Cannabis sativa (Cannabis or marijuana) is a widely used recreational drug which alters sensory perception and causes euphoria (Tibirica 2010). It has been promoted as a treatment for a variety of diseases such as cancer, glaucoma and autoimmune diseases (Hill 2015). Cannabis has also been hypothesized to improve disease activity in Crohn’s disease via modulation of the endocannabinoid system (Tibirica 2010). The endocannabinoid system has been shown to help regulate brain function and the immune system (Klein 2006).
Studies have found a higher prevalence of cannabis use in patients with IBD who claim it relieves symptoms such as abdominal pain, diarrhea, and reduced appetite (Lal 2011; Weiss 2015). It is unclear if this is due to the known psychotropic effects of cannabis such as analgesia and euphoria or if it is related to anti-inflammatory effects demonstrated in recent studies and experimental animal models (Hasenoehrl 2016; Klein 2006; Singh 2012). There is also evidence that cannabis use in patients with Crohn's disease has potential for harm. Cannabis has been associated with higher risk of surgery in people with Crohn's disease (Storr 2014). Cannabinoids have been associated with an increased risk of transient adverse events including weakness, dizziness, and diarrhea (Whiting 2015). Despite these conflicting data, physicians are often asked to prescribe cannabis in the context of a rapidly growing medical marijuana industry (Fletcher 2013).
There were no placebo-controlled trials evaluating the use of cannabis in IBD patients until the first prospective, placebo-controlled trial was published in 2013 (Naftali 2013). This study raised important questions regarding the exact role of cannabis in treating patients with Crohn’s disease: Does cannabis lead to symptomatic improvement only or does it also objectively reduce inflammation? Is cannabis safe?
Description of the condition
Crohn’s disease (CD) is a chronic immune-mediated condition of transmural inflammation in the gastrointestinal tract. CD is associated with significant morbidity and decreased quality of life (Lahat 2012; Rubin 2004). In North America, the prevalence of CD is estimated to range from 26 to 199 cases per 100,000 person-years (Friedman 2012).
CD can affect anywhere from the mouth to the perianal area. The pathophysiology of this condition is multifactorial and patients may have a genetic predisposition (Friedman 2012). CD is thought to arise from a dysregulated immune response towards commensal microbiota and dietary contents in the gastrointestinal tract (Friedman 2012). This leads to an inappropriate inflammatory cascade of activated T cells secreting excessive pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-α) (Friedman 2012). This results in damage to previously healthy tissues.
CD is characterized by periods of relapse and remission (Friedman 2012). Symptoms may include low grade fevers, malaise, diarrhea, crampy abdominal pain, or hematochezia (Friedman 2012). The site of inflammation influences the symptoms. Complications of CD include fistula and abscess formation, perforations and fibrotic strictures (Friedman 2012; Lahat 2012).
Usual treatment options for CD include anti-inflammatory and immunosuppressant agents (Friedman 2012). Commonly used drugs are 5-ASA, sulfasalazine, corticosteroids, thiopurine drugs, methotrexate and biologic therapies such as anti-TNF-α agents (Friedman 2012). Management includes control of acute exacerbations, induction of remission, and maintenance of remission.
Description of the intervention
Cannabis sativa consists of numerous compounds called cannabinoids, of which delta 9-tetrahydrocannabinol (THC) is the main psychotropic component (Klein 2006). Many natural and synthetic cannabinoids have been found and studied including cannabidiol, cannabinol, cannabigerol, and dronabinol (Klein 2006). Some of these cannabinoids are psychoactive, whereas other are not (Klein 2006). Multiple experimental animal models have shown anti-inflammatory properties of various cannabinoids (Klein 2006).
How the intervention might work
The endocannabinoid system helps regulate the central nervous sytem, peripheral tissues, and multiple immune cells (Tibirica 2010). This system consists of cannabinoid (CB) receptors 1 and 2, several endogenous ligands called 'endocannabinoids', and associated enzymes (Hasenoehrl 2016; Klein 2006). Multiple studies have shown that the endocannabinoid system helps control physiologic functions of the gut including motility, secretion and epithelial barrier integrity (Coutts 1998; Hasenoehrl 2016; Pinto 2002; Vianna 2012). This makes the endocannabinoid system a potential therapeutic target for gastrointestinal diseases. Cannabis and cannabinoids appear to influence this system via CB1 and CB2 receptors and other mechanisms (Hasenoehrl 2016; Klein 2006).
CB1 receptors are widely expressed in the gastrointestinal tract, central nervous system and peripheral tissues such as blood vessels (Hasenoehrl 2016; Klein 2006). In the GI tract, the CB1 receptors are found in the enteric nervous system, the epithelial lining, plasma cells, and smooth muscle cells of blood vessels (Hasenoehrl 2016). CB1 receptor activation may reduce gastric emptying, intestinal transit time, as well as reduce colonic propulsion (Pinto 2002). The brain-gut axis also influences motility and CB1 receptors in the vagus nerve are part of normal motility (Vianna 2012). CB1 receptors modulate the release of multiple neurotransmitters in the central nervous system causing central effects such as a reduction in pain and nausea (Klein 2006; Tibirica 2010). Activation of the CB1 receptor may enhance epithelial wound closure in the colon (Wright 2005). There is also evidence that upregulation of CB1 receptors and activation of CB1 receptors physiologically protects the colon during excessive inflammation in the colon (Massa 2004).
CB2 receptors are mainly expressed in immune cells, myenteric plexus neurons, and in epithelial cells during ulcerative colitis (Hasenoehrl 2016; Klein 2006; Marquez 2009). CB2 receptors are expressed on immune cells such B-cells, NK cells and macrophages (Klein 2006). CB2 activation leads to T-cell apoptosis and decreased proliferation in colitis (Singh 2012). CB2 activation also decreases the recruitment of neutrophils, T cells and macrophages to the inflamed colon (Singh 2012).
Other receptors in the GI tract have been found to be endocannabinoid-responsive through mechanisms separate from CB1 and CB2 receptors (Hasenoehrl 2016). These include the peroxisome proliferator-activated receptor alpha, the G-protein coupled receptor 55, and transient receptor potential cation channel subfamily V member 1 (Hasenoehrl 2016). Cannabinoids also help modulate chemokine and cytokine release (Klein 2006).
Why it is important to do this review
It is important to do this review to evaluate the strength of evidence for the use of cannabis and cannabinoids as treatment for CD. It will help clarify if this therapy leads to objective physiological improvement beyond subjective and psychotropic scores. Further, we hope to evaluate various modes of consumption and assess for adverse effects.