Category Archives: Endocannabinoid System

The Endocannabinoid System and Physical Activity-A Robust Duo in the Novel Therapeutic Approach against Metabolic Disorders

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“Rapidly increasing worldwide prevalence of obesity and related pathologies encompassing coronary heart disease, hypertension, metabolic syndrome, or type 2 diabetes constitute serious threats to global health and are associated with a significantly elevated risk of premature death. Considering the enormous burden of these pathologies, novel therapeutic and preventive patterns are indispensable.

Dysregulation of one of the most complex biological systems in the human body namely, the endocannabinoid system (ECS) may result in metabolic imbalance and development of insulin resistance, type 2 diabetes, or non-alcoholic fatty liver disease. Furthermore, many studies showed that physical exercises, depending on their type, intensity, and frequency, exert various alterations within the ECS.

Emerging evidence suggests that targeting the ECS via physical activity may produce robust beneficial effects on the course of metabolic pathologies. However, the data showing a direct correlation between the ECS and physical activity in the aspect of metabolic health are very scarce. Therefore, the aim of this review was to provide the most up-to-date state of knowledge about the interplay between the ECS activity and physical exercises in the novel therapeutic and preventive approach toward metabolic pathologies.

We believe that this paper, at least in part, will fulfill the existing gap in knowledge and encourage researchers to further explore this very complex yet interesting link between the ECS, its action in physical activity, and subsequent positive outcomes for metabolic health.”

https://pubmed.ncbi.nlm.nih.gov/35328503/

“To the best of our knowledge, this is the first review directly and comprehensively discussing the uncharted link between physical activity and its influence on the endocannabinoid signaling in the aspect of beneficial effects in the management of metabolic disorders. Considering the very alarming worldwide prevalence of these diseases as well as the unexplored potential of the topic, we believe that this paper, at least in part, will encourage researchers toward investigating this interesting, yet very complicated interplay. ECS and physical activity constitute robust and valuable therapeutic and preventive approaches that may significantly contribute to the decreased socioeconomic burden and the reduced annual number of patients suffering from obesity and other metabolic disorders. The future investigation should primarily encompass further discovery of the link between physical activity, alterations within endocannabinoid signaling and subsequently improved metabolic status of overweight, obese, and diabetic individuals.”

https://www.mdpi.com/1422-0067/23/6/3083/htm


“Exercise activates the endocannabinoid system”

https://pubmed.ncbi.nlm.nih.gov/14625449/

Cannabidiol improves thyroid function via modulating vitamin D 3 receptor in vitamin D 3 deficiency diet-induced rat model

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“The study was evaluated the impact of cannabidiol (CBD) on thyroid hormones by modulation cannabinoid receptor-2 (CB2) and vitamin D receptor (VDR) in rats fed with vitamin D3 deficiency diet (VDD).

CB2-receptors were analyzed by RT-PCR method and others biomarkers by ELISA. The relative expression of CB2 (thyroid ~ 4 folds), VDR protein (liver, 151.72%), and (kidney, 66%) was significantly increased in CBD-60 compared to VDD. Vitamin D3 metabolites were significantly increased serum (189.42%), kidney (73.84%), and liver (58.11%) in CBD-60 than VDD. Increased thyroxine (59.9%) and calcitonin (213.59%); while decreased thyroid-stimulating hormone (36.15%) and parathyroid hormone (38.64%) was observed CBD treatment in VDD rats.

In conclusion, CBD treatment improves CB2 and VDR expression and the level of vitamin D3 metabolites, along with improved thyroid hormones, including calcitonin. This is the first report with an improved CB2 and VDR expression after CBD treatment in VDD induced animals.

Thus, CBD can be considered to use in hypothyroidism conditions and to maintain bone health.”

https://pubmed.ncbi.nlm.nih.gov/35872737/

https://link.springer.com/article/10.1007/s13197-022-05492-3

The anti-inflammatory effects of cannabidiol and cannabigerol alone, and in combination

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Pulmonary Pharmacology & Therapeutics

“Introduction/background and purpose: Studies with Cannabis Sativa plant extracts and endogenous agonists of cannabinoid receptors have demonstrated anti-inflammatory, bronchodilator, and antitussive properties in the airways of allergic and non-allergic animals. However, the potential therapeutic use of cannabis and cannabinoids for the treatment of respiratory diseases has not been widely investigated, in part because of local irritation of airways by needing to smoke the cannabis, poor bioavailability when administered orally due to the lipophilic nature of cannabinoids, and the psychoactive effects of Δ9-Tetrahydrocannabinol (Δ9-THC) found in cannabis. The primary purpose of this study was to investigate the anti-inflammatory effects of two of the non-psychotropic cannabinoids, cannabidiol (CBD) and cannabigerol (CBG) alone and in combination, in a model of pulmonary inflammation induced by bacterial lipopolysaccharide (LPS). The second purpose was to explore the effects of two different cannabinoid formulations administered orally (PO) and intraperitoneally (IP). Medium-chain triglyceride (MCT) oil was used as the sole solvent for one formulation, whereas the second formulation consisted of a Cremophor® EL (polyoxyl 35 castor oil, CrEL)-based micellar solution.

Results: Exposure of guinea pigs to LPS induced a 97 ± 7% and 98 ± 3% increase in neutrophils found in bronchoalveolar lavage fluid (BAL) at 4 h and 24 h, respectively. Administration of CBD and CBG formulated with MCT oil did not show any significant effects on the LPS-induced neutrophilia measured in the BAL fluid when compared with the vehicle-treated groups. Conversely, the administration of either cannabinoid formulated with CrEL induced a significant attenuation of the LPS induced recruitment of neutrophils into the lung following both intraperitoneal (IP) and oral (PO) administration routes, with a 55-65% and 50-55% decrease in neutrophil cell recruitment with the highest doses of CBD and CBG respectively. A combination of CBD and CBG (CBD:CBG = 1:1) formulated in CrEL and administered orally was also tested to determine possible interactions between the cannabinoids. However, a mixture of CBD and CBG did not show a significant change in LPS-induced neutrophilia. Surfactants, such as CrEL, improves the dissolution of lipophilic drugs in an aqueous medium by forming micelles and entrapping the drug molecules within them, consequently increasing the drug dissolution rate. Additionally, surfactants increase permeability and absorption by disrupting the structural organisation of the cellular lipid bilayer.

Conclusion: In conclusion, this study has provided evidence that CBD and CBG formulated appropriately exhibit anti-inflammatory activity. Our observations suggest that these non-psychoactive cannabinoids may have beneficial effects in treating diseases characterised by airway inflammation.”

https://pubmed.ncbi.nlm.nih.gov/34082108/

“The discovery of the endocannabinoid system (ECS) has enabled the growth of scientific evidence supporting the use of cannabis and cannabinoids as therapeutic agents for various diseases.

Various studies have suggested the use of cannabinoids as possible treatments for inflammatory diseases”

https://www.sciencedirect.com/science/article/abs/pii/S1094553921000596?via%3Dihub

Protective Effects of Cannabis sativa on chemotherapy-induced nausea in a rat: Involvement of CB1 receptors

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“Cyclophosphamide is an anticancer and immunosuppressive agent used in the treatment of various malignancies but causing gastrointestinal distress.

Cannabis sativa (C. sativa) and its derivatives have been used for the treatment of human gastrointestinal disorders. A purpose of this study was to investigate the effect of C. sativa on nausea induced by cyclophosphamide in rats.

Results showed that C. sativa ameliorates cyclophosphamide-induced emesis by increasing in body weight and normal diet intake with a decrease in kaolin diet intake after 7 days. Moreover, C. sativa significantly decreases (serotonin) 5HT, dopamine and noradrenaline, as well as, decreasing oxidative stress and inflammation. Administration of C. sativa significantly increased the expression of CB1R in intestinal homogenate. Treatment with C. sativa, also, improved the histological feature of an intestinal tissue.

These results suggested that C. sativa possess antiemetic, antioxidant and anti-inflammatory effects in chemotherapy-induced nausea in rats by activating CB1R.”

https://pubmed.ncbi.nlm.nih.gov/35861135/

https://onlinelibrary.wiley.com/doi/10.1111/fcp.12821

Endocannabinoid Modulation in Neurodegenerative Diseases: In Pursuit of Certainty

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“Neurodegenerative diseases are an increasing cause of global morbidity and mortality. They occur in the central nervous system (CNS) and lead to functional and mental impairment due to loss of neurons. Recent evidence highlights the link between neurodegenerative and inflammatory diseases of the CNS. These are typically associated with several neurological disorders. These diseases have fundamental differences regarding their underlying physiology and clinical manifestations, although there are aspects that overlap.

The endocannabinoid system (ECS) is comprised of receptors (type-1 (CB1R) and type-2 (CB2R) cannabinoid-receptors, as well as transient receptor potential vanilloid 1 (TRPV1)), endogenous ligands and enzymes that synthesize and degrade endocannabinoids (ECBs). Recent studies revealed the involvement of the ECS in different pathological aspects of these neurodegenerative disorders.

The present review will explore the roles of cannabinoid receptors (CBRs) and pharmacological agents that modulate CBRs or ECS activity with reference to Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD) and multiple sclerosis (MS).”

https://pubmed.ncbi.nlm.nih.gov/35336814/

“Neurodegenerative diseases represent an important cause of morbidity and mortality worldwide. Existing therapeutic options are limited and focus mostly on improving symptoms and reducing exacerbations. The endocannabinoid system is involved in the pathophysiology of such disorders, an idea which has been highlighted by recent scientific work. The current work focusses its attention on the importance and implications of this system and its synthetic and natural ligands in disorders such as Alzheimer’s, Parkinson’s, Huntington’s and multiple sclerosis.”

https://www.mdpi.com/2079-7737/11/3/440/htm


Impact of the cannabinoid system in Alzheimer’s diseases

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“Cannabinoids are compounds that were initially isolated from cannabis marihuana and are also widely present in both nervous and immune systems of animals.

In recent years, with in-depth research on cannabinoids, their clinical medicinal value has been evaluated, and many exciting achievements have been continuously accumulating, especially in the field of neurodegenerative disease.

Alzheimer’s disease is the most common type of neurodegenerative disease that causes dementia and has become a global health problem that seriously impacts human health today.

In this review, we discuss the therapeutic potential of cannabinoids for the treatment of Alzheimer’s disease.

How cannabinoids act on different endocannabinoid receptor subtypes to regulate Alzheimer’s disease, the roles of the endocannabinoid system in Alzheimer’s disease are outlined, and the underlying mechanisms are discussed.

Finally, we summarize the most relevant opportunities of cannabinoid pharmacology related to Alzheimer’s disease and discuss the potential usefulness of cannabinoids in the clinical treatment of Alzheimer’s disease.”

https://pubmed.ncbi.nlm.nih.gov/35105293/

https://www.eurekaselect.com/article/120593

Potential of cannabinoids as treatments for autism spectrum disorders

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Journal of Psychiatric Research

“Current treatments for autism spectrum disorders (ASD) are limited in efficacy and are often associated with substantial side effects. These medications typically ameliorate problem behaviors associated with ASD, but do not target core symptom domains. As a result, there is a significant amount of research underway for development of novel experimental therapeutics.

Endocannabinoids are arachidonic acid-derived lipid neuromodulators, which, in combination with their receptors and associated metabolic enzymes, constitute the endocannabinoid (EC) system. Cannabinoid signaling may be involved in the social impairment and repetitive behaviors observed in those with ASD. In this review, we discuss a possible role of the EC system in excitatory-inhibitory (E-I) imbalance and immune dysregulation in ASD.

Novel treatments for the core symptom domains of ASD are needed and phytocannabinoids could be useful experimental therapeutics for core symptoms and associated domains.”

https://pubmed.ncbi.nlm.nih.gov/33689997/

“Novel treatments for the core symptom domains of ASD are needed, and the endocannabinoid (EC) system could be a target for those therapies through the administration of exogenous cannabinoids.”

https://www.sciencedirect.com/science/article/abs/pii/S0022395621001266?via%3Dihub

“Healing autism spectrum disorder with cannabinoids: a neuroinflammatory story” https://pubmed.ncbi.nlm.nih.gov/33358985/

The role of the endocannabinoid system as a therapeutic target for autism spectrum disorder: Lessons from behavioral studies on mouse models

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Neuroscience & Biobehavioral Reviews

“Recent years have seen an impressive amount of research devoted to understanding the etiopathology of Autism Spectrum Disorder (ASD) and developing therapies for this syndrome. Because of the lack of biomarkers of ASD, this work has been largely based on the behavioral characterization of rodent models, based on a multitude of genetic and environmental manipulations.

Here we highlight how the endocannabinoid system (ECS) has recently emerged within this context of mouse behavioral studies as an etiopathological factor in ASD and a valid potential therapeutic target.

We summarize the most recent results showing alterations of the ECS in rodent models of ASD, and demonstrating ASD-like behaviors in mice with altered ECS, induced either by genetic or pharmacological manipulations. We also give a critical overview of the most relevant advances in designing treatments and novel mouse models for ASD targeting the ECS, highlighting the relevance of thorough and innovative behavioral approaches to investigate the mechanisms acting underneath the complex features of ASD.”

https://pubmed.ncbi.nlm.nih.gov/34813825/

“Autism Spectrum Disorder (ASD) is a complex pathology with unknown aetiology and developing therapeutic approaches.•

Recent mouse behavioural studies have highlighted the role of the endocannabinoid system (ECS) in ASD.•

Novel pharmacological treatments and new genetic mouse models for ASD can be identified and designed by targeting the ECS.”

https://www.sciencedirect.com/science/article/abs/pii/S014976342100525X?via%3Dihub


Endocannabinoid System Dysregulation from Acetaminophen Use May Lead to Autism Spectrum Disorder: Could Cannabinoid Treatment Be Efficacious?

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“Persistent deficits in social communication and interaction, and restricted, repetitive patterns of behavior, interests or activities, are the core items characterizing autism spectrum disorder (ASD). Strong inflammation states have been reported to be associated with ASD.

The endocannabinoid system (ECS) may be involved in ASD pathophysiology. This complex network of lipid signaling pathways comprises arachidonic acid and 2-arachidonoyl glycerol-derived compounds, their G-protein-coupled receptors (cannabinoid receptors CB1 and CB2) and the associated enzymes. Alterations of the ECS have been reported in both the brain and the immune system of ASD subjects.

ASD children show low EC tone as indicated by low blood levels of endocannabinoids. Acetaminophen use has been reported to be associated with an increased risk of ASD. This drug can act through the ECS to produce analgesia. It may be that acetaminophen use in children increases the risk for ASD by interfering with the ECS.”

https://pubmed.ncbi.nlm.nih.gov/33805951/

https://www.mdpi.com/1420-3049/26/7/1845

“Can autism be triggered by acetaminophen activation of the endocannabinoid system? Acetaminophen use in children has been associated with increased autism risk. Recent evidence suggests that acetaminophen’s analgesic actions result from activation of the endocannabinoid system, and activation of this system can have neuromodulatory consequences during development. This investigation was performed to determine if there is evidence to support the hypothesis that acetaminophen use can trigger autism by activation of the endocannabinoid system.”

https://pubmed.ncbi.nlm.nih.gov/20628445/

“Paracetamol (N-acetyl-p-aminophenol (APAP), otherwise known as acetaminophen) is the active ingredient in more than 600 medications used to relieve mild to moderate pain and reduce fever. APAP is widely used by pregnant women as governmental agencies, including the FDA and EMA, have long considered APAP appropriate for use during pregnancy when used as directed. However, increasing experimental and epidemiological research suggests that prenatal exposure to APAP might alter fetal development, which could increase the risks of some neurodevelopmental, reproductive and urogenital disorders.”

https://pubmed.ncbi.nlm.nih.gov/34556849/

“Healing autism spectrum disorder with cannabinoids: a neuroinflammatory story” https://pubmed.ncbi.nlm.nih.gov/33358985/

Therapeutic Potential of Cannabinoids on Tumor Microenvironment: A Molecular Switch in Neoplasia Transformation

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“The efficacy of chemotherapy depends on the tumor microenvironment. This microenvironment consists of a complex cellular network that can exert both stimulatory and inhibitory effects on tumor genesis.

Given the increasing interest in the effectiveness of cannabis, cannabinoids have gained much attention as a potential chemotherapy drug. Cannabinoids are a group of marker compounds found in Cannabis sativa L., more commonly known as marijuana, a psychoactive drug used since ancient times for pain management.

Although the anticancer potential of C. sativa, has been recognized previously, increased attention was generated after discovering the endocannabinoid system and the successful production of cannabinoid receptors.

In vitro and in vivo studies on various tumor models have shown therapeutic efficiency by modifying the tumor microenvironment.

This review summarizes the key literature surrounding the role of cannabinoids in the tumor microenvironment and their future promise in cancer treatment.”

https://pubmed.ncbi.nlm.nih.gov/35796303/

“Cannabis sativa L. is a natural source of valuable compounds that comprise cannabinoid agonists and antagonists, which have recently been scanned for future applications as anti-tumor drugs. Cannabinoids have mostly been used as a part of palliative care to alleviate pain, relieve nausea, and stimulate appetite in cancer patients. Although not yet approved for treating tumor progression, cannabinoid agonist/antagonists on the tumor microenvironment have been studied for the last 43 years. Research on cannabinoids and their potential therapeutic function has been ongoing since 1971. Numerous in vitro and in vivo studies have demonstrated the anti-cancer effects of cannabinoids in various cancer types.”

https://journals.sagepub.com/doi/10.1177/15347354221096766