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The present study was limited by the assessment of substance use and emotion

Although adolescents had two hours in the laboratory environment to acclimate to space and to rule out an arrival effect , there is a chance that adolescents who showed higher levels of salivary cortisol at baseline may have been stressed in anticipation of the TSST, in line with previous findings that adolescents with anticipatory reactivity may be at higher risk for substance use . An alternative possibility is that these youth tend to show chronically higher levels of cortisol output as well as dampened reactivity to the task, although this possibility seems somewhat unlikely given that there were no differences in cortisol across the recovery period. Associations between dampened cortisol responses and substance use only emerged for youth above the poverty line. This finding was particularly interesting given that this sample of adolescents was very low-income overall . We assessed differences by poverty status because youth living in poverty often experience additional stressors that can influence their risk for substance use. However, it is important to note that this sample is still low-income overall, such that results may not generalize to differences in socioeconomic status among wealthier adolescents. First, youth who experience relatively more adversity or more challenging home environments are more likely to show blunted cortisol responses to stress . Therefore, blunted cortisol reactivity to stress may be more consistently related to substance use among youth above the poverty line, whereas blunted responses relate to environmental factors among youth below the poverty line. Second, associations emerged only for alcohol and vaping nicotine,cannabis grow equipment which tend to be more commonly used among youth with higher family income . In this study, adolescents above the poverty line may have been more exposed to alcohol and vaping, specifically, compared to youth below the poverty line.

Importantly, irrespective of family poverty status, adolescents may still be able to access substances that they find at home. Third, poverty status may influence adolescents’ motivations for substance use; stress may relate to substance use for youth above the poverty line, whereas youth below the poverty line may turn to less costly means of stress relief or may also use substances for alternative reasons. For instance, adolescents with lower parental education engage in fewer pleasurable substance-free activities, and may aim to use substances to amplify positive emotions . High basal cortisol or dampened cortisol reactivity may be indicative of difficulties with emotion regulation , and difficulties with emotion regulation may more strongly relate to substance use for youth above the poverty line. Associations between stress responses and substance use may differ by levels of socioeconomic status, and it is important to note that the poverty rate was much higher in the present sample than in the county due to the inclusion criteria of the parent study. Therefore, findings may generalize to families who are lower on the distribution of income, but not to associations between income and substance use among more affluent families. Future research is needed to examine whether adolescents’ access to and motivation for substances can explain why associations between dampened cortisol reactivity to stress and alcohol use by age 14 and vaping by age 16 differ by poverty status, and whether similar associations are observed among affluent youth. In addition to HPA axis responses to stress, we found that dampened emotion reactivity to social-evaluative threat was related to alcohol, marijuana, and cigarette use, particularly among female adolescents. Substance use may have been related to dampened rather than exaggerated emotion responses to the TSST because of the nature of this laboratory stressor. Although modified to be culturally sensitive and to avoid eliciting undue distress , the TSST can be a particularly taxing stressor. This may have caused youth to disengage rather than actively cope with the task and thereby manifested in dampened stress reactivity . Engagement in strategies such as distraction has been related to emotional and behavioral difficulties specifically for youth who show blunted cortisol responses to social stress . Additionally, these youth have backgrounds of high adversity and life stress which may have contributed to dampened emotion responses.

Previous research has indicated that youth who experience adversity show reductions in activation of neural regions related to threat and emotion processing . Several associations between dampened emotion responses and substance use were unique to female adolescents, potentially related to sex differences in adolescents’ motivations for substance use . It is important to note that although emotion responses to stress were more related to substance use in female than in male adolescents, male adolescents tend to be at higher risk for earlier substance use . Our results suggest that stress responses may be particularly related to substance use and substance use initiation among female adolescents, although male adolescents may have different motivations that place them at higher risk for substance use more generally. Prior research has found that female adolescents are more motivated to use substances to reduce stress and negative emotion, whereas male adolescents are more motivated to use substances for social benefits , and that stress is more strongly related to substance use in female than in male adolescents . Future research should investigate the factors that contribute to male adolescents’ risk for substance use. Alcohol and marijuana use may have been more consistently related to emotion responses than cigarettes or vaping because alcohol and marijuana are the most commonly used substances during adolescence and are often used to reduce stress . Cigarette use may have only related to happiness reactivity but not sadness or anger reactivity because of the low prevalence of use in this sample, as cigarettes have declined in popularity over time especially among Latinx youth . Emotion reactivity may not have been related to vaping of nicotine because vaping is more frequently used for experimentation and taste rather than to influence stress and emotion . Further information on adolescents’ motivation for use may provide insight regarding the mechanisms relating substance use and emotion responses to stress. Finally, sadness and happiness reactivity were more consistently related to substance use than anger reactivity. Anger reactivity was only related to marijuana use by age 14 among female adolescents, and this association was not maintained after transforming the data to account for skew. Studies that examine whether anger reactivity and recovery relate to substance use can consider other paradigms or forms of stress that elicit a more robust change in anger.

Substances are commonly used to reduce sadness and stress and to increase positive emotion , which may explain why associations emerged between sadness and happiness reactivity, but not anger reactivity, and substance use. Although prior research has emphasized the role of negative emotions in motivation for substance use , dampened happiness reactivity was uniquely related to initiation of cigarette and marijuana use between ages 14 and 16 among female adolescents. We also found that female adolescents who used marijuana and cigarettes by age 16 reported lower levels of happiness at baseline than female adolescents who never used these substances by age 16, but no differences in other emotions. It is possible that these youth use substances to promote positive emotion,cannabis grow racks or that lower positive emotion reactivity may indicate lower reactivity to other positive daily activities and greater inclination to use substances. Positive emotion has received relatively less attention in the context of stress responses, but the present findings suggest that future studies incorporating social-evaluative threat would be well-positioned to examine how happiness and different dimensions of positive emotion relate to substance use in the context of stress. Further research is needed to understand how dampened positive emotion reactivity may confer risk for substance use in adolescence.Findings must be interpreted within the context of the study design. Results at age 14 may suggest that substance use can influence adolescents’ stress reactivity and ability to self regulate within the context of stress. In turn, stress reactivity at age 14 may relate to substance use at age 16 through various mechanisms, such as through greater inclination to use substances to relieve stress, greater risk-taking, or greater susceptibility to peer pressure, which should be explored in future studies. There were limitations in cortisol assessment. The present study lacked data regarding current use of anxiolytics and antidepressants, both of which could influence cortisol responses. Estimates of cortisol recovery may be affected because participants were debriefed shortly after completing the TSST. Whereas other protocols collect all saliva samples prior to debriefing, the TSST was highly distressing for many participants in this sample, and debriefing occurred earlier to ensure adolescents were not distressed for longer than necessary . This decision may have resulted in higher levels of recovery than would have been experienced otherwise. Although we utilized a social stressor given the high salience of social threats during adolescence, future studies can assess whether similar results are assessed with respect to nonsocial stressors . Also, due to the low number of assessments, we needed to anchor responses at the sample peak rather than at each participant’s peak. We could not use analytic techniques such as Landmark registration because we would be unable to assess recovery for a subset of participants who peaked at the fourth time point. Future studies should include multiple assessments of salivary cortisol throughout the recovery period so that this technique can be used.

Because adolescents reported whether they had ever used each substance at age 14 and again at age 16, items may assess experimentation, and it is possible that adolescents may have only used a substance once and never again . Frequency of use over the past month or past year may be a better indicator of adolescents’ substance use and risk for problems with substance use in adulthood, although these outcomes had limited variability in the current sample at these ages. Future studies with greater variability in frequency or with slightly older samples should examine how frequency of use is related to differences in the stress response. Furthermore, without items regarding the context of daily use, it is difficult to determine the mechanisms by which differences in stress reactivity relates to substance use. Another important limitation of the present study is that stress responses were measured only at age 14, such that we cannot assess the stability of responses at age 14 and age 16 and cannot determine whether stress responses at age 14 confer risk for substance use at age 16 over and above current concurrent stress responses at age 16. Additionally, only three discrete emotions were measured, and participants were not able to report how they felt at that moment during the TSST. Potentially by using a different stress paradigm or passive assessment tools, participants could report their emotion as they experienced the stressor rather than immediately afterward in order to limit bias due to retrospective report and maintain consistency across ratings. We also had multiple ratings of emotion across the recovery period, but only one measure of emotion prior to the TSST. Future studies should employ experimental paradigms that allow for incorporation of more assessments of emotion during the stress task and therefore enable better estimation of emotion reactivity to stress. Results could also potentially vary by analytic approach, and other approaches such as longitudinal structural equation modeling can be used. Given the design of this study, multilevel models allow for all available data to be included, while allowing for timing of individual assessments to vary across participants and allowing for random intercepts and random slopes of reactivity and recovery. Finally, analyses were tested in a primarily Mexican-origin sample of adolescents with high levels of adversity and poverty, who may be at heightened long-term risk for substance use. We studied youth with high substance use risk because of our interest in how stress responses relate to substance use, as has been done in previous studies . We anticipated that the stress responses may be more related to substance use among youth who experience more major negative life events and chronic daily stressors, as these youth may be more inclined to use substances as a means of decreasing negative emotion as opposed to other purposes such as increasing positive emotion compared to other populations . Therefore, although our results suggest dampened stress responses may predict substance use in this sample, effects may be weaker in other adolescent samples with less adversity.

It is clear that the down regulated genes had a higher expression in control organoids

Staining and single-cell RNA-seq analysis of cerebral organoids were used to show that the cerebral organoids we grew are models of the cortical section of the developing brain . Single-cell RNA-seq analysis was also used to evaluate the effects of METH treatment . Cerebral organoids contain cortical markers, neural stem cell markers, astrocyte markers, and proliferation markers which are also found in the developing brain, further supporting cerebral organoids as a model for the developing brain . The analysis of the single-cell RNA-seq data found that there were 10,135 cells from control organoids and 10,613 cells from METH treated organoids. These cells were clustered together using a clustering algorithm that groups cells with similar gene expression together in the same cluster. After the clustering algorithm was performed, these cells clustered into 16 distinct clusters, and the cells were plotted using the tSNE statistical method to visualize the clusters that are found . The clustering also shows that all clusters contain similar proportions of cells from both experimental groups, indicating that the data has been corrected for batch effects, a phenomenon in which cells cluster into groups based solely on their experimental condition . Cells should cluster based on their cell type rather than due to batch effects to decrease bias when comparisons between the experimental conditions are made. Furthermore, although we do see heterogeneity in the organoids, when clustered together we find that all organoids are expressed in each cell type,growing indoor cannabis which may suggest that the transcriptomes are conserved between the organoids.Known neural marker genes were used to identify the cell types of the distinct clusters, where clusters were labeled a specific cell type if they had a high expression of the cell type specific neural marker genes . The expression of these neural marker genes indicates that cerebral organoids contain most of the neural cells found in the developing brain.

These results demonstrate the neural progenitor cells, neurons, and glial cellular diversity within cerebral organoid models, thus showing that they contain neural cells found in the brain and may be used as a model for the developing brain.The next step in the analysis pipeline is to address organoid heterogeneity. Cerebral organoids are self-mapping and as a result, there is variability in each organoid. Thus, it is important to make sure that the results we see from comparing the drug treatments are due to the effects of the drugs and not just due to the organoid’s internal variability. In order to address this issue, we confirmed that our cell types are present in all of the organoids and that they represent fairly even cell counts per condition. Here are examples of three of our cell types and the percentage of cells from each organoid for each of the cell types . All of the organoids represent some proportion of our cell types. The percentages of each organoid represented vary and this is likely due to the fact that each organoid had different total cell counts. For example, the METH organoid M1 had a cell count of 811 vs another METH organoid had a cell count of 3602. We can see based on these numbers alone it is not possible to see a completely even representation of the organoids in each cell type because the total cell counts of the organoids themselves vary. Although the variability in our cell counts may still be an issue, when we compare overall gene expression, we compare groups of cells. We compare all the cells that were from METH treated organoids to all the cells that were from control organoids, which are more even cell counts, with 10,135 cells from control organoids and 10,613 cells from METH treated organoids.The changes in gene expression as a result of METH treatment were analyzed after determining the validity of our organoids as a model for the fetal brain. The top up regulated and down regulated genes as a result of METH treatment were found using Seurat integration analysis. There were only 48 down regulated genes, all of which are shown in Figure 3A. There were 89 up regulated genes and the top 50 of genes are shown in Figure 3B and these genes had a higher expression in METH treated organoids. The changes in expression can be clearly seen through the variations in colors, with yellow being up regulated and purple and light purple having a lower about of expression. These genes can be used to provide valuable insights into the pathways that are affected by METH treatment. Alone these genes do not serve much meaning, but pathway analysis can be used to translate these gene lists into biological insight.

Integration analysis comparing control and experimental organoids was used to show which pathways were affected as a result of METH treatment. Pathway analysis of the differentially expressed genes found to be up regulated as a result of METH treatment showed stress pathways were enriched . Furthermore, a total of 216 pathways were found to be up regulated , however, some notable ones include those related to immune response, inflammation, and apoptosis suggesting that there is neuroinflammation within our organoids . The pathways found to be down regulated by METH treatment, or with a lower expression in METH treated organoids, had primarily to do with development and neurogenesis suggesting that neural development is hindered . Next, we wanted to focus on the genes in specific pathways and examine their gene expression between the METH and control sets of data. Since some of the key pathways that were up regulated associated with apoptosis and stress, the next step was to focus on the specific genes found within these pathways and confirm their expression. When examining apoptotic genes, a subset of METH cells has greater expression of those genes in comparison to the control cells. METH is known to induce apoptosis via genes such as NUPR1, so these results are consistent with previous findings and suggest that METH may induce apoptosis in the developing brain as well. Furthermore, stress-related genes were also found to be up regulated as a result of METH treatment . These genes may lead to some of the neurotoxicity that is known to be associated with METH consumption. Furthermore, in the brain, astrocytes are responsible for maintaining homeostasis. The astrocyte clusters are clusters 1, 3, 6, and 7 and they all appear to have higher expression of the apoptotic and stress genes in comparison to the other cell types . Again, the characteristic side effects of METH consumption are present in the organoids, suggesting that METH may also have a detrimental effect on fetal brain development.Based on the expression of these immune response genes, we see the up regulation of immediate early response genes such as JUN, FOS, IER2, and B2M and A2M which are known to play a role in the immune system as they are part of pathways related to the immune system. In addition, we also see the up regulation of cytokines which include CXLCL8 . These results combined may show that the organoids are immunocompetent, and further suggests that METH treatment induces neuroinflammation within the organoids. In the brain, astrocytes have an immune function and can express MHC compatibility and act as a type of immune effector cells40. Again, we see that the astrocyte clusters 1, 3, 6, and 7 tend to have higher expression of these markers, especially clusters 1 and 3 . Since, we saw a greater expression of VIM, NES,indoor cannabis growing and GFAP it is possible that these astrocytes are also reactive, which may be further contributing to the neuroinflammation that may be occurring in our cerebral organoids. This further confirms that our labeling of astrocytes is accurate and our cerebral organoids can express a variety of brain cell types. The next analysis performed was looking at the effects of THC treatment on the cerebral organoids. This dataset consisted of 6 THC organoids and 5 control organoids for a total of 4421 THC organoid cells and 8455 control organoid cells. There is a clear discrepancy in the cell counts and as a result we took a slightly different approach in the analysis.

This was our attempt at bypassing the bias that we found in our datasets based on cell counts and ensure that the results that are not as skewed. After looking at the astrocyte and proliferative neural progenitor pathways up and down regulated by treatment, no major pathways were found to be up regulated. The proliferative neural progenitor pathways did show that after THC treatment, pathways related to gliogenesis were up regulated. When examining neurons, we decided to go further and identify neural sub-types in the brain to see if there were any changes in these sub-types caused by THC treatment. The brain contains a variety of neural sub-types including glutamatergic and GABAergic neurons. Moreover, investigating the effects of THC on the neural sub-types may provide new insights.The neuronal subset was clustered again and the markers for glutamatergic and GABAergic neurons were used to label the subsets 42. One cluster of cells, cluster 0 did not exhibit any of the known neural markers to a large degree. It did however express SOX11+ and MEIS2+ . Therefore, this cluster may potentially be a new neural cell type that has not previously been identified. After examining the enriched pathways determined by the gene lists, we found that glutamatergic neurons had pathways associated to generation of neurons up-regulated in the THC dataset, this was due to the expression of genes such NEUROD2 and NEUROD6 . When examining these genes closely, we can see that they are clearly expressed in THC glutamatergic neurons more heavily . The THC glutamatergic neurons also exhibit CNR1 or cannabinoid receptor 1 more heavily than control glutamatergic neurons which still express the markers GRIA, SNAP, and MAPT . The expression of NEUROD6 has been shown to be correlated with glutamatergic pyramidal fate and neurogenesis during embryogenesis. The overexpression of NEUROD6 in THC glutamatergic neurons may indicate that THC is leading to preferential differentiation into glutamatergic neurons and thereby altering glutamatergic neurons in the developing brain. Moreover, since the SOX2+ MEIS2+ cluster also expresses a similar phenotype to the glutamatergic neurons, it is possible that this cluster will preferentially differentiate to glutamatergic neurons. CB1 which is encoded CNR1 is typically shown to be decreased as a result of chronic THC exposure because THC acts as an antagonist for the receptor44. In our results, we see that CNR1 is up-regulated as a result of THC exposure in especially in glutamatergic neurons. At this time is not clear if overexpression of CNR1 will have a detrimental effect, but our data further suggests that THC may be altering glutamatergic neurons in the developing brain. The METH figures in the results section and the methods section for organoid generation are reprinted and paraphrased from Glial cell diversity and methamphetamine-induced neuroinflammation in human cerebral organoids as it appears in Mol Psychiatry , Dang, Jason; Tiwari, Shashi Kant; Agrawal, Kriti; Hui, Ashley; Qin, Yue; and Rana, Tariq. The thesis author was a primary investigator and author of this paper. The THC figures in the results section and the methods section are currently being prepared for submission for publication of the material. Dang, Jason; Tiwari, Shashi Kant; Agrawal, Kriti; and Rana, Tariq. The thesis author was a primary investigator and author of this paper.Cerebral organoids are a model for the developing brain3 . Single-cell RNA-seq analysis of control and METH treated organoids showed that organoids contain many of the major neural cell types found in the developing brain . We addressed organoid heterogeneity and found at all our organoids were present in each cluster at some percentage . Moreover, after single-cell RNA-seq differential gene expression was performed on the METH treated and control organoids, genes associated with neurogenesis and neuronal development were found to be down regulated in the METH treated organoids . These results suggest that the development of neurons in the brain and thus brain development as a whole may be hindered as a result of METH treatment. Furthermore, genes associated with inflammation, apoptosis, cytokines, and stress pathways were found to be a part of the 216 pathways up-regulated in METH treated organoids .

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The minimum amount of data for factor analyses was not satisfied, with a final sample size of 101 and 117 unique inflammatory analytes, there was less than 1 case per variable. Therefore, due to both low sample size and low levels of correlation between inflammatory variables EFA was not feasible for this sample. Subsequent analyses were completed using the NAPLS2 15-analyte z-score index as well as the individual analytes previously identified to be meaningfully associated with childhood trauma and psychosis symptom severity in existing research. This study sought to examine the associations between childhood trauma, psychosis risk symptoms, functioning, and inflammatory analytes in a sample of 67 CHR subjects and 34 UCs, thus contributing to a growing body of literature examining the effect of early life adversity on later life outcomes in individuals at risk for psychosis and identifying associated biological mechanisms. More specifically, this study sought to examine whether inflammation mediates the relationship between childhood trauma and clinical outcomes in individuals at risk for psychosis. This is one of few studies to explore whether inflammatory analytes mediate the relationship between childhood trauma and psychosis risk symptoms or functioning in CHR subjects, providing important implications for clinical intervention in youth at risk for psychosisby helping to uncover biological mechanisms for therapeutic intervention. However, this is the first study to evaluate this hypothesis using an enhanced sample of CHR subjects. The first primary aim of this study was to confirm known group differences between CHR and UC subjects in experience of childhood trauma, psychosis risk symptoms, and functioning,vertical grow racking system as well as evaluate groups differences across inflammatory analytes known to be associated with childhood trauma. First, we hypothesized that CHR subjects would demonstrate higher levels of pro-inflammatory markers known to be associated with experience of childhood trauma as well as the 15-Analyte Index developed by Perkins et al. relative to UC subjects.

Interestingly, CHR individuals in this sample demonstrated lower levels of TNF-a as compared to UCs, which is inconsistent with research demonstrating significantly elevated baseline blood plasma levels of TNF-a, CRP, and IL-6 in CHR individuals who endorsed a history of trauma . Significant differences were not revealed for Cortisol, CRP, IL-6 or the 15-Analyte Index between UC and CHR groups. The non-significant findings of differences in the 15-Analyte Index is attributable to the index being derived to discriminate between subjects who progress to psychosis, versus those that do not, and unaffected individuals, thus grouping the CHR subjects together resulted in non-significant differences between CHR and UC groups. Further, TNF-a is a pro-inflammatory cytokine, and thus, is involved in the initiation and aggravation of inflammatory responses, including cell apotosis. Interestingly, the biology of TNF in the brain allows for it to both protect neurons, as well as initiate their destruction through different protein activation processes . Although we are unable to evaluate this type of process in the current dataset, the observed decreased levels of TNF-a between CHR and UC subjects may relate to a meaningful narrative of complex inflammatory activation and suppression processes associated with enduring effects of childhood trauma such as increased stress reactivity in individuals at risk for psychosis . For example, Jeffries et al. reports that as compared to CHR-NC, CHR subjects who convert to psychosis demonstrate a striking loss of complexity in analyte correlation networks that could be prognostic, indicating that network imbalance in pro-inflammatory suppression and activation processes is an important feature of in understanding progression to psychosis. Second, we hypothesized that CHR subjects would demonstrate significantly higher incidence of childhood trauma, greater severity of psychosis risk symptoms, as well as lower global, social, and role functioning as compared to UC subjects. Consistent with our hypothesis, this sub-sample of CHR participants demonstrated significantly higher overall psychosis risk symptoms severity, as measured by the SOPS, and lower functioning on the GAF, GFS, and GFR as compared to UC subjects.

By definition, CHR individuals experience more psychosis risk symptoms and lower functioning as compared to unaffected individuals . Thus, the findings that CHR subjects in this sample demonstrated higher psychosis-risk symptoms and lower functioning is to be expected. More importantly, as compared to UC, CHR subjects in this sample demonstrated significantly higher total unique trauma, as well as higher incidence of trauma on most individual trauma sub-types, including, psychological bullying, physical bullying, emotional neglect, psychological abuse, and physical abuse. Three-fourths of CHR subjects in this sample reported history of childhood trauma, which is consistent with previous reports that prevalence of childhood trauma in individuals at risk for psychosis may be up to 90% ; however, this proportion is higher than larger sample from which this data was derived with approximately 60% of all CHR subjects reporting history of trauma. Thus, results from this study replicate previously demonstrated findings from Addington et al. , that CHR subjects experienced greater total number of unique trauma and bullying than UC subjects; however, this sub-sample of participants also demonstrates significant differences in emotional neglect, psychological abuse, and physical abuse, which was not demonstrated in the larger sample. Although only CHR subjects demonstrated a history of sexual abuse, the group differences between CHR and UC subjects was not significant. We can hypothesize that since the current sample of CHR subjects is enriched with a higher proportion of individuals who are known to have converted to psychosis , that increased childhood trauma is associated with poorer clinical outcomes in this CHR sample, which was further explored in Aim 4.

Finally, we hypothesized that CHR subjects who experienced history of childhood trauma would demonstrate higher levels of pro-inflammatory markers known to be associated with experience of childhood trauma as well as the 15-Analyte Index developed by Perkins et al , higher levels of baseline psychosis symptom severity, and lower baseline global/social/role functioning relative to CHR subjects with no history of childhood trauma and that these differences would vary by trauma sub-type. Inconsistent with our hypothesis, no differences were observed between CHRTrauma and CHRNoTrauma subjects in levels of the 15-Analyte Index, Cortisol, CRP, TNF-a, or IL-6. However, when analyzing groups by sub-type of trauma, it was revealed that CHR individuals who endorsed psychological bullying, physical abuse,vertical growing cannabis and sexual trauma also demonstrated higher total incidence of trauma as compared to CHR subjects that did not endorse one of those sub-types of trauma. Further, CHRTrauma subjects who endorsed a history of psychological bullying demonstrated significantly lower Cortisol than CHRTrauma individuals with no history of psychological bullying. While blunted morning salivary Cortisol response in has been observed in first episode psychosis subjects who experienced a higher incidence of childhood trauma , the opposite effect has been seen with blood based Cortisol. In this sample, higher levels of blood based markers of Cortisol were associated with conversion to psychosis in this sample and added as one of the 15-analytes in the Perkins et al. index. Further, reported that higher incidence of psychological bullying was associated with poorer global role functioning in CHR subjects. Thus, while we know increased levels of Cortisol are important to predicting conversion to psychosis and it is possible that the lower levels of Cortisol seen here as associated with higher levels of childhood trauma is associated with a different phenomenon . Put more simply, these results may indicate that the association or difference between blood-based Cortisol and childhood trauma is not clinically relevant for conversion to psychosis and that childhood trauma is independently predictive of clinical or functional outcomes, while higher levels of blood based Cortisol are predictive of conversion status.The second primary aim of this study was to identify highly correlated networks of inflammatory analytes using exploratory factory analysis. However, lack of correlation between inflammatory analytes and the relatively small sample size indicated that the sample was notsuitable for factor analysis. To our knowledge, only one study to date has used EFA to understand the correlation between inflammatory cytokines and severity of psychosis symptoms , demonstrating positive correlations between levels of cytokines and the Positive and Negative Symptoms Scale scores in subjects with schizophrenia. used unweighted co-expression network analyses to identify highly correlated networks of analytes in CHR and HC subjects, providing evidence of marked simplification of networks of correlated proteins that regulate tissue remodeling consistent with a hypothesis of blood-brain-barrier dysregulation in schizophrenia. Thus, the investigation of both clusters of inflammatory analytes and networks of inflammatory analytes is important to improving our understanding of high complex interplay between pro-inflammatory and anti-inflammatory processes in the development of psychosis and clinical outcomes. The third primary aim of this study was to determine the relationship between childhood trauma, psychosis risk symptom severity, and functioning in CHR. First, we hypothesized that there would be a significant positive relationship between childhood trauma, and psychosis risk symptom severity, as well as a significant negative relationship between childhood trauma and global/social/role functioning. Consistent with our hypothesis, partial correlation analyses revealed that total childhood trauma was associated with greater positive psychosis risk symptoms and lower global functioning .

Both findings are novel compared to Addington et al. ; however, we were unable to replicate the finding that total childhood trauma is associated with global role functioning in this smaller sub-sample. The association between childhood trauma and positive psychosis risk symptoms is consistent with existing research that higher incidence of trauma is associated with higher levels of positive symptoms in CHR . An extensive review on the relationship between childhood trauma and schizophrenia , concluded that childhood trauma is strongly related to symptoms of psychosis, specifically hallucinations and that the relationship may be dose-dependent. Second, we hypothesized that there would be a significant positive relationship between inflammation, total childhood trauma, psychosis risk symptom severity, and functioning, as well as a significant negative relationship between global/social/role functioning and inflammatory analytes in CHR subjects. Consistent with our hypothesis and replicating results from Perkins et al. , the 15-Analyte Index was positively correlated with all SOPS domains and negatively correlated with social, role, and global functioning in CHR subjects. However, a novel finding in this sample was revealed, a negative correlation between CRP and role functioning, indicating that higher levels of CRP are associated with lower scores on GFR. As GFR measures the level of impairment in academic, occupational, and homemaking roles, this is consistent with research linking blood levels of CRP to impaired cognitive performance in acute psychosis . Further, demonstrated that higher levels of CRP were associated with significantly worse working memory and inversely correlated with cortical thickness in individuals diagnosed with schizophrenia. Thus, the association between higher CRP and lower GFR may be a marker of impaired cognitive performance in CHR subjects. Inconsistent with our hypothesis, inflammatory analytes were not associated with total childhood trauma in CHR subjects. Previous research demonstrating the association between inflammation and childhood trauma and psychosis used a measure of childhood trauma that captured severity and chronicity of trauma occurrence. For example, demonstrated associations between TNF-a and severity of childhood trauma in first episode subjects using the CTQ which captures not only presence of trauma, but also severity and of the trauma experienced . Further, Hepgul et al. demonstrated associations between childhood trauma and CRP using The childhood experience of care and abuse scale: CECA.Q , which also measures severity of trauma. Thus, the measurement of childhood trauma used in this study did not capture severity or chronicity of the trauma experienced and thus were unable to be examined in the current study. Finally, we hypothesized that inflammation would partially mediate the relationship between childhood trauma and psychosis-risk symptom severity, as well as between childhood trauma and functioning in CHR youth. Using the information gathered from partial correlation analyses, we tested two mediation models. In Model 1, we explored whether the relationship between total childhood trauma and SOPSP was mediated by the 15-Analyte Index. In Model 2, we explored whether the relationship between total childhood trauma and GAF was mediated by the 15-Analyte Index. Inconsistent with our hypothesis, but consistent with the results from the partial correlation analyses, total childhood trauma and the 15-analyte index independently accounted for a significant proportion of variance in SOPS positive symptoms in Model 1. Further, total childhood trauma and the 15-analyte index independently accounted for a significant proportion of variance in GAF in Model 2.

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Even when the temporal stages of a psychiatric disorder cannot be so clearly delineated, it can be helpful to split diagnoses into endophenotypes that are associated with the disease of interest. For example, a recent GWAS of insomnia, which is a core symptom of multiple psychiatric disorders and a DSM criterion for MDD, identified 202 loci and showed strong genetic correlations with MDD and several other psychiatric conditions . Similarly, neuroticism, which shares a common genetic basis with MDD but can be more easily measured, could serve as a clinical stratifying factor for antidepressant actions. However, it can be difficult to determine what level of dissection is required; a recent study suggested that neuroticism reflected two genetic dimensions, one capturing depressed affect, and another capturing worry. Another example comes from several GWAS of impulsive personality, which has been proposed as an endophenotype for several psychiatric disorders including ADHD. The UPPS-P is a self-reported questionnaire that measures 5 different aspects of impulsive personality. Only two of those five were significantly associated with ADHD; in contrast, all three sub-scales of BIS-11, which is another impulsive personality questionnaire, were significantly associated with ADHD35. These examples illustrate how disease phenotypes can be dissected into component parts. Nonetheless, despite the original claim that endophenotypes would have a simpler genetic architecture, all studies conducted to date have shown that both disease diagnoses and endophenotypes are highly polygenic. Once the traits that reflect domains of normal function have been measured in genotyped cohorts,vertical grow racking system it becomes possible to explore their empirical relationships with one another beyond those that are already defined by traditional psychiatric nosology .

Genomic SEM and related techniques are now being used in a number of such efforts. Luningham et al used genomic SEM to test multiple models of psychopathology among fourteen psychiatric disorders and related traits. They identified three factors , and an uncorrelated Neuro developmental Disorders factor. These factors showed distinct patterns of genetic correlations and accounted for substantial genetic variance. These empirically identified clusters may provide better targets for GWAS than individual disorders. In another example, Baselmans et al showed that it was possible to increase power by using Genomic SEM to integrate multiple traits into a measure of “well-being spectrum”. By aggregating data from different sources of correlated traits, they reached a sample size of over 2.3 million individuals, which allowed them to identify 304 independent signals associated with well-being; a similar analysis suggested a two factor model that distinguishes “lower end” and “higher end” well-being factors. In a third example, Thorp et al used Genomic SEM to identify two factors, which they referred to as “psychological” and “somatic” from the 9-item Patient Health Questionnaire . Recently, several related methods have been developed . Using RGWAS, Dahl et al55 proposed a stress subtype in MDD, and identified three novel sub-types of metabolic traits. Using BUHMBOX , Han et al found that seropositive and seronegative rheumatoid arthritis could be subdivided to form a new subgroup within seronegative-like cases. Conversely, they identified a genetic correlation between MDD and SCZ, but there was no evidence that this correlation was due to subgroup heterogeneity.Clumping has been used to test the hypothesis, originally suggested by twin studies, that psychiatric disorders share a single common genetic factor. One of the earliest studies to use GWAS data to test this hypothesis showed that SNPs associated with schizophrenia were also associated with bipolar disorder.

Specific genes have been identified that confer risk for multiple psychiatric disorders . Evidence that the risk for substance abuse is shared across multiple substances is also consistent with earlier results from twin studies showing both substance-specific and substance-independent genetic risk. An example of this genetic overlap is the gene CADM2, which has been associated several substances and risky behavior. Joint analysis of correlated traits may outperform that of single phenotypes and allows the possibility to disentangle genetic effects that are specific to each trait from those that capture a latent construct . Clumping can also lead to new splits. For example, Bansal et al used GWAS results from two correlated traits: schizophrenia and educational attainment to propose two distinct etiologies of schizophrenia, one that resembled bipolar disorder and was characterized by high education, and another that reflected a cognitive disorder and was independent of education. Studies like this one provide greater flexibility to explore the phenotypic space, which can lead to novel insights and challenge established nosologies.Throughout this perspective, we have alluded to GWAS producing novel biological insights; however GWAS have numerous limitations and do not themselves produce actionable new knowledge. The influence of locus on a phenotype may be due to a coding difference or a regulatory difference.Indeed, a recent meta-analysis indicated that among those with ED, the lifetime prevalence rate of a comorbid SUD was 21.9% . Tobacco, caffeine, and alcohol are reported as the most prevalent SUDs for individuals with EDs . Sedatives, cannabis, stimulants, and over-the-counter products such as laxatives, diuretics, and diet pills are also commonly abused . Research suggests that ED patients with co-occurring SUDs experience lower rates of treatment response, higher relapse rates, more severe medical complications, greater impairment, poorer long-term outcome, and are at higher risk of early mortality . Given the high-risk nature of individuals with co-occurring EDs and SUDs , and poor outcomes associated with their treatment, it is important to identify whether effective treatment interventions for this population.

A major barrier to identifying treatment targets for ED-SUD is the paucity of research comprehensively characterizing the treatment-seeking ED-SUD patient population. Below, we outline the existing literature characterizing ED-SUD and associated features.Separately, EDs and SUDs have the highest and second-highest mortality rates of all psychological disorders . Both EDs and SUDs often present with comorbid mood disorders, anxiety disorders, post traumatic stress disorder , and borderline personality disorder . Becker and Grilo found that among patients with binge eating disorder , those with both mood and substance use disorders had the most severe ED symptoms, and higher rates of personality disorders. In a retrospective chart review, Kirkpatrick et al. found that for adolescents with ED, those with comorbid SUD had higher rates of self-harm and purging, and had a higher BMI at intake. Finally, a small study of an inpatient sample showed that those with ED-SUD were more likely to be diagnosed with a Cluster B personality disorder compared with those with ED alone . ED Diagnosis. Several studies have investigated whether co-occurring SUD is more common in anorexia nervosa-restricting type , anorexia nervosabinge-purge type , or bulimia nervosa . Theoretically, it is believed that binge-purge behaviors are more closely linked to substance abuse, as there is evidence for an increased association between these behaviors and impulsivity and emotion regulation difficulties . One large study found that within ED patients, BN, and AN-BP patients had the highest prevalence of comorbid substance use, whereas AN-R participants generally had the lowest . Root et al. found that across eating disorder groups,vertical growing cannabis the BN and AN-BP groups were more likely to report alcohol abuse and diet pill use relative to the AN group, and the AN-BP group was more likely than the AN-R group to have alcohol abuse, use diet pills, stimulants, and engage in poly substance abuse. Along the same lines, Fouladi et al. found patients with BN used substances with higher frequencies compared to patients with ANR, BED, and EDNOS, and those with AN-BP were more likely to use substances than those with AN-R. Moreover, higher frequencies of binge eating and purging were associated with higher frequencies of substance use. Finally, a meta-analysis on this topic by Bahji et al. revealed that prevalence rates of SUD were significantly higher among individuals with binge-purge behaviors than those with only restrictive behaviors.Temperament and underlying emotion regulation difficulties serve as common risk and maintenance factors for EDs and SUDs. Recent research provides compelling support for theories of emotion regulation to explain the co-occurrence of disordered eating and substance abuse . Specifically, these theories posit that individuals engage in these maladaptive coping strategies to alleviate negative affect . In support of this, existing findings indicate that affective instability, impulsivity, negative urgency, and novelty seeking are common in individuals with EDs who engage in substance abuse .

For example, a study investigating temperament found that binge eating was associated with increased impulsivity and risky decision-making . Similarly, in a study of undergraduate men and women, researchers found that negative urgency, a component of emotion dysregulation that includes the tendency to act rashly when distressed, was significantly associated with problematic alcohol use and disordered eating . Finally, Loxton and Dawe found that adolescent girls who abused alcohol and engaged in disordered eating were more sensitive to reward than adolescent girls who did not engage in any of these behaviors. Overall, extant literature highlights the complex nature of ED-SUD presentations. Thus, traditional treatment programs have targeted EDs and SUDs sequentially. However, interest in integrated treatment approaches has grown , and research indicates that patients who do not receive integrated treatment have poorer treatment outcomes . Nevertheless, there is limited research on what such an integrated approach should optimally target, and there is no consensus in the field about the best treatment modality for the ED-SUD population. One potentially promising intervention for ED-SUD is Dialectical Behavior Therapy , which is a treatment based on an emotion regulation model . In DBT, psychoeducation on this model is provided, and patients are encouraged to accept and learn to tolerate their emotional experiences, while also learning alternative methods of coping with their emotions. DBT is a well-established treatment for individuals with multiple and severe psychological disorders , and has been adapted for use with EDs . Its further adaptation and testing for individuals with co-occurring SUDs and BPD support its use to target multiple problem areas in an integrated manner. Only one study has investigated the application of DBT for co-occurring EDs and substance use. Findings from this study are promising, suggesting that integrated DBT for EDSUD treatment is associated with decreased substance use severity and frequency, decreased emotional eating, and increased levels of confidence in ability to resist urges for substance use . Given the limited research on DBT for ED-SUD, a better understanding of factors associated with ED-SUD compared to ED or SUD alone may be helpful in identifying potential treatment targets to address both disorders simultaneously. The impetus for the current study was to add to this limited literature by reproducing previous research findings in a treatment-seeking ED population and discussing how these empirical findings can guide treatment recommendations for ED-SUD. Consequently, the present study examined differences between patients with EDs only to patients with ED-SUD on demographics, psychiatric comorbidity, and self-reported eating disorder and related psychopathology. Given previous research findings, we hypothesized that individuals with EDSUD would be more likely than ED only to engage in binge eating/purging, and to have a bulimic-spectrum eating disorder, BPD symptoms, higher rates of psychiatric comorbidities, self-harm, and suicidality, greater difficulties with emotion regulation, and more reward sensitivity.Participants with ED only and ED-SUD were compared on demographic variables, comorbidities, psychotropic medications, and self-report measures at treatment admission. Categorical variables were compared using chi-square analyses and continuous variables were compared using one-way analyses of variance. To control for multiple comparisons, the threshold for significance was set at p = .01. Values below the threshold of p < .05 are discussed as trends, given the exploratory nature of the analyses and limited data on this topic to date.The present study sought to describe differences between ED patients with and without a SUD at treatment admission. Results demonstrated that ED-SUD patients reported a greater number of comorbid psychiatric diagnoses and were more likely to be prescribed mood stabilizers. They also reported greater difficulty engaging in goal-directed activity, higher impulsivity, more limited access to emotion regulation strategies, and higher reward sensitivity. There were trend-level differences suggesting that individuals with ED-SUD were more likely to engage in objective binge episodes, be diagnosed with panic disorder and post traumatic stress disorder, and to report higher trait anxiety, global emotion dysregulation, and sensitivity to punishment.

We considered being unsheltered as indicative of the highest environmental exposure

Falls result from an interaction between an individual’s underlying vulnerabilities and their exposure to environmental conditions.People experiencing homelessness have a high prevalence of factors known to be associated with falls in the general population, including chronic diseases, functional impairment, alcohol and opioid use problems.Homeless older adults have high prevalence of other factors that could be associated with falls, such as substance use and heightened exposure to physical violence.People who are homeless live in a variety of environments, including homeless shelters and unsheltered spaces that expose them to environmental hazards and violence. In each of these settings, homeless individuals have limited control over their environment, especially when living in unsheltered environments. We examined the prevalence of and risk factors for falls in a longitudinal cohort of adults aged 50 and older who were homeless at study entry. We hypothesized that homeless adults would have a high prevalence of falls and high exposure to environmental hazards. We hypothesized that factors known to be associated with falls in the general population would be associated with falls in our cohort. We further hypothesized that several factors that are plausibly related, but have not been studied , would be associated. We conducted a 3-year prospective cohort study of 350 homeless adults aged 50 and older, the Health Outcomes in People Experiencing Homelessness in Older Middle agE study.We interviewed participants at baseline and every 6 months for three years; at each interview,vertical growing garden trained research staff administered a structured interview and conducted clinical assessments. The institutional review board of the University of California, San Francisco approved this study. The datasets we analyzed during the current study are available from the corresponding author on request.

Between July 2013 and June 2014, we recruited 350 adults age 50 or older who were homeless at study entry. We recruited from all local shelters open to older adults , all free and low-cost meal programs that served at least three meals a week , one recycling center, and areas where adults slept unsheltered in Oakland, California . To create a sample that best represented the target population, including the high number of people living unsheltered in Oakland, we randomly selected potential participants using sampling frames that included encampment sites, recycling centers, shelters, and meal programs.18 We describe our Methods in more detail elsewhere .Eligibility criteria included: homeless according to the Homeless Emergency Assistance and Rapid Transition to Housing Act definition that includes any person living unsheltered, staying in an emergency shelter, or facing eviction in the next 14 days, age 50 years or older, English-speaking, and able to provide informed consent as determined by a teach-back mechanism.Participants received $25 for the screening and enrollment interview, $5 for monthly check-ins, and $15 for follow-up interviews. Using modified questions from the National Health and Nutrition Examination Survey , we asked participants whether a healthcare provider told them they had: myocardial infarction, congestive heart failure, stroke, arthritis, diabetes, or chronic lung disease ; we included these as separate variables.If a participant reported a medical condition at any time point, we considered them to have that condition in subsequent visits. We assessed visual impairment using the Snellen test, and defined visual impairment as corrected visual acuity <20/100.We defined hearing impairment as self-reported difficulty hearing.To evaluate cognitive impairment, we used the Modified Mini-Mental State Examination . Those who scored below the 7th percentile or were unable to complete the assessment were defined as cognitively impaired.We asked participants about their ability to complete activities of daily living .

We defined an ADL impairment as reporting difficulty with bathing, transferring, toileting, dressing or eating.We assessed lower extremity function with the Short Physical Performance Battery test and classified those who scored ≤10 as having reduced physical performance.We assessed urinary incontinence in the past six months by asking participants whether they had “leaked urine, even a small amount.”We measured height and weight and calculated Body Mass Index , classifying a BMI ≥18 to <25 as normal weight, 25 to <30 as overweight, and ≥30 as obese.To assess exposure to environmental hazards at each visit, we used a residential follow-back calendar in which we asked participants to report each place they had stayed and number of nights in each setting during the prior six months.We defined an unsheltered environment as sleeping outdoors or any place not meant for human habitation . We categorized participants as having spent any nights versus no nights in unsheltered settings.In preliminary analyses, we evaluated nights unsheltered as a 3-level variable and as a 6-level variable . Neither alternative exhibited a dose-response effect. Therefore, we used a dichotomous measure of any nights unsheltered in our analysis. To identify risk factors for falls, we chose independent variables based on our hypotheses. We assessed bivariate associations between a priori independent variables and recent falls using generalized estimating equations . We built our multivariable model by including variables with bivariate Type 1 p-values <0.20. If a categorical variable had more than two levels, we included all levels in our multivariable model if any Type 1 p-value was p<0.20. We reduced the model using backwards elimination retaining variables with p-values <0.05 in our final multivariable model. We conducted our analysis in SAS 9.4 using complete case analysis and robust confidence intervals . In a sensitivity analysis, we assessed whether we had underestimated the probability of falls due to incomplete follow-up or mortality. We examined the prevalence of falls amongthose: 1) with complete follow-up, 2) who had died during follow-up, or 3) who had not died but had missed any study visits over the 36-month study period. We used GEE to examine whether those who had died or missed visits were more likely to have experienced a fall in the past 6 months than those with complete follow-up. We included participants with a minimum of two visits. We used weighted linear regression with a second order polynomial and zero intercept term to plot a trend line. In this longitudinal study of adults 50 and older who were homeless at study enrollment, we found a high prevalence of falls.

Despite a median age of 58 years, study participants reported a prevalence of falls higher than older adults with a mean age of 78 in the general population.3 Many participants fell repeatedly throughout the three-year study period; over a third of the cohort reported falls in at least half of their study visits. We found an association between falls and several factors known to increase fall risk within the general population, including older age, gender, functional impairment, urinary incontinence, use of an assistive device, and stroke. Our findings indicate that the increased risk for falls in homeless older adults results, in part, from a high prevalence of geriatric conditions and substance use known to increase fall risk.Some of these risk factors may be modifiable via physical and occupational therapy,vertical growing greenhouse although it is more difficult to intervene while someone is experiencing homelessness. As the average age of the homeless population continues to increase, the population will have increasing prevalence of geriatric risk factors.We identified novel risk factors: using marijuana, experiencing physical assault, and spending time unsheltered that contributed to the high fall prevalence in our population. Both opioid use and marijuana use were associated with increased odds of falling. Opioid use is associated with increased fall risk among older adults in the general population.However, despite research on marijuana use and injuries in community-dwelling older adults, little is known about how marijuana use impacts falls.Marijuana—like opioids—may increase falls by affecting the sensorium, inducing dizziness, confusion, and drowsiness.We found a high prevalence of marijuana use among study participants. People born in the study’s age cohort have had high prevalence of marijuana use their whole lives, including in older adulthood.As marijuana use among older adults increases, due to changes in legal status and cohort effects, there may be increased falls associated with its use. Experiencing physical assault is common among older adults who are homeless.Physical assault can increase fall risk directly , or indirectly, by causing injuries that enhance underlying individual vulnerabilities associated with falls.Future research should evaluate the role of marijuana use and physical assault in falls among housed older adults to determine whether these risk factors are unique to older adults experiencing homelessness. People who are unsheltered have increased exposure to unsafe environments, with minimal control. They may stay in isolated locations with uneven surfaces and physical barriers, such as abandoned buildings, under bridges, or along highways. Unsheltered environments lack lighting or protection against environmental hazards. Avoiding falls requires intact executive function and physical agility to be able to process external stimuli and modify movements to remain upright.For older adults with vulnerabilities—such as those common among homeless older adults—small external triggers may precipitate falls. Housed older adults are able to modify their behaviors to avoid high-risk environmental exposures that predispose them to falls. For example, they can decrease how often they walk outside on uneven surfaces or minimize their public transit use. In contrast, adults living in unsheltered settings have less ability to avoid high-risk environmental exposures.Our finding that non-Black race was associated with increased falls is consistent with research in housed adults.Homelessness is caused by an interaction between structural factors and individual risk factors. Because Black Americans face structural racism, Black Americans with less individual vulnerability are at risk for homelessness. While we adjusted for these conditions, there may be unmeasured confounders that we were unable to account for.Alcohol consumption, particularly heavy use, is prevalent among PWH with rising rates of consumption in older PWH . To date, most studies in older PWH have focused on the combined presence of heavy alcohol use and HIV disease as risk factors for mortality and the development of age-related, multi-system comorbidities . With respect to neurobehavioral health, there is evidence that heavy alcohol use compounds HIV-related neurotoxicity , thereby impairing higher-order neurocognitive abilities critical for daily functioning .

Despite the known adverse neurocognitive effects of heavy alcohol use among older PWH, it is poorly understood whether lower levels of alcohol use similarly increase risk for neurocognitive impairment or, conversely, confer a degree of neuroprotection as has been proposed in prior studies of HIV-seronegative adults . [Note: Definitions of light, moderate and heavy drinking have been arbitrarily characterized across the literature; therefore, we are using “low-risk” henceforth to represent less than heavy alcohol consumption] . The evidence supporting protective effects of alcohol, suggests an inverted J-shaped association between levels of alcohol consumed and risk for a multitude of diseases , such that there is a higher risk among heavy drinkers and abstainers compared to those with low-risk alcohol consumption . The existing literature examining the association between alcohol consumption and neurocognition among HIV- adults also suggests an inverted Jshaped association, such that low-risk alcohol consumption is associated with better neurocognition than alcohol abstinence, and heavy consumption is associated with the worst neurocognition compared to both no consumption and low-risk consumption . A longitudinal study using the UK Biobank found, among middle and older aged adults, a significant curvilinear association between alcohol consumption and neurocognition. Specifically, neurocognitive performance improved with increased alcohol use, up to one standard drink per day, at which point performance worsened . Results of studies examining this curvilinear association, however, have been inconsistent. Conflicting evidence suggests a positive linear association between neurocognition and alcohol consumption, rather than a curvilinear association . Previous literature suggests that neurocognitive deficits increase with heavier alcohol consumption among older adults . Furthermore, Parsons and Nixon suggest a potential threshold-effect, such that the deleterious effects of alcohol only occur after a specific threshold of consumption ; with heightened effects occurring at heavier levels of alcohol consumption . These inconsistent findings between a curvilinear, linear, and threshold association between alcohol consumption and neurocognition could result from confounding effects of other medical comorbidities, socioeconomic factors, and past alcohol use among current alcohol abstainers, that could contribute more strongly to neurocognitive deficits . The putative multi-system benefits of low-risk alcohol consumption in HIV- individuals have not been systematically investigated among PWH. Results of earlier studies suggest elevated rates of alcohol use among PWH while more recent reports show similar rates compared to the general population . The majority of alcohol-focused research among PWH has focused on the detrimental effects of heavy drinking or alcohol use disorders . For example, research has consistently shown combined detrimental effects of heavy drinking and HIV disease on neurocognitive function as well as gray and white matter integrity, with the worst outcomes among the heaviest drinkers .

An average T-score was then calculated for years when multiple informants completed the scales

The consistent link between common psychiatric problems and substance use has led researchers and practitioners to suggest that by intervening early in adolescence to treat psychiatric disorders, we could reduce substance use problems by late adolescence. However, two key questions need to be answered before we can conclude that intervening on psychiatric problems will be an effective strategy to reduce substance use in adolescence. First, do adolescents who exhibit an increase in their psychiatric problems exhibit a subsequent increase in their substance use? Longitudinal studies provide consistent evidence that youth with higher levels of psychiatric problems are more likely to engage in substance use during adolescence. Etiologic theories to explain this comorbidity are based on causal pathway models, in which conduct disorder, depression, and anxiety result in substance use. Frequent explanations for these relationships are that children and adolescents with conduct disorder gravitate towards social environments that facilitate problem behaviors such as substance use and that drugs like alcohol and marijuana are used to self-medicate or alleviate persistent symptoms of sadness and anxiety. However, existing studies have primarily examined whether youth with higher levels of psychiatric problems are more likely to use and abuse substances , rather than examining whether adolescents tend to increase their level of substance use during periods when their psychiatric problems increase . The latter approach represents a more direct examination of the self-medication hypothesis,mobile vertical grow racks where adolescents increase their substance use in an attempt to manage emerging psychiatric problems. Few longitudinal studies have examined the association between intra-individual changes in mental health problems and substance use.

By examining within-individual change, causal inference is enhanced because selection effects and all factors that vary between individuals are ruled out as potential confounds. It also provides a better indication of whether treating an adolescent’s psychiatric problems could potentially lead to a reduction in his substance use. The second key question is: Are there sensitive periods during adolescence when psychiatric problems play a particularly strong role in shaping substance use? Cerdá and colleagues found no evidence that there was a sensitive period in which acute and chronic psychiatric problems were more strongly related to the onset of alcohol and marijuana use from childhood to late adolescence. Specifically, both recent and cumulative conduct disorder problems were associated with earlier alcohol and marijuana use onset in a cohort of boys followed from ages, whereas cumulative, but not recent, depression problems were associated with earlier alcohol use onset. However, there was no particular age of substance use initiation when psychiatric problems mattered the most. In contrast, Maslowsky and colleagues and Gibbons and colleagues found evidence indicating that early conduct problems were a stronger predictor of alcohol and marijuana use in late adolescence than conduct problems in middle adolescence. However, these three studies focused on between-individual differences in psychiatric problems and substance use. Therefore, it is unclear whether there is a specific developmental period during adolescence when youth are more likely to escalate their drug and alcohol use in response to emerging psychiatric problems. One way to effectively address these two key questions is to use longitudinal data to examine whether youth tend to increase the frequency of their substance use after they experience an increase in their psychiatric problems, and test whether this association changes across development. This type of within-person change analysis eliminates the possibility that time-stable individual differences such as genotype, race/ethnicity, personality traits, family history of psychiatric problems and substance dependence, and parenting problems can explain the association between changes in psychiatric problems and substance use across adolescence. Hence, it controls for all unmeasured time-invariant confounders.

In addition, measured time-varying confounders can also be included as control variables . Using this approach, researchers have shown that change in alcohol abuse or dependence and nicotine dependence in early adulthood predicted change in major depression in a birth cohort in New Zealand. Additionally, increasing frequency of cannabis use was associated with concurrent increasing depression problems in four Australasian birth cohorts . But to our knowledge, no research has used this approach to establish the directionality of the relationship between common psychiatric problems and substance use: that is, to evaluate whether an increase in conduct disorder, depression and anxiety problems leads to a subsequent increase in alcohol and marijuana use; an increase in alcohol and marijuana use leads to a subsequent increase in conduct disorder, depression and anxiety; or a reciprocal relationship exists between psychiatric problems and substance use. Thus, the aims of the present study are to address the following questions: do adolescents experience an increase in the frequency and quantity of their alcohol and marijuana use following an increase in conduct disorder, depression, and anxiety problems? Are there specific periods during adolescence when increases in these mental health problems are more strongly related to escalations in substance use than others? We examine these questions in a longitudinal urban sample of males followed from ages 13 to 19, with yearly measures of psychiatric problems and substance use quantity and frequency. To establish the directionality of these associations, we examine both whether increases in alcohol and marijuana follow increases in conduct disorder, depression, and anxiety, and whether increases in conduct disorder, depression, and anxiety follow increases in alcohol and marijuana use. Data are from the youngest cohort of the Pittsburgh Youth Study. This sample has been described in depth elsewhere.Briefly, participants included first-grade boys enrolled in 31 public schools in Pittsburgh in 1987-1988. A random sample of boys was invited for an initial multi-informant screening. The screen involved assessing the boys’ conduct problems using ratings collected from the parents, teachers, and the boys themselves. Boys whose composite conduct problem scores fell within the upper 30th percentile, together with an approximately equal number of participants randomly selected from the remaining end of the distribution, were selected for longitudinal follow-up .

The sample is predominantly Black and White with 3% Asian, Hispanic, and mixed-race. Participants were assessed annually or semi-annually, depending on the measure, for thirteen years. Caretakers provided informed consent and adolescents provided assent until age and consent thereafter. We restricted analysis to adolescents at ages, as substance use by year was rare at younger ages: 93.9% and 84.5% did not use marijuana or alcohol, respectively, on any occasion between the ages of 7-12. Study procedures were approved by the Institutional Review Boards of the University of Pittsburgh School of Medicine and the Columbia University Mailman School of Public Health. Alcohol and marijuana use were assessed semi-annually by a 16-item Substance Use Scale adapted from the National Youth Survey. Adolescents were queried about timing, quantity, and frequency of alcohol and marijuana use. We defined “marijuana frequency” as the number of occasions of marijuana use in the past year. We defined “alcohol frequency” as the number of occasions of drinking in the past year. We defined “alcohol quantity” as the average number of drinks per occasion in the past year. For phases separated by only 6 months, past-year values were constructed by taking the average of the two semi-annual interviews. Affective, anxiety,vertical cannabis grow systems and conduct problems were measured with items from the Child Behavior Checklist , Teacher Report Form , Youth Self-Report , and Young Adult Self Report from the Achenbach system of assessment.DSM-oriented problem domains were measured with items rated as very consistent with DSM-IV symptoms of affective disorders, anxiety disorders, and conduct disorder by a group of mental health professionals.The scales were administered to caregivers and teachers from age 7 to 16, and youth from age 10 to 19. Items were scored as 0 = not true, 1 = somewhat or sometimes true, and 2 = very true or often true .In order to facilitate comparison across informants, total scores for each scale were converted to t-scores based on age- and gender-specific national norms .The average internal consistency coefficients for the caregiver, teacher, and youth depression scales were 0.82, 0.76, and 0.81, respectively. For the anxiety scales, the internal consistency coefficients for caregiver, teacher and youth scales were 0.72, 0.73, and 0.67, respectively. For the conduct disorder scale, the internal consistency coefficients were 0.91, 0.9, and 0.83 for caregiver, teacher, and youth scales, respectively.These scales have been shown to discriminate between clinic referred adolescents with depressive, anxiety, and conduct disorders and non-referred adolescents. All the scales used have previously shown acceptable concurrent and predictive validity in ROC analyses comparing the scales with official records of offense and delinquency or by assessing discrimination between adolescents referred to psychiatric clinics and non-referred adolescents.Several potential time-varying confounding factors were included in the current study to parse out the effect of psychiatric problems from the constellation of time-varying risk factors that could increase both psychiatric problems and substance use.

The selection of confounders was based on theory and a review of the literature, as detailed below. “Family factors” included changes in socioeconomic status , assessed yearly by applying the Hollingshead Index of Social Status to data provided by the primary caretaker or youth no longer living with family beginning at age 1632; changes in parental supervision/involvement, a 43-question scale concerning caretakers’ knowledge of the youths’ whereabouts, the frequency of joint discussions, planning, and activities, and the amount of time that the youth is unsupervised; positive parenting, a scale measuring perception of frequency of positive responses to youth behavior; parental stress, a 14-item scale measuring perceived stress levels and caretakers’ abilities to cope with stress in the previous month 18; and parental use of physical punishment, drawn from a scale that measures parental discipline strategies. “Peer Variables” consisted of changes in youth peer delinquency and peer substance use, a 15-item scale that corresponds to a self-reported delinquency scale.Analyses were conducted in R version 3.0.2 and 3.0.3. Missing data in the covariates were imputed using R package ‘mice’ for “multivariate imputation by chained equations,” an implementation of fully conditional specified models for imputation. The fully conditional approach differs from the more traditional joint modeling approach by specifying a multivariate imputation model on a variable-by-variable basis. This fully conditional approach is used as an alternative to traditional joint modeling when no suitable multivariate distribution can be found. We imputed 20 datasets, and in subsequent analyses used the R package ‘mitools to pool the results of functions runon the 20 data sets using Rubin’s Rules. We employed quasi-Poisson regression techniques to assess the fixed effects that one-year lagged changes in psychiatric problems had on subsequent changes in alcohol use frequency/quantity and marijuana use frequency from ages 13 to 19. Quasi-Poisson models are an approach to dealing with over-dispersion, which was apparent in initial Poisson models. They use the mean regression function and the variance function from Poisson generalized linear models but leave the dispersion parameter unrestricted and estimate it from the data. Unlike negative binomial models, the variance is assumed to be a linear function of the mean.This strategy leads to the same coefficient estimates as a standard Poisson model but standard errors are adjusted for over dispersion. Following the “dummy variable method” for fixed effects in Poisson models we included k – 1 dummy variables to represent the sample participants in each model. A series of models were fit sequentially to test the association of each one-year-lagged psychiatric problem domain with each substance use outcome. First, we regressed separately each one year-lagged shift in the average psychiatric problem T-scores on each substance use outcome. Within these models, age-related changes in substance use were controlled for using natural cubic splines. Natural cubic splines are a flexible smoothing approach for non-linear relationships, and are composed of piece wise polynomial functions that split the continuous age variable into separate line segments, each free to have its own shape. Segments are joined by “knots,” which we specified a priori to result in line segments for ages 13-14, 15-16, and 17-19. Slopes are constrained to converge at each knot . Second, we sequentially tested groups of potential confounders. All covariates were back-lagged two years, so that they would be modeled prior to the measurement of the exposure. This ensured that the estimated total effect of change in psychiatric problems on change in substance use included effects mediated through the covariates that occurred contemporaneous to changes in psychiatric problems. In our second set of models, we adjusted for age, SES, substance use variables that were not modeled as the outcome , and measures of psychiatric problems that were not the exposure of interest .

SUD treatment initiation and retention are key clinical goals for SUD patients

Difficulty getting necessities, experiencing more negative mental health effects, and greater worry about one’s children’s well-being was associated with greater depression and anxiety symptoms. In multi-variable models, controlling for demographic characteristics, negative mental health effects of the pandemic were the strongest correlate of substance use problems, depressive symptoms, and anxiety symptoms. Participants with high scores on this measure reported frequently thinking about COVID-19, worrying about their health and/or the health of their family and friends, experiencing stress due to changes in social contacts and their lifestyles, worsening of their mental/emotional health, and sleep disruptions. Findings suggest that the COVID-19 pandemic is producing major concerns that may contribute to mental health symptoms, including problematic substance use. Many individuals are using substances to cope with stress and uncertainty around the pandemic . A nationally representative sample of U.S. adults conducted early in the pandemic identified increased risk of depressive symptoms among people with lower income, fewer savings, and more stressors . People with problematic substance use may also be at elevated risk for depressive symptoms. While some evidence suggests that pandemic-induced psychological distress is lessening in the United States , people with problematic substance use are vulnerable to the negative effects of the pandemic . In this study, participants with more substance use problems were less likely to avoid bars and large gatherings, corroborating concerns that substance use may increase risk of contracting COVID-19 . Participants struggling to control their substance use may have found it difficult to avoid settings in which they use. Paradoxically, individuals with greater substance use problems also perceived greater personal growth from the pandemic in the forms of strengthened relationships, new possibilities, awareness of personal strength, spiritual change,vertical grow rack system and increased appreciation of life. People with problematic substance use often experience intense emotions . Experiencing intense emotions may have led individuals with substance use problems to be deeply affected by both positive and negative pandemic-related changes.

Additionally, perceiving greater personal growth was associated with lower likelihood of struggling with responsibilities at home and lower likelihood of avoiding large gatherings. Participants who perceived personal growth may be a subset whose daily lives were less strongly affected by the pandemic. Study data are cross-sectional, and causal pathways cannot be determined. There may be bidirectional relationships between substance use problems and pandemic-related mental health symptoms and stressors. While pandemic-related stress may have worsened mental health symptoms and substance use, it is also plausible that individuals with preexisting mental health symptoms and more substance use problems were negatively impacted by the pandemic than those with milder symptoms. Longitudinal research is needed to fully understand how substance use and pandemic-related circumstances may impact one another. The study was exploratory and was intended to be hypothesis-generating rather than hypothesis-confirming. Results are also subject to recall bias, as all measures were self-reported. Participants may have had difficulty accurately reporting their substance use and mental health symptoms from the past two weeks. Data were not collected on general life stressors unrelated to the pandemic. Individuals with high levels of stress may have experienced more pandemic-related stressors, mental health symptoms, and substance use problems. Lastly, the sample was predominantly non-Hispanic white. People of color are at increased risk of contracting and experiencing complications from COVID-19 . Moreover, Hispanic and Black individuals were more likely to report increased substance use than non-Hispanic white or Asian adults, potentially due to increased stress . Different vulnerabilities may interact to influence experiences of the pandemic. All participants were enrolled in a clinical trial, were not experiencing severe medical problems from their substance use, owned smartphones, and were proficient in English. Hence, findings may not generalize to more impoverished, medically complicated, or diverse groups. Future research into pandemic-related stressors and substance use should aim to recruit a more diverse sample. We explored correlations between trauma and mental health symptoms , and SSIS substance use scores . Our study indicated high rates of ACEs, substance use, and current mental health symptoms among homeless TAY in San Francisco.

Although substance use was not significantly correlated with trauma, it was significantly correlated with mental health symptoms, suggesting that a person’s response to trauma, and their lack of resources to process the trauma, may lead to unhealthy coping through substance use. This population may have even fewer resources than their housed counterparts to cope in healthy ways. These findings are consistent with existing scientific literature . TAY experiencing homelessness in this study reported a mean of 5.9 adverse childhood experiences before the age of 18, and over three-quarters of participants reported more than 4 ACEs. This finding parallels other research on childhood trauma exposure among these youth . Participants also reported high rates of mental health symptoms, with many reaching diagnostic thresholds for PTSD, depression, and/or anxiety, again similar to existing research . Most participants lived in and around San Francisco’s Tenderloin neighborhood, an area with high rates of poverty and violence, which may have contributed to their experiences of trauma and mental health symptoms. Although we measured experiences of trauma prior to the age of 18 years, and all participants were over the age of 18, living in an area with high rates of poverty and violence puts individuals at additional risk for trauma. This serves as a barrier to accessing care for the sequelae of traumas experienced previously. Homeless TAY frequently have difficulty accessing services such as shelter, medical care, mental health services, and employment due to stigma, a lack of knowledge about available resources, and a lack of services targeted to young individuals . Rates of substance use among our participants were high, and while much of their use fell within the range of moderate-risk of harm, adolescence and young-adulthood are times of life during which the risk of developing substance misuse problems and disorders is high, making even moderate-risk use worrisome . At the same time, youth misuse of substances may increase their risk for experiencing trauma, violence, and injury, and for contracting communicable diseases such as HIV and Hepatitis C . TAY whose substance use behavior falls within moderate-risk levels of harm are a population in high need of monitoring and interventions to minimize substance use as well as co-occurring issues. Our findings also indicated that substance use was significantly correlated with current PTSD symptoms. An integrative review examining literature on the relationship between early life stress, childhood trauma and abuse, substance use, and addiction found strong evidence that interpersonal childhood trauma is associated with an increased vulnerability to substance use disorders .

Reasons for this may be due to the permanent changes to the brain’s stress circuitry formed by early life stressors . This may help explain at the individual-level why our findings show a significant relationship between trauma symptoms and substance use. Interestingly,vertical growing system in our sample we did not identify correlations between ACEs and most types of substance use, although this has been observed in other literature. A community study recruiting youth ages 18-25 years found specific scores and types of ACEs to be significantly associated with substance use . Participants who have high or multiple exposures to ACEs were at higher risk for alcohol related problems, current substance use, and mental health symptoms when compared to participants who have none to low ACEs . The lack of correlation in the current study may be due to the high number of ACEs reported by our participants, on average. While there was little correlation between ACEs and substance use, there was a significant correlation between the longer-term consequences of trauma – PTSD, depression, anxiety – and substance use. We conducted a cross-sectional study, which limits our ability to conclude whether exposure to trauma or experiencing mental health symptoms directly influences participant use of substances. We also recruited participants using convenience sampling, which increases the risk for selection bias. In examining potential selection bias, we found that our participant demographics largely mirrored the 2019 homeless youth point-in-time count, with the exception of gender; in our study, 67% of participants identified as male, but only 48% identified as male in the point-in-time count . This could affect generalizability to the larger homeless TAY population in San Francisco. Additionally, since the study was conducted in San Francisco, these results may not be generalizable to other locations. One limitation of data collection instruments such as the NIDA-Modified ASSIST is their validation for use in adult populations rather than transitional-aged participants, which may affect reliability. Participants were asked intimate questions about their childhood trauma, mental health symptoms, and current and past use of substances which may have resulted in an under reporting of trauma, mental health symptoms, and substance use due to social desirability bias. The CBO suggested that data collection be completed through face-to-face interviews, and this may have resulted in social desirability bias.

Future research with this population should consider data collection methods that allow for both confidentiality and participation of individuals with lower reading skills. Our study did not categorize ACEs into types of trauma nor did we separate ACEs scores into low moderate and high categories due to our sample size. Our findings could be influenced by our methodology and sample size, potentially resulting in a type II error. Another limitation in determining links between childhood trauma and substance use is the proximity in time between adolescence and young adulthood. It is difficult to determine which adverse experiences began and ended prior to the age of 18 years and which have not. This is one possible reason why we did not find any significance between ACEs and substance use when studies among older populations have found such a relationship . Due to the length of the survey, we did not measure all potential sources of trauma . Thus, we are unable to assess whether recent trauma or specific types of trauma are more correlated with substance use than generalized adverse experiences in childhood. Health care reform in the United States has had major implications for people with substance use disorders , including greater opportunities to enroll in private insurance coverage, increased access to services, and changes in health care costs . The Affordable Care Act established state insurance exchanges to promote and offer health coverage, and mandated SUD and psychiatric disorder treatment as essential benefits. Practitioners expected these ACA mandates, implemented in 2014, to increase access to care . Following ACA implementation in 2014, the overall number of individuals living without insurance dropped . Evidence suggests a positive impact of the ACA on both SUD and psychiatry coverage , including an increase in insurance choices . The number of individuals with identified SUDs enrolled in health plans increased . But access to services remains a major concern , and much is still unknown regarding how ACA-associated enrollment through insurance exchanges and cost-sharing structures are associated with access to and use of SUD treatment and other health services in this complex patient population.Specific characteristics of the ACA, such as enrollment via new state insurance exchanges and increased patient cost sharing via higher deductibles, may influence treatment differentially for people with SUDs who may be new enrollees . Patient cost sharing may adversely impact both initiation and retention. If SUD treatment and psychiatry services are viewed as discretionary and less essential than primary care, they may be especially vulnerable to cost-sharing mechanisms . A previous evaluation of SUD patients enrolled in the same California healthcare system found that compared to a pre-ACA enrollment cohort with SUDs, post-ACA SUD patients had more psychiatric and medical conditions and greater enrollment in high-deductible plans. Although this prior work did not examine patterns of health service utilization, the findings suggest that newly enrolled patients post-ACA may have greater clinical needs as well as increased financial obstacles to accessing services . It is important to not only evaluate SUD treatment initiation and retention over time following implementation of the ACA, but also to evaluate how factors related to the ACA may influence utilization of other health services. The current study aimed to extend what is currently known about the consequences of healthcare reform by examining the potential relationship of ACA exchange enrollment and high deductible health plans to trends in health service utilization in a cohort of individuals who were newly enrolled in a healthcare system and had a documented SUD.

Understanding the comorbidity between psychopathology and marijuana use is complicated

Substance use will be the common outcomes in models including participants of both HIV statuses.For example, calculating the CER for adding contingency management to Matrix for non-responders would yield a CER equation. In calculating the CER of high vs. low intensity contingency management at the first randomization stage, the entire range of subsequent costs will be included. Costs of delivering the interventions will be derived from clinic records of time and other inputs, as well as incentive payments, thus providing an estimate of CER from the medical system perspective. We will also evaluate CERs from a societal perspective, using a broad definition of costs, including the social costs of incarceration. We will conduct sensitivity analyses to estimate the extent to which the CER calculation is affected by differences in assumptions about the size of the differences in intervention effect. In particular, we will determine how sensitive the CER is to assumptions that the difference in treatment effect is one standard deviation below or above the mean estimated effect size. Similarly, we will estimate the sensitivity of conclusions to costs that are one standard deviation below or above the estimated mean.We will first describe the extent and patterns of missingness within each variable and check for associations between missing and observed data to determine the mechanism of missingness, which could be missing completely at random, missing at random,vertical farming or missing not at random. Missing data will then be handled using multiple imputation. Appropriate imputation techniques will be chosen for the type of missing data and the statistical tools employed. For sensitivity analysis, we will conduct analyses with and without multiple imputations.

All participants will be analyzed on an intent-to-treat basis where the study outcomes are examined based on the random intervention assignment and not on the actual intervention received or adherence to the intervention.There is no planned interim analysis as the behavioral therapies used in this trial have no known serious adverse events and are consistently more efficacious than control conditions in treatment-seeking participants. The effect sizes of the behavioral therapies in this trial are in the moderate range. Furthermore, any interim analysis and decision to stop the trial would likely be based on under powered data and susceptible to error.Our data monitoring committee is composed of members of the Data and Safety Monitoring Board for Addiction Medicine of the University of California – Los Angeles. These members are not connected to the study in any way. The DSMBAM is independent from the National Institute on Drug Abuse —the sponsor of this study. The DSMBAM meets quarterly to monitor subjects’ progress in the trial and considers whether adverse social harms differentially accrue by condition. Although there are no prospective stopping rules for this trial, the DSMBAM is within its charge to review aggregate data, request statistical tests of differences in social or other harms, and then advise changes in intervention type or intensity if statistically significant differences emerge in adverse events by condition. Prior to each meeting, the study team will submit a performance report including all reports of SAEs for DSMBAM’s consideration. After each meeting, recommendations will be made in writing to the principal investigators.Hanoi Medical University and the staff in the STAR-OM study provide oversight of financial management. The Vietnam teams and US teams maintain frequent communication via emails and bi-weekly online meetings to report updates on the study progress, discuss scientific aspects of the study, and troubleshoot issues when they arise.

The teams in Hanoi and HCMC meet online once weekly and in-person quarterly during monitoring visits to discuss the study conduct. We submit annual research progress reports to the Ethics Committee of Hanoi Medical University. Any protocol amendments need to get ethical approval before implementation. The UCLA Addiction Medicine Data Safety Monitoring Board independently review our data and data management twice a year.Adverse events in this trial are defined as medical issues that do not require hospitalization. Serious adverse events are defined as life-threatening events such or other events that have a negative impact on participants’ life such as incarceration or compulsory drug rehabilitation. The clinic staff will communicate information about adverse events and serious adverse events to the study team right after they are informed by participants or participant families. The study coordinators in Hanoi and HCMC are responsible to report adverse events within 7 days and serious adverse events within 24 h on REDCap with the time of onset, seriousness, duration, and outcomes. The principal investigator will decide what serious adverse events need to be reported to the Ethics Committee.Prior to participation in the trial, the participant will be informed about the research. Participants will complete a short questionnaire about the study objectives and main activities to show how they understand the study. Research assistants will provide more explanation based on the results of the questionnaire. If participants agree to join the study, they will sign a consent form. Each participant will be assigned a unique identifier at the time of screening. Participant data will be linked to this identifier only. Participant personal identifiable information is stored in a separate locked cabinet to which only responsible study staff have access. All study staff sign a confidentiality agreement to non-disclosure of participant information. We make extra efforts to ensure nodisclosure of drug use information to anyone other than participants and the study staff.Between July and October 2020, we conducted 4 focus group discussions of a convenience sample of participants from four methadone clinics in the downtown and suburbs of Hanoi and HCMC to inform intervention content and refinement. Respondents reported information on local taxonomy and patterns of methamphetamine use, triggering situations, methamphetamine related sexual risks, motivations for seeking treatment, and perceived acceptability of the adaptive interventions.

The pilot implementation lasted 12 weeks from November 2020 through February 2021. It identified issues to be addressed before the full implementation. At the conclusion of the pilot, we conducted 2 FGD with patients and 1 FGD with providers participating in the pilot to gauge their feedback about the interventions.With the cut-off point of ASSIST ≥ 4 and methamphetamine-positive UDS as originally proposed, there were 26 and 52 eligible participants in two pilot clinics in Hanoi and HCMC, respectively . For the pilot implementation, we randomly recruited 42 participants with ASSIST score ≥ 4 or methamphetamine-positive UDS. After the front line intervention, 16 participants were non-responders and randomized into adaptive interventions. At least 50% of the original sample must transition to the adaptive phase for sufficient statistical power. Thus, we decided to recruit more participants with severe use of methamphetamine, as evidenced in both ASSIST score ≥ 10 and methamphetamine-positive UDS. Furthermore, to recruit enough participants for the front line intervention phase, given most other clinics are smaller than the two pilot ones,indoor cultivation we decided to use ASSIST score “OR” UDS instead of “AND” to increase the pool of potential participants. We kept the criterion of methamphetamine-positive UDS to compensate for participants with lower ASSIST scores due to desirability bias.The STAR-OM study is among the first studies to evaluate different combinations of EBIs for methamphetamine use among methadone patients in low-and-middle-income countries. The study will provide effectiveness and cost-effectiveness evidence for scaling up these interventions. The SMART design assesses different treatment strategies for participants who respond differently to front line interventions. The combination of trial and ethnographical study will provide insights on factors at multiple levels that need to be considered in decision making. The adaptation and pilot implementation of EBIs will make them culturally sound to local participants. As the interventions will be delivered by methadone providers at methadone clinics, they can be readily implemented if the trial demonstrates they help. The participation of some participants can be interrupted due to drug-related police arrest or methadone treatment fatigue. This limitation can be minimized as we will select clinics with low drop-out rates. We have officially informed the local police on the study implementation and received approval from both national and local authorities. While this measure does not prevent participants from being arrested, especially when they are involved in illegal activities, it could reduce attrition. Furthermore, the COVID-19 pandemic and containment measures could pose challenges for the study implementation. With the response plan developed for potential interruption scenarios, we believe the study will be implemented safely and will maintain a high-level of data quality and intervention fidelity.Marijuana is one of the most widely used illicit substances world-wide. Although it has been reported that marijuana use rate has stabilized or even decreased in recent years in most high-income countries, the continuing high prevalence of use among adolescents and young adults is a cause for concern. Such emerging trends have heightened interest in the link between mental health problems and adolescent marijuana use to inform policy and prevention efforts.Marijuana use is associated with numerous different psychiatric disorders, each of which tend to co-occur with one another.

Additionally complicating matters is the potential bidirectional nature of this association, with evidence that marijuana use may both predict and result from poor zmental health. A parsimonious explanation of this comorbidity may be that a small set of transdiagnostic psychopathological vulnerabilities that give rise to numerous mental health conditions may also contribute to and result from marijuana use. Such transdiagnostic vulnerabilities may account for the pervasive patterns of psychiatric comorbidity with use of marijuana and other substances. One such transdiagnostic vulnerability is anhedonia— diminished capacity to experience pleasure in response to rewards. As a subjective manifestation of deficient reward processing capabilities, anhedonia is believed to result from hypoactive brain reward circuitry. While anhedonia is a core feature in a DSM-defined major depressive episode, it has also been linked to other psychopathologies comorbid with drug use, including psychosis, borderline personality disorder, social anxiety, attention deficit hyperactivity disorder and post-traumatic stress disorder and has therefore been proposed to be a transdiagnostic process. Departing from its consideration as a ‘symptom’ of a disease state as in DSM-defined major depression, anhedonia has also been conceptualized as a continuous dimension, upon which there are substantial inter individual differences. Individuals at the lower end of the anhedonic spectrum experience high levels of pleasure and experience robust affective responses to pleasurable events, whereas those at the upper end of this spectrum exhibit more prominent deficits in their pleasure experience. Anhedonia operates as a ‘traitlike’ dimension that is stable yet malleable, which is empirically and conceptually distinct from other emotional constructs, such as reward sensitivity , alexithymia and emotional numbing , sadness and negative affect. Recent literature documents a consistent association between anhedonia and substance use in adults. To the best of our knowledge, there has been only prior study of the association between anhedonia and marijuana use in youth, which found higher anhedonia levels among treatment-seeking marijuana users than healthy controls in a cross-sectional analysis of 62 French adolescents and young adults. Given the absence of longitudinal data, it is unclear whether anhedonia is a risk factor for or consequence of adolescent marijuana use. Because youth with higher anhedonia levels experience little pleasure from routine rewards they may seek out drugs of abuse, such as marijuana, which stimulate neural circuitry that underlie pleasure pharmacologically. Alternatively, repeated tetrahydrocannabinol exposure during adolescence produces enduring deficits in brain reward system function and anhedonia-like behavior in rodent models. In observational studies of adults, heavy or problematic marijuana use is associated with subsequent anhedonia and diminished brain reward region activity during reward anticipation. Consequently, it is plausible that anhedonia may both increase risk of marijuana use and result from marijuana use. Because early adolescence is a period in which risk of marijuana use uptake is high and the developing brain may be vulnerable to cannabinoid-induced neuroadaptations, this study estimated the strength of bidirectional longitudinal associations between anhedonia and marijuana use among adolescents during the first 2 years of high school. The primary aim was to test the following hypotheses: greater baseline anhedonia would be associated with a faster rate of escalation in marijuana use across follow-up periods; and more frequent use of marijuana at baseline would be associated with increases in anhedonia across follow-ups.

The flow of blood marking not only the violation of a boundary but the opening between body and world

Given the multiple challenges faced by our study participants in New Mexico, and the extraordinary conditions that define the contours of struggle for coherence in their lives, a focus on the specific act of cutting offers a necessarily limited but existentially critical insight into the nature of their experience. Without a doubt this requires attending to the question of children’s agency as a capacity with which youth are endowed, as we have invoked by citing childhood studies literature and in our analysis of individual vignettes. Childhood studies scholars embrace a concept of agency as a reaction against models of childhood with more structural and chronological substrates, allowing children to be recognized as meaning makers rather than passive recipients of action . However, in the present context, we must also see agency as a fundamental human process that is no less fundamental for being challenged by illness . Specifically, self-cutting is a crisis in the agentive relation between adolescent bodies and the surrounding world, or put another way, a crisis of their bodily being in the life-world that they inhabit. In understanding embodiment as an indeterminate methodological field, this relationship between body and world is defined by three modes or moments of agency: the intentionality of our bodies in acting on the world or being-toward-the-world, the reciprocal interplay of body and world embedded in a habitus, and the discursive power of the world upon our bodies to establish expectation and shape subjectivity . To be precise, approaching the interpretation of cutting from the standpoint of agency in these troubled adolescents’ body-world relationship has the immediate effect of shifting interpretive attention from the wounded flesh to the relation between the active hand of the cutter and the self-inflicted wound. It is then not just a matter of the pain, the relief, or the blood that originates at the violated boundary between self and world, and the concomitant breach in bodily integrity.

In the first mode of agency,vertical farm tray regardless of the implement used to cut with, the cutter’s hand is an agent of self, and the opening of the wound and flow of blood are an emanation of personhood into the world. Cutting is a form of active being toward-the-world whether understood as a form of projecting outward or as a kind of leaking and draining into the world. This mode of agency is epitomized in the statements of identity such as “I am a cutter.” In the second mode or moment of agency, hand and flesh together instantiate the reciprocal relationship of body and world. The cutting hand interpellates the part of the animal and material world that is one’s very own body, and that precise fragment of the world responds with the opening of the flesh . In this way cutting highlights the simultaneity of body as both self and other.The reciprocity between body and world is highlighted in the simultaneous infliction of pain and the granting of relief. The cutter’s body is also the locus of an anguished subjectivity that elicits the application to itself by an agentive hand ambivalently cruel and kind, of an otherwise inert implement from the material world, whether it is a razor blade or a piece of glass. In the third mode of agency, both hand and flesh are no longer part of an inviolate self but conscripts of the world’s oppressive agency, and one’s body may as well not be one’s own but just a body, any body, “the” body as an object rather than a subject. The cutter’s hand is now the hand of the other, the wound is world-inflicted, and structural violence is incorporated at the most intimate bodily level. That is, it is inflicted by an anonymous oppressive world or the world dominated by the cruelty of others, and one’s flesh becomes an inert object alienated not only from self hood but from the trajectory of a possible life, isolated from others and immersed in the immediacy of present pain and unproductive bodily transformation. We must take care to distinguish what is specific to each young person and what is fundamental to their bodily experience in the account we have just given.

Attending to the immediate life worlds of individual youth reminds us that each has a distinct experience of cutting under distinct circumstances. Gender, ethnicity, and socioeconomic status matter to define these circumstances, while family relations and especially family instability are particularly insistent and frequent themes. Insofar as all the youth we have discussed were psychiatric inpatients, they can be counted among the more extreme instance of adolescent self-cutters, while exhibiting varied diagnostic profiles, levels of functioning, regimes of psychiatric medication, and phases of treatment and recovery. The combination of individual uniqueness and shared extremity across their situations has allowed us to elaborate a multilayered crisis of agency in the relation between body and world and highlights the existential profundity of cutting as a function of its mute immediacy in practice. The possibility for this kind of embodied existential analysis is that cutting is not an idiosyncratic occurrence but a culturally patterned act. Yet it cannot be accounted for just because other kids do it, and this is why it has been important to examine it in the lives of afflicted adolescents rather than simply as an element in the ethnography of “Emo” culture. The interpretive point is that the trajectory of our argument from experiential specificity on the individual level to the fundamental human process of agency does not define the ends of a continuum. We must instead understand the extraordinary conditions of suffering as simultaneous with the enactment of fundamental human process, because the relation between body and world is always embedded in a specific instance, and each specific instance points to our shared existential condition of embodiment. Identifying the wounded flesh as locus of agency at the intersection of body and world as we have done brings to the fore a particular configuration of relations between self as active and passive, strategy and symptom, subjectivity and subjectivation.

The moment of cutting is a fulcrum or hinge between the self as agent or as patient, with an intended pun on the medical sense of patient. From the standpoint of individual experience, cutting in the first sense is a strategy that is part of the self as agent, while in the second sense it is a symptom that is part of a disease process. As a cultural phenomenon, cutting in the first sense exhibits the body as existential ground of culture and wellspring of agentive subjectivity , while in the second sense cutting identifies the body as a site at which cultural practice and structural violence are inscribed and have the effect of subjectivation . In this respect, the distinction between subjectivation and subjectivity in the cut/cutting body is substantively parallel to the distinction between symptom and strategy in the afflicted person. Perhaps the analysis we have presented suggests that self-cutting may indeed be sufficiently complex to serve as the core of a distinct diagnostic category and too problematic with respect to agency to be defined as a symptom in the ordinary sense. Whether or not this proves to be the case, the existential complexity to which we have pointed is precisely what one would expect by bringing attention to bear on cutting as a crisis of agency with its locus at the intersection of body and world.Public health measures to contain the spread of COVID-19, the disease caused by the novel coronavirus SARS-CoV-2, have affected billions of people worldwide. In March 2020, approximately 1.7 billion people were under orders to remain at home or shelter-in-place . Such orders,vertical farming suppliers which mandate remaining at home except for essential activities and outdoor exercise with social distance , are crucial to slowing transmission of COVID-19, preserving healthcare systems’ capacities, and limiting deaths . However, successes in mitigating the spread of COVID-19 are paired with devastating economic, social, and psychological effects .Yet, engaging in regular PA can be challenging under even normal circumstances. In 2018, 54.2% of American adults engaged in light or moderate activity for 150+ minutes/week or vigorous activity for 75+ minutes per week . SIP orders may further reduce activity levels by decreasing incidental daily PA and exercise opportunities . As such, the World Health Organization issued recommendations for engaging in PA at home . Many people face serious challenges to being physically active during SIP. Many neighborhoods may not be conducive to safe, socially distant outdoor exercise. Moreover, many individuals have increased demands on their time during SIP, such as essential work, caring for family members, and standing in long lines to buy necessities.

Vulnerable communities, particularly communities of color, have been disproportionately affected by COVID-19 . On the other hand, SIP may facilitate greater PA for some individuals. Those who transitioned from commuting to working from home may have more free time for PA. Additionally, individuals and families may spend time outside to combat boredom and stress. Some stress management strategies that may be used during COVID-19 involve physical activity , while others are mostly sedentary . We hypothesized that adults who met PA guidelines during COVID-19 SIP would be less likely to report increased stress during SIP and would be more likely to report use of physically active stress management strategies. We also explored whether increased stress would be associated with PA pattern or associated with use of specific stress management strategies. Participants were recruited from the U.S. component of the Stanford WELL for Life initiative , a cohort of adults residing mostly in Northern California. Eligible participants for the WELL for Life cohort were age 18 or older, residing in the U.S., and able to complete the online survey in English. Participants were recruited through research registries, Stanford listservs, social media, and through existing community partnerships . WELL for Life cohort participants who had indicated willingness to participate in other studies were invited to participate in the present study examining well-being during COVID-19. Participants completed surveys in early SIP and mid-SIP . Participants provided informed consent and the study was approved by the Stanford University Institutional Review Board. The majority of participants resided in the San Francisco Bay Area, where a regional SIP order on 17 March 2020 affecting 6 Bay Area counties and the city of Berkeley mandated closure of indoor and outdoor recreation venues such as gyms, climbing walls, playgrounds, golf courses, basketball and tennis courts, and pools . Additionally, the state of California closed many state parks and beaches and instructed residents to stay close to home for recreation . Most restrictions remained in place through the end of May 2020 . Past-month PA was measured with the Stanford Leisure-Time Activity Categorical Item , a validated measure with excellent sensitivity to change in PA over time . Participants selected one of six descriptions that best matched their past month leisure time physical activity. Scoring was based on adherence to the 2007 American College of Sports Medicine/American Heart Association guideline of: a) 30+ minutes of moderate-intensity aerobic physical activity 5 days/week, b) 20+ minutes of vigorous-intensityaerobic physical activity 3 days/week, or c) a combination of the above . Responses were categorized as meeting/exceeding or not meeting PA guidelines. Participants responded to, “What are you currently doing to manage your stress?”. In early SIP, the question was open-ended. Participant responses from early SIP informed the 10 response options provided in mid-SIP: outdoor physical activities , indoor physical activities , yoga/meditation/prayer, calling/video-chatting with friends and family, watching TV/movies at home, reading, listening to music, gardening, sleeping more, and eating more. Participant characteristics Participants reported their age, gender, race, education, total combined family income, marital status, employment status, and the number of people living in their household. Participants also reported the number of days they drank alcohol in the past month and whether they used cannabis in the past two weeks . Current smoking status was derived from two items; participants were considered current smokers if they reported 100+ lifetime cigarettes and currently smoking “some days” or “every day” . Differences in participant characteristics by mid-SIP PA were tested using independent-samples t-tests and chi-square tests. PA pattern from early SIP to mid-SIP was coded as “remaining inactive” , “remaining active” , “becoming inactive” , or “becoming active” .

Stress-induced analgesia is mediated by the activation of endogenous pain inhibitory systems

We hypothesized that greater reductions in 12-step affiliation and meeting attendance would predict greater increases in drinking and drug use, and that these effects would mediate the superior long-term treatment effects observed for the ICBT condition. The sample for this study includes 201 veterans who participated in a trial of outpatient group psychotherapy for comorbid substance dependence and MDD . We included all participants from the trial who completed at least one follow-up assessment from end-of treatment to the one-year follow-up . Demographics of the sample are presented in Table 1. Study inclusion criteria were lifetime dependence on alcohol, cannabis, or stimulants with recent use, and major depressive disorder with at least one episode occurring independently of substance use. Exclusion criteria included opiate dependence with intravenous administration, bipolar or psychotic disorder, residing excessively far from the research facility, or memory impairments prohibiting accurate recall in study assessments.The procedures for this study were approved by the University of California, San Diego and VA San Diego Healthcare System Institutional Review Boards. Participant referrals were obtained from the VASDHS dual diagnosis clinic by research study staff, who conducted brief screenings prior to meeting with eligible veterans to explain study procedures and obtain informed consent. Participating veterans consented to 6 months of group psychotherapy, recording of sessions, psychotropic medication management appointments, random urine screens, and research assessments conducted at intake and at 3- month intervals for an 18-month period. Veterans agreed to receive no other formal treatment for substance use or depression for the duration of group psychotherapy. Participation in other formal intervention was allowed during follow-up.Group psychotherapy was initiated on a rolling basis,vertical aeroponics farming with starts occurring every 2 weeks. After completing the intake assessment participants were sequentially allocated to the treatment condition with the next start date.

For Twelve-Step Facilitation we modified the TSF protocol from Project MATCH to allow group delivery and discussion of multiple substances. For development of Integrated Cognitive-Behavioral Therapy , material was adapted from two empirically-supported treatments: group cognitive behavioral therapy for depression and cognitive-behavioral relapse prevention from Project MATCH . The two treatments were identically structured with a series of three modules, with each module designed to cover a specific 12-step or cognitive-behavioral topic. Group sessions occurred twice/week for the first 3 months of group treatment, when each topic was covered in a one-month block. Topics were reviewed in the next 3 months during weekly group sessions. The mean session attendance was similar across groups. Interventions were codelivered by senior clinicians and doctoral students trained via manual review, direct observation, and weekly supervision. Therapists were rotated across treatment conditions on a regular basis , and adherence to protocol was assessed via videotape review. Our longitudinal analyses utilized latent growth modeling in the structural equation modeling framework. In LGM a series of repeated measures are used to indicate each individual’s underlying latent “growth curve” on one or more variables. This process creates separate growth curves for each individual, described by “growth factors” such as latent intercept and latent slope . Estimates of the sample mean and variance are obtained for each growth factor, and covariates can be used to predict individual differences in the initial level or rate of change over time. One distinct advantage of LGM is the ability to examine relations between the rates of change in multiple longitudinal processes, as warranted by the aims of this study. Because we were primarily concerned with the 12-month follow-up period, the end-of-treatment time point served as the initial level for each LGM. Thus, in each LGM the latent intercept represents the level at end-of-treatment, while latent slopes represent rates of increase or decrease during the 12 months of follow-up . For each study variable we first fit unconditional growth models to determine the optimal shape of the growth trajectory, before incorporating treatment group as a predictor in conditional models. This allowed us to test whether treatment condition predicted variability in the intercepts and slopes. In the final LGMs for PDD and PDDRG we specified growth curve mediation models , to determine if the slope of 12- step affiliation or meeting attendance mediated the relationship between treatment group and the slope of PDD or PDDRG. To test the significance of mediated effects we used asymmetric 95% confidence intervals obtained with the bias-corrected bootstrap procedure , which has shown greater power to detect mediated effects than other formal mediation tests .

All LGMs utilized the maximum likelihood procedure, which incorporates all available data from each participant under the assumption of missing at random. We then used the LGMs for 12-step and affiliation to predict individual differences in the end-of-treatment level and rate of change in alcohol and drug use from Month 6 to Month 18. In separate models the slopes for 12-step affiliation and meeting attendance were utilized as mediating variables between treatment group and the slopes for PDD and PDDRG , to test whether the greater increases in PDD over time for TSF patients were explained by greater decreases in 12-step variables. Results from these analyses are presented in Table 3. The PDD intercept was significantly and negatively correlated with the intercepts for 12-step affiliation and meeting attendance, indicating that individuals with greater levels of affiliation and meeting attendance at end of-treatment were also drinking less frequently at end-of-treatment. The PDD intercept was significantly and positively correlated with the slopes for 12-step affiliation and attendance, indicating that individuals with lower PDD at end-of-treatment had greater decreases in their 12-step affiliation and attendance during follow-up. Finally, the slopes for 12-step affiliation and meeting attendance were strongly, negatively predictive of PDD slope. This indicated that individuals with greater decreases in 12-step affiliation and meeting attendance from Month 6 to Month 18 had greater increases in PDD over time. As shown by asymmetric 95% confidence intervals obtained via the bias-corrected bootstrap procedure, the indirect effects of treatment group on PDD through slopes of 12-step affiliation and meeting attendance were statistically significant. These results indicate that the greater relative increases in PDD for the TSF patients were mediated by their greater relative decreases in 12-step affiliation and meeting attendance. There were no significant relations between intercepts and slopes of the 12-step variables and PDDRG , indicating that the end-of-treatment level and change during follow-up for drug use frequency was unrelated to end-of-treatment level or change during follow-up for 12-step affiliation or meeting attendance. This study examined post-treatment change in 12-step affiliation and meeting attendance and related effects on substance use outcomes in a sample of veterans with comorbid substance dependence and major depression who received six months of group treatment with TSF or ICBT.

Because fewer studies of mediating variables have focused on substance dependent patients with psychiatric comorbidity, there is relatively less knowledge about processes that sustain long-term change in their substance use outcomes. This study adds to the existing literature by examining post-treatment trajectories of change in 12-step affiliation and attendance in comorbid patients, determining whether treatment condition predicts individual differences in these trajectories,vertical farm cannabis and reporting the mediational effects of reduced 12-step involvement on long-term substance use outcomes. Veterans in the TSF condition had greater levels of 12-step affiliation and meeting attendance at end-of-treatment than those in ICBT. This is consistent with prior studies of this sample and shows that a professionally-delivered TSF intervention can enable greater levels of 12-step involvement than other psychotherapies during active treatment. However, veterans in TSF also evinced a significant nonlinear decline in both 12-stepaffiliation and meeting attendance during the one year follow-up, while those in ICBT had no significant change. Previous studies of non-comorbid patients found no post-treatment decline in affiliation or meeting attendance following 12-step interventions . Our contrasting findings suggest comorbid MDD may interfere with continued attendance at 12- step meetings and affiliation with prescribed 12-step behaviors, even when patients are relatively successful at achieving these goals during active TSF. Potential explanatory mechanisms behind this finding are beyond our current scope, but could be related to persistent depressive symptoms and related low motivation, the sudden absence of accountability provided by a formal treatment group, or difficulty in establishing firm social bonds in 12-step meetings for patients with comorbid MDD. Some patients were evidently successful at sustaining 12-step affiliation as revealed by significant individual variance estimates, but modifications to TSF or continued contact may be necessary to achieve the desired long-term results in the majority of patients with comorbid MDD. Independent of treatment condition, individuals with greater decreases in 12-step affiliation and meeting attendance also had greater increases in drinking frequency during the one-year follow-up. As evidenced by strong standardized coefficients in our latent growth curve models, post-treatment change in 12-step involvement likely plays a large role in determining whether patients with comorbid substance dependence and MDD experience post-treatment increases in drinking. Similar to a prior report of follow-up substance use outcomes in this sample , the current study found patients in TSF had greater post treatment increases in drinking frequency than those in the ICBT condition. We also determined this group difference was mediated through reductions in 12-step affiliation and meeting attendance, which provides a possible explanation for the worse outcomes over time for TSF and supports the long-term efficacy of ICBT. During follow-up the ICBT group as a whole did not increase or decrease in 12-step affiliation or meeting attendance, but their mean levels of attendance and affiliation remained consistently greater than zero. Although it was not a prescribed element of treatment, there is apparently a subset of patients in ICBT who continue 12-step involvement. Superior long-term patterns in other mediating variables may have also occurred for the ICBT condition, and future studies will explore other potential factors related to their superior post-treatment drinking outcomes. Limitations of this study include the restricted demographic characteristics of the veteran sample which curtails the immediate generalizability of these findings. Because we tested relations between concurrent changes in 12-step involvement and substance use, we cannot make conclusions about causal relationships, but other elements of our design and findings enhance the plausibility of causal conclusions . Our measures did not differentiate between different types of 12-step meetings , which could have helped explain the lack of findings for drug use outcomes, and future work might benefit from more detailed measures of 12-step involvement. Also, because our 12-step measures were relatively brief, there may have been important aspects of these behaviors we did not consider.

Finally, while the results have important implications for the broader population of individuals with substance dependence and MDD, replication in other samples and settings is needed.Both opioid dependent and opioid-independent forms of SIA have been identified. These mechanisms are differentially activated according to stressor parameters and duration . SIA elicited by intermittent foot shock is blocked by opioid antagonists , whereas SIA elicited by continuous foot shock is blocked by cannabinoid antagonists . We recently demonstrated that this nonopioid form of SIA is mediated by mobilization of two endocannabinoids, 2-arachidonoylglycerol and anandamide, in the dorsal midbrain . Opioid and nonopioid SIA share similar neuroanatomical substrates. For example, opioid and cannabinoid receptors populate brain regions regulating nociceptive responding, such as the periaqueductal gray and the raphe nuclei of the medulla. Like opioids, cannabinoids modulate distinct circuits within the midbrain PAG and the brainstem rostral ventromedial medulla . The competitive CB1 antagonist/ inverse agonist SR141716A microinjected into either the dorsolateral PAG or RVM also attenuates SIA. By contrast, inhibition of endocannabinoid hydrolysis at these sites enhances SIA . These data support the existence of supraspinal sites of endocannabinoid analgesic action. Cannabinoids produce antinociception through spinal as well as supraspinal mechanisms . The antinociceptive and electrophysiological effects of cannabinoids are attenuated following spinal transection. Nonetheless, a long-lasting residual antinociception remains in spinally transected mice , suggesting the existence of spinal sites of endocannabinoid analgesic action. These data are consistent with the presence of CB1 receptors in the spinal dorsal horn . Intrathecally-administered cannabinoids also produce antinociception and suppress noxious stimulus-evoked neuronal activity in spinal nociceptive neurons , suggesting a functional role for spinal cannabinoid receptors in modulating nociceptive processing. Intrathecal administration of either rimonabant or CB1 antisense oligonucleotides also elicits hyperalgesia , suggesting that endocannabinoids may act tonically to suppress nociceptive responding. However, a physiological role for endocannabinoids at the spinal level has not been identified. Both 2-AG and anandamide fully qualify as endocannabinoids .