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 overactivity and intestinal inflammation

Abstract

“Cannabinoid receptors of type 1 and 2 (CB1 and CB2), endogenous ligands that activate them (endocannabinoids), and mechanisms for endocannabinoid biosynthesis and inactivation have been identified in the gastrointestinal system. Activation of CB1 receptors by endocannabinoids produces relaxation of the lower oesophageal sphincter and inhibition of gastric acid secretion, intestinal motility, and fluid stimulated secretion. However, stimulation of cannabinoid receptors impacts on gastrointestinal functions in several other ways. Recent data indicate that the endocannabinoid system in the small intestine and colon becomes over stimulated during inflammation in both animal models and human inflammatory disorders. The pathological significance of this “endocannabinoid overactivity” and its possible exploitation for therapeutic purposes are discussed here.”

 

“The endocannabinoid system of the gastrointestinal tract includes not only cannabinoid receptors but also endogenous agonists of these receptors, as well as mechanisms for their biosynthesis and inactivation”

 

“The main psychotropic constituent of the plant Cannabis sativa and marijuana, Δ9‐tetrahydrocannabinol, exerts its pharmacological effects by activating two G protein coupled cannabinoid receptors.1These are the CB1 receptor, present in central and peripheral nerves (including the human enteric nervous system), and the CB2 receptor, expressed abundantly in immune cells. In rodents, CB1 receptor immunoreactivity has been detected in discrete nuclei of the dorsovagal complex (involved in emesis), and in efferents from the vagal ganglia and in enteric (myenteric and submucosal) nerve terminals where they inhibit excitatory (mainly cholinergic) neurotransmission. In vivo pharmacological studies have shown that activation of CB1 receptors reduces emesis, produces inhibition of gastric acid secretion8 and relaxation of the lower oesophageal sphincter (two effects that might be beneficial in the treatment of gastro‐oesophageal reflux disease), and inhibits intestinal motility and secretion. Consistent with immunohistochemical data showing that CB2 receptors are particularly evident in colonic tissues from patients with inflammatory bowel diseases (IBD), evidence suggests that CB2 inhibits intestinal motility during certain pathological states.1″

 

“…endocannabinoids convey protection from enteric hypersecretory states (for example, cholera toxin induced diarrhoea), which is in agreement with anecdotal reports from folk medicine on the use of Cannabis sativa in the treatment of diarrhoea.

 

“Overactivity of the endocannabinoid system is becoming a well established concept in human intestinal conditions with an inflammatory component”

   

“The inhibitory effects of cannabinoids on intestinal inflammation, as well as on intestinal motility and secretory diarrhoea, observed in preclinical studies, increase the potential for their use in the treatment of IBD”

  

“There is great potential for the development of new therapeutic agents against intestinal inflammation from the endocannabinoid system”

 

“Conclusions: new therapies for the treatment of IBD from the endocannabinoid system”

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1856409/

Pot Chemical May Curb Inflammation – WebMD

“Marijuana’s active ingredient may curb inflammation and help treat skin allergies.

That news comes from researchers including Meliha Karsak, PhD, and Thomas Tuting, MD, of Germany’s University of Bonn.

Marijuana’s key compound, THC, is a type of chemical called a cannabinoid. The brain contains two types of cannabinoid receptors.

Karsak and colleagues studied mice born with or without cannabinoid receptors. The mice wore ear tags to identify them; those ear tags contained nickel.

The mice without cannabinoid receptors were particularly likely to have allergic skin reactions to the nickel in the ear tags.

The scientists reasoned that the mice’s allergies may have been linked to their lack of cannabinoid receptors.

Karsak’s team tested that theory in several experiments.

First, they turned off cannabinoid receptors in healthy mice. Those mice then became more likely to develop skin inflammation near their nickel ear tags.

Next, the researchers exposed other mice with cannabinoid receptors to a skin irritant. Some of the mice got THC shots after being exposed to the irritant. Others got a THC skin lotion before and after exposure to the irritant.

The THC shot and lotion both helped soothe the mice’s inflamed skin.

“If we dabbed THC solution onto the animals’ skin shortly before and after applying the allergen, a lot less swelling occurred than normal,” Tuting says in a University of Bonn news release.

In the journal Science, the researchers write that their study “strongly suggests” that the body’s cannabinoid system can help tame inflammation and that THC skin lotions have “promising potential” for treating skin allergies caused by contact with irritating chemicals.

However, the researchers didn’t test the THC lotion on skin allergies in people.”

http://www.webmd.com/allergies/news/20070607/pot-chemical-may-curb-inflammation

“Attenuation of allergic contact dermatitis through the endocannabinoid system…These results demonstrate a protective role of the endocannabinoid system in contact allergy in the skin and suggest a target for therapeutic intervention.”  http://www.ncbi.nlm.nih.gov/pubmed/17556587

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

Endocannabinoids and the regulation of their levels in health and disease.

Abstract

“PURPOSE OF REVIEW:

Endocannabinoids are defined as endogenous agonists of cannabinoid receptors, that is, of the two G-protein-coupled receptors for the Cannabis psychoactive principle Delta-tetra-hydrocannabinol. Two such endogenous mediators have been most thoroughly studied so far: anandamide and 2-arachidonoylglycerol. Here we review the mechanisms for the regulation of their levels under physiological and pathological conditions, and recent findings on their role in disease.

RECENT FINDINGS:

It is becoming increasingly clear that, although both anandamide and 2-arachidonoyl-glycerol are produced and degraded ‘on demand’, the levels of these two compounds appear to be regulated in different, and sometimes even opposing, ways, often using redundant molecular mechanisms. Alterations of endocannabinoid levels have been found in both animal models of pain, neurological and neurodegenerative states, gastrointestinal disorders and inflammatory conditions, and in blood, cerebrospinal fluid and bioptic samples from patients with various diseases.

SUMMARY:

Endocannabinoid levels appear to be transiently elevated as an adaptive reaction to re-establish normal homeostasis when this is acutely and pathologically perturbed. In some chronic conditions, however, this system also contributes to the progress or symptoms of the disorder. As a consequence, new therapeutic drugs are being designed from both stimulants and blockers of endocannabinoid action.”

http://www.ncbi.nlm.nih.gov/pubmed/17353660

[A role for the endocannabinoid system in obesity].

Abstract

“Endocannabinoids are the endogenous ligands for the cannabinoid receptors type 1 and 2. These membrane receptors are responsible for the psychotropic effects of Cannabis Sativa, when bound to its active component known as (-)-Delta(9)-tetrahydro-cannabinol. Cannabinoid receptors, endocannabinoids and the enzymes catalyzing their biosynthesis and degradation, constitute the endocannabinoid system (ECS), which has a remarkable role controlling energy balance, both at central nervous system and peripheral tissues. The ECS regulates food ingestion by stimulating a network of orexigenic neurons present in the hypothalamus and reinforcing motivation and reward to food consumption in the nucleus accumbens. Regarding peripheral tissues, this system controls lipid and glucose metabolism at different levels, reduces energy expenditure and leads energy balance to fat storage. Metabolic alterations, including excessive accumulation of abdominal fat, dyslipidaemia and hyperglicaemia, are suggested to be associated to a hyperactivated ECS. Since obesity is one of the major health problems in modern societies, in this review we discuss the role of the endocannabinoid system in metabolic pathways associated to control mechanisms of energy balance and its involvement in overweight and obesity. In addition, we also discuss therapeutic possibilities and emergent problems due to cannabinoid receptor type 1 antagonism utilized as treatment for such alterations.”

http://www.ncbi.nlm.nih.gov/pubmed/20668819

Targeted modulators of the endogenous cannabinoid system: future medications to treat addiction disorders and obesity.

Abstract

“The endogenous endocannabinoid system encompasses a family of natural signaling lipids (“endocannabinoids”) functionally related to (9)-tetrahydrocannabinol, the psychoactive ingredient of marijuana (cannabis), along with proteins that modulate the endocannabinoids, including enzymes, transporters, and receptors. The endocannabinoid system’s ubiquitous regulatory actions in health and disease underscore its importance to mammalian (patho)physiology and suggest discrete targets through which it may be modulated for therapeutic gain. Medications based on the endocannabinoid system are an important focus of contemporary translational research, particularly with respect to substance abuse and obesity, two prevalent disorders with a pathogenic component of endocannabinoid system hyperactivity. Pressing health care needs have made the rational design of targeted CB1 cannabinoid-receptor modulators a promising route to future medications with significant therapeutic impact against psychobehavioral and metabolic disturbances having a reward-supported appetitive component.”

http://www.ncbi.nlm.nih.gov/pubmed/17915075

Pharmacotherapeutic targeting of the endocannabinoid signaling system: drugs for obesity and the metabolic syndrome.

Abstract

“Endogenous signaling lipids (“endocannabinoids”) functionally related to Delta(9)-tetrahydrocannabinol, the psychoactive ingredient of marijuana (Cannabis), are important biomediators and metabolic regulators critical to mammalian (patho)physiology. The growing family of endocannabinoids, along with endocannabinoid biosynthetic and inactivating enzymes, transporters, and at least two membrane-bound, G-protein coupled receptors, comprise collectively the mammalian endocannabinoid signaling system. The ubiquitous and diverse regulatory actions of the endocannabinoid system in health and disease have supported the regulatory approval of natural products and synthetic agents as drugs that alter endocannabinoid-system activity. More recent data support the concept that the endocananbinoid system may be modulated for therapeutic gain at discrete pharmacological targets with safety and efficacy. Potential medications based on the endocannabinoid system have thus become a central focus of contemporary translational research for varied indications with important unmet medical needs. One such indication, obesity, is a global pandemic whose etiology has a pathogenic component of endocannabinoid-system hyperactivity and for which current pharmacological treatment is severely limited. Application of high-affinity, selective CB1 cannabinoid receptor ligands to attenuate endocannabinoid signaling represents a state-of-the-art approach for improving obesity pharmacotherapy. To this intent, several selective CB1 receptor antagonists with varied chemical structures are currently in advanced preclinical or clinical trials, and one (rimonabant) has been approved as a weight-management drug in some markets. Emerging preclinical data suggest that CB1 receptor neutral antagonists may represent breakthrough medications superior to antagonists/inverse agonists such as rimonabant for therapeutic attenuation of CB1 receptor transmission. Since obesity is a predisposing condition for the cluster of cardiovascular and metabolic derangements collectively known as the metabolic syndrome, effective endocannabinoid-modulatory anti-obesity therapeutics would also help redress other major health problems including type-2 diabetes, atherothrombosis, inflammation, and immune disorders. Pressing worldwide healthcare needs and increasing appreciation of endocannabinoid biology make the rational design and refinement of targeted CB1 receptor modulators a promising route to future medications with significant therapeutic impact against overweight, obesity, obesity-related cardiometabolic dysregulation, and, more generally, maladies having a reward-supported appetitive component.”

http://www.ncbi.nlm.nih.gov/pubmed/18155257

The Endocannabinoid System and the Brain.

Abstract

“The psychoactive constituent in cannabis, Δ(9)-tetrahydrocannabinol (THC), was isolated in the mid-1960s, but the cannabinoid receptors, CB1 and CB2, and the major endogenous cannabinoids (anandamide and 2-arachidonoyl glycerol) were identified only 20 to 25 years later. The cannabinoid system affects both central nervous system (CNS) and peripheral processes. In this review, we have tried to summarize research-with an emphasis on recent publications-on the actions of the endocannabinoid system on anxiety, depression, neurogenesis, reward, cognition, learning, and memory. The effects are at times biphasic-lower doses causing effects opposite to those seen at high doses. Recently, numerous endocannabinoid-like compounds have been identified in the brain. Only a few have been investigated for their CNS activity, and future investigations on their action may throw light on a wide spectrum of brain functions. Expected final online publication date for the Annual Review of Psychology Volume 64 is November 30, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.”

http://www.ncbi.nlm.nih.gov/pubmed/22804774

Neurobiology and systems physiology of the endocannabinoid system.

Abstract

“Endocannabinoids are synthesised from lipid precursors, are released from postsynaptic neurons in an activity-dependent way, and act as retrograde signalling messengers on specific G (i)-protein-coupled cannabinoid (CB (1)) receptors on presynaptic terminals. Hence, endocannabinoids are in a strategic position to regulate transmitter release. CB (1)-receptors are abundant on GABAergic, glutamatergic and dopaminergic synapses and play an essential role in a variety of cognitive processes and in the control of behaviour. The endocannabinoid system is not only the target of the psychoactive components of the hemp plant (tetrahydrocannabinol from hashish and marijuana) but has also been exploited for drugs acting as agonists (e.g. dronabinol) or antagonists (e.g. rimonabant) of the CB (1)-receptor. The former drugs exert orexigenic effects and can be used for the mitigation of anorexia e.g. in cancer patients, but have also been used for the treatment of multiple sclerosis. The latter have been used to treat adipositas. The role of the endocannabinoid system in the development of drug dependence has been discussed controversially, but recent evidence suggests that chronic stimulation of the endocannabinoid system may facilitate drug dependence.”

http://www.ncbi.nlm.nih.gov/pubmed/19434559