Category Archives: Endocannabinoid System

Classical cannabinoid receptors as target in cancer-induced bone pain: a systematic review, meta-analysis and bioinformatics validation

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“To test the hypothesis that genetic and pharmacological modulation of the classical cannabinoid type 1 (CB1) and 2 (CB2) receptors attenuate cancer-induced bone pain, we searched Medline, Web of Science and Scopus for relevant skeletal and non-skeletal cancer studies from inception to July 28, 2022. We identified 29 animal and 35 human studies. In mice, a meta-analysis of pooled studies showed that treatment of osteolysis-bearing males with the endocannabinoids AEA and 2-AG (mean difference [MD] – 24.83, 95% confidence interval [95%CI] – 34.89, – 14.76, p < 0.00001) or the synthetic cannabinoid (CB) agonists ACPA, WIN55,212-2, CP55,940 (CB1/2-non-selective) and AM1241 (CB2-selective) (MD – 28.73, 95%CI – 45.43, – 12.02, p = 0.0008) are associated with significant reduction in paw withdrawal frequency. Consistently, the synthetic agonists AM1241 and JWH015 (CB2-selective) increased paw withdrawal threshold (MD 0.89, 95%CI 0.79, 0.99, p < 0.00001), and ACEA (CB1-selective), AM1241 and JWH015 (CB2-selective) reduced spontaneous flinches (MD – 4.85, 95%CI – 6.74, – 2.96, p < 0. 00001) in osteolysis-bearing male mice. In rats, significant increase in paw withdrawal threshold is associated with the administration of ACEA and WIN55,212-2 (CB1/2-non-selective), JWH015 and AM1241 (CB2-selective) in osteolysis-bearing females (MD 8.18, 95%CI 6.14, 10.21, p < 0.00001), and treatment with AM1241 (CB2-selective) increased paw withdrawal thermal latency in males (mean difference [MD]: 3.94, 95%CI 2.13, 5.75, p < 0.0001), confirming the analgesic capabilities of CB1/2 ligands in rodents.

In human, treatment of cancer patients with medical cannabis (standardized MD – 0.19, 95%CI – 0.35, – 0.02, p = 0.03) and the plant-derived delta-9-THC (20 mg) (MD 3.29, CI 2.24, 4.33, p < 0.00001) or its synthetic derivative NIB (4 mg) (MD 2.55, 95%CI 1.58, 3.51, p < 0.00001) are associated with reduction in pain intensity.

Bioinformatics validation of KEGG, GO and MPO pathway, function and process enrichment analysis of mouse, rat and human data revealed that CB1 and CB2 receptors are enriched in a cocktail of nociceptive and sensory perception, inflammatory, immune-modulatory, and cancer pathways. Thus, we cautiously conclude that pharmacological modulators of CB1/2 receptors show promise in the treatment of cancer-induced bone pain, however further assessment of their effects on bone pain in genetically engineered animal models and cancer patients is warranted.”

https://pubmed.ncbi.nlm.nih.gov/38461339/

Cannabinoids in the treatment of glioblastoma

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“Glioblastoma (GBM) is the most prevalent primary malignant tumor of the nervous system. While the treatment of other neoplasms is increasingly more efficacious the median survival rate of GBM patients remains low and equals about 14 months. Due to this fact, there are intensive efforts to find drugs that would help combat GBM.

Nowadays cannabinoids are becoming more and more important in the field of cancer and not only because of their properties of antiemetic drugs during chemotherapy. These compounds may have a direct cytotoxic effect on cancer cells.

Studies indicate GBM has disturbances in the endocannabinoid system-changes in cannabinoid metabolism as well as in the cannabinoid receptor expression. The GBM cells show expression of cannabinoid receptors 1 and 2 (CB1R and CB2R), which mediate various actions of cannabinoids. Through these receptors, cannabinoids inhibit the proliferation and invasion of GBM cells, along with changing their morphology.

Cannabinoids also induce an intrinsic pathway of apoptosis in the tumor. Hence the use of cannabinoids in the treatment of GBM may be beneficial to the patients. So far, studies focusing on using cannabinoids in GBM therapy are mainly preclinical and involve cell lines and mice.

The results are promising and show cannabinoids inhibit GBM growth. Several clinical studies are also being carried out.

The preliminary results show good tolerance of cannabinoids and prolonged survival after administration of these drugs.

In this review, we describe the impact of cannabinoids on GBM and glioma cells in vitro and in animal studies. We also provide overview of clinical trials on using cannabinoids in the treatment of GBM.”

https://pubmed.ncbi.nlm.nih.gov/38457018/

https://link.springer.com/article/10.1007/s43440-024-00580-x

Targeting the endocannabinoid system for the management of low back pain

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“Low back pain (LBP) is a major unmet clinical need. The endocannabinoid system (ECS) has emerged as a promising therapeutic target for pain, including LBP. This review examines the evidence for the ECS as a therapeutic target for LBP. While preclinical studies demonstrate the potential of the ECS as a viable therapeutic target, clinical trials have presented conflicting findings. This review underscores the need for innovative LBP treatments and biomarkers and proposes the ECS as a promising avenue for their exploration. A deeper mechanistic understanding of the ECS in LBP could inform the development of new pain management strategies.”

https://pubmed.ncbi.nlm.nih.gov/38401317/

https://www.sciencedirect.com/science/article/pii/S1471489224000080?via%3Dihub

Targeting the Endocannabinoid System Present in the Glioblastoma Tumour Microenvironment as a Potential Anti-Cancer Strategy

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“The highly aggressive and invasive glioblastoma (GBM) tumour is the most malignant lesion among adult-type diffuse gliomas, representing the most common primary brain tumour in the neuro-oncology practice of adults. With a poor overall prognosis and strong resistance to treatment, this nervous system tumour requires new innovative treatment. GBM is a polymorphic tumour consisting of an array of stromal cells and various malignant cells contributing to tumour initiation, progression, and treatment response.

Cannabinoids possess anti-cancer potencies against glioma cell lines and in animal models.

To improve existing treatment, cannabinoids as functionalised ligands on nanocarriers were investigated as potential anti-cancer agents. The GBM tumour microenvironment is a multifaceted system consisting of resident or recruited immune cells, extracellular matrix components, tissue-resident cells, and soluble factors. The immune microenvironment accounts for a substantial volume of GBM tumours. The barriers to the treatment of glioblastoma with cannabinoids, such as crossing the blood-brain barrier and psychoactive and off-target side effects, can be alleviated with the use of nanocarrier drug delivery systems and functionalised ligands for improved specificity and targeting of pharmacological receptors and anti-cancer signalling pathways.

This review has shown the presence of endocannabinoid receptors in the tumour microenvironment, which can be used as a potential unique target for specific drug delivery. Existing cannabinoid agents, studied previously, show anti-cancer potencies via signalling pathways associated with the hallmarks of cancer. The results of the review can be used to provide guidance in the design of future drug therapy for glioblastoma tumours.”

https://www.mdpi.com/1422-0067/25/3/1371

“Cannabinoids may offer a more effective and tolerable treatment option for GBM patients.”

https://pubmed.ncbi.nlm.nih.gov/38338649/

Unravelling the landscape of Cannabis craving pharmacological treatments: a PRISMA-guided review of evidence

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“Currently, few treatments are available for craving in general, and none of them have received approval for cannabis craving.

The objective of this review is to evaluate existing studies analysing treatments for cannabis craving and explore novel treatment possibilities for these patients.

The current pharmacological treatments largely involve off-label drug use and the utilisation of cannabinoid-based medications, such as combinations of THC and lofexidine, oxytocin, progesterone, and N-acetylcysteine.

These emerging treatments show promise and have the potential to revolutionise current clinical practices, but further investigation is needed to establish their efficacy.”

https://pubmed.ncbi.nlm.nih.gov/38299652/

https://www.tandfonline.com/doi/full/10.1080/09540261.2023.2231540

Suppression of neuropathic pain in the circadian clock-deficient Per2m/m mice involves up-regulation of endocannabinoid system

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“Neuropathic pain often results from injuries and diseases that affect the somatosensory system. Disruption of the circadian clock has been implicated in the exacerbation of the neuropathic pain state. However, in this study, we report that mice deficient in a core clock component Period2 (Per2m/m mice) fail to develop tactile pain hypersensitivity even following peripheral nerve injury. Similar to male wild-type mice, partial sciatic nerve ligation (PSL)-Per2m/m male mice showed activation of glial cells in the dorsal horn of the spinal cord and increased expression of pain-related genes. Interestingly, α1D-adrenergic receptor (α1D-AR) expression was up-regulated in the spinal cord of Per2m/m mice, leading to increased production of 2-arachidonoylglycerol (2-AG), an endocannabinoid receptor ligand. This increase in 2-AG suppressed the PSL-induced tactile pain hypersensitivity. Furthermore, intraspinal dorsal horn injection of adeno-associated viral vectors expressing α1D-AR also attenuated pain hypersensitivity in PSL-wild-type male mice by increasing 2-AG production.

Our findings reveal an uncovered role of the circadian clock in neuropathic pain disorders and suggest a link between α1D-AR signaling and the endocannabinoid system.”

https://pubmed.ncbi.nlm.nih.gov/38239754/

https://academic.oup.com/pnasnexus/article/3/1/pgad482/7564865?login=false

How depression and antidepressant drugs affect endocannabinoid system?-review of clinical and preclinical studies

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“As major depressive disorder is becoming a more and more common issue in modern society, it is crucial to discover new possible grip points for its diagnosis and antidepressive therapy.

One of them is endocannabinoid system, which has been proposed as a manager of emotional homeostasis, and thus, endocannabinoid alterations have been found in animals undergoing various preclinical models of depression procedures as well as in humans suffering from depressive-like disorders.

In this review article, studies regarding those alterations have been summed up and analyzed. Another important issue raised by the researchers is the impact of currently used antidepressive drugs on endocannabinoid system so that it would be possible to predict reversibility of endocannabinoid alterations following stress exposure and, in the future, to be able to design individually personalized therapies.

Preclinical studies investigating this topic have been analyzed and described in this article. Unfortunately, too few clinical studies in this field exist, what indicates an urgent need for collecting such data, so that it would be possible to compare them with preclinical outcomes and draw reliable conclusions.”

https://pubmed.ncbi.nlm.nih.gov/38280009/

https://link.springer.com/article/10.1007/s00210-023-02938-z

Cannabidiol and its Potential Evidence-Based Psychiatric Benefits – A Critical Review

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“The endocannabinoid system shows promise as a novel target for treating psychiatric conditions.

Cannabidiol (CBD), a naturally occurring cannabinoid, has been investigated in several psychiatric conditions, with diverse effects and an excellent safety profile compared to standard treatments. Even though the body of evidence from randomised clinical trials is growing, it remains relatively limited in most indications.

This review comprises a comprehensive literature search to identify clinical studies on the effects of CBD in psychiatric conditions. The literature search included case studies, case reports, observational studies, and RCTs published in English before July 27, 2023, excluding studies involving nabiximols or cannabis extracts containing CBD and ∆9-tetrahydrocannabinol. Completed studies were considered, and all authors independently assessed relevant publications.Of the 150 articles identified, 54 publications were included, covering the effects of CBD on healthy subjects and various psychiatric conditions, such as schizophrenia, substance use disorders (SUDs), anxiety, post-traumatic stress disorder (PTSD), and autism spectrum disorders. No clinical studies have been published for other potential indications, such as alcohol use disorder, borderline personality disorder, depression, dementia, and attention-deficit/hyperactivity disorder.

This critical review highlights that CBD can potentially ameliorate certain psychiatric conditions, including schizophrenia, SUDs, and PTSD. However, more controlled studies and clinical trials, particularly investigating the mid- to long-term use of CBD, are required to conclusively establish its efficacy and safety in treating these conditions. The complex effects of CBD on neural activity patterns, likely by impacting the endocannabinoid system, warrant further research to reveal its therapeutic potential in psychiatry.”

https://pubmed.ncbi.nlm.nih.gov/38267003/

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-2228-6118

Research progress on the cannabinoid type-2 receptor and Parkinson’s disease

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“Parkinson’s disease (PD) is featured by movement impairments, including tremors, bradykinesia, muscle stiffness, and imbalance. PD is also associated with many non-motor symptoms, such as cognitive impairments, dementia, and mental disorders. Previous studies identify the associations between PD progression and factors such as α-synuclein aggregation, mitochondrial dysfunction, inflammation, and cell death.

The cannabinoid type-2 receptor (CB2 receptor) is a transmembrane G-protein-coupled receptor and has been extensively studied as part of the endocannabinoid system. CB2 receptor is recently emerged as a promising target for anti-inflammatory treatment for neurodegenerative diseases.

It is reported to modulate mitochondrial function, oxidative stress, iron transport, and neuroinflammation that contribute to neuronal cell death. Additionally, CB2 receptor possesses the potential to provide feedback on electrophysiological processes, offering new possibilities for PD treatment. This review summarized the mechanisms underlying PD pathogenesis. We also discussed the potential regulatory role played by CB2 receptor in PD.”

https://pubmed.ncbi.nlm.nih.gov/38264546/

“Cannabinoids, as an emerging therapeutic agent, have attracted wide attention for their great potential in the treatment of various diseases.”

https://www.frontiersin.org/articles/10.3389/fnagi.2023.1298166/full

[Research progress on anti-inflammatory effects of plant-derived cannabinoid type 2 receptor modulators]

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“Excessive and persistent inflammatory responses are a potential pathological condition that can lead to diseases of various systems, including nervous, respiratory, digestive, circulatory, and endocrine systems.

Cannabinoid type 2 receptor(CB2R) belongs to the G protein-coupled receptor family and is widely distributed in immune cells, peripheral tissues, and the central nervous system. It plays a role in inflammatory responses under various pathological conditions. The down-regulation of CB2R activity is an important marker of inflammation and and CB2R modulators have been shown to have anti-inflammatory effects.

This study explored the relationship between CB2R and inflammatory responses, delved into its regulatory mechanisms in inflammatory diseases, and summarized the research progress on CB2R modulators from plants other than cannabis, including plant extracts and monomeric compounds, in exerting anti-inflammatory effects. The aim is to provide new insights into the prevention and treatment of inflammatory diseases.”

https://pubmed.ncbi.nlm.nih.gov/38211986/