Cannabinoid-based drugs as anti-inflammatory therapeutics.
“In the nineteenth century, marijuana was prescribed by physicians for maladies ranging from eating disorders to rabies. However, as newer, more effective drugs were discovered and as the potential for abuse of marijuana was recognized, its use as a therapeutic became restricted, and only recently has its therapeutic potential been re-evaluated.
Recent studies in animal models and in humans have produced promising results for the treatment of various disorders – such as obesity, cancer, and spasticity and tremor due to neuropathology – with drugs based on marijuana-derived cannabinoids.
Moreover, as I discuss here, a wealth of information also indicates that these drugs have immunosuppressive and anti-inflammatory properties; therefore, on the basis of this mode of action, the therapeutic usefulness of these drugs in chronic inflammatory diseases is now being reassessed.”
Prospects for cannabinoids as anti-inflammatory agents.
Abstract
“The marijuana plant (Cannabis sativa) and preparations derived from it have been used for medicinal purposes for thousands of years. It is likely that the therapeutic benefits of smoked marijuana are due to some combination of its more than 60 cannabinoids and 200-250 non-cannabinoid constituents. Several marijuana constituents, the carboxylic acid metabolites of tetrahydrocannabinol, and synthetic analogs are free of cannabimimetic central nervous system activity, do not produce behavioral changes in humans, and are effective antiinflammatory and analgesic agents. One cannabinoid acid in particular, ajulemic acid, has been studied extensively in in vitro systems and animal models of inflammation and immune responses. This commentary reviews a portion of the work done by investigators interested in separating the medicinal properties of marijuana from its psychoactive effects. Understanding the mechanisms of the therapeutic effects of nonpsychoactive cannabinoids should lead to development of safe effective treatment for several diseases, and may render moot the debate about “medical marijuana”.”
Cannabinoids as novel anti-inflammatory drugs
“Cannabinoids are a group of compounds that mediate their effects through cannabinoid receptors. The discovery of Δ9-tetrahydrocannabinol (THC) as the major psychoactive principle in marijuana, as well as the identification of cannabinoid receptors and their endogenous ligands, has led to a significant growth in research aimed at understanding the physiological functions of cannabinoids. Cannabinoid receptors include CB1, which is predominantly expressed in the brain, and CB2, which is primarily found on the cells of the immune system. The fact that both CB1 and CB2 receptors have been found on immune cells suggests that cannabinoids play an important role in the regulation of the immune system. Recent studies demonstrated that administration of THC into mice triggered marked apoptosis in T cells and dendritic cells, resulting in immunosuppression. In addition, several studies showed that cannabinoids downregulate cytokine and chemokine production and, in some models, upregulate T-regulatory cells (Tregs) as a mechanism to suppress inflammatory responses. The endocannabinoid system is also involved in immunoregulation. For example, administration of endocannabinoids or use of inhibitors of enzymes that break down the endocannabinoids, led to immunosuppression and recovery from immune-mediated injury to organs such as the liver. Manipulation of endocannabinoids and/or use of exogenous cannabinoids in vivo can constitute a potent treatment modality against inflammatory disorders. This review will focus on the potential use of cannabinoids as a new class of anti-inflammatory agents against a number of inflammatory and autoimmune diseases that are primarily triggered by activated T cells or other cellular immune components.”
“Cannabis, commonly known as marijuana, is a product of the Cannabis sativa plant and the active compounds from this plant are collectively referred to as cannabinoids. For several centuries, marijuana has been used as an alternative medicine in many cultures and, recently, its beneficial effects have been shown in: the treatment of nausea and vomiting associated with cancer chemotherapy; anorexia and cachexia seen in HIV/AIDS patients; and in neuropathic pain and spasticity in multiple sclerosis. Cannabinoid pharmacology has made important advances in recent years after the discovery of the cannabinoid receptors (CB1 and CB2). Cannabinoid receptors and their endogenous ligands have provided an excellent platform for the investigation of the therapeutic effects of cannabinoids. It is well known that CB1 and CB2 are heterotrimeric Gi/o-protein-coupled receptors and that they are both expressed in the periphery and the CNS. However, CB1 expression is predominant in the CNS, especially on presynaptic nerves, and CB2 is primarily expressed on immune cells.”
“Cannabinoids are potent anti-inflammatory agents and they exert their effects through induction of apoptosis, inhibition of cell proliferation, suppression of cytokine production and induction of T-regulatory cells (Tregs).”
“Executive summary
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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).
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The cannabinoid system has been shown both in vivo and in vitro to be involved in regulating the immune system through its immunomodulatory properties.
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Cannabinoids suppress inflammatory response and subsequently attenuate disease symptoms. This property of cannabinoids is mediated through multiple pathways such as induction of apoptosis in activated immune cells, suppression of cytokines and chemokines at inflammatory sites and upregulation of FoxP3+ regulatory T cells.
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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.
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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.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828614/
The cannabinergic system as a target for anti-inflammatory therapies.
“Habitual cannabis use has been shown to affect the human immune system, and recent advances in endocannabinoid research provide a basis for understanding these immunomodulatory effects. Cell-based experiments or in vivo animal testing suggest that regulation of the endocannabinoid circuitry can impact almost every major function associated with the immune system.
These studies were assisted by the development of numerous novel molecules that exert their biological effects through the endocannabinoid system. Several of these compounds were tested for their effects on immune function, and the results suggest therapeutic opportunities for a variety of inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, allergic asthma, and autoimmune diabetes through modulation of the endocannabinoid system.”
Therapeutic potential of cannabinoid-based drugs.
Abstract
“Cannabinoid-based drugs modeled on cannabinoids originally isolated from marijuana are now known to significantly impact the functioning of the endocannabinoid system of mammals. This system operates not only in the brain but also in organs and tissues in the periphery including the immune system. Natural and synthetic cannabinoids are tricyclic terpenes, whereas the endogenous physiological ligands are eicosanoids. Several receptors for these compounds have been extensively described, CB1 and CB2, and are G protein-coupled receptors; however, cannabinoid-based drugs are also demonstrated to function independently of these receptors. Cannabinoids regulate many physiological functions and their impact on immunity is generally antiinflammatory as powerful modulators of the cytokine cascade. This anti-inflammatory potency has led to the testing of these drugs in chronic inflammatory laboratory paradigms and even in some human diseases. Psychoactive and nonpsychoactive cannabinoid-based drugs such as Delta9-tetrahydrocannabinol, cannabidiol, HU-211, and ajulemic acid have been tested and found moderately effective in clinical trials of multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain. Furthermore, although clinical trials are not yet reported, preclinical data with cannabinoid-based drugs suggest efficacy in other inflammatory diseases such as inflammatory bowel disease, Alzheimer’s disease, atherosclerosis, and osteoporosis.”
Toward drugs derived from cannabis.
Abstract
“Recent work aimed at the introduction of natural and synthetic cannabinoids as drugs is reviewed. Delta1-Tetrahydrocannabinol (delta1-THC) is mainly investigated as a potential drug against glaucoma and asthma, and as an antiemetic agent in cancer chemotherapy. Cannabidiol is being tried in the clinic against epilepsy and as a hypnotic. Numerous synthetic cannabinoids are currently being investigated as analgetics and as sedative-relaxants.”
News about therapeutic use of cannabis and endocannabinoid system.
“Growing basic research in recent years led to the discovery of the endocannabinoid system with a central role in neurobiology. New evidence suggests a therapeutic potential of cannabinoids in cancer chemotherapy-induced nausea and vomiting as well as in pain, spasticity and other symptoms in multiple sclerosis and movement disorders. Results of large randomized clinical trials of oral and sublingual Cannabis extracts will be known soon and there will be definitive answers to whether Cannabis has any therapeutic potential. Although the immediate future may lie in plant-based medicines, new targets for cannabinoid therapy focuses on the development of endocannabinoid degradation inhibitors which may offer site selectivity not afforded by cannabinoid receptor agonists.” http://www.ncbi.nlm.nih.gov/pubmed/15033046
[Cannabis and cannabinoids. Possibilities of their therapeutic use].
Abstract
“Newer aspects of therapeutic potentials of cannabis and cannabinoids are reviewed. The major active constituent of cannabis sativa, delta-9-tetrahydrocannabinol and synthetic cannabinoids are evaluated in several clinical trials on their antiemetic efficacy in cancer chemotherapy induced vomiting. 80% of patients refractory to standard antiemetic treatment could be improved with the synthetic cannabinoid levonantradol. Other therapeutic effects, which are presently investigated in clinical trials are analgesia, antispasticity, anticonvulsion and the reduction of intraocular pressure in glaucoma. The future goal of cannabinoid research is the separation between specific pharmacologic activities and undesirable psychotropic effects.”
Potential therapeutic agents derived from the cannabinoid nucleus.
Abstract
“Drugs derived from Cannabis sativa (Cannabinceae) were used until the 1940’s for their stimulant and depressant effects for treating somatic and psychiatric illnesses. Renewed interest in marihuana research began in the 1970’s and again pointed to the therapeutic potential of cannabinoids. Safer and more useful therapeutic agents may be generated from cannabinoids similarly to morphine, lysergic acid diethylamide, and cocaine which have structurally related analgesics, oxytoxics, and local anesthetics respectively. It has been shown that the C-ring in cannabinoids can be substituted with a variety of nitrogen and sulfur-containing rings without loss of CNS (central nervous system) activity. Cannabinoids have been shown to inhibit prostaglandin synthesis, intensify pressor effects of endogenous amines like norepinephrine, and enhance the stimulant effects of amphetamine. Cannabinoids’ therapeutic potential lies in the areas of analgesics and anticonvulsants, and for use as a sedative-hypnotic, an antiglaucoma agent, an antiasthmatic agent, an antidiarrheal agent, and possibly as an anticancer and immunosuppressant agent.”