Learn how terpenes and inflammation are related, and how utilizing them to our advantage may promote healing in the many conditions related to chronic. Let's look at some of the best cannabis cultivars for pain relief, based on your Jack Herer– Cannabis enthusiasts might recognize the name Jack Herer, as he. Learn how terpenes and inflammation are related, and how utilizing their chemistry to our advantage may promote healing.
For Best Terpenes What Be Inflammation? May
The protective role of the endogenous cannabinoid system was observed 24 h after DNBS treatment and became more evident on days 2 and 3. This gives further support to the notion that the endogenous cannabinoid system is protective against inflammatory changes. These data indicated that the activation of CB1 and the endogenous cannabinoid system is an early and important physiological step in self-protection of the colon against inflammation.
Pharmacological stimulation of cannabinoid receptors with the potent agonist HU also induced a reduction of experimental colitis. It has been reported that cannabinoid receptor stimulation could have a beneficial effect on experimental colitis [ 64 ]. Intraperitoneal application of ACEA, a CB1-selective agonist, and JWH, a CB2-selective agonist, inhibited oil of mustard OM -induced colitis and subsequent symptoms such as induced distal colon weight gain, colon shrinkage, inflammatory damage, diarrhea and histological damage.
This study demonstrated a role for CB2 activation in experimental colitis. The fact that both CB1 and CB2 agonists are active in colitis models lends additional support to the theory that signaling through cannabinoid receptors may mediate protective mechanisms in colitis. In the small intestine, the involvement of CB1 receptors in the control of intestinal motility during croton oil-induced inflammation was recently demonstrated.
It was further suggested that increased levels of CB1 receptor expression in inflamed jejuna may contribute to this protective effect. CB1 receptors were shown to modulate gastrointestinal motility during croton oil-induced inflammation in mice. Fatty acid amide hydrolase is the major enzyme involved in the degradation of several bioactive fatty amides, in particular anandamide [ 11 ], and its genetic deletion in mice leads to a strongly decreased ability to degrade this endocannabinoid and an increase of anandamide levels in several tissues [ 66 ].
In conclusion, cannabinoids have been shown to regulate the tissue response to excessive inflammation in the colon, mediated by both dampening smooth-muscular irritation caused by inflammation and suppressing proinflammatory cytokines, thus controlling the cellular pathways leading to inflammatory responses. These results strongly suggest that modulation of the physiological activity of the cannabinoid system during colonic inflammation might be a promising therapeutic tool for the treatment of several diseases characterized by inflammation of the GI tract.
During the past few years, awareness of the cannabinoid system in the pathophysiology of liver disease has gained momentum. Both CB1 and CB2 receptors have been shown to be upregulated in the early stages of liver injury [ 68 — 72 ].
Although embryonic liver has been shown to express CB2 receptor mRNA, adult liver hepatocytes and endothelial cells displayed only a faint physiological level of expression of CB1 receptors and were shown to produce low levels of endocannabinoids. CB1 receptors have been found to be upregulated in the vascular endothelium and in myofibroblasts located in fibrotic bands of cirrhotic livers in human and rodents [ 72 ].
CB2 receptors are also expressed in myofibroblasts, inflammatory cells and biliary epithelial cells [ 69 ]. There has been growing evidence in recent years to suggest that endocannabinoids may regulate the pathophysiology of liver diseases, including both acute forms of hepatic injury, liver fibrosis and cirrhosis. The endocannabinoids are found in low levels in normal liver, which may be due to high levels of expression of FAAH, which is responsible for the breakdown of AEA [ 11 ].
The levels of AEA have been shown to increase in the liver and serum during acute hepatitis and fatty liver disease [ 70 ]. Together, the above studies suggest that endocannabinoids and their receptors may play a critical role in regulating liver fibrogenesis; therefore, targeting the cannabinoid receptors may serve as a novel tool to prevent and treat liver injury.
While the mechanisms of inflammatory liver injury are unclear, they are accompanied by infiltration of activated polymorphonuclear leukocytes, activation of Kupffer cells, production of proinflammatory cytokines and generation of ROS. Many recent studies indicated strongly the increased upregulation of the endocannabinoid system during liver diseases involving hepatocyte injury, inflammation, fibrogenesis, hepatic encephalopathy, cirrhotic cardiomyopathy and portal hypertension [ 73 ].
Moreover, pretreatment of mice with JWH, a CB2 receptor agonist, was shown to decrease the degree of liver tissue injury and inflammatory cell infiltration and decrease serum levels of cytokines, chemokines and adhesion molecules [ 74 ]. The data also highlights the protective role of CB2 receptor activation in the inflammatory response associated with chronic liver diseases such as viral hepatitis and alcoholic or nonalcoholic fatty liver diseases.
Viral hepatitis, alcohol abuse and nonalcoholic fatty liver are some of the conditions that can induce chronic liver injury and inflammation, leading to activation of fibrogenesis as a wound-healing mechanism. However, persistence of fibrogenic stimuli can enhance deposition of the extracellular matrix by hepatic myofibroblasts, thus disrupting normal liver architecture and, ultimately, leading to cirrhosis and liver failure.
CB1 and CB2 receptors are shown to be markedly upregulated in cirrhotic human liver samples, demonstrating the impact of endocannabinoids in liver fibrogenesis.
In addition, increases in circulating levels of anadamide and hepatic 2-AG have also been reported in cirrhosis and liver fibrosis, respectively [ 73 ]. By contrast, activation of CB1 receptors was found to promote profibrotic response [ 72 ]. Further effects of the endocannabinoids have also been shown to be receptor independent.
AEA and 2-AG have been shown to induce necrosis and apoptosis, respectively, in activated hepatic stellate cells, through increased generation of ROS [ 76 ]. The abuse of cannabis has been shown to promote liver fibrosis in patients with chronic hepatitis C, indicating that cannabinoids may exacerbate liver fibrogenesis and that CB1 receptor antagonists may play a role as anti-fibrosing molecules [ 71 ].
However, an alternative explanation could be that marijuana can trigger immunosuppression. For example, CB2 activation in immune cells can trigger apoptosis and this, in turn, can have an immunosuppressive effect in patients with hepatitis C. As such patients require immunocompetent cells to keep hepatitis under control, chronic marijuana abuse may promote fibrogenesis through the activation of CB2 and consequent suppression of antiviral immunity [ 77 ].
Endocannabinoids may also regulate liver cirrhosis by acting as mediators of vascular and cardiac functions. Endocannabinoids can trigger vasorelaxation, while an upregulated CB1-mediated cannabinoid tone causes enhanced mesenteric vasodialation leading to portal hypertension [ 73 , 75 ]. A recent in vivo study by Batkai et al. Further improvement in contractile function of isolated papillary muscles was observed following treatment with AM, a CB1 receptor antagonist, suggesting therapeutic potential against cirrhotic cardiomyopathy [ 75 ].
There are limited, but reliable, data on the neuroprotective role of the endocannabinoid system in hepatic encephalopathy. It has been demonstrated in a murine model that, during fulminant hepatic failure, levels of 2-AG in the brain are elevated, potentially as a response to liver damage.
Thus, influencing the endocannabinoid system with exogenous cannabinoid derivates specific for the CB1 or CB2 receptor may have a beneficial therapeutic effect on neurological dysfunction in liver diseases [ 78 ].
Recently, we noted that both exogenous and endogenous cannabinoids protected mice from concanavalin-A ConA -induced acute hepatitis, a model that mimics viral or autoimmune hepatitis, in which T cells play a critical role in triggering liver injury. We found that administration of a single dose of THC or anandamide could ameliorate Con-A-induced hepatitis.
This overwhelming evidence shows that the cannabinoid system must play a major role in the pathophysiology of various liver diseases and its therapeutic potential should be exploited for the treatment of chronic liver injuries Figure 2. Endocannabinoids, CB1 antagonists and CB2 agonists as potential drugs for the treatment of liver injury.
The major immune cell populations involved in joint injury are macrophages, T cells, fibroblast-like synoviocytes and DCs. Cannabinoids and their anti-inflammatory properties have been studied in animal models of RA and on human cells from RA patients and these studies demonstrate the anti-arthritic properties of these natural plant compounds [ 32 , 82 — 84 ]. Interestingly, most of the studies on RA and cannabinoids focus on the use of nonpsychoactive cannabinoids.
CBD is the major nonpsychoactive component of the cannabis plant and its protective effect has been shown in murine collagen-induced arthritis [ 85 ]. Lymph node cells from HUtreated mice showed decreased proliferative responses when the cells from 7-day post-inflammation mice were incubated with collagen II. In a different study, Parker et al.
AjA also exerts its immunomodulatory effects by inducing apoptosis in mature osteoclast-like cells and, therefore, protecting the host from osteoclastogenesis.
The hallmarks of cancer-related inflammation include the presence of inflammatory cells in tumor tissue, and the regulation of tumor growth, metastasis and angiogenesis by inflammatory mediators e. The connection between inflammation and cancer is now generally accepted and nonsteroidal anti-inflammatory drugs have been shown to reduce varied cancer risk.
Hence, inflammation can be considered as a therapeutic opportunity in certain types of cancer. Recent applications of cannabinoids have been extended as antitumor agents [ 1 , 88 ], which relies on their ability to inhibit tumor angiogenesis [ 89 ] or induce direct apoptosis or cell cycle arrest in neoplastic cells [ 89 — 92 ].
A focus on the antiproliferative effects of these compounds in various tumors, such as breast and prostate cancers, pheochromocytoma and malignant gliomas, has been proposed [ 1 , 92 — 94 ]. Our laboratory reported that, in vitro , THC and other cannabinoids could induce apoptosis in transformed murine and human T cells [ 95 ], including primary acute lymphoblastic human leukemia cells. The role of endocannabinoids as potential endogenous tumor growth inhibitors has been suggested in a study where it was observed that levels of both AEA and 2-AG were higher in precancerous polyps than in fully developed carcinomas in the colon [ 98 ].
Recent in vivo studies proposed that selective targeting of CB2 receptors resulted in colorectal tumor growth inhibition via apoptosis, which was mediated through the stimulation of ceramide [ 98 ]. In a xenograft model of thyroid cancer, substances that blocked endocannabinoid degradation also increased the levels of AEA and 2-AG in the tissue and reduced tumor growth [ 99 ]. Various attempts have been made to inactivate cannabinoid-degrading enzymes, thereby increasing the local concentration of endocannabinoids at the tumor cell surface.
This leads to anti-tumor effects of CB receptor signaling in various cancer types, such as thyroid, brain and prostate cancer [ 99 — ]. Although the majority of the effects of cannabinoids are CB receptor mediated, AEA has been shown to induce its effects on cancerous cells by interacting with TRPV1 receptor [ , ] or cholesterol-rich lipid rafts [ ].
Furthermore, it has been reported that signaling pathways are differentially regulated by cannabinoids in normal cells versus cancer cells. In malignancies, such as thyroid cancer, lymphoma, melanoma, pancreas and breast cancer, the levels of cannabinoid receptors are often higher in the tumor compared with normal cells of the same origin, resulting in increased sensitivity to cannabinoids in the malignancies [ 89 , — ].
Moreover, many animal studies have reported antiproliferative and pro-apoptotic effects of cannabinoids on tumor cells but not on normal tissue [ 89 , 91 ]. Thus, the role of the cannabinoid system in cancer indicates that this system is involved in regulating many of the functions that are essential in cancer development.
Allergic asthma is a complex inflammatory disorder characterized by airway hyper-responsiveness, elevated serum IgE, recruitment of eosinophils into the lung and mucus hypersecretion by goblet cells [ ]. While most studies have shown that cannabinoids, such as THC, facilitate a Th1 to Th2 cytokine switch, as discussed previously, it is surprising that cannabinoids can also suppress allergic asthma triggered primarily by Th2 cytokines.
Previous findings indicated that aerosolized THC was capable of causing significant bronchodilatation with minimal systemic side effects, but had a local irritating effect on the airways [ ].
Further bronchodilator effects of cannabinoids administered orally or by aerosol to asthmatic patients have also been reported [ , ]. Similarly, endogenous cannabinoids have been shown to regulate airway responsiveness. It was reported that activation of CB1 receptors by locally released anandamide may participate in the control of bronchial contractility.
However, the authors further suggested that the effects of AEA may depend on the state of the bronchial muscle. During capsaicin-evoked bronchospasm, AEA may reduce the muscle contraction, whereas AEA may cause bronchoconstriction in the absence of vagus nerve-constricting tone [ ].
Cannabidiol has been shown to be effective in protecting endothelial function and integrity in human coronary artery endothelial cells HCAECs. In addition, proliferation and migration was markedly increased in activated cell populations. The use of CB2 agonists JWH and HU inhibited all activated pathways in a dose-dependent manner, establishing a novel use for these cannabinoid compounds [ ].
EAU was strongly inhibited when the CB2 was engaged and the effects of CB2 engagement appeared to be mediated predominantly through downregulation of T-cell function with a less-marked effect on antigen presentation [ ].
An impaired T-cell-proliferative response in leukocytes from JWHtreated mice was also accompanied by marked reductions in cytokine production. A study performed by Li et al. Similarly, CBD treatment has been shown to significantly inhibit and delay destructive insulitis and inflammatory Th1-associated cytokine production in nonobese diabetes-prone NOD female mice. A recent study indicated that treatment of 11—week-old female NOD mice, either in a latent diabetes stage after 14 weeks or with initial symptoms of diabetes appearing up to 14 weeks with CBD for 4 weeks, could lead to sustained inhibition of insulitis [ ].
CBD treatment inhibited specific destruction of the islets and reduced the infiltrates by mononuclear cells into the islets, thus preventing diabetes. Furthermore, cannabinoids have also been demonstrated to possess additional beneficial effects in animal models of diabetes. It has been reported that rats treated with CBD for periods of 1—4 weeks experienced significant protection from diabetic retinopathy [ ].
Cannabinoids have also been shown to alleviate neuropathic pain associated with the disease. Mice injected with a cannabis receptor agonist experienced a reduction in diabetic-related tactile allodynia compared with nontreated controls [ ].
Thus, cannabinoids can be considered useful for controlling T1D due to their anti-inflammatory properties. It is becoming increasingly clear that cannabinoid receptors and their endogenous ligands play a crucial role in the regulation of the immune system.
Exogenous cannabinoids have been shown to suppress T-cell-mediated immune responses by primarily inducing apoptosis and suppressing inflammatory cytokines and chemokines.
Such observations indicate that targeting cannabinoid receptor—ligand interactions may constitute a novel window of opportunity to treat inflammatory and autoimmune disorders. As CB2 receptors are primarily expressed on immune cells, targeting CB2 may result in selective immunomodulation without overt toxicity. The future challenges for the use of cannabinoids as anti-inflammatory drugs include synthesis of cannabinoid receptor agonists that are nonpsychoactive with anti-inflammatory activity and then identifying their mode of action.
Although current studies suggest that cannabinoids are useful therapeutic agents in the treatment of various inflammatory disorders, further evaluation of the mechanisms that account for their anti-inflammatory properties is necessary. Such studies may involve the use of cannabinoid receptor-knockout mice and use of receptor-specific compounds. Whether endocannabinoids and cannabinoid receptors play a critical role during normal inflammatory response also requires further consideration.
Moreover, cannabinoid receptor signaling and effect of cannabinoids on adhesion molecules, co-stimulatory molecules and chemokines require further study in order to increase our understanding of cannabinoids and their intricate effects on immune system disorders. Overall, cannabinoids have exhibited significant potential to be used as novel anti-inflammatory agents and specific targeting of CB2 receptors holds the promise of mediating immunosuppressive effects without exerting psychotropic side effects.
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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See other articles in PMC that cite the published article. Abstract Cannabinoids are a group of compounds that mediate their effects through cannabinoid receptors. Table 1 Selected cannabinoid molecules. Open in a separate window. Apoptotic effects of cannabinoids on immune cell populations One major mechanism of immunosupression by cannabinoids is the induction of cell death or apoptosis in immune cell populations. Cannabinoid action on cytokines Cytokines are the signaling proteins synthesized and secreted by immune cells upon stimulation.
Table 2 Effect of cannabinoids on cytokine and chemokine production. Cannabinoids and multiple sclerosis The three main cell types that are involved in demyelination of the nerve fibers and axons in the CNS include activated T-cells, microglia and astrocytes. Reactive oxygen species production by mitochondria. Future perspective It is becoming increasingly clear that cannabinoid receptors and their endogenous ligands play a crucial role in the regulation of the immune system. Executive summary Cannabinoids, the active components of Cannabis sativa, and endogenous cannabinoids mediate their effects through activation of specific cannabinoid receptors known as cannabinoid receptor 1 and 2 CB1 and CB2.
The cannabinoid system has been shown both in vivo and in vitro to be involved in regulating the immune system through its immunomodulatory properties. Cannabinoids suppress inflammatory response and subsequently attenuate disease symptoms. Cannabinoids have been tested in several experimental models of autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, colitis and hepatitis and have been shown to protect the host from the pathogenesis through induction of multiple anti-inflammatory pathways.
Cannabinoids may also be beneficial in certain types of cancers that are triggered by chronic inflammation. In such instances, cannabinoids can either directly inhibit tumor growth or suppress inflammation and tumor angiogenesis.
Sometimes, response to self antigens can trigger severe tissue injury. Footnotes For reprint orders, please contact moc. CA Cancer J Clin. Pollmann W, Feneberg W. Current management of pain associated with multiple sclerosis. Cannabinoids for control of chemotherapy induced nausea and vomiting: Croxford JL, Yamamura T.
Cannabinoids and the immune system: Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol. Cannabinoid receptors are coupled to nitric oxide release in invertebrate immunocytes, microglia, and human monocytes. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Biophys Res Commun. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides.
Identification of intracellular carriers for the endocannabinoid anandamide. The biochemistry of apoptosis. J Pharmacol Exp Ther. Cannabinoid treatment suppresses the T-helper cell-polarizing function of mouse dendritic cells stimulated with Legionella pneumophila infection. A comparative study on cannabidiol-induced apoptosis in murine thymocytes and EL-4 thymoma cells. Ajulemic acid, a nonpsychoactive cannabinoid acid, induces apoptosis in human T lymphocytes.
CB2 cannabinoid receptor agonist, JWH, triggers apoptosis in immune cells: Role of CB1 and CB2 receptors in the inhibitory effects of cannabinoids on lipopolysaccharide-induced nitric oxide release in astrocyte cultures. Cannabinoid-mediated neuroprotection, not immunosuppression, may be more relevant to multiple sclerosis. Genomic and functional changes induced by the activation of the peripheral cannabinoid receptor CB2 in the promyelocytic cells HL Possible involvement of the CB2 receptor in cell differentiation.
Effects of cannabinoid receptor agonist and antagonist ligands on production of inflammatory cytokines and anti-inflammatory interleukin in endotoxemic mice. Suppression of human macrophage interleukin-6 by a nonpsychoactive cannabinoid acid.
Inhibitory effect of synthetic cannabinoids on cytokine production in rheumatoid fibroblast-like synoviocytes. Anandamide, a natural ligand for the peripheral cannabinoid receptor is a novel synergistic growth factor for hematopoietic cells. Pharmacological modulation of the endocannabinoid system in a viral model of multiple sclerosis. Progesterone up-regulates anandamide hydrolase in human lymphocytes: The challenge of multiple sclerosis: Cannabinoids and multiple sclerosis.
CB2 cannabinoid receptors as an emerging target for demyelinating diseases: The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis. T- and B-cell responses to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis and multiple sclerosis. Aranami T, Yamamura T. Therapeutic action of cannabinoids in a murine model of multiple sclerosis.
A cannabinoid agonist interferes with the progression of a chronic model of multiple sclerosis by downregulating adhesion molecules. Stimulation of cannabinoid receptor 2 CB2 suppresses microglial activation. Even cooler, caryophyllene has been found to relieve stress to such a great extent in C. The belief is that this effect can also be experienced by humans.
Multiple studies have shown beta-caryophyllene to be a promising treatment for cancer. The terpene has been found to enhance the effectiveness of chemotherapy and fight the proliferation of cancer cells.
The most common terpene in the plant kingdom, pinene is known for its refreshing, crisp aroma. The alpha version of pinene smells like pine while the beta version smells like parsley, dill, and basil. This terpene has a host of therapeutic effects. It has antibacterial, anti-inflammatory, antiproliferative, and anti-oxidant properties. It also has the interesting ability to enhance memory retention.
Like myrcene, pinene also has the ability to directly affect the potency of your high. Unlike myrcene, it has an inhibiting rather than augmenting effect. Linalool is a sleep aid and an analgesic and has been used as an alternative therapy for chronic and acute pain.
Linalool may help breast cancer patients by keeping tumors receptive to drugs. This is extremely helpful since drug resistance is a major obstacle cancer patients face. Found in the rinds of citrus fruits, rosemary, peppermint, juniper, and pine needles, limonene is known for its use in perfumes, cleaning products, and medicines. Its therapeutic benefits are numerous. It has been used as an anti-inflammatory, antifungal, and an antibacterial.
It helps alleviate bronchitis. It can reduce heartburn because of its ability to mitigate gastric reflux. In addition to these wonderful physical effects, it is known to make people happy; It is a stress reliever and mood enhancer.
Additionally, its anti-inflammatory properties may prove to be cancer preventative since inflammation plays an important role in the development of cancer cells.
Cannabinoids as novel anti-inflammatory drugs
A new hemp oil study found that cannabis-derived terpenes can help guard against oxidative stress, inflammation, and pain. Here are some of the most well known terpenes right now, most of which High levels of limonene can be found in strains like O.G. Kush, Sour Like many other , pinene terpenes have an anti-inflammatory effect on humans. Studies suggest that terpenes may be responsible for the different effects anti- septic, anti-bacterial, anti-fungal, and anti-inflammatory.