A great deal of work in subsequent years has investigated mechanisms and extended these results to many other neurons and brain regions, suggesting endocannabinoids (likely, 2-AG) are a major contributor to short term synaptic plasticity reviewed by (89, 96, 97). Because of the pervasive social use of cannabis and the involvement of endocannabinoids in a multitude of biological processes, much has been learned about the physiological and pathophysiological roles of the ECS. Exogenous cannabinoids, such as tetrahydrocannabinol, produce their biological effects through their interactions with cannabinoid receptors. The most abundant cannabinoid receptor is the CB1 cannabinoid receptors, however CB2 cannabinoid receptors, transient receptor potential (TRP) channels, and peroxisome proliferator activated receptors (PPAR’s) are also engaged by some cannabinoids. In fact, intrauterine CBD exposure increases sensitivity to thermal pain in adult male offspring in a TRPV1 dependent manner (Swenson et al. 2023). Exposure to TRP agonists can increase thermal pain sensitivity (Cortright et al. 2007). Dysregulation of TRP channels can alter thermal pain sensation, as discussed by Cortright and colleagues (Cortright et al. 2007). TRPV4 is expressed in the brain, endocrine tissues, gastrointestinal tract, pancreas, reproductive tissues, and muscle tissues, among others (TRPV4 protein expression summary - The Human Protein Atlas n.d). Unfortunately, there is a lack of human studies about the effectiveness of CBD. Given the ongoing challenges of chronic pain management coupled with the consequences of the opioid epidemic, pain management practitioners and their patients are searching for effective and safer alternatives to opioids to alleviate pain. If you or a loved one is suffering from chronic pain, you already know the heavy burden. By its nature, chronic pain is a complex and multidimensional experience. The ECS has increasingly become a target of research linking its regulation to potential tumor control. Adaptive clinical trial designs and closer integration between preclinical and clinical research could accelerate the progress of ECS-targeted cancer treatments (44, 45). Preclinical models, including cell cultures and animal studies, often fail to fully represent the complexity of human tumors. The inhibition of Hsp70 also intensified apoptosis, suggesting that CBD could be a promising therapeutic approach for colorectal cancer (33). Unraveling the Mechanisms of Cannabidiol’s Pharmacological Actions: A Comprehensive Research Overview This leads to direct and indirect changes that have crucial effects on angiogenesis in a cancerous environment. Blazquez et al. investigated the role of cannabinoid agonists (THC, JWH-133, and anadamide) on MMP-2 expression inside glioma cell cultures and glioma-bearing mice , and found that THC administration decreased tumor growth and the expression of MMP-2 in C6.9 glioma cells. The effect of cannabinoids on sphingomyelin breakdown, resulting in increased intracellular ceramide levels, has been also observed . Cannabinoid receptors are also coupled to activation of serine/threonine protein kinase B/Akt (PKB), resulting in increased phosphorylation of glycogen synthase kinase-3 (GSK3) on serine 21 residue . This suggests that cannabinoids might also be involved in other pathways important for cell survival, such as MAPK . Finally, the use of highly potent, highly efficacious cannabinoid receptors agonists typically present in synthetic marijuana preparations (“spice”) results in a greater incidence of adverse psychiatric effects, that may be attributable to their higher intrinsic efficacy (130). In addition to inducing several forms of synaptic plasticity, endocannabinoids, particularly 2-AG, also can directly suppress neuronal excitability through a process termed slow-self inhibition (SSI) (113) (Fig. 3D). Mechanistically diverse forms of endocannabinoid-induced LTD have also been described, which either involve (111), or don’t involve (112) CB1 receptors. As action potential propagation increases neurite outgrowth (Fields et al. 1990), CBD may hinder neurite outgrowth and subsequent neuronal connections. GPR12 is expressed in the brain, eye, and gastrointestinal tract (GPR12 protein expression summary - The Human Protein Atlas n.d). In sympathetic neurons, KV7.2/3 activity mediates repetitive discharges and conversion from phasic to tonic firing, and in hippocampal pyramidal neurons, KV7.2/3 activity mediates repetitive discharges of the neuron (Brown and Passmore 2009). CBD may impact temperature sensation by agonizing or antagonizing transient potential receptors, or TRPs (Table 2, Fig. 3) (Petrocellis et al. 2011; Anand et al. 2020; Petrocellis et al. 2012). For example, in HEK 293A cells that exogenously express CB1 receptors, and in a Huntington’s Disease model striatal cell line (STHdhQ7/Q7), application of CBD induced noncompetitive negative allosteric modulation of CB1 receptors with CB1 agonists (Laprairie et al. 2015) (Table 1, Fig. 2). CBD has multiple effects on CB1 receptors, including inversely agonizing CB1 (Pertwee 2008) and serving as a negative allosteric modulator of CB1 (Laprairie et al. 2015), depending on the cellular context (Table 1, Fig. 2). To facilitate thematic analysis, extracted data were grouped by body system (e.g., nervous, endocrine, immune) and categorized by the specific receptor or enzyme involved. I conducted a comprehensive literature search to compile evidence regarding cannabidiol (CBD) interactions with receptors, enzymes, and biological processes, organized by body systems. For instance, one of them, PrNMI (Figure 3) showed potent acute antinociceptive effect on spontaneous pain in the syngeneic murine model of cancer-induced bone pain . Despite its efficacy in reducing food intake and body weight in overweight or obese humans with beneficial effects on different metabolic and cardiovascular parameters, serious psychiatric problems overcame the benefits of rimonabant . Nowadays, among peripherally acting cannabinoids, CB1 antagonists are much more developed than CB1 agonist or CB2 ligands. Systematic functional profiling of reported cannabinoids as well as design of novel biased ligands is nowadays to be considered in order to find optimized therapeutics for specific pathologies. Moreover, phytocannabinoids such as Δ9-THC have also shown functionally selective responses at CB1 and CB2. Some progenitors of the main subclasses of pytocannabinoids derived from condensation of olivetolic acid and geranyl pyrophosphate are illustrated in Fig. Two possible numberings of the C21 phytocannabinoids have been proposed, depending on either the dibenzopyran or monoterpenoid scaffold. From a biochemical point of view, all subclasses of phytocannabinoids originate from cannabigerol-type (CBG) molecules, according to the diverse cyclization products of this precursor Fig. Phytocannabinoids are physiologically produced in plant cell substructures called trichomes in the form of resin. Phytocannabinoids are well-known natural products that are extracted and isolated from the Cannabis sativa L. Metalloproteinases production is stopped by the activation of both cannabinoid type 1 and type 2 receptors.It was shown that the activation of CB2 induces heat generation with consequent energy expenditure in adipose tissue and that chronic stimulation of CB2 attenuates body weight gain.However, translating the therapeutic potential of the Endocannabinoid System (ECS) into clinical applications for cancer treatment presents significant challenges.In 2001 three groups published the finding that endocannabinoids are likely the retrograde messenger for DSI and DSE in hippocampus and cerebellum (92–94).On the contrary, under basal conditions,ubiquitous CB2receptor deficiency did not lead to impairments in NSC proliferation.115Reduced proliferation was also observed in rodents treated with specific CB1- and CB2receptor antagonists.116On the other hand, the enhancement of eCB signaling through the genetic inactivationof the AEA-degrading enzyme FAAH38and the pharmacological blockade of the 2-AG–degrading enzyme MAGL117led to increased NSC proliferation.The ECS has increasingly become a target of research linking its regulation to potential tumor control.However, Sjogren and co-workers have expressed GPR55 in HEK293 cells; there, nanomolar concentrations of many cannabinoid agonists stimulated GTPγS binding . Endocannabinoids work by binding to receptors (CB1 and CB2 receptors) in the endocannabinoid system that are located on almost every cell in the body, triggering various physiological processes and helping maintain homeostasis. The endocannabinoid system works through a combination of endocannabinoids, receptors, and enzymes. We are immunologists who have been studying the effects of marijuana cannabinoids and vertebrate endocannabinoids on inflammation and cancer for more than two decades. These supplementary assays could provide a more comprehensive understanding of potential effects on P450, including mechanisms beyond direct enzyme inhibition. Notwithstanding the elevated clinical expectations that pertain to the development of drugs based on the modulation of the endocannabinoid system, setbacks are also present (Di Marzo, 2018). Similarly, if the ARC were to be activated through α2-adrenoreceptors consequently, it would lead to the release of growth hormone, which could subsequently interfere with the expression of specific P450 isoforms. This effect does not occur locally by acting on CB1 receptors in the locus coeruleus. CB1 receptors are, similarly to α1 receptors, present on presynaptic elements in the nucleus accumbens, an integral part of the mesolimbic neuronal pathway (Chevaleyre et al., 2006; Mitrano et al., 2012). Cannabidiol (CBD) The relative roles of cannabinoid receptors and TRP channels in anandamide’s actions appear variable. Cerebellar CB1 receptors are found in parallel and climbing fibers, as well as in basket cells (20, 21). Both CB1 and CB2 cannabinoid receptors are G protein-coupled receptors (GPCR’s), which primarily couple to G proteins of the Gi and Go classes (4). Cannabinoids are chemical compounds that trigger cannabinoid (and other) receptors. Research on marijuana’s effects led directly to the discovery of a hitherto unknown biochemical communication system in the human body, the Endocannabinoid System, which plays a crucial role in regulating our physiology, mood, and everyday experience. CBD offers hope for a non-toxic therapy to treat aggressive cancer without the painful side effects of chemotherapy. The first question is which type of cannabinoids should be used to treat cancer patients — natural or synthetic? Some results also suggest that patterns of cannabinoid receptor expression could be used in differential diagnosis of kidney cancers. Neurogenesis in the embryo and early postnatal brain Once you’ve received a recommendation from a doctor and registered as a medical cannabis patient in Florida, you can begin using CBD oils, lotions, and other CBD products for symptom relief. We recommend consulting with your healthcare professional before using any products recommended on this site. Gleb Oleinik is a freelance CBD & cannabis writer from Vancouver, Canada. It is possible to get a fatal overdose by swallowing too many THC pills at once, whereas documented evidence of death simply from smoking too much cannabis does not seem to exist. If THC is the active agent in cannabis, and approved, orally-effective THC medications exist, why the impetus for medical marijuana? The most direct route of THC administration is by smoking marijuana or other forms of cannabis. Which effects predominated was a matter of individual variation, and it had to be assumed that widespread use of rimonabant would put many people at risk for serious adverse consequences. The beneficial effects of rimonabant and its downsides both arose from the same source. CBD mainly affects serotonin production, among other brain chemicals. CBD, in contrast, has no psychoactive effects and won’t make you high. THC is the more psychoactive cannabinoid agent that causes highs. Cannabinoids have a special molecular structure that enables them to interact with the ECS, making them quite different from THC in terms of effects. They have also shown that these effects were mediated by increasing DNA methylation through mitogen-activated protein kinase (MAPK)-dependent pathways (p38, p42/44) triggered by CB1 activation . Maccarrone et al. have elegantly demonstrated that AEA, locally produced in the cells, inhibited the differentiation of cultured NHEK and HaCaT keratinocytes, as evidenced by the transcriptional downregulation of keratin 1, keratin 5, involucrin and transglutaminase-5 and suppression of the formation of cornified envelopes. However, the involvement of TRPV1-coupled signaling in the cellular actions of AEA on cell growth, differentiation, proliferation and survival might exert marked cell-type specificity in the skin, and depending on the cell type it can be synergistic, antagonistic or independent from the CB1/2 receptor stimulation 41,42,45,51,52. Once endocannabinoids have restored the homeostatic balance, metabolic hormones destroy it. Both of these endocannabinoids are made up of fatty molecules, and they are typically found on the cell membrane. If you were to look at an endocannabinoid system diagram, you would see how the neurons and receptors interact with each other and the retrograde cycle. Because your endocannabinoid system is always present, you can boost the ECS function without introducing cannabis into the body. Everyone has an endocannabinoid system that is active within the body at all times; this means it’s active with or without the presence of cannabis. For example, the endocannabinoid known as anandamide has its effects are boosted with CBD.In their research article, Iden et al. used selected animal models to investigate the hypothesis that CB2 might have a protective role in suppressing tumorigenesis in colorectal cancer.Several studies support GPR3, GPR6, and GPR12 as potential targets for neurodegenerative disorders such as AD or PD .Factors that influence the expression of CB1 in immune cells are the type and activation status of the cells, the immune stimulus, and the presence of endocannabinoids (11, 12).The ECS assists with homeostasis through the management of processes like inflammation, pina, hunger, sleep, mood, inflammation, and the immune system.CBD » The Science of Cannabidiol CBD and How It Interacts with the Human Endocannabinoid SystemCannabinoids also have an important influence on cancer cells themselves, what was mentioned before in this manuscript.Pharmacodynamics explores the small-scale effects of CBD on the body.Moreover, recent studies discovered the intracellular presence of CB2R in prefrontal cortical pyramidal neurons where it modulates neuronal excitability through the regulation of Ca2+-activated Cl− channel .Recent studies have demonstrated that diverse synthetic CB ligands can exhibit biased signaling (previously reviewed 39,44,48). Interaction with PPAR- γ nuclear receptor leads to regulation of gene transcription (Roque-Bravo et al., 2023). The concentration of active constituents in medical cannabis must be precisely specified, with THC and CBD content typically ranging from approximately 0.1%–20%, as determined by accredited laboratory analysis. Both agencies emphasize the need for well-controlled studies, pharmacovigilance plans, and clear evidence of benefit over risk. About this article They also showed that in healthy individuals, the concentration of the endocannabinoid 2-AG in blood plasma is higher than in bone marrow plasma. CBD is also an inverse agonist of the receptors GPR3, GPR6, and GPR12 and elevates AEA levels 20,28,29. Several reports have demonstrated that CBD act as an agonist of the receptors/channels TRPA1, TRPV1, TRPV2, TRPV3, PPARγ, 5-HT1A, A2 and A1 adenosine, and as an antagonist of the receptors GPR55, GPR18, and 5-HT3A. In addition, THC can act as an agonist of the receptors/channels GPR55, GPR18, PPARγ, transient TRPA1, TRPV2, TRPV3, and TRPV4, and as an antagonist of the receptors/channels TRPM8 and 5-HT3A. The accumulated discoveries on the endocannabinoid system triggered the search for targeted cannabinoid-based therapeutics . Since 2007, Daniel and colleagues (Wójcikowski et al., 2007; 2008; Wójcikowski and Daniel, 2008; 2009) have demonstrated the relation between the brain dopaminergic system and the regulation of P450 enzymes. This action on the P450 protein levels and activity is mediated by the hypothalamic-pituitary axis, which can stimulate or suppress hormone release, including growth hormone, corticosterone, and thyroid hormones. Neurotransmitters such as noradrenaline, dopamine, serotonin, and glutamate are indirectly involved in regulating the P450 enzymes, and cannabinoid signaling affects these neurotransmitters. This nuclear receptor further leads to increased expression of the CYP2E1 enzyme (see Table 3). In recent years, multiple studies have been conducted to demonstrate their influence on the P450 enzyme system (Nguyen et al., 2017; Lněničková et al., 2018; Šadibolová et al., 2019) and the results are summarized in Table 3. Because the ECS is involved in so many essential functions, cannabis has a wide range of medical and therapeutic applications. Regulating immune response and inflammation, making it helpful for conditions like arthritis and autoimmune disorders. Blocking FAAH, which helps keep anandamide levels higher, leading to mood-boosting effects. If you ask health care providers about the most challenging condition to treat, chronic pain is mentioned frequently. Beginning with the history and timeline of the discovery of the ECS, the sections of this chapter examine the components, anatomy, and physiologic effects of the ECS in each organ system. CBD was recently shown to have therapeutic potential in a variety of medical disorders such as epilepsy. They are a critical part of the endocannabinoid system, helping to regulate various physiological processes. If they're activated on immune cells, it might result in reduced inflammation. Learn about the endocannabinoid system, how it works, and what signs may tell you if you have an endocannabinoid deficiency. Specifically, altered expression of the CB1R and other elements of the endocannabinoid system have been observed in various neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD) . These facts underscore the significance of understanding and manipulating the endocannabinoid system in a condition-specific manner. The CB1R is also involved in physiological and pathological conditions in the PNS and peripheral tissues, including pain, energy metabolism, cardiovascular and reproductive functions, inflammation, glaucoma, cancer, and liver and musculoskeletal disorders . A recent study in huntingtin knock-in striatal neuronal cells showed that CB1R protected neurons against excitotoxicity via PI3K/Akt signaling-mediated increase in brain-derived neurotrophic factor (BDNF) expression . For example, it is activated when we suffer from a physical injury, when we encounter pathologic microbes, and when we feel emotional pain or are under stress. She lectures on microbiology and is the dean of the master’s program of Ecoremediations at the Faculty Alma Mater Europaea. Even THC alone is poorly tolerated or appreciated by patients,98 and standardized whole cannabis extracts that contain additional synergistic and buffering components, such as CBD and cannabis terpenoids, are certainly preferable.93 Alternatively, FAAH inhibitors will also raise AEA levels, but only CBD among them has achieved current legal commercial market availability. In 1992, the first endogenous cannabinoid that bound CB1 was isolated, called arachidonoylethanolamide, or anandamide (AEA) (Devane et al. 1992).While some regions have established clear guidelines, others maintain restrictive policies, excluding many from potential benefits (54, 65).Phyto-cannabinoids, most notably Δ9-tetrahydrocannabinol (THC), have been the main focus of research for mechanistic and therapeutic studies4.Cognitive deficits in AD patients correlate with cerebral disturbances in sensitive brain areas, largely in the frontal cortex and hippocampal regions, which are rich in CB1Rs.It has been suggested that membrane composition and dynamics heavily influence the cannabinoid receptor35.Low response to ICI during cannabis use may be, therefore, linked to the fact that cannabinoids exert immunosuppressive effects (48).The ECS got its name because its discovery was a result of human use of cannabis.It is important to note, however, that ideally these topical medications should contain such phyto- and/or synthetic ECS-acting substances that, on absorption to the blood, do not penetrate the brain and hence do not exert psychoactive effects. THC is the cannabinoid that causes that psychoactive high that alters your perception and attaches to the brain’s CB1 receptors. Even though CBD doesn’t trigger or bind strongly to cannabinoid receptors, it can still alter their activity in another manner. Moreover, CBD can interact with receptors responsible for how we feel pain, which in turn can decrease pain signals that travel to the brain. Although they’re both cannabinoids, they have strikingly different effects on the human body. Some synthetic THC analogues, such as HU-210 show activity that is 100-fold higher than THC . They are found primarily in the brain but are present in almost all human tissues . Recently, new evidence of other therapeutic activities of CBD has been found in the treatment of cancer and neurodegenerative disorders 24, 25. In contrast with THC, CBD does not exhibit psychomimetic activities and is capable of antagonizing these effects. Cannabinol is a weak psychoactive cannabinoid isolated from Cannabis sativa L. CBD is a non-psychoactive cannabinoid, meaning it is non-intoxicating. Cannabidiol (CBD) is a non-psychoactive cannabinoid with a different mechanism of action than THC. Tetrahydrocannabinol (THC) is the primary psychoactive compound in cannabis. How THC and CBD Interact with the Endocannabinoid System 2-AG binds to both CB1 and CB2, yet 2-AG is rarely used to evaluate mutations of either receptor. Further complicating this picture is the discovery of additional ECS-related receptors, such as GPR55 and TRPV1, which form functional heteromers with CB1 and CB2. However, their effects in breast cancer are complex, with evidence indicating both antitumor and protumor roles depending on the biological context. AEA induces apoptosis in ovarian cancer cells via ceramide accumulation and caspase activation (34), while 2-AG promotes cell death in glioblastoma through suppression of the anti-apoptotic protein Bcl-2 (20). However, in the context of receptor activation, few studies elucidate the differential impact of CBD from the major metabolites, including 7-OH CBD, CBD-glucuronide, and 10-OH-7-COOH-CBD (Ujváry and Hanuš 2016). Because the body of research on CBD varies in methodologies (cell culture, animal model, and concentration) the effects of CBD cannot be directly compared. It is possible that at low doses, CBD binds and interacts with a subset of receptors, while at high doses it interacts with a different subset of receptors in addition to high-affinity receptors. As CBD does not cause many of the side effects that accompany other nausea medications, like constipation and headache (Tincello and Johnstone 1996), it is a promising area of clinical investigation. Additionally, understanding the potential impact of CBD on fetal development, and the impact of co-consumption of CBD with migraine medications, would help inform these patients to the safety, risks, or drug-drug interactions that are possible with CBD. Additionally, it is theorized that 5HT3A antagonism in the area postrema in the brainstem, known as the vomiting center, decreases the nausea and vomiting response in small mammals (Higgins et al. 1989). Even though studies have been reported some years ago on the efficacy of the CB1 NAM PSNCBAM-1 in food intake and body weight in an acute rat feeding model, few in vivo evidences have been provided. Enormous efforts need to be devoted to understand the complex mechanism of action of allosteric cannabinoids . More than discovering new CB1 allosteric scaffolds, recent studies have been focused on the identification of CB1 receptor allosteric sites, on the mechanism of action at cellular level and on the therapeutic usefulness. CBD is just one of many cannabinoid agents you can extract from the marijuana plant. Research so far has linked it to the betterment of conditions involving sleep, pain, and anxiety. The potential health benefits of CBD rotos from how it interacts with the ECS. Some cannabinoids have shown to interact with one or more of these channels showing a different functional profile . A wide variety of cannabinoids have been reported to modulate a specific subset of TRP channels. Their lipophilic nature enhances their ability to reach a wide variety of biological tissues and therefore modulate receptors of different nature such as nuclear receptors, TRP or ligand-gated ion channels. Activation of CB1 receptors stimulates cell signaling through Gi and Go activation, while on the other hand, CB2 increases signaling only with Gi . At this point, cannabinoid research expanded to the study of cannanioids’ therapeutic effects. Initially, it was believed that cannabinoids, which are highly hydrophobic, mediate their action by binding directly to biomembrane proteins. Functions of the Endocannabinoid System The intrinsic efficacy of the endogenous cannabinoids varies—2-AG is a high efficacy agonist for both CB1 and CB2 receptors, however anandamide is a low efficacy agonist at CB1 receptors and a very low efficacy agonist at CB2 receptors (1, 2). An important feature of these endocannabinoids is that their precursors are present in lipid membranes. The first discovered and best-characterized endocannabinoids are anandamide (arachidonoyl ethanolamide) and 2-arachidonoyl glycerol (2-AG). Despite similarities in chemical structure, 2-AG and anandamide are synthesized and degraded by distinct enzymatic pathways, which impart fundamentally different physiological and pathophysiological roles to these two endocannabinoids. Different cannabinoids seem to have different effects on various cancer types, which may be caused by the different expression of cannabinoid receptors in various cancer types. Endogenous cannabinoids, or endocannabinoids, are capable of binding to CB receptors; they are lipid-like structures corresponding to those depicted in Fig. However, the underlying mechanisms through which cannabinoids and cannabinoid receptors inhibit proliferation and migration, and induce apoptosis of cancer cells, remain obscure. At the same time, new peptide-like cannabinoids of animal origin arrived on the scene, with potential therapeutic effects in vivo on cannabinoid receptors 212,213. The endocannabinoid system is one of the principal constituents of pathways involved in many physiological and mental functions. The endocannabinoid system orchestrates complex regulatory signals and reactions, influencing cognition, immunity, and more. Endocannabinoids like anandamide and 2-arachidonoylglycerol serve as natural ligands. CB1, abundant in the central nervous system, and CB2, found in peripheral tissues, are crucial for psychoactivity and diverse physiological effects. Chemical elucidation of Cannabis, particularly key phytocannabinoids like cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC), unfolded in the last century. In addition, further concerns were raised considering the possible side effects of this weight loss pill on the reproductive functions and human infertility (Bari et al., 2011). O-3853 and O-1966, two selective CB2 agonists, administrated 1 h before transient middle cerebral artery occlusion, significantly decreased the mobilization of white blood cells and their adherence to vascular endothelial cells, reduced the infarct size, and improved motor function after transient focal ischemia (Zhang et al., 2007, 2009). It has been reported that the administration of the CB1 synthetic agonist WIN 55.212–2 attenuated the neurological damage and reduced infarct size in artery occlusion induced in rats (Nagayama et al., 1999), and additionally it reduced the glial damage after hypoxic-ischemic brain injury in preterm lambs (Alonso-Alconada et al., 2010). Overall, our mechanistic studies suggest that the terpenes tested generally although selectively increase the behavioral effects of the cannabinoid WIN55,212-2, supporting the potential modulation of cannabinoids by terpenes. When endocannabinoids attach to a cannabinoid receptor, they become active. Endocannabinoids, for example, could reduce pain by targeting CB1 receptors in the spinal nerve. CBD also reaches beyond the main ECS system and gently connects with other parts of the body, like those that affect mood, stress, pain, and even sleep. THC is one of the best-known phytocannabinoids. This is why cannabis can influence how your body feels since your ECS is already built to respond to it. The clinical development of the FAAH inhibitor BIA 10–2474 for the treatment of anxiety, chronic pain, multiple sclerosis, PD, cancer and hypertension had to be discontinued due to a fatal outcome in a phase II trial. The illicit consumption of highly potent CB1 synthetic cannabinoids such as AMB-FUBINACA that caused deaths and serious adverse health events sounded the bell 11-13. However, regarding the synthetic cannabinoids, two events that occurred in 2016 have seeded bitter disappointments in the field. This endogenous cannabinoid system is conserved throughout evolution from coelenterates to man . However, the limited evidence-based data on the efficacy and side effects of different Cannabis-based treatments in various medical conditions, prevents many physicians from suggesting such treatments to their patients. In Chinese medicine, Cannabis was used to treat rheumatic pain, constipation, malaria, beriberi, and gynecological disorders. In addition, we discuss the complexities of using cannabinoid-based treatments in each of these conditions. Cannabinoids affect the nervous system and play significant roles in the regulation of the immune system. The synergistic effect between cannabinoid and opioid system could be readily observed at the behavioral levels. The resulting implications of the interaction between cannabinoid and opioid system are clinically profound. The interactions between cannabinoid and opioid system also play a role in the behavioral-related reward and reinforcement. However, under chronic scenario, the administration of subclinical doses of synthetic cannabinoid (CP-55,940) into morphine-tolerant rats still significantly induced analgesia, whereas the administration of morphine to cannabinoid-tolerant rats did not exhibit any analgesic effect. They also operate under the same cellular transduction mechanisms, including modulation of potassium conductance via protein kinase C signaling, inhibition of calcium channel influx, and affecting the release of neurotransmitters upon its receptor binding and activation (Cohen et al. 2019). Effects of the endocannabinoid system on cancer biology: cell proliferation, cell death, and tumor angiogenesis Considering the relevance of mitochondrial function, targeting mtCB1 receptors could be a promising strategy for these pathologies. Their internalization and their biosynthesis were believed to lead to non-functional intracellular receptors . In the CNS, CB1 receptors are usually considered to be plasma membrane receptors with expression preferably at pre- and postsynaptic neurons and at astrocytes. Often, CBD is preferred due to its lack of the traditional effects of cannabis. When this happens, either CBD or Delta-9-tetrahydrocannabinol (THC) can be utilized to break down the fatty acids amide hydrolase, increasing the overall functioning of the endocannabinoid system. Sometimes, however, fatty acid amide hydrolase — an enzyme — binds to each receptor type, breaking them down, and limiting the effectiveness of the receptors. These are the CB(1) and CB(2) receptors we mentioned previously. After all, scientists discovered the endocannabinoid system just a few decades ago and are still learning new things about the human body’s unique network of receptors that interact with all cannabinoids, including CBD, THC, CBG, CBN and others. In summary, the interactions of THC, CB1, and the endocannabinoids are more complex than THC simply “hijacking” CB1 receptors as another agonist and need to be carefully considered. Interestingly, tonic activation of CB1 receptors by endocannabinoids is evident at several inhibitory synapses (98, 99), which may have important functional consequences when these synapses are exposed to THC. Taken together, all of these results suggest that the hydroxyl in the anandamide head group is not essential for receptor interaction, but that the cannabinoid receptor can accomodate both hydrophobic and hydrophilic head groups, possibly in two different subsites.The focus is on finding CB1 receptor antagonists and CB2 receptor agonists in the plant world.One of the primary receptors that has been researched is known as CB1.Given endocannabinoid high lipophilicity, the deduction of how such a movement across the cleft occurs will be a very great contribution to the field.When something happens that requires our body’s response, it creates these endocannabinoids that then “unlock” or bind to endocannabinoid receptors, which help our body adjust to whatever situation we’re facing.1As a result, the nerves are calmer, less inflammation occurs, and less pain is felt.Long-term effects, especially on neurocognitive development in children, remain poorly understood, underscoring the need for rigorous research and guidelines to ensure patient safety (70).Allosterism at GPCRs is currently proving to be a viable drug discovery strategy such as shown by the entrance in clinical phase I of HTL , a selective NAM for the metabotropic glutamate (mGlu) receptor 5 subtype (mGlu5).Haanen J, Obeid M, Spain L, Carbonnel F, Wang Y, Robert C, et al. Medical & Wellness These studies collectively contribute in bringing about new healthcare ideas. The effects of daily CBD oil usage depend on your conditions and how your body reacts. It’s also “medicinal” enough to reduce inflammation, protect your brain, and mitigate pain. In vitro activity in AD models indicates that indazole derivatives 5 and 6 (Figure 4) could be promising structures for further investigations. Moreover, multitarget indazolylketones have been proposed as potential therapeutic tools for the treatment of AD . The neuroprotective effects of this molecule were proved to be mediated by activation of PPAR-γ. CB1 receptors have shown G protein coupling promiscuity (Gαi, Gαs and Gαq), while CB2 primarily couple to Gαi-type G proteins 42,43. Activation of CB receptors elicits a cascade of intracellular signals upon coupling to different effector proteins, including G proteins and β-arrestins . In a neuronal model involving the endocannabinoid 2-AG, GAT211 and ZCZ011 modulated the synaptic transmission in autaptic hippocampal neurons . For instance, GAT211 showed antinociceptive efficacy in models of neuropathic and inflammatory pain without eliciting psychotropic effects and physical dependence . Fibromyalgia is also related to deficiencies in the endocannabinoid system and is characterized by acute and chronic widespread musculoskeletal pain throughout the body.CBD increases ERK1/2 and p38 activity within the MAPK pathway (Hwang et al. 2017; Vrechi et al. 2021) (Table 6, Fig. 7).Cannabinoid receptor-2 agonist inhibits macrophage induced EMT in non-small cell lung cancer by downregulation of EGFR pathway.A newly published review paper has discussed the preclinical and clinical studies on the role of endocannabinoids in the control of inflammatory and neuropathic pain in details .Comprising cannabinoid receptors (CB1 and CB2), endogenous ligands (endocannabinoids), and the enzymes responsible for their synthesis and degradation, the ECS has attracted increasing attention in cancer research. Figure 4. The endocannabinoid system was discovered in the late 20th century through a series of research developments. In the endocannabinoid system, enzymes are like workers creating and breaking down important molecules. They are particularly abundant in areas of the brain that control functions like mood, memory, motor control, and pain perception. Other functions that cannabinoids influence are the regulation of appetite, memory, mood, and fertility. Cannabinoids help your body stay in balance when it is expressing symptoms like physical pain and joint inflammation, as well as mental anxiety and depression. A compound that is one of the main constituents of the most common varietals of cannabis, having very little to no psychoactive effects. Felder and co-workers have reported that virodhamine has antagonist properties at the CB1 cannabinoid receptor . The first endogenous cannabinoid, N-arachidonoylethanolamine (AEA, also called anandamide, 5, Chart 2), was isolated from porcine brain by Mechoulam and co-workers . SR141716A (4) has been shown to act as a competitive antagonist and inverse agonist in host cells transfected with exogenous CB1 receptor, as well as in biological preparations endogenously expressing CB1 24–26. The AAIs, on the other hand, bear no obvious structural similarities with the classical/non-classical cannabinoids. The non-classical cannabinoids clearly share many structural features with the classical cannabinoids, e.g. a phenolic hydroxyl at C-1 (C2’), and alkyl side chain at C-3 (C-4’), as well as, the ability to adopt the same orientation of the carbocyclic ring as that in classical cannabinoids . Indeed, almost all skin cell populations (including those of the pilosebaceous unit) are capable of producing and releasing pro- and/or anti-inflammatory mediators that, by acting on neighboring cell types, can then fine-tune the overall immune response of the skin 1,3,5.In human studies, variability in cannabinoid formulations—ranging from pure CBD isolates to full-spectrum extracts with other cannabinoids—further complicates comparisons across trials.Medicine continues to struggle in its approaches to numerous common subjective pain syndromes that lack objective signs and remain treatment resistant.The Endocannabinoid System (ECS) plays a critical role in maintaining physiological homeostasis, influencing a range of processes such as neuroprotection, inflammation, energy metabolism, and immune responses.Nevertheless, targeting the cutaneous ECS for therapeutic gain remains an intriguing and provocative possibility warranting future studies.Endocannabinoids are also released in response to pain.Rhodopsin based models of the CB1 186–191 and CB2 184, 188, 191–194 receptors have been published by several research groups and new CB1 195, 196 and CB2 models based on the β2-AR crystal structure have recently been described.Additional ion channels involved in seizure activity modulation are KV7.2 and KV7.3 (Miceli et al. 2015), which CBD activates (Zhang et al. 2022) (Table 2, Fig. 3).By understanding this system, we begin to see a mechanism that could connect brain activity and states of physical health and disease.CBG (cannabigerol) is sometimes called “the mother of all cannabinoids” because it’s the precursor from which CBD, THC, and other cannabinoids are created. The three main parts of ECS include the endocannabinoids, the cannabinoid receptors, and enzymes. The ECS is a complicated network composed of enzymes, receptors, and endocannabinoids (hence its name). In addition to increasing the levels of endocannabinoids by delaying their reuptake and metabolic breakdown, CBD can also alter and adjust how your cannabinoid receptors function. Wrapping up endocannabinoid function Some experts think that an endocannabinoid deficiency could cause migraines, irritable bowel syndrome, and fibromyalgia. Therefore, it makes sense that deficient endocannabinoid levels would manifest as disorders through similar predictable channels. It was thought that CBD could help with sleep issues based on its interaction with GABA and serotonin receptors. It is not currently recommended to use cannabis as a replacement for other medications prescribed by your doctor because of the lack of clinical studies to prove its effectiveness. The group of cannabinoids comprise phytocannabinoids, endocannabinoids, and synthetic cannabinoids. Additionally, high-dose exposure has the potential to downregulate certain receptors, leading to decreased receptor expression and activity. Previous studies demonstrate that individual ligands act as allosteric modulators for multiple receptors, dramatically increasing the number of biological effects a single ligand can have (Wang et al. 2009). Given the widespread distribution of CB1Rs in the human body, it is reasonable for one to speculate a broad spectrum of physiological roles of the CB1R 3,9,63,126. Typically, the CB1R is coupled to Gi/o and inhibits the activity of adenylyl cyclase (AC), formation of cyclic adenosine monophosphate (cAMP), and the activity of protein kinase A (PKA). A previous study in mice demonstrated that acute administration of THC activated the PI3K/Akt pathway, but not ERK1/2 in several brain regions . Similarly, in rat cortical cultured neurons, a CB1R selective agonist, HU-210, exerts neuroprotective effects against the neurotoxin (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid through activation of the PI3K/Akt pathway but not MAPK pathways . Studies using β-arrestin 2 knockout mice have suggested a critical role of β-arrestin 2 in the regulation of CB1R activity 116,117. CB1R expression was also identifiable in the peripheral nervous system (PNS) as well as various circulating immune cells, including resident microglia, which later thought to have a role in regulating neuroinflammation through inhibition of nitric oxide secretion (Scotter et al. 2010).One of the most common uses of CBD is to treat pain, including chronic pain.JNK activation has been shown in transfected CHO-K1 cells, where G proteins, PI3K and Ras were involved in the transduction .Besides the aforementioned multitarget approaches, some ligands have been designed as probes for cannabinoid homo- or heterodimers.THC has an affinity for CB1, while CBD, CBC and CBG show a stronger preference for CB2 receptors.These cells contribute to tumor development by secreting various pro-tumor factors or by inducing immunosuppression.In fact, at the clinical levels, individuals who initially used opioid for their chronic pain were able to reduce the use of opioid by 40–60% after concomitant treatment with cannabis (Bellnier et al. 2018; Boehnke et al. 2016; Haroutounian et al. 2016).When activated, these CB1s block transmission of the pain signals to the brain—basically what topical anesthetics like novocaine do—and pain signals unable to reach the brain are not felt. In a (Tissue expression of CNR2 - Summary - The Human Protein Atlas n.d) SGTPγS binding assay using CHO cell membranes transfected with CB2 receptors (hCB2-CHO), 1 μM CBD showed a significantly lower KB than Ki, highlighting its function as an inverse agonist for CB2 (Thomas et al. 2007). Additionally, CBD alters the kinetics of internalization of CB1 receptors into the cell through β-arrestin recruitment (Table 1, Fig. 2) (Laprairie et al. 2015). CB1 and CB2 are G-protein-coupled receptors that confer intracellular signaling cascade activation when bound by ligands (Houston and Howlett 1998). When cannabinoids like CBD and THC enters the body, they interact with the body’s cannabinoid receptors. Endocannabinoids bind to CB1 receptors in a spinal nerve to reduce pain. The body has two major endocannabinoid and cannabinoid receptors, CB1 and CB2. Then there are endocannabinoid and cannabinoid receptors found all around the body. The difference between endocannabinoids and cannabinoids is that the body makes endocannabinoids while cannabinoids are not. The review begins more generally, however, by discussing the entire endocannabinoid system, of which the cannabinoid receptors are part. Furthermore, SNPs in ECS components11can also be investigated using human organoids generated from induced pluripotentstem cells,184,185with the additional potential of genomic manipulation using CRISPR/Castechnology186and pharmacological interventions, for example, with cannabinoids,187together with state-of-the-art analyses, such as single-cell RNA-seq.188These approaches will further strengthen mechanistic insights into the roles of theECS in psychiatric disorders. The early generationof such compounds often did not have high efficacy and selectivity173; however, recently, a series of compounds have been developed that lack activity oncannabinoid receptor, eCB-degrading enzymes, and binding to fatty-acid bindingprotein.174,175Inhibition of such a transporter is expected to enhance the availability ofextracellular eCBs, as eCBs cannot be transported into cells for degradation. Influence of DSP-4 and 5,7-DHT on hormones and P450 activity. The intracerebral administration of DSP-4, a noradrenergic toxin, and 5,7-dihydroxytryptamine (5,7-DHT), a serotonergic toxin, changed P450 enzyme activity (see Table 7). Influence of tryptophan-free diet on P450 activity. The use of cannabinoids in cancer treatment raises complex ethical and regulatory challenges, particularly due to gaps in registration and certification processes (67). Cannabinoids have shown potential in cancer treatment, especially in palliative care, but their antitumor effects depend on the type of tumor and dose (65). In tumors with high heterogeneity, the pleiotropic effects of cannabinoids vary widely across subpopulations, complicating the prediction of uniform therapeutic responses (28, 50). CB2, primarily expressed in immune cells, has demonstrated potential to limit inflammatory processes and modulate immunosuppression in the tumor microenvironment, thereby acting as a barrier against metastasis. A great deal of attention is being given to incorporating nonpsychotropic cannabinoids into medicinal preparations, although in most cases the actual effects of these agents on the nervous system are unknown. Depending on the nervous system regions and maladies involved, either stimulating or inhibiting the endocannabinoid system could have beneficial effects. Conversely, cannabinoids are good pain relievers that work in part by stimulating CB1s on peripheral pain sensory neurons. Psychotropic side effects of cannabis are caused exclusively by turning on or off brain CB1s. In 2020, the Global Cancer Observatory (GCO) recorded 19,976,499 new cases, with lung, breast, colorectal, prostate, stomach, and liver cancers being the most common. Dysfunction of this system can lead to a variety of pathological conditions, including cancer, reinforcing the importance of a thorough understanding of the ECS for developing new therapeutic approaches. In addition to these functions, the ECS is extensively studied in cancer. Additional applications could arise from studies on bone physiology, as blockage of CB2 has been reported to protect from bone loss in ovariectomized mice .Research so far has linked it to the betterment of conditions involving sleep, pain, and anxiety.With the legalization of marijuana in many states and resulting cultural acceptance of this drug for recreational and medical use, there has been an increased interest in using cannabis for a myriad of medical problems, including pain.In solid tumors like breast, lung, and prostate cancers, intratumoral variability is further amplified by clonal evolution, phenotypic plasticity, and interactions with the tumor microenvironment, presenting significant challenges to therapeutic efficacy (49–51).Cannabinoids produced in the laboratory to structurally or functionally mimic endocannabinoids or phytocannabinoids are synthetic cannabinoids.These findings further corroborate the anti-tumorigenic role of CB2 in colon cancer and suggest that this receptor might represent a promising target in cancer treatment.CBD treatment completely inhibited TNF-α production via p38 MAPK pathway (Figure 1) in microglial cells isolated from the retinas of newborn rats treated with endotoxin or LPS for acute ocular inflammation.This system includes cannabinoid receptor types 1 and 2 (CB1 and CB2), arachidonic acid-derived endocannabinoids, and enzymes involved in endocannabinoid metabolism. Treatment with CBD blocked all these effects (El-Remessy et al., 2008). CBD treatment completely inhibited TNF-α production via p38 MAPK pathway (Figure 1) in microglial cells isolated from the retinas of newborn rats treated with endotoxin or LPS for acute ocular inflammation. CBD is also a selective antagonist of GPR55, another G protein-coupled receptor present in human macrophages (Figure 1). In newborn pigs with HI brain injury, CBD administration reduced inflammation and prevented the increase in brain IL-1 levels. Getting High on the Endocannabinoid System. Although concepts and accumulating lines of evidence have been established, the challenges still remain in the cannabinoid research field and clinical practice. I believe that this special issue will promote further efforts to apply cannabinoid ligands as the therapeutic strategies for treating a variety of diseases. Xia et al. intent to answer another important question in cannabinoid research field, the heterogeneity. These behavioral effects were selectively additive with WIN55,212, suggesting terpenes can boost cannabinoid activity. One of the most common cannabinoids present in cannabis is tetrahydrocannabinol (THC). To avoid overcorrecting the condition, the enzymes break down the cannabinoids once the ECS has restored balance to the body. Others may connect to a CB2 receptor in your immune cells to signal inflammation, a typical symptom of autoimmune illnesses. A range of physiologic activities occurs when cannabinoid receptors are triggered.