Category Archives: Endocannabinoid System

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


Cannabis: Chemistry, extraction and therapeutic applications

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Chemosphere

“Cannabis, a genus of perennial indigenous plants is well known for its recreational and medicinal activities. Cannabis and its derivatives have potential therapeutic activities to treat epilepsy, anxiety, depression, tumors, cancer, Alzheimer’s disease, Parkinson’s disease, to name a few.

This article reviews some recent literature on the bioactive constituents of Cannabis, commonly known as phytocannabinoids, their interactions with the different cannabinoids and non-cannabinoid receptors as well as the significances of these interactions in treating various diseases and syndromes.

The biochemistry of some notable cannabinoids such as tetrahydrocannabinol, cannabidiol, cannabinol, cannabigerol, cannabichromene and their carboxylic acid derivatives is explained in the context of therapeutic activities.

The medicinal features of Cannabis-derived terpenes are elucidated for treating several neuro and non-neuro disorders. Different extraction techniques to recover cannabinoids are systematically discussed. Besides the medicinal activities, the traditional and recreational utilities of Cannabis and its derivatives are presented. A brief note on the legalization of Cannabis-derived products is provided.

This review provides comprehensive knowledge about the medicinal properties, recreational usage, extraction techniques, legalization and some prospects of cannabinoids and terpenes extracted from Cannabis.”

https://pubmed.ncbi.nlm.nih.gov/34838836/

“Cannabinoids have therapeutic effects against various health disorders.•

Medicinal effects are due to the interactions of cannabinoids with bio-receptors.•

Cannabinoids can be extracted from Cannabis plant products by eco-friendly extraction methods.”

https://www.sciencedirect.com/science/article/abs/pii/S0045653521034846?via%3Dihub

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Cannabinoid 1 and mu-opioid receptor agonists synergistically inhibit abdominal pain and lack side effects in mice

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Society for Neuroscience - Publications

“While effective in treating abdominal pain, opioids have significant side effects. Recent legalization of cannabis will likely promote use of cannabinoids as an adjunct or alternative to opioids, despite a lack of evidence.

We aimed to investigate if cannabinoids inhibit mouse colonic nociception, alone or in combination with opioids at low doses.

Experiments were performed on C57BL/6 male and female mice. Visceral nociception was evaluated by measuring visceromotor responses (VMR), afferent nerve mechanosensitivity in flat-sheet colon preparations, and excitability of isolated dorsal root ganglion (DRG) neurons. Blood oxygen saturation, locomotion and defecation were measured to evaluate side effects.

An agonist of cannabinoid 1 receptor (CB1R), arachidonyl-2′-chloroethylamide (ACEA), dose-dependently decreased VMR. ACEA and HU-210 (another CB1R agonist) also attenuated colonic afferent nerve mechanosensitivity. Additionally, HU-210 concentration-dependently decreased DRG neuron excitability, which was reversed by the CB1R antagonist AM-251. Conversely, cannabinoid 2 receptor (CB2R) agonists did not attenuate VMR, afferent nerve mechanosensitivity or DRG neuron excitability.

Combination of sub-analgesic doses of CB1R and µ-opioid receptor (MOR) agonists decreased VMR; importantly, this analgesic effect was preserved after 6 days of twice daily treatment. This combination also attenuated afferent nerve mechanosensitivity and DRG neuron excitability, which was inhibited by neuronal nitric oxide synthase (nNOS) and guanylate cyclase inhibitors. This combination avoided side effects (decreased oxygen saturation and colonic transit) caused by analgesic dose of morphine. Activation of CB1R, but not CB2R, decreased colonic nociception both alone and in synergy with MOR.

Thus, CB1R agonists may enable opioid dose reduction and avoid opioid-related side effects.

SIGNIFICANCE STATEMENTOne of the most cited needs for patients with abdominal pain are safe and effective treatment options. The effectiveness of opioids in the management of abdominal pain is undermined by severe adverse side effects. Therefore, strategies to replace opioids or reduce the doses of opioids to suppress abdominal pain is needed. This study in mice demonstrates that cannabinoid 1 receptor (CB1R) agonists inhibit visceral sensation. Furthermore, a combination of sub-analgesic doses of µ-opioid receptor agonist and CB1R agonist markedly reduce abdominal pain without causing the side effects of high dose opioids. Thus, CB1R agonists, alone or in combination with low-dose opioids, may be a novel and safe treatment strategy for abdominal pain.”

https://pubmed.ncbi.nlm.nih.gov/35790401/


[GPR18 receptor – the structure and the role in the physiology and pathophysiology]

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“G-protein coupled receptors constitute the largest family of membrane receptors and they participate in the maintenance of the homeostasis in the body. Some of these receptors still remain orphan receptors as there is insufficient research and ambiguous evidence concerning their function and endogenous ligands.

For a long time, GPR18 belonged to this group, but recently it has been classified as an endocannabinoid receptor due to its affinity to cannabinoid ligands.

GPR18 receptor is expressed in the encephalon, thyroid gland, leukocytes, lungs and testicles. The modulatory role of GPR18 receptor has been proven in the regulation of intraocular pressure, neuroimmunomodulation, regulation of arterial blood pressure and in metabolic disorders.

In this article we summarize the current knowledge concerning the GPR18 receptor – its expression, ligands and the in the physiological processes and the pathophysiological conditions.”

https://pubmed.ncbi.nlm.nih.gov/35792647/

https://postepybiochemii.ptbioch.edu.pl/index.php/PB/article/view/399

Mechanisms of Cannabidiol (CBD) in Cancer Treatment: A Review

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“Cannabis sativa L. (Cannabis) and its bioactive compounds, including cannabinoids and non-cannabinoids, have been extensively studied for their biological effects in recent decades. Cannabidiol (CBD), a major non-intoxicating cannabinoid in Cannabis, has emerged as a promising intervention for cancer research.

The purpose of this review is to provide insights into the relationship between CBD and cancer based on recent research findings.

The anticancer effects of CBD are mainly mediated via its interaction with the endocannabinoid system, resulting in the alleviation of pain and the promotion of immune regulation. Published reviews have focused on the applications of CBD in cancer pain management and the possible toxicological effects of its excessive consumption.

In this review, we aim to summarize the mechanisms of action underlying the anticancer activities of CBD against several common cancers. Studies on the efficacy and mechanisms of CBD on cancer prevention and intervention in experimental models (i.e., cell culture- and animal-based assays) and human clinical studies are included in this review.”

https://pubmed.ncbi.nlm.nih.gov/35741337/

“Emerging evidence suggests positive outcomes from the use of CBD as a cancer treatment. CBD can relieve cancer pain and ease the side effects of chemotherapy; however, there is less research about the mechanism of CBD’s anticancer effects. In this article, recent studies on the efficacy and mechanisms of CBD’s anticancer effects in cell- and animal-based models and human clinical studies are reviewed.”

https://www.mdpi.com/2079-7737/11/6/817


Biosynthetic origins of unusual cannabimimetic phytocannabinoids in Cannabis sativa L: A review

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Phytochemistry

“Plants of Cannabis sativa L. (Cannabaceae) produce an array of more than 160 isoprenylated resorcinyl polyketides, commonly referred to as phytocannabinoids. These compounds represent molecules of therapeutic importance due to their modulation of the human endocannabinoid system (ECS).

While understanding of the biosynthesis of the major phytocannabinoids Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) has grown rapidly in recent years, the biosynthetic origin and genetic regulation of many potentially therapeutically relevant minor phytocannabinoids remains unknown, which limits the development of chemotypically elite varieties of C. sativa.

This review provides an up-to-date inventory of unusual phytocannabinoids which exhibit cannabimimetic-like activities and proposes putative metabolic origins. Metabolic branch points exploitable for combinatorial biosynthesis and engineering of phytocannabinoids with augmented therapeutic activities are also described, as is the role of phytocannabinoid remodelling to accelerate therapeutic portfolio expansion in C. sativa.”

https://pubmed.ncbi.nlm.nih.gov/35718133/

https://www.sciencedirect.com/science/article/abs/pii/S0031942222001984?via%3Dihub

Phytocannabinoids and Cannabis-Based Products as Alternative Pharmacotherapy in Neurodegenerative Diseases: From Hypothesis to Clinical Practice

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Archive of "Frontiers in Cellular Neuroscience". - PMC

“Historically, Cannabis is one of the first plants to be domesticated and used in medicine, though only in the last years the amount of Cannabis-based products or medicines has increased worldwide.

Previous preclinical studies and few published clinical trials have demonstrated the efficacy and safety of Cannabis-based medicines in humans. Indeed, Cannabis-related medicines are used to treat multiple pathological conditions, including neurodegenerative disorders.

In clinical practice, Cannabis products have already been introduced to treatment regimens of Alzheimer’s disease, Parkinson’s disease and Multiple Sclerosis’s patients, and the mechanisms of action behind the reported improvement in the clinical outcome and disease progression are associated with their anti-inflammatory, immunosuppressive, antioxidant, and neuroprotective properties, due to the modulation of the endocannabinoid system.

In this review, we describe the role played by the endocannabinoid system in the physiopathology of Alzheimer, Parkinson, and Multiple Sclerosis, mainly at the neuroimmunological level. We also discuss the evidence for the correlation between phytocannabinoids and their therapeutic effects in these disorders, thus describing the main clinical studies carried out so far on the therapeutic performance of Cannabis-based medicines.”

https://pubmed.ncbi.nlm.nih.gov/35707521/

“Based on scientific evidence, the use of Cannabis-based products or Cannabis-based medicine (CBM) has been growing among patients diagnosed with neurodegenerative diseases. Most reports of clinical trials also describe significant improvement in disease-related primary and/or secondary symptoms, besides general improvement in life quality.”

https://www.frontiersin.org/articles/10.3389/fncel.2022.917164/full


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

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Frontiers in Pharmacology welcomes new Field Chief Editor – Science & research news | Frontiers

“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

Promoting Oligodendrocyte Differentiation from Human Induced Pluripotent Stem Cells by Activating Endocannabinoid Signaling for Treating Spinal Cord Injury

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SpringerLink

“Transplantation of oligodendrocyte progenitor cell (OPC) at the injury site is being developed as a potential therapeutic strategy for promoting remyelination and locomotor function recovery after spinal cord injury (SCI). To this end, the development of expandable and functional human OPCs is crucial for testing their efficacy in SCI.

In mice and rats, the endocannabinoid signaling system is crucial for the survival, differentiation, and maturation of OPCs. Similar studies in humans are lacking currently. Endocannabinoids and exogenous cannabinoids exert their effects mainly via cannabinoid receptors (CB1R and CB2R). We demonstrated that these receptors were differentially expressed in iPSC-derived human NSCs and OPCs, and they could be activated by WIN55212-2 (WIN), a potent CB1R/CB2R agonist to upregulate the endocannabinoid signaling during glial induction.

WIN primed NSCs generated more OLIG2 + glial progenitors and migratory PDGFRα + OPC in a CB1/CB2 dependent manner compared to unprimed NSCs. Furthermore, WIN-induced OPCs (WIN-OPCs) robustly differentiated into functional oligodendrocytes and myelinate in vitro and in vivo in a mouse spinal cord injury model. RNA-Seq revealed that WIN upregulated the biological process of positive regulation of oligodendrocyte differentiation. Mechanistically, WIN could act as a partial smoothed (SMO) inhibitor or activate CB1/CB2 to form heteromeric complexes with SMO leading to the inhibition of GLI1 in the Sonic hedgehog pathway.

The partial and temporal inhibition of GLI1 during glial induction is shown to promote OPCs that differentiate faster than control’s. Thus, CB1R/CB2R activation results in more efficient generation of OPCs that can mature and efficiently myelinate.”

https://pubmed.ncbi.nlm.nih.gov/35725998/

https://link.springer.com/article/10.1007/s12015-022-10405-0