Cannabinoid-based drugs targeting CB1 and TRPV1, the sympathetic nervous system, and arthritis.

Posted on September 8, 2015 by David

“Chronic inflammation in rheumatoid arthritis (RA) is accompanied by activation of the sympathetic nervous system, which can support the immune system to perpetuate inflammation. Several animal models of arthritis already demonstrated a profound influence of adrenergic signaling on the course of RA.

Peripheral norepinephrine release from sympathetic terminals is controlled by cannabinoid receptor type 1 (CB1), which is activated by two major endocannabinoids (ECs), arachidonylethanolamine (anandamide) and 2-arachidonylglycerol.

These ECs also modulate function of transient receptor potential channels (TRPs) located on sensory nerve fibers, which are abundant in arthritic synovial tissue. TRPs not only induce the sensation of pain but also support inflammation via secretion of pro-inflammatory neuropeptides.

In addition, many cell types in synovial tissue express CB1 and TRPs.

In this review, we focus on CB1 and transient receptor potential vanilloid 1 (TRPV1)-mediated effects on RA since most anti-inflammatory mechanisms induced by cannabinoids are attributed to cannabinoid receptor type 2 (CB2) activation.

We demonstrate how CB1 agonism or antagonism can modulate arthritic disease.

The concept of functional antagonism with continuous CB1 activation is discussed.

Since fatty acid amide hydrolase (FAAH) is a major EC-degrading enzyme, the therapeutic possibility of FAAH inhibition is studied.

Finally, the therapeutic potential of ECs is examined since they interact with cannabinoid receptors and TRPs but do not produce central side effects.”

http://www.ncbi.nlm.nih.gov/pubmed/26343051

HU-444, A Novel, Potent Anti-Inflammatory, Non-Psychotropic Cannabinoid.

Posted on August 15, 2015 by David

“Cannabidiol (CBD) is a component of cannabis, which does not cause the typical marijuana-type effects, but has a high potential for use in several therapeutic areas.

In contrast to Δ9-tetrahydrocannabinol (Δ9-THC) it binds very weakly to the CB1 and CB2 cannabinoid receptors. It has potent activity in both in vitro and in vivo anti-inflammatory assays. Thus, it lowers the formation of TNF-α, a proinflammatory cytokine, and was found to be an oral anti-arthritic therapeutic in murine collagen-induced arthritis in vivo.

However in acidic media it can cyclize to the psychoactive Δ9-THC. We report the synthesis of a novel CBD derivative, HU-444, which cannot be converted by acid cyclization into a Δ9-THC-like compound.

In vitro HU-444 had anti-inflammatory activity (decrease of reactive oxygen intermediates and inhibition of TNF-a production by macrophages); in vivo it led to suppression of production of TNF-α and amelioration of liver damage as well as lowering of mouse collagen-induced arthritis. HU-444 did not cause Δ9-THC- like effects in mice.

We believe that HU-444 represents a potential novel drug for rheumatoid arthritis and other inflammatory diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/26272937

The endocannabinoid system and its therapeutic implications in rheumatoid arthritis.

Posted on March 21, 2015 by David

“Since the discovery of the endogenous receptor for Δ9-tetrahydrocannabinol, a main constituent of marijuana, the endocannabinoid system (comprising cannabinoid receptors and their endogenous ligands, as well as the enzymes involved in their metabolic processes) has been implicated as having multiple regulatory functions in many central and peripheral conditions, including rheumatoid arthritis (RA).

RA is an immune-mediated inflammatory disease that is associated with the involvement of many kinds of cells (such as fibroblastlike synoviocytes [FLSs], osteoclasts, T cells, B cells, and macrophages) and molecules (such as interleukin-1β, tumor necrosis factor-α, interleukin-6, matrix metalloproteinases [MMPs], and chemokines). Increasing evidence suggests that the endocannabinoid system, especially cannabinoid receptor 2 (CB2), has an important role in the pathophysiology of RA.

Many members of the endocannabinoid system are reported to inhibit synovial inflammation, hyperplasia, and cartilage destruction in RA.

In particular, specific activation of CB2 may relieve RA by inhibiting not only the production of autoantibodies, proinflammatory cytokines, and MMPs, but also bone erosion, immune response mediated by T cells, and the proliferation of FLSs.

In this review, we will discuss the possible functions of the endocannabinoid system in the modulation of RA, which may be a potential target for treatment.”

http://www.ncbi.nlm.nih.gov/pubmed/25791728

http://www.thctotalhealthcare.com/category/rheumatoid-arthritis-2/

Activation of cannabinoid receptor 2 attenuates synovitis and joint distruction in collagen-induced arthritis.

Posted on January 22, 2015 by David

“Recent studies have suggested immunomodulatory and anti-inflammatory effects of cannabinoid receptor 2 (CB2R) activation, which is devoid of psychoactivity. We have demonstrated the expression of CB2R in synovial tissue from patients with rheumatoid arthritis (RA), and its specific activation shows inhibitory effects on fibroblast-like synoviocytes. However, it is still unclear whether selective activation of CB2R inhibits joint inflammation or protects joint damage in RA.

CONCLUSIONS:

Activation of CB2R by HU-308 has therapeutic potential for RA to suppress synovitis and alleviate joint destruction by inhibiting the production of autoantibodies and proinflammatory cytokines.”

http://www.ncbi.nlm.nih.gov/pubmed/25601571

http://www.thctotalhealthcare.com/category/arthritis/

Tapping into the endocannabinoid system to ameliorate acute inflammatory flares and associated pain in mouse knee joints.

Posted on September 28, 2014 by David

“During the progression of rheumatoid arthritis (RA), there are frequent but intermittent flares in which the joint becomes acutely inflamed and painful.

Although a number of drug therapies are currently used to treat RA, their effectiveness is variable and side effects are common.

Endocannabinoids have the potential to ameliorate joint pain and inflammation, but these beneficial effects are limited by their rapid degradation.

One enzyme responsible for endocannabinoid break down is fatty acid amide hydrolase (FAAH). The present study examined whether URB597, a potent and selective FAAH inhibitor, could alter inflammation and pain in a mouse model of acute synovitis.

Conclusions: These results suggest that the endocannabinoid system of the joint can be harnessed to decrease acute inflammatory reactions and the concomitant pain associated with these episodes.”

http://www.ncbi.nlm.nih.gov/pubmed/25260980

http://www.thctotalhealthcare.com/category/rheumatoid-arthritis-2/

More Evidence Pot Treats Auto-Immune Diseases

Posted on June 9, 2014 by David

“Researchers at the University of South Carolina have another clue as to why patients with auto-immune diseases like multiple sclerosis, psoriasis, rheumatoid arthritis, Crohn’s and celiac disease sometimes respond to medical marijuana therapies, according to Science World Reports.

The main active ingredient in pot, THC, regulates gene expression in immune cells, effectively switching off runaway inflammation at the DNA level.

The researchers used mice cells in vivo and the results suggest that “THC activates the expression of a subset of genes while suppressing the expression of another subset of genes.” The net result is less inflammatory response, which can severely damage and kill cells.

Autoimmune diseases involve an abnormal immune response of the body, causing immune cells to attack healthy cells instead of pathogens. Autoimmune diseases — a collection of about 80 diseases — are the 10th leading cause of death of women in all age groups up to 65 years old.

Despite the safety and efficacy of medical cannabis, providers remain under attack across America. California senators Barbara Boxer and Dianne Feinstein currently support the war on pot patients and providers. The Drug Policy Alliance has started a new campaign today to help citizens lobby Senators to defund the war on medical marijuana.”

http://www.eastbayexpress.com/LegalizationNation/archives/2014/06/03/more-evidence-pot-treats-auto-immune-diseases

Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression.

Posted on June 9, 2014 by David

Fig. 1

“Cannabinoids are a group of compounds found in the marijuana plant (Cannabis sativaL.). Marijuana has been used both for recreational and medicinal purposes for several centuries.

Cannabinoids have been shown to be effective in the treatment of nausea and vomiting associated with cancer chemotherapy, anorexia and cachexia seen in HIV/AIDS patients, as well as neuropathic pain, and spasticity in multiple sclerosis.

More recently, the anti-inflammatory properties of cannabinoids are drawing significant attention. In the last 15 years, studies with marijuana cannabinoids led to the discovery of cannabinoid receptors (CB1 and CB2) and their endogenous ligands, which make up what is known as the endocannabinoid system.

Cannabinoids are a group of compounds present in Cannabis plant (Cannabis sativa L.). They mediate their physiological and behavioral effects by activating specific cannabinoid receptors. With the recent discovery of the cannabinoid receptors (CB1 and CB2) and the endocannabinoid system, research in this field has expanded exponentially.

Cannabinoids have been shown to act as potent immunosuppressive and anti-inflammatory agents and have been shown to mediate beneficial effects in a wide range of immune-mediated diseases such as multiple sclerosis, diabetes, septic shock, rheumatoid arthritis, and allergic asthma.

Cannabinoid receptor 1 (CB1) is mainly expressed on the cells of the central nervous system as well as in the periphery. In contrast, cannabinoid receptor 2 (CB2) is predominantly expressed on immune cells. The precise mechanisms through which cannabinoids mediate immunosuppression is only now beginning to be understood…

In this review, we will focus on apoptotic mechanisms of immunosuppression mediated by cannabinoids on different immune cell populations and discuss how activation of CB2 provides a novel therapeutic modality against inflammatory and autoimmune diseases as well as malignancies of the immune system, without exerting the untoward psychotropic effects…

…cannabinoids do induce apoptosis in immune cells, alleviating inflammatory responses and protecting the host from acute and chronic inflammation.

The cumulative effect of cannabinoids on all cell populations of the immune system can be beneficial, when there is a need for immune suppression.

For example, in patients with autoimmune diseases such as multiple sclerosis, arthritis and lupus, or in those with septic shock, where the disease is caused by activated immune cells, targeting the immune cells via CB2 agonists may trigger apoptosis and act as anti-inflammatory therapy.

CB2 select agonists are not psychoactive and because CB2 is expressed primarily in immune cells, use of CB2 agonists could provide a novel therapeutic modality against autoimmune and inflammatory diseases.

In addition to the use of exogenous cannabinoids, in vivo manipulation of endocannabinoids may also offer novel treatment opportunities against cancer and autoimmune diseases.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005548/

Expression of cannabinoid receptor 2 and its inhibitory effects on synovial fibroblasts in rheumatoid arthritis.

Posted on January 21, 2014 by David

“Recent studies have suggested immunomodulatory and anti-inflammatory effects of cannabinoid receptor 2 (CB2R) activation, which shows no psychoactivity…

These data suggest that CB2R may be a potential therapeutic target of RA.”

http://www.ncbi.nlm.nih.gov/pubmed/24440992

Therapeutic potential of cannabinoid medicines.

Posted on September 6, 2013 by David

Drug Testing and Analysis

“Cannabis was extensively used as a medicine throughout the developed world in the nineteenth century but went into decline early in the twentieth century ahead of its emergence as the most widely used illicit recreational drug later that century. Recent advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid system (ECS) have re-ignited interest in cannabis-based medicines.

The ECS has emerged as an important physiological system and plausible target for new medicines. Its receptors and endogenous ligands play a vital modulatory role in diverse functions including immune response, food intake, cognition, emotion, perception, behavioural reinforcement, motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption, and various aspects of hormonal control. In disease it may act as part of the physiological response or as a component of the underlying pathology.

In the forefront of clinical research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their contrasting pharmacology will be briefly outlined. The therapeutic potential and possible risks of drugs that inhibit the ECS will also be considered. This paper will then go on to review clinical research exploring the potential of cannabinoid medicines in the following indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS, psychosis, epilepsy, addiction, and metabolic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/24006213

http://onlinelibrary.wiley.com/doi/10.1002/dta.1529/abstract

Cannabidiol (CBD): Fighting Inflammation & Aggressive Forms of Cancer

Posted on June 7, 2013 by David

“Marijuana contains at least 60 known chemicals called cannabinoids, which activate cannabinoid receptors in your body. Tetrahydrocannabinol, or THC, is the main component responsible for the psychoactive effects, or “high,” marijuana is known for. While THC is known to have some medicinal value, there has been recent investigation into a new cannabinoid that is rumored to have more medicinal benefits than any single pharmaceutical drug on the market.”

“What is Cannabidiol (CBD)?

This cannabinoid is known as Cannabidiol (CBD), and is the second most abundant cannabinoid in cannabis. Research done by G.W. Pharmaceuticals suggests that CBD could be used for treating symptoms of rheumatoid arthritis and other autoimmune diseases, diabetes, nausea, bowel disorders, and many other hard-to-control side effects. According to an article from Projectcbd.com, CBD has even demonstrated neuroprotective effects, and its anti-cancer potential is currently being explored.

While it was originally believed that THC is a breakdown product of CBD, it is now known that both THC and CBD are actually metabolites of their decarboxylated acidic forms, THCa and CBDa. These acidic precursors are decarboxylated (essentially dried) by heat or extraction to produce THC and CBD; only then do they become psychoactive. The compound has medicinal benefits without the “high” that some patients do not desire. This makes CBD appealing to patients who are looking for an alternative to their current meds, which often have opiate-like effects.”

More: http://www.medicaljane.com/2012/12/20/cannabidiol-cbd-medicine-of-the-future/