“Endogenous and exogenous cannabinoids modulate many physiological and pathological processes by binding classical cannabinoid receptors 1 (CB1) or 2 (CB2) or non-cannabinoid receptors.
Cannabinoids are known to exert antiproliferative, apoptotic, anti-migratory and anti-invasive effect on cancer cells by inducing or inhibiting various signaling cascades.
In this chapter, we specifically emphasize the latest research works about the alterations in endocannabinoid system (ECS) components in malignancies and cancer cell proliferation, migration, invasion, angiogenesis, autophagy, and death by cannabinoid administration, emphasizing their mechanism of action, and give a future perspective for clinical use.”
“Despite the significant advances in neurology, the cure for neurodegenerative conditions remains a formidable task to date. Among various factors arising from the complex etiology of neurodegenerative diseases, neuroinflammation and oxidative stress play a major role in pathogenesis. To this end, some phytocannabinoids isolated from Cannabis sativa (widely known as marijuana) have attracted significant attention as potential neurotherapeutics. The profound effect of ∆9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, has led to the discovery of the endocannabinoid system as a molecular target in the central nervous system (CNS). Cannabidiol (CBD), the major non-psychoactive component of cannabis, has recently emerged as a potential prototype for neuroprotective drug development due to its antioxidant and anti-inflammatory properties and its well-tolerated pharmacological behavior. This review briefly discusses the role of inflammation and oxidative stress in neurodegeneration and demonstrates the neuroprotective effect of cannabidiol, highlighting its general mechanism of action and disease-specific pathways in Parkinson’s disease (PD) and Alzheimer’s disease (AD). Furthermore, we have summarized the preclinical and clinical findings on the therapeutic promise of CBD in PD and AD, shed light on the importance of determining its therapeutic window, and provide insights into identifying promising new research directions.”
“Autism spectrum disorder (ASD) is a neurodevelopmental disorder, onset in early childhood and associated with cognitive, social, behavioral, and sensory impairments. The pathophysiology is still unclear, and it is believed that genetic and environmental factors are fully capable of influencing ASD, especially cell signaling and microglial functions. Furthermore, the endocannabinoid system (ECS) participates in the modulation of various brain processes and is also involved in the pathophysiological mechanisms of this condition. Due to the health and quality of life impacts of autism for the patient and his/her family and the lack of effective medications, the literature has elucidated the possibility that Cannabis phytocannabinoids act favorably on ASD symptoms, probably through the modulation of neurotransmitters, in addition to endogenous ligands derived from arachidonic acid, metabolizing enzymes and even transporters of the membrane. These findings support the notion that there are links between key features of ASD and ECS due to the favorable actions of cannabidiol (CBD) and other cannabinoids on symptoms related to behavioral and cognitive disorders, as well as deficits in communication and social interaction, hyperactivity, anxiety and sleep disorders. Thus, phytocannabinoids emerge as therapeutic alternatives for ASD.”
“Cannabidiol’s (CBD) safety profile and broad action has made it a popular treatment option for anxiety and co-occurring sleep disturbance. However, its efficacy in healthy and clinical populations, treatment duration, formulation and doses for optimal therapeutic benefits remains unclear. Selected databases were examined from inception to October 2022. Study selection, data extraction and Cochrane Risk of Bias assessments were conducted according to PRISMA guidelines and registered on the PROSPERO database (CRD42021247476) with 58 full-text studies meeting the eligibility criteria and administered CBD only or with Δ-9-tetrahydrocannabinol (THC) across healthy and clinical populations. In healthy populations and certain non-cannabis using clinical populations, CBD had greater anxiolytic effects without prominent effects on sleep. An inverted U-shaped dose relationship, and CBD ratio to THC in combined treatments likely moderated these effects. Mechanistically, observed CBD effects occurred via primary modulation of the endocannabinoid system and secondary regulation of neuroendocrine function. Additional research is needed to understand CBD mechanisms of action across diverse groups.”
“Growing evidence suggests that stress may contribute to the pathophysiology of depression. The alleviation of depressive symptoms is one of the most attractive medical applications of cannabis. Here, we investigated the antidepressant-like actions of synthetic cannabinoid-HU210 in acute despair response and explored the possible underlying mechanisms. Acute stress, induced by forced-swimming, induced depression-like behavior in the sucrose preference test (SPT). HU-210 (50 μg/kg) displayed anti-depressant like effect in the forced swim test in naïve mice and decreased depression-like behavior in the SPT, induced by forced swim stress. Pretreatment with AM251, an inhibitor of CB1R or inhibition of long-term depression (LTD) at hippocampal CA3-CA1 synapses by Tat-GluR2 attenuated the antidepressant like action of HU-210. These results indicate that HU210 produces antidepressant-like effects in acute stress and its underlying mechanism may be related to CB1R activation and hence hippocampal LTD production invivo. Synthetic cannabis or cannabis-related drugs may be used as an early intervention after acute stress exposure to prevent or at least reduce depression-like behaviors.”
“Opportunities for developing innovative and intelligent drug delivery technologies by targeting the endocannabinoid system are becoming more apparent. This review provides an overview of strategies to develop targeted drug delivery using the endocannabinoid system (ECS). Recent advances in endocannabinoid system targeting showcase enhanced pharmaceutical therapy specificity while minimizing undesirable side effects and overcoming formulation challenges associated with cannabinoids. This review identifies advances in targeted drug delivery technologies that may permit access to the full pharmacotherapeutic potential of the ECS. The design of optimized nanocarriers that target specific tissues can be improved by understanding the nature of the signaling pathways, distribution in the mammalian body, receptor structure, and enzymatic degradation of the ECS. A closer look at ligand-receptor complexes, endocannabinoid tone, tissue distribution, and G-protein activity leads to a better understanding of the potential of the ECS toolkit for therapeutics. The signal transduction pathways examine the modulation of downstream effector proteins, desensitization, signaling cascades, and biased signaling. An in-depth and overall view of the targeted system is achieved through homology modeling where mutagenesis and ligand binding examine the binding site and allow sequence analysis and the formation of libraries for molecular docking and molecular dynamic simulations. Internalization routes exploring receptor-mediated endocytosis and lipid rafts are also considered for explicit signaling. Furthermore, the review highlights nanotechnology and surface modification aspects as a possible future approach for specific targeting.”
“Specific targeting of the endocannabinoid system seems to be a good starting point towards developing a sophisticated cannabinoid drug design void of undesirable side effects but the future of commercialized ECS products calls for exploration from a broader perspective. Further study into the complexity of the expanded endocannabinoidome is required to consider the dynamics and interconnections it has with other regulatory systems. As the ECS is interconnected with other lipid-based signaling systems and cannabinomimetic compounds have been identified in a variety of foods, research into the link between diet and the synthesis and release of endocannabinoids and related mediators will do well to guide a better understanding of the endocannabinoidome and epigenetics of the ECS.”
“Vasculogenesis (the process of differentiation of angioblasts toward endothelial cells and de novo formation of crude vascular networks) and angiogenesis (the process of harmonized sprouting and dispersal of new capillaries from previously existing ones) are two fundamentally complementary processes, obligatory for maintaining physiological functioning of vascular system. In clinical practice, however, the later one is of more importance as it guarantees correct embryonic nourishment, accelerates wound healing processes, prevents uncontrolled cell growth and tumorigenesis, contributes in supplying nutritional demand following occlusion of coronary vessels and is in direct relation with development of diabetic retinopathy. Hence, discovery of novel molecules capable of modulating angiogenic events are of great clinical importance. Recent studies have demonstrated multiple angio-regulatory activities for endocannabinoid system modulators and endocannabinoid-like molecules, as well as their metabolizing enzymes. Hence, in present article, we reviewed the regulatory roles of these molecules on angiogenesis and described molecular mechanisms underlying them.”
“Activation of the endocannabinoid system has various cardiovascular and metabolic expressions, including increased lipogenesis, decreased blood pressure, increased heart rate, and changes in cholesterol levels. There is a scarcity of data on the metabolic effects of exogenous cannabis in older adults; therefore, we aimed to assess the effect of exogenous cannabis on endocannabinoid levels and the association with changes in 24 h ambulatory blood pressure and lipid levels. We conducted a prospective study of patients aged 60 years or more with hypertension treated with a new prescription of herbal cannabis. We assessed changes in endocannabinoids, blood pressure, and metabolic parameters prior to and following three months of cannabis use. Fifteen patients with a mean age of 69.47 ± 5.83 years (53.3% male) underwent complete evaluations. Changes in 2-arachidonoylglycerol, an endocannabinoid, were significantly positively correlated with changes in triglycerides. Changes in arachidonic acid levels were significantly positively correlated with changes in C-reactive protein and with changes in mean diastolic blood pressure. Exogenous consumption of cannabidiol was negatively correlated with endogenous levels of palmitoylethanolamide and oleoylethanolamide. On average, cannabis treatment for 3 months does not result in a significant change in the levels of endogenous cannabinoids and thus has a safe metabolic risk profile.”
“The endocannabinoid system is a complex cell-signaling system that has numerous effects on the human body, including on the heart, blood vessels, and metabolism. In this study, we aimed to assess the effects of exogenous herbal medical cannabis use on the components of the endocannabinoid system among older adults with a diagnosis of hypertension. Medical cannabis is a product containing cannabinoids used for medical purposes. Herbal cannabis contains many types of cannabinoids, the most well-known of which are Δ9-tetrahydrocannabinol and cannabidiol. We followed people aged 60 years and older and conducted a number of tests, including endocannabinoids levels, before they started using cannabis and following three months of daily cannabis treatment. Fifteen patients (53.3% male; mean age, 69.5 years) underwent complete evaluations. We found positive correlations between the components of the endocannabinoid system and blood lipids, markers of inflammation, and blood pressure. On average, cannabis treatment for 3 months does not result in a significant change in the levels of endogenous cannabinoids and thus has a safe metabolic risk profile. This study provides additional evidence for the safety of medical cannabis use among older adults.”
“The endocannabinoid system (ECS) dynamically regulates many aspects of mammalian physiology. ECS has gained substantial interest since growing evidence suggests that it also plays a major role in several pathophysiological conditions due to its ability to modulate various underlying mechanisms. Furthermore, cannabinoids, as components of the cannabinoid system (CS), have proven beneficial effects such as anti-inflammatory, immunomodulatory, neuromodulatory, antioxidative, and cardioprotective effects. In this comprehensive review, we aimed to describe the complex interaction between CS and most common age-related diseases such as neuro-degenerative, oncological, skeletal, and cardiovascular disorders, together with the potential of various cannabinoids to ameliorate the progression of these disorders. Since chronic inflammation is postulated as the pillar of all the above-mentioned medical conditions, we also discuss in this paper the potential of CS to ameliorate aging-associated immune system dysregulation.”
“The cannabinoid system has the potential to ameliorate different underlying mechanism involved in the progression of aging-related diseases. Additionally, ECS may represent a promising approach not only for the treatment, but also for the alleviation of age-related disorder-associated symptoms and/or for increasing the efficacy of existing drugs. Moreover, our findings show that cannabinoids may be able to modulate various mechanisms rather than targeting a single dysregulated pathway in age-related diseases. Natural as well as synthetic cannabinoids ameliorate the balance between neurodegeneration and neuroinflammation in neurodegenerative diseases. In addition, they may play an important role in modulating the complex physio-pathology of MS and may be used as immune modulators, neuroprotectors, or remyelination promoters. The modulation of pro-inflammatory cytokines through the endogenous cannabinoid system may have beneficial effects on MS, AD, PD, aging-related musculoskeletal changes, and CVDs. On the other hand, it is clearly now that targeting the ECS with various natural or synthetic compounds may have the theoretical potential of an improved control of cancer progression.”
“The number of people diagnosed with diabetes mellitus and its complications is markedly increasing worldwide, leading to a worldwide epidemic across all age groups, from children to older adults. Diabetes is associated with premature aging. In recent years, it has been found that peripheral overactivation of the endocannabinoid system (ECS), and in particular cannabinoid receptor 1 (CB1R) signaling, plays a crucial role in the progression of insulin resistance, diabetes (especially type 2), and its aging-related comorbidities such as atherosclerosis, nephropathy, neuropathy, and retinopathy. Therefore, it is suggested that peripheral blockade of CB1R may ameliorate diabetes and diabetes-related comorbidities. The use of synthetic CB1R antagonists such as rimonabant has been prohibited because of their psychiatric side effects. In contrast, phytocannabinoids such as cannabidiol (CBD) and tetrahydrocannabivarin (THCV), produced by cannabis, exhibit antagonistic activity on CB1R signaling and do not show any adverse side effects such as psychoactive effects, depression, or anxiety, thereby serving as potential candidates for the treatment of diabetes and its complications. In addition to these phytocannabinoids, cannabis also produces a substantial number of other phytocannabinoids, terpenes, and flavonoids with therapeutic potential against insulin resistance, diabetes, and its complications. In this review, the pathogenesis of diabetes, its complications, and the potential to use cannabinoids, terpenes, and flavonoids for its treatment are discussed.”
“Cannabis components (phytocannabinoids and terpenes) may exert antagonistic activity on CB1R signaling without causing deleterious side effects. Hence, phytocannabinoids and terpenes may be excellent potential candidates for the treatment of diabetes and its complications.”
