cbd gastrointestinal

“There’s little regulation of cannabis, and the THC levels are extremely high now,” Andrews says. Thirty years ago, the percentage of THC in typically accessible marijuana was in the single digits, he says, whereas these days THC is often 20% or higher. With these higher concentrations, “we have no idea what they will do to the [body’s] cannabinoid system long term,” Andrews says.

“A lot of people perceive this as a more natural therapy and preferentially want this over immunosuppressants for inflammatory bowel disease,” says Dr. Byron Vaughn, an associate professor of medicine and co-director of the IBD program at the University of Minnesota in Minneapolis. But if anything, experts see the primary role for cannabis as an adjunctive therapy, not as a replacement for medications that are used to treat IBD and other GI disorders.

For centuries, marijuana, which is derived from the plant Cannabis sativa, has been used for both medicinal and recreational purposes. On the medicinal front, cannabinoids—a group of compounds that constitute the active ingredients in the marijuana plant—have been found to help alleviate chronic pain, as well as the nausea and vomiting that stem from chemotherapy for cancer. The U.S. Food and Drug Administration (FDA) has even approved specific cannabinoid products for chemotherapy-induced nausea and vomiting in cancer patients and to stimulate appetite in patients with AIDS who have lost weight.

Finally, remember that experts primarily view cannabis as adjunctive therapy—a potential addition on an as-needed basis—for GI disorders. “This is not a panacea or a miracle drug,” Vaughn says. “For some people, it helps their symptoms, and for some people it doesn’t.”

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A little background about cannabis: while it contains hundreds of compounds, the most well-known are THC and CBD. THC is responsible for marijuana’s psychoactive effects (that “high” sensation), whereas CBD is not psychoactive but seems to modulate the effects of THC, explains Dr. Christopher N. Andrews, a clinical professor of gastroenterology at the University of Calgary.

Whether cannabis actually improves the underlying causes of GI disorders is less clear. “In the test tube, all cannabinoids have some anti-inflammatory effects,” says Dr. Jordan Tishler, an instructor of medicine at Harvard Medical School and president of the Association of Cannabinoid Specialists, a professional organization dedicated to education about cannabinoid medicine. “In human studies, if you look for blood markers of inflammation, you don’t see any change after using cannabis.” When it comes to treating IBD, “there isn’t a lot of evidence that cannabis really modifies the underlying disease process,” Tishler says. “But it treats the symptoms people have.”

A cautionary note: there’s a tipping point with using cannabis for GI disorders. “Cannabinoids reduce the tone of the lower esophageal sphincter, which can increase heartburn and reflux symptoms,” Kinnucan says. “They also decrease gut motility, causing the stomach to empty more slowly, which can increase nausea and be problematic for patients with gastroparesis,” a disorder that delays the movement of food from the stomach to the small intestine.

Wherever you live, “you need to talk to your doctor about whether this is right for you,” Vaughn says. “It’s good to be open—your doctor is not going to be judgmental.” While this may seem like a privacy issue, it’s important to realize there could be medical risks. For one thing, cannabis can have potential interactions with other medications, such as warfarin (an anti-coagulant), benzodiazepines and barbiturates, Kinnucan warns. Cannabis use is also more likely to cause problems with certain groups of people, like those who are pregnant or breastfeeding, who have significant psychiatric disorders or who have a history of substance abuse, Poppers says.

All that said, it’s possible that the impacts of cannabinoids on symptoms could have trickle-down effects that decrease the need for other prescription drugs. For example, a study in a 2019 issue of the European Journal of Gastroenterology & Hepatology found that when patients with IBD used medical cannabis to treat their symptoms, their need for other medications was significantly reduced over the course of a year because their symptoms improved.

Due to the complex anti-inflammatory action cannabinoids can efficiently inhibit the development of colitis. Table ​ 4 4 provides a list from different non-selective and selective CB1 and CB2 receptor agonists, which proved to be protective in animal models of IBD. In general, these studies demonstrated that cannabinoids given peripherally significantly reduce the animals weight loss and diarrhea, the macroscopic and histological colonic damage, neutrophil migration and MPO activity, as well as the production of various inflammatory cytokines (like TNF-α or IL-1β). The protective effect was counteracted by pharmacological or genetic blockade of CB1 [95, 128] or CB2 receptors [105, 114], confirming the involvement of both receptors in the action.

Epithelial damage and breach of the intestinal barrier are important factors in the pathomechanism of IBD, which allow bacterial products and other antigens to cross the epithelium and enter the lamina propria, resulting in inflammation and tissue damage [134-136]. Restoration of the barrier function therefore represents an important approach to treat IBD patients. In this respect, it is of relevance that the endocannabinoids AEA and noladin ether, as well as the CB1 receptor agonist arachidonylcyclopropylamide (ACPA), but not the CB2 receptor agonist JWH-133 induced wound-closure in human colonic epithelial cell lines [82], implying that CB1 receptor activation can improve the impaired mucosal barrier in IBD. This concept is underpinned by studies demonstrating that ∆ 9 -THC and CBD prevented EDTA- and cytokine-induced increased paracellular permeability in the Caco-2 cell culture model and increased the expression of the tight-junction protein zonula occludens 1, which effects were sensitive to CB1-, but not to CB2-antagonism [118, 137]. On the other hand, the latter studies also showed that apical, but not basolateral application of AEA and 2-AG exerted opposite effect, and increased Caco-2 cell permeability, which was also mediated by CB1 receptors and was at least partly due to down-regulated expression of claudin-1, another tight-junction protein [118, 137]. These in vitro results suggest that CB1 receptor ligands can induce opposing effects on inflammation-induced intestinal permeability and may initiate different signaling pathways, leading to changes in different tight junction proteins. The complex (and yet not fully understood) role of cannabinoids on intestinal permeability is also indicated by in vivo studies. Zoppi et al. [113], for example, provided evidence for the mucosal protective effect of the ECS, because immobilization and acoustic stress induced greater inflammation and colonic barrier dysfunction (characterized by lower IgA secretion, higher paracellular permeability to 51Cr-EDTA and higher bacterial translocation) in CB1 (-/-) mice. In contrast, the study of Muccioli et al. [138] suggests that CB1 receptor activation is rather detrimental for the epithelial barrier function, because the CB1 receptor antagonist SR141716A improved gut barrier functions and reduced gut permeability in obese ob/ob mice, while chronic (4-week) infusion of the CB1/CB2 agonist HU-210 increased gut permeability in lean wild-type mice. Thus, the accumulated evidence indicates that CB receptor ligands able to directly modulate intestinal epithelial permeability by acting mainly on CB1 receptors, but further studies are warranted to resolve the apparent contradictions reported thus far. It also has to be considered that the anti-inflammatory effect of cannabinoids can indirectly modify their action on intestinal permeability and improve barrier functions [98].

Originally definitive differences in distribution of CB1 and CB2 receptors have been suggested. While CB1 receptors have been shown to be widely distributed throughout the central, peripheral and enteric nervous system [1], CB2 receptors were thought to be located peripherally mainly in the immune tissues (spleen and macrophages) [46]. However, recent findings suggest functionally relevant expression of CB2 receptors in specific regions of the brain, such as in primed microglia [47] and in neurons in the brainstem [48]. Moreover, this subtype was also shown in several peripheral non-immune tissues, e.g. in myocardium, gut, endothelial, vascular smooth muscle, pancreas, bone, reproductive organs/cells, and in different tumors [49]. Furthermore, inflammation or tissue injury results in increase of local endocannabinoid levels and changes in CB2 receptor expressions. Such alteration was observed not only experimentally but also in several human diseases, for example in cardiovascular, gastrointestinal, kidney, neuro-degenerative, psychiatric, bone, skin, autoimmune and pulmonary disorders (see review [49]).

Inhibition of Motility and Secretion

Inflammatory bowel diseases (IBDs) are chronic, relapsing inflammatory conditions of the gastrointestinal tract. The two major forms are Crohn’s disease (CD) and ulcerative colitis (UC), which share similar symptoms, such as diarrhea, abdominal pain and weight loss [80]. The pathogenesis of both forms is complex, involving various predisposing environmental and genetic factors, which together with the altered intestinal flora can induce mucosal disruption and result in penetration of luminal antigens into the gut wall [80, 81]. The activation of immune cells by these antigens and the chronic, uncontrolled inflammation is a key component of the pathogenesis of IBDs, and the patients are mainly treated today with anti-inflammatory and immunosuppressive agents, such as 5-aminosalicylic acid derivatives, corticosteroids, purine antimetabolites, methotrexate, calcineurin inhibitors or monoclonal antibodies targeting primarily TNF-α [81]. The long-term use of these medications, however, can induce severe adverse reactions, and a large effort is currently put into finding new therapeutic approaches [81]. Beside developing new antibodies targeting various anti-inflammatory cytokines and attempting to restore the altered microbiota, one promising approach is the activation of cannabinoid receptors in the gut, which does not only suppresses many of the IBD-related symptoms, such as diarrhea and visceral hypersensitivity, but also inhibits the inflammatory reaction.

In order to exploit the beneficial effects of cannabinoids and avoid their unacceptable side effects, four different therapeutic strategies could be pursued.

As described in the introduction, AEA and 2-AG are synthesized on-demand from membrane lipid precursors [87], and their primary biosynthetic enzymes, N-acylphosphatidylethanolamine selective phospholipase D (NAPE-PLD) and diacylglycerol lipase (DAGL)-α and -β, respectively, have been identified in the small and large intestines of mice and humans [78, 79, 83, 88, 89]. Immuno-histochemical studies revealed that both synthetic enzymes are localized in the epithelium, in lamina propria plasma cells, in both layers of muscularis externa and in nerve fibers of the myenteric plexus [78, 83], suggesting an active endocannabinoid synthesis in the healthy gut. Accordingly, 2-AG and (in considerably lower amount) AEA have been demonstrated in the intestines of different species [79, 90-92].

Inhibition of Visceral Hypersensitivity

Beside inhibiting the inflammation, MAGL inhibitors also improved intestinal barrier functions and delayed GI transit, [94, 98], while the AEA uptake inhibitor VDM 11 reduced visceral hypersensitivity by modulating the firing of intestinal afferent nerves [158]. These findings together corroborate the concept that modulation of the ECS might be a promising way to treat IBD.

Interestingly, the intestinal level of 2-AG in most studies remained unchanged [79, 91, 92, 98], which implies that this endocannabinoid does not have important role in IBD. An alternative explanation, however, can be that both the synthesis and degradation of 2-AG accelerate in inflammation, which results in a more rapid turnover without altering its tissue level. This assumption is supported by the findings of Marquez et al. [83], who measured elevated DAGL-α and MAGL levels in colon mucosal biopsies of patients with UC.