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  • Nonetheless several questions remain to be answered

    2022-01-14

    Nonetheless, several questions remain to be answered about FAAH inhibition to address cannabis use disorder. The trial was of short duration (4 weeks), whereas most clinical trials in this field have been for 8–12 weeks., , , Although motivational deficits are commonly present in cannabis users and in people with cannabis use disorder, baseline levels of motivation to quit cannabis use in D'Souza and colleagues' trial were varied. By comparison, most treatment trials in cannabis use disorder have used standardised levels of baseline motivation to quit cannabis use (eg, with a validated measure of motivation to quit substance use, such as the University of Rhode Island Change Assessment). Moreover, like most initial proof-of-concept trials, the study was confined to men, and future studies should assess sex differences in treatment response to FAAH inhibition. Finally, no assessments of cannabis-related functional impairment (eg, with scales such as the Cannabis Use Disorder Identification Test) were done, and thus the effect on functional outcomes achieved during this FAAH inhibitor trial is not clear. Most pharmacotherapy trials in addiction have sought to develop medications as adjuncts to behavioural interventions. The development of FAAH inhibitors as putative pharmacotherapies for cannabis use disorder should therefore make use of behavioural supports in both abstinence initiation and relapse-prevention designs. In particular, the use of cognitive-behavioural therapy in combination with contingency management could be the optimal approach to testing of putative cannabis pharmacotherapies, because they are most effective in achieving initial abstinence, facilitating the study of relapse-prevention efficacy, which might be the most sensitive test for medications development. The population studied seemed not to include adults with psychiatric comorbidity, but it will be important to include these patients in future studies as they seem to be at much higher risk for the initiation and maintenance of cannabis use disorder. Finally, the endurability of FAAH inhibition needs to be rigorously tested with sufficient follow-up assessment periods (eg, 3–6 months after treatment). Nonetheless, if these questions are resolved satisfactorily, FAAH inhibition might prove to be a safe and effective treatment approach to address an important public health problem in the era of cannabis legalisation.
    Introduction Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are associated with aberrant regulation of the mucosal immune system, resulting in recruitment of inflammatory reboxetine synthesis to the intestinal tract. IBD affects over a million people in the United States alone; its symptoms include abdominal pain, diarrhea, rectal bleeding, weight loss, and poor ability to digest food. The precise cause of IBD is unknown, but common agreement among scientists has converged on environmental and genetic factors, as well as immune dysregulation and, particularly the role of commensal microbiota in the intestine (Braegger and MacDonald, 1994, Dohi et al., 2000, Podolsky, 2002, Sartor, 2006, Sartor, 2008). Abnormalities in the gut immune microenvironment, enteric persistent infection, trauma, and inflammation may initiate and cause the progression of IBD (Mayer and Collins, 2002). Intestinal inflammation is normally associated with infiltration of immune cells, including macrophages, neutrophils, and type 1 T helper (Th1) cells into the colon, which secrete the proinflammatory cytokines TNF-α and IFN-γ (Strober et al., 2007, Strober et al., 2002). The available conventional treatments of IBD are useful and advance our understanding of the underlying pathologies, but patients are often resistant to these treatments and experience many side effects, justifying continued search for new, safe, and effective therapeutic approaches. In recent years, there has been increasing recognition of the role of endogenous cannabinoid receptors 1–2 (CB1 and CB2) in the regulation of inflammation-associated with colitis. Anandamide (AEA) is the endogenous signaling lipid that binds and activates CB1 and CB2, receptors and AEA levels are tightly regulated by the catabolic enzyme FAAH. Further, FAAH is an integral membrane hydrolase with a single n-terminus transmembrane domain. Many distinct classes of FAAH inhibitors have been reported (Salaga et al., 2014). A study focusing on FAAH and intestinal inflammation demonstrated that CB1 receptor-deficient mice are more sensitive to experimental colitis than are control mice and that a CB1 antagonist increased the severity of experimental colitis (Massa et al., 2004). Other studies (Cluny et al., 2010, Engel et al., 2010, Kimball et al., 2006, Massa et al., 2004, Storr et al., 2008, Storr et al., 2009) have suggested that endogenous CB receptor activation may ameliorate colitis. Storr et al. (2008) showed that FAAH mRNA increased 3days after trinitrobenzene sulfonic acid (TNBS) induction. Further, elevated levels of endogenous AEA resulting from deficiency or inhibition of FAAH are significantly more resistant to TNBS-induced colitis than are controls (Izzo and Sharkey, 2010). AEA can activate both CB1 and CB2 receptors and decrease the level of proinflammatory cytokines (Izzo and Camilleri, 2009).