Category Archives: Endocannabinoid System

Decoding the Therapeutic Potential of Cannabis and Cannabinoids in Neurological Disorders

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“For millennia, Cannabis sativa has served diverse roles, from medicinal applications to recreational use. Despite its extensive historical use, only a fraction of its components have been explored until recent times.

The therapeutic potential of Cannabis and its constituents has garnered attention, with suggestions for treating various conditions such as Parkinson’s disease, epilepsy, Alzheimer’s disease, and other Neurological disorders.

Recent research, particularly on animal experimental models, has unveiled the neuroprotective properties of cannabis. This neuroprotective effect is orchestrated through numerous G protein-coupled receptors (GPCRs) and the two cannabinoid receptors, CB1 and CB2.

While the capacity of cannabinoids to safeguard neurons is evident, a significant challenge lies in determining the optimal cannabinoid receptor agonist and its application in clinical trials. The intricate interplay of cannabinoids with the endocannabinoid system, involving CB1 and CB2 receptors, underscores the need for precise understanding and targeted approaches. Unravelling the molecular intricacies of this interaction is vital to harness the therapeutic potential of cannabinoids effectively.

As the exploration of cannabis components accelerates, there is a growing awareness of the need for nuanced strategies in utilizing cannabinoid receptor agonists in clinical settings. The evolving landscape of cannabis research presents exciting possibilities for developing targeted interventions that capitalize on the neuroprotective benefits of cannabinoids while navigating the complexities of receptor specificity and clinical applicability.”

https://pubmed.ncbi.nlm.nih.gov/39410886/

https://www.eurekaselect.com/article/143747

An overview of major depression disorder: The endocannabinoid system as a potential target for therapy

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“Major depressive disorder is the psychiatric disease with the highest global prevalence, impacting social functioning and decreasing the quality of life. The partial pathophysiological knowledge of the disease, the economic burden and the low remission rates are sufficient justification to carry out an update on the subject in the search for new therapeutic approaches and targets.

The endocannabinoid system has been linked to the development of depression, and its stimulation or antagonism is a promising approach in the treatment of major depressive disorder.

Cannabidiol (CBD) and its properties have been widely studied recently; its analgesic, anti-inflammatory, antineoplastic and neuroprotective roles have even been reported in animal models and clinical trials, achieving its approved use for certain neurodegenerative pathologies. The use of CBD in depression biomodels and clinical trials has not been the exception, and here we contrast the current evidence of its administration and pharmacology against the pathological mechanisms of major depressive disorder.”

https://pubmed.ncbi.nlm.nih.gov/39370369/

“This focused review discusses the prevalence of major depressive disorder (MDD) globally, its impact on social functioning and quality of life, and the need for new therapeutic approaches. It highlights the role of the endocannabinoid system in MDD and the potential of cannabidiol (CBD) in treating depression due to its various beneficial properties. CBD’s effectiveness is supported by research in animal models and clinical trials, offering promise as a treatment for MDD by targeting its pathological mechanisms.”

https://onlinelibrary.wiley.com/doi/10.1111/bcpt.14089

“Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866040/

The Potential Role of Cannabidiol in Cosmetic Dermatology: A Literature Review

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“Cannabidiol (CBD) is a non-psychotropic cannabinoid with multiple pharmacological properties. Cannabidiol has attracted growing attention in the cosmetic industry, with an increasing number of CBD-containing skincare products on the market in recent years.

The aim of this review is to evaluate the current evidence on the use of CBD for cosmetic purposes. Following an overview of CBD and the endocannabinoid system in the skin, we summarize pre-clinical and clinical studies that address the potential of CBD in cosmetic dermatology.

Available in vitro and in vivo evidence suggests that CBD has anti-oxidant, anti-inflammatory, moisturizing, anti-acne, wound-healing, and anti-aging properties. However, only a few clinical studies have been conducted on the use of CBD in the skin. In addition, there is a critical need to develop an efficient drug-delivery system for topical/transdermal application of CBD. Further research, including clinical and pharmacokinetic studies, are needed to fully evaluate the role of CBD in cosmetic dermatology.”

https://pubmed.ncbi.nlm.nih.gov/39369127/

“Available evidence suggests that CBD has multiple beneficial properties in cosmetic dermatology, including anti-oxidant, anti-inflammatory, and anti-aging effects. Indeed, the skin is an ideal delivery route for CBD, enabling high local concentrations while minimizing systemic side effects. Given its highly lipophilic nature, delivering CBD through the stratum corneum into deeper skin layers requires specialized delivery systems, which are still under research and development.”

https://link.springer.com/article/10.1007/s40257-024-00891-y

Identification of the TRPA1 Cannabinoid-Binding Site

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“Chronic pain accounts for nearly two-thirds of conditions eligible for medical cannabis licenses, yet the mechanisms underlying cannabis-induced analgesia remain poorly understood.

The principal phytocannabinoids, the psychoactive Δ9-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD), exhibit comparable efficacy in pain management. Notably, THC functions as an agonist of cannabinoid receptor 1 (CB1), whereas CBD shows minimal activity on CB1 and CB2 receptors.

Elucidating the molecular targets through which phytocannabinoids modulate the pain system is required for advancing our understanding of the pain pathway and optimizing medical cannabis therapies.

Transient receptor potential ankyrin 1 (TRPA1), a pivotal chemosensor in the pain pathway, has been identified as a phytocannabinoid target. Unlike most TRPA1 activators, phytocannabinoid activation is not mediated through the electrophilic binding site, suggesting an alternative mechanism. Here, we identified the human TRPA1 channel cannabinoid-binding site (CBS) and demonstrated that mutations at residue Y840 abolished responses to both THC and CBD at saturating concentrations, indicating a shared primary binding site. Molecular modeling revealed distinct interactions of THC and CBD with the Y840 residue within the CBS. Additionally, CBD binds to the adjacent general anesthetic binding site at oversaturating concentrations.

Our findings define the CBS of TRPA1 as overlapping with and adjacent to binding sites for other allosteric activators, suggesting that TRPA1 possesses a highly adaptable domain for binding non-electrophilic activators. This underscores its unique role as a chemosensor in the pain pathway. Furthermore, our results provide new insights into the molecular mechanisms of cannabinoid-induced analgesia and identify novel targets for pain management therapies.”

https://pubmed.ncbi.nlm.nih.gov/39368566/

https://www.sciencedirect.com/science/article/pii/S104366182400389X?via%3Dihub

Maternal obesity induces sex-specific changes in the endocannabinoid system of the hypothalamus and dorsal hippocampus of offspring associated with anxiety-like behavior in adolescent female rats

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“Maternal obesity during perinatal period increases the risk of metabolic and behavioral deleterious outcomes in the offspring, since it is critical for brain development, maturation, and reorganization. These processes are highly modulated by the endocannabinoid system (ECS), which comprises the main lipid ligands anandamide and 2-arachidonoylglycerol, cannabinoid receptors 1 and 2 (CB1R and CB2R), and several metabolizing enzymes.

The ECS is overactivated in obesity and it contributes to the physiological activity of the hypothalamus-pituitary-adrenal (HPA) axis, promoting stress relief. We have previously demonstrated that maternal high-fat diet during gestation and lactation programmed the food preference for fat in adolescent male offspring and adult male and female offspring.

In the present study, we hypothesized that maternal diet-induced obesity would induce sex-specific changes of the ECS in the hypothalamus and dorsal hippocampus of rat offspring associated with dysregulation of the HPA axis and stress-related behavior in adolescence. Rat dams were fed a control (C) or an obesogenic high-fat high-sugar diet (OD) for nine weeks prior to mating and throughout gestation and lactation. Maternal obesity differentially altered the CB1R in the hypothalamus of neonate offspring, with significant increase in male but not in female pups, associated with decreased CB2R prior to obesity development. In adolescence, maternal obesity induced anxiety-like behavior only in adolescent females which was associated with increased content of CB1R in the dorsal hippocampus.

Our findings suggest that the early origins of anxiety disorders induced by maternal exposome is associated with dysregulation of the brain ECS, with females being more susceptible.”

https://pubmed.ncbi.nlm.nih.gov/39362071/

“The prevalence of obesity has reached pandemic proportions worldwide, and it is important to better understand the impact of maternal obesity on offspring metabolic health and susceptibility to neurodevelopmental and neuropsychiatric disorders such as anxiety and depression. In the present study, we used a rat model of maternal diet-induced obesity to explore these interactions. The main findings of this study were that maternal obesogenic diet elicited sex-specific molecular changes on the ECS.”

https://www.sciencedirect.com/science/article/abs/pii/S0018506X24001739?via%3Dihub

Cannabis sativa L. Extract Alleviates Neuropathic Pain and Modulates CB1 and CB2 Receptor Expression in Rat

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“Introduction: Cannabis sativa L. (CSL) extract has pain-relieving potential due to its cannabinoid content, so the effects of two CSL extracts on alleviating neuropathic pain were investigated in vivo. Methods and groups: Male Wistar rats (n = 130) were divided into groups and received vincristine (0.1 mg/kg) and gabapentin (60 mg/kg) to induce and relieve neuropathic pain or CSL extracts (D and B). The mRNA and protein expression of the cannabinoid receptors type 1 and 2 (CB1R, CB2R) were evaluated in the cerebral cortex, hippocampus, and lymphocytes. Behavioural tests (Tail-Flick and von Frey) were performed on all animals.

Results: VK-induced neuropathic pain was accompanied by decreased CB1R protein level and CB2R mRNA expression in the cortex. Gabapentin relieved pain and increased CB1R protein levels in the hippocampus compared to the vincristine group. Hippocampus CB1R protein expression increased with the administration of extract D (10 mg/kg, 40 mg/kg) and extract B (7.5 mg/kg, 10 mg/kg) compared to VK group. In the cerebral cortex CSL decreased CB1R protein expression (10 mg/kg, 20 mg/kg, 40 mg/kg of extract B) and mRNA level (5 mg/kg, 7.5 mg/kg of extract B; 20 mg/kg of extract D) compared to the VK-group.CB2R protein expression increased in the hippocampus after treatment with extract B (7.5 mg/kg) compared to the VK-group. In the cerebral cortex extract B (10 mg/kg, 20 mg/kg) increased CB2R protein expression compared to VK-group.

Conclusion: Alterations in cannabinoid receptor expression do not fully account for the observed behavioural changes in rats. Therefore, additional signalling pathways may contribute to the initiation and transmission of neuropathic pain. The Cannabis extracts tested demonstrated antinociceptive effects comparable to gabapentin, highlighting the antinociceptive properties of Cannabis extracts for human use.”

https://pubmed.ncbi.nlm.nih.gov/39334832/

“Furthermore, both tested Cannabis sativa L. extracts demonstrated antinociceptive effects comparable to gabapentin, highlighting the potential medical value of Cannabis extracts for human use.”

https://www.mdpi.com/2218-273X/14/9/1065

The endocannabinoid system as a therapeutic target in neuropathic pain: a review

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“Introduction: This review highlights the critical role of the endocannabinoid system (ECS) in regulating neuropathic pain and explores the therapeutic potential of cannabinoids. Understanding the mechanisms of the ECS, including its receptors, endogenous ligands, and enzymatic routes, can lead to innovative treatments for chronic pain, offering more effective therapies for neuropathic conditions. This review bridges the gap between preclinical studies and clinical applications by emphasizing ECS modulation for better pain management outcomes.

Areas covered: A review mapped the existing literature on neuropathic pain and the effects of modulating the ECS using natural and synthetic cannabinoids. This analysis examined ECS components and their alterations in neuropathic pain, highlighting the peripheral, spinal, and supraspinal mechanisms. This review aimed to provide a thorough understanding of the therapeutic potential of cannabinoids in the management of neuropathic pain.

Expert opinion: Advances in cannabinoid research have shown significant potential for the management of chronic neuropathic pain. The study emphasizes the need for high-quality clinical trials and collaborative efforts among researchers, clinicians, and regulatory bodies to ensure safe and effective integration of cannabinoids into pain management protocols. Understanding the mechanisms and optimizing cannabinoid formulations and delivery methods are crucial for enhancing therapeutic outcomes.”

https://pubmed.ncbi.nlm.nih.gov/39317147/

“Research on the modulation of the endocannabinoid system in nervous tissue related to neuropathic pain reveals complex mechanisms of pain modulation. Dysregulation of the endocannabinoid system, microglial activation, and interactions between various signaling pathways contribute to the onset and persistence of neuropathic pain. Understanding these molecular and cellular processes is crucial for developing targeted therapies that leverage the endocannabinoid system to alleviate neuropathic pain.”

https://www.tandfonline.com/doi/full/10.1080/14728222.2024.2407824

“Smoked Cannabis Proven Effective In Treating Neuropathic Pain”

https://www.sciencedaily.com/releases/2007/10/071024141745.htm

Unleashing the therapeutic role of cannabidiol in dentistry

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“Cannabidiol (CBD) found in Cannabis sativa is a non-psychoactive compound which is capable of binding to CB1 and CB2 receptors. CBD has recently gained interest in dentistry although it has not been explored sufficiently yet.

The therapeutic effects of CBD include anti-inflammatory, analgesic, antioxidant, biological and osteoinductive properties. The aim of this review is to highlight these effects with respect to various oral conditions and shed light on the current limitations and prospects for the use of CBD in maintaining oral health.”

https://pubmed.ncbi.nlm.nih.gov/39296277/

“CBD are potent non-psychoactive drug which when used in appropriate proportions under proper guidelines hold the potential to drastically change the current state of dental sciences. However, future researches are imperative focusing on the nature, mechanism, formulations as well as modes of administration to understand this drug thoroughly. Nonetheless, due to its properties such as anti-inflammation, antioxidation, biological nature, analgesia as well as osteoinduction; it is a drug with promising future in dentistry.”

https://www.sciencedirect.com/science/article/pii/S2212426824001258?via%3Dihub

The endocannabinoid system in appetite regulation and treatment of obesity

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“The endocannabinoid system (ECS) is a complex cell-signaling system that is responsible for maintaining homeostasis by modulating various regulatory reactions in response to internal and environmental changes. The influence of ECS on appetite regulation has been a subject of much recent research, however, the full extent of its impact remains unknown.

Current evidence links human obesity to ECS activation, increased endocannabinoid levels in both central and peripheral tissues, along with cannabinoid receptor type 1 (CBR1) up-regulation. These findings imply the potential pharmacological use of the ECS in the treatment of obesity.

Here, we present various pathophysiological processes in obesity involving the ECS, highlighting different pharmacological options for modulating endocannabinoid activity to treat obesity. However, the potential of those pharmacological possibilities remains under investigation and requires further research.”

https://pubmed.ncbi.nlm.nih.gov/39292202/

Disease-Modifying Symptomatic Treatment (DMST) Potential of Cannabinoids in Patients with Multiple Sclerosis

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“With the recent introduction of a number of highly effective disease-modifying treatments (DMTs) and the resulting almost complete prevention of acute relapses in many patients with multiple sclerosis (MS), the interest of MS clinicians has gradually shifted from relapse prevention to counteraction of disease progression and the treatment of residual symptoms.

Targeting the cannabinoid system with nabiximols is an approved and effective strategy for the treatment of spasticity secondary to MS.

Recently, the concept of spasticity plus syndrome (SPS) was introduced to account for the evidence that spasticity often appears in MS patients in clusters with other symptoms (such as pain, bladder dysfunction, sleep, and mood disorders), where cannabinoids can also be effective due to their broader action on many immune and neuronal functions. Interestingly, outside these symptomatic benefits, extensive pre-clinical and clinical research indicated how the modulation of the cannabinoid system results in significant anti-inflammatory and neuroprotective effects, all potentially relevant for MS disease control.

This evidence makes nabiximols a potential disease modifying symptomatic treatment (DMST), a concept introduced in an attempt to overcome the often artificial distinction between DMTs and symptomatic therapies (STs).”

https://pubmed.ncbi.nlm.nih.gov/39279696/

https://www.eurekaselect.com/article/143047