Nabiximols effect on blood pressure and heart rate in post-stroke patients of a randomized controlled study

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“Background: Cannabinoids may be useful to treat pain, epilepsy and spasticity, although they may bear an increased risk of cardiovascular events. This study aims to evaluate the cardiovascular safety of nabiximols, a cannabis-based drug, in patients with spasticity following stroke, thus presenting an increased cardiovascular risk.

Methods: This is an ancillary study stemming from the SativexStroke trial: a randomized double-blind, placebo-controlled, crossover study aimed at assessing the effect of nabiximols on post-stroke spasticity. Patients were treated with nabiximols oromucosal spray or placebo and assessed before and after two phases of 1-month duration each. Only the phase with the active treatment was considered for each patient who completed the study. The average values of blood pressure (diastolic, systolic, differential) and heart rate from the first 5 days of the phase (lowest nabiximols dosage) were compared to the average values recorded during the last 5 days at the end of the phase (highest nabiximols dosage). Baseline comparisons between gender, stroke type and affected side and correlation between age and blood pressure and heart rate were performed. The study was registered with the EudraCT number 2016-001034-10.

Results: Thirty-four patients completed the study and were included in the analysis. Thirty-one were taking antihypertensive drugs and, among these, 12 were taking beta-blockers. During the study, no arrhythmic events were recorded, blood pressure and heart rate did not show pathological fluctuations, and no cardiovascular or cerebrovascular events occurred. At baseline blood pressure and heart rate were comparable concerning gender, stroke type and affected side. A significant direct correlation emerged between differential blood pressure and age and an inverse correlation between diastolic blood pressure and age. No correlation emerged between systolic blood pressure or heart rate and age. Blood pressure and heart rate did not change during nabiximols treatment compared to the baseline condition.

Conclusion: This ancillary study adds evidence that, in patients who already underwent a cerebrovascular accident, nabiximols does not determine significant blood pressure and heart rate variation or cardiovascular complications. These data support the cardiovascular safety of nabiximols, encouraging more extensive studies involving cannabinoids characterized by slow absorption rates.”

https://pubmed.ncbi.nlm.nih.gov/36386386/

“In conclusion, an interesting result of this pilot study is the good cardiovascular safety profile of nabiximols in patients with stroke. In these patients, the possible beneficial effect of cannabinoids, such as delaying atherosclerotic progression and inflammation, may deserve further investigation. Furthermore, because of the rapidly changing landscape of cannabis laws and marijuana use in western countries, there is a pressing need for refined policy, education of both clinicians and the public, and new research. Carefully designed, prospective, short- and long-term studies are needed to obtain conclusive data on the safety and efficacy of cannabinoid drugs.”

https://www.frontiersin.org/articles/10.3389/fcvm.2022.990188/full

Cannabidiol Exerts a Neuroprotective and Glia-Balancing Effect in the Subacute Phase of Stroke

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“Pharmacological agents limiting secondary tissue loss and improving functional outcomes after stroke are still limited. Cannabidiol (CBD), the major non-psychoactive component of Cannabis sativa, has been proposed as a neuroprotective agent against experimental cerebral ischemia. The effects of CBD mostly relate to the modulation of neuroinflammation, including glial activation. To investigate the effects of CBD on glial cells after focal ischemia in vivo, we performed time-lapse imaging of microglia and astroglial Ca2+ signaling in the somatosensory cortex in the subacute phase of stroke by in vivo two-photon laser-scanning microscopy using transgenic mice with microglial EGFP expression and astrocyte-specific expression of the genetically encoded Ca2+ sensor GCaMP3. CBD (10 mg/kg, intraperitoneally) prevented ischemia-induced neurological impairment, reducing the neurological deficit score from 2.0 ± 1.2 to 0.8 ± 0.8, and protected against neurodegeneration, as shown by the reduction (more than 70%) in Fluoro-Jade C staining (18.8 ± 7.5 to 5.3 ± 0.3). CBD reduced ischemia-induced microglial activation assessed by changes in soma area and total branch length, and exerted a balancing effect on astroglial Ca2+ signals. Our findings indicate that the neuroprotective effects of CBD may occur in the subacute phase of ischemia, and reinforce its strong anti-inflammatory property. Nevertheless, its mechanism of action on glial cells still requires further studies.”

https://pubmed.ncbi.nlm.nih.gov/36361675/

“Overall, the present findings suggest that the functional and structural protective effects of cannabidiol (CBD) are closely associated with anti-inflammatory activity in the subacute phase of ischemia. Even though the mechanisms of action of CBD are not yet fully understood, our data have heuristic value to inspire further studies investigating the effect of CBD using different treatment schedules, for example, when administered for longer periods or later after the onset of ischemia. In conclusion, our data highlight the potential of CBD as a neuroprotective compound in stroke.”

https://www.mdpi.com/1422-0067/23/21/12886/htm

Cannabidiol’s Multifactorial Mechanisms Has Therapeutic Potential for Aneurysmal Subarachnoid Hemorrhage: a Review

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“Subarachnoid hemorrhage (SAH) is a major health burden that accounts for approximately 5% of all strokes. The most common cause of a non-traumatic SAH is the rupture of a cerebral aneurysm. The most common symptom associated with SAH is a headache, often described as “the worst headache of my life.” Delayed cerebral ischemia (DCI) is a major factor associated with patient mortality following SAH and is often associated with SAH-induced cerebral vasospasm (CV).

Cannabidiol (CBD) is emerging as a potential drug for many therapeutic purposes, including epilepsy, anxiety, and pain relief. We aim to review the potential use of CBD as a treatment option for post-SAH critically ill patients. Through a literature review, we evaluated the known pharmacology and physiological effects of CBD and correlated those with the pathophysiological outcomes associated with cerebral vasospasm following subarachnoid hemorrhage. Although overlap exists, data were formatted into three major categories: anti-inflammatory, vascular, and neuroprotective effects.

Based on the amount of information known about the actions of CBD, we hypothesize the anti-inflammatory effects are likely to be the most promising therapeutic mechanism. However, its cardiovascular effects through calcium regulation and its neuroprotective effects against cell death, excitotoxicity, and oxidative stress are all plausible mechanisms by which post-SAH critically ill patients may benefit from both early and late intervention with CBD. More research is needed to better understand if and how CBD might affect neurological and vascular functions in the brain following injury such as subarachnoid hemorrhage.”

https://pubmed.ncbi.nlm.nih.gov/36109476/

https://link.springer.com/article/10.1007/s12975-022-01080-x

Neuroprotection of Cannabidiol, Its Synthetic Derivatives and Combination Preparations against Microglia-Mediated Neuroinflammation in Neurological Disorders

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“The lack of effective treatment for neurological disorders has encouraged the search for novel therapeutic strategies. Remarkably, neuroinflammation provoked by the activated microglia is emerging as an important therapeutic target for neurological dysfunction in the central nervous system. In the pathological context, the hyperactivation of microglia leads to neuroinflammation through the release of neurotoxic molecules, such as reactive oxygen species, proteinases, proinflammatory cytokines and chemokines.

Cannabidiol (CBD) is a major pharmacologically active phytocannabinoids derived from Cannabis sativa L. CBD has promising therapeutic effects based on mounting clinical and preclinical studies of neurological disorders, such as epilepsy, multiple sclerosis, ischemic brain injuries, neuropathic pain, schizophrenia and Alzheimer’s disease.

A number of preclinical studies suggested that CBD exhibited potent inhibitory effects of neurotoxic molecules and inflammatory modulators, highlighting its remarkable therapeutic potential for the treatment of numerous neurological disorders. However, the molecular mechanisms of action underpinning CBD’s effects on neuroinflammation appear to be complex and are poorly understood.

This review summarises the anti-neuroinflammatory activities of CBD against various neurological disorders with a particular focus on their main molecular mechanisms of action, which were related to the downregulation of NADPH oxidase-mediated ROS, TLR4-NFκB and IFN-β-JAK-STAT pathways. We also illustrate the pharmacological action of CBD’s derivatives focusing on their anti-neuroinflammatory and neuroprotective effects for neurological disorders. We included the studies that demonstrated synergistic enhanced anti-neuroinflammatory activity using CBD and other biomolecules.

The studies that are summarised in the review shed light on the development of CBD, including its derivatives and combination preparations as novel therapeutic options for the prevention and/or treatment of neurological disorders where neuroinflammation plays an important role in the pathological components.”

https://pubmed.ncbi.nlm.nih.gov/35956911/

“Cannabinoids are a group of terpenophenolic compounds derived from the Cannabis sativa L. plant. The preclinical studies summarised in this review supported the therapeutic use of CBD in treating neurological disorders from its action in addressing microglia-mediated neuroinflammation. The findings of this review shed light on the development of CBD and relevant compounds as novel and more advantageous therapeutics to prevent or treat neurological disorders by targeting microglia-mediated neuroinflammation.”

https://www.mdpi.com/1420-3049/27/15/4961/htm


Cannabinoids as Glial Cell Modulators in Ischemic Stroke: Implications for Neuroprotection

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“Stroke is the second leading cause of death worldwide following coronary heart disease. Despite significant efforts to find effective treatments to reduce neurological damage, many patients suffer from sequelae that impair their quality of life. For this reason, the search for new therapeutic options for the treatment of these patients is a priority.

Glial cells, including microglia, astrocytes and oligodendrocytes, participate in crucial processes that allow the correct functioning of the neural tissue, being actively involved in the pathophysiological mechanisms of ischemic stroke. Although the exact mechanisms by which glial cells contribute in the pathophysiological context of stroke are not yet completely understood, they have emerged as potentially therapeutic targets to improve brain recovery.

The endocannabinoid system has interesting immunomodulatory and protective effects in glial cells, and the pharmacological modulation of this signaling pathway has revealed potential neuroprotective effects in different neurological diseases. Therefore, here we recapitulate current findings on the potential promising contribution of the endocannabinoid system pharmacological manipulation in glial cells for the treatment of ischemic stroke.”

https://pubmed.ncbi.nlm.nih.gov/35721207/

“In summary, due to the profound implication of glial cells in stroke, the pharmacological modulation of the glial endocannabinoid system (ECS) could represent a significant advantage to help reduce/limit neuronal damage and stroke-associated sequelae.”

https://www.frontiersin.org/articles/10.3389/fphar.2022.888222/full

Antioxidant and anti-apoptotic effects of cannabidiol in model of ischemic stroke in rats

“One of the main non-psychoactive phytocannabinoids of cannabis is cannabidiol (CBD), which has attracted much attention for its neuroprotective roles. The present study was designed to assess whether pretreatment of CBD can attenuate two of the destructive processes of cerebral ischemia, including oxidative stress and cell death. The male rats were randomly divided into 6 main groups (control, MCAO, vehicle, and CBD-treated groups). Using stereotaxic surgery, a cannula was inserted into the right lateral ventricle of the rat brain. CBD was injected at doses of 50, 100 and 200 ng/rat for five consecutive days. After pretreatment, middle cerebral artery (MCA) was blocked for 60 min using the intraluminal filament technique. 24 h after reperfusion, each main group was considered for measurement of infarct volume, superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), p53 gene expression, pathological alterations, and expression of Bax, Bcl-2, cytochrome C, and caspase-3 proteins. The results revealed that CBD at dose of 100 ng/rat reduced the infarction volume and MDA level in cortical and striatal areas of rat brain compared with vehicle group. In addition, the CBD at dose of 100 ng/rat elevated the activity of SOD enzyme in cortex and striatum. The increase in the activity of CAT was also seen at dose of 100 ng/rat in cortex. Furthermore, the Bcl-2/Bax ratio was significantly diminished by the dose of 100 ng/rat CBD in cortex. Moreover, a decrease in expression of cytosolic cytochrome C was observed by CBD at doses of 100 and 200 ng/rat in cortex. CBD at doses 100 and 200 ng/rat also reduced the expression of caspase-3 in cortical and striatal areas, respectively. P53 was downregulated following administration of CBD at dose of 100 ng/rat. Moreover, histological analysis showed the decrease in the percentage of pyknotic neurons in 100 and 200 ng/rat CBD-received groups. CBD played the anti-apoptosis and anti-oxidant roles in cerebral ischemia by affecting the pathways of intrinsic apoptosis, endogenous antioxidant enzymes, and lipid peroxidation.”

https://pubmed.ncbi.nlm.nih.gov/35031355/

Thromboembolic Outcomes in Tetrahydrocannabinol-Positive Trauma Patients With Traumatic Brain Injury

“Introduction: Traumatic brain injury (TBI) is a significant source of morbidity and mortality in the United States. Recent shifts in state legislation have increased the use of recreational and medical marijuana. While cannabinoids and tetrahydrocannabinol (THC) have known anti-inflammatory effects, the impact of preinjury THC use on clinical outcomes in the setting of severe TBI is unknown. We hypothesized that preinjury THC use in trauma patients suffering TBI would be associated with decreased thromboembolic events and adverse outcomes.

Methods: The American College of Surgeons Trauma Quality Improvement Program was used to identify patients aged ≥18 y with TBI and severe injury (Injury Severity Score ≥ 16) in admit year 2017. Patients with smoking or tobacco history or missing or positive toxicology tests for drug and/or alcohol use other than THC were excluded. Propensity score matching was used to compare THC+ patients to similar THC- patients.

Results: A total of 13,266 patients met inclusion criteria, of which 1669 were THC+. A total of 1377 THC+ patients were matched to 1377 THC- patients. No significant differences were found in in-hospital outcomes, including mortality, length of stay, cardiac arrest, pulmonary embolism, deep vein thrombosis, or acute respiratory distress syndrome. No patients had ischemic stroke, and THC+ patients had significantly decreased rates of hemorrhagic stroke (0.5% versus 1.5%, P = 0.02, odds ratio 0.41 [95% confidence interval 0.18-0.86]).

Conclusions: Preinjury THC use may be associated with decreased hemorrhagic stroke in severely injured patients with TBI, but there was no difference in thromboembolic outcomes. Further research into pathophysiological mechanisms related to THC are needed.”

https://pubmed.ncbi.nlm.nih.gov/35305485/

“THC linked to lower hemorrhagic stroke risk in people with traumatic brain injury”

https://vancouversun.com/cannabis-news/thc-use-may-be-associated-with-lower-hemorrhagic-stroke-risk-in-people-with-traumatic-brain-injury/wcm/a3ae3f22-2b3f-439f-987d-6364c7425eb8/amp/

Administration of Δ 9-Tetrahydrocannabinol Following Controlled Cortical Impact Restores Hippocampal-Dependent Working Memory and Locomotor Function

“Hypothesis: Administration of the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) will enhance brain repair and improve short-term spatial working memory in mice following controlled cortical impact (CCI) by upregulating granulocyte colony-stimulating factor (G-CSF) and other neurotrophic factors (brain-derived neurotrophic factor [BDNF], glial-derived neurotrophic factor [GDNF]) in hippocampus (HP), cerebral cortex, and striatum. Results: Δ9-THC-treated mice exhibited marked improvement in performance on the Y-maze indicating that treatment with the phytocannabinoid could reverse the deficit in working memory caused by the CCI. Δ9-THC-treated mice ran on the rotarod longer than vehicle-treated mice and recovered to normal rotarod performance levels at 2 weeks. Δ9-THC-treated mice, compared with vehicle-treated animals, exhibited significant upregulation of G-CSF as well as BDNF and GDNF in the cerebral cortex, striatum, and HP. Levels of 2-AG were also increased in the Δ9-THC-treated mice. Conclusion: Administration of the phytocannabinoid Δ9-THC promotes significant functional recovery from traumatic brain injury (TBI) in the realms of working memory and locomotor function. This beneficial effect is associated with upregulation of brain 2-AG, G-CSF, BDNF, and GDNF. The latter three neurotrophic factors have been previously shown to mediate brain self-repair following TBI and stroke.”

https://pubmed.ncbi.nlm.nih.gov/34747647/

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.”

https://pubmed.ncbi.nlm.nih.gov/34353019/

“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. ”

https://pubs.acs.org/doi/10.1021/acs.jafc.1c01487

Tetrahydrocannabinol and cannabidiol as an oromucosal spray in a 1:1 ratio: a therapeutic option for patients with central post-stroke pain syndrome?

BMJ Journals - Northern Devon Healthcare NHS Trust“Central pain after stroke due to brainstem infarction is very rare. Treatment is difficult and specific guidelines are lacking. This is the report of a 61-year-old female patient who, after a posterolateral left medulla oblongata insult with incomplete Wallenberg syndrome, subsequently developed a burning and tingling pain in the contralateral leg and a burning and shooting pain in the ipsilateral face in trigeminal branches 1 and 2. More than 3 years of therapy with amitriptyline, gabapentin, pregabalin and various grade II and III opioids was ineffective or showed intolerable side effects. The administration of tetrahydrocannabinol and cannabidiol as an oromucosal spray in a 1:1 ratio improved the pain situation and quality of life quickly and permanently. The encouraging results in the present case may suggest that treatment with medical cannabis should be considered in similar cases when standard therapies are insufficient.”

https://pubmed.ncbi.nlm.nih.gov/34230048/

https://casereports.bmj.com/content/14/7/e243072