The EITC differs from the minimum wage in that the EITC is paid as a lump sum to eligible families once a year after they file their taxes, typically between February and April.To examine whether we find a similar pattern in the estimated reductions in mortality, we estimate a set of models of suicide mortality by calendar month of death. The results, shown in Appendix figure 4, do indicate that the estimated effects are larger in March relative to other calendar months. While these point estimates are not statistically significantly different from each other, the pattern is consistent with a substantial lump sum of money relieving distress and despair. As we would expect given the nature of the policy, no similar pattern is found for minimum wages. Finally, we address the issue of possible policy complementarities: EITCs could be a more effective anti-poverty policy when pre-tax wages are higher. Similarly, a high binding minimum wage could help counteract downward pressure on wages that might otherwise arise in equilibrium as higher EITCs increase labor supply. To estimate whether such policy complementarities have effects on mortality, we estimate augmented regression specifications: We expand equation to include an interaction term between the log minimum wage and state EITC policy.Overall, these models fail to give consistent indications of policy complementarities. The estimated main effect coefficients on the minimum wage and the EITC remain similar,cannabis grow set up though the point estimate for the EITC is no longer statistically significant. The interaction term meanwhile is close to zero.

Between 1999 and 2017, the age-adjusted rate of drug overdose deaths increased by 256 percent, while suicides grew by 33 percent . U.S. health policy makers and researchers across a broad array of disciplines have sought to understand the causes of and effective policy responses to these disconcerting mortality trends. Here, we summarize the ongoing debate, then discuss briefly how our findings contribute to this discussion. Case and Deaton suggest declining economic opportunity among working class whites as a cause, pointing to an accompanying increase in chronic pain, social distress and the deterioration of institutions such as marriage and childbearing. Case further notes that inflows of cheap heroin and fentanyl followed the initial opioid epidemic. In Case’s interpretation, these three epidemics have interacted with ongoing poor economic conditions for less-educated workers, increasing the number of deaths that she would characterize as deaths of despair. Case and Deaton’s compelling description of the correlates of observed mortality trends builds upon on a large literature of previous work showing the importance of economic factors on mental health, alcohol use, substance abuse and premature mortality. Our findings for suicide are consistent with other recent research identifying economic correlates of suicide– nonemployment, lack of health insurance, home foreclosures and debt crises . For example, higher incomes generated by minimum wage increases have been shown to substantially improve credit ratings, reducing the cost of credit and easing debt problems . On the other hand, an emerging literature has questioned the focus on economic causes. For example, in an examination of U.S. mortality trends from 1980 to 2014, Masters and colleagues find little evidence of the distress and despair hypothesis, arguing that Case and Deaton’s analysis masks important gender heterogeneity in mortality rates that are inconsistent with the despair narrative. They suggest that more likely causes include the U.S. obesity epidemic, the current prescription opioid crisis, and the lagged effects of the HIV/AIDS epidemic. Ruhm focuses on mortality increases due to fatal drug overdoses . He also concludes that drug-related deaths are not primarily caused by economic conditions.

Rather, his results point toward “supply-side” characteristics, such as drug availability and costs, as the primary causes of higher death rates. Ruhm’s conclusions are supported by the recent surge in drug overdose deaths attributable to the spread of prescription opioid substitutes, such as heroin and synthetic fentanyl. The increase in poisoning deaths associated with these drugs and the dramatic rise in overdose deaths among men and young adults relative to other demographic groups does suggest that poor economic conditions constitute only a part of the explanation of declining life expectancy . Finkelstein and colleagues arrive at similar conclusions. Leveraging data on cross-county migration among disabled Medicare beneficiaries, these authors demonstrate the importance in opioid abuse rates of place-specific supply factors as opposed to demand-side factors. Our estimated panel models do not find effects of higher minimum wages or EITCs on drug overdoses, whether unintentional or intentional. These results support the claims made by Ruhm, Finkelstein and others. Meanwhile, we do find that these same policies significantly reduce non-drug suicides, supporting the claims made by Case and Deaton. In conclusion, we note that the magnitude of changes to EITCs and minimum wages across our sample period since 1999 are not large enough to explain aggregate changes in mortality. Furthermore, the recent 2014-17 period of life expectancy decline occurred at a time of only slightly declining real federal minimum wage and increasing minimum wages in various states. Nevertheless, we estimate a substantial public health benefit of expanding the EITC and increasing minimum wages, suggesting the importance of pursuing demand-side income policies to combat the high and increasing levels of deaths of despair. After the 2019–2020 outbreak of e-cigarette or vaping product use-associated lung injury in which the Centers for Disease Control and Prevention reported over 2,800 hospitalizations of patients displaying symptoms of acute respiratory distress, serious public health concerns have been raised about the safety of e-cigarettes. In the initial investigations, evidence has supported that vaping of vitamin E acetate , a synthetic form of vitamin E that was used to “cut” or dilute black market or homemade tetrahydrocannabinol , was a major cause of the onset of EVALI symptoms.

Several different mechanisms of toxicity have been proposed since the outbreak, yet the exact causative agents and molecular mechanisms through which VEA vaping emissions resulted in lung toxicity are still not well understood. VE and VEA alone are considered safe for dermatological application in skin-care products and as well as for consumption in foods and dietary supplements.Several studies since the outbreak, however, have found that e-liquids like VEA undergo major thermal decomposition during the vaping process to form products that are often more toxic than the parent oil VEA in particular has been found to decompose into a wide range of emission products including VE, alkenes such as 1-pristene, alcohol-containing compounds such as 3,7,11-trimethyl-1-dodecanol, durohydroquinone , and durohydroquinone monoacetate, and carbonyl-containing compounds such as ketene, 4-acetoxy-2,3,5-trimethyl-6-methylene-2,4-cyclohexadienone, and duroquinone. Still, the overall risk of exposure of each identified product to those who vaped VEA is unclear. For example, ketene gas has been hypothesized to form from the cleavage of the acetate group of VEA. However, this reaction has been calculated to only be feasible at temperatures exceeding 500˚C–temperatures that are likely to only occur under “dry puff” conditions. The operating temperature of the vape device is one of many parameters–including the model of e-cigarette used, puff duration, interval between puffs, etc.–that a user may alter to customize their vaping experience. A few studies to date have investigated the impact of increased temperature on the size and volume distribution of emitted vaping aerosols, reporting that greater coil temperatures result in larger puff volumes, but decrease the size of emitted particles. A recent study in 2021 found that the emission of volatile degradation products, including various carbonyl-containing species,horticulture rack was significantly enhanced when temperature was increased from 170 to 280˚C. In addition, increased coil temperature and characteristics of the vape device have also been found to influence other aspects of vaping emissions, such as the release of metals and the level of carbonyl-containing compounds or radical species . E-cigarette atomizers and heating elements are often comprised of various transition metals including nickel, iron, and chromium which not only pose a risk of metal toxicity to vape users, but may play a role in the catalysis of thermal degradation of the e-liquid. One study by Saliba et al. found that e-cigarette filament wires had a significant impact on the production of carbonyl-containing compounds from propylene glycol vaping, lowering the temperature required to form carbonyl species by nearly 200˚C. However, the factors affecting the chemical composition of e-cigarette degradation products have yet to be fully characterized. The objective of this study was to examine the influence of variable temperature on the product distribution of e-cigarette vaping emissions, using VEA as a model e-liquid. To do so, we performed a non-targeted analysis of the aerosol-phase constituents at relevant, mid-range vaping temperatures using gas chromatography/mass spectrometry . We hypothesized that elevated temperature of the heating coil during vaping could enhance thermaldegradation of VEA, causing a shift in emission product distribution and toxicity in vapers. VEA vaping emissions were produced at coil temperatures ranging between 176 to 356˚C using a variable voltage vape pen and analyzed using GC/MS with electron ionization to assess how emission product identity and concentration changes as a function of temperature. In addition, pure pyrolysis of VEA without the influence of the device was also investigated using a tube furnace to investigate potential catalysis by the device itself.

The results from this study contribute to our current understanding of the toxicity mechanisms underlying VEA vaping emissions and have significant implications for the potential health risks associated with the use of other e-liquids.A pen-style e-cigarette battery was used as a model variable voltage e-cigarette for this study. This vape pen has set nominal voltages of 3.3, 3.8, 4.3, and 4.8 V. These voltages were confirmed using a multi-meter to measure the actual voltage of the battery upon activation. The set-up of the temperature measurements can be seen in S1 Fig in S1 File. The protocol for the thermocouple measurement of the e-cigarette coil and oil temperatures was adapted from Chen et al. To measure the temperature at each voltage setting, the pen was connected to a fresh cartridge that was filled with VEA standard oil until the oil level sat just above the atomizer base. The oil level in the cartridge was kept consistent between each reading, as the amount of oil in the cartridge has been previously shown to affect the temperatures the coil may reach. Three 1 mm grounded k-type thermocouple wires were connected to a 4-channel data logger . One thermocouple was kept suspended to measure the temperature of ambient air as a device control. The second thermocouple was inserted into the air flow tube of the cartridge and allowed to rest on the surface of the ceramic coil. This position was chosen to record temperature across all voltage settings as it not only provided the most consistent measurements, but certain positioning of the probe resulted in the battery shutting off, likely to prevent overheating or burning in the event of the air flow tube being blocked during real-use scenarios. The third thermocouple was inserted into the glass casing of the cartridge to submerge the end of the probe in VEA oil in contact with the atomizer. The thermocouples allowed for simultaneous measurement of the coil and the parent oil in the cartridge when the battery was activated. Temperatures were recorded by the data logger every 1 s over a 1 min cycle. The vape pen was activated by holding the power button for 4 s to heat the coil, then allowed to rest for the remainder of the cycle. A total of 13 cycles–including 3 initial preconditioning cycles–were measured.The procedure for collection of VEA vaping emissions at each temperature setting was adapted from previous studies. Prior to each collection, a fresh cartridge was filled with VEAstandard oil, weighed, and preconditioned by taking 3–5 puffs. The vaping emissions were collected using a cold trap apparatus maintained at -40˚C . The particle collection efficiency of the cold trap system at the flow rate used in this study has been reported previously. To collect aerosol emissions, one 4 s puff was taken at intervals of 1 min to maintain consistency with the temperature measurement procedure. Puffs were generated at each temperature using a 0.4 L min-1 air flow rate, which was controlled by a 0.46 L min-1 critical orifice connected a diaphragm pump .

In practice these criteria are rarelymet, as many interventions have failed to produce differential change on theoretical mediators . However, these “failed” investigations of mediating variables can still be informative about common therapeutic processes, because they still identify modifiable characteristics that explain individual differences in substance use treatment outcome . Our research provides examples of both specific and common mediators in veterans treated for substance dependence and MDD. In Study 1 we found that greater 12-step meeting attendance for veterans in TSF mediated their superior within-treatment depression outcomes, while Study 2 found that greater reductions in 12-step meeting attendance and affiliation following treatment mediated poorer post-treatment drinking outcomes in the TSF group. Both of these findings highlight the impact of differential levels of engagement with community, self-help resources that were specifically tied to the TSF condition. Independent of treatment group, levels of self-efficacy and substance use in the social network predicted future alcohol and drug use in the year following treatment, suggesting these variables were common determinants of substance use in both treatment conditions. These studies also highlighted the value of investigating mediating variables with respect to individual differences in distal risk factors, by finding that neurocognitive impairment impacted substance use indirectly through self-efficacy, 12- step affiliation, and depression. We demonstrated that mediation analyses can assist in explaining the positive impact of specific therapeutic processes, by finding that the impact of greater attendance at 12-step meetings on future drinking were explained by lower levels of depressive symptoms. Altogether these studies provided new information with respect to explaining how treatment processes or individual characteristics relate to differences in substance use outcomes, cannabis grow facility highlighting the value of examining mediating processes in persons receiving treatment for substance dependence and MDD.

In the presence of moderation , the magnitude of association between two variables depends on the level of a third variable . While studies of mediators typically ask how or why, studies of moderators are perhaps best suited to determine for whom or under what conditions treatments are most effective. Treatment related studies of moderators typically examine if a preexisting characteristic influences effects of treatment on substance use outcomes. In previous examples of moderation, TSF was the most effective therapy for patients with social networks supportive of drinking , and CBT was more effective for cocaine users with greater severity at intake . In tune with the shift towards examining therapeutic process variables, there is perhaps greater current interest in identifying moderators that influence relations between process variables and substance use . Statistical recommendations for testing moderated mediation, or “conditional mediation” are now available , with clinical examples published in recent literature . These studies help illustrate heterogeneous pathways to recovery, because the magnitude of benefits conferred by a proximal variable may depend on some other distal risk factors. Because certain distal characteristics are prevalent and relatively intractable in substance-dependent patients, it is critical to explore these complex relationships in the context of addictions treatment. Investigations of such moderators provided further information about the complex associations between therapeutic process variables and treatment outcome for individuals with substance dependence and MDD. While social network characteristics were predictive of future substance use in the sample at-large, moderation analyses revealed these effects were attenuated for certain individuals. More specifically, the predictive effects of social network variables were reduced for veterans who resided in controlled contexts for longer periods of time. Neurocognitive impairment was also found to moderate process variable effects, as veterans with greater impairment experienced relatively stronger benefits from 12-step affiliation, especially when they were severely depressed.

These findings are significant as they reveal the benefits or risks conferred by certain processes are not similar across all recipients of treatment, and that certain contextual factors or individual characteristics impact the relations between these processes and substance use outcomes. The major goal in process-oriented research is frequently to discover factors that explain group differences, especially with respect to differences between treatment conditions. Whether group differences are consistent or inconsistent with hypotheses, studies of mediating variables can provide useful and potentially explanatory information, and our studies provide several examples of this type of contribution. In perhaps the most surprising finding of our controlled trial, the TSF group had superior reductions in depression during treatment, as compared to ICBT which targeted both depressive symptoms and substance use . While reductions in depression during follow-up were greater for ICBT, it was still perplexing that the “addiction-focused” treatment performed better than an intervention designed to target depression. Results of Study 1 provided some insight, suggesting that greater reductions in depression for TSF were likely attributable to greater attendance at community 12-step meetings. In fact, when controlling for meeting attendance, TSF and ICBT were similar on depression. In another unexpected finding, patients with poorer neurocognitive functioning had better substance use outcomes if assigned to ICBT . Patients with poorer cognitive functioning were expected to do worse in ICBT, because CBT is theoretically more cognitively-demanding. A key finding of Study 4 here was that patients with greater neurocognitive impairment had lower 12- step affiliation, suggesting that the poorer outcomes in TSF were likely attributable to difficulties engaging in TSF’s principal therapeutic targets: attendance at 12-step meetings and engagement with prescribed 12-step behaviors. These studies also illustrate that both dynamic, contextual factors and static, distal factors can moderate the effects of therapeutic process variables on treatment outcomes. In Study 3 we examined “controlled contexts”, environments where patients had restricted access to substances , and found these contexts moderated social network effects.

If more time was controlled, having a greater density of network drinking was less predictive of one’s own drinking. For other populations in which utilization of these controlled contexts is fairly common, studies that ignore these moderating contextual effects might underestimate associations between mediating variables and clinical outcomes. Furthermore, our findings demonstrate that effects of certain contextual variables may depend on other contextual factors in predicting substance use or other maladaptive behaviors. In Study 4 the effects of 12-step affiliation on future drinking were moderated by neurocognitive impairment, with stronger effects for the neurocognitively impaired. This interaction was further modified by depression: among patients with greater impairment, having more severe depressive symptoms increased the influence of 12-step affiliation on future drinking. This finding, in particular, reinforces the value of examining proximal variables in conjunction with distal risks and other dynamic processes in the prediction of complex behaviors such as substance use . Study 4, in particular, illustrates there are specific times for particular patients at which certain self regulatory behaviors are especially powerful, and elucidating these complex relationships is an important goal for future clinical research in addictions and other conditions. The strengths of repeated, frequent measurement of variables and specification of appropriate longitudinal models were also illustrated by this series of studies. Establishment of temporal precedence is one of many criteria for identifying a mechanism of change . In our studies time-varying predictors were used in a lagged fashion, with prior levels of process variables predicting future substance use outcomes. While these tests are not sufficient for indication of causation,cannabis grow system establishing temporal precedence increases confidence that adjusting/altering the predictor will result in changes in the outcome variable . Compared to correlational tests, our methods provided stronger evidence that changing 12-step affiliation, negative affect, self-efficacy, and social network variables could alter substance use in patients with substance dependence and MDD. This is an important distinction that strengthens the rationale to target these specific processes in therapy or to design treatments around these goals. Furthermore, we were able to estimate individual patterns of change in process variables and examine associations with changes in outcomes. Many psychological constructs change over time, and this is typically the goal of psychological treatments: to change an adverse condition. However, process variables and outcomes are often studied without consideration of change over time, which can produce biased or distorted results . By modeling within individual change in Study 2, we have stronger support to conclude that within-individual change in 12-step involvement is an important determinant of changes in post-treatment drinking. Adults with substance dependence and MDD historically have poor outcomes from substance use treatment, and are responsible for disproportionate levels of treatment costs and disability. Because these individuals are so commonly represented in SUD treatment settings but have rarely been the focus of treatment outcome or process research, we considered it paramount to explore clinically relevant determinants of substance use within this population. Our sample, in particular, was characterized by low levels of occupational and social functioning, with low rates of employment and marriage. The average participant in our sample had multiple prior inpatient treatments for substance dependence and multiple inpatient episodes for psychiatric problems, highlighting the debilitating and refractory nature of these co occurring conditions. However, it was encouraging to find that, in general, the therapeutic processes with empirically-validated benefits in patients without co-occurring disorders also appeared to confer therapeutic benefits in our sample of adults with substance dependence and MDD.

Because the current studies elucidated relationships between a variety of coping-oriented behaviors, contextual processes, and individual characteristics in the prediction of alcohol and drug use, the clinical implications of these studies are numerous. Several of our findings suggest facilitating 12-step involvement can be a useful component of interventions for patients with substance dependence and MDD. In Study 1 patients in TSF had greater reductions in depression that were mediated by 12-step meeting attendance. Furthermore, greater attendance at 12-step meetings had unique effects on depressive symptoms , which in turn predicted lower future drinking. It has been suggested that patients with co-occurring psychiatric problems may receive amplified benefits from social interaction inherent to self-help meetings, perhaps due to greater severity of social problems and isolation , which may have contributed to improved depression and drinking in our sample. During post-treatment follow-up , maintaining greater 12-step attendance and affiliation over time predicted less increase in drinking, suggesting that continued involvement in 12-step practices can be a beneficial post-treatment maintenance strategy for patients with co-occurring depression. However, one unfavorable finding was that patients in TSF had difficulty sustaining high levels of 12- step meeting attendance and affiliation after conclusion of the formal intervention phase. This suggests that patients with substance dependence and MDD may need some level of ongoing, therapeutic support to continue high levels of 12-step engagement, perhaps through the use of brief motivational/facilitation interventions . These studies were also helpful in elucidating the impact of negative affect in the maintenance of substance use for patients with substance dependence and MDD. We previously found that changes in depressive symptoms and substance use were highly correlated in this sample . The current studies built upon that work by highlighting more specific and unique roles of depressive symptoms. We found that reduced depressive symptoms during treatment were predicted by greater 12-step meeting attendance, independent of current drinking, and mediated the relation between meeting attendance and future drinking. Patients with substance dependence and MDD can likely experience reductions in depressive symptoms by attending 12-step meetings frequently, and these mood changes may help buffer against future drinking. Our findings also suggest that patients who are attending meetings frequently and fail to improve in depression should receive additional intervention or alteration to ongoing treatments to avoid future drinking. Results of Study 4 also indicated that greater depressive symptoms represent a distinct exacerbation of risk for cognitively impaired patients, during which they should engage in greater levels of protective behaviors to reduce the odds of increased drinking. Studies also confirmed significant roles of self-efficacy and social network substance use in the maintenance of abstinence in adults treated for substance dependence and MDD. During post-treatment follow-up, individuals who were generally at higher levels of self-efficacy had lower drinking and drug use. Self-efficacy has predicted good outcomes in a variety of studies and increased significantly during treatment in our sample . Our results only suggest that following the conclusion of formal treatment, patients with low confidence in their ability to abstain from substance use in risky situations are at greater risk for increased frequency of use in the future and may benefit from higher levels of care.

Individuals with substance dependence and MDD typically have more severe psychopathology as MDD is associated with prolonged course of dependence , greater treatment costs , and greater risk of suicide . The high prevalence of co-occurring MDD is also reflected in substance dependence treatment settings, with estimates ranging from 26-67% . Although many adults with co-occurring MDD do benefit from alcohol/drug treatment, they typically have worse outcomes than those without MDD . Despite these high prevalence rates and strong evidence of poorer treatment outcomes, few research studies have examined processes that predict post-treatment substance use within this population. Studies examining mechanisms of substance use treatment outcomes have not typically selected individuals with co-occurring psychiatric conditions, but have identified variables that likely translate to those with SUDs and MDD. As recognized by recent reviews, self-efficacy is a key construct involved in maintenance of abstinence following treatment for substance dependence , and is one of the most potent predictors of substance use treatment outcomes . Typically defined as the confidence/belief that one can resist using substances in high- risk situations, abstinence self-efficacy has consistently predicted treatment outcomes for both alcohol and drug users , in both inpatient/residential and outpatient settings . Studies also suggest enhanced self-efficacy is a common therapeutic element across treatment models as diverse as Alcoholics Anonymous , cognitive-behavioral therapy , and motivational enhancement therapy . Overall,marijuana grow system these studies indicate self-efficacy has a critical role in long-term treatment outcomes in substance-dependent population.

The role of social network characteristics in managing SUDs following treatment has also received considerable attention. As reducing contacts with users and developing sober relationships is frequently a component of treatment, of particular interest is whether the level of use in one’s social network actually predict post-treatment drinking and drug use. This has largely been supported in studies of alcohol users, as the overall frequency of drinking in the network, the proportion of network members abstinent, and the proportion of heavy drinkers in the network have all predicted post-treatment drinking . Network effects on drug use have not been studied in the context of formal treatment, but observational studies of drug users have had similar findings . Overall, these studies suggest social network characteristics could be a critical determinant of post-treatment use for patients with substance dependence and MDD. Despite extensive study of self-efficacy and social networks in general treatment samples, it is relatively unknown whether these process variables hold the same benefit for patients with SUDs and MDD, or if these patients can sustain self-efficacy and supportive social networks following formal treatment. However, some previous studies generally support the value of self-efficacy and social support among patients with SUDs and co-occurring mental health disorders. Among residential treatment patients with substance dependence and mixed co-occurring disorders including MDD, baseline self efficacy and general social support predicted six month substance use , and at follow-up self-efficacy was significantly associated with alcohol use . Among participants of dual-focus self-help groups, social support for abstinence mediated relations between greater group attendance and future substance use , while greater self-efficacy predicted greater quality of life . While these findings are promising, no known study has examined longitudinal, prospective effects of self efficacy or social networks on substance use following outpatient, professional psychotherapy for substance dependence and MDD.

Other treatment process variables were found to be less potent or more difficult to sustain for patients with MDD , which highlights the need to systematically evaluate effects of self-efficacy and social networks in patients with substance dependence and MDD.Within our sample, a potential moderator is living in environments that explicitly constrain alcohol/drug use, either via restricted access to substances or strong contingencies against using . Studies demonstrate that placement into halfway houses does achieve the intended effects of reducing substance use or achieving treatment milestones . Because substance use is more constrained by these environments, intrapersonal and interpersonal mechanisms like self-efficacy and social networks may be less crucial for individuals living in these “controlled contexts”. Investigation of these contextual effects is especially relevant for patients with substance dependence and MDD, who are especially likely to utilize residential or inpatient services . The moderating role of context has scarcely been investigated, but in one prior study the effects of the client-provider relationship on substance use were weaker for those in residential treatment . Thus, it is possible that controlled contexts moderate self-efficacy and social network effects, but to our knowledge no previous studies have investigated these relationships. The overall goal of this study was to examine prospective effects of self-efficacy and social network variables, the effects of controlled context, and their interactions in the prediction of post treatment substance use for veterans with substance dependence and MDD. Study participants received six months of either group Twelve-Step Facilitation or Integrated Cognitive-Behavioral Therapy for treatment of alcohol or drug dependence and MDD. Previous reports of this sample found that both groups increased in substance use during the one-year follow-up, with the ICBT group having comparatively less increase .

This study builds upon those findings by examining group differences and change over time in self-efficacy and substance-specific social network variables over the 12-months following treatment. We hypothesized that better post-treatment substance use outcomes would be predicted by greater self-efficacy and lower network substance use. Furthermore, we hypothesized that greater time in controlled context would be associated with lower alcohol/drug use, and that controlled context would moderate the effects of self-efficacy and network substance use on future drinking and drug use. This study involved secondary data analysis of veterans participating in a trial of outpatient group psychotherapy for co-occurring substance dependence and MDD, conducted at the San Diego Veterans Affairs Healthcare System . Participants met DSM-IV criteria for lifetime dependence on alcohol , cannabis , or stimulants with recent use, and DSM-IV criteria for MDD with at least one depressive episode occurring during a 3- month period of abstinence from substances. Exclusion criteria included dependence on opiates with intravenous administration, bipolar or psychotic disorder, living excessively far from the SDVAHS, or severe memory impairments limiting recall in assessments. With our current focus on the post-treatment period, we included all veterans completing at least one assessment from end-of-treatment to the one-year follow-up . The University of California, San Diego and VASDHS Institutional Review Boards approved the procedures for this study, which were explained in greater detail previously and are described briefly here. Study staff received referrals from the VASDHS dual diagnosis clinic, contacted veterans to conduct brief screenings, and met with eligible veterans to explain the procedures and obtain informed consent. Study participants consented to 6 months of group psychotherapy and 12 months of quarterly follow-up assessments, recording of group sessions,cannabis vertical farming psychotropic medication management appointments, random toxicology screens, and review of electronic medical records. All participating veterans consented to receive no additional formal treatment for substance use or depression for the duration of the treatment phase except for the psychotherapy and pharmacotherapy of the study, while participation in other formal interventions was allowed during follow-up.Veterans entered into group psychotherapy on a rolling basis, with start dates occurring every 2 weeks. After completing the intake assessment, veterans were sequentially allocated to the treatment condition with the next start date. Both interventions were manualized and were 6 months in duration, with twice-weekly sessions for 3 months followed by weekly sessions for the final 3 months. Group sessions were co-delivered by a senior clinician and doctoral trainee who were trained to criterion via manual review, direct observation, and weekly review and supervision. The protocol for Twelve-Step Facilitation was modified from TSF in Project MATCH for group delivery and targeting both drugs and alcohol. The Integrated Cognitive-Behavioral Therapy intervention was developed by adapting material from two empirically supported treatments: cognitive-behavioral relapse prevention from Project MATCH and group cognitive-behavioral therapy for depression . Both treatments were identically structured with a series of three modules, with each module covering a broad content area specific to 12-step or cognitive-behavioral principles. Each topic was introduced over a one-month block for the first 3 months of treatment, with review occurring in the final 3 months. Mean session attendance was not significantly different between TSF and ICBT . All veterans were offered pharmacotherapy management with VA physicians. Nearly all utilized medication management, with a mean attendance of 4.61 visits during treatment and 4.79 visits during follow-up. We utilized hierarchical linear modeling to examine process variables, controlled context, and their interaction in the prediction of post-treatment alcohol and drug use. The use of HLM was preferred for this study due to inclusion of multiple time points nested within individuals, use of both static and time-varying covariates/predictors, and inclusion of all available data via maximum likelihood estimation.

Maximum likelihood estimation is preferred when data contain missing values assumed missing-at random , and no significant differences were found any study variables between those with complete data and those with any missing data, supporting this assumption. With the exception of group and time effects, all predictor variables were grand-mean centered prior to inclusion in analyses. All statistical analyses were performed in Stata 10.1 .In preliminary models we examined static predictors of PDD and PDDRG to control for potential confounding variables , and then tested effects of treatment group, time, and the group x time interaction to model group differences in these outcomes. To examine group differences and time effects for self-efficacy, social network, and controlled context, these variables were analyzed as outcomes in HLM with group, time, and group x time as predictors. To examine prospective relations between process variables and substance use, lagged self-efficacy and each social network variable were used as time-varying predictors of PDD and PDDRG in HLM. Each social network variable was substance-specific . For these longitudinal analyses with time-varying covariates, the repeated measures contain confounded information about between-person and within-person differences, and disaggregation of these effects has been recommended when dictated by substantive interest . In this study, both effects were of interest: between-person differences or within person differences could predict future substance use. To disaggregate the between- and within-person effect, raw scores were de-composed into two variables representing the person-mean and time specific deviations from the person mean , and both variables were included in HLM to examine independence of these effects. To examine effects of controlled context, the controlled context variable was entered as a time-varying covariate of current PDD and PDDRG. The final HLMs examined interactions of lagged process variables with concurrent controlled context, to examine whether controlled context moderated effects of lagged process variables on PDD and PDDRG. Prior to testing core hypotheses, preliminary HLMs examined intake covariates of post-treatment PDD and PDDRG. Greater years of education predicted lower PDD , being employed predicted lower PDDRG , and pretreatment frequency of use predicted PDD and PDDRG . Models examining effects of treatment group, time, and the group x time interaction revealed that PDD and PDDRG increased significantly following treatment, independent of treatment group. Furthermore, the group x time interaction was statistically significant for PDD, replicating the previous findings of relatively greater 3 increase in substance use in the TSF group during follow-up . All subsequent models of PDD and PDDRG accounted for these significant covariate effects. By testing effects of treatment group, time, and the group x time interaction in HLM, the next series of models examined group differences in mean levels, change over time, and group differences in change over time in self-efficacy, social network variables, and controlled context during the 12-month post-treatment follow-up. As shown in Table 9, estimates of variance components revealed significant variability at both the between individual and within-individual level for self-efficacy and social network variables, justifying the use of HLM and disaggregation of these effects. A significant group x time interaction was found for social support for drug use , percent-network abstinent from drugs , and percent network using drugs . Inspection of means revealed that at month 6 the TSF group had relatively greater percent-network abstinent from drugs, with lower levels of mean network drug use and percent-network using drugs.

The competitive CB1 antagonist/ inverse agonist SR141716A micro-injected into either the dorsolateral PAG or RVM also attenuates SIA. By con trast, inhibition of endocannabinoid hydrolysis at these sites enhances SIA . These data support the existence of supraspinal sites of endo cannabinoid analgesic action. Cannabinoids produce antinociception through spinal as well as supraspinal mechanisms . The antinociceptive and electrophysiological ef fects of cannabinoids are attenuated following spinal transec tion. Nonetheless, a long-lasting residual antinociception remains in spinally transected mice , suggesting the existence of spinal sites of endocannabi noid analgesic action. These data are consistent with the pres ence of CB1 receptors in the spinal dorsal horn . Intrathecally-administered cannabinoids also produce antino ciception and suppress noxious stimulus-evoked neuronal activity in spinal nociceptive neurons , suggesting a function al role for spinal cannabinoid receptors in modulating nociceptive processing. Intrathecal administration of either rimonabant or CB1 antisense oligonucleotides also elicits hyperalgesia , suggesting that endo cannabinoids may act tonically to suppress nociceptive responding. However, a physiological role for endocannabi noids at the spinal level has not been identified. Both 2-AG and anandamide fully qualify as endocannabi noids . These lipids are synthe sized and released on-demand, activate cannabinoid CB1 receptors with high affinity, and are metabolized in vivo by distinct hydrolytic pathways. Within the CNS, 2-AG is present in quantities 170e1000 times greater those of anandamide . 2-AG serves as a full agonist at CB1 and CB2 ,cannabis growing whereas anan damide is less efficacious . 2-AG is preferentially degraded by monoacylglycerol li pase , whereas anandamide is preferentially hydrolyzed by fatty-acid amide hydrolase.

Mutant mice lacking the FAAH gene are impaired in their ability to de grade anandamide and display reduced pain sensation that is reversed by the CB1 antagonist rimonabant . Immunocytochemical studies have revealed a heterogeneous distribution of FAAH through out the brain and moderate staining of FAAH-positive cells in the superficial dorsal horn of the spinal cord . In brain, the regional distribution of MGL partially overlaps with that of the CB1 receptor . Inhibition of MGL in the midbrain PAG increases 2-AG accumulation and enhances SIA in a CB1-dependent manner , supporting a physiological role for 2-AG in neural signaling. Thus, the anatomical distributions of FAAH and MGL are consistent with a role for these enzymes in terminating the activity of endocannabinoids. The present studies were conducted to investigate the con tribution of endocannabinoids acting at spinal CB1 receptors to nonopioid SIA. We used high-performance liquid chromatog raphy/mass spectrometry to examine the contribution of 2-AG and anandamide at the spinal level to SIA. We examined the time-course of changes in endocannabinoid lev els in the lumbar spinal cord of control rats and rats subjected to foot shock stress. Moreover, we used selective inhibitors of MGL and FAAH to further elucidate the roles of these en docannabinoids in SIA. We additionally evaluated effects of intrathecal administration of arachidonoylserotonin , a FAAH inhibitor that is inactive at phospholipase A2 and CB1 receptors, on SIA. We hypothe sized that intrathecal administration of these inhibitors would potentiate nonopioid SIA via a CB1 mechanism. Preliminary results have been reported .We have previously demonstrated that nonopioid SIA is mediated by mobilization of two endocannabinoids, 2-AG and anandamide, in the midbrain PAG . The present results extend those findings and suggest that endocannabinoid actions at spinal CB1 receptors modulate SIA. Foot shock stress induced time-dependent changes in the levels of 2-AG, but not anandamide, in the lumbar spinal cord. However, intrathecal administration of rimonabant failed to attenuate nonopioid SIA.

Nonetheless, selective inhibitors of MGL and FAAH, administered via the same route, increased both the magnitude and duration of SIA through a CB1- dependent mechanism. A parsimonious interpretation of these findings is that inhibition of MGL or FAAH prevented the de activation of spinal 2-AG and anandamide, respectively, mag nifying nonopioid SIA. Thus, our findings suggest that spinal endocannabinoids regulate, but do not mediate, nonopioid SIA. It is possible that the placement of chronic indwelling intrathecal catheters elevated anandamide levels in the behavioral studies, and that this change in endocannabinoid tone was augmented by the FAAH inhibitors. However, changes in endo cannabinoid tone due to catheter placement appear unlikely because intrathecal rimonabant administration did not alter tail-flick latencies in the presence or absence of foot shock. Moreover, Fos immunocytochemical studies suggest that spinal compression induced by catheter placement does not induce appreciable neuronal activation .Electrophysiological studies have provided evidence both for and against the existence of a tonic endocannabinoid tone at the spinal level. However, in our study, intrathecal rimonabant administration failed to suppress either basal noci ceptive thresholds or nonopioid SIA. Hyperalgesic effects of spinal rimonabant may reflect sensitivity of supraspinally-organized relative to spinally or ganized pain behaviors in measuring lowered nociceptive thresholds. It is also possible that exposure to un controlled stress mobilizes endocannabi noids in behavioral studies , thereby resulting in a CB1-dependent apparent hyperalgesia. Although high doses of anandamide activate transient re ceptor potential vanilloid 1 , several observations suggest that this mechanism is not responsible for the enhancements of SIA observed here. First, systemic administration of the TRPV1 antagonist capsazepine, at a dose that completely blocks capsaicin-induced antinociception, does not alter non opioid SIA in our paradigm . Second, CB1 and TRPV1 show minimal colocalization at the axonal level in the spinal cord, with CB1 localized predominantly to laminae I and II interneurons and TRPV1 localized primarily to nociceptive primary affer ent terminals . Third, anandamide activation of CB1 and TRPV1 typically induces opposing effects with distinct time courses .

However, we ob served only enhancementsdnot attenuationdof SIA follow ing intrathecal administration of FAAH inhibitors and no change in SIA following antagonist treatment. Fourth, rimona bant completely blocked the potentiation of SIA induced by intrathecal administration of inhibitors of MGL or FAAH, at doses that were insufficient to reverse SIA when administered alone. Together, these observations suggest that anandamide acts through CB1 rather than TRPV1 at the spinal level to modulate SIA. The foot shock-induced increases in 2-AG levels were smaller than those observed previously in the dorsal midbrain of the same subjects . This observation is consistent with the inability of spinally administered rimo nabant to block nonopioid SIA. By contrast, a tenfold lower dose of rimonabant produced a robust suppression of SIA when micro-injected into the dorsolateral PAG. Our results col lectively suggest that supraspinal sites of action play a pivotal role in endocannabinoid-mediated SIA. Our data suggest that spinal inhibition of MGL prolongs the duration of action of 2-AG, thereby enhancing endocannabi noid tone at spinal CB1 receptors to magnify SIA. This en hancement occurred in the absence of reliable changes in spinal anandamide levels. Thus, the antinociceptive effects of MGL inhibitors are not dependent upon concurrent eleva tions in anandamide that were induced in the midbrain PAG following exposure to the same stressor .However,cannabis grow tray foot shock did not reliably increase spinal anandamide levels. Our failure to observe en hancements in anandamide accumulation may reflect lower absolute levels of anandamide relative to 2-AG and conse quently higher variability in these measurements. Our data are consistent with the ability of FAAH inhibitors to selectively enhance accumulation of anandamide, but not 2-AG . FAAH may regulate both the distance endo cannabinoids diffuse to engage CB1 receptors and the duration of endocannabinoid actions to increase accumulation of tonically released anandamide. It is also pos sible that the extent of on-demand anandamide synthesis may be underestimated in the present work due to the rapid metab olism of this lipid by FAAH. Mapping the distribution of MGL, FAAH and CB1 in the spinal cord could further eluci date the anatomical and functional relationship between cells that degrade 2-AG and those expressing CB1. Cannabinoid receptor agonists such as D9 -tetrahydrocan nabinol have limited therapeutic applications at present, mainly because of their undesirable psychoactive effects. However, pharmacological agents that protect endocannabi noids such as 2-AG and anandamide from inactivation may lead to a more circumscribed spectrum of physiological re sponses than those produced by direct cannabinoid agonists. Ideally, this strategy would enhance endocannabinoid activity only at sites with on-going biosynthesis and release, thereby averting undesirable side effects. The possible use of drugs that inhibit endocannabinoid hydrolysis to treat pain in hu mans has thus propagated both hope and concern . FAAH is widely distributed throughout the body and implicated in the metabolism of a variety of anandamide analogues . Our data demonstrate that local enhancements of endocannabinoid actions at the spinal level are sufficient to potentiate SIA. Additional experiments will be necessary to determine whether inhibitors of endocannabinoid degrada tion may find therapeutic applications in the treatment of pain and stress-related disorders.Substance use disorders are among the most prevalent and costly psychiatric disorders in the United States.

The 12-month prevalence of alcohol use disorders among American adults was recently estimated at 8.46%, while the prevalence of drug use disorders was 2.0% . Individuals with SUDs often incur greater treatment costs than patients with chronic medical conditions and other behavioral health disorders . They also have an elevated risk of negative psychosocial outcomes, including intimate-partner and non-partner violence , incarceration , and absenteeism from work . Among individuals diagnosed with a SUD, the prevalence of other psychiatric disorders is greater than in the general population. In recent epidemiological research the prevalence of mood disorders among those with SUDs was 20.13%, compared to 8.19% for the non substance-disordered population . Major depressive disorder is the most common co-occurring disorder, with a prevalence of 15.5% among individuals diagnosed with a SUD. Although many types of co-occurring conditions are associated with negative outcomes, the additional burdens associated with MDD have been especially well-characterized. Patients with SUD and MDD incur substantially greater costs in mental health, substance abuse, and medical care and utilize high-cost emergency department and inpatient care more frequently . The annual cost of treating a patient with SUD and MDD has been estimated at $5,318, compared to $1,246 for those with a SUD alone . In addition to these excess cost burdens, having MDD in addition to SUD is associated with a multitude of negative psychosocial outcomes, including greater risk of suicide attempts , worse quality of life , and higher rates of social problems and work disability. Pre-treatment levels of problem severity across multiple domains are often worse for patients with SUD and MDD . Perhaps the most important clinical characteristic of adults with SUD and MDD is evidence that they typically have poorer outcomes from treatment for substance use. In naturalistic studies of inpatient alcohol treatment, having MDD at baseline predicted earlier relapse and greater post-treatment depressive symptoms were associated with a greater risk of relapse . In Project MATCH greater depressive symptoms predicted poorer drinking outcomes, and in patients with alcohol and tobacco dependence, depressive symptoms predicted non-abstinence and level of drinking at every follow-up assessment . Findings are similar in studies of treatment for users of illicit drugs. Cocaine dependent patients with MDD have exhibited poorer outcomes from cognitive-behavioral therapy . In the Methamphetamine Treatment Project, greater severity of depressive symptoms predicted poorer adherence and worse treatment outcomes, and patients with MDD had more frequent methamphetamine use and lower odds of abstinence at follow-up. Among adolescents in marijuana dependence treatment, MDD was associated with a greater likelihood of relapse and more total relapses . Adults with SUD and MDD may resist participation in community 12-step activities and derive less benefit from 12-step involvement . Although some past studies found no relationship between depression and substance use treatment outcomes, there is a growing body of evidence supporting the negative impact of depression on treatments for various substances in a variety of settings. Historically, those with substance dependence and a co-occurring psychiatric disorder could not receive integrated treatments that simultaneously target both disorders in a single setting . More recently, researchers have advocated for the evaluation and implementation of integrated treatments that could be superior to treatments that target substance use alone . However, very few well designed studies have examined the efficacy of integrated treatment for substance dependence and MDD, with a recent meta-analysis identifying only five controlled trials comparing integrated treatment to treatment of substance use alone . Overall, integrated treatments performed significantly better on substance use outcomes, but not on depression or retention.

The low expectation group could be driven by not wanting to have a child or experience of infertility. However, among people who reported having problems getting pregnant, the expected fertility variable had a higher mean than among those who did not report it. This implies that the expectation measure is largely capturing pregnancy intention. Income and wealth are highly correlated with risk preferences. Although much literature in economics assumes, a priori, that risk preferences precede income, empirical research reports evidence for both causal directions. I, therefore, exclude poverty as a control in the main models because it may be on the causal pathway between risk preferences and sexual and reproductive behavior. I, however, include a measure of poverty in the sensitivity analyses. Demand for insurance is correlated with risk tolerance, and at times itself used as a measure or risk tolerance . Therefore, I treat insurance status in the same manner as poverty, excluding it from the main models and including it for sensitivity analyses. Insurance status is coded as any insurance versus no insurance at the time of interview. The risk preference measure was missing in 3.1% of 3,821 women interviewed in 2010 or 2011. Of the 118 missing responses, 103 answered don’t know to the first gamble question. Of the 3,703 women with risk preferences measures, 530 were excluded due to reporting no sexual behavior with a member of the opposite sex in the preceding year. An additional 4% of the 3,173 responses were excluded from the analyses due to missing all of the sexual and contraceptive behavior outcomes, leaving a final analytic sample of 3,045 women. The distribution of risk tolerance for the study sample included 56.6% in the very strongly risk averse category, 23.0% in the strongly risk averse category, 10.0% in the moderately risk averse category and 10.4% is the weakly risk averse category.

These estimates parallel those reported in the literature,cannabis grow kit with one third to one half of participants falling into the most risk averse category.Table 1a shows the distribution of risk aversion by covariates in the sample. Measures of risk aversion appear similar across non-Hispanic white, non-Hispanic black and Hispanic respondents, with non-Hispanic blacks displaying slightly more responses in both risk averse and risk tolerant categories. The low numbers in the mixed/other racial group prevent any meaningful comparisons. The age range in the study sample included 25 to 31 year olds at the time of interview. With the exclusion of these 25 and 31 year olds that had low numbers of respondents, the risk preference measures appear largely stable over the age range. Higher education corresponded to decreased risk aversion and increased risk tolerance in this sample , as is consistent with the literature. As expected, risk aversion differed by marital/partnership status, with the never married/not cohabitating group showing lowest risk aversion and highest risk tolerance. Cohabitating but not married respondents also have higher risk tolerance and lower risk aversion than their married counterparts, with separated/divorces/and widowed in between. Respondents with no children ranked higher on risk tolerance and lower on risk aversion, than those with 1, 2, or 3 plus children. Insurance status, a marker for access to contraception and also SES, differed by risk aversion. Examining poverty and risk aversion also revealed expected differences. Those with lower income to poverty ratios displayed the highest degree of risk tolerance, and the wealthiest showed the highest degrees of risk aversion. Finally, risk preferences varied by expectation of future children with those that 100% expect children in the next five years, and those that 0% expect children in the next five years exhibited stronger risk aversion. Sensitivity analyses are shown in the appendices. First, I confirmed that the choice to code the second order “don’t know” responses to the middle categories of risk aversion did not alter results. All measures of effect remained unchanged. Categorizing risk preference as a linear measure of tolerance according to the adjusted mean values reported in Barsky, led to similar results . An increase in risk tolerance was associated with number of partners [RR= 1.25, 95% CI ], but not with likelihood of having a having a high-risk sexual partner.

Consistency of use results persisted for unmarried/not cohabitating women: the linear risk tolerance measure was associated with increased relative risk of inconsistent contraceptive use [RR= 3.20, 95% CI ]. The results with nonuse were attenuated from the categorical measure from the measures for the married group. Finally, for effectiveness, a one-unit increase in the linear risk tolerance measure was associated with decreased risk of using a medium effectiveness [RR=0.06, 95% CI ] or high effectiveness [RR=0.03, 95% CI ] method use versus low effectiveness methods among the unmarried/not cohabitating group. The confidence intervals for an increased relative risk of medium and highly effective method use among the married or cohabitating group contained the null. For individual methods, only the relationship with the patch or ring and sterilization persisted with the continuous risk tolerance measure. Models including the natural log of poverty and health insurance as covariates attenuated results for number of sexual partners . The consistency of contraception and effectiveness of method relationships remained similar in magnitude. To my knowledge, this is the first paper to report a relationship between risk preferences and contraceptive use, an important determinant of unintended pregnancy. In a nationally representative sample of women aged 25-31, I found that among unmarried and not cohabitating or separated women, greater risk tolerance was associated with inconsistent contraceptive use, as well as decreased use of more effective methods of contraception. Among married and cohabitating women, the highest level of risk tolerance is associated with an increased likelihood of using a more effective method of contraception. This likely indicates distinct pathways through which propensity to risk may operate in regard to reproductive behavior. I further found evidence of risk tolerance and sexual behavior, as reported number of sexual partners increased with risk tolerance. The unadjusted relationship between risk tolerance and sex with a high-risk partner did not remain after covariate adjustment. As only three percent of the sample engaged in this behavior, it may be measuring a greater level of risk taking than is captured by the four categories of risk preferences measures by the lottery question.

Despite extensive research into reproductive decisions, little attention has been paid to risk preferences. Standard economic models generally view women as rational actors who adjust fertility behavior to maximize utility. This view is inconsistent with the work from reproductive epidemiology that shows a complex set of factors influence reproductive decision making, and that women’s stated pregnancy intentions and behavior do not always converge. This paper uses a well-studied measure from economics to explain variation in reproductive risk taking. The results suggest that the propensity to assume financial risk may imply a more general risk-taking that extends to reproductive behavior. I found that partnership status modified the relationship of risk preference and contraceptive use. These results are consistent with previous work finding earlier marriage and divorce propensity are related to risk preferences.Among unpartnered women, decreasing risk aversion was associated with increased inconsistent method use. This result supports the hypothesis that more risk tolerant unmarried or separated women may accept a greater risk of pregnancy versus potential negative cost of consistently using contraception. Also less likely to use more effective methods,cannabis grow supplies this risk tolerant group may serve as a potential target of intervention. The stratified models for married or cohabitating women paint a different picture of the risk preference relationship with contraceptive use, showing that the most risk tolerant women had less use of medium and highly effective methods. This direction was the opposite of that I hypothesized. This apparent increase in method effectiveness with increasing risk tolerance may be explained by unmeasured confounding by pregnancy intention. Previous work has noted that risk tolerant women may be more likely to use less effective contraception early in life but also may be most likely to delay childbearing until later in life, despite reductions in fecundity. This latter theory may be at work in this married and cohabitating sample. The effect modification by partnership status suggests that partnership status may serve as a source of differentiation of pregnancy intention as well relationship context. If a true relationship exists between risk preferences and contraceptive behavior it may be moderated by fertility intention. Undoubtedly, inconsistent or nonuse of contraception is capturing both those women trying to become pregnant, those ambivalent to pregnancy, and those trying to avoid pregnancy. My hypothesis would operate in a different direction in the latter two groups than the former. In the absence of any measure of pregnancy planning or intention, the expectation measure may serve as a proxy for this construct. However, examining the relationship among those with low expectations of a child in 5 years did not change the results. The results by individual contraceptive methods reveal some compelling differences. The most risk averse appeared more likely to use IUDs, the most effective reversible form of contraception. Patch and ring use was higher among the most risk tolerant women, while sterilization was associated high-risk aversion. While more work on method types is needed, these results suggest that assessing women’s risk propensity may be an important determinant of appropriate contraceptive counseling. There has been a substantial push towards long acting reversible contraception for women in the US. A patient centered decision-making process could involve a discussion on only of risks of each particular method but of women’s tolerance of such risks. Indeed women may value particular features of contraceptive methods over others according to their risk preferences.

The temporal ordering of measures of risk preference and sexual and contraceptive behavior is a strength of this analysis. Economic models frequently assume that preferences are trait characteristics, and can therefore be studied at any point in time with validity. Conversely, other literature has noted fluctuation of preferences with demographic changes and life events. There is mixed evidence around potential alteration of risk preferences following childbearing. Temporal ordering may not be an issue for this analysis, however additional measures of risk preference would be beneficial to establish the preference consistency and look at contraception and pregnancy outcomes over time. The age at which risk preferences were elicited poses a substantial limitation to the theory connecting risk tolerance to fertility and contraceptive behavior. The women in this analysis were in their late twenties at the time of elicitation of risk preferences. In order to rule out problematic temporal ordering, I chose to examine only proximate contraceptive use and sexual risk behavior. However, the hypothesized relationship between risk tolerance and sexual and reproductive behavior may operate differently for women at younger and older ages than I was able to explore in this sample of 25-31 year olds. Much work in adolescent development and neuroscience shows different adaptive responses to risk . As adolescents exhibit more high-risk sexual behaviors and higher rates of unintended pregnancy, this age group would serve as a particularly important focus of further study of risk preferences and reproductive decision-making. The relationship of risk tolerance and fertility may be nonlinear with age, as Schmidt suggests. Early in fertility risk tolerant women may be less likely to use contraception while later they may be more likely to delay childbearing. Schmidt postulated that her finding that highly risk tolerant women experienced earlier first birth, was due to increased sexual risk behavior and reduced contraceptive use. While I saw no relationship with age in this sample, I may not have had enough variability in age in this time period to notice an effect. Schmidt also notes that at high education levels, risk tolerance may lead to a postponement of childbearing. While I did not see any evidence of interaction by education in this sample, additional analyses to explore subgroup differences are warranted. Over half of the sample fell into the most risk averse category. While consistent with other representative studies, this measure may miss levels of granularity in risk preference that would be important to reproductive behavior. Other questions have attempted to improve the measure to capture more heterogeneity in risk response, however, those questions were not available in the NLSY97.

These systematic deviations offer a window into drivers of health behavior and potential points of intervention. My dissertation applies decision-making constructs from behavioral economics to reproductive health outcomes. Specifically, I examine the trade offs between risk and reward and between now and later. These preferences are fundamental characteristics of decision-making. Risk tolerance and temporal discounting have been demonstrated to be drivers of financial behavior, and these same concepts have now been extended to the study of health behavior. Sexual behavior and pregnancy decision-making are an understudied and, as I demonstrate, particularly relevant area for exploration. National and international public health priorities include reduction of unintended pregnancy. Defined as pregnancies that are mistimed or unwanted, unintended pregnancies comprised 45% of all pregnancies to women aged 15-44 in the United States in 2011. Half of those pregnancies ended in abortion. Reproductive health literature reports inconsistencies between intention and behavior regarding contraceptive use and pregnancy. Nonuse or inconsistent use of contraception is common among women at risk of unintended pregnancy, meaning those sexually active with a stated desire not to get pregnant. Misperception of pregnancy risk may also result in reduced contraceptive use and subsequent unintended pregnancy, regardless of knowledge of available methods. In my second chapter, I conduct a systematic scoping review of the literature on temporal and risk preferences,cannabis grow supplier and sexual and reproductive health behavior. Temporal discounting is the rate at which people devalue delayed rewards in comparison to more temporally present rewards.

Higher discount rates indicate less willingness to exchange current consumption for future consumption. Individual decision-making is also shaped by perception of risk. Prospect theory describes decision-making in the context of risk. Risk preferences are generally measured as willingness to take gambles with income. People willing to take fewer gambles are generally deemed risk averse and those more willing to take gambles risk tolerant. I examine the consistency of findings from 20 studies identified to meet my inclusion criteria. Mapping the literature can identify common themes and gaps in current knowledge. While the majority of studies concern sexual risk behavior, I draw comparisons to outcomes of unintended pregnancy and contraceptive use. Finally, I make recommendations for future avenues of research based on the existing literature. I expand the empirical research on economic preferences and reproductive behavior in my third chapter, which examines risk preferences and sexual and contraceptive behavior in the 1997 cohort of the National Longitudinal Survey of Youth . I test the hypothesis that the propensity to take risk manifests not only in the financial decisions commonly studied by decision theorists, but also in less-well studied choices that affect reproductive health. I investigate the association of risk tolerance with several proximate determinants of unintended pregnancy, including high-risk sexual behavior, contraceptive non-use, inconsistent contraceptive use, and the effectiveness of contraceptive method type. In addition to risk preferences and discounting, uncertainty affects reproductive decision making and behavior. Variation in economic context may influence contraceptive and sexual behavior, thereby altering risk of unintended pregnancy and decision-making once a pregnancy has occurred. My fourth chapter examines how the recent Great Recession and economic uncertainty affect unintended pregnancy and pregnancy decision-making. I use the National Survey of Family Growth , a nationally representative sample of reproductive aged women. Understanding how the economy affects pregnancy intention and decision-making brings insight to the discussion of decision-making and reproductive outcomes as well economic drivers of fertility.

The goal of this dissertation is to improve understanding of behavioral drivers of reproductive health. The incorporation of concepts from behavioral economics into reproductive health frameworks may improve our predictions of distributions of disease and also generate hypotheses of pathways between social environment and health [1]. It may be especially useful for behaviors that offer benefits, or “rewards”, in the present that offset future negative consequences, or “costs”, to health later. The chapters show that economic preferences and measures of uncertainty have implications for our understanding of mechanisms underlying choices that drive reproductive health. This is an important step towards predicting who will be at highest risk of adverse outcomes and potentially develop models for intervention. Although sexually transmitted infections and unintended pregnancy have long been major public health concerns worldwide, unprotected sex and ineffective contraceptive use persist. Much literature shows that decisions affecting sexual behavior and fertility result from a complex process that involves norms, resources, knowledge, power, and individual tolerance for risk and propensity to make impulsive choices. The fact that unhealthy behaviors persist despite knowledge of risk has perplexed public health practitioners and led them to consider whether insights might be gleaned from behavioral economics – a field committed to explaining why humans act in ways inconsistent with rational self interest. Economists have theorized that individual behavior results from a desire to maximize utility, which varies based on individual preferences. These preferences, elaborated by behavioral economics, include the trade offs between risk and reward and between now and later, and are fundamental characteristics of decision-making. Risk and temporal preferences have been demonstrated to be drivers of financial behavior, and these same concepts have now been extended to the study of health behavior.

Sexual and reproductive behaviors are particularly relevant to study in the context of behavioral economics because the results of risky sex have delayed and uncertain consequences to health, in the form of pregnancy or STI acquisition, and so risk and temporal preferences are particularly salient. This review summarizes the scope of the literature relating temporal and risk preferences to sexual and reproductive behavior, to determine if discounting or risk tolerance are reliable correlates of choice relating to sex, pregnancy and STI risk. I first describe background literature on sexual and reproductive health that is relevant to the application of temporal discounting and risk tolerance. Next, I briefly define temporal discounting and risk preferences and discuss relevant literature in other health domains. This background motivates the systematic scoping review of the literature on temporal discounting or risk tolerance and sexual and reproductive outcomes, which follows. Nearly half of pregnancies to women aged 15-44 in the United States are unintended. These unintended pregnancies are associated with negative outcomes for mothers and children, including delayed prenatal care, maternal depression,cannabis drainage system lower quality of maternal-child relationship, and higher rates of preterm birth. Unintended pregnancies, like many public health problems, concentrate among low income women and women from minority racial/ethnic groups . Young age, low education, previous pregnancies, non-married status, and urbanicity explain much but not all of the concentration of unintended pregnancy among poor and minority women in developed contexts. The consequences of unintended pregnancy are more severe in the developing world, and lead to excess maternal mortality, morbidity from births, and unsafe abortions. Research reports inconsistencies in behavior and intention regarding contraceptive use and pregnancy. Nonuse or inconsistent use of contraception is common among sexually active women with a stated desire to avoid pregnant. Lack of information about method availability, especially long acting methods, appears more common among women reporting unintended pregnancy. Contraceptive use is influenced by a variety of system level factors, such as access and cost, as well as individual decision-making. Research on attitudes toward contraceptives has, moreover, reported that fear of side effects or differences between desired and available method features also affect use. Misperception of risk may also result in reduced contraceptive use and subsequent unintended pregnancy regardless of knowledge of available methods. A study of family planning patients found, for example, that nearly 46% of women who engaged in unprotected intercourse in the past 3 months underestimated the risk of conception and that underestimation predicted unprotected sex.

Similarly, a study of women seeking abortion services found that the majority of women thought themselves to have an inaccurate risk of pregnancy prior to conception. A California study following young women who initiated a new method of contraception and who reported not wanting to be pregnant within a year found high rates of discontinuation over the year. Similarly in the field of sexual risk behavior, risk reduction strategies including condom distribution, increasing HIV/AIDS risk perception, and education have proven successful strategies at reducing some but not all sexual risk behavior. A strong body of literature shows that sexual decision-making is often spontaneous and unplanned, especially in the context of alcohol or substance use. The intuitive connection between individual decision-making and unintended pregnancy and STI risk behavior has lead reproductive health researchers to explore the field of behavioral economics. In a white paper, the Behavioral Economics in Reproductive Health Initiative noted the opportunity to apply behavioral economics to global reproductive health concerns. They describe the importance of trade-offs between today versus tomorrow and of beliefs about probability in individual calculation of pregnancy or STI risk in reproductive decision-making. These notions apply to earlier cited literature showing that people misestimate the risks of pregnancy and STIs and make impulsive decisions relating to sex.Given the importance and persistence of sexual risk behavior and the gap between contraceptive use and intention, behavioral economics concepts would seem particularly useful for research concerned with reproductive health. Temporal discounting is the rate at which people devalue delayed rewards in comparison to more temporally present rewards . Higher discount rates indicate less willingness to exchange current consumption for future consumption. Delay discounting is typically assessed with hypothetical questions about different monetary amounts in the present or in the future. Most people would choose a higher amount of money over a lower amount if both were offered at the same time. However as the higher amount is delayed, individuals may switch to preferring the lower but sooner amount to the higher but later amount. The amount and delay at which the switch occurs is called the indifference point and can used to calculate individual discount rates. Those with very high discount rates discount the future value of a reward steeply as the delay increases and, therefore, show a present bias. Those with lower discount rates seem to value the future more similarly to the present. The preference for smaller pleasures in the present to larger benefits in the future can explain certain behaviors like smoking again one day after you quit. Probability discounting is similar to delay discounting, except that it measures a person’s sensitivity to uncertainty rather than delay of rewards. While delay discounting assesses the trade off between an immediate and delayed reward, probability discounting assesses the trade off between a certain and probabilistic reward. In discounting tasks, if both larger and smaller rewards are certain, most people would prefer a larger amount. However as the probability of the larger amount decreases, there is a shift to the smaller, certain amount. Similar to delay discounting, the point at which a person switches from a larger less probable rewards to a smaller certain reward is considered the indifference point of probability discounting. Probability discounting is closely tied to the concept of risk tolerance, as it is a measure of the degree of monetary risk someone is willing to assume. Behavioral economists have posited that discount function is nonlinear over time and instead fits a hyperbolic shape, meaning that there is attenuation in the rate of devaluation with increasing delays. Hyperbolic discounting reflects inconsistencies between long term goals and short-term rewards, and explains “impulsive” decisions as the value is discounted more steeply with shorter delays. Present biased individuals make far sighted plans when rewards are distant but often reverse their choices in favor of short term rewards as the decision-point is reached. Literature linking temporal discounting to health behavior has emerged. Researchers have proposed that temporal discounting relates to unhealthy behavior and explains inconsistencies between exhibited behavior and stated intention. Health behaviors, including sexual risk behavior, often involve the present/future trade offs that are central to the concept of discounting. Unhealthy behaviors also typically have a delayed effect on health, such that one might not immediately experience loss of health or functioning. Indeed, the immediate rewards of the behavior often are so strong that they overpower the risk of future negative outcomes . This has led researchers to propose that unhealthy choices may be related to an individual’s temporal discount rate, or the degree to which they value present rewards versus future outcomes.

The second visit was used for this cross-sectional analysis because questions about past 48-hour drug use were added to the questionnaire starting with that visit; thus, it was the first available time point for comparison and validation of self-reported use and urine testing. Women were asked about type of ATS use ; frequency and route of use since their last visit; number of days of use in the past month; and use in the past five days, with specific questions including “today,” “yesterday,” and “two,” “three,” “four,” and “five” days ago. Urine toxicology testing was conducted to qualitatively screen for recent ATS, opiate, and cannabis use. Women were asked to void into prelabeled sterile collection cups in a private lavatory; the specimens were passed through a private window to the on site laboratory for testing. The test included four strips, which yielded positive results for amphetamine and/or methamphetamine if either exceeded 1000 ng/mL; for opi ates if morphine in urine exceeded 2000 ng/mL; and for cannabis if the concentration 11-nor-Δ9-tetrahydrocanna binol-9-carboxylic acid exceeded 50 ng/mL. A positive amphetamine or methamphetamine screen was considered indicative of ATS use in the past 48 hours.Overall, results suggest high validity of self-reported ATS use among FSW when compared with urine toxicology screening. In almost all cases where women reported no ATS use in the past two days, negative urinalysis corroborated self-report. The majority of participants with positive urine tests reported ATS use during the same detection period. However, only 81% of participants who reported ATS use had positive urine tests.

One possible explanation of the low positive predictive value is that women in the study actually used ATS but in such a small quantity that the urine tests failed to detect it. Since ATS is illegal and its purity is unknown,cannabis drying trays some women could have used the less pure forms of ATS, which may not have been potent enough to be detected by urine testing. The NACD has reported that, among 151 pill samples of ATS tested, 25% of the samples had purities below 10%. Al though the proportion of women self-reporting ATS use was slightly higher than the urine test results , these rates are not inconsistent and are near perfect. Other studies have documented higher self reported use compared with urinalysis results, leading to recommendations that multiple methods be used to assess drug use exposures. The high concordance between self-report and test results are suggestive of high internal validity of self-report of ATS in our study population. Some differences were seen in the performance of self report compared with urinalysis when examined by age, HIV status, and sex-work setting. Most notably, there was lower precision between positive self-report and urinalysis tests among younger women and among women working in entertainment or service settings. The lower PPV may relate to lower prevalence of ATS use among these subgroups. We have previously shown that women working in entertainment and service sec tors in Cambodia are less likely to use ATS than women working in brothels. Prevalence of ATS among younger women is slightly lower but not significantly so. Importantly, specificity was high overall, with subgroup analyses showing valid self-report of no ATS use in our sample. This is import ant for further studies of ATS exposure in this population, for public health surveillance, and potentially for intervention and implementation of drug prevention programs. The high validity of self-report may be associated with several factors. The women in this study were not reluctant to answer the survey questions or to take the test, as indicated by the high participation rate. This could be due, at least in part, to the fact that the participants were recruited by a known and trusted community-based agent, our collaborating partner , and were comfortable with the staff involved in data collection.

Moreover, the women in the study knew that providing truthful responses about their drug use would not result in negative consequences or punitive action. This study had several limitations. Due to the small sample size and non-systematic sampling, our estimates lack precision and results may not be representative of all young women engaged in sex work in Phnom Penh or Cambodia. This is particularly true for the stratified analyses, where cell sizes were very small in some cases and prevalence of ATS was lower. Poor recall may have contributed to some discordance, including the relatively low PPV found overall. Approximately one in five women incorrectly reported recent ATS use. Recall of ATS use could be affected by recent ATS use and its side effects, including sleep deprivation and confusion. It is unknown if this would result in over- or underestimating of self-report. Since women were all informed about the testing as part of the informed consent process and ongoing study-procedure education, some women may have over reported use for the periods about which they were queried. Moreover, urine toxicology tests are not perfectly accurate. Although the urinalysis test is widely accepted as a “gold standard” for substance use validation, exclusive reliance on such results does not necessarily improve valid ity because of problems with false negatives. Many studies comparing self-report, urine, and hair testing results suggest that hair analyses provide higher rates of recent drug use than can be detected by either urine tests or self reports. Various authors suggest multi-modal testing for the most accurate results. Despite these limitations, our results suggest a high level of concordance between self-reported ATS use and urine toxicology results in this group of women. Results indicate high prevalence of ATS use among FSW, who are also at elevated risk of HIV and other sexually transmit ted infections. There are few, if any, community-based options for ATS users in Cambodia. The finding that self report, especially specificity, is valid among young FSW is important because of potential utility in surveillance as well as drug prevention and intervention programs in this population.

There is a significant need for evidence-based prevention and drug treatment resources in Cambodia, including potentially cognitive behavioral therapy, contingency management, and possibly new pharmacotherapies to reduce ATS use. The forthright self-reporting of drug use by women participating in this study shows that, in a safe and non-punitive setting, disclosure of accurate drug use is possible. These findings, which are consistent with other studies showing high validity of self-reported drug use, may also be relevant to other vulnerable populations in Cambodia reported to have high rates of ATS use and who may also be in need of interventions, including children, young adults,heavy duty propagation trays and men who have sex with men. Indeed, with escalating manufacture and use of ATS throughout Southeast and East Asia, and in consideration of the need for expanded surveillance of drug use to more accurately inform public health and policy responses, self reported use may be a reliable data collection method. For surveillance, research, and health-care settings, it is import ant that providers and others address drug-related health issues in a nondiscriminatory manner and without punitive consequences in order to accurately assess and effectively address health and safety issues in high-risk populations.The COVID-19 pandemic has created a pressing need for tools to combat the spread of misinformation. Since the pandemic affects the global community, there is a wide audience seeking information about the topic, whose safety is threatened by adversarial agents invested in spreading misinformation for political and economic reasons. Furthermore, due to the complexity of medical and public health issues, it is also difficult to be completely accurate and factual, leading to disagreements that get exacerbated with misinformation. This difficulty is compounded by the rapid evolution of knowledge regarding the disease. As researchers learn more about the virus, statements that seemed true may turn out to be false, and vice versa. Detecting this spread of pandemic-related misinformation, thus, has become a critical problem, receiving significant attention from government and public health organizations , social media platforms , and news agencies . In this paper, we introduce the COVIDLIES dataset for misconception detection on Twitter. COVIDLIES comprises of 62 common misconceptions about COVID-19 along with 6591 related tweets, identified and annotated by researchers from the UCI School of Medicine. Given a tweet, we annotate whether any of the known misconceptions, curated by the researchers, are expressed by the tweet. If they are not, then they are considered No Stance. If they are, we further identify whether the tweet propagates the misconception or is informative by contradicting it . Example misconception-tweet pairs for each label are illustrated in Figure 1.1. We provide benchmark results for each of these sub-tasks. First, we evaluate text similarity models on their ability to detect whether a tweet is relevant to a given misconception . Next we evaluate zero-shot and few-shot models for the ability to detect the stance of each towards retrieved misconceptions For the zero-shot setting we train on the pre-existing tasks of natural language inference and fact verification. For the few-shot setting we train on COVID-19 Health Risk Assessment task combined with a dataset of COVID-19 tweet-misconception pairs annotated for stance by researchers from the UCI School of Medicine.

Our results show that existing models struggle at both tasks , however improve considerably after domain adaptation ; 74.3 Hits@1 for retrieval and 46.3 macro F1 on zero-shot stance detection. We see some further improvement on stance detection when using the few-shot setting . While our initial results using domain adaptation and few-shot learning are encouraging, they leave much room for improvement. There is still much work that needs to be done before NLP systems can be seriously considered for combating COVID-19-related misinformation, and we hope COVIDLIES will be useful to help researchers understand when such systems are ready to be deployed. Due to limited availability of labeled data specific to this problem, we expect that models will need to be supervised on other, related tasks. For misconception retrieval, for example, relevant misconceptions can be ranked by measuring the semantic similarity between the tweet and each misconception, e.g., using cosine similarity between average word embeddings or more recent transformer-based methods such as BERTSCORE . For the stance detection sub-task we perform zero-shot learning by training on the pre-existing tasks of natural language inference and fact verification. We also perform few-shot learning by training on COVID-19 Health Risk Assessment task combined with a dataset of COVID-19 tweet-misconception pairs annotated for stance by researchers from the UCI School of Medicine. The current dataset contains 62 misconceptions, along with 6591 annotated tweet-misconception pairs. Statistics about the distribution of labels are provided in Table 3.2. The distribution is heavily skewed, containing mostly No Stance tweets, and a higher proportion of Agree tweets than Disagree. The heavy skew towards No Stance tweets could be a due to the dataset construction methodology, specifically using BERTSCORE without fine-tuning to retrieve tweets per misconception. As we show in 4.0.2, domain adaptation significantly improves misconception matching. Further, presence of more Agree than Disagree tweets could be due to a bias in BERTSCORE towards scoring agreement higher. Top misconceptions for each class are shown in Table 3.1. We only consider misconceptions with more than 80 annotated tweets, and rank the misconceptions for each class by the proportion of tweets that are annotated as that class. We present the top three misconceptions for each class with their corresponding percentage. There are misconceptions for which 100% of the paired annotated tweets express No Stance, which we do not see for the other two classes. We notice there is a misconception with nearly 50% of paired tweets labeled as Agree; and the highest proportion of Disagree labeled tweets found for any misconception in the Disagree class was 51%. COVIDLIES, however, is an evolving dataset; annotation is not yet complete for all 62 Wikipedia misconceptions matched to 100 tweets using BERTSCORE, and we are continually identifying additional misconceptions, as well as collecting more recent tweets for annotation. Further, we will gather more relevant tweets by using domain-adapted retrieval models, which, as we will see in the next section, considerably outperform the current approach to retrieval, BERTSCORE. We obtain vectorized representations of tweets and misconceptions using word embeddings.

The outcome of interest was a first episode of suicidality, defined as responding ‘yes’ to having thought about or attempted suicide in the last 6months. Time fixed variables examined included age , gender/sexual minority , indigenous ancestry , being an immigrant/migrant worker , education and physical and/or sexual childhood abuse . Variables treated as time-updated covariates based on biannual follow-up data included HIV/STI serostatus, recent homelessness, recent physical and/or sexual violence by clients, recent police harassment and/or arrest and primary place to solicit clients in the last 6 months. Time-updated injection and non-injection drug use variables included lifetime use of psychedelics , cannabis, pharmaceutical opioids , crack, cocaine, crystal methamphetamine and heroin. Using extended Cox regression, unadjusted hazard ratios and adjusted hazard ratios and 95% CI were calculated to identify predictors of suicidality. Psyche delic drug use, hypothesised a priori to be a predictor of suicidality, and variables that were significantly correlated with the outcome at the p<0.10level in bivariate analyses were subsequently fitted into a multi-variable Cox model. Backward model selection was used to determine the final multi-variable model with the best overall fit, as indicated by the lowest Akaike information criterion value. A complete case analysis was used, where observations with missing data were excluded from analyses, and participants who were lost to follow-up were right censored at their most recent study visit. All statistical analyses were performed using SAS software V.9.4. Two-sided p values are reported.This study demonstrated that among marginalised women, many of whom are street-involved and experience a disproportionate burden of violence, trauma, psycho logical distress and suicide, naturalistic psychedelic drug use predicted a significantly reduced hazard for suicidality.

Crystal methamphetamine use and childhood abuse predisposed women to suicidality corresponding to more than a threefold increased hazard. Suicidality was highly prevalent,cannabis indoor grow system with almost half of women reporting lifetime suicidality at baseline, and 11% reporting a first episode of suicidality in the last 6months during follow-up. Few studies have longitudinally examined predictors of suicidality among marginalised sex workers, and of the avail able data, most are cross-sectional and/or conducted in lower-income and middle-income settings.The present study, based on a community-based, prospective cohort of marginalised women, adds to a growing body of literature documenting the protective and therapeutic potentials of psychedelic substances.Data were self-reported, and questions pertaining to events that occurred in the past may be subject to recall bias. Variables examined included sensitive and highly stigmatised topics such as childhood trauma, violence and illicit drug use, which introduce the potential for social desirability and reporting bias. However, the likelihood of these biases is reduced by the community-based nature of the study. While lifetime psychedelic drug use was found to reduce the hazard of suicidality, the associations uncovered in this analysis cannot be determined as causal. However, the use of Cox regression analysis in this study was able to determine a temporal relationship between psychedelic use and suicidality. The sample was restricted to participants who had not experienced suicidal ideation or attempt at baseline, ensuring that psychedelic use preceded suicidality and thus providing evidence that psychedelics have a protective effect.

Due to a lack of statistical power, analyses evaluating the effects of more nuanced indicators of psychedelic use , as well as separate analyses for ideation and attempt outcomes, were not feasible. Further examination of these variables would certainly be interesting and important in future analyses with additional data from follow-up questionnaires. Suicidality is influenced by complex individual, interpersonal and structural variables, and not all potential confounding variables could be controlled for in this study. For example, women who use psychedelics may also possess some characteristic associated with a reduced likelihood of being suicidal , which were not examined in this study. Despite the relative safety of psychedelic drug use as evidenced from the clinical and non-clinical literature,it should be noted that the use of psychedelics, particularly with unknown doses sourced from unregulated street markets, is not without risk, highlighting the importance of set and setting; the doses and contexts of psychedelic use among women in the present study could not be determined. The SE for the association between psychedelic use and suicidality was somewhat high, resulting in a wider CI. However, a large and significant protective effect was demonstrated in multi-variable analysis, despite the relatively small number of events for suicidality over follow-up. With a larger sample size, we would expect a narrower CI for this association. The study population included women from a wide-ranging representation of sex work environments, yet findings may not be fully generalisable to sex workers in other settings. The mapping of working areas and time–location sampling helped to ensure a representative sample and to minimise selection bias.

To the best of our knowledge, this study is the first to longitudinally investigate associations with suicidality among marginalised and street-involved sex workers in North America and builds on prior cross-sectional research highlighting significantly elevated rates of suicidality and unmet mental health needs in this population. For example, a study conducted in Sydney, Australia demonstrated significant links between depression, trauma, and suicidality, where an estimated 42% of street-based female sex workers reported attempting suicide and 74% reported lifetime suicidal ideation.While estimates of mental illness vary significantly across sex work settings, up to three-quarters of street-involved and drug-involved sex workers in a US study reported severe depression, anxiety or PTSD.Notably, our study demonstrated a lower risk of suicidality among women working indoors in bivariate analysis , lending support to the critical role of safer workplace environments in mitigating risk. In studies conducted in Asia, recent suicide attempts ranged from 19% among sex workers in Goa, India to 38% among sex workers in China,many of whom work in marginalised settings with few workplace protections. Transgender women involved in sex work, a sub-population experiencing significant psychosocial vulnerability and discrimination, report notably further elevated rates of suicidality: three-quarters of participants in San Francisco reported suicide ideation, of whom 64% attempted suicide.The global evidence is unequiv ocal that in settings where sex work is criminalised, sex workers are unable to access essential social, health and legal protections , highlighting the need for structural and community-led interventions to improve health and human rights.A structural approach to mitigating suicidality risk requires a reform of laws and policies that perpetuate stigma, discrimination,cannabis equipment violence and unequal access to health and social supports among sex workers. Increased support for community-driven interventions that are gender and culturally appropriate are urgently needed, and any clinical treatmentutilising psychedelics must be developed alongside sex worker-led interventions and community empowerment. Our findings extend on research on associations between lifetime use of illicit drugs and increased risk for suicidality: in bivariate analysis, all classes of illicit drugs were demonstrated to increase the hazard of suicidality with the exception of psychedelics. In multivariable analysis, psychedelics were independently associated with a 60% reduced hazard for suicidality, contributing to emergent evidence on the potential of psychedelics to mitigate risks for suicide. Among the various scientific studies examining the potential benefits of psychedelic drug use, a recent and large population study conducted among adult respondents in the USA demonstrated that psychedelics are associated with reduced psychological distress and suicidality.A recent open-label trial conducted in the UK demonstrated the safety and efficacy of psilocybin for treating major depression,and another open-label trial in Brazil found rapid and sustained antidepressant effects from the Amazonian psychedelic brew ayahuasca administered in a clinical setting.The ways in which psychedelics may alleviate suffering associated with some mental illness is undoubtedly a complex phenomenon. It has been hypothesised that psychedelics modify neurobiological processes that may be involved in suicidality by down regulating 5-HT2A serotonin receptors, as increased binding of this receptor has been implicated in major depression and suicide.Further more, there is evidence that psychedelics alter neural network connectivity and enhance recall of autobiograph ical memories, which may facilitate positive reprocessing of trauma.Recent randomised, placebo-controlled, crossover studies found that psilocybin and LSD were associated with increased positive mood and psychological well-being, supporting other work demonstrating the antidepressive/ anxiolytic effects of psychedelics.

The potential of psychedelics to elicit ‘mystical-type’ experiences, with profound and sustained positive changes in attitudes and mood, may play a key role in addiction treatment interventions.For example, psilocybin-assisted psychotherapy demonstrated high success in smoking cessation outcomes at 6months follow-up , and mystical experiences generated from the psilocybin sessions were significantly correlated with elevated ratings of personal meaningfulness, well-being and life satisfaction.Randomised control trials in the USA and Switzerland have demonstrated significant long term improvements among patients with treatment-resistant PTSD following MDMA-assisted psychotherapy,and further research is continuing in an international multisite phase t3 clinical trial. Marginalised and street-based sex workers experience complex and synergistic effects between trauma, lack of workplace safety and mental health/substance use comorbidities that elevate risk of suicidality. Marginal ised women and sex workers who use drugs report high rates of childhood abuse,which is associated with an increased likelihood of experiencing subsequent physical or sexual violence, as well as initiating injection drug use.For those suffering from emotional trauma stemming from violence, including indirect violence , there may be a proclivity to use drugs for self-medication.Violence and sexual coercion have been found to be significantly associated with suicidality among sex worker populations in China and India.As demonstrated in this study, having an early traumatic life event is a key risk factor for suicide among sex workers, a high proportion of whom are Indigenous, and experiencing historical trauma can have harmful intergenerational impacts.Given that historical experiences of violence and trauma denote significant risk for suicide, there is an urgent need to provide integrated, trauma-informed intervention services for sex workers and other marginalised populations. Currently available interventions and pharmaco logical treatments for suicidality show limited efficacy, and concerted efforts should be made to increase access to evidence-based treatments and to explore alternative approaches to improving mental health and well-being. Emerging research and evidence show positive outcomes with psychedelic-assisted treatments, which have demon strated an excellent record of safety with few to no serious adverse effects reported.This study suggests psychedelic substances may hold promise as useful tools in addressing mental health issues and remediating risks for psychological distress and suicide.The increasing spread of marijuana use, especially among adolescents and young adults , has heightened societal awareness of the risks associated with this drug and has highlighted the need to fully understand its mechanism of action. Basic research has shown that D9 -tetrahydrocannabinol , the main active constituent of marijuana, produces its effects by combining with selective receptors present on the membrane of cells in the brain, the vasculature and the immune system . Research has also revealed that a group of lipid-derived substances produced by the body engages these receptors and participates in bio logical processes as diverse as painperception, memory formationand blood pressure regulation. This knowledge has allowed researchers to interpret the pharmacological properties of marijuana, but remains inadequate to the task of developing strategies for the medicinal management of marijuana dependence. No such strategies exist at present , despite the fact that pharmacotherapy—alone or in combination with behavioral therapy—is considered a primary treatment option for drug dependence when abuse prevention fails . Several basic questions, which are relevant to the pharmacotherapy of marijuana dependence, remain unanswered. For example, while it is clear that D9 -THC acts by hijacking the brain endocannabinoid system, its impact on the various components of this system—synthetic and catabolic enzymes, transporters, and receptors—is still largely undefined. Does D9 -THC produce rapid adaptive changes in neuronal endocannabinoid signaling, as recent evidence indicates ? And, if so, do such changes contribute to the pharmacological actions of the drug? Does prolonged exposure to D9 -THC cause stable alterations in endocannabinoid signaling? And, if so, do such alterations contribute to marijuana dependence and, most importantly, can they be safely reversed to restore normality? Answering these questions may not only help develop effective therapeutic strategies for marijuana dependence, but in light of the broad roles played by the endocannabinoid system in the control of brain reward processes , might also shed new light on fundamental mechanisms of drug addiction. To accomplish this task, it seems important to move forward in two convergent directions: the molecular characterization of endocannabinoid signaling, much of which is still uncharted; and the development of pharmacological agents that interfere with specific components of this system.

A possible explanation for increased FA could be the variety of neurogenic properties of nicotine. In addition to maintaining and reinforcing smoking behavior, nicotine is reported to have other properties, such as anxiolytic properties and learning and memory-enhancing properties. Despite the proposal that chronic nicotine exposure may ultimately bring no benefits on mood and cognition, nicotine per se is known to be a neuroprotective agent, and prevents arachidonic acid induced injury to neurons and apoptotic cell death. Also, previous studies have revealed that nicotine upregulates calcium binding proteins, increases the levels of intracellular calcium measured and stimulates nerve growth factor, which could also be neuroprotective. These previous reported neuropro tective effects could be consistent with increased FA from chronic cigarette smoking. However, increased FA in white matter of brain in chronic cigarette smokers may not be beneficial. For example, Hoeft et al reported that increased FA of right superior longitudinal fasciculus in Williams syndrome individuals was associated with deficits in visuospatial construction. Similarly, a study of attention deficit hyperactivity disorder also found a correlation between increased FA with deficits in cognitive function. Increased FA is also reported in euthymic bipolar patients. Furthermore, evidence from previous studies reveals that increased FA could be a marker of acute inflammatory processes affecting neural tissue, indicating greater inflammation or less myelination. Thus,grow tray stand our result of increased FA in white matter might be associated with inflammatory changes and axonal damage in fronto-parietal cortex in chronic cigarette smokers.

An alternate interpretation for increased FA in chronic cigarette smoking and some psychiatric disorders could be that they reflect the compensatory mechanisms and could be the result of increases in local white matter density. The higher FA found here is consistent with another study using DTI in 10 chronic cigarette smokers. However, we did not replicate their finding of increased FA in the body and whole corpus callosum in chronic cigarette smokers. Also, a recent study found that both prenatal exposure and adolescent exposure to tobacco smoke were associated with increased FA in anterior cortical white matter.Gazdzinski et al, examined the impact of smoking on alcohol-dependent individuals and found that the combination of cigarette smoking and alcohol dependence results in significantly larger volumes of temporal and frontal white matter; recently, they further confirmed the increased FA result in a abstinent smoking and non-smoking alcoholics study. However, Gons RA et al studied 503 small-vessel disease subjects aged between 50–85 years and found that cigarette smoking is associated with the reduction of FA in cerebral white matter. Age, use of medical drugs and co-morbid medical conditions may the leading cause of the inconsistent results. In our study, increased FA was found in parietal-frontal white matter in the chronic cigarette smokers relative to healthy non-smokers. This discrepancy might arise from sample differences, such as differences in ethnicity, levels of cigarette smoking , age and psychiatric comorbidity . Results of our study indicate that the maintenance of cigarette smoking might involve fronto-parietal circuitry. Scientific evidence indicaties that the fronto-parietal cortex is one of the crucial units that functionally connects interrelated brain regions. Dosenbach et al indicated that this fronto-parietal circuitry initiates and adjusts control. There is also evidence that there is a network of frontal and parietal areas, which shows significant interactions between changes to a particular stimulus dimension and the current focus of attention.

Findings from a previous study suggest that during nicotine withdrawal, functional integration of fronto-parietal networks is abnormal in cannabis users. Previous studies and our results may indicate altered connectivity within a cognitive network that is mediated by abnormal neurogenic functional activation in chronic nicotine exposure. In order to fully understand the mechanism of structural alteration in fronto-parietal cortex of chronic smoking, further studies using techniques such as adaptation or multi-voxel pattern analysis will be needed. A number of limitations to our study should be addressed. First of all, possible sex differences in the response to nicotine may exist. We did not evaluate sex differences because of the relatively small number of female participants, which is a limitation of the study, although we matched for the gender proportion between smokers and healthy non-smokers. Second, education level was significant ly higher in the nonsmoker group compared to the smoker group. However, when we explicitly explored the impact of education level on bilateral fronto-parietal white matter in the smoker group, we found no significant correlation . This suggests that our findings cannot simply be explained in terms of this variable. In conclusion, our DTI data further support the hypothesis that smokers and non-smokers differed in bilateral fronto-parietal white matter integrity. These findings support the hypothesis that chronic cigarette smoking involves alteration of fronto-parietal connectivity.The homeless population is aging . People born in the second half of the “baby‐boom” have an elevated risk of homelessness . Homeless adults develop aging‐related conditions, including functional impairment, earlier than individuals in the general population. For this reason, homeless adults aged 50 and older are considered “older” despite their relatively young age . The homeless population has a higher prevalence of mental health and substance use problems than the general population . Individuals experiencing homelessness report barriers to mental health services, due to lack of insurance coverage, high cost of care, and inability to identify sources of care . These barriers can prevent their using services to treat mental health and substance use problems, such as outpatient counseling, prescription medication, and community‐based substance use treatment.

Without these, homeless populations may experience more severe behavioral health problems and rely on acute care to address these chronic conditions. Homeless individuals have higher rates of Emergency Department use for mental health and substance use concerns , and are more likely to use psychiatric inpatient or ED services and less likely to use outpatient treatment than those who are housed . Homeless adults with substance use disorders face multiple barriers to engaging in substance use treatment. Competing needs , financial concerns, lack of knowledge about or connection to available services, and lack of insurance are barriers to substance use treatment among homeless adults . Older adults face additional barriers to mental health or substance use treatment due to cognitive and functional impairment, such as difficulty navigating and traveling to healthcare systems . However, there is little known about older adults experiencing homelessness. According to Gelberg and Anderson’s Behavioral Model for Vulnerable Populations, predisposing factors, enabling factors, and need,garden racks wholesale shape health care utilization . Although prior research has used this model for homeless populations, this work has not included older homeless adults . Little is known about the prevalence of mental health or substance use problems in older homeless adults, the level of unmet need for services, or the factors associated with that need. To understand the factors associated with unmet need for mental health and substance use treatment in older homeless adults, in a population‐based sample of homeless adults age 50 and older, we identified those with a need for mental health and substance use services. Then, we applied the Gelberg and Anderson model to examine predisposing and enabling factors associated with unmet need, which we defined as not receiving mental health and substance use treatment among participants with mental health or substance use problems .We defined having a need for mental health treatment by having a positive screen for depressive symptoms or post traumatic stress disorder symptoms or reporting symptoms of other mental health problems, including anxiety, hallucinations, thoughts of suicide, or attempted suicide in the past 6 months. To assess current depressive symptoms, we used the Center for Epidemiologic Studies Depression Scale , considering a score of ≥22 to be evidence of depressive symptoms . We evaluated current PTSD symptoms using the Primary Care PTSD Screen , which asks participants to report whether they experienced any of four symptoms in the previous month due to a past experience: nightmares, avoidance of situations that reminded them of it, hypervigilance, or emotional numbing to their surroundings . We considered a score of four to be consistent with PTSD symptoms. To assess additional mental health problems , we used questions from the National Survey of Homeless Assistance Providers and Clients , as adapted from the Addiction Severity Index  and considered a report of any of those symptoms to be evidence of other mental health problems. We considered anyone who met criteria for depressive symptoms, PTSD symptoms or other mental health problems to have a mental health need.Drawing on Gelberg and Anderson’s model, we examined factors associated with not having received mental health treatment among those with a mental health need . We included the factors listed above, which we identified a priori. In the model with unmet need for mental health services, we examined whether having an alcohol or drug use problem was associated with unmet need, considering them to be need factors . We conducted a separate analysis to examine factors associated with not having received substance use treatment amongst those with an identified need; we again used the Gelberg and Anderson model and used factors listed above, which we identified factors a priori. In the substance use model, we tested whether having depressive symptoms, PTSD symptoms, or additional mental health problems, conceptualized as need factors, were associated .

We used logistic regression in these analyses. To construct our models, we included only hypothesized variables with a bivariate p value of <0.20 in the full multivariate model. To define our reduced model, we conducted backward elimination, retaining independent variables with p ≤ .05. Due to a skip pattern error, we incorrectly assessed 33 individuals using the AUDIT. To correct for this, we used multiple imputation to estimate the relationship between the treatment variables and the total AUDIT scores. We conducted multiple imputation analysis in STATA 14.2 . We used SAS 9.4 to conduct our descriptive and logistic regression analyses. In a population‐based sample of older adults experiencing homelessness, we found a high prevalence of unmet need for mental health and substance use treatment. While the majority of participants had mental health and substance use problems, few received treatment. One‐third of those with mental health need received mental health care. Fewer than 13% of those with substance use need received substance use treatment. We identified predisposing and enabling factors associated with unmet treatment need. Adults aged 65 and over had a higher odds of unmet need for mental health treatment. Older adults are more likely to have competing demands, including higher physical health needs, which can interfere with receiving behavioral healthcare . Due to a shortage of geriatric psychiatrists and geriatric mental health care services, older adults may not have access to treatment when they seek care . The homeless population age 65 and older is expected to triple by the year 2020 . Thus, there is a need to design care that meets the needs of this growing, but underserved, population. We found that having a regular healthcare provider was associated with less unmet need. Having a regular provider can increase engagement because primary care providers may help identify needs and refer to care. In safety‐net systems, such as the ones in which our participants receive care, primary care providers may be the primary source of mental health treatment, by prescribing psychotropic medication. Primary care providers are responsible for an increasing proportion of prescriptions for psychotropic medication . In addition to prescribing medication for mental health conditions, primary care providers can refer patients to outpatient mental health counseling and treatment with specialist staff or providers. In some safety‐net settings, mental health services may be colocated with physical health services via collaborative care models.Collaborative care models can enhance information sharing and treatment plan collaboration and reduce barriers to care .CCMs are cost‐efficient and can increase the capacity of resource‐constrained settings to provide care for patients with complex needs . Federally Qualified Health Centers can bill for both a medical and mental health visit on the same day , and recent changes to FQHC payment codes allow billing for behavioral health care management services in addition to the FQHC billable visit. Pay‐for‐performance programs link public hospitals’ payments to care coordination and mental health treatment metrics .

Consistent with our second hypothesis, we found a novel interaction with age and HIV/Binge drinking group such that the HIV+/Binge+ group displayed a stronger negative relationship between age and three domain-specific neurocognitive outcomes compared to the HIV-/Binge- group. Importantly, the alcohol-related detriments to neurocognition appeared to be specific to binge drinking, as total 30-day alcohol consumption was not a significant independent predictor of any neurocognitive outcome in our statistical models. These findings suggest that recent, discrete episodes of heavy alcohol exposure relate to poorer brain function and highlight the need for interventions to reduce binge drinking behavior among PWH, especially older PWH, in order to promote cognitive health. The findings showing additive main effects of HIV and binge drinking are consistent with several other studies demonstrating additive, but not synergistic, effects of HIV and heavy alcohol use on neurocognitive functioning . In fact, there is only onestudy to our knowledge that has shown an interactive effect of HIV and heavy alcohol on neurocognition, specifically in the domains of motor and visuomotor speed . Our finding of HIV/Binge group differences in neurocognitive domains of processing speed, delayed recall, and working memory is also consistent with the frontostriatal and frontolimbic neural damage that has been observed in studies of adults with HIV and heavy alcohol use . As briefly discussed, there are a number of possible mechanisms underlying the relationship between heavy alcohol use and adverse neurocognitive outcomes in HIV, including those related to antiretroviral therapy ; possible pharmacokinetic interactions with alcohol . Recent research, however,rolling grow table has revealed neuroinflammatory and neuro-immunological effects as major pathways underlying the relationship between heavy alcohol use and neurobiological damage , with several of these neuroimmune pathways overlapping with effects from HIV .

Although these immunobiological underpinnings are still poorly understood in the context of comorbid HIV and heavy drinking, this represents an important line of research needed to develop potential targeted interventions for reducing the incidence and/or severity of neurocognitive impairment in this population. The current study also uniquely found that the negative relationship between age and neurocognitive functioning was steepest among the PWH who reported binge drinking in the last 30 days, particularly in the domains of learning, delayed recall, and motor skills. Our findings are consistent with what is known about the greater vulnerability to brain atrophy and neurocognitive deficits in older PWH and older adults who drink heavily . Furthermore, this result showing an age by HIV/Binge group interaction is also similar to findings from a previous study in which age was found to be a significant predictor of demographically-corrected episodic memory scores only among individuals with comorbid HIV and AUD . Speculation about accelerated aging or neurocognitive decline cannot be made from our data, as they are cross-sectional; however, this result does suggest that older adults are the most susceptible to adverse neuropsychological outcomes in the context of HIV and binge drinking. Notably, this result also held when restricting the maximum age range to 60 years old for all groups, indicating that HIV/ Binge group differences in delayed recall and motor skills emerge even in the earlier stages of older adulthood. Notably, findings from this report appear to be driven specifically by our binge drinking variable, as total 30-day alcohol consumption did not significantly predict any neurocognitive outcome above and beyond binge drinking. Although there are a dearth of studies examining the specific impact of binge drinking on neuropsychological outcomes compared to that of chronic drinking over a longer span of time, some evidence suggests that the repeated periods of high level of intoxication and withdrawal from binge drinking exacerbates the detrimental neurobiological effects of alcohol .

Future research is needed to examine chronicity of binge drinking and whether there may be a specific threshold associated with the greatest level of CNS risk. Still, given evidence that binge drinking may be at least as detrimental to the central nervous system as alcohol dependence, public safety measures that aim to reduce binge drinking behavior may have widespread benefits, especially among older PWH. While this study has strengths in novelty, use of a comprehensive neuropsychological battery, and clinical relevance, it also has several limitations. First, the HIV/Binge group-specific sample sizes were relatively small, particularly in Binge+ groups. Although this limited our ability to examine a full factorial three-way interaction between age, HIV status, and binge drinking status, we were still able to examine the novel age by HIV/Binge group interaction with adequate statistical power. Next, our assessment of binge drinking is based solely on self-report and may be subject to error by recall bias, memory difficulties, and/or social desirability bias; however, the majority of alcohol and substance use research relies on self-report of use. In addition, while binge drinking data specifically pertained to use within the last 30 days, we do not know exact amounts of time between participants’ last binge episode and their participation in the study, limiting our ability to comment on how recency relates to cognitive performance. Future research may benefit from the use of more objective measures of alcohol use in daily life to more accurately characterize alcohol use patterns . Finally, our exclusion of participants with current non-alcohol substance use disorders limits generalizability to others with binge drinking behavior and/or alcohol use disorder among whom polysubstance use is common. In summary, the current study demonstrated detrimental additive effects of HIV and binge drinking on neurocognitive functioning, and that older adults appear to be most vulnerable to these adverse effects particularly in the neurocognitive domains of learning, delayed recall, and motor skills. Our findings support the need for clinical screening for binge drinking behavior given that many adults who engage in binge drinking behavior do not meet criteria for an AUD, as well as psychoeducation and psychosocial interventions targeting the reduction of binge drinking among older PWH.

Additionally, given evidence that improvements in neurocognitive functioning may be possible after sustained sobriety following AUD recovery among HIV- populations , future work is needed to understand whether this may also be true among PWH who reduce or cease binge drinking behavior. Alcohol problems typically develop in late adolescence and early adulthood, though they can manifest at any time during adult life. Early age at first drink has been shown in many analyses to be a powerful predictor of an alcohol use disorder .Males are more likely than females to develop alcohol use disorders ,indoor plant table and this is true within families of alcohol-dependent probands as well as the general population . Recent data have shown that, in the US, African Americans are less likely to develop an AUD than European- Americans  though analysis over different age groups suggests that a different developmental course may characterize AUDs in African-Americans, with relatively later onset of disorders in comparison to EA groups . It must be borne in mind that these rates are a moving target and there is evidence for relative increases of AUD in women and AA subjects compared to EA males over recent years . There is also a known risk relationship between other psychiatric disorders and alcohol use disorders. Persons with a mood disorder have an increased lifetime risk for an alcohol use disorder, as compared with persons without mood disorders . The increased risk for a substance use disorder following onset of a mood disorder is perhaps most precisely demonstrated by Plana Ripoll et al. 2019, using a study of the Danish population that showed a cumulative risk of 20% for men and 10% for women for an SUD during the fifteen years following the onset of a mood disorder. This represents a hazard ratio of ~5 for a disorder severe enough to come to clinical attention. Adolescents with a mood disorder are at increased risk for onset of alcohol problems and vice versa . Mood disorder may be associated with the course of alcohol problems as well as onset . Scores on an internalizing scale were correlated with risk for alcohol and other drug use disorders in a prior analysis of the Collaborative Study on the Genetics of Alcoholism subjects . There is an extensive literature supporting the relationship of externalizing disorders to subsequent development of AUDs and this has formed the basis of certain typologies of AUD, including Types 1 and 2 and Types A and B . Type 2 subjects are characterized by high novelty seeking, low harm avoidance, and low reward dependence . They are more likely to be diagnosed with antisocial personality disorder and less likely to be able to abstain from alcohol. Type B subjects are more likely to have a history of childhood aggression and conduct disorder and less likely to have a sustained response to treatment in comparison to Type A subjects . More recent studies also emphasize the role of externalizing disorders, such as conduct disorder and attention deficit hyperactivity disorder in increasing the risk for alcohol problems . Cannabis and tobacco use are also associated with increased risk for concomitant alcohol problems . We studied a sample at risk for the development of alcohol use disorder on the basis of family history. Initial assessment was done on all subjects in the age range 12–21.

These subjects have been followed over time with assessments every two years for up to 10 years. The present report evaluates the relationship of comorbid externalizing and internalizing disorders to age of onset of an AUD in a group of adolescents/young adults at high risk for AUDs. We also compare the onset of two alcohol milestones in groups divided by AUD severity. We hypothesized that persons developing AUDs following the onset of externalizing and internalizing disorders would show earlier onset than those without those baseline disorders. We also hypothesized that more severe AUDs would show an earlier onset of alcohol-related developmental milestones such as age of first drink and age of first regular drinking. The present report is one of the first we are aware of that tracks the development of AUDs in the context of multiple comorbid disorders in a high risk group, and it shows that some subjects are at great risk for alcohol problems in very early adolescence. Our subjects were participants in the adolescent to young adult Prospective sample of COGA . The COGA study started in 1989 and families were recruited between 1989 and 1995. Each family was recruited through a proband with an alcohol use disorder , targeting successive admissions to treatment facilities. There was a family size requirement with the idea of prioritizing larger families. All first-degree relatives were interviewed and families were extended through affected subjects . The subjects in the present study were offspring of the proband . The response rate for recruitment was about 70% or more . More information about the COGA study may be found in Bucholz et al., 2017 and Reich et al., 1998. All offspring in the age range at the start of follow-up were included. Offspring reaching the age of 12 during the course of the study were also included. Subjects were interviewed at two-year intervals with the Semi-Structured Assessment for the Genetics of Alcoholism interview Bucholz et al., 1994. The mean age at first interview was 16.1 and the mean age at last interview 23.1 . Subjects had an average of 4.0 interviews . 50.9% were female, 64.9% were EA and 30.9% AA. Ethnicity was assigned based on genotypic data, or by self-report if genotypes were not available. Subjects were members of a case family or a comparison family . Non-drinkers were not excluded from the sample. The study was approved by The Indiana University Institutional Review Board . Written informed consent for the research was obtained from all participants in the study. All subjects in the study were invited to participate in interviews at two-year intervals. Detailed information on participation is provided in Bucholz et al., 2017. Information on all available interviews for each subject was combined in the present analysis with age of onset assigned according to the earliest description of psychopathology and a judgment of severity based on the time when the most symptoms were described. Every subject with at least one complete interview was included in the analysis.