Modulation Of Endocannabinoid System Research Articles

The endocannabinoid system: A new frontier in addressing psychosomatic challenges

Psychosomatic disorders (PSD), alternatively referred to as psychophysiologic disorders, are characterized by hypothalamic-pituitary-adrenal (HPA) axis activation, posing a substantial challenge in clinical practice. These disorders constitute a collection of intricate medical conditions marked by the considerable impact of psychological and emotional factors on the onset, intensification, or persistence of physical symptoms. The endocannabinoid system, a complex regulatory network consisting of endocannabinoids, cannabinoid receptors, and associated enzymes, emerges as a key player in modulating the body’s stress response, emotional regulation, and immune function. This review delves into the bidirectional relationship between the endocannabinoid system and the HPA axis, elucidating the impact of endocannabinoid system modulation on stress responsiveness, immune modulation, and the intricate interplay between emotional well-being and physical symptoms. Through the synthesis of current scientific knowledge, this review aims to provide a comprehensive understanding of the role of the endocannabinoid system in PSD, offering insights that may pave the way for novel therapeutic approaches.

Mulberry (Morus alba L.) leaf water extract attenuates type 2 diabetes mellitus by regulating gut microbiota dysbiosis, lipopolysaccharide elevation and endocannabinoid system disorder

Ethnopharmacological relevanceMulberry (Morus alba L.) leaf is a well-known herbal medicine and has been used to treat diabetes in China for thousands of years. Our previous studies have proven mulberry leaf water extract (MLWE) could improve type 2 diabetes mellitus (T2D). However, it is still unclear whether MLWE could mitigate T2D by regulating gut microbiota dysbiosis and thereof improve intestinal permeability and metabolic dysfunction through modulation of lipopolysaccharide (LPS) and endocannabinoid system (eCBs). Aim of studyThis study aims to explore the potential mechanism of MLWE on the regulation of metabolic function disorder of T2D mice from the aspects of gut microbiota, LPS and eCBs. Materials and methodsGut microbiota was analyzed by high-throughput 16S rRNA gene sequencing. LPS, N-arachidonoylethanolamine (AEA) and 2-ararchidonylglycerol (2-AG) contents in blood were determined by kits or liquid phase chromatography coupled with triple quadrupole tandem mass spectrometry, respectively. The receptors, enzymes or tight junction protein related to eCBs or gut barrier were detected by RT-PCR or Western blot, respectively. ResultsMLWE reduced the serum levels of AEA, 2-AG and LPS, decreased the expressions of N-acylphophatidylethanolamine phospholipase D, diacylglycerol lipase-α and cyclooxygenase 2, and increased the expressions of fatty acid amide hydrolase (FAAH), N-acylethanolamine-hydrolyzing acid amidase (NAAA), alpha/beta hydrolases domain 6/12 in the liver and ileum and occludin, monoacylglycerol lipase and cannabinoid receptor 1 in the ileum of T2D mice. Furthermore, MLWE could change the abundances of the genera including Acetatifactor, Anaerovorax, Bilophila, Colidextribacter, Dubosiella, Gastranaerophilales, Lachnospiraceae_NK4A136_group, Oscillibacter and Rikenella related to LPS, AEA and/or 2-AG. Moreover, obvious improvement of MLWE treatment on serum AEA level, ileum occludin expression, and liver FAAH and NAAA expression could be observed in germ-free-mimic T2D mice. ConclusionMLWE could ameliorate intestinal permeability, inflammation, and glucose and lipid metabolism imbalance of T2D by regulating gut microbiota, LPS and eCBs.

Topical Analgesics for Acute Corneal Pain: Current Options and Emerging Therapeutics.

Acute corneal pain is a common complaint that causes significant distress to patients and continues to challenge therapeutic avenues for pain management. Current topical treatment options have marked limitations in terms of both efficacy and safety, thus often prompting the adjunctive use of systemic analgesics, including opioids. In general, there have not been extensive advancements in pharmacologic options for the management of corneal pain over the past several decades. Despite this, multiple promising therapeutic avenues exist which hold the potential to transform the ocular pain landscape, including druggable targets within the endocannabinoid system. This review will summarize the current evidence base for topical NSAIDs, anticholinergic agents, and anesthetics before focusing on several potential avenues in the setting of acute corneal pain management, including autologous tear serum, topical opioids and endocannabinoid system modulators.

Wistar-Kyoto rats and chronically stressed Wistar rats present similar depression- and anxiety-like behaviors but different corticosterone and endocannabinoid system modulation

The interplay of social, psychological, and biological stresses can trigger mental health conditions such as major depressive disorder (MDD), adjustment disorder, and posttraumatic stress disorder (PTSD). The endocannabinoid system (ECS), comprising endocannabinoids and cannabinoid receptors, is the critical pathway that mediates responses to stress stimuli. This study aimed to investigate the ECS's impact on responding to chronic social instability stress (SIS). Wistar (WIS) rats and an endogenously depressed rat model, Wistar-Kyoto (WKY), were used to evaluate depression- and anxiety-like behavioral responses, cognitive function, hormone levels, and ECS function. The animals in the stress group (WIS-STS and WKY-STS) were exposed to TMT (predator odor) for 10 mins (two exposures in total: one in light cycle and one in dark cycle) and daily roommate changes (30 days in total), while the control group (CTL) rats were exposed to a sham odor stimulus (distilled water) and did not undergo roommate changes.The results in the open field test suggest that WKY rats had significantly lower locomotor activity than WIS rats. In contrast, WKY rats and chronically stressed WIS rats presented similar depression- and anxiety-like behaviors and impaired cognitive function in the elevated plus maze, forced swimming test, and novel objective recognition test. However, chronic SIS did not exacerbate these behavioral changes in WKY rats. ELISA and Western blot analysis indicated that chronic SIS did not induce further upregulation of endocannabinoids and CB1R downregulation in WKY rats compared to WIS rats. In addition, the Luminex assay revealed that WKY rats showed a higher resilience on the HPA-axis modulation towards chronic SIS, distinguished by the hyperactivity of the HPA-axis modulation in WIS rats.Overall, the study revealed that the chronic SIS animal model (stressed WIS rats) and an animal model of endogenous depression (WKY rats) can generate similar behavioral changes in anxious behavior, behavioral despair, and cognitive impairment. Both animal models present hyperactivity of the ACTH modulation and ECS activity, while WKY rats are more resilient on CORT modulation towards chronic SIS.

P16-007-23 Fish Oil and Heat Treatment Induce Metabolic Benefits Against Post-Menopausal Obesity via the Activation of HSP70/TRPV1 Axis and Modulation of Endocannabinoid System

P16-007-23 Fish Oil and Heat Treatment Induce Metabolic Benefits Against Post-Menopausal Obesity via the Activation of HSP70/TRPV1 Axis and Modulation of Endocannabinoid System

Expression of Cytokines and Neurodegeneration in the Rat Hippocampus and Cortex in the Lithium-Pilocarpine Model of Status Epilepticus and the Role of Modulation of Endocannabinoid System.

A significant body of evidence shows that neuroinflammation is one of the key processes in the development of brain pathology in trauma, neurodegenerative disorders, and epilepsy. Various brain insults, including severe and prolonged seizure activity during status epilepticus (SE), trigger proinflammatory cytokine release. We investigated the expression of the proinflammatory cytokines interleukin-1β (Il1b) and interleukin-6 (Il6), and anti-inflammatory fractalkine (Cx3cl1) in the hippocampus, entorhinal cortex, and neocortex of rats 24 h, 7 days, and 5 months after lithium-pilocarpine SE. We studied the relationship between cytokine expression and neuronal death in the hippocampus and evaluated the effect of modulation of endocannabinoid receptors on neuroinflammation and neurodegeneration after SE. The results of the present study showed that inhibition of endocannabinoid CB1 receptors with AM251 early after SE had a transient neuroprotective effect that was absent in the chronic period and did not affect the development of spontaneous seizures after SE. At the same time, AM251 reduced the expression of Il6 in the chronic period after SE. Higher Cx3cl1 levels were found in rats with more prominent hippocampal neurodegeneration.

Maternal immune activation impairs endocannabinoid signaling in the mesolimbic system of adolescent male offspring

Prenatal infections can increase the risk of developing psychiatric disorders such as schizophrenia in the offspring, especially when combined with other postnatal insults. Here, we tested, in a rat model of prenatal immune challenge by the viral mimic polyriboinosinic–polyribocytidilic acid, whether maternal immune activation (MIA) affects the endocannabinoid system and endocannabinoid-mediated modulation of dopamine functions. Experiments were performed during adolescence to assess i) the behavioral endophenotype (locomotor activity, plus maze, prepulse inhibition of startle reflex); ii) the locomotor activity in response to Δ9-Tetrahydrocannabinol (THC) and iii) the properties of ventral tegmental area (VTA) dopamine neurons in vivo and their response to THC; iv) endocannabinoid-mediated synaptic plasticity in VTA dopamine neurons; v) the expression of cannabinoid receptors and enzymes involved in endocannabinoid synthesis and catabolism in mesolimbic structures and vi) MIA-induced neuroinflammatory scenario evaluated by measurements of levels of cytokine and neuroinflammation markers. We revealed that MIA offspring displayed an altered locomotor activity in response to THC, a higher bursting activity of VTA dopamine neurons and a lack of response to cumulative doses of THC. Consistently, MIA adolescence offspring showed an enhanced 2-arachidonoylglycerol-mediated synaptic plasticity and decreased monoacylglycerol lipase activity in mesolimbic structures. Moreover, they displayed a higher expression of cyclooxygenase 2 (COX-2) and ionized calcium-binding adaptor molecule 1 (IBA-1), associated with latent inflammation and persistent microglia activity. In conclusion, we unveiled neurobiological mechanisms whereby inflammation caused by MIA influences the proper development of endocannabinoid signaling that negatively impacts the dopamine system, eventually leading to psychotic-like symptoms in adulthood.

Endocannabinoid levels in peripheral blood mononuclear cells of multiple sclerosis patients treated with dimethyl fumarate

The endocannabinoid system (ECS), a signalling network with immunomodulatory properties, is a potential therapeutic target in multiple sclerosis (MS). Dimethyl fumarate (DMF) is an approved drug for MS whose mechanism of action has not been fully elucidated; the possibility exists that its therapeutic effects could imply the ECS. With the aim of studying if DMF can modulate the ECS, the endocannabinoids 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) were determined by liquid chromatography-mass spectrometry in peripheral blood mononuclear cells from 21 healthy donors (HD) and 32 MS patients at baseline and after 12 and 24 months of DMF treatment. MS patients presented lower levels of 2-AG and PEA compared to HD. 2-AG increased at 24 months, reaching HD levels. AEA and PEA remained stable at 12 and 24 months. OEA increased at 12 months and returned to initial levels at 24 months. Patients who achieved no evidence of disease activity (NEDA3) presented the same modulation over time as EDA3 patients. PEA was modulated differentially between females and males. Our results show that the ECS is dysregulated in MS patients. The increase in 2-AG and OEA during DMF treatment suggests a possible role of DMF in ECS modulation.

Endocannabinoids and related compounds as modulators of angiogenesis: Concepts and clinical significance.

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.

Antidepressant Potential of Daidzein Through Modulation of Endocannabinoid System by Targeting Fatty Acid Amide Hydrolase

In recent decades, the identification of natural compounds that modulate the endocannabinoid system by fatty acid amide hydrolase (FAAH) inhibition has provided an interesting area of research. Daidzein, which is an isoflavone, has neurobiological activities that are effective against several neurological disorders which include depression. This study aimed to investigate the FAAH inhibitory activity of Daidzein through in-silico analysis via Molecular Operating Environment software together with the in-vitro FAAH inhibitory assay. Furthermore, the anti-depressive effect of Daidzein (20 mg/kg) was examined via open field test and forced swim test in both male and female mice groups. Finally, the level of depression and stress was measured by the plasma corticosterone level. Molecular docking has shown the probable binding of Daidzein with the FAAH enzyme via its ser-ser-lys catalytic triad. Daidzein binds to the active pocket of FAAH with excellent binding energy of -64.77 Kcal/mol and binding affinity of -11.77 Kcal/mol. The findings reported that Daidzein inhibited the FAAH enzyme with IC50 value at 1.3±0.13 µM concentration. The open field test showed that Daidzein had no significant effect on locomotory activity in both male and female groups compared to fluoxetine and Arch-5HT group. Daidzein has significantly decreased the immobility time in forced swim test, which is an indicator of an anti-depressive effect. The corticosterone level that regulates depression was significantly decreased in both male and female Daidzein-treated mice groups. This study highlighted the role of Daidzein as a therapeutic agent for depression via the inhibition of FAAH and modulation of corticosterone levels.

Cannabis Use in Autism: Reasons for Concern about Risk for Psychosis.

Being particularly vulnerable to the pro-psychotic effects of cannabinoid exposure, autism spectrum individuals present with an increased risk of psychosis, which may be passed on to their own children. More specifically, cannabis exposure among autism spectrum individuals seems to exert disruptive epigenetic effects that can be intergenerationally inherited in brain areas which play a critical role in schizophrenia pathophysiology. Additionally, because of such cannabinoid-induced epigenetic effects, autism candidate genes present with bivalent chromatin markings which make them more vulnerable to subsequent disruption, possibly leading to psychosis onset later in life. Thus, findings support a developmental trajectory between autism and psychosis, as per endocannabinoid system modulation. However, such evidence has not received the attention it deserves.

Inhibition of Monoacylglycerol Lipase by NSD1819 as an Effective Strategy for the Endocannabinoid System Modulation against Neuroinflammation-Related Disorders.

Neuroinflammation is a key pathological event shared by different diseases affecting the nervous system. Since the underlying mechanism of neuroinflammation is a complex and multifaceted process, current pharmacological treatments are unsatisfactory—a reason why new therapeutic approaches are mandatory. In this context, the endocannabinoid system has proven to possess neuroprotective and immunomodulatory actions under neuroinflammatory status, and its modulation could represent a valuable approach to address different inflammatory processes. To this aim, we evaluated the efficacy of a repeated treatment with NSD1819, a potent β-lactam-based monoacylglycerol lipase inhibitor in a mouse model of neuroinflammation induced by lipopolysaccharide (LPS) injection. Mice were intraperitoneally injected with LPS 1 mg/kg for five consecutive days to induce systemic inflammation. Concurrently, NSD1819 (3 mg/kg) was daily per os administered from day 1 until the end of the experiment (day 11). Starting from day 8, behavioral measurements were performed to evaluate the effect of the treatment on cognitive impairments, allodynia, motor alterations, anhedonia, and depressive-like behaviors evoked by LPS. Histologically, glial analysis of the spinal cord was also performed. The administration of NSD1819 was able to completely counteract thermal and mechanical allodynia as highlighted by the Cold plate and von Frey tests, respectively, and to reduce motor impairments as demonstrated by the Rota rod test. Moreover, the compound was capable of neutralizing the memory loss in the Passive avoidance test, and reducing depressive-like behavior in the Porsolt test. Finally, LPS stimulation caused a significant glial cells activation in the dorsal horn of the lumbar spinal cord that was significantly recovered by NSD1819 repeated treatment. In conclusion, NSD1819 was able to thwart the plethora of symptoms evoked by LPS, thus representing a promising candidate for future applications in the context of neuroinflammation and related diseases.

Maternal high-fat diet alters thermogenic markers but not muscle or brown adipose cannabinoid receptors in adult rats

AimsThe endocannabinoid system (ECS) increases food intake, appetite for fat and lipogenesis, while decreases energy expenditure (thermogenesis), contributing to metabolic dysfunctions. We demonstrated that maternal high-fat diet (HFD) alters cannabinoid signaling in brown adipose tissue (BAT) of neonate and weanling male rat offspring, which have increased adiposity but also higher energy expenditure in adulthood. In this study, the main objective was to investigate the ECS expression in thermogenic tissues as BAT and skeletal muscle of adult rats programmed by maternal HFD. We hypothesized that maternal HFD would modulate ECS and energy metabolism markers in BAT and skeletal muscle of adult male offspring. Materials and methodsFemale rats received standard diet (9.4 % of calories as fat) or isocaloric HFD (28.9 % of calories as fat) for 8 weeks premating and throughout gestation and lactation. Male offspring were weaned on standard diet and euthanatized in adulthood. Key findingsMaternal HFD increased body weight, adiposity, glycemia, leptinemia while decreased testosterone levels in adult offspring. Maternal HFD did not change cannabinoid receptors in BAT or skeletal muscle as hypothesized but increased the content of uncoupling protein and tyrosine hydroxylase (thermogenic markers) in parallel to changes in mitochondrial morphology in skeletal muscle of adult offspring. SignificanceIn metabolic programming models, the ECS modulation in the BAT and skeletal muscle may be more important early in life to adapt energy metabolism during maternal dietary insult, and other mechanisms are possibly involved in muscle metabolism long-term regulation.

CB1R, CB2R and TRPV1 expression and modulation in in vivo, animal glaucoma models: A systematic review.

The endocannabinoid system (ECS) is a complex biological regulatory system. Its expression and functionality have been widely investigated in ocular tissues. Recent data have reported its modulation to be valid in determining an ocular hypotensive and a neuroprotective effect in preclinical animal models of glaucoma. This study aimed to explore the available literature on cannabinoid receptor 1 (CB1R), cannabinoid receptor 2 (CB2R), and transient receptor potential vanilloid 1 (TRPV1) expression in the trabecular meshwork (TM), ciliary body (CB), and retina as well as their ocular hypotensive and neuroprotective effects in preclinical, in vivo, animal glaucoma models. The study adhered to both PRISMA and SYRCLE guidelines. Sixty-nine full-length articles were included in the final analysis. Preclinical studies indicated a widespread distribution of CB1R, CB2R, and TRPV1 in the TM, CB, and retina, although receptor-, age-, and species-dependent differences were observed. CB1R and CB2R modulation have been shown to exert ocular hypotensive effects in preclinical models via the regulation of inflow and outflow pathways. Retinal cell neuroprotection has been achieved in several experimental models, mediated by agonists and antagonists of CB1R, CB2R, and TRPV1. Despite the growing body of preclinical data regarding the expression and modulation of ECS in ocular tissues, the mechanisms responsible for the hypotensive and neuroprotective efficacy exerted by this system remain largely elusive. Research on this topic is advocated to further substantiate the hypothesis that the ECS is a new potential therapeutic target in the context of glaucoma.

Cannabinoid and endocannabinoid system: a promising therapeutic intervention for multiple sclerosis.

Multiple sclerosis (MS) is a chronic and complex neurodegenerative disease, distinguished by the presence of lesions in the central nervous system (CNS) due to exacerbated immunological responses that inflict oligodendrocytes and the myelin sheath of axons. In recent years, studies have focused on targeted therapeutics for MS that emphasize the role of G protein-coupled receptors (GPCRs), specifically cannabinoids receptors. Clinical studies have suggested the therapeutic potential of cannabinoids derived from Cannabis sativa in relieving pain, tremors and spasticity. Cannabinoids also appear to prevent exaggerated immune responses in CNS due to compromised blood-brain barrier. Both, endocannabinoid system (ECS) modulators and cannabinoid ligands actively promote oligodendrocyte survival by regulating signaling, migration and myelination of nerve cells. The cannabinoid receptors 1 (CB1) and 2 (CB2) of ECS are the main ones in focus for therapeutic intervention of MS. Various CB1/CB2 receptors agonists have been experimentally studied which showed anti-inflammatory properties and are considered to be effective as potential therapeutics for MS. In this review, we focused on the exacerbated immune attack on nerve cells and the role of the cannabinoids and its interaction with the ECS in CNS during MS pathology.

Modulation of Endocannabinoid System in the Paraventricular Nucleus of the Hypothalamus on the Autonomic, Cardiovascular and Neuroendocrine Responses in a Rat Hemorrhagic Shock Model

Modulation of Endocannabinoid System in the Paraventricular Nucleus of the Hypothalamus on the Autonomic, Cardiovascular and Neuroendocrine Responses in a Rat Hemorrhagic Shock Model

The role of cannabinoids in neurodevelopmental disorders of children and adolescents.

Neurodevelopmental disorders have a multifactorial etiology that results from the interaction between biological and environmental factors. The biological basis of many of these disorders is only partially understood, which makes therapeutic interventions, especially pharmacological ones, particularly difficult. The impact of medical cannabis on neurological and psychiatric disorders has been studied for a long time. This study aimed to review the currently available clinical and pre-clinical studies regarding the use of cannabinoids in pediatric neurodevelopmental disorders and to draw attention to the potential therapeutic role of cannabidiol in this field. Cannabidiol is an endocannabinoid system modulator and exerts its effects on both developing and mature brains through numerous mechanisms. Cannabidiol holds a relatively high toxicity limit and current literature suggests that it may have anxiolytic, antipsychotic, and neuroprotective properties. Clinical evidence suggests that early treatment with cannabidiol might be a promising therapy for neurodevelopmental disorders, including intellectual disability, autism spectrum disorders, tics, and attention/deficit hyperactivity disorder. This review hopefully draws attention to an emerging body of evidence concerning cannabidiol's significant potential to safely improve many of the common symptoms affecting children and adolescents with neurodevelopmental disorders, especially autism spectrum disorder.

Endocannabinoid System and Tumour Microenvironment: New Intertwined Connections for Anticancer Approaches.

The tumour microenvironment (TME) is now recognised as a hallmark of cancer, since tumour:stroma crosstalk supports the key steps of tumour growth and progression. The dynamic co-evolution of the tumour and stromal compartments may alter the surrounding microenvironment, including the composition in metabolites and signalling mediators. A growing number of evidence reports the involvement of the endocannabinoid system (ECS) in cancer. ECS is composed by a complex network of ligands, receptors, and enzymes, which act in synergy and contribute to several physiological but also pathological processes. Several in vitro and in vivo evidence show that ECS deregulation in cancer cells affects proliferation, migration, invasion, apoptosis, and metastatic potential. Although it is still an evolving research, recent experimental evidence also suggests that ECS can modulate the functional behaviour of several components of the TME, above all the immune cells, endothelial cells and stromal components. However, the role of ECS in the tumour:stroma interplay remains unclear and research in this area is particularly intriguing. This review aims to shed light on the latest relevant findings of the tumour response to ECS modulation, encouraging a more in-depth analysis in this field. Novel discoveries could be promising for novel anti-tumour approaches, targeting the microenvironmental components and the supportive tumour:stroma crosstalk, thereby hindering tumour development.

Cannabinoids: an Effective Treatment for Chemotherapy-Induced Peripheral Neurotoxicity?

Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most frequent side effects of antineoplastic treatment, particularly of lung, breast, prostate, gastrointestinal, and germinal cancers, as well as of different forms of leukemia, lymphoma, and multiple myeloma. Currently, no effective therapies are available for CIPN prevention, and symptomatic treatment is frequently ineffective; thus, several clinical trials are addressing this unmet clinical need. Among possible pharmacological treatments of CIPN, modulation of the endocannabinoid system might be particularly promising, especially in those CIPN types where analgesia and neuroinflammation modulation might be beneficial. In fact, several clinical trials are ongoing with the specific aim to better investigate the changes in endocannabinoid levels induced by systemic chemotherapy and the possible role of endocannabinoid system modulation to provide relief from CIPN symptoms, a hypothesis supported by preclinical evidence but never consistently demonstrated in patients. Interestingly, endocannabinoid system modulation might be one of the mechanisms at the basis of the reported efficacy of exercise and physical therapy in CIPN patients. This possible virtuous interplay will be discussed in this review.

The Endocannabinoid System and Cannabidiol: Past, Present, and Prospective for Cardiovascular Diseases.

In the past, cannabis was commonly associated with mysticism and illegality. Fortunately, in recent years perspectives and discourses have changed. More prominence has been given to the rigorous scientific effort that led to the discovery of cannabis’ many physiological actions and endogenous signalling mechanisms. The endocannabinoid system is a complex and heterogeneous pro-homeostatic network comprising different receptors with several endogenous ligands, numerous metabolic enzymes and regulatory proteins. Therefore, it is not surprising that alterations and dysfunctions of the endocannabinoid system are observed in almost every category of disease. Such high degree of pathophysiological involvement suggests the endocannabinoid system is a promising therapeutic target and prompted the translation of resurgent scientific findings into clinical therapies. Shifting attitudes toward cannabis also raised other matters such as increased patient awareness, prescription requests, self-medication, recreational use, recognition of new knowledge gaps, renewed scientific activity, and seemingly exponential growth of the cannabis industry. This review, following a general overview of cannabis and the endocannabinoid system, assiduously describes its role within the context of cardiovascular diseases, paying particular attention to the Janus influence that endocannabinoid system modulators can have on the cardiovascular system.