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The fact that the cannabinoid antagonist SR141716A prevents these effects suggests that AM404 may act by preventing anandamide inactivation and enhancing its interactions with cannabinoid receptors. Importantly, however, AM404 also can be transported inside cells , where it may reach levels that are sufficient to inhibit anandamide degradation by FAAH . The target selectivity of AM404 has been investigated in some detail. Initial studies showed that AM404 has no affinity for a panel of 36 potential targets, including G protein-coupled receptors, ligand-gated channels, and voltage-dependent channels . Subsequent work suggested, however, that AM404 may activate the capsaicin sensitive VR1 vanilloid receptor in vitro . It is unlikely that this effect occurs in vivo, since AM404 does not display any of the pharmacological properties of a vanilloid agonist . Yet, these findings underscore the need to design novel inhibitors of anandamide transport endowed with greater target selectivity. Ongoing research efforts in this direction have led to the development of several arachidonic acid derivatives that are equivalent or slightly superior to AM404 in inhibiting anandamide transport in vitro and in vivo, with effects similar to those of AM404 . Consistent with its low affinity for CB1 receptors, AM404 does not act as a direct cannabinoid agonist when administered to live animals. The compound has no antinociceptive effects in the mouse hot-plate test and does not reduce arterial blood pressure in the urethaneanesthetized guinea pig . In the same models, however, AM404 magnifies the responses elicited by exogenous anandamide, actions that are prevented by the CB1 antagonist SR141716A . Furthermore, when administered alone, AM404 reduces motor activity , attenuates apomorphine-induced yawning , decreases the levels of circulating prolactin , and alleviates the motor hyperactivity induced in the rat by striatal 3-nitropropionic acid lesions . These actions resemble those of anandamide and are blocked by SR141716A ,growing cannabis outdoors suggesting that endogenous anandamide may be involved. In keeping with this notion, systemic administration of AM404 in the rat causes a time-dependent increase in circulating anandamide levels .

The participation of anandamide in the effects of AM404 in vivo has been questioned based on the ability of this compound to interact with vanilloid receptors in vitro . Yet, the fact that SR141716A blocks the motor inhibitory actions of AM404 at doses that are selective for CB1 receptors strongly argues for a predominant, if not unique, role of the endocannabinoid system in the behavioral response to AM404 administration. Furthermore, the pharmacological properties of AM404 are very different, often opposite to those of capsaicin and other vanilloid agonists. For example, capsaicin produces pain and bronchial smooth muscle constriction , whereas AM404 has no such effect when administered alone, and in fact enhances anandamide’s analgesic and bronchodilatory actions . The ability of intraperitoneal capsaicin to inhibit movement, described by Di Marzo et al. , superficially mimics one property of AM404, but should be viewed with caution, as it most likely results from the strong visceral pain and subsequent “freezing response” elicited by capsaicin. In conclusion, current evidence suggests that AM404 may magnify the actions of anandamide primarily by inhibiting the clearance of this compound from its sites of action.Almost a decade before anandamide was discovered, Schmid and collaborators identified a hydrolase activity in rat liver that catalyzes the hydrolysis of fatty acid ethanolamides to free fatty acid and ethanolamine . That anandamide may be a substrate for such an activity was first suggested by biochemical experiments and then demonstrated by molecular cloning, heterologous expression, and genetic disruption of the enzyme involved . FAAH is an intracellular membrane-bound protein whose primary structure displays significant homology with the “amidase signature family” of enzymes . It acts as a hydrolytic enzyme for fatty acid ethanolamides such as anandamide, but also for esters such as 2-AG and primary amides such as oleamide . Site-directed mutagenesis experiments indicate that this unusually wide substrate preference may be due to a novel catalytic mechanism involving the amino acid residue lysine-142. This residue may act as a general acid catalyst, favoring the protonation and consequent detachment of reaction products from the enzyme’s active site . This mechanism was recently confirmed by the solution of the crystal structure of FAAH complexed with the active site-directed inhibitor methoxy arachidonyl fluorophosphonate .

In addition to FAAH, other enzymes may participate in the breakdown of anandamide and its fatty acid ethanolamide analogs. A PEA-hydrolyzing activity distinct from FAAH was described in rat brain membranes and human megakaryoblastic cells . This activity was purified to homogeneity from rat lung and shown to possess a marked substrate preference for PEA over anandamide . PEA does not bind to any of the known cannabinoid receptors but produces profound analgesic and anti-inflammatory effects , which are prevented by the CB2-preferring antagonist SR144528 . Future studies will undoubtedly address the relative roles of FAAH and this newly discovered enzyme in the biological disposition of PEA and anandamide. The ability of FAAH to act in reverse has generated some confusion as to the mechanism of anandamide formation. Early reports of anandamide synthesis from free arachidonate and ethanolamine have now been unambiguously attributed to the reverse of the FAAH reaction . Because high concentrations of arachidonic acid and ethanolamine are needed to drive FAAH to work in reverse, it is unlikely that this reaction plays a physiological role in anandamide generation . One possible exception is represented by the rat uterus, where substrate concentrations in the micromolar range are required for the synthetic reaction to occur, implying that FAAH or a similar enzyme might contribute to anandamide biosynthesis in this tissue .Systematic structure-activity relationship investigations have identified several general requisites for substrate recognition by FAAH. First, FAAH accommodates a wide range of fatty acid amide substrates, but reducing the number of double bonds in the fatty acid chain generally results in a decrease in hydrolysis rate . Second, replacing the ethanolamine moiety with a primary amide yields excellent substrates. For example, the rate of hydrolysis of arachidonamide is two to three times greater than anandamide’s . Third, anandamide congeners containing a tertiary nitrogen in the ethanolamine moiety are poor substrates . Fourth,introduction of a methyl group at the C2, C1, or C2 positions of anandamide yields analogs that are resistant to hydrolysis, probably due to increased steric hindrance around the carbonyl group . Fifth, substrate recognition at the FAAH active site is stereoselective, at least with fatty acid ethanolamide congeners containing a methyl group in the C1 or C2 positions .

Finally, fatty acid esters such as 2-AG also are excellent substrates for FAAH activity in vitro .Early biochemical experiments showed that FAAH activity is abundant throughout the CNS, with particularly high levels in the neocortex,mobile vertical rack the hippocampus, and the basal ganglia . Subsequent investigations have confirmed this wide distribution. Thus, in situ hybridization studies in the rat have found that FAAH mRNA expression is higher in the neocortex and hippocampus; intermediate in the cerebellum, thalamus, olfactory bulb, and striatum; and lower in the hypothalamus, brain stem, and pituitary gland . Immuno histochemical experiments suggest that large principal neurons in the cerebral cortex, hippocampus, cerebellum, and olfactory bulb have the highest levels of FAAH immunoreactivity . For example, large pyramidal neurons in the neocortex are prominently stained together with their apical and basal dendrites in layer V . Moderate immunostaining is observed also in the amygdala, the basal ganglia, the ventral and posterior thalamus, the deep cerebellar nuclei, the superior colliculus, the red nucleus, and motor neurons of the spinal cord . A more recent study reported staining of principal cells and astrocytes in various regions of the human brain . However, the protein recognized by the antibody utilized in these experiments has an apparent molecular mass of 50 kDa , which does not correspond to that of native FAAH . Many FAAH-positive neurons throughout the brain are found in close proximity to axon terminals that contain CB1 cannabinoid receptors , providing important evidence for a role of FAAH in anandamide deactivation. Yet, there are multiple other regions of the brain where there is no such correlation, a discrepancy that likely reflects the participation of FAAH in the catabolism of other bio-active fatty acid ethanolamides, such as OEA and PEA .A number of inhibitors of anandamide hydrolysis have been described, including fatty acid trifluoromethylketones, fluorophosphonates, -keto esters and -keto amides , bromoenol lactones , and nonsteroidal anti-inflflammatory drugs . These compounds lack, in general, target selectivity and biological availability; thus attempts to use them in vivo should be interpreted with caution.The first are fatty acid sulfonyl flfluorides, such as palmitylsulfonylfluoride . AM374 irreversibly inhibits FAAH activity with an IC50 of 10 nM and displays a 50-fold preference for FAAH inhibition versus CB1 receptor binding . Systemic administration of AM374 enhances the operant lever-pressing response evoked by anandamide administration, but exerts no overt behavioral effect per se , raising the possibility that AM374 may protect anandamide from peripheral metabolism but may not have access to the brain. The second group of FAAH inhibitors is represented by a series of substituted -keto-oxazolopyridines, which are both reversible and extremely potent , but whose pharmacological selectivity and in vivo properties are not yet known. The third group is constituted by a class of aryl-substituted carbamate derivatives . The most potent member of this class, the compound URB597, inhibits FAAH activity with an IC50 value of 4 nM in brain membranes and an ID50 value of 0.1 mg/kg in live rats.

This compound has 25,000-fold greater selectivity for FAAH than cannabinoid receptors, which is matched by an apparent lack of cannabimimetic effects in vivo . The pharmacological profile of URB597, which is currently under investigation, includes profound antianxiety effects accompanied by modest analgesia .The generation of mutant mice in which the faah gene was disrupted by homologous recombination has shed much light on the role of FAAH in anandamide inactivation . FAAH /_x0005_ mice cannot metabolize anandamide and are therefore extremely sensitive to the pharmacological effects of this compound: doses of anandamide that are inactive in wild-type mice exert profound cannabimimetic effects in these mutants. FAAH /_x0005_ mice also have markedly elevated brain anandamide levels and reduced nociception . This finding is consistent with the roles of anandamide in the modulation of pain sensation and is supported by the analgesic activity of FAAH inhibitors . Recently, a single nucleotide polymorphism in the human gene encoding for FAAH, which produces a proteolysis-sensitive variant of the enzyme, was found to be strongly associated with street drug and alcohol abuse . This important observation reinforces the central role played by the endocannabinoid system in the control of motivation and reward .The fact that FAAH catalyzes the hydrolysis of 2-AG along with anandamide’s has prompted the suggestion that this enzyme may be responsible for eliminating both endocannabinoids. There is, however, strong evidence against this hypothesis. First, inhibitors of FAAH activity have no effect on [3 H]2-AG hydrolysis at concentrations that completely block anandamide degradation . Second, 2-AG hydrolysis is preserved in mutant FAAH /_x0005_ mice, which do not degrade either endogenous or exogenous anandamide . In agreement with these results, a 2-AG hydrolase activity distinct from FAAH has been identified and partially purified from porcine brain . This activity likely corresponds to monoglyceride lipase , a cytosolic serine hydrolase that converts 2- and 1-monoglycerides to fatty acid and glycerol . Several findings support this conclusion . First, heterologous expression of rat brain MGL confers strong 2-AG-hydrolyzing activity and MGL immunoreactivity to HeLa cells. Second, adenovirus mediated transfer of the MGL gene in intact neurons increases MGL expression and shortens the life span of endogenously produced 2-AG, without any effect on either 2-AG synthesis or anandamide degradation. Third, MGL mRNA and protein are discretely distributed in the rat brain, with highest levels in regions where CB1 receptors are also present . The distribution of MGL in the rat hippocampus is particularly noteworthy. The high density of MGL immunore activity in the termination zones of the glutamatergic Schaffer collaterals suggests a presynaptic localization of this enzyme at CA3-CA1 synapses.

But most clients do not quit using; on the contrary, many significantly increase their daily dose, so the intervention reduces their disorder on some criteria while possibly increasing their disorder by other criteria. Figure 1F, reproduced from Cramer et al. , illustrates the kind of elaborate causal network that Borsboom, Kendler, and their colleagues have recently proposed as a more realistic model for many traits. In their framework, latent constructs neither cause observed manifestations nor does an explicit subset of observed variables constitute the latent construct . Rather, the latent construct is an emergent property of the entire network. An implication of the causal structure in Figures 1E,F is even when simple 1- factor models fit the data, the fit may be spurious in that the model assumed by the equations may be very different than the model that validly describes the processes that generated the data. Moreover, combining them in an “any two of the following” recipe will obscure the valuable information contained in that causal structure. Judging from past experience, we might expect the next DSM to surface in about a decade. So in the spirit of constant improvement, I respectfully urge DSM developers to consider pursuing, in parallel, at least three kinds of alternative DSM candidates: a pure reflective model, a pure formative model, and a pure causal network model. One of the three may emerge as superior. But diagnostic systems attempt to serve multiple goals, and it may be advantageous to use different systems for different purposes. These arguments for greater theoretical and psychometric coherence might seem to have a sort of ivory-tower fastidiousness, if not outright neuroticism. After all, the perfect is surely the enemy of the good, indoor grow cannabis and the DSM does a good job much of the time, at least as judged by the utility that clinicians and managed care organizations seem to find in it. But I think there are good practical reasons for improving the coherence of the DSM substance use.

One is that it might provide a better linkage to drug policy. A decade ago, I argued that contemporary thinking about addiction was surprisingly inconsequential for major public policy debates about drug use, or for empirical drug policy analysis . The DSM-5 probably helps to close that gap, as it emphasizes the harmful consequences that citizens care about. On the other hand, the gap between the DSM and drug science may be growing rather than shrinking. For example, a recent review of seven major scientific theories of drug addiction examines whether each theory can account for various “addictive phenomena.” Of the seven theories, four offer an account of withdrawal and three an account of tolerance – two explicit DSM criteria. Six offer accounts of relapse, and four an account of binging – two phenomena that aren’t directly mentioned in the DSM but are closely related to other DSM criteria. But all seven offer accounts of craving, a criterion that only recently entered the DSM checklist. And four address “sensitization” – which is increasingly recognized as a signature feature of the etiology of addiction but receives no mention in the DSM.Judging from past experience, we might expect the next DSM to surface in about a decade. So in the spirit of constant improvement, I respectfully urge DSM developers to consider pursuing, in parallel, at least three kinds of alternative DSM candidates: a pure reflective model, a pure formative model, and a pure causal network model. One of the three may emerge as superior. But diagnostic systems attempt to serve multiple goals, and it may be advantageous to use different systems for different purposes. These arguments for greater theoretical and psychometric coherence might seem to have a sort of ivory-tower fastidiousness, if not outright neuroticism. After all, the perfect is surely the enemy of the good, and the DSM does a good job much of the time, at least as judged by the utility that clinicians and managed care organizations seem to find in it. But I think there are good practical reasons for improving the coherence of the DSM substance use. One is that it might provide a better linkage to drug policy.

A decade ago, I argued that contemporary thinking about addiction was surprisingly inconsequential for major public policy debates about drug use, or for empirical drug policy analysis . The DSM-5 probably helps to close that gap, as it emphasizes the harmful consequences that citizens care about. On the other hand, the gap between the DSM and drug science may be growing rather than shrinking. For example, a recent review of seven major scientific theories of drug addiction examines whether each theory can account for various “addictive phenomena.” Of the seven theories, four offer an account of withdrawal and three an account of tolerance – two explicit DSM criteria. Six offer accounts of relapse, and four an account of binging – two phenomena that aren’t directly mentioned in the DSM but are closely related to other DSM criteria. But all seven offer accounts of craving, a criterion that only recently entered the DSM checklist. And four address “sensitization” – which is increasingly recognized as a signature feature of the etiology of addiction but receives no mention in the DSM.Historically, molecular genetic research on AAB has been limited to the examination of a small number of candidate genes with purported biological relevance; only recently have researchers begun to conduct atheoretical genome-wide scans for this phenotype.In our genome-wide investigation, we found that autosomal SNPs accounted for ~ 25% of the variation in a dimensional measure of AAB. Although this estimate was not statistically significant ,growing cannabis which is likely attributable to our modest sample size, it maps nicely to meta-analytic findings that additive genetic influences account for 32% of the variation in antisocial behavior.Our finding also maps to recent GCTA analyses in a community-based sample, where it was found that common genetic variation accounted for 26% of the variation in a behavioral disinhibition phenotype.No SNP reached genome-wide significance in our GWAS of AAB. Our most associated SNP, rs4728702, was located in ABCB1 on chromosome. In our gene-based tests, ABCB1 was significant at the genome-wide level; however, we did not find an association for this gene in our replication sample. In expression analyses, we also found that ABCB1 is robustly expressed in human brain. This provides some biologically plausible evidence that ABCB1 variation could be associated with behavioral outcomes.

ABCB1 codes for a member of the adenosine triphosphate-binding cassette transporters, ABCB1 or P-glycoprotein, which transportmolecules across cellular membranes and also across the blood– brain barrier. ABCB1 is considered a pharmacogenetic candidate gene in view of ABCB1 transporters’ ability to change drug pharmacokinetics. Variation in ABCB1 has been previously associated with a number of psychiatric phenotypes, including opioid and cannabis dependence, as well as with treatment outcomes for depression and addiction.The related rodent gene, Abcb1a, is differentially expressed in three brain regions of alcohol preferring animals compared with non-preferring animals.Furthermore, ethanol exposure changes ABCB1 expression. An in vitro study of human intestinal cells found that ethanol exposure increased messenger RNA ABCB1 expression level, and that these increases were maintained even after a week of ethanol withdrawal.Similarly, ABCB1 expression was increased in lymphoblastoid cell lines following ethanol exposure,and in rodents, Abcb1a expression was increased in the nucleus accumbens of alcohol-preferring rats following alcohol exposure.Taken as a whole, this pattern suggests that ABCB1 has pleiotropic effects across a number of externalizing spectrum behaviors/disorders, and that its expression is affected by ethanol exposure. The former is consistent with findings from the twin and molecular genetics literature, demonstrating that common externalizing disorders and behaviors share genetic influences,and that this shared genetic factor is highly heritable .Supplementary analyses in our own sample were consistent with this hypothesis, and we found evidence that ABCB1 variation was associated with alcohol and cocaine dependence criterion counts. However, we did not find associations between ABCB1 and marijuana or opioid dependence criterion counts. We also found evidence for enrichment across multiple canonical pathways and gene ontologies including cytokine activity, Jak-STAT signaling pathway, toll-like receptor signaling pathway, antigen processing and presentation, cytokine receptor binding and natural killer cell-mediated cytotoxicity. Although the immediate biological relevance of these categories to AAB is not clear, these enrichment findings include many immune-related pathways and may be best interpreted in light of the associations among AAB and alcohol, cannabis, cocaine and opioid dependence criterion counts in the sample. Immune and inflammatory pathways have been hypothesized to be associated with psychiatric disorders across the internalizing and externalizing spectra.For example, it is known that alcohol alters cytokine activity,induces changes in neuroimmune signaling in the brain and that alcohol dependence is associated with low-grade systemic inflammation.

Likewise, the monocytes of individuals who are cocaine dependent show decreased expression of tumor necrosis factor-α and interleukin-6 proinflammatory cytokines in response to a bacterial ligand relative to controls.Four of the top genes to emerge in our analysis are genes for type I interferon , which reside in a cluster on chromosome 9p. Previous studies demonstrate that interferon A treatment of hepatitis C patients can induce multiple psychiatric symptoms including depression51 and impulsivity.Although we did not find significant enrichment for these pathways in our replication sample, these results add preliminary evidence to a growing literature that variation in genes in immune-relevant pathways may predispose individuals to AAB and closely related behaviors. The present study expands upon the initial AAB GWAS by Tielbeek et al. as well as more recently published GWAS of a behavioral disinhibition phenotype,in two important ways. First, we used a case–control sample where the cases met criteria for alcohol dependence. By virtue of the association between alcohol dependence and AAB, and the relatively high rates of individuals meeting clinical cutoffs for criterion A for ASPD in the present sample compared with American population-based prevalence estimates, it is likely that the sample was enriched for genetic variants predisposing individuals toward externalizing spectrum behaviors such as AAB. Previous work indicates that the genetic influences on AAB completely overlap with the genetic influences on alcohol dependence, other drug abuse/dependence and conduct disorder—that is, AAB does not have unique genetic influences above and beyond those shared with these other externalizing disorders.In view of this, gene identification efforts for AAB are likely to be more successful in more severely affected samples or in samples where participants high in AAB also tend to have comorbid alcohol or substance-use disorders, such as the COGA sample. In contrast, for example, only 6% of the participants in the Tielbeek et al. community-based sample met their nondiagnostic AAB case criteria. This sample may also have had low rates of comorbid alcohol and other drug diagnoses, limiting the ability to find genome-wide significant effects. Second, we used a dimensional measure of AAB, which is more powerful than a binary diagnostic variable, and better represents the underlying dimensional structure of AAB.These differences may explain, in part, why we were able to detect a significant genetic association in the present sample.First, our sample size was relatively small. Second, because the COGA case–control alcohol dependence sample is highly affected by AAB, the findings emerging from our study may not generalize to lower-risk populations or other types of high-risk populations. Our null replication attempt may be attributable, in part, to the replication sample being relatively less affected than the discovery sample. There are other instances where genetic associations for externalizing behaviors have replicated within highly affected samples, but not less-affected samples. For example, GABRA2 is associated with alcohol dependence in samples where alcohol-dependent cases came from clinically recruited samples and families densely affected by alcoholism,but not community-based samples.A sample recruited for this purpose is likely to be enriched for genetic variation that predisposes individuals to a range of externalizing behavior problems, including AAB;however, whether our findings generalize to other populations at high risk for AAB is unknown. Third, because we limited the current analyses to European-Americans, our results may not generalize to other racial and ethnic groups. Fourth, similar to all psychiatric outcomes, antisocial behavior has a developmental component, and evidence from the twin literature suggests that there are genetic influences on adolescent and adult antisocial behavior that are distinct from genetic influences on child antisocial behavior.

Importantly, we examined the association of alcohol use and ART adherence in the context of other important variables such as use of other substances , major depressive disorder , global cognitive function. We hypothesized that PLWHA who are at-risk drinkers will have lower ART adherence than PLWHA who are not at-risk drinkers, and that at-risk alcohol use will still be significantly predictive of ART adherence when controlling for substance use, MDD, and global cognitive function. Participants consisted of 535 HIV-infected adults enrolled in NIH-funded research studies at the University of California, San Diego HIV Neuro behavioral Research Program from 2003 to 2015. The current study is a secondary analysis of existing data from each participant’s baseline visit at the HNRP. All participants were receiving ART at the time of the visit and reported drinking alcohol in the previous 30 days. Measures Non-adherence to ART was determined based on 1) response to part of the self-report AIDS Clinical Trial Group Questionnaire indicating any missed ART doses in the previous four days, or 2) detectable plasma HIV RNA .Alcohol use was measured using the HNRP Substance Use History form, which is a timeline follow-back measure of the amount of daily alcohol used in the previous 30 days. Participants were stratified based on the daily limit defined by the NIAAA guideline for individuals at risk for developing an AUD: >3 drinks per day for women and >4 drinks per day for men, hereafter referred to as “at-risk drinking.” Individuals who consume more than these daily limits are at a near fourfold increase risk of developing alcohol abuse and a seven fold increase risk of developing alcohol dependence compared to those who drink within those limits. Current and lifetime substance use disorders and major depressive disorder were identified via the Composite International Diagnostic Interview .

Global cognitive function was measured via a standardized battery of well-validated neurocognitive tests [see Heaton et al. for descriptions of tests in this battery]. For all neurocognitive measures,vertical grow shelf raw scores were converted to demographically adjusted T scores used to construct one summary Global Mean T score. Unadjusted association between at-risk drinking and adherence was assessed using simple logistic regression. A multi-variable logistic model was used to regress the adherence measure on at-risk drinking adjusted for covariates. Potential covariates included demographic characteristics ; current AUD and current cannabis use; lifetime AUD; lifetime substance use disorder for cannabis, cocaine, hallucinogens, inhalants, methamphetamine, opioids, phencyclidine , sedatives, and other substances combined; current and lifetime major depressive disorder ; global cognitive function; estimated years of HIV infection; and ART regimen type. Current use disorders for substances other than alcohol and cannabis were not considered in this analysis because of low frequencies of participants with such diagnoses. Covariates were considered for inclusion into a multi-variable model if they either showed an association with the adherence measure or differed between drinking level groups at a 0.10 significance level. Group comparisons were done with two-sample t-tests for numeric covariates and chi-square or Fisher’s exact tests for categorical covariates. Backward model selection was applied and the final model was chosen to include only the predictor of primary interest and the covariates with pvalues less than 0.05. Odds ratio was used as the effect size for the strength of these associations, such that OR>1 would indicate a predictor’s association with higher odds of adherence. All analyses were performed using R version 3.2.1 statistical software .Seventy-nine participants endorsed missing an ART dose in the last four days, 46 of whom also had detectable plasma viral load. An additional 192 participants had detectable plasma viral load without reporting a missed ART dose in the last four days. Based on our criteria determining ART non-adherence , 271 participants were identified as ART non-adherent.

See Table 1 for a full list of sample characteristics. Approximately a quarter of the cohort met the criterion for at-risk drinking . Table 2 shows comparisons of demographic, psychiatric, and substance use characteristics between the two drinking level groups. Participants meeting the criterion for at-risk drinking were younger, less educated, and more likely to be diagnosed with lifetime alcohol use and lifetime cocaine use disorders. Table 3 lists results of univariable and multi-variable analyses. In unadjusted analyses, the at-risk drinking group was associated with significantly lower odds of adherence . 57.1% of the participants in the at-risk drinking group were identified as non-adherent compared to 40.3% of the participants in the not at-risk drinking group . Among covariates, older age, greater education, absence of lifetime cocaine substance use disorder and absence of lifetime MDD were associated with greater adherence at a 0.10 significance level. These covariates were included into multi-variable model selection along with three additional covariates that differed by group at a 0.10 level . Following the stepwise procedure, the final model included only at-risk drinking and education. The effects for the remaining covariates did not achieve a 0.05 significance level in the  multi-variable analysis. The adjusted effect of at-risk drinking remained significant . Education wasthe only other significant predictor, with OR=1.09, p=0.009 per one year increase. See Figure 2 for odds ratios and corresponding confidence intervals for at-risk drinking and education in the final model. Understanding the factors associated with ART non-adherence is critical for developing strategies to improve patient outcomes for those living with HIV/AIDS. Although alcohol use is broadly associated with worse ART adherence among PLWHA, there is little existing literature on the level of alcohol use that portends ART non-adherence. Results of the current study showed that persons with lower education and persons who meet the NIAAA criteria for at-risk drinking, which indicate consumption of a high level of alcohol per day, are more likely to be ART non-adherent compared to not-at-risk drinkers. This finding is consistent with the studies that have found a positive relationship between level of alcohol use and non-adherence to medications in samples of HIV-positive and HIV-negative participants . The most notable of those found that regardless of HIV status, binge drinking veterans were more likely to be non-adherent to medications on drinking days, post-drinking days, and non-drinking days compared to non-binge drinking veterans .

They also found a temporal association within each drinking level group, meaning that participants were most likely to be non-adherent to medications on drinking days, followed by post-drinking days and non-drinking days. For non-binge drinkers, this trend was significantly stronger in HIV+ participants compared to matched HIV- participants. For binge drinkers, the strength of the trend was comparable for HIV+ and HIV- participants,cannabis grow indoor suggesting that PLWHA may be more susceptible to medication non-adherence at lower levels of alcohol consumption compared to HIV- counterparts. The current study supports and augments these previous findings by demonstrating a similar alcohol-adherence association using the widely accepted NIAAA guideline that defines a daily level of alcohol consumption that puts individuals at risk for developing an AUD. Research has shown that individuals who drink within the NIAAA limits are at a much lower risk of having an AUD compared to those who drink beyond those limits . These standard NIAAA criteria are easy to assess and are a consistent method of stratifying alcohol use severity. The criteria for binge drinking, on the other hand, are defined differently by different governmental organizations , welcoming inconsistencies across studies that use binge drinking to stratify drinking level groups. The current study demonstrates that the daily limit defined by the NIAAA guideline for at-risk drinking provides a meaningful demarcation of drinking level in the context of ART adherence among PLWHA. Notably, after consideration of all potential covariates, education was the only other significant predictor in the final logistic regression model besides drinking level. The results showed that at-risk drinking was a better predictor of ART adherence than lifetime cocaine use and methamphetamine use. Although cocaine and methamphetamine use have been shown to have associations with ART adherence , there are several potential reasons why the results of this study found these relationships non-significant. First, alcohol is more widely used in our sample, as the studies conducted at the HNRP generally exclude participants who are current users of drugs other than alcohol and marijuana. Second, it is more socially and societally acceptable to report high levels of alcohol use than it is to report use of cocaine and methamphetamine. Last, we used a more informative variable for alcohol use compared to our variables for cocaine use and methamphetamine use .

That is, the results presented here do not necessarily point to alcohol use as more detrimental to ART adherence than use of other substances. In fact, poly-substance use was very high in our sample and level of alcohol use was found to be significantly associated with lifetime cocaine SUD. A potential future direction may be to more closely examine poly-substance use in the context of level of use for each substance. Despite the lack of significant associations between ART adherence and use of other substances, education showed a strong association to ART adherence. Previous research suggests that low education may be correlated with decreased ART adherence because each is associated with health literacy . Health literacy is defined as the ability to process and understand information about health and health services in order to make the best health-related decisions . Studies of health literacy among PLWHA have shown that higher education is associated with increased health literacy and that greater health literacy is associated with health status and ART adherence . The results of the current study may suggest that PLWHA with higher education may be more likely to understand and appreciate the importance of staying adherent to their ART regimen, even in the context of at-risk drinking. Education and health literacy among PLWHA who drink alcohol, however, has yet to be studied on its own. This is an important topic for future research and subsequent development of better interventions for improving health status among PLWHA, as level of education is immutable but health literacy can be easily enhanced. There are several strengths of the current study including the large sample size and a relatively large group of at-risk drinkers; however, this study also has some limitations. First, alcohol use data are self-reported. The HNRP Substance Use History form is a retrospective self-report assessment that relies on participants’ memory of past drinking patterns. Although most studies rely on self-report to measure alcohol use, requiring participants to give day-by-day or real-time reports may be more reliable. Additionally, we were not able to calculate weekly alcohol quantity from this measure. This might have aided our classification of at-risk drinkers, as the NIAAA guideline also specifies a weekly drinking limit for at-risk drinking ; however, previous research has shown that exceeding the daily limit is associated with a much greater risk of developing an AUD compared to that of exceeding the weekly limit . We also did not administer other alcohol screening tools such as the Alcohol Use Disorders Identification Test , which may have aided our characterization of severity of participants’ drinking patterns. Our adherence measure, using either self-reported non-adherence in the last four days or plasma HIV viral load detectability, also has limitations. We attempted to overcome the social desirability bias that is expected of self-reported adherence by using plasma viral load detectability as a proxy for adherence. Although viral load detectability does not equal nonadherence, non-adherence is likely the greatest indicator of viral detectability. Other reasons for viral load detectability, including virologic failure, drug resistance, and transient viral blips, are not very common and are often associated with ART non-adherence . Further, we did not collect data on other characteristics related to viral load and ART adherence, including drug-resistant genotype, homelessness, and criminal justice history. We did, however, assess for ART regimen type, which may represent a particularly important variable in the use of viral load detectability as a proxy for adherence, as some forms of ART have longer half-lives and are thus more forgiving with missed doses. We found no differences in ART regimen type across drinking groups or adherence groups, providing further evidence in support of our use of viral load detectability as a proxy for ART adherence. Lastly, however, using viral load detectability as a proxy for ART nonadherence does not give as detailed information about medication adherence as would a real-time measure.

The physical environment also plays a role. Varying wind direction and speed lead to the transitory nature of odors, and multiple sources in the vicinity lead to difficulty in source attribution. Even temperature and humidity play roles in the perception of odor, which is often overlooked during exposure sampling and analysis. In addition to the large number of chemical compounds present in malodorous air, their typically low concentrations challenge the limits of even the best instruments . Known as the “odor gap,” the human nose can usually detect odors well below analytical instrument detectors’ capabilities . Methods that use human panels to evaluate odors have been standardized over the years and can work well in parallel with traditional analytical instrument methods. The vision is to have analytical instruments that completely mimic the human nose and sense of smell.The measurement and evaluation of exposure to conventional air pollutants is considered more evolved than that for odors . The framework and methodology applied to conventional air pollutants – risk assessment – offers grounding principles and useful conventions that have evolved over time. Both fields evaluate human responses to chemicals in the air. Although risk assessments are often predictive of future events, they may also be conducted retrospectively as an investigative technique.Risk is, by definition, is the probability of an adverse outcome and its severity. For chemical exposures, risk is a function of hazard and exposure . The fundamental framework for risk assessment was established in the 1980s . Figure 3.1 provides an overview of the various steps. These steps begin with the generation of basic information, proceed through identifying the hazards of the chemical under evaluation, predicting how adverse effects vary with dose,greenhouse tables and end with combining that information with exposure data to determine the incidence of adverse effects in a population.

Beyond risk assessment, and beyond the scope of this paper, is subsequent regulatory, management and communication steps based on the risk assessment’s output and other factors. Given the variety of information required in a risk assessment, the field is truly multidisciplinary. The data and assumptions made along the way are evaluated for how much uncertainty they contribute to the results. Often an order of magnitude or more of uncertainty and variability are inherent in the output, which needs to be explained transparently to not “over sell” the results with a false sense of precision and accuracy.A pragmatic approach to risk assessment is to first conduct a screening-level assessment based on crude approaches likely to overestimate risk. If the risk is found to be reasonable from such an approach, no further work is necessary. If not, then a more detailed, refined assessment is conducted. For the exposure assessment , the focus of this paper, a conceptual model guides the evaluation. The conceptual model traces the origin of the chemical , indicates how it is released, allows for transport of the chemical, includes possible routes of exposure, and indicates who might be exposed . Odors are released from a variety of sources, travel through the air and then are inhaled by local populations. Risk varies across a population due to biological differences , culture, lifestyle, level of exposure and prior exposures. To protect vulnerable sub-populations, a safety factor is usually applied. Perhaps the greatest challenge for both odor assessment and risk assessment is mixtures. We are exposed to a wide variety of chemicals through food, medicine and the environment, yet risk assessment often focuses on a single chemical in isolation. Odor assessment follows suit, focusing often on only one odorant. Such an unrealistic approach is destined to produce highly skewed or biased results, probably in unknown directions . Odor assessment has the advantage of tests being performed by human panels, which can evaluate the whole mixture of the sample. Risk assessment relies on epidemiological reconstructions for human data.Risk assessment, however, has developed approaches for mixtures. A simple, screening level approach is to determine the risk-driver for the mixture. Adding up the individual effects is another crude approach. A simplifying aspect for odor exposure assessment is that human olfaction has evolved to differentiate between only a few significant stimuli.

Typically, around 3 or 4 odors are sensed at a time, which decreases the complexity of the mixture . Those odorants that trigger intense, familiar or unpleasant sensations are more likely to be noticed while the remainder are lost in the signal “noise” or sensory filters. Or this limitation may due to inability to name a substance, rather than failure to detect the difference between odors . Both risk assessment and the evaluation of odors suffer from high degrees of uncertainty and variability. The personal nature of odor perception introduces fundamental variability. The health effects evaluated in risk assessment have a similar range of variability due to the biological variability of humans, which is increased further by the extrapolation of animal studies to humans. Therefore, each health effect benchmark value, such as a toxic reference dose, is typically presented with one significant figure due to the inherent uncertainty, which typically spans an order of magnitude. Exposure results, too, are uncertain due to modeling assumptions or analytical imprecision, as well as sample collection issues. In reality, one significant figure is a misrepresentation, and a range would be more accurate. Making judgements using ranges, however, is difficult so single values are typically used. A sensitivity analysis helps show the possible range of results.Transparency each step of the way is paramount, otherwise overconfidence in shaky results may occur. Both the best practices and draft guidance include a tiered approach to odor evaluations. Such has long been used in risk assessment to streamline the work. First, a screening-level evaluation is performed using crude assumptions and approaches. If the exposure is deemed acceptably low, there is no need for further work. The same applies to odor investigations. If a straightforward evaluation by an air inspector identifies the source and resolves the issue, no complex further investigation need ensue. In both cases, if the screening-level approach identifies concerns, then a detailed analysis is undertaken.Describing an odor in detail is often difficult, so most complainants start with saying “something smells bad” and then struggle to give further details. Unlike other senses with broad vocabularies, smell is anchored in the source of the odor and the person’s history with that source. In a way, our sense of smell is learned.

Attributing words and meanings to odors occurs over a lifetime and even changes over time. The food and beverage industry has attempted to make a science out of sensory description. Beer, wine and coffee are prime examples. Perfume formulation takes this to another level. To avoid complaints,vertical farming the drinking water industry has developed taste-and-odor assessment protocols.Environmental odors are typically mixtures of chemicals . The rare exception is the release of a single odorant from a chemical industry facility. The various odorants within a mixture trigger the olfactory sense in “concert” similar to the various notes in an orchestral piece of music. The perfume and fragrance industries are built largely upon this principle. The interplay of odorants in a mixture can be complex, with both synergistic and antagonistic effects taking place. Perfume has the function of covering up other odors. In odor terminology, this is called “masking.” Landfill and bio-waste sites are known to use scents such as “cherry” at their perimeter , yet in an evaluation of commercially available masking products only 4 out of 26 were able to mask odors successfully . All 4 were neutralizing agents that reacted with odorants. Within an environmental odor sample, certain odorants may mask others. Only upon dilution to a point where the major odorants are no longer perceptible are the minor odorants noticed. This dilution effect has been termed “peeling the onion” , where one layer of odor leads to another. Further discussion of this effect is in the section on odor intensity. The odorants within a mixture are subject to the same physicochemical processes and dispersion as any conventional air pollutant. The same exposure models, such as fate and transport, apply; however, the identities and concentrations of the individual odorants are often unknown, rendering such modeling impossible. To get around this issue, a pseudo-concentration approach has been developed, which is discussed in Section 4.2. The overwhelming majority of the molecules in air are odorless. These include nitrogen, oxygen, water, hydrogen, helium and carbon monoxide. Rather uniquely, carbon dioxide is odorless until it reaches 200-fold above background levels , at which point is triggers the nasal trigeminal receptors rather than the olfactory receptors.Colors have agreed-upon descriptions, and graphic artists often use Pantone® numbers as specific identifiers. Musical notes have frequencies assigned to them and arranged into scales . Odorants, too, have descriptors, known as “notes,” the term used in ISO 5492:2008 . For example, “fishy,” “swampy,” “rotten egg,” “pungent,” or “tingly” are odor notes. An atlas of panel-derived odor notes has been published . The odor note, however, may change with the concentration . Hydrogen sulfide at levels above 20 ppm changes from its characteristic “rotten egg” odor note to a “sweet” odor note, and at even higher concentrations, which are toxic, hydrogen sulfide becomes odorless. The response to an odor is highly personal and depends on “odor memory” – previous exposure and knowledge about the odor source . Common descriptors associated with specific odorants, however, may aid in determining the source of an odor.

Odor wheels have been developed for specific odor notes associated with certain sources, such as landfills, composting and WWTPs . Odors as mixtures make assigning odor notes more complex. As with wine tasting, several dominant notes may be present, along with several subtle notes. These, too, change as the mixture is diluted or ages, or as temperature and humidity change.As with sound and color, some odor notes may be perceived as pleasant or unpleasant. This is the “odor hedonic tone,” also known as the acceptability of the odor. Dravnieks published on this topic, and a scoring system is named after him. Odor hedonic tone is a highly subjective determination, open to large variation across a population and appears to be learned rather innate . Odor hedonic tone varies as the odorants increase or decrease, sometimes progressing through flip-flops between pleasant and unpleasant .Odor intensity – the magnitude or strength of an odor – has received considerable attention. Unlike odor notes and hedonic tones, which can be fairly subjective for the untrained, odor intensity is pursued as a quantifiable, even scalable, attribute of odor perception. The belief is that odor intensity is akin to brightness or loudness, which are quantifiable through physics, yet odors are a chemical sense with accompanying complexities. Nonetheless, two approaches have been attempted: assigning words or numeric scores to intensity levels, or determining the amount of dilution required until the intensity is no longer detectable. For a single odorant, intensity appears to be linked to the odorant’s concentration. In mixtures, such a link is tenuous or absent. Although odors are typically mixtures, it is much easier to study individual odorants. The mathematical connection between odorant concentration and perceived intensity is called the Steven’s power law . Whether the concentration is used directly or divided by a reference concentration does not impact the relationship between intensity and concentration. The inclusion of an intercept, however, fundamentally changes the slopes of the lines and does fundamentally alter the relationship. The original Weber-Fechner law included no intercept . Researchers added the 0.5 intercept to account for “the definition of the odour threshold concentration which states that 50% of the panellists perceive weak odour while the others perceive no odour” and proceeded to use an intensity scale that ranged from 0 to 5 . Other researchers also used the equation with the 0.5 intercept, but the intensity scale ranged from 0 to 6 . The effect of the 0.5 intercept in both of these studies was to assign an intensity score of 0.5 to the ODTC50 concentration, which had nothing to do with the percent of the panelists perceiving or not perceiving and odor. Another researcher allowed the intercept to float uniquely for each odorant and used a 0 to 12 intensity scale , which scale been used in flavor and drinking water profiling .

Subjects were defined as having DM if they answer ‘yes’ to the question ‘Have you ever been told you have sugar/diabetes?’ or had a fasting blood glucose level $126 mg/dl . Of the 719 patients with DM, 418 answered the question about whether they take insulin and 116 reported that they do take insulin. Of those, nine reported that they began using insulin at age #20 years, the majority being likely to have type 1 DM, although a few may have had type 2 DM. Thus, we estimate that 1.5% of patients with DM had type 1 DM, and because of this low number, we analysed all subjects with DM together. There was no difference in any of our analyses if the nine patients of age #20 years were excluded. The study included 151 pregnant women . Of them, eight women had diabetes. There was no difference in the use of marijuana by DM. Because of the low number in the diabetes category, we included them in the analysis. A series of sensitivity analyses excluding the pregnant women showed no difference. Plasma glucose and whole blood haemoglobin A1c were measured at the University of Missouri Columbia School of Medicine Department of Child Health, Diabetes Reference Laboratory, Columbia, Missouri, by David Gold stein, MD, director.Subjects were classified as obese/non-obese according to the BMI level using a cut-off of 30 kg/m2 . We analysed data related to DM, age, gender, race/ ethnicity, education level, family history of DM, physical activity, BMI, cigarette smoking, cocaine use, alcohol use, total serum cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, serum 25-hydroxy vitamin D , HbA1c,vertical outdoor farming fasting plasma glucose level, C reactive protein level and the serum levels of less robust inflammatory markers count and uric acid that have been previously used in NHANES III analysis.

Physical activity was assessed using self-report to several questions . For the physical activity variable, subjects were classified as inactive if they did not report engaging in any of the following activities during the previous month: walking, jogging, bike riding, swimming, aerobics, dancing, calisthenics, gardening, lifting weights or other physical activity outside their occupation. Physical activity was classified as moderate or vigorous intensity based on metabolic equivalent intensity levels. Individuals were considered to fulfil national recommendations for physical activity if they reported five or more episodesper week of moderate-intensity physical activity or three or more episodes per week of vigorous-intensity physical activity.Descriptive statistics were used to characterise the subjects . To test the statistical difference between the groups, we used c2 test for categorical variables and two-sided t tests for continuous variables. A p value of <0.05 was considered significant. Univariate and multivariate logistic regression analyses were used to determine the relationship between DM and marijuana use. We used multivariate logistic regression to adjust for confounding variables and reported the OR and the 95% CI. Variables considered as possible confounders in the multivariate analysis were age, gender, race/ ethnicity, BMI, education level, cigarette smoking, alcohol use, physical activity, serum total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, vitamin D, CRP, ferritin, fibrinogen, WBC count and uric acid. In order to confirm that marijuana use was associated with DM and not due to confounders, we analysed how each potential confounder changed the OR of having DM. Variables that changed the OR by $10% were considered as confounders and included in the multivariate model. We performed stratified analysis to test for effect modification. For effect modifier variable, multivariate logistic regression model was constructed for each subgroup.

In addition, to help adjust for selection bias, we analysed the data using the propensity score matching and estimated the average treatment effect for the treated, bootstrap SE and t statistics. We added the propensity score to the logistic regression model as inverse weight, blocks that satisfy the balancing property and quartiles. Data were analysed using SAS and the survey module of STATA . Sample weights, provided by the National Center for Health Statistics, were used to correct for differential selection probabilities and to adjust for non-coverage and non-response.Among NHANES III participants aged 20e59 years, there were 6667 non-marijuana users, 3346 past marijuana users, 557 light current users and 326 heavy current users. As shown in table 1, current and past marijuana users tended to be <40 years old, be male, had a BMI of <30 kg/m2 , smoked cigarettes and used alcohol and cocaine more frequently compared to non-marijuana users. Compared to non-marijuana users, past users tended to be white and to have a college education, while current users included more white and black subjects and were more likely to have a high school education or less. Non-marijuana users, past and current marijuana users had a similar percentage of family history of DM but significantly different percentage of physical activity levels , with past and current marijuana users being more active than non-marijuana users. As shown in supplement table 1, marijuana users had a lower adjusted prevalence of DM, but not hypertension, stroke, myocardial infarction or heart failure compared to non-marijuana users. The unadjusted prevalence of DM for non-marijuana users, past marijuana users, current light marijuana users and current heavy marijuana users was 6.3%, 2.9%, 1.9% and 3.0%, respectively, and there was a statistically significant difference between the groups . For subjects without DM , 46.4% were marijuana users and 53.6% were non-marijuana users . For subjects with DM , 26.9% were marijuana users and 73.1% were non-marijuana users . The difference in % of marijuana users between those with and without DM was highly significant .

As shown in table 1, all marijuana users had a higher prevalence of serum HDL cholesterol >40 mg/dl, total cholesterol <240 mg/dl and triglycerides <200 mg/dl compared to non-users . Current marijuana users had a higher prevalence of LDL cholesterol <160 mg/dl . All marijuana users had a higher prevalence of CRP <0.5 mg/dl . Past users, but not current users, had a lower prevalence of vitamin D level <70 nmol/l compared to non-users . All marijuana users had a higher prevalence of plasma HbA1c <6.0% . Serum glucose levels and BMI were lower in all marijuana user groups compared to non-marijuana users . We then examined the variation of markers of inflammation with marijuana use . Serum CRP and fibrinogen were significantly lower in past marijuana users compared to current and non-marijuana users suggesting lower inflammation in past marijuana users. In contrast, serum ferritin levels were higher in past and current heavy users, and lower in light users,rolling grow table compared to non-users. Serum uric acid levels were higher in past and lower in current users compared to non-users. WBC count was higher among current users relative to non-users and past users. In order to confirm that marijuana use was associated with a decreased prevalence of DM and not due to confounders, we analysed how each potential confounder changed the OR of having DM. Variables that changed the OR by $10% were considered as confounders . Table 2 shows the unadjusted as well as the cumulative effect of the confounders, including race/ethnicity, physical activity and those variables that showed changes of $10% in the OR of having DM among all marijuana users relative to non-users in a series of regression models. Of note, race/ethnicity and physical activity did not change the OR by $10%, but we included them in the model because they are known risk factors. The interaction effect of the marijuana use and age was significant in the model indicating that age is an effect modifier . Stratified analysis by age group found an association between marijuana use and DM among subjects aged >40 years and no association among subjects aged #40 years . The association of DM and marijuana was significant in both the overall and older age group even after adjusting for social variables , laboratory variables , inflammatory marker and the comorbidity variable to the previous model. Using the propensity score matching, we found similar results showing a lower prevalence of DM among marijuana users relative to non-users. The average treatment effect for the users ¼0.024, bootstrap SE¼0.005 and t¼4.46, p<0.05 . When we added the propensity score to the logistic regression model, marijuana users still had lower odds of DM than non-users . Adding it as inverse weight, yielded an OR¼0.52 . We also added it as blocks and found an OR¼0.53 . Adding it as quartiles yielded an OR¼0.51 . All still revealed a lower odds of DM with marijuana use. For age group 41e59 years, adding the propensity score as quartiles to the model, we found an OR¼0.55 , whereas for age group 20e40 years, OR¼0.88 . We examine whether DM as diagnosed by self-report as compared to laboratory evidence of hyperglycaemia was correlated with different prevalence of marijuana use. As shown in the supplement table 2, there was no difference in marijuana use among those with DM by self-report and those with DM who were included based on an elevated fasting glucose . Patients with DM by self-report who were hyper glycaemic at the time of sampling had a statistically similar rate of marijuana use as those whose DM was well controlled at the time of sampling , although there was a trend for patients with a history of DM by self-report who were euglycaemia at the time of sampling to be associated with a lower rate of non-marijuana use.

Those with DM by self-report and those with DM who were included based on an elevated fasting glucose had similar rates of the type of marijuana use . Additionally, for subjects who did not have DM by self-report and did not have an elevated fasting glucose level but had an elevated HbA1c , their prevalence of non-marijuana use was similar to the prevalence of non-marijuana use among subjects with DM . We then examined the prevalence of all marijuana users among subjects with different fasting glucose levels. As shown in figure 1, the highest prevalence of marijuana users was found in those with the lowest glucose levels. As the glucose levels increased, the prevalence of marijuana users decreased. For subjects with DM , the prevalence of marijuana users was 23.6%. Similarly, the highest prevalence of marijuana users was found in those subjects with the lowest plasma HbA1c values . As the HbA1c levels increased, the prevalence of marijuana users decreased. Furthermore, we analysed the data using logistic regression to assess the odds of having DM, an elevated glucose value or an elevated HbA1c for the categories of marijuana use. The OR for all marijuana users to have DM was 0.42 , which was statistically significant . Relative to non-marijuana users, past marijuana users had an OR of having DM of 0.44 , current light marijuana users had an OR of 0.29 and current heavy marijuana users had an OR of 0.47 , all were statistically significant from non-marijuana users . Relative to non-marijuana users, marijuana users had significantly lower odds of having glucose level of >125 mg/dl and HbA1c level >7.0% .Our analyses of adults aged 20e59 years in the NHANES III database showed that participants who used marijuana had lower prevalence of DM and had lower odds of DM relative to non-marijuana users. We did not find an association between the use of marijuana and other chronic diseases, such as hypertension, stroke, myocardial infarction and heart failure. This could be due to the smaller prevalence of stroke, myocardial infarction and heart failure in the examined age group. We noted the lowest prevalence of DM in current light marijuana users, with current heavy marijuana users and past users also having a lower prevalence of DM than non-marijuana users. The finding that past marijuana users had lower odds of prevalent DM than non-users suggests that early exposure to marijuana may affect the development of DM and a window of time of marijuana exposure earlier in life could be a factor to study. Similarly, our findings of a significant association between marijuana use and DM was only found in those aged $40 years suggest that the possibility of some protection from marijuana use may require many years before they become manifested.

In the US, the refusal to enfranchise Blacks or Native Americans led to the development of racial categories, and these categories were in the US census from the beginning. In some of the federated states of the US, there were laws, including the “one drop of blood” rule that determined that to have any Black ancestors meant that one was de jure Black .Native Americans appeared in 1820, Chinese in 1870, Japanese in 1890, Filipino, Hindu and Korean in 1920, Mexican in 1930, Hawaiian and Eskimo in 1960. In 1977, the Office of Management and Budget , which sets the standards for racial/ethnic classification in federal data collections including the US Census data, established a minimum set of categories for race/ethnicity data that included 4 race categories and two ethnicity categories . In 1997, OMB announced revisions allowing individuals to select one or more races, but not allowing a multiracial category. Since October 1997, the OMB has recognized 5 categories of race and 2 categories of ethnicity . In considering these classifications, the extent to which dominant race/ethnic characterizations are influenced both by bureaucratic procedures as well as by political decisions is striking. For example, the adoption of the term Asian-American grew out of attempts to replace the exoticizing and marginalizing connotations of the externally imposed pan-ethnic label it replaced, i.e. “Oriental”. Asian American pan-ethnic mobilization developed in part as a response to common discrimination faced by people of many different Asian ethnic groups and to externally imposed racialization of these groups. This pan-ethnic identity has its roots in many ways in a racist homogenizing that constructs Asians as a unitary group , and which delimits the parameters of “Asian American” cultural identity as an imposed racialized ethnic category . Today,vertical rack the racial formation of Asian American is the result of a complex interplay between the federal state, diverse social movements, and lived experience.

Such developments and characterizations then determine how statistical data is collected. In fact, the OMB itself admits to the arbitrary nature of the census classifications and concedes that its own race and ethnic categories are neither anthropologically nor scientifically based . Issues of ethnic classification continue to play an important role in health research. However, some researchers working in public health have become increasingly concerned about the usefulness or applicability of racial and ethnic classifications. For example, as early as 1992, a commentary piece in the Journal of the American Medical Association, challenged the journal editors to “do no harm” in publishing studies of racial differences . Quoting the Hippocratic Oath, they urged authors to write about race in a way that did not perpetuate racism. However, while some researchers have argued against classifying people by race and ethnicity on the grounds that it reinforces racial and ethnic divisions; Kaplan & Bennett 2003; Fullilove, 1998; Bhopal, 2004, others have strongly argued for the importance of using these classifications for documenting health disparities . Because we know that substantial differences in physiological and health status between racial and ethnic groups do exist, relying on racial and ethnic classifications allows us to identify, monitor, and target health disparities . On the other hand, estimated disparities in health are entirely dependent upon who ends up in each racial/ethnic category, a process with arguably little objective basis beyond the slippery rule of social convention .If the categorization into racial groups is to be defended, we, as researchers, are obligated to employ a classification scheme that is practical, unambiguous, consistent, and reliable but also responds flexibly to evolving social conceptions . Hence, the dilemma at the core of this debate is that while researchers need to monitor the health of ethnic minority populations in order to eliminate racial/ethnic health disparities, they must also “avoid the reification of underlying racist assumptions that accompanies the use of ‘race’, ethnicity and/or culture as a descriptor of these groups. We cannot live with ‘race’, but we have not yet discovered how to live without it” .

Reinarman and Levine have argued that investigations of ethnicity in alcohol and drugs research have typically taken the form, whether intentionally or not, of linking “a scapegoated substance to a troubling subordinate group – working-class immigrants, racial or ethnic minorities, or rebellious youth” . Different minority ethnic groups have often been framed at one time or another by their perceived use of alcohol and illicit drugs, regardless of their actual substance using behaviors and regardless of their relative use in comparison with drug and alcohol use among whites . Such framing arguably has led to extensive stereotyping of minority cultures, their characters, and their behaviors. For example, in the 18th century, white settlers in the US used stereotypical portrayals of Native drinking to justify the confiscation and exploitation of Native lands . In the early part of the 19th century, Chinese immigrants were victimized and controlled for their supposed opium use, despite the fact that only 6% at the time used opium . In the early 1900s, cannabis was relatively plentiful along the Texas border brought to the US by Mexican migrants, and its popularity among ethnic minorities practically ensured that it would be classified as a narcotic and attributed with addictive qualities . By the early 1930s, cannabis had been prohibited in 30 states. In 1937 the Marijuana Tax Act was passed by Congress which banned cannabis at the Federal level . And, the most recent drug scare, which fueled the development of the War on Drugs, linked crack cocaine to impoverished African Americans and Latinos in inner city neighborhoods .These statistics lie in sharp contrast to the available empirical data on differential rates of alcohol and substance use between whites and non-whites . The evidence from Monitoring the Future – a longstanding and reliable source of data on drug use among youth in the US – suggests that crack cocaine cannot be considered a drug consumed primarily by Blacks in American nor can marijuana be considered a drug used primarily by Latino/as. Rather, white youth have higher rates of use for most drugs of abuse. For example, Terry McElrath and colleagues reviewing 30 years’ worth of data from MTF, found that for all drugs except heroin, past year prevalence rates were significantly higher among whites compared to blacks and Latinos .

In spite of the backdrop, the vast majority of alcohol and drug research has failed to mention the injustices of drug laws and high rates of imprisonment of ethnic minority youth. Instead of situating research within a context of oppression and inequality,microgreen flood table researchers have tended to ignore this situation and instead focus on risk factors associated with drug use among racial/ethnic groups, an approach that dominates alcohol and drugs research today. This trajectory in alcohol and drug research is unfortunate in light of recent debates in social epidemiology about the importance of examining health disparities within a framework that considers “social structures and social dynamics that encompass individuals” . Social epidemiologists have argued that mainstream research tends “to focus on the body, lifestyle, behaviour, sex/gender, race/ethnicity and perhaps the personality, emotional state or socioeconomic status of the single person” . Just as mainstream epidemiology has been criticized for having little regard for social structures, social dynamics, and social theory , most existing studies of ethnicity within drug and alcohol research can similarly be critiqued for failing to adopt a structural approach as well as neglecting contemporary social science theories of and debates about ethnicity. In mainstream drug and alcohol research, traditional ethnic group categories continue to be assessed in ways which suggest little critical reflection in terms of the validity of the measurement itself. This is surprising given that social scientists since the early 1990s have critiqued the propensity of researchers to essentialize identity as something ’fixed’ or ’discrete’ and to neglect to consider how social structure shapes identity formation. Recent social science literature on identity suggests that people are moving away from rootedidentities based on place and towards a more fluid, strategic, positional, and context-reliant nature of identity . This does not mean, however, that there is an unfettered ability to freely choose labels or identities, as if off of a menu . An individual’s ability to choose an identity is constrained by social structure, context, and power relations. Structural constraints on identity formation cannot be ignored, as people do not exist as free floating entities but instead are influenced and constrained in various ways by their socioeconomic and geographical environment . As such, an identity is not just claimed by an individual but is also recognized and validated by an audience, resulting in a dialectical relationship between an individual and the surrounding social structures . Similarly, a ‘new’ perspective on ethnic identity specifically has emphasized the fluidity and contextually-dependent nature of ethnicity, minimizing notions about ethnicity as a cultural possession or birthright and instead emphasizing ethnicity as a socially, historically, and politically located struggle over meaning and identity . Ethnicity or ethnic identity is not some immutable sense of one’s identity but rather something produced through the performance of socially and culturally determined boundaries . Hence, individuals are not passive recipients of acquired cultures but instead active agents who constantly construct and negotiate their ethnic identities within given social structural conditions .

In spite of these sociological contributions, which have enriched our understanding of identity generally and ethnicity specifically, the alcohol and drugs fields have not adequately integrated these perspectives, thwarting our ability to understand the relationships between ethnicity and substance use. As such, the field is ripe with correlations between ethnic group categories and substance use problems, resulting in solutions to problems that focus on reifying questionable social group categorizations and revealing little about how drugs are connected to identities and shaped by broader social and cultural structures. It is important to note that we do not intend to argue that existing categories of ethnicity be disregarded in the alcohol and drugs fields. As Krieger and colleagues have noted in another context , surveillance data documenting health disparities, in our case in substance use, are exceedingly important in terms of identifying potential inequities in health. However, without understanding the complexity of ethnic identity and its relationship to substance use, these surveillance data may perpetuate stereotypes and the victimization of specific socially-delineated ethnic groupings, obfuscate the root causes of substance use and elated problems, and reify politicized categories of ethnicity which may have little meaning for the people populating those categories. While acknowledging that socially-deliented ethnic categories are important for documenting social injustices, we must also be vigilant about questioning the appropriateness of those categories. Conceptually this type of critical approach is important for considering how substance use is related to negotiations of ethnicity over time and place and bounded by structure. Maintaining a static and homogenous approach towards ethnic categorizations in the alcohol and drugs fields presents at least two problems. First, it risks overlooking how drugs and alcohol play into a person’s negotiation of identity, particularly ethnic identity, thus revealing little about the pathways that lead to substance use. Cultural researchers have long emphasized the importance of commodity consumption in the construction of identities and lifestyles , particularly within youth cultures , and how it can be an important factor in demarcating and constituting social group boundaries . A limited body of research in the alcohol and drugs field has emphasized the role of substance use in constructing and performing identities , particularly ethnic identities , uncovering how subgroups within traditionally-defined ethnic minority categories use drugs and alcohol to distinguish themselves from ethnically similar others. For example, in a qualitative study of Asian American youth in the San Francisco Bay area in the US, narratives illustrated how youths’ drug use and drug using practices were a way of constructing an identity which differentiated them from “other Asian” youth groups, specifically allowing them to construct an alternative ethnic identity that set them apart from the “model minority” stereotype . Thus taste cultures and consumption-oriented distinctions highlight the continuing salience of and interconnections not just between substance use and changing notions of ethnicity but also between substance use, class and ethnicity. Ethnic identity gets translated into social captial which in turn has ramifications for one’s economic and social standing . Second, failing to critically appraise our use of fixed and homogenous ethnicity categories in the alcohol and drugs fields jeopardizes our ability to identify the broader social and structural determinants of alcohol and drug use and related problems—like poverty, social exclusion, and discrimination—which are crucial issues for addressing social injustices.

Conservative estimates showed that care in the first year of life for a PTB infant costs $47,100 per infant, while an alternative algorithm estimated that costs could be up to $78,000 per preterm infant . We used the most conservative lower bounds of the published cost estimates in all analyses.Two logistic regressions analogous to those published were fit with policy indicators as the exposure and odds of LBW and odds of PTB as outcomes. Each policy indicator was coded as 0 if it was not in effect for the mother’s state of residence during the month/year of conception and 1 if it was in effect during the month/year of conception; this method of linking the policy indicators to the month and year of conception improves the accuracy of exposure timing. Both regressions adjusted for all policies simultaneously, as well as individual- and state-level covariates, fixed effects for state and year, and state-specific time trends; previously published analyses found no differences when controlling for all policies together simultaneously vs. each policy individually. Individual-level covariates were maternal age, race, marital status, education, nativity, parity, and version of birth certificate. State-level covariates were state- and year- specific poverty, unemployment, per capita cigarette consumption, and per capita total ethanol consumption,microgreen rack for sale as well as indicators for whether government control of wine sales and government control of spirit sales were in effect for that state in that year. Predicted margins for each significant policy were calculated and used to compute the excess proportion of low birthweight and preterm births under each significant policy. These proportions and their 95% confidence intervals were then applied to the number of births for 2015 in all U.S. states to estimate the number of excess LBW and PTBs in 2015.

Finally, using marginal effects and the most conservative lower bounds of published cost estimates obtained from, costs associated with excess LBW and PTB under each policy were estimated.Multiple state alcohol/pregnancy policies–specifically MWS, PTPREG, LCP, and CACN–lead to thousands of babies born low birthweight or preterm each year. These increased rates of adverse birth outcomes cost hundreds of millions of dollars in health care and related costs annually. The actual prevalence and associated costs indicate that the harms related to alcohol/ pregnancy policies are not only statistically significant, but also significant from a public health and public policy perspective. As most alcohol/pregnancy policies also apply to drugs, findings from this study for all policies other than MWS can be interpreted as applying to alcohol+drug/pregnancy policies rather than specific to alcohol/ pregnancy policies. The MWS finding in particular, though, suggests that as states continue to legalize recreational cannabis, public health policy makers may want to exercise caution before expanding MWS to apply to cannabis. Findings of adverse outcomes associated with MWS and CACN are plausible given previous literature showing that the fear of being reported to CPS and fear of having already irreversibly harmed ones baby are reasons women avoid prenatal care. However, explanations for findings related to both LCP and PTPREG are not as intuitive. One possible explanation comes from the historical context in which these particular policies emerged. Neither LCP nor PTPREG emerged as public health policies developed through a public health policy-making process, but rather emerged as advocacy arguments in response to the War on Drugs-related criminalization and punishment of pregnant women who used crack cocaine. It is also worth noting that that limits on criminal prosecution focuses primarily on limiting use of medical test results in criminal prosecutions related to alcohol/drug use during pregnancy– thus, states that adopt this policy could have more criminal prosecutions related to use during pregnancy.

Priority treatment policies could be a marker of a state that does not have sufficient treatment slots either in general or for pregnant women, and thus the findings could be due to the lack of treatment availability for pregnant women, for women prior to becoming pregnant, or for women’s partners. Future research should examine these mechanisms. In the meantime, our findings strongly suggest that new policy approaches to alcohol/drug use during pregnancy are needed. Strengths of this study include rigorously coded policy data and an outcome dataset that does not rely on self-report and that encompasses the entire population of singleton births for more than 40 years. Another strength is that analyses were able to incorporate state-specific time trends in addition to multiple individual and state-level controls and fixed effects for state and year. Adjusting for state-specific time trends helps address endogeneity and provides more confidence that the results we observe are due to the policies rather than the reverse. Limitations include that Vital Statistics data are not collected for research purposes, that they may not include key individual-level control variables, and that the measurement of some key variables have changed over time. However, our adjustment for birth certificate version and inclusion of fixed effects for state and year alleviates concerns regarding changes in birth certificate data collection over time.College-going individuals in the United States may have unique attitudes toward substance use behavior and tobacco use, including shifts in attitudes and behaviors that are associated with the constantly changing product landscape of alternative tobacco products , such as electronic-cigarettes . Psychosocial behaviors and campus culture, including class attendance, peer socializing, campus policies, and residential environments, may also facilitate these unique attitudes toward favorability of smoking among college subgroups, while also introducing a unique risk environments for tobacco initiation, uptake, transition, and use .

In addition, part of the variation explaining these health behaviors may be influenced by the specific demographic and socioeconomic characteristics of a college campus population and community. Data from social media platforms are often used to self-report and publicly communicate health-related attitudes and behaviors . Young adults [ages 18–25 ] in the United States are much more likely than older populations to actively use social media, including popular platforms Twitter, Snapchat, and Instagram . Infoveillance research, which uses online information sources to detect trends about the distribution and determinants of disease, including health knowledge and behaviors, has been used to develop insights on numerous public health issues including infectious diseases, vaccination sentiment, opioid use disorder, mental health issues, and, relevant to the exploratory aims of this study, tobacco and alternative tobacco use attitudes and behavior . However, smoking-related discussions on social media tied to specific colleges with geographic specificity has not been widely investigated. Existing studies using social media to examine tobacco-related attitudes and behaviors in college aged populations have primarily focused on evaluating the impact of social media health promotion anti-tobacco campaigns, recruiting hard-to-reach college populations using social media platforms, and examining the influence of exposure to tobacco-related social media content and marketing on current and future behavior and use . Other research on college-aged populations has focused on assessing tobacco initiation and transition of use patterns,cannabis grow facility layout particularly as new alternative and emerging tobacco products become available . Accelerating research using social media to assess tobacco-related attitudes/inflfluences among youth has also been supported by U.S. Federal initiatives, including projects funded by the National Cancer Institute and U.S. Food and Drug Administration Tobacco Centers of Regulatory Science, which for have identified and characterized e-cigarette advertisements on image-focused social media sites and tobacco user experiences with little cigars and e-cigarettes as discussed on Twitter . Changes in local, state, and national health policy related to tobacco and other products smoked or used concurrently with tobacco and electronic cigarettes can also have an impact on attitudes and behaviors of these populations. For example, recent debate in the United States regarding the legalization of marijuana/cannabis may positively influence marijuana-related attitudes for college populations, who tend to skew toward more liberal policies regarding decriminalization, legalization, and increased access . Similarly, the 2019 outbreak of e-cigarette and vaping-related lung injury associated with products containing tetrahydrocannabinol may dissuade tobacco or THC use in certain young adult populations, particularly since they were most heavily impacted by the disease . Examining the changing public attitudes and behaviors of college-aged smokers is particularly salient for the State of California, USA. As of January 2014, all campuses in the statewide University of California system became tobacco free , and the California State University system followed suit in 2017 . In addition, voters in California approved Proposition 56 in late 2016, which added a $2.00 increase to the cigarette tax effective April 2017, with an equivalent increase on other tobacco products and electronic cigarettes . Voters in 2016 also approved Proposition 64, which legalized the use of recreational cannabis in November 2016 . During this time, the popularity of e-cigarettes in the United States was increasing . These changes in policy and preferences underscore the interconnected nature of the Triangulum of tobacco products , including potential for dual-use, transition between products, and challenges associated with conducting surveillance and implementing cessation programs .

This changing policy landscape supporting tobacco control measures, as reflected in the shift of California’s public university systems to become smoke-free, is a key impetus for this study. The ability of these colleges to eliminate on-campus smoking relies in large part on understanding past and existing knowledge and attitudes held by the campus smoking populations, along with their perceptions and behaviors that may be associated with compliance or non-compliance to smoke free campus policies. In response, this study conducted exploratory research on the popular micro-blogging platform Twitter. specifically, we used big data, data mining, and geospatial approaches to identify and characterize tweets originating from Twitter users specifically geolocated at California 4-year university campuses. Our primary objective was to assess types of tobacco and ATP products mentioned by users, the distribution of user sentiment toward tobacco and smoking behavior, and to assess the feasibility of detecting self-reported smoking behavior that may represent a violation of campus smoke free policies. Secondarily, we also sought to conduct a cross-campus assessment to determine how these factors vary across different university and college communities and over time. The objective of the study’s data collection approach was to obtain a highly refined subset of tweets, which were both posted from college campus’ geolocated coordinates in California and also included user discussions about smoking, in preparation for manual review to more purposefully identify tweets that specifically discussed different types of tobacco and smoking products, sentiment of users toward smoking behavior, and self reported smoking behavior on campus. Data were collected from the Twitter public streaming Application Programming Interface using the cloud-computing service Amazon Web Services . The public streaming API was set with filters to collect all tweets that included metadata containing latitude and longitude coordinates, initially with no filter for keywords. Tweets were collected continuously from 2015 to 2019. All tweets collected included the text of the tweet and associated metadata, including the date and time of tweets. The use of the public Twitter streaming API to collect data pre-filtered only for tweets including latitude and longitude coordinates represent a subset of all tweets posted during the time frame of the study. There exists the potential for sampling bias associated with different Twitter APIs that are not representative of all Twitter data , and data filtered only for geocoded data may omit many conversations from college aged populations about topics, such as smoking, which may be linked to college-related user groups . Though resulting in a much smaller volume of data, our approach nevertheless allows for detection of tweets in specific geospatial bounds at the high resolution of latitude and longitude coordinates in the state of California. Therefore, by using this data collection approach, we were able to isolate tweets originating from geospatial coordinates within the formal spatial boundaries of all 4-year universities in California. To enable this geolocation, a base map of California 4-year universities from the Stanford Prevention Research Center was obtained and cross-referenced. Tweet geolocated points were spatially joined to campus polygons using ArcGIS software.College areas were comprised of multiple polygons for different campuses and associated properties, though aggregation was conducted at the overall college level to enable comparison across different colleges. Tweets were then filtered for 37 keywords which were broadly related to tobacco-related topics, including the names and brands of different tobacco and ATPs and descriptive terms associated with smoking and vaping as expanded upon from those used in prior studies . specifically, the following keywords were used: bidis, cigarette, cigarettes, cigarillos, cigars, cigie, class, dip, e-cig, hookah, huqqa, joint, JUUl, kereteks, Marlboro, Newport, njoy, pipe, roll-up, shag, smoke, smoking, snuff, snus, tobacco, vape, vaped, vapejuice, vaper, vapes, vaping, vapor, water pipe, waxpen, and weed.

Combined NRT with patch and a more immediate acting product results in higher quit rates than single NRT [Cochrane meta-analysis: risk ratio , 1.34; 95% confidence interval , 1.18 to 1.48] . The combination of varenicline and nicotine patch has been evaluated with mixed results . The mechanism for why NRT should augment effects of varenicline is unclear, but the combination appears to be safe. The combination can be considered in a smoker who does not quit with dual NRT or varenicline. Bupropion in combination with nicotine patch or dual NRT increases quit rates compared to these drugs given alone . One trial reported promising results with the combination of varenicline and bupropion, although neuropsychiatric adverse effects were greater in the first 2 weeks compared to varenicline alone .Many smokers would like to quit but are not prepared to commit to a quit date when seen by a healthcare provider. Starting pharmaco therapy while the smoker is still smoking with the expectation that quitting will be easier at a later date has been studied with the use of nicotine patches and varenicline. The pharmacological basis for this approach is that NRT, by desensitizing nicotinic receptors and reducing withdrawal symptoms between cigarettes, and varenicline, by antagonizing effects of nicotine from cigarettes and also providing relief of withdrawal symptoms, will reduce satisfaction from smoking and decrease the number of cigarettes smoked per day. Preloading trials with nicotine patches have shown mixed benefit on quitting with a weak overall effect, although some trials showed large beneficial effects.Varenicline trials have shown benefit with a flexible quit date, and this approach is approved by the FDA .

The attraction of precessation pharmacotherapy is that the clinician can now approach every patient who smokes,trim tray pollen regardless of whether they are prepared to quit at the time of the visit, with a pharmacological intervention along with communication that this will help with quitting smoking in time, just as the clinician would advise every patient with hypertension to take medication to prevent future disease. In this regard, a small trial involving heavy smokers with COPD, who were initially unprepared to quit, prescribed varenicline for as long as they wanted, without a fixed quit date, and by 18 months, most had quit .Personalized medicine aims to use individual patient characteristics to select the most effective and/or safest medications for their medical problem. With long-term quit rates of 30% or less in most smoking cessation trials, there is interest in individualizing treatment to enhance efficacy.Rapid metabolizers of nicotine, on average, smoke more cigarettes and take in more nicotine per day compared to slower metabolizers, presumably to maintain desired levels of nicotine in the body . Rapid metabolizers also have more severe withdrawal symptoms when not smoking . The nicotine metabolite ratio is a phenotypic marker of the rate of nico tine metabolism, which can be measured in blood, saliva, or urine . In a prospective clinical trial, smokers were stratified as slow or normal metabolizers and treated with nicotine patch, varenicline, or placebo. In slow metabolizers, varenicline and nicotine patch were equally effective [odds ratio , 1.13; P = 0.56], but in rapid metabolizers, varenicline was more effective . Side effects were greater for varenicline in slow metabolizers. The results indicate that slow metabolizers can be successfully treated with nicotine patch, at lower cost and with fewer side effects, but normal metabolizers are better treated with varenicline.

More research is needed for confirmation.While not approved by the FDA, nortriptyline and clonidine have demonstrated efficacy in clinical trials for smoking cessation . These drugs are used primarily by smoking cessation specialists for patients who have not responded to other treatment. Nortriptyline is a tricyclic antidepressant that blocks neuronal reuptake of nor epinephrine, thereby increasing levels of the neurotransmitter in the brain. These actions simulate some of the actions of nicotine on brain neurotransmitters. Clonidine is a central 2 adrenergic receptor agonist that reduces sympathetic activity, resulting in sedation and anxiolysis. The benefit of clonidine is thought to be mediated by its anxiolytic and calming effects and appears to be most useful in smokers with anxiety as a major withdrawal symptom.A number of medications have been considered as possible candidates for smoking cessation . While animal and/or small studies in people show effects on nicotine reward or smoking behavior, none of these medications alone has been shown in adequately sized clinical trials to be effective in promoting cessation, including serotonin agonists , acetylcholinesterase inhibitors , drugs affecting GABA recep tors , and N-methyl-daspartate receptor modulators . A promising new medication is lorcaserin, a selective 5-hydroxytryptamine 2c receptor agonist. The drug induces food satiety by increasing pro-opiomelanocortin production in the hypo thalamus and is FDA approved for weight loss in overweight individuals. Lorcaserin has also been reported to reduce nicotine self-administration in rodents. Because weight gain after stopping smoking is common and sometimes triggers relapse, lorcaserin alone or in combination with other smoking cessation medications has been of interest. In a placebo-controlled trial combining lorcaserin with varenicline, the combination significantly increased 3-month continuous abstinence versus placebo , and weight gain was significantly less.

Medications evaluated in clinical trials and judged ineffective for quitting smoking include mecamylamine, serotonin-specific uptake inhibitors, anxiolytics , MAO inhibitors , modafenil, naltrexone, rimonabant, silver acetate, ondansetron, lobeline, nicotine vac cines, and Nicobrevin .A general discussion of e-cigarettes and other tobacco products for harm reduction, including consideration of benefits versus risks, is presented in the “Discussion: What Evidence Is Needed” section. Here, we specifically discuss evidence regarding e-cigarettes for smoking cessation. To date, no e-cigarette company has undergone FDA review and approval for use of e-cigarettes as a therapeutic aid for quitting smoking. Less than a handful of randomized controlled trials of e-cigarettes for smoking cessation have been published, and none has been conducted in the United States; hence, most of the evidence to date is observational. E-cigarettes produce an aerosol from a liquid that typically contains nicotine. The e-cigarette concept is to deliver nicotine by an inhaled route without generating products of tobacco combustion. NRT medications can aid cessation as discussed previously, but most smokers do not find NRT very satisfying, and quit rates are modest. The performance of e-cigarettes as nicotine delivery devices has evolved over time. The earliest devices looked like cigarettes but delivered very low levels of nicotine. The two clinical trials per formed with these devices were encouraging, but the quality of evidence was low . Recently, a randomized clinical trial with 886 smokers treated in the United Kingdom’s National Health Service evaluated a second-generation e-cigarette refillable tank–type device to patients’ choice of NRT provided free of cost for up to 3 months . All received standard behavioral support. At 1 year, the sustained abstinence rate in the e-cigarette group was twofold greater than the NRT group . Among participants randomized to the e-cigarette arm who quit smoking, 80% were still using e-cigarettes at 1 year; in comparison,trim bin tray among those randomized to the NRT arm, continued use of NRT was 9% for those who quit smoking. While e-cigarettes were found to significantly increase smoking cessation, some have expressed concern about the unknown health risks of long-term e-cigarette use. Adverse effects reported during the trial included greater throat or mouth irritation in the e-cigarette group and more nausea in the NRT group. Overall, adverse effects were minor in severity.Population-based observational studies report different results depending on the intention of the smokers to quit, how e-cigarettes are used, and where the study was conducted. A four-country comparison found the likelihood of quitting with e-cigarettes to differ by the regulatory environment . In Canada and Australia, which have more restrictive e-cigarette regulations, e-cigarette use was associated with a significantly lower likelihood of quitting smoking relative to unassisted quitting , whereas in the United States and United Kingdom, which have less restrictive e-cigarette regulatory environments, e-cigarette use was associated with increased quitting, consistent with other reports . The United Kingdom estimates that, annually, 22,000 to 57,000 long-term cigarette quitters are associated with e-cigarette use, more than quits attributed to NRT or other forms of pharmacotherapy .

In the United States and United Kingdom, daily use of e-cigarettes is associated with a greater likelihood of quitting smoking than nondaily use . In a study from France, e-cigarette use was associated with not only higher smoking cessation rates but also greater relapse to smoking . In conclusion, with respect to e-cigarettes, there is evidence that e-cigarettes can aid smoking cessation. This can occur both in the general population, where e-cigarette use is adopted as an acceptable and safer alternative to cigarette smoking, and in the context of a health service. The risks of long-term e-cigarette use are still unknown, and some medical professionals oppose the use of e-cigarettes for that reason. As discussed in the “Discussion: What Evidence Is Needed” section, there are also concerns about the use of e-cigarettes by children possibly creating a new epidemic of primary nicotine addiction, leading some U.S. public health professionals to conclude that the potential benefits of e-cigarettes for smoking cessation in adults are outweighed by the risks to youth.U.S. population-based and policy approaches successful for tobacco control include mass media tobacco education campaigns, expanded healthcare coverage for tobacco cessation treatment, excise taxation on tobacco products, clean air laws, and Tobacco 21 policies, which raise the minimum legal age to purchase tobacco products to age 21 . Other population-based interventions to reduce tobacco use have faced challenges in the United States at the federal level , and even state tobacco taxes and clean air laws have slowed . In contrast, interventions in the tobacco retail environment are increasing rapidly at the local level . Also gaining traction at the FDA, and discussed in the “Discussion: What Evidence Is Needed” section, is an effort to reduce the amount of nicotine in combusted tobacco products to reduce its addictive effects.An important component of comprehensive tobacco control pro grams, mass media tobacco education campaigns are composed of paid and earned media on TV, radio, community placements , magazines, newspapers, and digital/ social media platforms. Well-designed mass media campaigns implemented with sufficient reach, intensity, and duration can help counter pro-tobacco marketing, build support for tobacco control policies, increase awareness of tobacco’s harmful effects, promote quitting, and reduce smoking prevalence . Here, we describe the success of two ongoing U.S. campaigns.The CDC’s Tips national mass media tobacco education campaign has been implemented annually since 2012. Tips profiles real people living with serious long-term health consequences from smoking and secondhand smoke exposure based on evidence that messages graphically depicting the physical consequences of smoking-related diseases can encourage quit attempts . While Tips primarily targets adult smokers, secondary audiences include family members, healthcare providers, and faith communities able to reach people who smoke. Campaign goals include building public awareness of tobacco’s harms to self and others, encouraging smokers to quit, and making free help available . Tips has been effective at increasing population-level quit intentions, quit attempts, and sustained quits, with effectiveness persisting over time . In 2016, Tips ads featured Rebecca, a former smoker with depression. In a national evaluation, greater exposure to the Rebecca ads was associated with a greater likelihood of intending to quit and with making a quit attempt specifically among smokers with mental health conditions . National media campaigns are an important population-level strategy for reaching specific population groups, such as people living with mental health conditions, who are experiencing tobacco-related disparities.Healthcare reform legislation can increase receipt of tobacco cessation treatment for smokers from disparity groups. The U.S. Affordable Care Act mandated comprehensive coverage for tobacco treatment for most private health plans and newly eligible Medicaid beneficiaries in states that expanded Medicaid, including at least two tobacco cessation attempts per year and four tobacco cessation counseling sessions and prohibited cost-sharing and previous authorization restrictions for FDA-approved tobacco cessation medication. The ACA also removed coverage limits and preexisting condition exclusions. Concerning, however, was the ACA’s allowance for states to decide whether employers could charge smokers up to 50% more in premiums. Several states rejected the surcharge outright, while other states capped the maximum penalty at a lower level.

Adjusted analyses included an e-cigarette dependence propensity score covariate calculated from a prediction model of e-cigarette dependence status regressed on 25 baseline variables, as detailed in the eAppendix in the Supplement. Additional and supplemental sensitivity analyses were conducted. Analyses were tested in Mplus statistical software version 7 using full information maximum likelihood estimating to account for missing data, and participants’ high school was accounted for using complex modeling. For primary analyses, Benjamini Hochberg multiple-testing corrections20 were applied to control study wise false-discovery rate at 0.05, based on 2-tailed corrected P values. Data were analyzed from March 2019 to December 2019. Sensitivity analyses of cross-tobacco product comparisons of dependence prevalence, severity, and symptom patterns that adjusted for age at onset and past 30-day use frequency of the 2 respective products yielded results that were similar to the primary results . Additional cross-product analyses restricted to dual users who vaped nicotine found differences on the same dependence outcomes as the primary results, although differences were less robust . Youth who use multiple tobacco products may have difficulty distinguishing the source of dependence symptoms; however, baseline past-year combustible cigarette use did not significantly moderate associations of e-cigarette dependence symptoms with subsequent vaping at 6-month follow-up . For descriptive purposes to examine whether results generalized across sex and non-nicotine substance use, tests of differences in cross-sectional and prospective analyses stratified by sex and number of nonnicotine substances used are reported in Tables 7, 8, 9,drying cannabis and 10 in the Supplement. They did not show marked differences by sex and concomitant substance use.

Past-month e-cigarette and combustible cigarette use patterns by past-month nicotine vaping days are presented in eTable 11 in the Supplement for descriptive purposes. Associations with additional behavioral health outcomes were tested for exploratory purposes, and analyses found that e-cigarette dependence was significantly associated with increases in ADHD symptom level at 6-month follow-up ; this association was amplified by the number of other substances used . Additionally, reporting 1 or more e-cigarette dependence symptoms at baseline was associated with heavier combustible cigarette smoking at follow-up, including more cigarette smoking days and more cigarettes smoked per day .This cohort study provides some of the most detailed evidence to date on the prevalence and symptom presentation of e-cigarette dependence and its association with future e-cigarette use among youth, to our knowledge. Previous studies have provided less comprehensive characterizations of e-cigarette dependence, without comparisons with combustible cigarette dependence.To our knowledge, this is also the first prospective longitudinal investigation of the association of e-cigarette dependence symptoms with subsequent vaping patterns. Our results suggest that e-cigarette dependence symptoms may be associated with future vaping patterns. In this study, the prevalence of e-cigarette dependence symptoms was relatively low and, consistent with prior research,primarily characterized by cravings and a perceived need to vape. Although prevalence and severity of dependence symptoms were approximately 2-fold as large for combustible cigarettes as e-cigarettes in users of both products, the most common and least common symptoms were similar across the 2 products, as were the qualitative profiles across all 10 symptoms. Importantly, the cross-product comparisons were conducted within-persons among dual users, eliminating confounding differences between smokers and vapers. Unlike combustible cigarettes, e-cigarettes and e-liquids vary in nicotine content and delivery.Few youth in this study likely used the now-popular pod mod–style e-cigarette products that deliver large amounts of nicotine efficiently.

Considering the elevated dependence symptoms reported among youth who vaped nicotine in this study despite low probability of pod mod use, these results suggest that e-cigarette dependence may be of notable clinical and public health significance. Electronic cigarette dependence symptoms were elevated in certain subgroups expected to be at higher risk, including youth who vaped recently, used e-cigarettes that contained nicotine, or used both e-cigarettes and combustible cigarettes. A 2018 study found that dual users had higher levels of nicotine biomarkers than users of e-cigarettes only. To our knowledge, this is among the first investigations to find that e-cigarette dependence symptoms were experienced even among youth who reported using only e-cigarettes without nicotine—a sizeable proportion of youth e-cigarette users.Nicotine-containing products may have been mislabeled, or youth with histories of nicotine vaping in early adolescence who later switched to only nicotine-free vaping over the past year may have experienced cravings triggered by cues associated with the act of vaping.Youth who used e-cigarettes and reported at least 1 e-cigarette dependence symptom were more likely to continue vaping and to vape more frequently and intensely 6 months later than their peers who did not report any dependence symptoms. This finding is consistent with a 2019 study that suggested that vaping continuation, with escalation of use frequency and dependence symptoms, is common. Our study further suggests that youth with dependence symptoms are at elevated risk for continuation and escalation. Symptoms of e-cigarette dependence may directly increase motivation to use, and increased use may recapitulate a cycle of worsening dependence. Although our observational study design precludes such causal inferences,ebb flow findings suggest that e-cigarette dependence may be associated with subsequent vaping patterns even after adjusting for dependence propensity defined by numerous potentially confounding influences.

In clinical settings, e-cigarette dependence symptom screening questions may identify youth at risk for vaping progression who may benefit from intervention. In regulatory decision-making, dependence is a potential health consequence of e-cigarette use that should be considered. Adolescents are particularly vulnerable to nicotine exposure,and our findings suggest that dependence symptoms associated with nicotine exposure via e-cigarettes are associated with greater risk for escalation of vaping behavior. The development of dependence in youth is an important public health consequence that should not be overlooked.This study has some limitations. First, all participants were recruited from high schools in Los Angeles, California; therefore, extension to different regions would be informative. Second, data were collected in the 2016 to 2017 school year, before high-nicotine e-cigarettes became popular among youth.Third, all measures were self-reported and did not include clinical diagnosis of nicotine dependence. While the measure of dependence was selected for its presumed applicability to both tobacco products and its ability to capture key features of the dependence syndrome ,other measures of e-cigarette dependence that are correlated with nicotine exposure merit inclusion in future research to address varying aspects of the dependence syndrome.6 Fourth, the follow-up period was limited to 6 months, leaving unclear the long-term association of e-cigarette dependence with future use.Combusted tobacco use remains a major cause of premature disability and death around the world . Cigarette smoke contains an estimated 7000 different chemical compounds, of which at least 70 are proven or suspected human carcinogens including arsenic, benzene, formaldehyde, lead, nitrosamines, and polonium 210. Tobacco smoke also contains poisonous gasses: carbon monoxide, hydrogen cyanide, butane, toluene, and ammonia.Tobacco smoking causes about half a million U.S. deaths annually, of which 50,000 are among nonsmokers exposed to secondhand smoke . More than half of all long-term smokers die from a tobacco-caused disease, with an average loss of at least 10 years of life . Smoking causes 87% of lung cancer deaths, 61% of pulmonary disease deaths [chronic obstructive pulmonary disease and emphysema], and one in three cancer deaths. In the 50 years following the U.S. Surgeon General’s first report on tobacco , 20 million Americans died from smoking, and an estimated 1 billion people will die worldwide this century . For every person who dies from smoking, at least 30 people live with serious smoking-related illnesses costing >$300 billion annually, with nearly $170 billion in direct medical costs and $156 billion in lost worker productivity . The health harms of combusted tobacco use are now undeniable . With market and regulatory pressures to reduce the harms of nicotine delivery by combustion, the tobacco product landscape has diversified . Nicotine now comes in smokeless tobacco prepackaged pouches , in electronic devices that heat nicotine to an inhalable aerosol from a plug of tobacco or from an e-liquid , and in pharmaceutical grade nicotine replacement therapies . Cigars come in a variety of sizes down to little filtered cigars, some discernible from cigarettes only by their tobacco leaf wrapper.

Despite the diversification, conventional combusted cigarettes remain, by far, the most common nicotine product used by adults in the United States and in most places globally. Worldwide, there are approximately 1 billion smokers . While products of tobacco combustion are the main cause of smoking-induced disease, nicotine addiction sustains tobacco use . Nicotine addiction, in the form of cigarette smoking, causes more harm to public health than any other drug addiction. Reflected in the quote above, at least since the 1950s, the tobacco industry has researched and recognized, decades before it became generally understood in the scientific community, that nicotine is an addictive drug and central to their business . An understanding of the clinical features of nicotine addiction and the behavioral conditioning that occurs with frequent nicotine dosing is important for informing pharmacologic and behavioral treatment targets. We review current advances in research on nicotine addiction treatment and recovery. The “Tobacco Product Use and Nicotine Addiction” section covers the changing landscape of nicotine products with comparison of use patterns among adults and adolescents in the United States. The pharmacology of nicotine and effects on the brain are then reviewed, with consideration of particularly vulnera ble populations. The “Treating Nicotine Addiction in Adults, with a Focus on Conventional Cigarettes” section focuses on treatment of nicotine addiction with attention to counseling and behavioral approaches and cessation medications. The tobacco treatment literature is far more developed for combusted cigarettes and relatively sparse in other product areas. We focus on adults given develop mental differences in adolescents’ preferred nicotine product type, use patterns, addiction profile, and treatment efficacy. The tobacco treatment literature with adolescents largely consists of failed smoking cessation trials , and while youth nicotine vaping is drawing public health concern and policy attention, no study, to date, has evaluated an intervention to treat e-cigarette use in adolescents. The “Tobacco Control Population-Based and Policy Approaches” section gives greater attention to use in youth with review of the evidence for tobacco control policy interventions. The “Discussion: What Evidence Is Needed” section closes with discussion of emerging areas and consideration of new directions for advancing the field.Nicotine is a tertiary amine that can exist in a charged or uncharged form, depending on pH. Nicotine is a weak base with a pKa of 8.0 such that, at physiological pH , 69% is ionized and 31% is unionized. The unionized form of nicotine passes readily though membranes, such as the buccalmucosa, such that the pH of smokeless tobacco influences the rate and extent of systemic nicotine absorption. The more alkaline , the more rapidly nicotine is absorbed from smokeless tobacco. Cigarette smoke has an acidic pH of about 5.5 to 6, so little nicotine is absorbed through the mouth, while large cigars have an alkaline pH, facilitating oral absorption. The differences in pH of tobacco products depends on the strains of tobacco used and curing processes, as well as on chemicals used in processing. The pH of nicotine solutions also influences the pharmacology of e-cigarettes. The earliest forms of e-cigarette liquid contained mostly nicotine in free base form , which results in a considerable nicotine-related harshness during inhalation. Recently, e-liquids have used nicotine salts , with acidic pH , similar to that of cigarettes. This results in less irritation with inhalation and has been implicated in the current popularity of e-cigarette use in never-smoker adolescents . When cigarette smoke is inhaled, nicotine moves quickly to the lungs, arterial blood, and the brain in only 15 to 20 s , where it exerts its addiction-related effects. Rapidity of delivery to the brain is thought to be an important factor in the abuse liability of inhaled nicotine compared to other routes of nicotine administration. The importance of rapid delivery relates to higher arterial concentrations, nearly immediate psychological effects, and the ability to titrate doses to desired effects. Higher arterial levels also allow the smoker to overcome effects of tolerance to the desired psychological effects of nicotine. Inhaled nicotine from e-cigarettes potentially carries a similar abuse liability to that of tobacco cigarettes, but empirical data, to date, suggest that it is not the case.

An alternate pathway is possible, whereby 2-AG could be formed by the sequential actions of phospholipase A1 and lysophospholipase C enzymes. The primary route for 2-AG hydrolysis in neurons is afforded by the enzyme monoacylglycerol lipase. Recently, a pharmacologically distinct monoglyceride lipase activity in microglial cells has been reported. In order to understand better the role endocannabinoids might have in CB1-regulated behaviors, a number of pharmacological tools, which target events in endocannabinoid metabolism, have been developed. Anandamide deactivation is prevented by the transport inhibitors AM404, UCM707, OMDM-1 and OMDM-2, and VDM11, and the FAAH-selective anandamide hydrolysis inhibitors URB597and OL-135. 2-AG hydrolysis is blocked by the MGL inhibitor URB602. Pharmacological inhibition of endocannabinoid deactivation has been shown to produce anxiolytic, analgesic, and antidepressant-like effects. The antidepressant-like effects of anandamide deactivation inhibitors will be discussed in detail later in the present article.Limited, but compelling evidence indicates that the endocannabinoid system is altered during stress-related states in both rodents and humans. The chronic mild or chronic unpredictable stress protocol are two related models of depression that produce sequelae reminiscent of those observed in humans afflicted with the disease. These include, among others, a reduction in body weight gain and ingestion of palatable foods. In rats subjected to 3 weeks of CUS, Hill and colleagues found a significant reduction of 2-AG content, as well as levels of CB1 receptor protein in the hippocampus. Stressed animals also showed impairment of reversal learning in the Morris water maze,mobile vertical rack which was corrected by administration of the cannabinoid agonist HU 210, suggesting that this effect was due to decreased endocannabinoid signaling. Similarexperiments in our lab have shown that after 10 weeks of CMS, CB1 receptor mRNA is increased in the prefrontal cortex and decreased in the rat midbrain.

Anandamide levels in the hippocampus, prefrontal cortex, midbrain, thalamus, and striatum were not significantly altered in these studies. 2-AG was similarly unchanged in the hippocampus, prefrontal cortex, midbrain, and striatum, but was reduced in the thalamus of stress-exposed rats.In a study of 20 human subjects, Hungund et al. found an increase in both CB1 receptor mRNA and CB1 receptor-stimulated [35S]GTPγS binding in the dorsolateral prefrontal cortex of subjects with a life-time diagnosis of major depression who committed suicide, compared to normal controls who died by accident or natural causes. Miller and colleagues reported reduced serum 2-AG levels in drug-free females diagnosed with major depression compared to demographically-matched controls, with levels of 2-AG negatively correlated to the duration of the depressive episode. In the latter study, serum anandamide was not associated with major depression, but was negatively correlated with measures of anxiety. The results of these studies of both rodents and humans provide evidence that endocannabinoid signaling is changed – at least in some brain regions and, perhaps, in the periphery – during depression. The alterations observed in the hippocampus, prefrontal cortex, and thalamus are of particular interest, given the likely involvement of these neural structures in the regulation of emotion. In humans, Δ 9 -THC, the natural cannabinoid agonist that is the major psychoactive component of marijuana, produces subjective feelings of relaxation and euphoria, but also promotes anxiety and dysphoria in a context- and dose-dependent manner. Similarly, when administered to rodents, exogenous cannabinoid agonists produce mixed effects on mood related behavior. Low doses of cannabinoid agonists are usually anxiolytic, while moderate to high doses are anxiogenic, but these dose-dependent effects are also contingent on other factors, including strain, age, sex, environment and previous experience with the drug. In mice, Δ 9 -THC produced anxiolytic effects in the light/dark box at a dose of 0.3 mg-kg−1 , i.p., but at 5 mg-kg−1 , i.p., induced anxiogenic effects.

HU 210, a highly potent cannabinoid receptor agonist, at a dose of 0.1 mg-kg−1 , i.p., has also been reported to produce anxiogenic effects in the defensive-withdrawal test after acute administration, but, when this same dose was administered for 10 days it exerted antidepressant-like effects in the novelty suppressed feeding and forced swim tests. Comparable dose- and context-dependent effects on mood-related behavior in the elevated-plus maze and social interaction tests have been noted following treatment with another synthetic cannabinoid agonist, CP 55,940.Data from experiments with CB1 knockout mice suggest that prevention of cannabinoid signaling either increases or has no effect on anxiety- and depression-related behaviors, depending on the conditions of the test. Notably, in these studies, CB1 knockout mice displayed increased anxiety-like behavior compared to wild-type controls under conditions that are stressful to the animals . Additionally, CB1 receptor knockout mice have increased sensitivity to develop anhedonia in the CUS model of depression, and display several other behavioral responses that are similar to the symptoms of melancholic depression . Likewise, several researchers have reported that administration of the CB1 receptor antagonists SR141716 and AM251 produced anxiogenic-like effects. By contrast, few groups reported anxiolytic- and antidepressant-like effects of CB1 receptor antagonists. However, in clinical trials of rimonabant for the treatment of obesity, anxiety and depression are among the most frequent adverse events reported. Together, these studies suggest that CB1 receptor signaling is important for coping behavior, especially during intense or prolonged stress. As described in the previous section, changes in endocannabinoid activity might occur during depression in animal models and, possibly, in humans. Furthermore, direct activation or reduction of CB1 receptor signaling has important effects on mood and stress-related behaviors. These findings raise the intriguing possibility that modulation of endogenous cannabinoid signaling could be a useful target for depression therapy.

Indeed, enhancement of endocannabinoid signaling by pharmacological inhibitors of anandamide degradation has been shown to modulate stress-related behavior in assays for antidepressant-like drug activity – the forced swim test and tail suspension test – and in a rodent model of depression – chronic mild stress . The anandamide transport inhibitor, AM404, at a dose of 5 mg-kg−1 , was reported to decrease immobility time in the rat FST. Likewise, the fatty acid amide hydrolase inhibitor, URB597 , decreased immobility – presumably by increasing swimming behavior – in the rat FST, and also increased struggling behavior in the mouse TST. These effects of URB597 in the FST and TST were sustained after 4 days of repeated dosing. In each of these tests, the antidepressant-like activity of AM404 or URB597 was prevented by preadministration of a selective CB1 receptor antagonist. Given that symptoms of anxiety are often present during depression, it is noteworthy that anandamide deactivation inhibitors also appear to have anxiolytic-like effects. Administration of URB597 decreased isolation-induced ultrasonic vocalizations in rat pups, and increased the time spent in the open arms of the elevated zero and plus mazes. Similarly, AM404 dose-dependently reduced isolation-induced ultrasonic vocalizations in rat pups,vertical grow rack and increased the time spent in the open arms of the elevated plus maze or in the open field during the defensive withdrawal test. However, it appears that the effects of inhibition of anandamide deactivation on stress-coping behaviors are sensitive to environmental conditions. In a recent report, Naidu and colleagues failed to find a reduction of immobility in the TST or an increase in the percentage of time spent in the open arms in the elevated plus maze in FAAH−/− mice or in wild type mice treated with URB597 when conducted under normal laboratory lighting. However, when they adopted lighting conditions similar to those used by Patel and Hillard in the elevated plus maze , or Gobbi and colleagues in the TST , they did observe anxiolytic and antidepressant-like effects of FAAH deletion or inhibition. The reported sensitivity of the anxiolytic- and antidepressant-like effects of URB597 to the lighting conditions is consistent with recent findings in our lab, which show that the anxiolytic-like effect of URB597 in the elevated plus maze varies with experimental context. It is important to note that both the tail suspension and forced swim tests are only assays for antidepressant-like drug activity, not models of depression. In the reports cited above, the experiments were performed in undiseased animals, demonstrating an enhancement of active stress-coping behavior by URB597 or AM404 in a manner similar to standard antidepressant drugs during normal physiological conditions, but under specific environmental contexts. The ability of inhibitors of anandamide degradation to regulate stress-related behaviors under pathophysiological conditions should be more indicative of their efficacy in the treatment of depression. In the CMS model, administration of URB597 for 5 weeks at a dose of 0.3 mg kg−1 reversed chronic stress-induced reductions in sucrose consumption and in body weight gain. In this same study, treatment with URB597 also opposed the increases in CB1 mRNA expression in the prefrontal cortex and midbrain that were observed after 10 weeks of CMS. The magnitude and time course for the antidepressant-like effect of URB597 in this study was comparable to that seen in the treatment of depression with the known antidepressant compound, imipramine. These findings are important because they demonstrate, for the first time, the ability of an anandamide deactivation inhibitor to reverse behavioral symptoms observed in a model of depression with high construct and face validity.

It is important to note though, that alterations in 2-AG are observed both in depressed humans and in animal models of depression, and the significance of these changes are unclear. FAAH inhibitors have proven to be valuable tools for investigating the role of anandamide in mood disorders, and DGL and MGL inhibitors will no doubt further elucidate the interaction between endogenous cannabinoid signaling and stress-related behaviors. For example, the MGL inhibitor, URB602, when injected locally into the dorsolateral periaqueductal grey of the midbrain, produced an enhancement of stress-induced analgesia, demonstrating a role for 2-AG in a specific stress-coping response. Inhibition of MGL has also identified 2-AG asa mediator of synaptic plasticity in the hippocampus, a structure likely involved in the effects of chronic stress and antidepressant treatment on behavior. Unfortunately, URB602 has low potency and cannot be administered systemically to study the effects of global in vivo modulation of 2-AG on stress-coping behavior. As inhibitors of DGL and MGL are developed and tested in behavioral models of emotional reactivity, we will have a better understanding of the functions of both endocannabinoid signaling molecules, perhaps each with distinct roles in stress-coping and mood disorders. This is the first population-based study of HCV screening among US Medicaid patients with and without schizo phrenia. As hypothesized, we found that HCV screening varied over time, across states, and by patient demographic and comorbid characteristics. However, contrary to our hypothesis, screening was higher for patients with schizo phrenia compared to controls. We also found that despite 1998 CDC guidelines to target high-risk populations for annual screening,over 95% of Medicaid patients with schizophrenia who were eligible for screening were not screened for HCV within any clinical setting in 2012. Among patients with schizophrenia, states in the northeast had the highest HCV screening rates and increases in screening from 2002 to 2012. Large state level rises in HCV screening were potentially due to various integration of care initiatives implemented state wide, warranting further examination that is beyond the scope of our exploratory study. For example, by 2012, several northeastern states had active initiatives to reduce Medicaid fragmentation and were among the highest in Medicaid spending per enrollee.There were also state wide integration initiatives aimed to decrease hepatitis transmission. For instance, New York State launched the 2004 Viral Hepatitis Strategic Plan modeled after the HIV/AIDS prevention and care continuum.Similarly in 2008, the Massachusetts’ Office of HIV/AIDS was created to integrate strategies for HIV prevention with HCV programs.Also, Connecticut stakeholders partnered with the CDC to develop the Viral Hepatitis Prevention Plan that was released in 2004.Despite these efforts however, CMS reports that chronic HCV prevalence for Medicaid only enrollees in 2012 was still higher than the national average in Connecticut and New York , but not Massachusetts.It is conceivable that a nationwide comprehensive integrated prevention program could have wide ranging positive impacts on HCV screening and prevention efforts; however, the low rate of HCV screening found during the current study period suggests that national CDC guidelines were insufficient when compared to state-level efforts. In addition to new CDC recommendations for universal HCV screening in adults, expanding statewide HIV prevention policies to include HCV might mitigate traditional clinical challenges in HCV screening among this vulnerable population.