Can Physical Activity Support the Endocannabinoid System in the Preventive and Therapeutic Approach to Neurological Disorders?

ijms-logo“The worldwide prevalence of neurological and neurodegenerative disorders, such as depression or Alzheimer’s disease, has spread extensively throughout the last decades, becoming an enormous health issue.

Numerous data indicate a distinct correlation between the altered endocannabinoid signaling and different aspects of brain physiology, such as memory or neurogenesis. Moreover, the endocannabinoid system is widely regarded as a crucial factor in the development of neuropathologies. Thus, targeting those disorders via synthetic cannabinoids, as well as phytocannabinoids, becomes a widespread research issue.

Over the last decade, the endocannabinoid system has been extensively studied for its correlation with physical activity. Recent data showed that physical activity correlates with elevated endocannabinoid serum concentrations and increased cannabinoid receptor type 1 (CB1R) expression in the brain, which results in positive neurological effects including antidepressant effect, ameliorated memory, neuroplasticity development, and reduced neuroinflammation. However, none of the prior reviews presented a comprehensive correlation between physical activity, the endocannabinoid system, and neuropathologies.

Thus, our review provides a current state of knowledge of the endocannabinoid system, its action in physical activity, as well as neuropathologies and a possible correlation between all those fields. We believe that this might contribute to finding a new preventive and therapeutic approach to both neurological and neurodegenerative disorders.”

https://pubmed.ncbi.nlm.nih.gov/32545780/

https://www.mdpi.com/1422-0067/21/12/4221

Isolation, Purification, and Antimicrobial Characterization of Cannabidiolic Acid and Cannabidiol From Cannabis sativa L

biomolecules-logo“The emergence of multi-drug resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) causes a major threat to public health due to its limited therapeutic options.

There is an urgent need for the development of new effective antimicrobial agents and alternative strategies that are effective against resistant bacteria.

The parallel legalization of cannabis and its products has fueled research into its many therapeutic avenues in many countries around the world.

This study aimed at the development of a reliable method for the extraction, purification, characterization, and quantification of cannabidiolic acid (CBDA) and its decarboxylated form cannabidiol (CBD) present in the fiber type Cannabis sativa L.

Overall, CBD exhibited a strong antimicrobial effect against Gram-positive strains and could serve as an alternative drug for tackling MRSA.”

https://pubmed.ncbi.nlm.nih.gov/32545687/

https://www.mdpi.com/2218-273X/10/6/900

Localisation of Cannabinoid and Cannabinoid-Related Receptors in the Equine Dorsal Root Ganglia

Publication cover image“Growing evidence recognises cannabinoid receptors as potential therapeutic targets for pain. Consequently, there is increasing interest in developing cannabinoid receptor agonists for treating pain.

As a general rule, to better understand the actions of a drug, it would be of extreme importance to know the cellular distribution of its specific receptors. The localisation of cannabinoid receptors in the dorsal root ganglia of the horse has not yet been investigated.

Conclusions: This study highlighted the expression of cannabinoid receptors in the sensory neurons and glial cells of the dorsal root ganglia. These findings could be of particular relevance for future functional studies assessing the effects of cannabinoids in horses to manage pain.”

https://pubmed.ncbi.nlm.nih.gov/32524649/

https://beva.onlinelibrary.wiley.com/doi/abs/10.1111/evj.13305

Cannabinoid 1 Receptor (CB1R) Antagonists Play a Neuroprotective Role in Chronic Alcoholic Hippocampal Injury Related to Pyroptosis Pathway

 Alcoholism: Clinical and Experimental Research“Alcohol use disorders affect millions of people worldwide and there is growing evidence that excessive alcohol intake causes severe damage to the brain of both humans and animals.

Numerous studies on chronic alcohol exposure in animal models have identified that many functional impairments are associated with the hippocampus, which is a structure exhibiting substantial vulnerability to alcohol exposure. However, the precise mechanisms that lead to structural and functional impairments of the hippocampus are poorly understood.

Herein, we report a novel cell death type, namely pyroptosis, which accounts for alcohol neurotoxicity in mice.

Conclusions: Alcohol induces hippocampal pyroptosis, which leads to neurotoxicity thereby indicating that pyroptosis may be an essential pathway involved in chronic alcohol-induced hippocampal neurotoxicity. Further, cannabinoid receptors are regulated during this process, which suggests promising therapeutic strategies against alcohol-induced neurotoxicity through pharmacologic inhibition of CB1R.”

https://pubmed.ncbi.nlm.nih.gov/32524615/

https://onlinelibrary.wiley.com/doi/abs/10.1111/acer.14391

Targeting the Endocannabinoid CB1 Receptor to Treat Body Weight Disorders: A Preclinical and Clinical Review of the Therapeutic Potential of Past and Present CB1 Drugs

biomolecules-logo“Obesity rates are increasing worldwide and there is a need for novel therapeutic treatment options.

The endocannabinoid system has been linked to homeostatic processes, including metabolism, food intake, and the regulation of body weight.

Rimonabant, an inverse agonist for the cannabinoid CB1 receptor, was effective at producing weight loss in obese subjects. However, due to adverse psychiatric side effects, rimonabant was removed from the market.

More recently, we reported an inverse relationship between cannabis use and BMI, which has now been duplicated by several groups.

As those results may appear contradictory, we review here preclinical and clinical studies that have studied the impact on body weight of various cannabinoid CB1 drugs. Notably, we will review the impact of CB1 inverse agonists, agonists, partial agonists, and neutral antagonists.

Those findings clearly point out the cannabinoid CB1 as a potential effective target for the treatment of obesity. Recent preclinical studies suggest that ligands targeting the CB1 may retain the therapeutic potential of rimonabant without the negative side effect profile. Such approaches should be tested in clinical trials for validation.”

https://pubmed.ncbi.nlm.nih.gov/32512776/

https://www.mdpi.com/2218-273X/10/6/855

A Pilot Randomised Placebo-Controlled Trial of Cannabidiol to Reduce Severe Behavioural Problems in Children and Adolescents With Intellectual Disability

 British Journal of Clinical Pharmacology“Introduction: Severe Behavioural Problems (SBP) are a major contributor to morbidity in children with Intellectual Disability (ID). Medications used to treat SBP in ID are associated with a high risk of side effects. Cannabidiol has potential therapeutic effects in SBP. This pilot study aimed to investigate the feasibility of conducting a randomized placebo-controlled trial of cannabidiol to reduce SBP in children with ID.

Methods: Double-blind, placebo-controlled, two-armed, parallel-design, randomised controlled trial of cannabidiol in children aged 8 – 16 years with ID and SBP. Participants were randomized 1:1 to receive either 98% cannabidiol in oil (Tilray, Canada) or placebo orally for 8 weeks. The dose was up-titrated over 9 days to 20mg/kg/day in two divided doses, with a maximum dose of 500mg twice/day. The feasibility and acceptability of all study components were assessed.

Results: Eight children were randomised, and all completed the full study protocol. There were no Serious Adverse Events or drop-outs. Protocol adherence for key study components was excellent: study visits 100%, medication adherence 100%, blood tests 92%, and questionnaire completion 88%. Parents reported a high degree of acceptability with the study design. All parents reported they would recommend the study to other families with children with similar problems. There was an efficacy signal in favour of active drug.

Conclusions: The findings suggest that the study protocol is feasible and acceptable to patients with ID and SBP and their families.”

https://pubmed.ncbi.nlm.nih.gov/32478863/

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bcp.14399

Cannabinoid Receptor Type 2: A Possible Target in SARS-CoV-2 (CoV-19) Infection?

ijms-logo“In late December 2019, a novel coronavirus (SARS-CoV-2 or CoV-19) appeared in Wuhan, China, causing a global pandemic. SARS-CoV-2 causes mild to severe respiratory tract inflammation, often developing into lung fibrosis with thrombosis in pulmonary small vessels and causing even death. COronaVIrus Disease (COVID-19) patients manifest exacerbated inflammatory and immune responses, cytokine storm, prevalence of pro-inflammatory M1 macrophages and increased levels of resident and circulating immune cells. Men show higher susceptibility to SARS-CoV-2 infection than women, likely due to estrogens production. The protective role of estrogens, as well as an immune-suppressive activity that limits the excessive inflammation, can be mediated by cannabinoid receptor type 2 (CB2). The role of this receptor in modulating inflammation and immune response is well documented in fact in several settings. The stimulation of CB2 receptors is known to limit the release of pro-inflammatory cytokines, shift the macrophage phenotype towards the anti-inflammatory M2 type and enhance the immune-modulating properties of mesenchymal stromal cells. For these reasons, we hypothesize that CB2 receptor can be a therapeutic target in COVID-19 pandemic emergency.”

https://pubmed.ncbi.nlm.nih.gov/32471272/

https://www.mdpi.com/1422-0067/21/11/3809

Acute Inflammation and Pathogenesis of SARS-CoV-2 Infection: Cannabidiol as a Potential Anti-Inflammatory Treatment?

Cytokine & Growth Factor Reviews

“Cannabidiol to decrease SARS-CoV-2 associated inflammation.

Cannabidiol (CBD) is a phytocannabinoid with various clinical applications and has proven efficacy for certain medical conditions, along with a favorable safety and tolerability profile.

Cannabinoids can suppress immune activation and inflammatory cytokine production, suggesting their potential for tempering excessive inflammation.

Therefore, as SARS-CoV2 induces significant damage through pro-inflammatory cytokine storm mediated by macrophages and other immune cells and based on the fact that CBD has broad anti-inflammatory properties, CBD might represent as a potential anti-inflammatory therapeutic approach against SARS-CoV2-induced inflammation.

As CBD is already a therapeutic agent used in clinical medicine and has a favorable safety profile, the results of in vitro and animal model proof-of-concept studies would provide the necessary supporting evidence required before embarking on costly and labor-intensive clinical trials.”

https://pubmed.ncbi.nlm.nih.gov/32467020/

https://www.sciencedirect.com/science/article/pii/S1359610120301040?via%3Dihub

Does Cannabidiol Have Antiseizure Activity Independent of Its Interactions With Clobazam? An Appraisal of the Evidence From Randomized Controlled Trials

 Epilepsia“Four pivotal randomized placebo-controlled trials have demonstrated that adjunctive therapy with cannabidiol (CBD) improves seizure control in patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).

Between 47% and 68% of patients allocated to CBD treatment in these trials were receiving clobazam (CLB), which shows complex interactions with CBD resulting, in particular, in a 3.4- to 5-fold increase in plasma concentration of the active metabolite norclobazam. This raises concern as to the role played by these interactions in determining the reduction in seizure frequency in CBD-treated patients, and the question of whether CBD per se has clinically evident antiseizure effects.

We appraised available evidence on the clinical consequences of the CBD-CLB interaction, focusing on subgroup analyses of seizure outcomes in patients on and off CLB comedication in the pivotal CBD trials, as provided by the European Medicines Agency Public Assessment Report.

Evaluation of the results of individual trials clearly showed that improvement in seizure control over placebo was greater when CBD was added on to CLB than when it was added on to other medications. However, seizure control was also improved in patients off CLB, and despite the small sample size the difference vs placebo was statistically significant for the 10 mg/kg/d dose in one of the two LGS trials.

Stronger evidence for an antiseizure effect of CBD independent of an interaction with CLB emerges from meta-analyses of seizure outcomes in the pooled population of LGS and DS patients not receiving CLB comedication.

Although these results need to be interpreted taking into account methodological limitations, they provide the best clinical evidence to date that CBD exerts therapeutic effects in patients with epilepsy that are independent of its interaction with CLB. Greater antiseizure effects, and a greater burden of adverse effects, are observed when CBD is combined with CLB.”

https://pubmed.ncbi.nlm.nih.gov/32452568/

https://onlinelibrary.wiley.com/doi/abs/10.1111/epi.16542

A Balanced Approach for Cannabidiol Use in Chronic Pain

Frontiers in Pharmacology (@FrontPharmacol) | Twitter “Cannabidiol (CBD), the major non-psychoactive constituent of Cannabis sativa L., has gained traction as a potential treatment for intractable chronic pain in many conditions. Clinical evidence suggests that CBD provides therapeutic benefit in certain forms of epilepsy and imparts analgesia in certain conditions, and improves quality of life.

CBD continues to be Schedule I or V on the list of controlled substances of the Drug Enforcement Agency of the United States. However, preparations labeled CBD are available publicly in stores and on the streets. However, use of CBD does not always resolve pain. CBD purchased freely entails the risk of adulteration by potentially hazardous chemicals. As well, CBD use by pregnant women is rising and poses a major health-hazard for future generations.

In this mini-review, we present balanced and unbiased pre-clinical and clinical findings for the beneficial effects of CBD treatment on chronic pain and its deleterious effects on prenatal development.”

https://pubmed.ncbi.nlm.nih.gov/32425793/

https://www.frontiersin.org/articles/10.3389/fphar.2020.00561/full

www.frontiersin.org