Cannabinoids, Endocannabinoids, and Related Analogs in Inflammation.

“This review covers reports published in the last 5 years on the anti-inflammatory activities of all classes of cannabinoids, including phytocannabinoids such as tetrahydrocannabinol and cannabidiol, synthetic analogs such as ajulemic acid and nabilone, the endogenous cannabinoids anandamide and related compounds, namely, the elmiric acids, and finally, noncannabinoid components of Cannabis that show anti-inflammatory action. It is intended to be an update on the topic of the involvement of cannabinoids in the process of inflammation. A possible mechanism for these actions is suggested involving increased production of eicosanoids that promote the resolution of inflammation. This differentiates these cannabinoids from cyclooxygenase-2 inhibitors that suppress the synthesis of eicosanoids that promote the induction of the inflammatory process.”

 

“INTRODUCTION

This review is intended to be an update on the topic of the involvement of cannabinoids in the process of inflammation. Other reviews cover certain aspects of this subject and the reader is referred to them for a discussion of earlier reports. In this review are reports published in the last 5 years on the activities of all classes of cannabinoids, including the endogenous cannabinoids such as anandamide, related compounds such as the elmiric acids (EMAs), and noncannabinoid components of Cannabis that show anti-inflammatory action. An interesting recently published example of the latter one is caryophyllene, an abundant component of Cannabis oil that shows anti-inflammatory activity and has high affinity for cannabinoid receptor 2 (CB2; 5).”

 

“Phytocannabinoids: Tetrahydrocannabinol and Cannabidiol”

 

“PLANT PREPARATIONS AND NONCANNABINOID CONSTITUENTS OF CANNABIS”

“Cannabis sativa is a complex botanical, and it is not unlikely that the therapeutic benefits of marijuana are due to some of the more than 60 cannabinoids and 200–250 noncannabinoid constituents of the plant. One noncannabinoid, the geranylated flavone cannflavin A (Fig. 5), is 30 times more potent than aspirin as an inhibitor of prostaglandin E2 . These potentially important findings have been overlooked, as most attention in marijuana research has been directed to the analgesic effects of the plant and to mechanisms of psychoactivity. A further example that this line of inquiry has remained dormant is a series of overlooked observations, which demonstrate potent anti-inflammatory actions of a crude marijuana extract and of the nonpsychoactive Cannabis constituents, CBD, cannabinol, and cannabichromene in the carrageenan paw edema model of acute inflammation in rats. Volatile oil products of the plant also have biological activity. Thus, pyrolysis products may add to the therapeutic properties of smoked marijuana. Several of the most abundant cannabinoid and noncannabinoid constituents of C. sativa are nonpsychoactive.”

“Flavonoids are ubiquitous plant phenolic compounds that consist of two aromatic rings linked by a three carbon bridge. They are attracting interest because of their antioxidant, antitumor, anti-inflammatory, and antimicrobial activities. The flavone luteolin, a constituent of C. sativa, is also found in spices and in vegetables such as celery and green pepper. When added to peripheral blood mononuclear cells in vitro, luteolin suppresses production of the inflammatory cytokines TNFα, IL-1b, and IL-6, actions that relate to a selective reduction in numbers of monocytes. Perhaps more importantly, luteolin inhibits growth of Plasmodium falciparum in vitro and protects against induction of colon cancer in mice.”

“CONCLUSIONS

Possibly the very earliest literature reference on Cannabis describes its use as an anti-inflammatory agent. The Chinese emperor Shen-nung (ca. 2000 B.C.), in a work called Pen-ts’ao Ching, noted many of the effects of Cannabis in humans. Among other properties, it was claimed that cannabis “undoes rheumatism”, suggesting possible anti-inflammatory effects. The reports described in this review of the current literature provide support for the claims made by the ancient Chinese healers. These more recent publications include relief from chronic neuropathic pain, fibromyalgia, rheumatoid arthritis, and postoperative pain. In addition, a large body of preclinical data on all classes of cannabinoids, including the endogenous examples, point to a variety of therapeutic targets for cannabinoids and important roles for the endocannabinoids in the physiology of inflammation.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664885/

Endocannabinoid chemical biology: a tool for the development of novel therapies.

Abstract

“The identification of the major psychoactive constituent of Cannabis and marijuana, Delta(9)-tetrahydrocannabinol, opened the way first to the cloning of the G-protein-coupled cannabinoid CB(1) and CB(2) receptors, and then to the isolation and characterisation of their endogenous agonists, the endocannabinoids. Considerable progress has been made in the characterisation of pathways and enzymes for the biosynthesis and degradation of anandamide and 2-arachidonoylglycerol, the two best-known endocannabinoids, as well as of endocannabinoid-related molecules, such as the N-acylethanolamines, which, as in the case of N-palmitoylethanolamine and N-oleoylethanolamine, may interact with other receptor types. However, it is still not fully understood how other plant cannabinoids, of which cannabidiol is the most studied representative, exert their pharmacological effects. Together with these issues, this first review article on the endocannabinoids describes the synthetic pharmacological tools that have been designed so far to interact with the proteins of the ‘endocannabinoid system’ and that can potentially be used as templates for the development of new therapies.”

http://www.ncbi.nlm.nih.gov/pubmed/19457702

Pharmacological actions of cannabinoids.

Abstract

“Mammalian tissues express at least two types of cannabinoid receptor, CB1 and CB2, both G protein coupled. CB1 receptors are expressed predominantly at nerve terminals where they mediate inhibition of transmitter release. CB2 receptors are found mainly on immune cells, one of their roles being to modulate cytokine release. Endogenous ligands for these receptors (endocannabinoids) also exist. These are all eicosanoids; prominent examples include arachidonoylethanolamide (anandamide) and 2-arachidonoyl glycerol. These discoveries have led to the development of CB1- and CB2-selective agonists and antagonists and of bioassays for characterizing such ligands. Cannabinoid receptor antagonists include the CB1-selective SR141716A, AM251, AM281 and LY320135, and the CB2-selective SR144528 and AM630. These all behave as inverse agonists, one indication that CB1 and CB2 receptors can exist in a constitutively active state. Neutral cannabinoid receptor antagonists that seem to lack inverse agonist properties have recently also been developed. As well as acting on CB1 and CB2 receptors, there is convincing evidence that anandamide can activate transient receptor potential vanilloid type 1 (TRPV1) receptors. Certain cannabinoids also appear to have non-CB1, non-CB2, non-TRPV1 targets, for example CB2-like receptors that can mediate antinociception and “abnormal-cannabidiol” receptors that mediate vasorelaxation and promote microglial cell migration. There is evidence too for TRPV1-like receptors on glutamatergic neurons, for alpha2-adrenoceptor-like (imidazoline) receptors at sympathetic nerve terminals, for novel G protein-coupled receptors for R-(+)-WIN55212 and anandamide in the brain and spinal cord, for novel receptors for delta9-tetrahydrocannabinol and cannabinol on perivascular sensory nerves and for novel anandamide receptors in the gastro-intestinal tract. The presence of allosteric sites for cannabinoids on various ion channels and non-cannabinoid receptors has also been proposed. In addition, more information is beginning to emerge about the pharmacological actions of the non-psychoactive plant cannabinoid, cannabidiol. These recent advances in cannabinoid pharmacology are all discussed in this review.”

http://www.ncbi.nlm.nih.gov/pubmed/16596770

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

Study: Marijuana Could Stop Growth of Colon Cancer Cells

“The administration of the non-psychotropic cannabis plant constituent cannabidiol (CBD) is protective in an experimental model of colon cancer, according to preclinical trial data published online in the Journal of Molecular Medicine.

Investigators at the University of Naples assessed the effect of CBD on colon carcinogenesis in mice. Researchers reported that CBD administration was associated with cancerous tumor reduction and reduced cell proliferation.

Authors wrote: “Although cannabidiol has been shown to kill glioma cells, to inhibit cancer cell invasion and to reduce the growth of breast carcinoma and lung metastases in rodents, its effect on colon carcinogenesis has not been evaluated to date. This is an important omission, since colon cancer affects millions of individuals in Western countries. In the present study, we have shown that cannabidiol exerts (1) protective effects in an experimental model of colon cancer and (2) antiproliferative actions in colorectal carcinoma cells.”

Authors also acknowledged that CBD possesses “an extremely safe profile in humans.” They concluded, “[O]ur findings suggest that cannabidiol might be worthy of clinical consideration in colon cancer prevention.””

http://www.opposingviews.com/i/society/drug-law/latest-science-non-psychotropic-cannabinoid-inhibits-colon-cancer-cell

Induction of apoptosis by cannabinoids in prostate and colon cancer cells is phosphatase dependent.

Abstract

“AIM:

We hypothesized that the anticancer activity of cannabinoids was linked to induction of phosphatases.

MATERIALS AND METHODS:

The effects of cannabidiol (CBD) and the synthetic cannabinoid WIN-55,212 (WIN) on LNCaP (prostate) and SW480 (colon) cancer cell proliferation were determined by cell counting; apoptosis was determined by cleavage of poly(ADP)ribose polymerase (PARP) and caspase-3 (Western blots); and phosphatase mRNAs were determined by real-time PCR. The role of phosphatases and cannabinoid receptors in mediating CBD- and WIN-induced apoptosis was determined by inhibition and receptor knockdown.

RESULTS:

CBD and WIN inhibited LNCaP and SW480 cell growth and induced mRNA expression of several phosphatases, and the phosphatase inhibitor sodium orthovanadate significantly inhibited cannabinoid-induced PARP cleavage in both cell lines, whereas only CBD-induced apoptosis was CB1 and CB2 receptor-dependent.

CONCLUSION:

Cannabinoid receptor agonists induce phosphatases and phosphatase-dependent apoptosis in cancer cell lines; however, the role of the CB receptor in mediating this response is ligand-dependent.”

http://www.ncbi.nlm.nih.gov/pubmed/22110202

Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer.

Abstract

“Colon cancer affects millions of individuals in Western countries. Cannabidiol, a safe and non-psychotropic ingredient of Cannabis sativa, exerts pharmacological actions (antioxidant and intestinal antinflammatory) and mechanisms (inhibition of endocannabinoid enzymatic degradation) potentially beneficial for colon carcinogenesis. Thus, we investigated its possible chemopreventive effect in the model of colon cancer induced by azoxymethane (AOM) in mice. AOM treatment was associated with aberrant crypt foci (ACF, preneoplastic lesions), polyps, and tumour formation, up-regulation of phospho-Akt, iNOS and COX-2 and down-regulation of caspase-3. Cannabidiol-reduced ACF, polyps and tumours and counteracted AOM-induced phospho-Akt and caspase-3 changes. In colorectal carcinoma cell lines, cannabidiol protected DNA from oxidative damage, increased endocannabinoid levels and reduced cell proliferation in a CB(1)-, TRPV1- and PPARγ-antagonists sensitive manner. It is concluded that cannabidiol exerts chemopreventive effect in vivo and reduces cell proliferation through multiple mechanisms.”

http://www.ncbi.nlm.nih.gov/pubmed/22231745

Dixie X Hemp CBD Wellness Products Online Store Now Open!

“At long last, Dixie X the revolutionary hemp CBD powered wellness products from Dixie Elixirs & Edibles are now available for sale over the Internet at dixiex.com.

Medical Marijuana Inc. (OTC: MJNA), a leading hemp industry innovator, is pleased to announce a new on-line sales website for its Hemp-based Dixie X line of products:  www.dixiex.comThis announcement supports the company’s large scale national launch of on-line sales of its Hemp-based Cannabidiol (CBD) enriched health and wellness Dixie X products.

According to the company, since Dixie X is manufactured from non-THC high CBD concentrate industrial Hemp it can be legally shipped to consumers in all 50 states in the U.S. as well as internationally.”

http://dixieelixirs.com/dixie-x-store-open/

Cancer-fighting Potential of Cannabidiol Bodes Well for Dixie X Hemp Products

“Research by California Pacific Medical Center indicating that cannabidiol (CBD), a non-psychotropic compound found in hemp, may arrest the spread of aggressive, metastatic cancer cells, is drawing the attention of the medical community. John Malanca of medical cannabis resource UnitedPatientsGroup.com believes this encouraging news will also bring CBD to the attention of health-minded consumers.

“Many people want the health benefits of CBD, but they don’t want to get ‘high,’” said Malanca. “Dixie X products deliver a new option, and as our understanding and awareness of the health benefits of CBD grow, so does the attractiveness of Dixie X CBD wellness products.”

http://www.prweb.com/releases/cbd-pills/medical-cannabis-resource/prweb9985704.htm

Can Cannabidiol (CBD) Fight Metastatic Cancer? According to the latest research the answer is yes.

“Medical Marijuana Inc. (OTC: MJNA), a leading hemp industry innovator, is pleased to report on a September 18 San Francisco Chronicle Article, “Pot compound seen as tool against cancer.”

The article states that scientists at California Pacific Medical Center who have been researching marijuana’s compounds for the 20 years have found that Cannabidiol, or CBD, has the ability to “turn off” the DNA that causes “breast and other types of cancers” to metastasize. CBD is the second-most abundant cannabinoid within marijuana, but does not cause the psychotropic high of THC.

As stated in the article: “We started by researching breast cancer,” said scientist Pierre Desprez. “But now we’ve found that Cannabidiol works with many kinds of aggressive cancers–brain, prostate–any kind in which these high levels of ID-1 are present.”

According to the Chronicle article, when scientists first exposed metastatic cancer cells to Cannabidiol in a petri dish, “the cells not only stopped acting crazy but they also started to revert to a normal state. Both scientists were shocked…But they got the same results each time they did it.”

“This article and the findings it reports just confirm what many have known, that Cannabidiol or CBD have tremendous health and wellness potential. We are pleased that our Dixie X line of products are available right now to patients who have an immediate need for CBD and are searching for an easy way to find it,” states Ted Caligiuri, Interim President of MJNA. “We take great pride in knowing that our Dixie X line may be of significant health benefit to not only all cancer patients, but those in late stages of metastatic disease. We are also looking forward to the clinical trials that will soon be underway and thank the National Institute of Health, Susan G. Komen Foundation and others for their unwavering commitment to funding this necessary research.”

https://www.prnewswire.com/news-releases/can-cannabidiol-cbd-fight-metastatic-cancer-according-to-the-latest-research-the-answer-is-yes-170681736.html