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Published Online: 21 April 2023

Chronic Effects of Oral Cannabidiol Delivery on 24-h Ambulatory Blood Pressure in Patients with Hypertension (HYPER-H21-4): A Randomized, Placebo-Controlled, and Crossover Study

Publication: Cannabis and Cannabinoid Research


Background: Recent data indicate that cannabidiol (CBD), a nonintoxicating constituent of cannabis, is involved in several aspects of cardiovascular regulation, including blood pressure (BP). However, the impact of chronic CBD administration on 24-h BP and vascular health has not been previously examined in patients with hypertension. The primary aim of this randomized, triple-blind, placebo-controlled, and crossover study was to examine the influence of chronic CBD on 24-h ambulatory BP and arterial stiffness in hypertensive patients.
Methods: Seventy patients with mild or moderate primary hypertension, who were untreated or receiving standard of care therapy, were randomly assigned to receive either 5 weeks of oral CBD or placebo-matched controls. Following a >2-week washout period, patients were crossed over to alternate therapy. The primary outcome of the study was dynamic in 24-h ambulatory BP and was assessed using two-way repeated measure analysis of variance.
Results: Administration of CBD reduced average 24 h mean, systolic, and diastolic BP after 2.5 weeks (−3.22±0.90 mmHg [95% confidence interval −1.01 to −5.44 mmHg], −4.76±1.24 mmHg [−1.72 to −7.80 mmHg], and −2.25±0.80 mmHg [−0.30 to −6.01 mmHg], respectively (all p<0.05); however, these values largely remained stable following the uptitration of CBD dosing. There were no changes in liver enzymes or serious adverse events (AEs). There was no significant difference in pulse wave velocity (group×factor interaction: F=1.50, p=0.226) at different time points, regardless of the intervention arm.
Conclusions: In conclusion, chronic administration of CBD reduces ambulatory BP in those with untreated and treated hypertension. In addition, lack of serious AEs implies safety and tolerability of the above-noted CBD formulation. ID: NCT05346562, Registered April 6th 2022.

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1. Mills KT, Stefanescu A, He J. The global epidemiology of hypertension. Nat Rev Nephrol 2020;16(4):223–237.
2. Appel LJ. The effects of dietary factors on blood pressure. Cardiol Clin 2017;35(2):197–212.
3. Fu J, Liu Y, Zhang L, et al. Nonpharmacologic interventions for reducing blood pressure in adults with prehypertension to established hypertension. J Am Heart Assoc 2020;9(19):25.
4. Stanley CP, Hind WH, O'Sullivan SE. Is the cardiovascular system a therapeutic target for cannabidiol? Br J Clin Pharmacol 2013;75(2):313–322.
5. Ali RM, Al Kury LT, Yang KH, et al. Effects of cannabidiol on contractions and calcium signaling in rat ventricular myocytes. Cell Calcium 2015;57(4):290–299.
6. Booz GW. Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. Free Radic Biol Med 2011;51(5):1054–1061.
7. Sultan SR, Millar SA, England TJ, et al. A systematic review and meta-analysis of the haemodynamic effects of cannabidiol. Front Pharmacol 2017;8:81.
8. Kicman A, Toczek M. The effects of cannabidiol, a non-intoxicating compound of cannabis, on the cardiovascular system in health and disease. Int J Mol Sci 2020;21(18):6740.
9. Sultan SR, O'Sullivan SE, England TJ. The effects of acute and sustained cannabidiol dosing for seven days on the haemodynamics in healthy men: A randomised controlled trial. Br J Clin Pharmacol 2020;86(6):1125–1138.
10. Jadoon KA, Tan GD, O'Sullivan SE. A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study. JCI Insight 2017;2(12):15.
11. Arout CA, Haney M, Herrmann ES, et al. A placebo-controlled investigation of the analgesic effects, abuse liability, safety and tolerability of a range of oral cannabidiol doses in healthy humans. Br J Clin Pharmacol 2022;88(1):347–355.
12. Millar SA, Maguire RF, Yates AS, et al. Towards better delivery of cannabidiol (CBD). Pharmaceuticals 2020;13(9):219.
13. Kumric M, Bozic J, Dujic G, et al. Chronic effects of effective oral cannabidiol delivery on 24-h ambulatory blood pressure and vascular outcomes in treated and untreated hypertension (HYPER-H21-4): Study protocol for a randomized, placebo-controlled, and crossover study. J Personal Med 2022;12(7):1037.
14. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018;39(33):3021–3104.
15. Winnicki M, Canali C, Mormino P, et al. Ambulatory blood pressure monitoring editing criteria: is standardization needed? Hypertension and Ambulatory Recording Venetia Study (HARVEST) Group, Italy. Am J Hypertens 1997;10(4 Pt 1):419–427.
16. Campos AC, Ortega Z, Palazuelos J, et al. The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: Involvement of the endocannabinoid system. Int J Neuropsychopharmacol 2013;16(6):1407–1419;
17. Maione S, Piscitelli F, Gatta L, et al. Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action. Br J Pharmacol 2011;162(3):584–596.
18. Wolf SA, Bick-Sander A, Fabel K, et al. Cannabinoid receptor CB1 mediates baseline and activity-induced survival of new neurons in adult hippocampal neurogenesis. Cell Commun Signal 2010;8(12):8–12.
19. Leishman E, Manchanda M, Thelen R, et al. Cannabidiol's upregulation of N-acyl ethanolamines in the central nervous system requires N-acyl phosphatidyl ethanolamine-specific phospholipase D. Cannabis Cannabinoid Res 2018;3(1):228–241.
20. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2012;2(3):15.
21. Cathel AM, Reyes BA, Wang Q, et al. Cannabinoid modulation of alpha2 adrenergic receptor function in rodent medial prefrontal cortex. Eur J Neurosci 2014;40(8):3202–3214.
22. Baranowska-Kuczko M, Kozłowska H, Kloza M, et al. Vasodilatory effects of cannabidiol in human pulmonary and rat small mesenteric arteries: Modification by hypertension and the potential pharmacological opportunities. J Hypertens 2020;38(5):896–911.
23. Stanley CP, Hind WH, Tufarelli C, et al. Cannabidiol causes endothelium-dependent vasorelaxation of human mesenteric arteries via CB1 activation. Cardiovasc Res 2015;107(4):568–578.
24. Mathew RJ, Wilson WH, Humphreys D, et al. Middle cerebral artery velocity during upright posture after marijuana smoking. Acta Psychiatr Scand 1992;86(2):173–178.
25. Remiszewski P, Jarocka-Karpowicz I, Biernacki M, et al. Chronic cannabidiol administration fails to diminish blood pressure in rats with primary and secondary hypertension despite its effects on cardiac and plasma endocannabinoid system, oxidative stress and lipid metabolism. Int J Mol Sci 2020;21(4):1295.
26. Patrician A, Versic-Bratincevic M, Mijacika T, et al. Examination of a new delivery approach for oral cannabidiol in healthy subjects: A randomized, double-blinded, placebo-controlled pharmacokinetics study. Adv Ther 2019;36(11):3196–3210.
27. Verdecchia P, Gentile G, Angeli F, et al. Influence of blood pressure reduction on composite cardiovascular endpoints in clinical trials. J Hypertens 2010;28(7):1356–1365.
28. Wright JT Jr., Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373(22):2103–2116.
29. Kumric M, Dujic G, Vrdoljak J, et al. CBD supplementation reduces arterial blood pressure via modulation of the sympatho-chromaffin system: A substudy from the HYPER-H21-4 trial. Biomed Pharmacother 2023;160:114387.
30. Green DJ, Dawson EA, Groenewoud HM, et al. Is flow-mediated dilation nitric oxide mediated?: A meta-analysis. Hypertension 2014;63(2):376–382.
31. Larsen C, Shahinas J. Dosage, efficacy and safety of cannabidiol administration in adults: A systematic review of human trials. J Clin Med Res 2020;12(3):129–141.
32. Pacher P, Steffens S, Haskó G, et al. Cardiovascular effects of marijuana and synthetic cannabinoids: The good, the bad, and the ugly. Nat Rev Cardiol 2018;15(3):151–166.
33. Watkins PB, Church RJ, Li J, et al. Cannabidiol and abnormal liver chemistries in healthy adults: Results of a phase I clinical trial. Clin Pharmacol Ther 2021;109(5):1224–1231.
34. Zendulka O, Dovrtělová G, Nosková K, et al. Cannabinoids and cytochrome P450 interactions. Curr Drug Metab 2016;17(3):206–226.
Cite this article as: Dujic G, Kumric M, Vrdoljak J, Dujic Z, Bozic J (2023) Chronic effects of oral cannabidiol delivery on 24h ambulatory blood pressure in patients with hypertension (HYPER-H21-4): a randomized, placebo-controlled, and crossover study, Cannabis and Cannabinoid Research X:X, 1–11, DOI: 10.1089/can.2022.0320.

Information & Authors


Published In

cover image Cannabis and Cannabinoid Research
Cannabis and Cannabinoid Research
PubMed: 37093160


Published online: 21 April 2023




Goran Dujic
Clinical Department of Diagnostic and Interventional Radiology, University Hospital of Split, Split, Croatia.
Department of Pathophysiology, University of Split School of Medicine, Split, Croatia.
Josip Vrdoljak
Department of Pathophysiology, University of Split School of Medicine, Split, Croatia.
Zeljko Dujic* [email protected]
Department of Integrative Physiology, University of Split School of Medicine, Split, Croatia.
Department of Pathophysiology, University of Split School of Medicine, Split, Croatia.


Address correspondence to: Zeljko Dujic, MD, PhD, Department of Integrative Physiology, University of Split School of Medicine, Soltanska 2, Split 21000, Croatia. [email protected]
Address correspondence to: Josko Bozic, MD, PhD, Department of Pathophysiology, University of Split School of Medicine, Soltanska 2, Split 21000, Croatia. [email protected]

Authors' Contributions

G.D.: Participated in conceptualization, methodology, investigation, formal analysis, and original draft preparation. M.K. and J.V.: Participated in visualization, investigation, formal analysis, and original draft preparation. Z.D. and J.B.: Participated in conceptualization, funding acquisition, resources, project administration, and reviewing and editing of the article.

Author Disclosure Statement

Not applicable.

Funding Information

The study was sponsored by Lexaria Bioscience Corp (Grant number: 2181-198-01-01-22-0002). All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

Ethics Considerations

The Ethics Committee of the University of Split School of Medicine approved the study on December 15, 2021 (Class: 003-08/21-03/0003; Reg. No.: 2181-198-03-04-21-0091), and all patients signed a written informed consent after they were informed about the procedures, safety, and purpose of this research.

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