It is possible that participants in our study were obtaining care in safety‐net primary care settings with CCMs. Alternatively, the reduced odds of unmet need amongst those who had regular care providers could reflect other factors that we did not measure. For example, having a regular care provider may be a marker for increased system engagement and reduced barriers to any type of care. Those who seek primary care may be more organized, knowledgeable about safety‐net service availability, and have more access to transportation and other enabling resources. . Having a case manager was associated with less mental health and substance use treatment need. In the case management brokerage model, case managers help people navigate care systems and provide a linkage to services. In the clinical case management model, case managers serve as care providers and may provide both mental health and substance use services directly . In some models, such as intensive case management, case managers provide both brokerage and direct services . It is possible that the association between having a case manager and decreased odds of unmet need for both mental health and substance use services is a result of reverse causality; treatment programs may assign a case manager. We found that participants who first became homeless at age 50 or older had a higher odds of unmet substance use treatment need. Those with late onset homelessness had led more “typical” lives, with a higher likelihood of having been continuously employed and having been married or partnered . They were less likely to have had early onset of substance use problems, thus, they may have developed substance use problems more recently. These individuals may have been less aware of safety‐ net resources in general or resources for substance use treatment in particular. Spending time in jail/prison in the past 6 months was associated with reduced unmet substance use treatment need. It is possible that participants initiated substance use treatment while incarcerated. However, most incarceration settings do not provide adequate treatment services.
Alternatively, as a condition of release,hydroponic racks participants may have been required to engage in substance use treatment.By giving medication‐assisted treatments, such as buprenorphine for opioid use disorder and naltrexone for alcohol use disorder in primary care settings, primary care providers can begin to address this unmet need . However, there is a need for greatly expanded substance use services. Our study has several limitations. We did not use a full psychiatric diagnostic interview. However, screening measures are important empirical tools for the referral of individuals to mental health treatment, especially when integrated care is available . We did not ask participants where they received mental health services, thus we cannot determine whether they received care colocated with primary care, or treatment in mental health specific settings.Historical descriptions of the stimulatory effects of Cannabis sativa on feeding are now explained by the ability of its psycho active constituent 9 -tetrahydrocannabinol to interact with CB1 cannabinoid receptors . Both THC and the endogenous cannabinoid anan damide promote overeating in partially satiated rats . Moreover, THC increases fat intake in laboratory animals and stimulates appetite in humans . The selective CB1 receptor antagonist SR141716A counteracts these effects and, when administered alone, decreases standard chow intake and caloric consumption , presumably by antagonizing the actions of endogenously released endocan nabinoids such as anandamide and 2-arachidonoylglycerol . These results suggest that endocannabinoid substances may play a role in the promotion of food intake, possibly by delaying satiety. It is generally thought that the hyperphagic actions of cannabinoids are mediated by CB1 receptors located in brain circuits involved in the regulation of motivated behaviors . Thus, infusions of anandamide in the ventromedial hypothalamus were shown to promote hyperphagia , whereas the anorectic effects of leptin were found to be associated with a decrease in hypothalamic anandamide levels . Nevertheless, evidence suggests that cannabinoids also may promote feeding by acting at periph eral sites. Indeed, CB1 receptors are found on nerve terminals innervating the gastrointestinal tract , which are known to be involved in mediating satiety signals that originated in the gut .
To test this hypothesis, in the present study we have examined the impact of feeding on intestinal anandamide accumulation, the effects of central versus peripheral systemic administration of cannabinoid receptor agonists on feeding behavior, and the effects of sensory deafferentation on cannabinoid-induced hyperphagia.Animals. Male Wistar rats were housed individually with food and water available ad libitum, except when restriction was required. All animal procedures met the National Institutes of Health guidelinesfor the care and use of laboratory animals and the European Commu nities directive 86/609/EEC regulating animal research. Surgery. For intracerebroventricular injections, stainless steel guide cannulas aimed at the lateral ventricle were implanted in the rats. The animals were anesthetized with equithesin and placed in a David Kopf Instruments stereotaxic instrument with the incisor bar set at 5 mm above the interaural line. A guide cannula was secured to the skull by using two stainless steel screws and dental cement and was closed with 30 gauge obturators . The implantation coordinates were 0.6 mm posterior to bregma,2.0 mm lateral, and 3.2 mm below the surface of the skull. These coordinates placed the cannula 1 mm above the ventricle. Aftera7d post surgical recovery period, cannula patency was confirmed by gravity flow of isotonic saline through an 8-mm-long, 30 gauge injector inserted within the guide to 1 mm beyond its tip. This procedure allowed the animals to become familiar with the injection technique. Chemicals. Capsaicin was purchased from Sigma , and cholecystokinin octapeptide sulfated , R–methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl) methanone monomethanesulfonate , and 1,4-dihydro-3–5H-pyrrolo[3,2-b]pyridin-5- one were obtained from Tocris Cookson . N-pip eridino-5–1–4-methylpyrazole-3- carboxamide was a gift from Sanofi Recherche . Anandamide and oleoylethanolamide were synthesized in the laboratory . Capsaicin was dissolved in 5% Tween 80, 5% propyleneglycol, and 90% saline. All other drugs were dissolved in dimethylsulfoxide and administered in 70% DMSO in sterile saline. HPLC/mass spectrometry analyses. Anandamide was solvent-extracted from tissues, fractionated by column chromatography, and quantified by HPLC/mass spectrometry with an isotope dilution method, as described previously . Drug treatments. Capsaicin was administered subcutaneously in rats anesthetized with ethyl ether.
The total dose of capsaicin was divided into three injections . Control rats received vehicle injections. Experiments were performed 10 d after capsaicin treatment in rats that had lost the corneal chemosensory reflex , and showed enhanced water intake 10 d after capsaicin treatment.For intracerebroventricular administration, the obturator was removed from the guide cannula and an 8 mm injector that was connected to 70 cm of calibrated polyethylene-10 tubing was lowered into the ventricle. The tubing was then raised until flow began, and 5l of drug solution was infused over a 30–60 sec period. The injector was left in the guide cannula for an additional 30 sec and then removed. The stylet was immediately replaced. Animals were tested 5 min after injections. The intracerebroventricular cannula placements were evaluated after each experiment by dye injection. Only rats with proper intracerebroventricular placements were included in the data analysis. Food intake studies. The effects of drugs on feeding behavior were analyzed in animals deprived of food for 24 hr and habituated to handling or in partially satiated animals . To this end, 48 hr before testing,indoor garden table the bedding material was removed from the cage and a small can containing food pellets was placed inside the cage for 4 hr. The animals were then food-deprived for 24 hr, with access to water ad libitum. The animals were returned to their home cage 15 min after drug administration; there, a can with a measured amount of food and a bottle containing 250 ml of fresh water were placed. Food pellets and food spillage were weighed at 60, 120, and 240 min after starting the test, and the amount of food eaten was recorded. At the end of the test, the amount of water consumed was also measured. For partial satiation of animals, 24 hr food-deprived rats were allowed to eat from the can for 1 hr. The can was replaced and intake was recorded. Fifteen minutes after drug injections, the food was again presented, and the amount consumed was recorded hourly for the next 4 hr. Open-field test. Motor behaviors in the open field were studied in an opaque open field as described previously . The field was illuminated using a ceiling halogen lamp regulated to yield 350 lux at the center of the field. Rats were habituated to the field for 10 min the day before testing. On the experimental day, the animals were treated and placed in the center of the field, and locomotor activity and rearing and grooming behavior were scored for 5 min at 5, 30, 60, and 120 min after drug injection. Behavior was scored by trained observers who were unaware of the experimental conditions. Statistics. Statistical significance was assessed by one-way or multi-factorial ANOVA, as required. After a significant F value, post hoc analysis was performed. Calculations were done using the BMDP statistical package .We first investigated whether starvation and refeeding affect anandamide content in intestinal tissue, where various intrinsic signals modulating food intake, such as CCK and OEA , are generated. As shown in Figure 1, food deprivation was accompanied by a seven fold increase in anandamide content in the small intestine, an effect that was reversed on refeeding. In contrast, no such increase was observed in brain or stomach tissues . The change in intestinal anandamide did not result from the inhibition of anandamide degradation. Indeed, fatty acid amidohydrolase activity, which catalyzes the deactivating hydro lysis of anandamide, was not affected by the feeding status .The small intestine produces both anandamide, which stimulates food intake , and OEA, which inhibits food intake by acting on peripheral sensory fibers . However, the intestinal levels of the two compounds appear to be reciprocally regulated. Thus, the OEA content decreases , whereas the anandamide content increases during starvation. To examine the possible interaction of these fatty acid ethanolamides on feeding, we studied whether OEA blocks AEA-induced hyperphagia and whether blockade of CB1 receptors with a low, sub-threshold dose of SR141716A potentiates the inhibitory actions of OEA on food intake.
The results, illustrated in Figure 4A, indicate that pretreatment with OEA inhibits AEA-induced hyperphagia in partially satiated rats, whereas SR141716A and OEA act synergistically to decrease eating in food-deprived animals . The effects were ob served during the 240 min period of testing. The inhibitory actions of combined SR141716A and OEA lasted for at least 24 hr , a prolonged effect that these drugs do not elicit separately.The present results suggest, first, that systemically administered cannabinoid agents affect food intake predominantly by engaging peripheral CB1 receptors localized to capsaicin-sensitive sensory terminals and, second, that intestinal anandamide is a relevant signal for the regulation of feeding. Two observations support the idea that cannabinoid agents modulate feeding through a peripheral mechanism. First, the lack of effect of central administration of cannabinoid antagonists such as SR14116A and 6-iodo-2-methyl-1-[2-ethyl]-[1H]-indol-3-yl methanone on food intake in food-deprived animals and, second, the ability of capsaicin-induced deafferentation to prevent changes in feeding elicited by the peripheral administration of cannabinoid drugs. Moreover, the similar pattern of expression of the early gene c-fos on hypothalamic and brainstem areas regulating food intake after both the peripheral administration of either CB1 agonists and antagonists and the acute administration of peripherally acting satiety modulators such as gastrointestinal hormones or feeding inhibitors such as OEA further support the peripheral actions of cannabinoids on food intake. Finally, the fact that the CB1 receptor antagonist SR141716A was active only after intraperitoneal or oral administration but not after subcutaneous injection further supports this hypothesis. These results do exclude the possibility that peripheral anandamide also modulates feeding by acting on specific hypothalamic areas involved in caloric homeostasis . However, they do suggest that the predominant effects of systemically administered SR141716A are mediated by peripheral CB1 receptors, which may thus represent a potential target for anorexic agents. The concentration of anandamide in intestinal tissue increases during food deprivation, reaching levels that are threefold greater than those needed to half maximally activate CB1 receptors . This surge in anandamide levels, the mechanism of which is unknown, may serve as a short-range hunger signal to promote feeding. This idea is supported by the ability of SR141716A to reduce food intake after systemic but not central administration.