Inflammatory bowel disease (IBD) is an affliction that affects approximately one million Americans, with incidence rates much higher in developing countries. IBD is characterized by illnesses such as Crohn’s disease and ulcerative colitis. Excessive inflammatory response in the gastrointestinal tract results in intestinal damage and disturbances in motility and secretion. Serious pain follows, as well as a range of other pervasive symptoms. Currently no cures are known, and treatment is measured by reduction of symptoms and suppression of flare-ups. Alleviation of IBD is currently accomplished with a number of medications that induce and retain remission. Steroidal treatment is another pathway that is currently used. These drugs possess limited efficacy however, and many contain unwanted side effects.
Cannabis Indica (nomenclature 2004 IU), the marijuana plant, has a long and storied history in medical application. Extracts of Cannabis were used in the USA a century ago for the treatment of abdominal pain and diarrhea. Anectodal accounts have been very prevalent regarding the effective use of Cannabis for IBD.
Self-medication under state medical cannabis laws is used by a generous subset of IBD patients for its analgesic activity in the abdomen, as well as the increase in appetite and reduction of diarrhea. However, the greatest limitation to exploring the full efficacy of cannabis on inflammation and other IBD symptoms lies with the activation of CB1 and CB2 (cannabinoid) receptors by delta-9 THC and the resulting psychoactive effect. CBD, however, does not activate CB1 or CB2, and therefore is devoid of psychoactive properties. The anti-inflammatory and antioxidant properties of CBD therefore have great potential as a candidate for medically-accepted relief from IBD symptoms and inhibition of flare-ups.
Cannabidiol and IBD
Determining the exact pathway of CBD activity in reduction of inflammatory symptoms is a necessary step to exploiting the cannabinoid as a therapeutic agent. The precise pathway must be uncovered in order to determine possible interactions with other drugs, as well as to maximize the effectiveness of a cannabis-derived therapeutic agent.
It has been proposed numerous times that CBD modulates endocannabinoid function through its ability to inhibit the enzyme fatty acid amide hydrolase (FAAH), the enzyme responsible for the hydrolysis of anandamide (the endogenous mimic of THC). FAAH inhibition results in an intestinal anti-inflammatory effect, which has led many scientists to propose the efficacy of CBD in relation to IBD symptom is linked to its role in FAAH inhibition. However, CBD also has potent antioxidant properties, as well as possible interactions with other cytokines or cell signaling molecules. Therefore a set of broad studies with all possible permutations of CBD interaction must be explored to elucidate the specifics of CBD and IBD.
The role of FAAH inhibition and CBD with relief from IBD symptoms (in other words, inhibition of motility) was explored in 2008 by Capasso et al. CBD had been shown to have a putative inhibition of FAAH. Capasso et al selectively inhibited FAAH mRNA in mice and found an increase in endocannabinoid levels (anandamide and 2-AG). This increase would result in activation of CB1 and CB2 receptors, thus leading to the anti-inflammatory action that has been observed. It is then logical that an inhibition of FAAH by CBD would result in this same effect as seen by inhibition of FAAH mRNA in mice, which is in a sense the hypothesis of Capasso et al.
However, Borrelli et al further explored this topic in 2010 in order to present a more solid hypothesis of CBD interaction. They found, surprisingly, that although CBD did have a putative inhibitory effect on FAAH expression, colonic endocannabinoid levels were in fact decreased (opposite to the expected increase). They also found that FAAH mRNA expression was unchanged with the CBD-treated mice. This cuts out the possibility of activation of CB1 or CB2 via CBD (at least through an FAAH pathway), and therefore the anti-inflammatory action of CBD must occur through a separate pathway.
Capasso et al did however find that CBD did not affect transit (present results) or defecation in the control rats, which suggests that the compound is only pharmacologically active in the presence of an intestinal inflammatory stimulus. This is important since it underlines the specificity of CBD activity on altering body conditions.
Anti-spasmodic activity of CBD was demonstrated by Capasso et al. Induced contractions via ACh was reduced by CBD. However, this effect was shown to occur in both the inflamed and the healthy intestine. Therefore the antispasmodic effect of CBD occurs separate from an inflammatory or mucosal stimulus.
An experimental model of colitis induced by a sulfonic acid (DNBS) was employed by Borrelli et al to test the effect of CBD on colonic inflammation. The introduction of CBD drastically reduced inflammation and the wet weight/colon length of the inflamed colonic tissue, which is a reliable indicator of the severity of inflammatory response. As seen with human cases of IBD, induction of colitis via DNBS led to many deleterious effects on the mice, the first of which studied was the reducing effect on body weight. Mice treated with CBD had been shown to decrease this colitis-induced reduction in weight; in other words, they lost less weight than those not treated. This CBD-related increase in weight is a correlation between reduction in inflammation via CBD and a resulting increase in appetite (in other words, this reduction in inflammation increases appetite much more than CBD’s slight appetite suppressant property). This provides an extremely valuable therapeutic insight to CBD with regards to inflammatory diseases, especially since loss of weight and appetite is a reported symptom of IBD.
Since the previously-accepted anti-inflammatory pathway of CBD via FAAH inhibition had been dethroned, Borrelli et al decided to test its effect on four cell signaling or mediating molecules (the last two are cytokines – cell signaling molecules central to, amongst other things, the development of intestinal inflammation). These encompass molecules that mediate inflammation as well as those that have a profound effect on oxidation and the resulting oxidative damage.
- inducible nitric oxide synthase (iNOS) – CBD reduced the overexpression of iNOS in response to colitis. iNOS overexpression is well correlated with disease activity with colitis, and inhibitors of iNOS lead to improvement in experimental models of IBD. iNOS results in high-output production of NO, which results in oxidative damage to the intestine via reactive oxygen species (ROS).
- cyclooxygenase-2 (COX-2) – no appreciable effect. COX-2 is heightened with IBD, but COX-2 inhibitors may both exacerbate and ameliorate the severity of experimental colitis. The fact that CBD has no effect on COX-2 is helpful in reducing the pathways that CBD may take that could present potential problems in a subset of patients.
- interleukin-1β – levels significantly increased with experimental colitis. CBD was shown to restore levels. IL-1β is shown to have potent pro-inflammatory activity and thus heightens the inflammatory response that leads to intestinal injury. IL-1β amplifies the production of inflammatory leukocytes (immune system cells), resulting in an increase of inflammation.
- interleukin-10 – levels significantly decreased with experimental colitis. CBD was shown to restore levels. IL-10 has anti-inflammatory activity by inhibiting the release of pro-inflammatory cytokines. Restoration of IL-10 activity is critical to intestinal health.
The CBD-induced reduction of iNOS expression is important largely in relation to the reduction of oxidative damage caused by experimental models of colitis. Therefore the levels of reactive oxygen species (ROS) were measured by Borrelli et al in vivo. Reactive oxygen species cause extensive tissue damage as free radicals, and have been extensively correlated with increases in iNOS expression and levels of nitric oxide (NO). CBD was found to reduce levels of ROS in the affected intestinal cells. Lipid peroxidation (a large factor in oxidative damage) was reduced, both in a dose-dependent manner. ROS production is a signification contributor to the pathogenesis of IBD as it constitutes a powerful tissue-destructive force. The reduction of iNOS and ROS by CBD, along with the reduction of lipid peroxidation, elucidates important therapeutic action of CBD in reduction of colonic inflammation by indirect reduction of oxidative damage.
The dysregulation of IL-1B and IL-10 is a well-known disruption caused by IBD. The restoration of these interleukins to normal behavior by CBD, although the specific pathway is unknown, is another important therapeutic action that CBD has on reduction of colonic inflammation. The normalization of these cytokines has a profound effect on the number of lymphocytes infiltration the affected area, thereby regulating the localization of these lymphocytes and regulating inflammation. **** CBD and THC Cannabis self-medication is currently the de facto method that IBD patients use in order to exploit its therapeutic benefit. Although this is not the ideal method of delivery as compared to a clinically-tested cannabinoid medication, it does present a complexity with regards to the co-administration of THC as well as CBD. The anti-inflammatory ability of THC is documented, as it activates cannabinoid receptors that are known to result in anti-inflammatory response. As discussed previously, the psychoactive component of THC is generally an unwanted side effect in medical application. Since THC is generally present with CBD in an impure preparation, it is useful to study the effect of THC alone and with CBD as a therapeutic agent towards IBD.
Jamontt et al demonstrated amelioration of IBD symptoms via the application of THC and CBD in a murine model. Colitis was induced by TNBS (a trinitrobenzene sulfonic acid that is very similar to DNBS used by Borrelli et al). The amelioration was similar to that of sulphasalazine, the standard prescription medication for treatment of IBD symptoms.
Cannabinoid normalization of IBD symptoms was argued to be a more protective, or a more effective therapeutic agent than sulphasalazine. The breadth of therapeutic effects that these cannabinoids carry is the reason for this hypothesis. As mentioned above, the cannabinoids help to mediate cytokines responsible for inflammation. In addition, Jamontt et al demonstrated the ability of the cannabinoids to increase cholinergic contractions and relaxant responses in the colitis models. In other words, the cannabinoids improved the function of both the excitatory and inhibitory nerves and therefore was much “more protective of the myenteric plexus” (a central component to the gastrointestinal nervous system).
The administration of THC and CBD was shown to be at a more effectiveness than a dose of THC without CBD. The reinforcement by both cannabinoids demonstrates that although they share some of the same pathways, they do carry distinct pathways that relieve IBD symptoms (ie cholinergic motor function improvement with THC vs none with CBD). A therapeutic preparation of both cannabinoids therefore may be the most potent in reducing IBD symptoms. However, it would carry the psychoactive side effect. Therefore, a therapeutic preparation of CBD would be the most medically effective and accepted model of cannabinoid treatment.
Works Cited
Borrelli, Francesca, Gabriela Aviello, Barbara Romano, Pierangelo Orlando, Raffaele Capasso, Francesco Maiello, Federico Guadagno, Stefiana Petrosino, Francesco Capasso, Vincenza Di Marzo, and Angelo A. Izzo. “Cannabidiol, a Safe and Non-psychotropic Ingredient of the Marijuana Plant Cannabis Sativa, Is Protective in a Murine Model of Colitis.” J Mol Med 87 (2009): 1111-121. Print.
Capasso, R., F. Borrelli, G. Aviello, B. Romano, C. Scalisi, F. Capasso, and AA Izzo. “Cannabidiol, Extracted from Cannabis Sativa, Selectively Inhibits Inflammatory Hypermotility in Mice.” British Journal of Pharmacology 154 (2008): 1001-008.