Cannabidiol inhibits febrile seizure by modulating AMPA receptor kinetics through its interaction with the N-terminal domain of GluA1/GluA2

Pharmacological Research “Cannabidiol (CBD) is a major phytocannabinoid in Cannabis sativa. CBD is being increasingly reported as a clinical treatment for neurological diseases.

Febrile seizure is one of the most common diseases in children with limited therapeutic options. We investigated possible therapeutic effects of CBD on febrile seizures and the underlying mechanism.

Use of a hyperthermia-induced seizures model revealed that CBD significantly prolonged seizure latency and reduced the severity of thermally-induced seizures. Hippocampal neuronal excitability was significantly decreased by CBD. Further, CBD significantly reduced the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) mediated evoked excitatory postsynaptic currents (eEPSCs) and the amplitude and frequency of miniature EPSCs (mEPSCs).

Furthermore, CBD significantly accelerated deactivation in GluA1 and GluA2 subunits. Interestingly, CBD slowed receptor recovery from desensitization of GluA1, but not GluA2. These effects on kinetics were even more prominent when AMPAR was co-expressed with γ-8, the high expression isoform 8 of transmembrane AMPAR regulated protein (TARPγ8) in the hippocampus. The inhibitory effects of CBD on AMPAR depended on its interaction with the distal N-terminal domain of GluA1/GluA2.

CBD inhibited AMPAR activity and reduced hippocampal neuronal excitability, thereby improving the symptoms of febrile seizure in mice. The putative binding site of CBD in the N-terminal domain of GluA1/GluA2 may be a drug target for allosteric gating modulation of AMPAR.”

https://pubmed.ncbi.nlm.nih.gov/32805354/

“Cannabidiol (CBD) significantly prolonged seizure latency and reduced seizure severity.”

https://www.sciencedirect.com/science/article/abs/pii/S1043661820314365?via%3Dihub

Medical cannabis for chronic pain: can it make a difference in pain management?

SpringerLink “Globally, chronic pain is a major therapeutic challenge and affects more than 15% of the population. As patients with painful terminal diseases may face unbearable pain, there is a need for more potent analgesics.

Although opioid-based therapeutic agents received attention to manage severe pain, their adverse drug effects and mortality rate associated with opioids overdose are the major concerns. Evidences from clinical trials showed therapeutic benefits of cannabis, especially delta-9-tetrahydrocannabinol and cannabinoids reduced neuropathic pain intensity in various conditions. Also, there are reports on using combination cannabinoid therapies for chronic pain management.

The association of cannabis dependence and addiction has been discussed much and the reports mentioned that it can be comparatively lower than other substances such as nicotine and alcohol. More countries have decided to legalise the medicinal use of cannabis and marijuana. Healthcare professionals should keep themselves updated with the changing state of medical cannabis and its applications.

The pharmacokinetics and safety of medical cannabis need to be studied by conducting clinical research. The complex and variable chemically active contents of herbal cannabis and methodological limitations in the administration of cannabis to study participants, make the clinical research difficult.”

https://pubmed.ncbi.nlm.nih.gov/31535218/

https://link.springer.com/article/10.1007%2Fs00540-019-02680-y

The interaction between the endocannabinoid system and the renin angiotensin system and its potential implication for COVID-19 infection

 Journal of Cannabis Research | Home“Coronavirus disease 2019 (COVID-19) is spreading fast all around the world with more than fourteen millions of detected infected cases and more than 600.000 deaths by 20th July 2020. While scientist are working to find a vaccine, current epidemiological data shows that the most common comorbidities for patients with the worst prognosis, hypertension and diabetes, are often treated with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).

Body: Both ACE inhibitors and ARBs induce overexpression of the angiotensin converting enzyme 2 (ACE-2) receptor, which has been identified as the main receptor used by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to enter into the alveolar cells of the lungs. While cannabinoids are known to reduce hypertension, the studies testing the hypotensive effects of cannabinoids never addressed their effects on ACE-2 receptors. However, some studies have linked the endocannabinoid system (ECS) with the renin angiotensin system (RAS), including a cross-modulation between the cannabinoid receptor 1 (CB1) and angiotensin II levels.

Conclusion: Since there are around 192 million people using cannabis worldwide, we believe that the mechanism underlying the hypotensive properties of cannabinoids should be urgently studied to understand if they can also lead to ACE-2 overexpression as other antihypertensive drugs do.”

https://pubmed.ncbi.nlm.nih.gov/32835160/

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-020-00030-4

Anti-proliferative and cytotoxic effect of cannabidiol on human cancer cell lines in presence of serum

 BMC Research Notes | Home page“Objective: Cannabinoids are able to reduce tumor growth in xenograft models, but their therapeutic potential as anti-cancer drugs in humans is unclear yet. In vitro studies of the effect of cannabinoids on cancer cells are often carried out in absence of serum or in low serum concentration (i.e. 0.5% serum), conditions that limit cellular growth and therefore can increase the response of cells to additional challenges such as the presence of cannabinoids. However, the tumor microenvironment can be teaming with growth factors. In this study we assessed the viability and proliferation of cancer cells treated with cannabidiol in presence of a serum concentration that commonly sustains cell growth (10% serum).

Results: The results show that cannabidiol exerts a markedly different effect on the viability of the human HT-29 cancer cell line when cultured in presence of 0.5% serum in comparison to 10% serum, displaying a cytotoxic effect only in the former situation. In presence of 10% serum, no inhibitory effect of cannabidiol on DNA replication of HT-29 cells was detected, and a weak inhibition was observed for other cancer cell lines. These results indicate that the effect of cannabidiol is cell context-dependent being modulated by the presence of growth factors.”

https://pubmed.ncbi.nlm.nih.gov/32819436/

“The cannabis plant has a therapeutic potential to treat a wide range of diseases, including cancer.”

https://bmcresnotes.biomedcentral.com/articles/10.1186/s13104-020-05229-5

Cannabinoid-profiled agents improve cell survival via reduction of oxidative stress and inflammation, and Nrf2 activation in a toxic model combining hyperglycemia+Aβ 1-42 peptide in rat hippocampal neurons

Neurochemistry International “Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder linked to various converging toxic mechanisms. Evidence suggests that hyperglycemia induces oxidative stress, mitochondrial dysfunction, inflammation and excitotoxicity, all of which play important roles in the onset and progression of AD pathogenesis.

The endocannabinoid system (ECS) orchestrates major physiological responses, including neuronal plasticity, neuroprotection, and redox homeostasis, to name a few. The multi-targeted effectiveness of the ECS emerges as a potential approach to treat AD.

Here we characterized the protective properties of the endocannabinoids arachidonylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), the synthetic cannabinoids CP 55-940 and WIN 55,212-2, and the fatty acid amide hydrolase (FAAH) inhibitor URB597, on a combined hyperglycemia+oligomeric amyloid β peptide (Aβ1-42) neurotoxic model in primary hippocampal neurons which exhibit several AD features.

All agents tested preserved cell viability and stimulated mitochondrial membrane potential, while reducing all the evaluated toxic endpoints in a differential manner, with URB597 showing the highest efficacy. The neuroprotective efficacy of all cannabinoid agents, except for URB597, led to partial recruitment of specific antioxidant activity and Nrf2 pathway regulation.

Our results support the neuroprotective potential of these agents at low concentrations against the damaging effects of GLU+Aβ1-42, affording new potential modalities for the design of AD therapies.”

https://pubmed.ncbi.nlm.nih.gov/32781098/

“All cannabinoid agents prevented the GLU + Aβ1-42 toxicity in a differential manner. All cannabinoid agents recruited Nrf2 signaling to protect cells.”

https://www.sciencedirect.com/science/article/abs/pii/S0197018620302084?via%3Dihub

Cannabis and the Gastrointestinal Tract

“Cannabis has been used for its medicinal purposes since ancient times. Its consumption leads to the activation of Cannabis receptors CB1 and CB2 that, through specific mechanisms can lead to modulation and progression of inflammation or repair. The novel findings are linked to the medical use of Cannabis in gastrointestinal (GI) system.

Purpose: The objective of the present paper is to elucidate the role of Cannabis consumption in GI system. An additional aim is to review the information on the function of Cannabis in non-alcoholic fatty liver disease (NAFLD).

Methods and results: This review summarizes the recent findings on the role of cannabinoid receptors, their synthetic or natural ligands, as well as their metabolizing enzymes in normal GI function and its disorders, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) and possible adverse events. The synergism or antagonism between Cannabis’ active ingredients and the “entourage” plays a role in the efficacy of various strains. Some elements of Cannabis may alter disease severity as over-activation of Cannabis receptors CB1 and CB2 can lead to changes of the commensal gut flora. The endocannabinoid system (ECS) contributes to gut homeostasis. The ability of ECS to modulate inflammatory responses demonstrates the capacity of ECS to preserve gastrointestinal (GI) function. Alterations of the ECS may predispose patients to pathologic disorders, including IBD. Clinical studies in IBD demonstrate that subjects benefit from Cannabis consumption as seen through a reduction of the IBD-inflammation, as well as through a decreased need for other medication. NAFLD is characterized by fat accumulation in the liver. The occurrence of inflammation in NAFLD leads to non-alcoholic-steatohepatitis (NASH). The use of Cannabis might reduce liver inflammation.

Conclusions: With limited evidence of efficacy and safety of Cannabis in IBD, IBS, and NAFLD, randomized controlled studies are required to examine its therapeutic efficacy.”

https://pubmed.ncbi.nlm.nih.gov/32762830/

https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/31242

Cannabis use is associated with a lower risk of diabetes in chronic hepatitis C-infected patients (ANRS CO22 Hepather cohort)

 Medscape | J Viral Hepat - Content Listing“Chronic hepatitis C virus (HCV) infection is a risk factor of insulin resistance, and HCV-infected patients are at a high risk of developing diabetes.

In the general population, research has shown the potential benefit of cannabis use for the prevention of diabetes and related metabolic disorders.

We aimed to test whether cannabis use is associated with a lower risk of diabetes in chronic HCV-infected patients.

After multivariable adjustment, current (AOR [95%CI]: 0.49 [0.38-0.63]) and former (0.81 [0.67-0.98], p<.001) cannabis use were both associated with a reduced odds of diabetes. Conversely, male gender, tobacco use, elevated BMI, poverty, being a migrant and advanced fibrosis were associated with increased odds of diabetes. The association between cannabis use and diabetes was maintained in the stratified analysis.

In this large cross-sectional study of chronic HCV-infected patients, cannabis use was associated with a lower risk of diabetes independently of clinical and socio-behavioral factors. Further studies are needed to elucidate a potential causal link and shed light on cannabis compounds and mechanisms involved in this relationship.”

https://pubmed.ncbi.nlm.nih.gov/32810343/

Substance use disorders and risk of severe maternal morbidity in the United States

Drug and Alcohol Dependence “The contribution of substance use disorders to the burden of severe maternal morbidity in the United States is poorly understood. The objective was to estimate the independent association between substance use disorders during pregnancy and risk of severe maternal morbidity.

Results: Pregnant women with an opioid use disorder had an increased risk of severe maternal morbidity compared with women without an opioid use disorder (18-34 years: aOR: 1.51; 95 % CI: 1.41,1.61, >34 years: aOR: 1.17; 95 % CI: 1.00,1.38). Compared with their counterparts without stimulant use disorders, pregnant women with a simulant use disorder (amphetamines, cocaine) had an increased risk of severe maternal morbidity (18-34 years: aOR: 1.92; 95 % CI: 1.80,2.0, >34 years: aOR: 1.85; 95 % CI: 1.66,2.06). Cannabis use disorders were not associated with an increased risk of severe maternal morbidity.

Conclusion: Substance use disorders during pregnancy, particularly opioids, amphetamines, and cocaine use disorders, may contribute to severe maternal morbidity in the United States.”

https://pubmed.ncbi.nlm.nih.gov/32846369/

“Cannabis use disorder was not associated with increased risk of severe maternal morbidity.”

https://www.sciencedirect.com/science/article/abs/pii/S0376871620304014?via%3Dihub

Cannabis Improves Obsessive-Compulsive Disorder-Case Report and Review of the Literature

Archive of "Frontiers in Psychiatry". “Although several lines of evidence support the hypothesis of a dysregulation of serotoninergic neurotransmission in the pathophysiology of obsessive-compulsive disorder (OCD), there is also evidence for an involvement of other pathways such as the GABAergic, glutamatergic, and dopaminergic systems.

Only recently, data obtained from a small number of animal studies alternatively suggested an involvement of the endocannabinoid system in the pathophysiology of OCD reporting beneficial effects in OCD-like behavior after use of substances that stimulate the endocannabinoid system.

In humans, until today, only two case reports are available reporting successful treatment with dronabinol (tetrahydrocannabinol, THC), an agonist at central cannabinoid CB1 receptors, in patients with otherwise treatment refractory OCD. In addition, data obtained from a small open uncontrolled trial using the THC analogue nabilone suggest that the combination of nabilone plus exposure-based psychotherapy is more effective than each treatment alone.

These reports are in line with data from a limited number of case studies and small controlled trials in patients with Tourette syndrome (TS), a chronic motor and vocal tic disorder often associated with comorbid obsessive compulsive behavior (OCB), reporting not only an improvement of tics, but also of comorbid OCB after use of different kinds of cannabis-based medicines including THC, cannabis extracts, and flowers.

Here we present the case of a 22-year-old male patient, who suffered from severe OCD since childhood and significantly improved after treatment with medicinal cannabis with markedly reduced OCD and depression resulting in a considerable improvement of quality of life. In addition, we give a review of current literature on the effects of cannabinoids in animal models and patients with OCD and suggest a cannabinoid hypothesis of OCD.”

https://pubmed.ncbi.nlm.nih.gov/32848902/

https://www.frontiersin.org/articles/10.3389/fpsyt.2020.00681/full

Rapid Antibacterial Activity of Cannabichromenic Acid against Methicillin-Resistant Staphylococcus aureus

antibiotics-logo “Methicillin-resistant Staphylococcus aureus (MRSA) has proven to be an imminent threat to public health, intensifying the need for novel therapeutics.

Previous evidence suggests that cannabinoids harbour potent antibacterial activity.

In this study, a group of previously inaccessible phytocannabinoids and synthetic analogues were examined for potential antibacterial activity.

The minimum inhibitory concentrations and dynamics of bacterial inhibition, determined through resazurin reduction and time-kill assays, revealed the potent antibacterial activity of the phytocannabinoids against gram-positive antibiotic-resistant bacterial species, including MRSA.

One phytocannabinoid, cannabichromenic acid (CBCA), demonstrated faster and more potent bactericidal activity than vancomycin, the currently recommended antibiotic for the treatment of MRSA infections. Such bactericidal activity was sustained against low-and high-dose inoculums as well as exponential- and stationary-phase MRSA cells. Further, mammalian cell viability was maintained in the presence of CBCA. Finally, microscopic evaluation suggests that CBCA may function through the degradation of the bacterial lipid membrane and alteration of the bacterial nucleoid.

The results of the current study provide encouraging evidence that cannabinoids may serve as a previously unrecognised resource for the generation of novel antibiotics active against MRSA.”

https://pubmed.ncbi.nlm.nih.gov/32824356/

https://www.mdpi.com/2079-6382/9/8/523