Characterisation of the haemodynamic effects of cannabidiol in humans using duplex ultrasound and other techniques

The two main phytocannabinoids, ∆9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) are agents already licensed for clinical use (i.e. Sativex®and Epidiolex®). THC and CBD have numerous cardiovascular effects in vitro; however, their effects on haemodynamics in vivoin humans remain unclear. Two systematic reviews and meta-analysis were established to evaluate the effects of THC and CBD on the haemodynamics in vivoin animals and humans. Our analysis showed that THC acts differently according to species and experimental conditions, causing bradycardia, hypotension and increased blood flow (BF) in animals, and increased heart rate (HR) in humans. However, CBD has no effect on blood pressure (BP) or HR under control conditions, but reduces BP and HR in stressful conditions, and increases cerebral BF in mouse models of stroke. Both systematic reviews and meta-analysis highlighted the limited data available in humans and further studies should be considered. Our group’s recent study in healthy men showed that acute oral administration of CBD (600 mg) causes a reduction in BP at rest and in response to stress. Because of this, three human studies were conducted to see if the findings from our previous study are reproducible, as well as if tolerance develops and if other vascular endpoints were affected post-CBD. Continuous beat-to-beat haemodynamics was assessed at rest and in response to stress (isometric exercise) using Finometer®. Arterial stiffness and aortic blood pressure were assessed using Vicorder®.Duplex ultrasound was used to assess changes in cerebral blood flow, extra-cranial arterial diameter, and brachial artery endothelial function after CBD administration. In the first human study, 26 healthy men were given 600 mg of CBD or placebo orally for seven days in a randomised, placebo-controlled, double-blind, parallel trial (n=13 per group). Cardiovascular parameters were assessed after single (acute) and repeated (chronic) dosing for seven days. CBD reduced mean arterial pressure after acute dosing at rest and reduced systolic BP after acute and chronic dosing in response to stress. Repeated CBD dosing reduced arterial stiffness, induced vasodilation and augmented BF volume in the internal carotid artery and improved endothelial function compared to single CBD dosing. Based on these findings, the second study was conducted to investigate the effect of a single dose of CBD in healthy men on arterial stiffness and cerebral BF to determine whether the effects seen after repeated dosing of CBD can also be seen after a single dose compared to baseline. Ten healthy men were given a single dose of placebo and CBD (600 mg) orally with a washout period of at least a week between the two treatments in a randomised, placebo-controlled, double-blind, crossover trial. The cardiovascular system was assessed before and after receiving the treatment. No effect was seen on arterial stiffness or cerebral BF following acute CBD administration. Due to the lack of studies assessing the effects of CBD on the cardiovascular system in women, a third study was conducted to establish the acute effect of CBD on the haemodynamics in women. Thirteen healthy females were given a single dose of placebo and CBD (600 mg) orally with a washout period of at least a week between the two treatments in a randomised, placebo-controlled, double-blind, crossover trial. The cardiovascular system was assessed after receiving the treatment. No effects wereseen following acute CBD administration. The findings of this thesis indicate that CBD may induce positive effects on human haemodynamics and on vascular function following chronic administration, and that sex-difference could impact its effects and should be considered in future studies investigating the effect of CBD on the human cardiovascular system. Further research is needed with larger sample sizes in dose-escalation trials and patient populations with vascular diseases

The effects of acute and sustained cannabidiol dosing for seven days on the haemodynamics in healthy men: A randomised controlled trial

© 2020 The British Pharmacological Society Background: In vivo studies show that cannabidiol (CBD) acutely reduces blood pressure (BP) in men. The aim of this study was to assess the effects of repeated CBD dosing on haemodynamics. Methods: Twenty-six healthy males were given CBD (600 mg) or placebo orally for seven days in a randomised, placebo-controlled, double-blind, parallel study (n = 13/group). Cardiovascular parameters were assessed at rest and in response to isometric exercise after acute and repeated dosing using Finometer®, Vicorder® and Duplex ultrasound. Results: Compared to placebo, CBD significantly reduced resting mean arterial pressure (P =.04, two-way ANOVA, mean difference (MD) –2 mmHg, 95% CI -3.6 to −0.3) after acute dosing, but not after repeated dosing. In response to stress, volunteers who had taken CBD had lower systolic BP after acute (P =.001, two-way ANOVA, MD −6 mmHg, 95% CI –10 to −1) and repeated (P =.02, two-way ANOVA, MD −5.7 mmHg, 95% CI –10 to −1) dosing. Seven days of CBD increased internal carotid artery diameter (MD +0.55 mm, P =.01). Within the CBD group, repeated dosing reduced arterial stiffness by day 7 (pulse wave velocity; MD −0.44 m/s, P =.05) and improved endothelial function (flow mediation dilatation, MD +3.5%, P =.02, n = 6 per group), compared to day 1. Conclusion: CBD reduces BP at rest after a single dose but the effect is lost after seven days of treatment (tolerance); however, BP reduction during stress persists. The reduction in arterial stiffness and improvements in endothelial function after repeated CBD dosing are findings that warrant further investigation in populations with vascular diseases

Associations of carotid atherosclerosis with cognitive function and brain health: Findings from a UK tri-ethnic cohort study (Southall and Brent Revisited)

BACKGROUND: Cognitive function has an important role in determining the quality of life of older adults. Cardiovascular disease (CVD) is common in older people and may compromise cognitive performance; however, the extent to which this is related to carotid atherosclerosis is unclear. AIM: We investigated associations between carotid atherosclerosis and cognitive function and neuroimaging markers of brain health in a UK multi-ethnic community-based sample including older people of European, South Asian, and African-Caribbean ethnicity. METHODS: Carotid plaques and intima-media thickness (cIMT) were assessed using ultrasound in 985 people (mean age 73.2y, 56 % male). Associations of carotid atherosclerosis with cognitive function (memory, executive function, language and CSI-D, a global measure of cognitive state) and neuroimaging measures (total brain volume, hippocampal volume, white matter (WM) lesion volume and coalescence score) were analysed using regression analyses, with and without adjustment for potential confounders using two models: 1) adjustment for age, sex, and ethnicity; 2) model 1 plus education, physical activity category, body mass index, hypertension, diabetes, total and high density lipoprotein cholesterol, atrial fibrillation, smoking, previous CVD, alcohol consumption, and presence of chronic kidney disease. RESULTS: People with carotid plaque or higher cIMT had lower CSI-D score, poorer memory poorer executive function and higher WM lesion volume and coalescence. Language was poorer in people with plaque but was not correlated with cIMT. Associations with plaque were preserved after full adjustment (model 2) but relationships for cIMT were attenuated. Associations with other plaque characteristics were generally unconvincing after adjustment. CONCLUSIONS: This multi-ethnic cohort study provides evidence that presence of carotid plaque, is associated with poorer cognitive function and brain health

Is carotid artery atherosclerosis associated with poor cognitive function assessed using the Mini-Mental State Examination? A systematic review and meta-analysis

OBJECTIVES: To determine associations between carotid atherosclerosis assessed by ultrasound and the Mini-Mental State Examination (MMSE), a measure of global cognitive function. DESIGN: Systematic review and meta-analysis. METHODS: MEDLINE and EMBASE databases were searched up to 1 May 2020 to identify studies assessed the associations between asymptomatic carotid atherosclerosis and the MMSE. Studies reporting OR for associations between carotid plaque or intima-media thickness (cIMT) and dichotomised MMSE were meta-analysed. Publication bias of included studies was assessed. RESULTS: A total of 31 of 378 reviewed articles met the inclusion criteria; together they included 27 738 participants (age 35-95 years). Fifteen studies reported some evidence of a positive association between measures of atherosclerosis and poorer cognitive performance in either cross-sectional or longitudinal studies. The remaining 16 studies found no evidence of an association. Seven cross-sectional studies provided data suitable for meta-analysis. Meta-analysis of three studies that assessed carotid plaque (n=3549) showed an association between the presence of plaque and impaired MMSE with pooled estimate for the OR (95% CI) being 2.72 (0.85 to 4.59). An association between cIMT and impaired MMSE was reported in six studies (n=4443) with a pooled estimate for the OR (95% CI) being 1.13 (1.04 to 1.22). Heterogeneity across studies was moderate to small (carotid plaque with MMSE, I2=40.9%; cIMT with MMSE, I2=4.9%). There was evidence of publication bias for carotid plaque studies (p=0.02), but not cIMT studies (p=0.2). CONCLUSIONS: There is some, limited cross-sectional evidence indicating an association between cIMT and poorer global cognitive function assessed with MMSE. Estimates of the association between plaques and poor cognition are too imprecise to draw firm conclusions and evidence from studies of longitudinal associations between carotid atherosclerosis and MMSE is limited. PROSPERO REGISTRATION NUMBER: CRD42021240077

A systematic review and meta-analysis of the in vivo haemodynamic effects of Δ9-Tetrahydrocannabinol

∆9-Tetrahydrocannabinol (THC) has complex effects on the cardiovascular system. We aimed to systematically review studies of THC and haemodynamic alterations. PubMed, Medline, and EMBASE were searched for relevant studies. Changes in blood pressure (BP), heart rate (HR), and blood flow (BF) were analysed using the Cochrane Review Manager Software. Thirty-one studies met the eligibility criteria. Fourteen publications assessed BP (number, n = 541), 22 HR (n = 567), and 3 BF (n = 45). Acute THC dosing reduced BP and HR in anaesthetised animals (BP, mean difference (MD) −19.7 mmHg, p < 0.00001; HR, MD −53.49 bpm, p < 0.00001), conscious animals (BP, MD −12.3 mmHg, p = 0.0007; HR, MD −30.05 bpm, p < 0.00001), and animal models of stress or hypertension (BP, MD −61.37 mmHg, p = 0.03) and increased cerebral BF in murine stroke models (MD 32.35%, p < 0.00001). Chronic dosing increased BF in large arteries in anaesthetised animals (MD 21.95 mL/min, p = 0.05) and reduced BP in models of stress or hypertension (MD −22.09 mmHg, p < 0.00001). In humans, acute administration increased HR (MD 8.16 bpm, p < 0.00001). THC acts differently according to species and experimental conditions, causing bradycardia, hypotension and increased BF in animals; and causing increased HR in humans. Data is limited, and further studies assessing THC-induced haemodynamic changes in humans should be considered

Characterisation of the haemodynamic effects of cannabidiol in humans using duplex ultrasound and other techniques

The two main phytocannabinoids, ∆9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) are agents already licensed for clinical use (i.e. Sativex®and Epidiolex®). THC and CBD have numerous cardiovascular effects in vitro; however, their effects on haemodynamics in vivoin humans remain unclear. Two systematic reviews and meta-analysis were established to evaluate the effects of THC and CBD on the haemodynamics in vivoin animals and humans. Our analysis showed that THC acts differently according to species and experimental conditions, causing bradycardia, hypotension and increased blood flow (BF) in animals, and increased heart rate (HR) in humans. However, CBD has no effect on blood pressure (BP) or HR under control conditions, but reduces BP and HR in stressful conditions, and increases cerebral BF in mouse models of stroke. Both systematic reviews and meta-analysis highlighted the limited data available in humans and further studies should be considered. Our group’s recent study in healthy men showed that acute oral administration of CBD (600 mg) causes a reduction in BP at rest and in response to stress. Because of this, three human studies were conducted to see if the findings from our previous study are reproducible, as well as if tolerance develops and if other vascular endpoints were affected post-CBD. Continuous beat-to-beat haemodynamics was assessed at rest and in response to stress (isometric exercise) using Finometer®. Arterial stiffness and aortic blood pressure were assessed using Vicorder®.Duplex ultrasound was used to assess changes in cerebral blood flow, extra-cranial arterial diameter, and brachial artery endothelial function after CBD administration. In the first human study, 26 healthy men were given 600 mg of CBD or placebo orally for seven days in a randomised, placebo-controlled, double-blind, parallel trial (n=13 per group). Cardiovascular parameters were assessed after single (acute) and repeated (chronic) dosing for seven days. CBD reduced mean arterial pressure after acute dosing at rest and reduced systolic BP after acute and chronic dosing in response to stress. Repeated CBD dosing reduced arterial stiffness, induced vasodilation and augmented BF volume in the internal carotid artery and improved endothelial function compared to single CBD dosing. Based on these findings, the second study was conducted to investigate the effect of a single dose of CBD in healthy men on arterial stiffness and cerebral BF to determine whether the effects seen after repeated dosing of CBD can also be seen after a single dose compared to baseline. Ten healthy men were given a single dose of placebo and CBD (600 mg) orally with a washout period of at least a week between the two treatments in a randomised, placebo-controlled, double-blind, crossover trial. The cardiovascular system was assessed before and after receiving the treatment. No effect was seen on arterial stiffness or cerebral BF following acute CBD administration. Due to the lack of studies assessing the effects of CBD on the cardiovascular system in women, a third study was conducted to establish the acute effect of CBD on the haemodynamics in women. Thirteen healthy females were given a single dose of placebo and CBD (600 mg) orally with a washout period of at least a week between the two treatments in a randomised, placebo-controlled, double-blind, crossover trial. The cardiovascular system was assessed after receiving the treatment. No effects wereseen following acute CBD administration. The findings of this thesis indicate that CBD may induce positive effects on human haemodynamics and on vascular function following chronic administration, and that sex-difference could impact its effects and should be considered in future studies investigating the effect of CBD on the human cardiovascular system. Further research is needed with larger sample sizes in dose-escalation trials and patient populations with vascular diseases

A systematic review and meta-analysis of the haemodynamic effects of cannabidiol

Despite cannabidiol (CBD) having numerous cardiovascular effects in vitro, its haemodynamic effects in vivo are unclear. Nonetheless, the clinical use of CBD (Epidiolex) is becoming more widespread. The aim of this systematic review was to establish whether CBD is associated with changes in haemodynamics in vivo. Twenty-five studies that assessed the haemodynamic effects of CBD (from PubMed, Medline and EMBASE) were systematically reviewed and meta-analyzed. Data on blood pressure (BP), heart rate (HR), and blood flow (BF) were extracted and analyzed using random effects models. Twenty-two publications assessed BP and HR among 6 species (BP n = 344 and HR n = 395), and 5 publications assessed BF in 3 species (n = 56) after acute dosing of CBD. Chronic dosing was assessed in 4 publications in 3 species (total subjects BP, n = 6; HR, n = 27; BF, n = 3). Acute CBD dosing had no effect on BP or HR under control conditions. Similarly, chronic dosing with CBD had no effect on HR. In models of stress, acute CBD administration significantly reduced the increase in BP and HR induced by stress (BP, mean difference (MD) −3.54, 95% CI −5.19, −1.9, p < 0.0001; HR, MD −16.23, 95% CI −26.44, −6.02, p = 0.002). In mouse models of stroke, CBD significantly increased cerebral blood flow (CBF, standardized mean difference (SMD) 1.62, 95% CI 0.41, 2.83, p = 0.009). Heterogeneity among the studies was present, there was no publication bias except in HR of control and stressful conditions after acute CBD dosing, and median study quality was 5 out of 9 (ranging from 1 to 8). From the limited data available, we conclude that acute and chronic administration of CBD had no effect on BP or HR under control conditions, but reduces BP and HR in stressful conditions, and increases cerebral blood flow (CBF) in mouse models of stroke. Further studies are required to fully understand the potential haemodynamic effects of CBD in humans under normal and pathological conditions

B-mode ultrasound characteristics of carotid plaques in symptomatic and asymptomatic patients with low-grade stenosis.

Carotid plaque features assessed using B-mode ultrasound can be useful for the prediction of cerebrovascular symptoms. Therefore, the aim of this retrospective study was to determine the ability of ultrasound B-mode imaging to differentiate between carotid plaques causing less than 50% stenosis in symptomatic and asymptomatic patients. A dataset of 1,593 patients with carotid disease who underwent carotid ultrasound between 2016 and 2021 was evaluated retrospectively between January and April of 2022. A total of 107 carotid plaques from 35 symptomatic and 52 asymptomatic patients causing low-grade stenosis on B-mode images were included in the analysis. Chi-square, independent t-test and Mann-Whitney U test were used to compare the variables. There was a significant association between hypertension and the presence of cerebrovascular symptoms (p = 0.01). Predominantly hypoechoic and hyperechoic carotid plaque were significantly associated with the presence and absence of cerebrovascular symptoms, respectively (predominantly hypoechoic: p = 0.01; predominantly hyperechoic: p = 0.02). Surface irregularity was significantly associated with the presence of cerebrovascular symptoms (p = 0.02). There is was a significant difference in the carotid plaque length and area between the symptomatic and asymptomatic patients (plaque length: symptomatic median 9 mm, interquartile range [IQR] 6 mm; asymptomatic median 6 mm, IQR 4.5 mm, p = 0.01; plaque area: symptomatic median 24 mm, IQR 30 mm; asymptomatic median 14 mm, IQR 17 mm, p = 0.01); however, this difference was not significant for plaque thickness (p = 0.55), or common carotid artery intima-media thickness (p = 0.7). Our findings indicate that hypertension patients with predominantly hypoechoic carotid plaques and plaques with an irregular surface are associated with the presence of cerebrovascular symptoms. In addition, the carotid plaques in symptomatic patients were longer and larger compared to asymptomatic patients

Is carotid artery atherosclerosis associated with poor cognitive function assessed using the Mini-Mental State Examination? A systematic review and meta-analysis

Objectives: To determine associations between carotid atherosclerosis assessed by ultrasound and the Mini-Mental State Examination (MMSE), a measure of global cognitive function. Design: Systematic review and meta-analysis. Methods: MEDLINE and EMBASE databases were searched up to 1 May 2020 to identify studies assessed the associations between asymptomatic carotid atherosclerosis and the MMSE. Studies reporting OR for associations between carotid plaque or intima-media thickness (cIMT) and dichotomised MMSE were meta-analysed. Publication bias of included studies was assessed. Results: A total of 31 of 378 reviewed articles met the inclusion criteria; together they included 27 738 participants (age 35–95 years). Fifteen studies reported some evidence of a positive association between measures of atherosclerosis and poorer cognitive performance in either cross-sectional or longitudinal studies. The remaining 16 studies found no evidence of an association. Seven cross-sectional studies provided data suitable for meta-analysis. Meta-analysis of three studies that assessed carotid plaque (n=3549) showed an association between the presence of plaque and impaired MMSE with pooled estimate for the OR (95% CI) being 2.72 (0.85 to 4.59). An association between cIMT and impaired MMSE was reported in six studies (n=4443) with a pooled estimate for the OR (95% CI) being 1.13 (1.04 to 1.22). Heterogeneity across studies was moderate to small (carotid plaque with MMSE, I2=40.9%; cIMT with MMSE, I2=4.9%). There was evidence of publication bias for carotid plaque studies (p=0.02), but not cIMT studies (p=0.2). Conclusions: There is some, limited cross-sectional evidence indicating an association between cIMT and poorer global cognitive function assessed with MMSE. Estimates of the association between plaques and poor cognition are too imprecise to draw firm conclusions and evidence from studies of longitudinal associations between carotid atherosclerosis and MMSE is limited. PROSPERO registration number: CRD42021240077.</p

Gender and cytoarchitecture differences: Functional connectivity of the hippocampal sub-regions

Introduction: The hippocampus plays a significant role in learning, memory encoding, and spatial navigation. Typically, the hippocampus is investigated as a whole region of interest. However, recent work has developed fully detailed atlases based on cytoarchitecture properties of brain regions, and the hippocampus has been sub-divided into seven sub-areas that have structural differences in terms of distinct numbers of cells, neurons, and other structural and chemical properties. Moreover, gender differences are of increasing concern in neuroscience research. Several neuroscience studies have found structural and functional variations between the brain regions of females and males, and the hippocampus is one of these regions. Aim: The aim of this study to explore whether the cytoarchitecturally distinct sub-regions of the hippocampus have varying patterns of functional connectivity with different networks of the brain and how these functional connections differ in terms of gender differences. Method: This study investigated 200 healthy participants using seed-based resting-state functional magnetic resonance imaging (rsfMRI). The primary aim of this study was to explore the resting connectivity and gender distinctions associated with specific sub-regions of the hippocampus and their relationship with major functional brain networks. Results: The findings revealed that the majority of the seven hippocampal sub-regions displayed functional connections with key brain networks, and distinct patterns of functional connectivity were observed between the hippocampal sub-regions and various functional networks within the brain. Notably, the default and visual networks exhibited the most consistent functional connections. Additionally, gender-based analysis highlighted evident functional resemblances and disparities, particularly concerning the anterior section of the hippocampus. Conclusion: This study highlighted the functional connectivity patterns and involvement of the hippocampal sub-regions in major brain functional networks, indicating that the hippocampus should be investigated as a region of multiple distinct functions and should always be examined as sub-regions of interest. The results also revealed clear gender differences in functional connectivity