Even so, “I didn’t feel well—my mind was cloudy and I was in pain,” says Silverman, now 47, the co-founder of the PSMC5 Foundation, which is dedicated to beating rare genetic disorders like the PSMC5 gene mutation (which his son has). So in 2013, he tried a new approach: he began getting intravenous infusions of an immunosuppressive drug at four- to eight-week intervals to reduce inflammation in the lining of his intestines. “It helped, but I still had nausea, brain fog, discomfort and trouble sleeping,” says Silverman.
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Other experts agree. “When you tease it out, this is more of a symptom-based therapy,” Vaughn says. “With IBD, there seems to be a calming effect on symptoms such as nausea, vomiting, pain and diarrhea.” Vaughn reports that he sees patients with Crohn’s disease get more of an effect from cannabis than those with ulcerative colitis.
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.”
In spite of these concerns, the numerous experimental data and preliminary clinical studies are convincing, and the ECS represents a promising target in the treatment of inflammatory bowel diseases and gastric mucosal lesions, ulceration and inflammation. The intensive research focusing to develop new structures that modulate the ECS without inducing the central undesired side effects, gives the hope that in the near future safe, effective compound(s) could be translated into clinical practice.
Another promising phytocannabinoids are CBG and CBC: the first is a partial agonist of CB1 and CB2 receptors as well as an AEA reuptake inhibitor , which exerted both preventive and curative effects in DNBS-induced colitis, and also attenuated both nitrite production in macrophages and ROS production in intestinal epithelial cells , while CBC is a potent TRPA1 agonist and weak anandamide reuptake inhibitor, which also ameliorated DNBS colitis in mice  and reduced croton oil-induced increased motility .
The concept that the ECS is altered in IBD is supported by several animal and human studies, and (Tables 2 2 ) and 3 3 provide a brief overview of the observed changes. At the first glance these results are rather contradictory, since both elevated, depressed and unchanged expressions of the various components have been described, but a closer look reveals some important similarities.
In the majority of studies, the expression of CB1 receptor was elevated in the inflammed gut, and this was evident in both epithelial cells, lamina propria mononuclear cells and myenteric neurons [79, 95, 96]. Although in the case of CB2 receptor the findings are more erratic, an increased epithelial expression has been consistently observed [82, 83, 96]. These findings suggest that disruption of the epithelial barrier and the concomitant inflammatory reaction upregulate the expression of both CB receptors, which may explain the enhanced GI effects of CB receptor ligands in inflammation (see below).
SUMMARY AND CONCLUSIONS
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.
Abbreviations: 2-AG: 2-arachidonoylglycerol; AEA: anandamide; COX: cyclooxygenase; ECS: endocannabinoid system; FAAH: fatty acid amide hydrolase; MAGL: monoacylglycerol lipase; i.c.v.: intracerebroventricularly; i.p.: intraperitoneally; i.v.: intravenously; p.os: orally; s.c.: subcutaneously.
Activation of cannabinoid receptors by exogenous or endogenous ligands has been shown to decrease the formation of different types of experimental gastric ulcers. For example Δ 9 -THC reduced mucosal damage induced by pylorus ligation . It also attenuated diclofenac-induced gastric mucosal lesions given either orally or intra-peritoneally (i.p.) in a CB1 receptor-dependent fashion, and it proved to be more potent in exerting gastroprotective effect than producing classical cannabimimetic actions, such as locomotor immobility, antinociception, hypothermia and catalepsy [66, 67]. Gastric lesions induced by water immersion and restraint stress were reduced by AEA as well as by WIN 55,212-2 (both given i.p.), and their gastroprotective action was mediated also by CB1 receptors [68, 69]. The protective effect of AEA was associated with an increase in gastric mucosal blood flow and mucosal DNA synthesis and with reduced level of pro-inflammatory interleukin-1β (IL-1β) . Involvement of CB1 receptors in gastroprotection was further supported by the results with the selective cannabinoid CB1 receptor agonist ACEA, which effectively reduced the aspirin-induced gastric mucosal lesions (given i.p.) .
Using Non-psychotropic Phytocannabinoids
The first, and probably most evident approach is the selective stimulation of CB2 receptors, which does not induce psychoactive effects , in spite of the presence of functional CB2 receptors within the central nervous system [48, 162]. As depicted above, CB2 receptors are abundant on immune cells, their intestinal expression is increased in inflammation and their activation significantly ameliorates the development of colitis in numerous animal models [96, 105, 114, 133]. Moreover, CB2 receptor agonists also suppress the inflammation-induced hypermotility [86, 147] and visceral hypersensitivity [115, 155-157]. These data, obtained mainly from animal experiments, foreshadow an important role of CB2 receptor agonists in the therapy of IBD, but future trials are warranted to confirm their clinical efficacy and safety.
Among the endocannabinoids the intestinal level of AEA during inflammation almost always differed significantly from the level measured in healthy tissues, however, both elevation [92, 93] and reduction [40, 79, 89] have been reported. These diverging results can be partly explained by different experimental conditions. For example, the measured levels of AEA and its synthetic and degrading enzymes seem to vary at different time points during the course of the disease. Storr et al.  observed significantly reduced FAAH mRNA in the early phase of various colitis models (TNBS, oxazolone, DSS), but this reduction disappeared at later time points, or even changed to an elevation. This finding suggests that the level of AEA increases in the initial phase of colitis, which may have important protective effect, but with the progression of the disease this endogenous protective mechanism deteriorates. Beside this time-dependence AEA levels also differ in various segments of the gut, as well as in different regions of the gut wall. For instance, Izzo et al.  reported a significant decrease of AEA level in the jejunum of croton oil-treated mice, but not in the duodenum or ileum, and in the study of D’Argenio et al.  TNBS-treatment induced significant rise of AEA in the submucosa, but not in the mucosa of rat colon. In brief, these studies clearly demonstrate that intestinal inflammation alters the tissue level of AEA, but further studies are needed to get a clear picture of its role in the pathomechanism.