The cannabinoid system and immune modulation

Figure 1.

“Studies on the effects of marijuana smoking have evolved into the discovery and description of the endocannabinoid system. To date, this system is composed of two receptors, CB1 and CB2, and endogenous ligands including anandamide, 2-arachidonoyl glycerol, and others. CB1 receptors and ligands are found in the brain as well as immune and other peripheral tissues. Conversely, CB2 receptors and ligands are found primarily in the periphery, especially in immune cells. Cannabinoid receptors are G protein-coupled receptors, and they have been linked to signaling pathways and gene activities in common with this receptor family. In addition, cannabinoids have been shown to modulate a variety of immune cell functions in humans and animals and more recently, have been shown to modulate T helper cell development, chemotaxis, and tumor development. Many of these drug effects occur through cannabinoid receptor signaling mechanisms and the modulation of cytokines and other gene products.

It appears the immunocannabinoid system is involved in regulating the brain-immune axis and might be exploited in future therapies for chronic diseases and immune deficiency.”

“The medicinal uses of marijuana were described centuries ago for diseases such as asthma, migraine, pain, convulsions, and anxiety (reviewed in ref.). More recently, emphasis has been placed on marijuana’s putative, beneficial effects on appetite, glaucoma, spasticity in multiple sclerosis, pain, and inflammation.

Recent experimental evidence supports marijuana’s therapeutic potential in some of these maladies.

The active plant ingredients in marijuana belong to the C21-cannabinoid compounds including the primary psychoactive compound, Δ9-tetrahydrocannabinol (THC). This cannabinoid along with others such as Δ8-THC, cannabidiol, and cannabinol, as well as chemical analogs, have been extensively studied over the years for their biological and therapeutic properties. Some of the properties of these agents have included effects on immunity ranging from suppression of resistance to infection to enhancement of IL-1 production by macrophages. These early studies about the immunomodulating effects of these drugs have been the subject of previous overviews and will not be reviewed here. Instead, we will briefly summarize the general features of the cannabinoid system and review recent findings on the structure and function of the cannabinoid system components in the immune system. For convenience, we will refer to this as the “immunocannabinoid” system.

CANNABINOID SYSTEM

Marijuana cannabinoids, analogs, and endocannabinoids”

https://jlb.onlinelibrary.wiley.com/doi/full/10.1189/jlb.0303101?sid=nlm%3Apubmed

Cannabinoids and the immune system.

“The effect of cannabimimetic agents on the function of immune cells such as T and B lymphocytes, natural killer cells and macrophages has been extensively studied over the past several decades using human and animal paradigms involving whole animal models as well as tissue culture systems.

From this work, it can be concluded that these drugs have subtle yet complex effects on immune cell function and that some of the drug activity is mediated by cannabinoid receptors expressed on the various immune cell subtypes.

However, the overall role of the cannabinoid system of receptors and ligands in human health and disease is still unclear and requires extensive elucidation.

Further studies will define the precise structure and function of the putative immunocannabinoid system, the potential therapeutic usefulness of these drugs in chronic diseases such as acquired immune deficiency syndrome and multiple sclerosis, the effects of these agents on tumour growth and induction of apoptosis, and the potential anti-inflammatory and proinflammatory properties of cannabimimetic compounds.

It is likely that the cannabinoid system, along with other neuroimmune systems, has a subtle but significant role in the regulation of immunity and that this role can eventually be exploited in the management of human disease.”

Cannabinoids and the immune system: an overview.

“Cannabinoids can influence the immune network. Data on the impact of exogenous cannabinoid ligands on immune function serve not only to understand how the endocannabinoid system modulates immune phenomena associated with infection or inflammation, but also to identify therapeutic targets for immune diseases.

Cannabinoids can modulate immune reactions in the periphery but also in the brain, influence T cell subset balance and cytokine expression and play a role in the balance between neuroinflammation and neurodegeneration. Immune cells can synthesize endocannabinoids and also be influenced by cannabinoid analogues.

Cannabinoid receptors show different expression on immune cells depending on activation status and stimuli. The complexity of relation between cannabinoid ligands of various classes and cannabinoid receptors brought the need to refine the simple conceptual frame of agonist-antagonists and offered potential implications for understanding interactions in pathological conditions.

The immune influence of cannabinoid ligands is not fully elucidated. However, aspects of their immunomodulatory effects provide the basis for a context-dependent targeted therapeutic approach, thus leading to the possibility for the use of cannabinoids in the treatment of inflammatory disease.”

Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis.

Abstract

“The endogenous cannabinoid (CB) (endocannabinoid) signaling system is involved in a variety of (patho)physiological processes, primarily by virtue of natural, arachidonic acid-derived lipids (endocannabinoids) that activate G protein-coupled CB1 and CB2 receptors. A hyperactive endocannabinoid system appears to contribute to the etiology of several disease states that constitute significant global threats to human health. Consequently, mounting interest surrounds the design and profiling of receptor-targeted CB antagonists as pharmacotherapeutics that attenuate endocannabinoid transmission for salutary gain. Experimental and clinical evidence supports the therapeutic potential of CB1 receptor antagonists to treat overweight/obesity, obesity-related cardiometabolic disorders, and substance abuse. Laboratory data suggest that CB2 receptor antagonists might be effective immunomodulatory and, perhaps, anti-inflammatory drugs. One CB1 receptor antagonist/inverse agonist, rimonabant, has emerged as the first-in-class drug approved outside the United States for weight control. Select follow-on agents (taranabant, otenabant, surinabant, rosonabant, SLV-319, AVE1625, V24343) have also been studied in the clinic. However, rimonabant’s market withdrawal in the European Union and suspension of rimonabant’s, taranabant’s, and otenabant’s ongoing development programs have highlighted some adverse clinical side effects (especially nausea and psychiatric disturbances) of CB1 receptor antagonists/inverse agonists. Novel CB1 receptor ligands that are peripherally directed and/or exhibit neutral antagonism (the latter not affecting constitutive CB1 receptor signaling) may optimize the benefits of CB1 receptor antagonists while minimizing any risk. Indeed, CB1 receptor-neutral antagonists appear from preclinical data to offer efficacy comparable to or better than that of prototype CB1 receptor antagonists/inverse agonists, with less propensity to induce nausea. Continued pharmacological profiling, as the prelude to first-in-man testing of CB1 receptor antagonists with unique modes of targeting/pharmacological action, represents an exciting translational frontier in the critical path to CB receptor blockers as medicines.”

http://www.ncbi.nlm.nih.gov/pubmed/19249987

Pharmacology of cannabinoids.

Abstract

“Dronabinol (Delta 9-tetrahydocannabinol, THC), the main source of the pharmacological effects caused by the use of cannabis, is an agonist to both the CB1 and the CB2 subtype of cannabinoid receptors. It is available on prescription in several countries. The non-psychotropic cannabidiol (CBD), some analogues of natural cannabinoids and their metabolites, antagonists at the cannabinoid receptors and modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues including spleen, leukocytes; reproductive, urinary and gastrointestinal tracts; endocrine glands, arteries and heart. Five endogenous cannabinoids have been detected so far, of whom anandamide and 2-arachidonylglycerol are best characterized. There is evidence that besides the two cannabinoid receptor subtypes cloned so far additional cannabinoid receptor subtypes and vanilloid receptors are involved in the complex physiological functions of the cannabinoid system that include motor coordination, memory procession, control of appetite, pain modulation and neuroprotection. Strategies to modulate their activity include inhibition of re-uptake into cells and inhibition of their degradation to increase concentration and duration of action. Properties of cannabinoids that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, anti-inflammation, anti-allergic effects, sedation, improvement of mood, stimulation of appetite, anti-emesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects.”

http://www.ncbi.nlm.nih.gov/pubmed/15159677

The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis

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“The therapeutic potential of cannabidiol (CBD), the major nonpsychoactive component of cannabis, was explored in murine collagen-induced arthritis (CIA).

CBD was administered after onset of clinical symptoms, and in both models of arthritis the treatment effectively blocked progression of arthritis. CBD was equally effective when administered i.p. or orally.

Clinical improvement was associated with protection of the joints against severe damage.

Taken together, these data show that CBD, through its combined immunosuppressive and anti-inflammatory actions, has a potent anti-arthritic effect in CIA.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC16904/

“In the present study, we report that CBD has a beneficial therapeutic action on established CIA, and we explore its mode of action.”   http://www.pnas.org/content/97/17/9561.long

Anti-Inflammatory Effect of the Endocannabinoid Anandamide in Experimental Periodontitis and Stress in the Rat

“Periodontitis is an infectious disease leading to inflammation and destruction of tissue surrounding and supporting the tooth”. Considering: “Anti-Inflammatory Effect of the Endocannabinoid Anandamide in Experimental Periodontitis and Stress in the Rat” and the important “Involvement of the endocannabinoid system in periodontal healing”

http://www.ncbi.nlm.nih.gov/pubmed/22777139

Cannabinoids for gastrointestinal diseases: potential therapeutic applications

“…pharmacological modulation of the endogenous cannabinoid system could provide new therapeutics for the treatment of a number of gastrointestinal diseases, including nausea and vomiting, gastric ulcers, irritable bowel syndrome, Crohn’s disease, secretory diarrhoea, paralytic ileus and gastroesophageal reflux disease. Some cannabinoids are already in use…”

http://www.ncbi.nlm.nih.gov/pubmed/12517253

Rheumatoid arthritis, cannabis based medicine eases pain and suppresses disease

“The first study to use a cannabis-based medicine (CBM) for treating rheumatoid arthritis has found that it has a significant effect on easing pain and on suppressing the disease”

http://www.medicalnewstoday.com/releases/33376.php