 0.01; Figure 5B). An equal rise in SBP and MAP was seen with both CBD and placebo in the first half of this stress test. However, while the blood pressure (SBP and MAP) continued to rise in the placebo group, it plateaued in volunteers who had taken CBD, and therefore both SBP and MAP were significantly lower in volunteers after CBD (mean difference –8 mmHg [95% CI, –4 to –12, P < 0.01] and –6 mmHg [95% CI, –2 to –11, P < 0.01]). Post-hoc analysis showed that DBP was also significantly lower in those who had taken CBD in the latter half of the stress period (Figure 5B; P < 0.001).

Figure 5 Cardiovascular response to cold stress after a single dose (600 mg) of cannabidiol (CBD) in healthy volunteers (n = 9). The effects of placebo (closed square) and CBD (open square) on systolic blood pressure (SBP) (A), diastolic blood pressure (DBP) (B), mean arterial blood pressure (MAP) (C), heart rate (HR) (D), stroke volume (SV) (E), cardiac output (CO) (F), ejection time (EJT) (G), total peripheral resistance (TPR) (H), and forearm blood flow (I), measured continuously just before, during, and after cold pressor test (dotted line denotes stress test period), except for forearm blood flow. Measurements for forearm blood flow were made over a 2-minute window just before, during, and after the stress test. Repeated measures 2-way ANOVA; mean ± SEM (*/+/#P < 0.05, **/++P < 0.01, ***/+++P < 0.001, ****P < 0.0001 using Bonferroni post-hoc analysis; + and # denote significant change in a parameter during the stress period seen with placebo and CBD, respectively).

Looking at the individual response to the cold pressor test, 8 of 9 subjects had a lower SBP during the cold stress and in the recovery period after taking CBD (Figure 2). Six of 9 subjects had a lower DBP during the cold pressor, and 7 of 9 subject had a lower DBP in the recovery period after taking CBD (Figure 2).

As before, HR was higher in volunteers who had taken CBD (mean difference 7 bpm; 95% CI: 2–13; P < 0.05; Figure 5D), and EJT was lower (mean difference -0.01 sec; 95% CI: 0 to –0.02; P < 0.05; Figure 5G). Sidak post-hoc analysis showed that SV was significantly lower with CBD throughout (Figure 5E; P < 0.05 to < 0.0001), but there was no decline in cardiac output (Figure 5F).

The cold pressor test caused a significant rise in TPR (as expected) in the placebo group only (Figure 5H; P < 0.01) and rise in forearm skin blood flow with both CBD and placebo (Figure 5I; P < 0.05). The overall trend was for lower TPR and forearm skin blood flow in those who had taken CBD, with post-hoc analysis showing a reduction in both just before and in the latter half of cold stress (Figure 5H [P < 0.05 to < 0.0001] and Figure 5I [P < 0.001]).