Category Archives: Endocannabinoid System

Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5R59X knock-in mice

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“Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is caused by a loss-of-function mutation in CDKL5 gene, encoding a serine-threonine kinase highly expressed in the brain. CDD manifests with early-onset epilepsy, autism, motor impairment and severe intellectual disability.

While there are no known treatments for CDD, the use of cannabidiol has recently been introduced into clinical practice for neurodevelopmental disorders. Given the increased clinical utilization of cannabidiol, we examined its efficacy in the CDKL5R59X knock-in (R59X) mice, a CDD model based on a human mutation that exhibits both lifelong seizure susceptibility and behavioural deficits.

We found that cannabidiol pre-treatment rescued the increased seizure susceptibility in response to the chemoconvulsant pentylenetetrazol (PTZ), attenuated working memory and long-term memory impairments, and rescued social deficits in adult R59X mice. To elucidate a potential mechanism, we compared the developmental hippocampal and cortical expression of common endocannabinoid (eCB) targets in R59X mice and their wild-type littermates, including cannabinoid type 1 receptor (CB1R), transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), G-coupled protein receptor 55 (GPR55) and adenosine receptor 1 (A1R). Many of these eCB targets were developmentally regulated in both R59X and wild-type mice. In addition, adult R59X mice demonstrated significantly decreased expression of CB1R and TRPV1 in the hippocampus, and TRPV2 in the cortex, while TRPV1 was increased in the cortex.

These findings support the potential for dysregulation of eCB signalling as a plausible mechanism and therapeutic target in CDD, given the efficacy of cannabidiol to attenuate hyperexcitability and behavioural deficits in this disorder.”

https://pubmed.ncbi.nlm.nih.gov/38654472/

“The current report is the first to show experimental evidence that cannabidiol can mitigate some of the memory and social deficits as well as seizure susceptibility in a well-characterized CDD mouse model. These findings continue to support the emerging clinical observational data that cannabidiol-based compounds have efficacy in CDD patients, especially those in later childhood and adulthood.”

https://onlinelibrary.wiley.com/doi/10.1111/ejn.16350

Exploring Cannabinoids with Enhanced Binding Affinity for Targeting the Expanded Endocannabinoid System: A Promising Therapeutic Strategy for Alzheimer’s Disease Treatment

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“Despite decades of rigorous research and numerous clinical trials, Alzheimer’s disease (AD) stands as a notable healthcare challenge of this century, with effective therapeutic solutions remaining elusive.

Recently, the endocannabinoid system (ECS) has emerged as an essential therapeutic target due to its regulatory role in different physiological processes, such as neuroprotection, modulation of inflammation, and synaptic plasticity. This aligns with previous research showing that cannabinoid receptor ligands have the potential to trigger the functional structure of neuronal and brain networks, potentially impacting memory processing.

Therefore, our study aims to assess the effects of prolonged, intermittent exposure (over 90 days) to JWH-133 (0.2 mg/kg) and an EU-GMP certified Cannabis sativa L. (Cannabixir® Medium Flos, 2.5 mg/kg) on recognition memory, as well as their influence on brain metabolism and modulation of the expanded endocannabinoid system in APP/PS1 mice. Chronic therapy with cannabinoid receptor ligands resulted in reduced anxiety-like behavior and partially reversed the cognitive deficits. Additionally, a reduction was observed in both the number and size of Aβ plaque deposits, along with decreased cerebral glucose metabolism, as well as a decline in the expression of mTOR and CB2 receptors. Furthermore, the study revealed enlarged astrocytes and enhanced expression of M1 mAChR in mice subjected to cannabinoid treatment.

Our findings highlight the pivotal involvement of the extended endocannabinoid system in cognitive decline and pathological aspects associated with AD, presenting essential preclinical evidence to support the continued exploration and assessment of cannabinoid receptor ligands for AD treatment.”

https://www.mdpi.com/1424-8247/17/4/530

“In conclusion, our current findings suggest that pharmacological activation of the expanded ECS via the selective CB2 agonist JWH-133 or Cannabixir® Medium Flos—15.6% THC and <1% CBD ameliorates the Alzheimer-like phenotype in APP/PS1 mice by mitigating neuroinflammation and accumulation of Aβ plaque deposits, reducing cerebral glucose metabolism, and increasing glial reactivity. These results support the notion that targeting the ECS using cannabinoid receptor ligands, which lack psychoactive side effects, is a promising target for the development of novel therapeutic approaches against AD.”

https://pubmed.ncbi.nlm.nih.gov/38675490/

“Prevention of Alzheimer’s Disease Pathology by Cannabinoids. Our results indicate that cannabinoid receptors are important in the pathology of AD and that cannabinoids succeed in preventing the neurodegenerative process occurring in the disease.”

https://www.jneurosci.org/content/25/8/1904

Phytocannabinoids: Exploring Pharmacological Profiles and Their Impact on Therapeutical Use

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“Phytocannabinoids, a diverse group of naturally occurring compounds extracted from the Cannabis plant, have attracted interest due to their potential pharmacological effects and medicinal uses.

This comprehensive review presents the intricate pharmacological profiles of phytocannabinoids while exploring the diverse impacts these substances have on biological systems. From the more than one hundred cannabinoids which were identified in the Cannabis plant so far, cannabidiol (CBD) and tetrahydrocannabinol (THC) are two of the most extensively studied phytocannabinoids.

CBD is a non-psychoactive compound, which exhibits potential anti-inflammatory, neuroprotective, and anxiolytic properties, making it a promising candidate for a wide array of medical conditions.

THC, known for its psychoactive effects, possesses analgesic and antiemetic properties, contributing to its therapeutic potential.

In addition to THC and CBD, a wide range of additional phytocannabinoids have shown intriguing pharmacological effects, including cannabichromene (CBC), cannabigerol (CBG), and cannabinol (CBN).

The endocannabinoid system, made up of the enzymes involved in the production and breakdown of endocannabinoids, cannabinoid receptors (CB1 and CB2), and endogenous ligands (endocannabinoids), is essential for preserving homeostasis in several physiological processes. Beyond their effects on the endocannabinoid system, phytocannabinoids are studied for their ability to modify ion channels, neurotransmitter receptors, and anti-oxidative pathways.

The complex interaction between phytocannabinoids and biological systems offers hope for novel treatment approaches and lays the groundwork for further developments in the field of cannabinoid-based medicine. This review summarizes the state of the field, points out information gaps, and emphasizes the need for more studies to fully realize the therapeutic potential of phytocannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/38673788/

“Phytocannabinoids offer diverse therapeutic applications, ranging from pain management to neurological disorders and inflammatory diseases. Their antimicrobial and anti-inflammatory properties make them valuable candidates for combating antibiotic resistance and modulating inflammatory pathways. By leveraging the synergistic effects of combination therapies and targeting multiple disease pathways, phytocannabinoids hold immense potential to revolutionize the future of pharmacotherapy and improve human health outcomes. “

https://www.mdpi.com/1422-0067/25/8/4204

Effects of Cannabidiol, ∆9-Tetrahydrocannabinol, and WIN 55-212-22 on the Viability of Canine and Human Non-Hodgkin Lymphoma Cell Lines

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“In our previous study, we demonstrated the impact of overexpression of CB1 and CB2 cannabinoid receptors and the inhibitory effect of endocannabinoids (2-arachidonoylglycerol (2-AG) and Anandamide (AEA)) on canine (Canis lupus familiaris) and human (Homo sapiens) non-Hodgkin lymphoma (NHL) cell lines’ viability compared to cells treated with a vehicle.

The purpose of this study was to demonstrate the anti-cancer effects of the phytocannabinoids, cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC), and the synthetic cannabinoid WIN 55-212-22 (WIN) in canine and human lymphoma cell lines and to compare their inhibitory effect to that of endocannabinoids.

We used malignant canine B-cell lymphoma (BCL) (1771 and CLB-L1) and T-cell lymphoma (TCL) (CL-1) cell lines, and human BCL cell line (RAMOS). Our cell viability assay results demonstrated, compared to the controls, a biphasic effect (concentration range from 0.5 μM to 50 μM) with a significant reduction in cancer viability for both phytocannabinoids and the synthetic cannabinoid. However, the decrease in cell viability in the TCL CL-1 line was limited to CBD.

The results of the biochemical analysis using the 1771 BCL cell line revealed a significant increase in markers of oxidative stress, inflammation, and apoptosis, and a decrease in markers of mitochondrial function in cells treated with the exogenous cannabinoids compared to the control. Based on the IC50 values, CBD was the most potent phytocannabinoid in reducing lymphoma cell viability in 1771, Ramos, and CL-1. Previously, we demonstrated the endocannabinoid AEA to be more potent than 2-AG.

Our study suggests that future studies should use CBD and AEA for further cannabinoid testing as they might reduce tumor burden in malignant NHL of canines and humans.”

https://pubmed.ncbi.nlm.nih.gov/38672512/

“Our study demonstrated a significant moderate inhibitory effect of CBD, THC, and WIN on canine and human NHL cell viability. Our results also revealed that CBD, THC, and WIN decreased lymphoma cell viability because they increased oxidative stress, leading to downstream apoptosis.”

https://www.mdpi.com/2218-273X/14/4/495

Cannabis effectiveness on immunologic potency of pulmonary contagion

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“Respiratory illnesses and its repercussions are becoming more prevalent worldwide. It is necessary to research both innovative treatment and preventative techniques. Millions of confirmed cases and fatalities from the COVID-19 epidemic occurred over the previous two years.

According to the review research, cannabinoids are a class of medicines that should be considered for the treatment of respiratory conditions. Cannabinoids and inhibitors of endocannabinoid degradation have illustrated advantageous anti-inflammatory, asthma, pulmonary fibrosis, and pulmonary artery hypotension in numerous studies (in vitro and in vivo). It has been also noted that CB2 receptors on macrophages and T-helper cells may be particularly triggered to lower inflammation in COVID-19 patients.

Since the majority of lung tissue contains cannabinoid receptors, cannabis can be an effective medical tool for treating COVID-19 as well as pulmonary infections. Notably, CB2 and CB1 receptors play a major role in immune system modulation and anti-inflammatory activities.

In this review, we put forth the idea that cannabis might be helpful in treating pulmonary contagion brought on by viral integration, such as that caused by SARS-CoV-2, haemophilus influenza type b, Streptococcus pneumoniae, influenza virus, and respiratory syncytial virus.

Also, a detailed overview of CB receptors, intricate mechanisms, is highlighted connecting link with COVID-19 viral structural modifications along with molecular basis of CB receptors in diminishing viral load in pulmonary disorders supported through evident literature studies. Further, futuristic evaluations on cannabis potency through novel formulation development focusing on in vivo/in vitro systems can produce promising results.”

https://pubmed.ncbi.nlm.nih.gov/38635412/

https://www.degruyter.com/document/doi/10.1515/jbcpp-2023-0030/html

Potential Therapeutic Targets to Modulate the Endocannabinoid System in Alzheimer’s Disease

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“Alzheimer’s disease (AD), the most common neurodegenerative disease (NDD), is characterized by chronic neuronal cell death through progressive loss of cognitive function. Amyloid beta (Aβ) deposition, neuroinflammation, oxidative stress, and hyperphosphorylated tau proteins are considered the hallmarks of AD pathology. Different therapeutic approaches approved by the Food and Drug Administration can only target a single altered pathway instead of various mechanisms that are involved in AD pathology, resulting in limited symptomatic relief and almost no effect in slowing down the disease progression.

Growing evidence on modulating the components of the endocannabinoid system (ECS) proclaimed their neuroprotective effects by reducing neurochemical alterations and preventing cellular dysfunction. Recent studies on AD mouse models have reported that the inhibitors of the fatty acid amide hydrolase (FAAH) and monoacylglycerol (MAGL), hydrolytic enzymes for N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), respectively, might be promising candidates as therapeutical intervention.

The FAAH and MAGL inhibitors alone or in combination seem to produce neuroprotection by reversing cognitive deficits along with Aβ-induced neuroinflammation, oxidative responses, and neuronal death, delaying AD progression. Their exact signaling mechanisms need to be elucidated for understanding the brain intrinsic repair mechanism. The aim of this review was to shed light on physiology and pathophysiology of AD and to summarize the experimental data on neuroprotective roles of FAAH and MAGL inhibitors. In this review, we have also included CB1R and CB2R modulators with their diverse roles to modulate ECS mediated responses such as anti-nociceptive, anxiolytic, and anti-inflammatory actions in AD. Future research would provide the directions in understanding the molecular mechanisms and development of new therapeutic interventions for the treatment of AD.”

https://pubmed.ncbi.nlm.nih.gov/38612861/

https://www.mdpi.com/1422-0067/25/7/4050

Cannabidiol improves maternal obesity-induced behavioral, neuroinflammatory and neurochemical dysfunctions in the juvenile offspring

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“Maternal obesity is associated with an increased risk of psychiatric disorders such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While numerous studies focus on preventive measures targeting the mothers, only a limited number provide practical approaches for addressing the damages once they are already established.

We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on hypothalamic inflammation and metabolic disturbances, however, little is known about this relationship on behavioral manifestations and neurochemical imbalances in other brain regions. Therefore, here we tested whether CBD treatment could mitigate anxiety-like and social behavioral alterations, as well as neurochemical disruptions in both male and female offspring of obese dams.

Female Wistar rats were fed a cafeteria diet for 12 weeks prior to mating, and during gestation and lactation. Offspring received CBD (50 mg/kg) from weaning for 3 weeks. Behavioral tests assessed anxiety-like manifestations and social behavior, while neuroinflammatory and neurochemical markers were evaluated in the prefrontal cortex (PFC) and hippocampus.

CBD treatment attenuated maternal obesity-induced anxiety-like and social behavioral alterations, followed by rescuing effects on imbalanced neurotransmitter and endocannabinoid concentrations and altered expression of glial markers, CB1, oxytocin and dopamine receptors, with important differences between sexes.

Overall, the findings of this study provide insight into the signaling pathways for the therapeutic benefits of CBD on neuroinflammation and neurochemical imbalances caused by perinatal maternal obesity in the PFC and the hippocampus, which translates into the behavioral manifestations, highlighting the sexual dimorphism encompassing both the transgenerational effect of obesity and the endocannabinoid system.”

https://pubmed.ncbi.nlm.nih.gov/38608740/

https://www.sciencedirect.com/science/article/abs/pii/S0889159124003556?via%3Dihub

Cannabidiol exerts multitarget immunomodulatory effects on PBMCs from individuals with psoriasis vulgaris

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“Introduction: The involvement of endocannabinoid system (ECS) in the inflammatory cascade, and the ability of phytocannabinoids, endocannabinoids and their synthetic analogues to modulate it has become an interesting research area for new therapeutic approaches in inflammatory skin diseases. Cannabidiol (CBD) appears to be the most promising among phytocannabinoids, due to the lack of psychotropic effects and low toxicity profile. Its anti-inflammatory action has been highlighted in different preclinical models, ranging from experimental colitis to arthritis and neuroinflammation. Our aim was to evaluate CBD immune-modulatory effects in peripheral blood mononuclear cells (PBMC) of psoriasis individuals with particular attention to both innate and adaptative immune arms.

Methods: We performed in vitro immune functional experiments to analyze CBD action on various immune cells active in psoriatic lesions.

Results: The results showed that CBD produced a shift from Th1 to Th2 response, while boosting cytotoxic activity of Natural Killer (NK) cells. Furthermore, it also exerted a potent action on monocyte differentiation as, after CBD treatment, monocytes from psoriatic individuals were unable to migrate in response to inflammatory stimuli and to fully differentiate into mature dendritic cells. Finally, a M2 skewing of monocyte-derived macrophages by CBD also contributed to the fine tuning of the magnitude of immune responses.

Conclusions: These data uncover new potential immunomodulatory properties of this cannabinoid suggesting a possible therapeutic action in the treatment of multiple inflammatory skin diseases.”

https://pubmed.ncbi.nlm.nih.gov/38601151/

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1373435/full

Nutrition, endocannabinoids, and the use of cannabis: An overview for the nutrition clinician

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“The endocannabinoid system (ECs) is composed of multiple signaling compounds and receptors within the central and peripheral nervous system along with various organs, including the gut, liver, and skeletal muscle.

The ECs has been implicated in metabolism, gut motility, and eating behaviors. The ECs is altered in disease states such as obesity. Recent studies have clarified the role of the gut microbiome and nutrition on the ECs. Exogenous cannabinoid (CB) use, either organic or synthetic, stimulates the ECs through CB1 and CB2 receptors. However, the role of CBs is unclear in regard to nutrition optimization or to treat disease states.

This review briefly summarizes the effect of the ECs and exogenous CBs on metabolism and nutrition. With the increased legalization of cannabis, there is a corresponding increased use in the United States. Therefore, nutrition clinicians need to be aware of both the benefits and harm of cannabis use on overall nutrition status, as well as the gaps in knowledge for future research and guideline development.”

https://pubmed.ncbi.nlm.nih.gov/38555505/

https://aspenjournals.onlinelibrary.wiley.com/doi/10.1002/ncp.11148

Cannabinoids for the treatment of autoimmune and inflammatory skin diseases: A systematic review

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“In recent years, the medical use of cannabinoids has attracted growing attention worldwide. In particular, anti-inflammatory properties of cannabinoids led to their emergence as potential therapeutic options for autoimmune and inflammatory disorders.

Recent studies have also shown that cannabinoid receptors are widely expressed and have endogenous ligands in the skin, suggesting that the skin has its own endocannabinoid system. The aim of this review is to discuss the potential therapeutic effects of cannabinoids in autoimmune and inflammatory skin diseases.

Following an overview of cannabinoids and the endocannabinoid system, we describe the cellular and molecular mechanisms of cannabinoids in skin health and disease. We then review the clinical studies of cannabinoids in autoimmune and inflammatory skin diseases including systemic sclerosis (SSc), dermatomyositis (DM), psoriasis (Pso) and atopic dermatitis (AD). A primary literature search was conducted in July 2023, using PubMed and Web of Science. A total of 15 articles were included after excluding reviews, non-human studies and in vitro studies from 389 non-duplicated articles.

Available evidence suggests that cannabinoids may be beneficial for SSc, DM, Pso and AD. However, further studies, ideally randomized controlled trials, are needed to further evaluate the use of cannabinoids in autoimmune and inflammatory skin diseases.”

https://pubmed.ncbi.nlm.nih.gov/38532572/

“The available data support the safety and efficacy of cannabinoids in SSc, DM, Pso and AD, as well as highlight the need for further studies to confirm their therapeutic use. In conclusion, available evidence suggests that cannabinoids have the potential therapeutic benefit with good tolerability in SSc, DM, Pso and AD. “

https://onlinelibrary.wiley.com/doi/10.1111/exd.15064