Medical Cannabis and Cannabinoids : An Option for the Treatment of Inflammatory Bowel Disease and Cancer of the Colon?
Magdalena Grill, Carina Hasenoehrl, Martin Storr, Rudolf Schicho
Medical Cannabis and Cannabinoids, 2018, 1, 28–35
© 2018 The Author(s)
Published by S. Karger AG, Basel
E-Mail karger@karger.com www.karger.com/mca
DOI: 10.1159/000489036
Abstract :
In the past few years, we have witnessed a surge of new reports dealing with the role of cannabinoids, synthetic as well as herbal, in the mechanisms of inflammation and carcinogenesis. However, despite the wealth of in vitro data and anecdotal reports, evidence that cannabinoids could act as beneficial drugs in inflammatory bowel disease (IBD) or in neoplastic development of the human gastrointestinal tract is lacking. Some insight into the effects of medical Cannabis (usually meaning dried flowers) and cannabinoids in IBD has been gained through questionnaires and small pilot studies. As to colorectal cancer, only preclinical data are available. Currently, Δ9-tetrahydrocannabinol (THC) and its synthetic
forms, dronabinol and nabilone, are used as an add-on treatment to alleviate chronic pain and spasticity in multiple sclerosis patients as well as chemotherapy-induced nausea. The use of medical Cannabis is authorized only in a limited number of countries. None of the mentioned substances are currently indicated for IBD. This review is an update of our knowledge on the role of cannabinoids in intestinal inflammation and carcinogenesis and a discussion on their potential therapeutic use.
Keywords : THC · Cannabinoid treatment · Colorectal cancer · Inflammatory bowel disease · Intestinal inflammation
Introduction
The beneficial properties of cannabinoids on the gastrointestinal (GI) tract are built on the fact that the intestines are endowed with the endocannabinoid system (ECS), a regulatory network of cannabinoid receptors, enzymes, and ligands that play key roles in physiological as well as pathophysiological processes [1–4]. Thus, the gut expresses the classical cannabinoid receptors 1 and 2 (CB1, CB2) and cannabinoid-responsive non-CB1/CB2 receptors (G protein-coupled receptor 55 [GPR55], transient receptor potential cation channel subfamily V member 1 [TRPV1], and peroxisome proliferator-activated receptor gamma and alpha [PPARγ and PPARα]). Further, endocannabinoid (EC)-producing enzymes, such as Nacyl phosphatidylethanolamine-specific phospholipase D and diacylglycerol lipase, and EC-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), are found in the gut. CB1 and CB2 localize mainly to enteric nerves, the intestinal epithelium, and immune cells with variable expression [5– 7]. While CB1 is expressed at high levels on cholinergic enteric neurons [8], CB2 is largely expressed on immune cells [9]. Anandamide (AEA) and 2-arachidonoylglycerol (2-
AG) are the best described ECs which activate CB1, CB2, and the abovementioned non-CB1/CB2 receptors [10– 12]. In addition to these ECS components, EC-like lipids, mostly N-acylethanolamines like palmitoylethanolamide (PEA) and oleoylethanolamide, were found in the GI tract. There, they act on non-CB1/CB2 receptors like GPR55 and GPR119 and influence the signaling of AEA, also called “entourage effect” [13]. ECs are most likely involved in numerous regulatory mechanisms, e.g., keeping
the epithelial barrier intact [14, 15] and maintaining immune tolerance through controlling the expansion of the regulatory T cell subset Tr1 and the presence of immunosuppressive CX3CR1hi macrophages [16]. Not unexpectedly, changes in the levels of ECs and EC-like lipids have been reported in patients with inflammatory bowel disease (IBD) [17] and colorectal cancer (CRC) [18]. However, it is unknown whether these changes actually correlate with the disease progress. With regard to CRC, in vitro data from colon cancer cell lines convincingly show antiproliferative effects of cannabinoids [19] and, in fact, models of CRC in knockout mice suggest an anti-oncogenic role for at least CB1 [20, 21]. With regard to CB2, however, studies in human CRC patients show that its expression correlates with a decreased survival [22]. In a similar way, CB1 expression was shown to correlate with a poorer survival rate in stage II microsatellite stable CRC [23]. The reports from human and experimental studies, therefore, are controversial concerning a beneficial role of the ECS in CRC. The following chapters briefly summarize the latest results on the role of the ECS and the action of cannabinoids in IBD and CRC, followed by a discussion of a potential therapy with cannabinoids.
Cannabinoids and IBD
IBD, of which ulcerative colitis and Crohn’s disease (CD) are major manifestations, is characterized by chronic and relapsing inflammatory attacks of the GI tract [24]. Although the detailed mechanisms are still unknown, an uncontrolled and misdirected immune response against microbial antigens combined with genetic predisposition and environmental factors contribute to the multifactorial appearance of the disease [24, 25].
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