Given that historical experiences of violence and trauma denote significant risk for suicide, there is an urgent need to provide integrated, trauma-informed intervention services for sex workers and other marginalised populations. Currently available interventions and pharmacological treatments for suicidality show limited efficacy, and concerted efforts should be made to increase access to evidence-based treatments and to explore alternative approaches to improving mental health and well-being. Emerging research and evidence show positive outcomes with psychedelic-assisted treatments, which have demonstrated an excellent record of safety with few to no serious adverse effects reported.This study suggests psychedelic substances may hold promise as useful tools in addressing mental health issues and remediating risks for psychological distress and suicide.Gut-brain signaling plays an integral role in food intake, energy homeostasis, and possibly reward. Our understanding of the biochemical and molecular pathways involved in these processes and their dysregulation in obesity, however, remains incomplete. Several signals, including gut-derived peptides, have been identified that control neurotransmission from peripheral organs to the brain. These include cholecystokinin , which is released from sub-populations of enteroendocrine cells in the upper small-intestinal epithelium in response to the presence of nutrients in the lumen and controls food intake and meal size by activating the afferent vagus nerve. Recent studies in mice suggest that specialized enteroendocrine cells in the intestinal epithelium,drying racks termed “neuropods”, form functional synapses with gastric afferent vagal fibers and participate in the transduction of signals from food to neural signals carried by vagal afferent neurons to the brain.

Neuropods sense nutrients on their luminal side and, in turn, release glutamate and CCK in a coordinated manner that induces rapid or prolonged firing of vagal afferent neurons, respectively. These results highlight neuropods as a key cellular mechanism in nutrient sensing and associated gut-brain signaling. Other studies suggest that vagal afferent neurotransmission recruits brain reward circuits and may participate in food reward. For example, optogenetic activation of right gastric vagal afferent neurons increased dopamine release in central reward pathways, operant responses associated with self-stimulation of brain reward neurons, and conditioned flavor and place preferences. Specific biochemical and molecular signaling pathways that control these functions, however, remain unclear. The endocannabinoid system is a lipid-derived signaling pathway that controls food intake, energy homeostasis, and reward, and is hijacked by chemicals in the cannabis plant. In general, activating the eCB system increases food intake and inhibiting its activity reduces food intake. The eCB system is located throughout the brain and plays an important role in these functions; however, mounting evidence also suggests that the eCB system in peripheral organs, including the small-intestinalepithelium, serves an integral role. Indeed, pharmacological blockade of peripheral cannabinoid subtype-1 receptors reduces food intake and improves metabolic dysfunction associated with obesity in rodents similarly to brain-penetrant CB1R antagonists. These studies highlight the peripheral eCB system as a possible target for safe anti-obesity agents that are devoid of psychiatric side-effects associated with drugs that access CB1Rs in the brain. The eCB system in the rodent small-intestinal epithelium becomes activated during oral exposure to dietary fats, during a fast, and after chronic exposure to obesogenic diets. Moreover, pharmacological inhibition of peripheral CB1Rs blocked cephalic-phase consumption of dietary fats in rats, refeeding after a fast in rats, hyperphagia associated with western diet-induced obesity in mice, and restored nutrient-induced secretion of satiation peptides in western diet-induced obese mice.

These studies suggest a critical role for eCB signaling in the gut in the intake of palatable foods. We will review recent experiments that expand our understanding of roles for the eCB system in the gut in gut-brain neurotransmission associated with food intake, energy homeostasis, and reward. An emphasis will be on studies that reveal both indirect and direct mechanisms of control for CB1Rs over gut-brain signaling and dysregulation of these pathways in rodent models of diet-induced obesity. The eCB system is expressed in cells throughout all organs in the body and is comprised of lipid-derived signaling molecules including the primary eCBs, 2-arachidonoyl-snglycerol and arachidonoyl ethanolamide , their metabolic enzymes, and cannabinoid receptor sub-type 1 , cannabinoid receptor sub-type-2 , and possibly others. The eCB system in the brain is extensively studied for its roles in controlling the intake and reward value of palatable food. In addition to central sites, recent evidence suggests that the eCB system located in cells lining the intestinal epithelium is an integral component of a gut-brain axis that controls the intake of palatable foods. For example, a sham-feeding protocol in rats was utilized to test if eCB signaling in the gut is associated with positive reinforcement that drives intake of food based on its orosensory properties. During sham feeding, rats are allowed to freely consume a liquid diet that drains from a surgically-implanted, reversible, cannulae in the stomach before it reaches the small intestine. Therefore, sham feeding enables isolation of the cephalic phase of food intake and effectively eliminates post-ingestive consequences of food intake.Separate groups of rats were given access for 30 min to a fixed amount of dietary fats , sucrose, or protein, and levels of 2-AG and anandamide were measured in the upper small-intestinal epithelium by liquid chromatography/mass spectrometry. Tasting dietary fats—but not sucrose or protein—triggered production of eCBs in the upper small-intestinal epithelium, but not in other peripheral organs tested or in micro-punches obtained from brain regions associated with food intake and reward. This effect was also specific for mono- and di-unsaturated fats , but not saturated or polyunsaturated fats. Moreover, production of eCBs in the small-intestinal epithelium was absent in sham feeding rats that received full sub-diaphragmatic vagotomy, which suggests that efferent vagal signaling participates in the biosynthesis of eCBs.

Furthermore, intra-duodenal administration of a low-dose cannabinoid receptor subtype-1 inverse agonist or a peripherally-restricted CB1R antagonist blocked sham feeding of fats. Collectively, these studies suggest that tasting dietary fats recruits an eCB mechanism in the gut that provides positive feedback to the brain and promotes intake of fatty foods. The aforementioned studies utilized pharmacological, biochemical, and behavioral approaches to identify roles for peripheral CB1Rs in the intake of palatable food. At the time of these studies, however, appropriate tools were not available to directly ask if CB1Rs in the intestinal epithelium are required in these processes. To test the necessity for CB1Rs in the intestinal epithelium in the intake of palatable foods,greenhouse benches we developed transgenic mice that are conditionally deficient in CB1Rs in the intestinal epithelium. Mice were maintained on standard rodent chow low in fats and sugars, then given access for the first time to a palatable western-style diet high in fats and sugars , and preferences for western diet were measured. This specific western diet was chosen due to its macro-nutrient composition that more closely matches the human diet when compared to other obesogenic diets routinely used in rodent studies. Control mice with functional CB1Rs in the intestinal epithelium displayed large preferences for western diet when compared to chow, with over 90% of total kilocalories consumed from western diet over the testing period. In contrast to controls, preferences for western diet were reduced for up to 12 h in IntCB1-/- mice. These results provide direct evidence that CB1Rs in the murine intestinal epithelium are required for acute preferences for palatable foods. Similar to rodents, humans prefer fatty and sweet foods when given a choice, and their consumption is associated with elevated levels of eCBs in blood. Moreover, levels of eCBs are increased in blood in both human and rodent obesity; however, the impact that circulating eCBs may have on gut-brain function associated with food intake, dietary preferences, and obesity is unknown. Nonetheless, it is plausible that circulating eCBs act as a humoral signal that interacts with cannabinoid receptors along the gut-brain axis to facilitate these processes.Mounting evidence suggests that eCB signaling in the periphery controls food intake by mechanisms that include both indirect and direct interactions with the afferent vagus nerve. We will first review evidence of an indirect mechanism for CB1Rs in the control of gut-brain signaling and its possible dysregulation in diet-induced obesity.Recent studies in mice suggest that CB1Rs in cells lining the small-intestinal epithelium control food intake by blocking nutrient-induced secretion of the satiation peptide, cholecystokinin , which leads to increased caloric intake and meal size under conditions of heightened local eCB tone. Upon arrival of nutrients in the small-intestinal lumen, CCK is released from sub-populations of enteroendocrine cells and controls meal size and satiation by directly activating CCKA receptors on vagal afferent neurons and possibly in the brain.

Immunoreactivity for CB1Rs was found on CCK-containing cells in the upper small-intestinal epithelium in a CCK-reporter mouse that expresses eGFP selectively in these cells [C57BL/6-Tg2Mirn/J]. CCK-eGFP cells were then isolated by fluorescence-activated cell sorting and expression of messenger RNA for components of the eCB system, including CB1Rs , was analyzed. CCK-eGFP-positive cells were enriched with mRNA for CB1Rs when compared to CCK-eGFP-negative cells, which confirms earlier reports of expression of mRNA for CB1Rs in I cells in another CCK-reporter mouse line. We next asked if pharmacological activation of CB1Rs with the general cannabinoid receptor agonist, WIN 55,212-2, impacts nutrient-induced release of the bioactive form of CCK, CCK-8. Circulating levels of CCK-8 were increased within 30-min following oral gavage of corn oil, an effect that was completely reversed by pretreatment with WIN 55,212-2. The inhibitory effects of WIN 55,212-2 on corn oil-induced elevations in CCK-8 in blood were blocked by the peripherally-restricted neutral CB1R antagonist, AM6545, which highlights a role for peripheral CB1Rs in this response. The study described above was performed in lean mice fed a low-fat and low-sugar diet, which express low levels of eCBs in the small-intestinal epithelium. Diet-induced obesity is associated with high levels of eCBs in the small-intestinal epithelium, and pharmacological inhibition of this heightened eCB activity at peripheral CB1Rs blocked overeating resulting from increased meal size and daily caloric intake. These experiments suggest that elevated eCB tone in the small-intestinal epithelium drives the over consumption of high-energy foods and promotes obesity; however, the mechanism in this response were unclear. Therefore, we tested the hypothesis that heightened eCB signaling at CB1Rs in the small-intestinal epithelium in our mouse model of western diet-induced obesity drives overeating by blocking nutrient-induced release of CCK-8. Mice were maintained for 60 days on western diet , which is a time when levels of eCBs are elevated in the intestinal epithelium. Oral gavage of corn oil increased levels of CCK-8 in blood in lean mice with low levels of eCBs in the intestinal epithelium. In contrast to lean mice, corn oil failed to increase levels of CCK-8 in blood in mice fed a western diet for 60 days; however, pretreatment with the peripherally-restricted CB1R antagonist, AM6545, restored the ability for nutrients to increase levels of CCK-8 in blood. These results suggest that under conditions of heightened eCB activity at CB1Rs in the small-intestinal epithelium , CCK-8 release is inhibited, which leads to delayed satiation and overeating. Indeed, inhibition of peripheral CB1Rs with AM6545 in obese mice attenuated overeating associated with increased meal size and total caloric intake. Moreover, the hypophagic effects of AM6545 were reversed by pretreatment with a lowdose of the CCKA receptor antagonist, devazepide, which suggests that acute hypophagic effects AM6545 occurs by a mechanism that includes restoring nutrient-induced satiation signaling. Collectively, these studies indicate a key inhibitory role for CB1Rs in the small intestinal epithelium in nutrient-induced secretion of satiation peptides. Thus, CB1Rs in the intestinal epithelium are thought to indirectly control gut-brain neurotransmission via regulating the release of gut-derived peptides that directly interact with the vagal afferent neurons. Furthermore, these processes become dysregulated in diet-induced obesity, which leads to overeating and possibly obesity. Future studies will be important to elucidate specific intracellular signaling pathways in enteroendocrine cells that link eCB signaling at local CB1Rs with blockade of secretion of satiation peptides, the impact of eCB activity at CB1Rs in the intestinal epitheliumon activity of gastric vagal afferent neurons, and the impact that this signaling has on recruitment of brain circuits associated with food reward.Recent studies suggest that CB1Rs in stomach cells influence alcohol intake and preference in mice by controlling local formation of the bio-active appetite-stimulating hormone, ghrelin, which directly interacts with growth hormone secretagogue receptor on vagal afferent neurons and the brain.