Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal system which ‘comes and goes’ often. Ulcerative colitis and Crohn’s disease are the two main types of IBD, which occurs after uncontrolled intestinal inflammation worsens over time. IBD requires prolonged medical treatment and some patients may require surgical interventions. Untreated IBD patients may suffer diarrhea, abdominal pain, bowel obstruction, blood and/or mucus in the stools, fever and worsening quality of life. Although the exact cause of IBD is unknown, it is believed to be the result of a complex interplay between four factors, such as overt intestinal immune response, genetic variations, an altered gut microbiome and environmental factors.
To treat IBD and to achieve maximum remission, the treatment strategy must be focused on suppression of inflammation and restoration of immune response. As of now, several drugs, including aminosalicylates, biologics and immunosuppressants are being prescribed. Despite the reported efficacy, the adverse events limit the long-term use of these drugs. Therefore, we are in need of newer therapies that offer effective and safer IBD treatment.
The ECS and the Gut
The presence of the endocannabinoid system (ECS) in the gastrointestinal tract’s immune, epithelial and neural cells has been adequately demonstrated in research studies. The role of the ECS in various physiological and pathophysiological processes — including satiety, secretion, bowel movements, emesis, immunoregulation, inflammation and pain — is evident. Although the role of the ECS in the pathogenesis of inflammatory bowel disease (IBD) is not completely understood, the dysregulated ECS, particularly the intestinal immune system dysregulation and altered gut microbiome response, is believed to be the main contributor of IBD pathogenesis.
The up-regulation of the ECS during inflammatory processes occurs either due to increased expression of cannabinoid receptors or by surged endocannabinoid biosynthesis. Studies have shown that administration of CB1 agonists or inhibitors of endocannabinoid membrane transport and FAAH agonists has suppressed inflammation. Immunohistochemistry studies have identified the presence of CB1 receptors in submucosal and myenteric plexi of normal colonic tissues in humans and it may be involved in the modulation of colonic neural input, in addition to colonic motility and secretion. Similarly, CB2 expression was observed in the enteric nervous system of human ileum and may be involved in colonic immunomodulation.
In mild to moderate ulcerative colitis patients, higher levels of CB2 receptor expression in the mucosal epithelium have been reported, which implicates the dysregulated tone in the colonic ECS. However, there is no remarkable increase in CB2 receptor expression in severe cases, possibly due to diminished ECS response to inflammatory insult. In IBD patients, the imbalance in the intestinal immunity and commensal response contributes to increased intestinal epithelial cell permeability and leaky intestinal barrier (AKA leaky gut), which is further worsened by the release and action of pro-inflammatory cytokines. This complex interaction between the nervous and intestinal immune system is mediated by enteric neurons, glia, intestinal epithelial cells and certain neurotransmitters.
In IBD patients, the down regulation of CB2 receptors further complicates the disease by promoting the onset of fibrosis and bowel cancer. Fibrosis results from chronic transmural inflammation and stricture formation, while persistent/chronic intestinal inflammation can increase the risk of developing bowel cancers and adenomatous polyps in IBD patients.
CB2 agonists inhibit the release of pro-inflammatory cytokines, such as IL-8 and TNF-alpha, which are implicated in the pathogenesis of IBD. In dysregulated conditions, the modulation of ECS with agonists may restore the immune homeostasis and treat the underlying problem.
Phytocannabinoids inhibit cellular proliferation in human colonic epithelial cells via CB1 receptor activation and the modulation of cyclooxygenase-2, which plays a vital role in inflammatory processes.
Based on the available information, it is clear that the modulation of cannabinoid receptors could alter sensory processing in the gut, modulate gut-brain axis, treat intestinal inflammation and restore normal bowel functions. These benefits are also useful to treat even the low-grade intestinal inflammation that can also trigger IBD episodes.
Presence of CB2 receptors in the intestinal lamina propria is believed to be an immunomodulator, while CB1 receptors are implied in the epithelial wound healing in the inflammatory state. Cannabinoids can activate both receptors and treat IBD in a holistic manner.
With the available evidence, it makes sense that the modulation of the ECS could be helpful for the treatment of IBD.
Cannabinoids for IBD
Phytocannabinoids from cannabis plants have been used for the treatment of a variety of illnesses including inflammatory disorders, chronic pain, neurological disorders and gastrointestinal conditions such as abdominal pain, diarrhea, emesis and diabetic gastroparesis.
Research evidence has pointed out that the ECS plays a vital role in most of the major immune events in the gastrointestinal tract. With their ECS activating potential, phytocannabinoids might have the therapeutic potential to safely treat IBD. However, the clinical trials to demonstrate the safety and efficacy of cannabinoids in IBD are inadequate.
The anti-inflammatory effects of cannabis can downregulate the production and release of pro-inflammatory cytokines such as TNFα and IL-1β, by which the altered immune response can be restored in IBD patients. The anti-inflammatory benefits are mostly attributed to CB1 receptors. These findings were confirmed by an experimental study which concluded that knockout mice lacking CB1 receptors were more sensitive to inflammatory insults.
We cannot refute that CB1 receptor agonists, including delta (9)-tetrahydrocannabinol, act in various sites of the gastrointestinal tract and promote optimal GI health. Studies have confirmed phytocannabinoids’ vagus nerve-specific action and control of vomiting, gastric acid secretion, lower esophageal sphincter pressure and gastric pressure.
In pre-clinical studies, cannabinoids attenuate inflammatory reaction in colitis animal models. An observational human study that enrolled 30 Crohn’s disease patients found that marijuana improved disease activity and significantly reduced the use of conventional treatment drugs. A placebo-controlled clinical trial involving 21 Crohn’s disease patients reported statistically significant improvement in disease activity in the treated subjects, compared to the placebo group. Among them, complete remission was observed in nearly 50% of the cannabis treated patients. However, the reported benefit was not evident in low-dose CBD treatment group patients. When it comes to assessment of drug efficacy, the dose-response is a critical factor.
More controlled clinical trials are required to ensure the effective route of administration and to optimize the safest and most effective dose in IBD treatment to achieve maximum therapeutic benefits without causing any adverse events.
A comparative experimental study examined the benefits of CB2 agonists in the treatment of gastrointestinal inflammation and concluded that CB2 receptor agonists modulated inflammatory pathways by inhibiting cyclooxygenase metabolites, platelet-activating factor (PAF) and inducible nitric oxide synthase (NOS). Although this evidence is preliminary, the possible involvement of CB2 agonists in the abrogation of the intestinal inflammatory pathway can be understood. Adding more volume to this finding, independent researchers have reported that TNF-α induced release of pro-inflammatory cytokines were suppressed by the phytocannabinoids via action on the CB2 receptors of the human colonic epithelial cells and maintained optimal intestinal immune balance.
It is clear that cannabis not only treats intestinal inflammation but also relieves IBD-associated symptoms including vomiting, abnormal GI motility, diarrhea and pain.
We are well aware of the appetite-stimulating effects of cannabis, which we refer to as ‘munchies’. IBD patients, particularly Crohn’s disease patients, are more prone to malnutrition and weight loss due to lack of appetite, nausea and other GI symptoms. Marijuana can improve appetite and other GI symptoms and help treat weight loss.
If we want to avoid any unwanted psychoactive side effects of THC and related CB1 receptor activation, we can choose CBD — which is also effective to treat intestinal hypermotility and inflammatory stimulus. CBD can also be used to re-establish normal gastric transit. Further exploratory studies are needed to understand the gut-specific therapeutic role of CBD in IBD patients.