CBD supplementation reduces arterial blood pressure via modulation of the sympatho-chromaffin system: A substudy from the HYPER-H21-4 trial

Biomedicine & Pharmacotherapy

“Data concerning the effects of cannabidiol (CBD) on blood pressure (BP) is controversial. HYPER-H21-4 was a randomized, placebo-controlled, crossover trial which sought to elucidate if 5-week administration of CBD will reduce BP in hypertensive patients. In the substudy of this trial, we aimed to establish the mechanistic background of CBD-induced BP reduction. Specifically, we explored the dynamic of catestatin, a sympathoinhibitory peptide implicated in the pathophysiology of hypertension. In the present analysis, 54 patients with Grade 1 hypertension were included. 5-week administration of CBD but not placebo reduced serum catestatin concentration in comparison to baseline (13.50 [10.85-19.05] vs. 9.65 [6.37-12.26] ng/mL, p < 0.001). Serum catestatin levels at the start of the treatment period demonstrated a negative correlation with the extent of reduction in mean arterial pressure (r = -0.474, p < 0.001). Moreover, the extent of change in catestatin serum levels showed a strong correlation with the extent of mean arterial pressure reduction (r = 0.712, p < 0.001). Overall, the results of the present study imply that the antihypertensive effects of CBD may be explained by its interaction with the sympatho-chromaffin system, although further research is warranted.”


“CBD supplementation reduces office blood pressure (BP) and serum catestatin levels.”

“Overall, the results of the present study imply that antihypertensive effects of CBD may be explained by its interaction with the sympatho-chromaffin system, although further research is warranted.”


Association between cannabis use and blood pressure levels according to comorbidities and socioeconomic status

Scientific Reports

“The associations between blood pressure and cannabis use remain inconsistent. The purpose of our study was to examine gender stratified associations of cannabis use and blood pressure [systolic, diastolic blood pressure (BP), pulse pressure (PP)] levels among the general UK Biobank population based study. Among 91,161 volunteers of the UK Biobank population, cannabis use status was assessed by questionnaire and range as heavy, moderate, low and never users. Associations between cannabis use and BP were estimated using multiple gender linear regressions.

In adjusted covariates models, lifetime heavy cannabis use was associated with decrease in both SBP, DBP and PP in both genders, but with a higher effect among women (for SBP in men, b = − 1.09 (0.27), p < 0.001; in women, b = − 1.85 (0.36), p < 0.001; for DBP in men, b = − 0.50 (0.15), p < 0.001; in women, b = − 0.87 (0.17), p < 0.001; and for PP in men, b = − 0.60 (0.20), p < 0.001; in women, b = − 0.97 (0.27), p < 0.001. Among men, lower SBP and DBP levels were observed with participants without dyslipidemia and lower PP in participants with high income levels. Among women, lower SBP, DBP and PP were observed with current smokers, moderate/low alcohol levels and participants without dyslipidemia.

Current cannabis use was associated with lower SBP levels in men (b = − 0.63 (0.25), p = 0.012) and in women (b = − 1.17 (0.31), p < 0.001). Same results were observed for DBP and PP. Negative association between BP in men was found but not in women. The small association in BP differences between heavy users and never users remains too small to adopt cannabis-blood pressure public policy in clinical practice.”


Cannabidiol inhibits lung proliferation in monocrotaline-induced pulmonary hypertension in rats

Biomedicine & Pharmacotherapy

“Cannabidiol (CBD) is a safe and well-tolerated plant-derived drug with anti-proliferative properties. Pulmonary hypertension (PH) is a rapidly progressive and still incurable disease. CBD diminishes monocrotaline (MCT)-induced PH, including reduced right ventricular systolic pressure, pulmonary vascular hypertrophy, and right ventricular remodeling. The aim of our study was to investigate the effect of chronic administration of CBD (10 mg/kg once daily for 21 days) on selected remodeling parameters in the lung of MCT-induced PH rats. In MCT-induced PH, we found an increase in profibrotic parameters, e.g., transforming growth factor β1 (TGF-β1), galectin-3 (Gal-3), procollagen I, collagen I, C-propeptide, matrix metalloproteinase 9 (MMP-9) and an increased number of mast cells. In our study, we observed that the TGF-β1, Gal-3, procollagen I, collagen I, C-propeptide, and mast cell levels in lung tissue were decreased after CBD administration to MCT-treated rats. In summary, CBD treatment has an anti-proliferative effect on MCT-induced PH. Given the beneficial multidirectional effects of CBD on PH, we believe that CBD can be used as an adjuvant PH therapy, but this argument needs to be confirmed by clinical trials.”



Sustained cannabis use does not predispose clinical hypertension: Findings from a national survey

“Cannabis is among the most used recreational and medicinal drugs in the United States. The effects of chronic use on hypertension remain poorly understood.

Our study retrospectively evaluated data collected by the National Health and Nutrition Examination Survey from 2017 to 2018. Cannabis use was measured with five metrics: (1) sustained use at any point in the past, (2) sustained use within the past year, (3) frequency of use, (4) age of first cannabis use, and (5) current use. Hypertension status was determined by individuals reporting having been diagnosed in the past. Multivariable logistic regressions were performed, controlling for age, race, and gender. A total of 4565 respondents were identified, of which 867 (19.0%) reported sustained cannabis use in the past.

Participants who reported past sustained cannabis use did not have statistically different odds of having hypertension (OR: 1.12; 95% CI: .66-1.91; p = .6). Moderate (OR: 1.08; 95% CI: .36-3.25; p = .8) and highly-frequent users (OR: 1.30; 95% CI: .56-3.03; p = .4) did not have different odds of having hypertension than infrequent users. No relationship between the age of first cannabis use and hypertension was observed. The recency of sustained cannabis use was not associated with hypertension status. Current cannabis users had similar odds of hypertension as past users (OR: 1.03; 95% CI: .59-1.79; p = .9).

The findings of this study indicate that neither past nor current cannabis use is associated with clinical hypertension.”


“The findings of this study indicate that neither past nor current cannabis use are associated with the likelihood of having clinical hypertension. Among cannabis users, frequency of use was not associated with hypertension. Similarly, the age of first cannabis use was not associated with hypertension status.”


Treatment with Cannabidiol Results in an Antioxidant and Cardioprotective Effect in Several Pathophysiologies

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“Cannabis sativa has chemically active compounds called cannabinoids, where Δ9- tetrahydrocannabinol (THC) and Cannabidiol (CBD) are the major ones responsible for the various pharmacological effects.

The endocannabinoid system is an endogenous system considered a unique and widespread homeostatic physiological regulator. It is made up of type 1 (CB1) and type 2 (CB2) cannabinoid receptors. CBD, in turn, has a low affinity for CB1 and CB2 receptors, and regulates the effects arising from THC as a CB1 partial agonist, which are tachycardia, anxiety, and sedation. It also acts as a CB2 inverse agonist, resulting in anti-inflammatory effects.

Furthermore, its anticonvulsant, neuroprotective, antipsychotic, antiemetic, anxiolytic, anticancer, and antioxidant effects seem to be linked to other discovered receptors such as GRP55, 5TH1a, TRPV I, TRPV II and the regulation of the intracellular concentration of Ca2+. Regarding oxidative stress, O2- can act as an oxidizing agent, being reduced to hydrogen peroxide (H2O2), or as a reducing agent, donating its extra electron to NO to form peroxynitrite (ONOO-). The ONOO- formed is capable of oxidizing proteins, lipids, and nucleic acids, causing several cell damages.

In this sense, CBD can prevent cardiac oxidative damage in many conditions, such as hypertension, diabetes, or even through the cardiotoxic effects induced by chemotherapy, which makes it a potential target for future clinical use to minimize the deleterious effects of many pathophysiologies.”



Cannabidiol Improves Antioxidant Capacity and Reduces Inflammation in the Lungs of Rats with Monocrotaline-Induced Pulmonary Hypertension


“Cannabidiol (CBD) is a plant-derived compound with antioxidant and anti-inflammatory properties. Pulmonary hypertension (PH) is still an incurable disease. CBD has been suggested to ameliorate monocrotaline (MCT)-induced PH, including reduction in right ventricular systolic pressure (RVSP), a vasorelaxant effect on pulmonary arteries and a decrease in the white blood cell count. The aim of our study was to investigate the effect of chronic administration of CBD (10 mg/kg daily for 21 days) on the parameters of oxidative stress and inflammation in the lungs of rats with MCT-induced PH. In MCT-induced PH, we found a decrease in total antioxidant capacity (TAC) and glutathione level (GSH), an increase in inflammatory parameters, e.g., tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), nuclear factor kappa B (NF-κB), monocyte chemoattractant protein-1 (MCP-1), and cluster of differentiation 68 (CD68), and the overexpression of cannabinoid receptors type 1 and 2 (CB1-Rs, CB2-Rs). Administration of CBD increased TAC and GSH concentrations, glutathione reductase (GSR) activity, and decreased CB1-Rs expression and levels of inflammatory mediators such as TNF-α, IL -1β, NF-κB, MCP-1 and CD68. In conclusion, CBD has antioxidant and anti-inflammatory effects in MCT-induced PH. CBD may act as an adjuvant therapy for PH, but further detailed preclinical and clinical studies are recommended to confirm our promising results.”



Acute Cannabigerol Administration Lowers Blood Pressure in Mice

“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.”



Vasoprotective Endothelial Effects of Chronic Cannabidiol Treatment and Its Influence on the Endocannabinoid System in Rats with Primary and Secondary Hypertension

“Our study aimed to examine the endothelium (vascular)-protecting effects of chronic cannabidiol (CBD) administration (10 mg/kg once daily for 2 weeks) in aortas and small mesenteric (G3) arteries isolated from deoxycorticosterone-induced hypertensive (DOCA-salt) rats and spontaneously hypertensive rats (SHR). CBD reduced hypertrophy and improved the endothelium-dependent vasodilation in response to acetylcholine in the aortas and G3 of DOCA-salt rats and SHR. The enhancement of vasorelaxation was prevented by the inhibition of nitric oxide (NO) with L-NAME and/or the inhibition of cyclooxygenase (COX) with indomethacin in the aortas and G3 of DOCA-salt and SHR, respectively. The mechanism of the CBD-mediated improvement of endothelial function in hypertensive vessels depends on the vessel diameter and may be associated with its NO-, the intermediate-conductance calcium-activated potassium channel- or NO-, COX-, the intermediate and the small-conductance calcium-activated potassium channels-dependent effect in aortas and G3, respectively. CBD increased the vascular expression of the cannabinoid CB1 and CB2 receptors and aortic levels of endocannabinoids with vasorelaxant properties e.g., anandamide, 2-arachidonoylglycerol and palmitoyl ethanolamide in aortas of DOCA-salt and/or SHR. In conclusion, CBD treatment has vasoprotective effects in hypertensive rats, in a vessel-size- and hypertension-model-independent manner, at least partly via inducing local vascular changes in the endocannabinoid system.”


The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

ijms-logo“The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems.

In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development.

The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development.

The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases.

This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.”




“Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment”


Antioxidant and Angiotensin I-Converting Enzyme (ACE) Inhibitory Peptides Obtained from Alcalase Protein Hydrolysate Fractions of Hemp ( Cannabis sativa L.) Bran

Go to Journal of Agricultural and Food Chemistry “Proteins from hemp bran (HPB), a byproduct of the hemp seed food-processing chain, were chemically extracted, hydrolyzed by Alcalase, and separated by membrane ultrafiltration into four fractions (MW <1, 1-3, 3-5, and >5 kDa).

The antioxidant and antihypertensive properties of the initial extract and the fractions were evaluated by in vitro assays for their ability to scavenge radical species, bind with metal ions, reduce ferric ions, and inhibit angiotensin-converting enzyme (ACE) activity.

The hydrolysate was strongly antioxidant and ACE-inhibiting; the most bioactive peptides were further concentrated by ultrafiltration. Of the 239 peptides identified, 47 (12 antioxidant and 35 ACE-inhibitory) exhibited structural features correlated with the specific bioactivity.

These results highlight the promise of hydrolysate and size-based HPB fractions as natural functional ingredients for the food or pharmaceutical industry.”


“In conclusion, this study highlights the potential use of HPB hydrolysate and fractions as multifunctional ingredients for the development of new healthy foods or for the pharmaceutical industry. ”