Tolerance to baclofen may also develop with chronic administration

Posted on July 24, 2023 by hemp2022

Not all individuals with AUD consider abstinence to be a goal of their recovery; only 2–6% of goals set in patient-driven treatment center on attaining alcohol abstinence. Non-abstinent recovery, including reductions in drinking and heavy drinking in particular , has been recognized to have health and societal value and has gained traction as a treatment target . Indeed, non-abstinent AUD recovery has been shown to be sustainable for up to 10 years following treatment. Despite growing recognition of the benefits of harm reduction, however, the most commonly prescribed pharmacotherapy to treat AUD remains disulfram, a medication advised strictly for abstinence. Furthermore, the heterogeneity of AUD suggests that it will be unlikely that one single medication will be effective for all individuals with an AUD. Therefore, there is a pressing need for the development of novel, diverse, and effective pharmacological treatment options for AUD with the hopes of increasing utilization and improving care. The focus of the current review is to summarize pharmacotherapies for AUD with a clinical perspective. Specifically, this review provides a brief overview of currently approved medications and identifies new and repurposed agents “on the horizon” for which evidence indicates a potentially effective application toward AUD treatment.The following sections examine pharmacotherapies approved or in-development for AUD. Medications were selected for this qualitative review by considering gaps in existing review articles and the expertise of all authors; information was gathered via qualitative PubMed literature searches. This review is organized into sections based on drug approval status, namely approved medications, rolling vertical grow racks repurposed medications, and novel agents. Within each medication section, we examine the basic mechanism of action, evaluate preclinical research testing the efficacy of the medication in mitigating alcohol-related behaviors in animal models, and review clinical findings from human laboratory studies and randomized controlled trials where available.

We also examine the tolerability and potential personalized applications of each drug by identifying populations in which the drug may be particularly effective, and indicate treatment targets . This information is summarized in Table 1. We conclude by discussing future directions for the development of pharmacological treatments and precision medicine for AUD.This section briefly describes medications currently approved by agencies in many countries including the US FDA and EMA for the treatment of AUD: disulfram, acamprosate, and naltrexone , as well as nalmefene, which is EMA-approved. This section also reviews baclofen and sodium oxybate, which are medications approved for AUD treatment by agencies in European countries but not by the FDA or EMA. As many of these pharmacotherapies have been extensively discussed in the literature, our review of these medications primarily focuses on clinical trials and recent meta-analyses.Disulfram, the first medication FDA-approved for AUD treatment , is an aldehyde dehydrogenase inhibitor that acts by blocking the metabolism of alcohol, increasing acetaldehyde concentration. Acetaldehyde, a toxic metabolite of ethanol, produces an alcohol-induced aversive response, characterized by nausea, vomiting, sweating, flushing, and heart palpitations. Unsurprisingly, these unpleasant effects give disulfram a relatively poor adherence rate. Disulfram may also act on dopamine systems, as its major metabolite inhibits the enzyme dopamine betahydroxylase , which aids in metabolizing dopamine into noradrenaline. Serum DBH activity is associated with withdrawal symptoms, and disulfram has been shown to reduce serum DBH levels. A meta-analysis of 22 RCTs found that disulfram saw increased success rates compared to placebo in open-label studies only—blinded trials yielded no statistical significance between disulfram and placebo. However, while these findings do not appear to support the use of disulfram for treating AUD, this outcome may be due to placebo effects. Research showed that placebo-treated individuals showed decreases in cue-reactivity to alcohol stimuli in a sample of 38 participants, and experiencing an acetaldehyde reaction did not necessarily improve treatment response in a sample of 46 participants . Instead, a patient simply being aware of a potential adverse reaction appears to be enough to influence drinking behavior.

Disulfram ingestion under supervision saw significantly better success rates compared to non-supervised treatment, suggesting that supervised administration of disulfram may still have a place in treating individuals struggling to attain sobriety, and unsupervised disulfram may also be helpful for individuals highly motivated for abstinence. However, adherence management issues limit the utility of disulfram in the treatment of AUD, and the disulfram-ethanol interaction can sometimes present as a medical emergency. Therefore, disulfram is only recommended in the maintenance of abstinence; using this medication to reduce drinking is not advised.While the specific mechanisms through which acamprosate works to treat AUD remain under investigation, it is thought to act on the glutamatergic system as an N-methyl-d-aspartic acid receptor partial co-agonist. This may reduce neuronal hyperexcitability, a phenomenon that occurs in acute withdrawal and protracted abstinence from alcohol. A meta-analysis of 27 RCTs with a total of 7519 participants found that acamprosate treatment reduced risk of abstinent patients returning to any drinking, but did not reduce rates of binge drinking. A number of trials have also found that acamprosate did not show a significant beneft over placebo. In particular, a large scale trial , which compared acamprosate, naltrexone, and behavioral therapies, both individually and combined with each other, against placebo , found that acamprosate had no significant effect on drinking in comparison to placebo, either alone or in combination with naltrexone and/or behavioral intervention. Placebo effects in this trial may explain some of these negative outcomes, as might differences in trial design and patient characteristics: COMBINE required 4 days of pre-trial abstinence while European trials with positive outcomes were typically conducted in inpatient populations requiring complete detoxifcation. Overall, however, a Cochrane meta-analysis of 24 RCTs with 6915 participants found that acamprosate significantly reduced the risk of any drinking and increased cumulative duration of abstinence. Acamprosate is generally well tolerated and may also have neuroprotective effects. As chronic alcohol abuse is associated with neuronal changes related to NMDA receptors, this neuroprotection may be particularly important in AUD treatment.

Acamprosate is recommended for the achievement and maintenance of complete abstinence, rather than for the reduction of drinking or prevention of relapse in the event of drinking. It is FDA-approved for abstinence maintenance in AUD patients who are abstinent when beginning treatment.Naltrexone, the best-studied of these three commonly approved medications, was originally approved to treat opioid use disorder. Naltrexone is an antagonist of the mu opioid receptor . By attenuating alcohol-induced opioidergic activity in the mesolimbic dopamine system, opioid antagonists like naltrexone, modulate the rewarding effects of alcohol , thereby reducing alcohol consumption. In 1994, the FDA approved oral naltrexone to treat alcohol dependence after two independent 12-week trials, which included 97 and 70 participants, respectively, found that naltrexone significantly decreased drinking days and relapse rates. Additional recent trials demonstrate that naltrexone reduces the rewarding effects of alcohol, alcohol craving, drinks per drinking day, and relapse rates, strengthening the initial findings. Extended-release injectable naltrexone , administered once monthly by a medical professional, may be beneficial for individuals who are more sensitive to naltrexone’s adverse side effects or have difficulty adhering to oral medication. A six-month multisite trial of 380 mg injectable naltrexone in 624 patients with alcohol dependence found significant reductions in heavy-drinking days versus placebo . However, evidence for naltrexone remains mixed. Another RCT reported no significant differences between naltrexone and placebo , and that the clinical utility of naltrexone was limited by its adverse effects. Additionally, clinical trials of naltrexone often yield modest effect sizes. A meta-analysis of 53 naltrexone RCTs with a total of 9140 participants found naltrexone to significantly reduce both the risk of return to any drinking and return to binge drinking; however, both of these associations were modest in magnitude. Oral and injectable naltrexone show similar decreases in likelihood of binge drinking and both are generally well tolerated,vertical cannabis grow racks with fairly mild side effects. Importantly, however, naltrexone does block the therapeutic effects of opioid analgesics and can precipitate opioid withdrawal in patients who have developed physical dependence to opioids; therefore, individuals who are prescribed naltrexone for AUD must be monitored for opioid use and withdrawal. Of note, naltrexone is contraindicated for patients with acute hepatitis or liver failure, and should be “carefully considered” in patients with acute liver disease, potentially limiting its use in the alcohol-associated liver disease population. In summary, naltrexone appears to have a moderate effect on the reduction of alcohol use.Nalmefene works in a similar manner to naltrexone as an antagonist at the mu and delta opioid receptor, but is also a kappa opioid receptor partial agonist. Via its kappa agonist activity, particularly centered in dopaminergic nucleus accumbens circuitry, nalmefene may reduce motivation for self-administration and withdrawal-induced alcohol consumption. Nalmefene was approved by the EMA in 2013 for the reduction of alcohol consumption among patients with AUD.

Approval followed findings from three multicenter 6-month clinical trials enrolling 604, 667, and 718 individuals, respectively, in which participants took the medication or placebo on an as-needed basis. In these trials, nalmefene decreased total alcohol consumption and heavy-drinking days. However, the drug’s approval based on these studies has received criticism due to limited evidence of efficacy, especially as these trials were conducted only against placebo rather than an active medication comparison. A more recent meta-analysis of the efficacy of nalmefene, which included fve RCTs , found that participants treated with nalmefene had 1.65 fewer heavy-drinking days per month than participants treated with placebo after 6 months. Studies indicate that nalmefene is associated with more adverse events and study dropouts compared to placebo, and the most frequently reported of these are dizziness, nausea, vomiting, insomnia, and headache. Overall, while nalmefene may reduce heavy-drinking rates, its effects on other outcomes remain small-to-moderate, and study withdrawals related to adverse events are common in nalmefene trials. However, similar to naltrexone, this medication may appeal to patients with goals of reducing alcohol consumption and those reluctant to engage in abstinence based treatment.Baclofen acts on the γ-amino butyric acid system as a GABAB agonist. It was approved for treatment of AUD in France in 2018 and has been used of-label for AUD for over a decade in other countries, especially other European countries and Australia. Clinical trials of baclofen have produced mixed results. A recent meta-analysis of 12 RCTs showed that baclofen in comparison to placebo was associated with higher abstinence rates; however, it did not increase abstinent days or decrease craving, heavy drinking, depression, or anxiety. Another meta-analysis of 13 RCTs indicated that baclofen was associated with longer time to relapse and a larger percentage of abstinent patients. Furthermore, greater alcohol use at baseline was correlated with a greater treatment effect. In contrast, however, another recent meta-analysis of 12 RCTs with 1128 total participants found no significant differences between baclofen and placebo in primary or secondary outcomes of interest ; however, baclofen did increase depression and adverse effects including sedation and vertigo. Baclofen’s significant adverse side effects include drowsiness, sedation, headache, vertigo, confusion, perspiration, muscle stiffness and/or abnormal movements, slurred speech, and numbness.Additionally, dose and sex may moderate baclofen tolerability and response; escalation of dosage in response to developing tolerance can increase sedative side effects, which affect women significantly more than men at the same dose. Importantly, cessation or reduction in dose can precipitate potentially life-threatening withdrawal syndrome. The variability in baclofen’s effectiveness seen across studies may be partially explained by high baclofen pharmacokinetic variability seen among individuals with AUD. This heterogeneity is an important factor to take into account when considering baclofen as an AUD treatment . Of note, there is also some evidence that baclofen might be particularly useful in treatment of AUD among individuals with liver disease. In summary, baclofen seems to effectively promote abstinence; however, it shows mixed results regarding its clinical effects on non-abstinence outcomes , significant adverse side effects, and inter-individual variability in response. As such, baclofen as a treatment of AUD—as well as its optimal dosage—continues to be debated.Sodium oxybate , the sodium salt of gamma-hydroxybutyrate , has been utilized as a medication for a number of disorders. SMO is approved in Italy and Austria for the treatment of AUD. SMO acts on the GABA system both directly as a GABAB partial agonist and indirectly through GHB-derived GABA. A Cochrane meta-analysis of 13 RCTs with a total of 649 participants found that SMO was effective compared to placebo in the treatment of alcohol withdrawal syndrome and in preventing relapses in previously detoxifed participants, and that SMO was more effective than naltrexone and disulfram in maintaining abstinence.Another recent meta-analysis found that SMO, compared to placebo, increased abstinence rates by up to 34% in a sample of 711 participants with very high drinking risk levels.

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The study also revealed additional findings regarding BUP dose and treatment retention

Posted on July 21, 2023 by hemp2022

Other findings of the study are also consistent with prior literature, including higher dose related to longer retention, use of other drugs associated with lower retention, and opiate use during treatment negatively related to dose for both groups. The unique contribution of the present study is that these findings were confirmed with this randomized trial conducted in community treatment programs in the U.S.First, approximately 25% of the BUP participants dropped out within first 30 days of treatment, suggesting a critical period calling for special efforts in retaining these participants. Second, of those who remained in treatment, positive opiate urine results were significantly lower among BUP relative to MET participants during the first 9 weeks of treatment. This finding confirms the advantage of BUP requiring a much shorter time for induction than MET. Third, there was a linear positive relationship between BUP dose and the treatment completion rate, suggesting the benefit of dosing greater than the common practice of a maximum dose of 16mg. However, even with the highest BUP dose level of 30–32mg allowed in this trial, the retention rate was less than the rate in the MET group , and approximately 30% of the participants continued opioid use. Besides additional strategies focusing on retaining BUP participants beyond 30 days of treatment, these findings suggest that participants may yet fare better with BUP doses higher than the 32mg used in this study. Given the generally high safety profile of BUP and the lack of any significant side effects and other adverse effects at the high dose range observed in this study, we believe with proper monitoring safety will not be a clinical concern in such an effort.Finally, the study has identified additional participant characteristics predicting dropout, including being young, Hispanic, and concomitant use of heroin or other drugs such as cannabinoids,grow cannabis cocaine or amphetamine during treatment. Treatment programs may consider paying special attention to patients with these characteristics to prevent dropout. It should be noted that our finding on cannabinoids is in contrast to most prior studies that have found no effect of the use of cannabis on methadone treatment outcomes including treatment retention.

A potential explanation for this discrepancy may be that strains of marijuana available more recently, when the current study was conducted, have been deliberately bred to have high concentrations of delta-9-tetrahydrocannabinol making them much more potent and potentially more destabilizing for patients on opioid maintenance therapy. The study has several limitations. There were limited measures of participant motivation and program and community characteristics that are likely to influence treatment retention. Reasons for dropout were coarsely recorded; although the data did indicate that many more BUP participants simply discontinued their treatment. A qualitative study of this sample has suggested that BUP participants reported negative physical reactions or did not like BUP,being previously familiar with MET, and thus dropped out.The findings must also be taken in the context of an open-label, unblinded clinical trial. Despite these limitations, the study revealed several important findings as discussed earlier. Given the linear trend of higher BUP dose related to increased retention, future studies should investigate if BUP doses greater than 32mg should be considered to increase retention, and perhaps to further reduce opioid use during treatment. One study which examined BUP doses of 24–56mg/d among 650 patients showed a retention rate over 92% at 30 months and, similar to the present investigation, decreasing rates of illicit substance use at the higher doses.In research or clinical practice, BUP is often prescribed at a dose of 16mg or lower, as BUP is an opioid partial agonist with a ‘ceiling effect’ for respiratory depression and in previous human laboratory studies, higher doses of BUP revealed a flattening out of the dose-effect curve, i.e. increasing doses do not result in greater changes in subjective measures or respiratory rate.A recent review article indicates that the risk of respiratory depression associated with BUP is lower than with other opioids including methadone.It appears that the current common practice of prescribing at a dose of 16mg per day and not to exceed 32mg maximum is driven by the ceiling effect observed and a few PET scan studies showing high mu receptor occupancy as well as concerns about diversion.However, these studies were based on small samples and do not take into account inter-individual variation and the other potential non-mu effects of BUP.

History has taught that for about 20 years it was common to have MET dose ceilings of 40mg per day, but it is now well established that this is inadequate to maintain the necessary plasma concentrations to be effective; the effective range is between 60mg and 120mg or higher per day for most patients.The current study suggests the possibility of BUP at a dose of 32mg or higher having a potential impact on improving treatment retention and outcome. Thus, further investigations of the safety, efficacy, and clinical utilities of higher doses of BUP should be considered. The high dropout rates at the early phase of BUP treatment suggest the need for early interventions to prevent dropout. It is possible that more intensive psychosocial support could help, although studies to date indicate little benefit to increased counseling for patients treated with buprenorphine.An alternative approach as propounded by Kakko et al. and demonstrated efficacious in a randomized trial is prompt, early transfer to MET of patients who do not quickly stabilize on BUP.A more widespread introduction of contingency management into opioid treatment programs could also help to optimize retention and outcomes for both BUP and MET.Finally, heroin-assisted treatment is used in several European countries with success, particularly for people with opioid dependence who continue intravenous heroin while on methadone maintenance or who are not enrolled in treatment.BUP retention may also be improved with take-home doses as permitted by regulation and as standard in office-based practice supervised by physicians, which obviates the need for daily attendance in clinic for dosing. As described earlier, the trial was conducted among community methadone maintenance programs and thus may not be optimal for delivering BUP treatment. The nine clinics were all federally licensed opioid treatment programs that have provided treatment with methadone for many years. All staff and most participants had previous experience with MET, and participants came to these programs for methadone treatment. Because BUP was delivered within these methadone maintenance programs, all programs delivered BUP following the same rules and regulations for methadone prescription ,indoor cannabis grow system precluding the flexibility and individualization possible in office-based treatment that may help to retain some patients.The differential retention of males by medication condition has no definitive explanation and deserves future investigation. Since opioids suppress the hypothalamic-pituitary-gonadal axis leading to lower testosterone levels, it may be that BUP, as a partial agonist, does so less than MET, and thus males find BUP more tolerable in that regard.

In conclusion, the study findings suggest the need to investigate the use of higher medication doses, particularly for BUP, address continued use of opiate and other drugs such as cocaine, amphetamines, and cannabinoids, and further study and identify factors/ strategies influencing BUP retention, particularly during the first 30 days of treatment in order to help in efforts to improve engagement and retention in opioid treatment programs.The cannabinoid system has an important impact on liver-related fibrosis, steatosis, regeneration, and portal hypertension. Endocannabinoid ligands are ubiquitous and interact with cannabinoid receptors 1 and 2, which have high affinity for tetrahydrocannabinol , the psychoactive mediator of marijuana. Under physiologic conditions, hepatic expression of CB1 and CB2 is weak or absent. However, both receptors are up-regulated in a variety of liver diseases, including alcoholic and nonalcoholic liver disease, liver fibrosis, chronic hepatitis C, primary biliary cirrhosis, and hepatocellular carcinoma. Limited studies have examined the impact of THC use and liver fibrosis progression, with conflicting results. Some cross sectional studies have shown evidence of increased fibrosis, and other longitudinal studies of relatively short duration suggest no impact on fibrosis progression. Data are lacking on the influence of long-term THC use on liver-related outcomes such as fibrosis in human immunodeficiency virus /hepatitis C virus –coinfected individuals. For this reason, we sought to examine the impact of THC use on liver fibrosis progression in a well-characterized cohort of women coinfected with HIV and HCV.The Women’s Interagency HIV Study is a prospective, multi-center, longitudinal observational cohort of adult women infected with HIV or at high risk of acquiring HIV, described in detail elsewhere. Approximately 30% of HIV-infected women enrolled were coinfected with HCV prior to enrollment in WIHS. A total of 4137 women have been enrolled in the first 3 enrollment cohorts . All women gave informed consent at entry, and the study was approved by each center’s institutional review board. Patients are seen in follow-up every 6 months, where detailed sociodemographic, medical, and behavioral data are collected through structured interviews, physical examination, and biologic specimen collection. As of visit 37 , a total of 790 women with HIV/HCV coinfection at baseline had enrolled in the WIHS into cohorts 1 and 2, and were included in our analysis. HIV infection was confirmed by positive HIV enzyme-linked immunosorbent assay and a confirmatory Western blot, and HCV infection was defined as a positive result for serum HCV RNA at entry into the study. THC use is prevalent in the WIHS; 14% of participants regularly use marijuana, and 6% report daily use. Liver biopsy is not performed as part of the WIHS observational study. However, noninvasive markers of liver fibrosis, aspartate aminotransferase to platelet ratio index , and FIB-4 have been validated in this cohort.Sociodemographic data including age, ethnicity, race, and past substance use were collected at entry into WIHS. Biologic specimens were collected at visits every 6 months with testing for liver enzymes, renal function, complete blood count, CD4 count, and HIV RNA load. HIV RNA was measured using the isothermal nucleic acid sequence–based amplification method with a lower limit of detection of 80 copies/mL.

Highly active antiretroviral therapy was defined by the contemporaneous US Department of Health and Human Services guidelines. Second- or third-generation enzyme immunoassays were utilized for HCV antibody detection and confirmed by documenting HCV RNA seropositivity and by reverse transcription polymerase chain reaction . Hepatitis B was tested within the first year of enrollment and was defined as hepatitis B surface antigenemia. Data including body mass index, history of hypertension, diabetes, and insulin resistance were collected. Diabetes was defined as any fasting glucose measurement of >126 mg/dL, hemoglobin A1c measured at ≥6.5%, or self-report of taking antidiabetic medication.Discrete variables were summarized using frequency and percentages; continuous variables were summarized using mean and standard deviation for normally distributed data, and median and interquartile range for non-normally distributed data. Comparisons between THC use groups were made using the χ2 or Fisher exact tests for categorical data and analysis of variance or Kruskal–Wallis tests for continuous data. The cumulative probability of progression to advanced fibrosis was estimated using the Kaplan–Meier method and compared by THC use category with the log-rank test. All analyses were 2 tailed, with P < .05 considered statistically significant. Risk of progression to advanced fibrosis was evaluated separately for FIB-4 and APRI outcomes using Cox proportional hazards regression. Hazard ratios and 95% confidence intervals were calculated from the models. To account for the fact that patients must remain alive to enter the study, age at study entry was treated as a left-truncated variable with age used as the time scale. Patients were followed until their first visit with significant fibrosis or were censored at the date of last fibrosis measurement for those not progressing to the event. Factors with a univariable P < .1 and THC use were evaluated in the multi-variable model. The model was selected by backward elimination with P > .05 for removal from the model. The final model included 2 additional variables: biologically relevant HCV RNA and evaluate whether long-term THC exposure impacted fibrosis progression. We also conducted sub-analyses in participants with at least mild fibrosis to evaluate whether the presence of some fibrosis is a prerequisite for THC to modulate fibrosis progression. Data were analyzed using SAS software version 9.4 .

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Outliers were determined as values greater than 3 standard deviations from the grand mean

Posted on July 20, 2023 by hemp2022

The objective of the current study was to assess everyday functional ability in four groups of individuals stratified based upon their HIV status and history of METH dependence, using the UPSA-2 to assess the individual and interactive effects of HIV and METH dependence on specific and essential domains of everyday functioning. We hypothesized that participants with both HIV infection and a history of METH dependence would have lower scores on the UPSA-2 than subjects with either condition alone and non-infected non-METH dependent comparison subjects. A secondary aim was to assess to what extent performance on the UPSA-2 measures would correlate with HIV illness features , and METH use characteristics within our HIV+ and METH-dependent participants, respectively. This investigation was a component of the Translational Methamphetamine AIDS Research Center , which is a multi-project center grant focused on translational approaches to understanding the combined effects of HIV and methamphetamine dependence on brain structure and function. The UCSD Human Research Protections Program approved the study. All human participants in the TMARC cohort were included. Participants were stratified by HIV and METH dependence status into one of four groups: HIV−/METH− , HIV−/METH+ , HIV+/METH− , and HIV+/METH+ . HIV infection was determined by Enzyme-linked immunosorbent assay and a confirmatory Western blot. The presence and history of METH use disorders were determined via the DSM-IV criteria for METH abuse and dependence as assessed by the Composite International Diagnostic Interview Version 2.1 [CIDI; ]. Participants who met criteria for both lifetime METH dependence and METH abuse or dependence within the past 18 months were included in the two METH+ groups. Potential participants were excluded if they reported histories of psychosis or significant medical or neurological conditions known to affect cognitive functions.

To minimize the confounding effects of acute drug use ,cannabis vertical farming participants who tested positive for METH or any other illicit drugs were also excluded. In the first domain, comprehension and planning skills were assessed by having participants read a fictional article about the opening of a theme park and then described the activities at the park and planned a trip to the recreational facility. Financial ability was evaluated by a counting change task and having the subjects identify important aspects of a utility bill. Communication skills were assessed through role-playing tasks that asked participants to use telephone to schedule a medical appointment. The Transportation domain involved reading and interpreting a generic bus route and planning the use of a public bus system. Household skills were assessed by requiring preparation of a shopping list for a specific cooking task based on food items presented in a mock pantry. Finally, for the Medication Management domain, participants were required to organize a medication routine where they were asked to role-play how they would take a number of different medications over the course of a single day. Administration of the UPSA-2 requires about 30 minutes. Each of the UPSA-2 domains generates a raw score that is converted to a domain score ranging from 0 to 20 points. The 6 domain scores are summed to create a total UPSA-2 score up to a maximum of 120 points, with higher scores indicating better performance. For the purpose of examining the UPSA-2 measures in relation to HIV disease characteristics and METH use patterns, participant characterization data were drawn from the TMARC parent study. Selected HIV disease-related variables included current and nadir CD4+ T-cell counts, plasma viral loads, and self-reported duration of HIV infection. Self reported METH use characteristics were collected using a comprehensive timeline follow back procedure and included age of first use of METH, days since last use of METH, total days of METH use, and total quantity of METH used.UPSA-2 total and sub-scale scores were examined for outliers, normality of distribution, and homogeneity of variance. In order to preserve the relative value of these data points and retain power, outliers were truncated to within 3 standard deviations of the mean, per published methods . A total of ten outliers were truncated .

Main effects of HIV, METH, and their interaction on UPSA-2 performance were examined for the Total Score and sub-scale scores using Univariate Analysis of Variance . Three between-subjects factors were entered into the models, as well as their interaction: METH status , HIV status , and education level . Years of education was selected a priori as an additional between-subjects factor given the difference in education among the groups, the significant relationship between education and UPSA scores , and previous reports of a significant relationship between education and UPSA scores . Planned contrasts were conducted on the four groups. When other demographics were associated with the sub-scales, those factors were included in the analysis to account for their effects . Pearson’s correlation coefficients were used to assess the relationship among UPSA-2 scores and HIV disease characteristics as well as METH use features. An independent samples test was used to assess difference in UPSA-2 scores between participants with and without a detectable plasma viral load. The HIV viral load measure and METH use measures were significantly positively skewed; log transformations of those variables were thus entered into the analyses. All analyses were performed using SPSS 20. Significance values were set at p < .05, and effect sizes were calculated using partial Eta-squared and Cohen’s d.See Table 1 for demographic information and HIV and METH features. The groups did not differ by age or ethnicity, but a greater proportion of the HIV−/METH− group were women. The HIV−/METH+ group had significantly fewer years of education and lower scores on the Wide Range Achievement Test than the other three groups. Consistent with previous literature , all three risk groups had higher scores on a depression scale, the Beck Depression Inventory , than the HIV−/METH− group. Global Deficit Scores , a gross index of neurocognitive deficits , were lower in the HIV−/METH− group but not significantly different among the three risk groups. Participants in the METH groups had a higher prevalence of lifetime substance use disorder than the METH-negative groups. Ten participants had a positive urine toxicology for cannabis; these participants did not have significantly different UPSA-2 scores than the remainder of the cohort. Better-educated participants performed better on the Financial and Communication sub-scales , with a trend toward Medication Management and Comprehension sub-scales . Thus, education level was included as a between-subjects factor in the analyses.

Higher WRAT-4 scores were positively correlated with higher scores on the Medication Management, Financial, Communication, Transportation, and Household Management scales . Given that WRAT-4 performance is an index of premorbid verbal intelligence, which in turn is highly dependent on education level, including education in the analyses was intended to account for the group differences in premorbid intelligence as reflected by both education and WRAT-4 scores. Men and women did not differ on most UPSA-2 measures although women performed better than men on the Communication sub-scale. The analysis involving Communication was thus repeated with gender as a between-subjects factor in a univariate ANOVA to account for its influence. The two HIV+ groups did not differ on any HIV illness features,cannabis drying racks and the two METH+ groups did not significantly differ on self-reported METH use history and characteristics. Approximately 70% of the HIV+ subjects reported current use of ART medications ; this proportion did not differ in the METH− vs. METH+ groups nor did the groups significantly differ on duration of ART treatment. All participants were taking a nucleoside reverse transcriptase inhibitor ; 56% were also on a protease inhibitor ; 33% were on a non-nucleoside reverse transcriptase inhibitor ; 15% were on an integrase inhibitor ; and 6% were on an entry inhibitor . A small proportion of participants on ART had a detectable plasma viral load; these participants were equally distributed in the two METH groups.People with METH dependence evidence difficulty with tasks of daily living , as do those with HIV infection , and in combination these risk factors result in an additive effect on self-reported everyday functioning . However, the combined effect of METH dependence and HIV has not previously been investigated with the use of performance-based functional measures that are likely a better reflection of an individual’s actual real-world functioning than self-report. We expected that there would be an additive deleterious effect of METH and HIV given previous findings of worse neurocognitive impairment in dually-affected participants. Contrary to our hypotheses, people with both HIV infection and METH dependence showed impairment on a performance-based measure, the UPSA-2, which was equivalent to that evidenced by individuals with either condition alone. It is important to note that the three risk groups performed comparably and it is unclear why having two risk factors did not result in disproportionately worse performance relative to those with single risk factors.

The lower level of education in the HIV−/METH+ group does not account for the findings, nor does use of ART. The number of individuals with a detectable viral load despite ART use, which may reflect sub-optimal adherence to ART but may also indicate non-responsivity to ART, was not different in the two HIV groups. We were likely under powered to detect effects of ART non-adherence and differential effects of specific ART regimens. Although Blackstone and colleagues did observe additivity of HIV and METH on a composite measure of everyday functioning that was largely comprised of self-reported information , the present findings are consistent with an earlier report of a lack of additive effect of METH and HIV on self-reported measures of functioning . Our group and others have previously observed an additive effect of METH and HIV on neurological and neurocognitive functions , but the current results are consistent with findings based on other neurobehavioral and neuroimaging markers. For example, additive effects of HIV and METH were not observed for behaviors associated with frontal systems dysfunction, including sensation-seeking, impulsivity/disinhibition, and apathy; moreover, a similar pattern of results was observed for impulsivity/disinhibition such that an HIV-by-METH interaction revealed an effect of METH among HIV-negative participants but not in the HIV-positive group . There is also some neuroimaging evidence that the combination of these two conditions mitigates brain changes that are seen in HIV infection or METH dependence alone . Additionally, though not assessed in the current study, age may be relevant. Although some cognitive functions such as impulsivity and risky decision making may decrease with age in the general population , a recent study found that older HIV+ individuals with a history of METH dependence did have substantially poorer functioning than younger participants, possibly suggesting increased vulnerability to combined risk factors in the context of aging. The average age of the current sample was just 40 years thus we could not examine the effects of aging. Studies are in progress to further investigate the impact of aging on cognition and functioning in METH and HIV. An alternate reason that the dual-risk group does not appear to have worse everyday functioning than either risk group alone may be the fact that METH users who must manage their HIV disease face challenges of everyday living when compared to their METH– dependent, HIV-negative counterparts that force them to develop skills that would detected by the UPSA-2. For example, they must navigate the medical system in order to obtain and maintain healthcare—relevant tasks would include transporting themselves to medical appointments, managing extensive and sometimes complex medication regimens, and other challenges that could negatively impact treatment adherence . Therefore, participants in this group may be relatively “practiced” at meeting the demands of everyday living. Social factors may be relevant; e.g., having an HIV-positive partner could result in the modeling of adaptive health behaviors such as medication adherence and drug abstinence . A comparison of the demographic, HIV illness features, and METH use features of the current dually-affected cohort and the relevant cohort in the Blackstone et al. study suggests a somewhat more cognitively intact and healthier group in the current study with higher WRAT-4 scores, more education, higher CD4 counts, higher prevalence of ART use, and less METH use compared to the Blackstone et al. participants.

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Exaggerated emotion reactivity to stress has been related to poorer health

Posted on July 19, 2023 by hemp2022

These results indicate that METH may not only hinder brain development and The present study examined how differences in the stress response related to substance use in a sample of Mexican-origin youth growing up in a low-income region with high levels of adversity . Using a longitudinal study design, we tested whether differences in HPA axis reactivity and emotion and recovery to stress at age 14 were associated with use of alcohol, marijuana, and cigarette use by age 14 ; use of alcohol, marijuana, cigarettes, and vaping of nicotine by age 16; and onset of alcohol, marijuana, and cigarette use between ages 14 and 16. Finally, we tested whether associations between stress reactivity, stress, recovery, and substance use varied by poverty status and sex. Substance use greatly increases during adolescence, as the percentage of students who have used an illicit drug doubles from 8th to 10th grade, and nearly half of students report using at least one substance by 12th grade . Although experimentation is common in adolescence, youth who use alcohol, tobacco, and marijuana earlier in adolescence are at higher risk for psychopathology and substance use disorders in adulthood . Previous research has also consistently found that use of alcohol and marijuana by ages 14 and 16 specifically are related to poorer adjustment and higher use later in adolescence and adulthood . Risk is particularly high for Latinx adolescents, who show higher lifetime use of varied substances by 8th grade and by 12th grade compared to White and Black youth, and tend to begin using cigarettes, alcohol, and other drugs at earlier ages than other ethnic minorities . Furthermore, prior research suggests that Mexican American adolescents, specifically, are more likely to have initiated substance use by the eighth grade than non-Latinx and other Latinx youth . People generally respond to stress by showing increased negative emotion, decreased positive emotion, and activation of the HPA axis, a biological system especially sensitive to social-evaluative stressors .However,cannabis grow kit inability to mount a response or showing blunted reactivity to stress may suggest disengagement and has also been related to poorer well-being .

Dampened reactivity and recovery following stress have also been related to poorer health including depression and externalizing problems . Individuals can show blunted rather than exaggerated stress reactivity and recovery for many reasons . Individuals who experience chronic or repeated stress may initially show heightened emotional and biological stress reactivity and recovery, and these responses may habituate and show a blunted profile over time . Therefore, whereas unpredictable, acute stressful life events may promote a profile of exaggerated reactivity to stress, living in adversity can serve as a chronic stressor and consequently can promote inflexibility of psychobiological systems over time, such that individuals are incapable of responding to acute stressors . Indeed, youth and adults who experience more adversity generally show blunted rather than enhanced cortisol and heart rate reactivity to acute stress , as well as reduced activation of neural regions involved in threat such as the amygdala . It has been posited that individuals who experience high levels of adversity may be inclined to disengage from stressors, which can attenuate psychobiological reactivity and recovery . Lastly, low reactivity may result from socialization from peers and parents . For instance, youth who experience adversity may interact with deviant peers or bullies who prompt them to be less responsive to stress and may be socialized by parents to be less affected by daily stressors . Just as heavy substance use can dysregulate HPA axis function , dysregulation of the HPA axis may also contribute to substance use risk. Youth with blunted HPA axis reactivity to stress may lack physiological inhibitory control, such that they may be less inhibited by the social consequences of risk-taking compared to adolescents who show greater cortisol reactivity to stress . Alternatively, adolescents with chronic under arousal may be generally more inclined to pursue risky behaviors to promote physiological arousal . Youth may not show cortisol reactivity to a stressor because they are not sensitive to that stressor, or because they have already become elevated in anticipation of a stressor .

That is, certain youth may be more responsive to the threat such that they already show elevated levels of cortisol prior to stress onset and consequently show no further elevation in cortisol thereafter. Both blunted cortisol reactivity and anticipatory cortisol have been associated with more frequent substance use later in adolescence, especially among youth with difficulties in emotion regulation . Dysregulation of HPA axis function may similarly promote risk for lifetime substance use during adolescence. Adolescents with higher basal cortisol had earlier onset of substance use, although cortisol was not assessed following stress , and blunted cortisol secretion in anticipation of a laboratory task has been linked to greater substance use in pre-pubertal boys . Given the potential for bidirectional associations between HPA axis function and substance use, longitudinal studies are needed to disentangle whether HPA axis reactivity to and recovery from stress relate to risk for substance use onset during adolescence. Specifically, it is well-established that heavy substance use—as opposed to substance use initiation or less frequent substance use—can dysregulate physiology , so researchers may be best positioned to examine the role of physiology on substance use risk during adolescence when youth are initiating substance use but have not yet engaged in heavy substance use. In addition to cortisol reactivity, emotion reactivity to stress may relate to substance use. There are several emotion-related risk factors for substance use and substance use disorders in both adults and adolescents, including greater negative emotions, emotional lability, and emotional dysregulation . Although it is well-established that emotions influence frequency of substance use among users, it remains unclear whether emotion reactivity to stress relate to adolescents’ risk for substance use initiation. Emotion reactivity to stress often includes increases in negative emotions of both high arousal and low arousal and decreases in positive emotion, and each form of emotional change can have unique implications for health . Youth with exaggerated and dampened stress reactivity and recovery with respect to emotion may be particularly at risk for earlier onset of substance use, especially for Mexican-heritage adolescents, who experience culturally-specific stressors .

Therefore, research is needed to determine whether emotion reactivity to stress and recovery from stress is related to substance use and the emergence of substance use among these youth.The impact of stress reactivity and recovery on substance use during adolescence may vary by sex. Adolescents’ motivations for substance use differ by sex . Male youth tend to be more motivated to use substances for social enhancement whereas female adolescents are more motivated to use substances to cope with negative emotion and stress . Further, female adolescents show higher comorbidity between substance use and depression relative to male adolescents,cannabis grow supplies suggesting that emotion and stress may be particularly tied to female adolescents’ substance use . Therefore, although male adolescents tend to show earlier and more frequent substance use relative to female adolescents , substance use may be particularly related to the stress response among female adolescents. Indeed, prior research regarding youth who have used substances by age 16 in this cohort of Mexican-origin adolescents has found that greater cortisol reactivity relates to earlier age of initiation of alcohol use for girls, whereas blunted cortisol reactivity was related to earlier initiation of marijuana use only for boys with less advanced pubertal status . It is critical to disentangle whether differences in stress reactivity and recovery precede substance use across the sexes.Poverty status may also moderate associations between responses to stress and substance for two reasons. First, early life adversity including poverty status has been found to influence psychobiology such that youth who experience early life adversity, including youth below the poverty line, tend to show profiles of blunted cortisol responses to stress . Because these youth are already at heightened risk for blunted cortisol responses, the association between these responses and substance use may be stronger among these youth. Second, poverty status may influence adolescents’ propensity for substance use. Youth below the poverty line may experience earlier exposure to substance use and substance-related crime, more targeted marketing of substances, and lower parental involvement . They may also be more motivated to use substances for reasons beyond stress, such as due to boredom, sensation seeking, and pursuit of enhancing effects in order to compensate for a lack of pleasurable substance-free daily activities . Poverty status may similarly influence the types of substances that adolescents use. Whereas cigarette use is more common among youth with lower socioeconomic status, marijuana, alcohol, and vaping are generally more prevalent among more affluent youth, potentially due to differences in cost, availability, and social norms . As a result, associations between stress reactivity and recovery and certain substances may differ by poverty status. The present study investigated whether adolescents’ HPA axis and emotion responses to the Trier Social Stress Test , a validated paradigm for eliciting social-evaluative threat, were related to the use of various substances among Mexican-origin youth growing up in a low income, high-risk agricultural setting . Responses to a social stressor were selected because adolescents tend to be particularly responsive to social threats, compared to younger children and adults , and youth often use substances in peer contexts to reduce social stress or enhance social experiences.

In line with prior research highlighting how people vary in the types of emotions they experience in response to stress , we examined changes in three emotions following stress: anger, sadness, and happiness. Discrete emotions have different functional purposes and have unique impacts on cognitions and judgments . Therefore, rather than aggregating across emotions, we assessed unique effects of each emotion. We tested whether stress reactivity and recovery related to substance use among adolescents at heightened risk for substance use, in line with previous studies that have examined substance use initiation in high-risk samples . Most prior studies examining stress responses and substance use have been conducted in the context of adult substance users or with cross-sectional designs . Therefore, we employed a longitudinal design to disentangle whether dampened psychobiological stress reactivity and recovery at age 14 precede the emergence of substance use initiation by age 16. Models examined whether differences in adolescents’ HPA axis and emotion reactivity and recovery to the TSST at age 14 were related to a) use of substances by age 14, b) use of substances by age 16, and c) emergence of substance use between ages 14 and 16, excluding youth who had already used by age 14. Given the high levels of adversity in this sample, dampened psychobiological stress reactivity and recovery were predicted to be associated with use of alcohol and marijuana among these youth, in line with previous research . Although not previously tested with use of cigarettes and vaping, we examined whether dampened psychobiological reactivity and recovery would similarly relate to these substances which are also commonly used in adolescence. Finally, models examined whether associations between HPA axis and emotion stress reactivity and recovery and substance use differ by sex and poverty status. Given that female adolescents may be more inclined than male adolescents to use substances to reduce negative emotion , we predicted that associations between dampened stress reactivity and recovery and substance use would be stronger for female adolescents than male adolescents. Because poverty status can promote profiles of dampened reactivity and can influence the types of substances that youth use , we tested whether associations differ by poverty status.Adolescents provided four 1-2 mL saliva samples via passive drool throughout the task. They provided the first sample after spending over two hours in the laboratory environment, during which they completed benign surveys, and then resting in the lab for 10 min. The second sample was collected immediately after the TSST was completed, roughly 15 min. after TSST onset. The third sample was collected 30 min. after TSST onset, and the fourth and final sample was collected 60 min. after TSST onset. This sampling procedure was similar to previous administrations of the TSST .

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Binge drinking in the past year was measured using standard cutoffs

Posted on July 18, 2023 by hemp2022

Evidence based psychotherapies for trauma that include focus on stress management and interpersonal effectiveness such as Skills Training in Affect and Interpersonal Regulation , may be particularly meaningful for CHR subjects who have a history of childhood trauma. Schafer and Fisher demonstrated the effectiveness and tolerability of STAIR for individuals at clinical high risk for psychosis with history of childhood trauma. However, there has been little research evaluating the effectiveness of evidence-based trauma-focused treatments in this complex population. Studies evaluating the effectiveness of trauma focused interventions may include individuals with psychosis as only a small sub-sample of participants included in the research, but co-occurring psychosis spectrum disorders are often included as exclusionary criteria in evaluation of trauma-focused treatments for individuals with a history of trauma . As previously discussed, compassion training, such as CBCT, may represent a unique category of psychosocial intervention that helps to improve stress reactivity in youth who have experienced early life adversity . Moreover, PoehlmannTynan et al. demonstrated when parents completed 8-10 weeks of CBCT their children demonstrated reduced cortisol, indicating that compassion training for parents may have cascading effects of cumulative stress on their children. Although difficult to achieve, prevention of the occurrence of childhood trauma would be an ultimate goal. Varese et al. maintain that if childhood trauma was removed from the population entirely, the number of individuals presenting with psychosis would be reduced by 33%. Thus, assessment of childhood trauma is an essential first step toward not only early intervention in,cannabis vertical grow racks but also ultimately prevention of psychosis spectrum disorders.Approximately 1 in 10 transitional age youth between the ages of 18 to 24 experience homelessness every year in the United States , representing 3.5 million youth annually.

Prior research has consistently demonstrated an increased prevalence of mental health disorders among this population, including high rates of depression, anxiety, substance use and post-traumatic stress disorder. Overall, the lifetime prevalence of psychiatric conditions among youth experiencing homelessness is twice that of their stably-housed peers. Further, unstably housed TAY experience high rates of co-occurring substance use disorders with either anxiety, or affective disorders including major depressive disorder or bipolar disorder, a phenomenon known as dual diagnosis. Among homeless TAY with multiple comorbid psychiatric conditions, major depressive disorder is the most common diagnosis, affecting anywhere from 41% to 73% of these individuals. Studies have also demonstrated that suicidal ideation and attempt are markedly higher among unstably housed TAY. For instance, 40% to 80% of homeless youth report suicidal ideation, and 23% to 67% report at least one prior suicide attempt. In San Francisco, one study found that the mortality rate among homeless TAY was 10-fold higher than stably-housed, age-matched peers, largely due to increased deaths from suicide and conditions associated with severe substance use disorder. The causes of homelessness among many TAY include violence and abuse, including physical, sexual or emotional abuse experienced in homes of origin. Following the onset of homelessness, many TAY continue to encounter victimization and abuse. For instance, one study found that 83% of youth reported one or more instances of physical or sexual victimization while living on the streets, which contributes to poor mental health outcomes. Experiences of violence and victimization vary by sexual orientation. For instance, lesbian, gay, bisexual or transgender youth are more likely to face sexual victimization and harassment from police compared to their counterparts, increasing their vulnerability to developing mental health disorders such as anxiety, PTSD and depression. Further, other homeless LGBT TAY report higher rates of depression and suicidality compared to their heterosexual and cisgender peers. While the high prevalence of various mental health disorders among unstably housed TAY is well-established in the literature, few studies to our knowledge have employed a syndemic approach to understand how the co-occurrence of anxiety, PTSD symptoms and poly substance use impact depression. Originally conceived in the early years of the HIV/AIDS pandemic by Merrill Singer, Syndemic Theory is a model for conceptualizing how two or more co-occurring health conditions can interact synergistically within a specific population and social context to mutually increase the overall burden of deleterious health outcomes.

Notably, the term ‘syndemics’ is not a synonym for comorbidities, but rather a phenomenon that develops under the co-occurrence of various adverse socio-structural conditions which in turn increases the risk of developing negative health outcomes. Since its conception, Syndemic Theory has been widely applied in medical, anthropological, and public health research to better understand the impact of disease clustering. Leveraging this framework to understand the synergistic effects of anxiety, PTSD and poly substance use on depression among unstably housed TAY may help inform service delivery methods to improve the overall health of this marginalized population.To address this knowledge gap, we studied marginally housed and homeless TAY between the ages of 18 and 24 in San Francisco, California to identify the prevalence and correlates of being at risk of clinical depression. Additionally, we employed a syndemics framework to examine whether the co-occurrence or clustering of multiple adverse psychosocial factors, including symptoms of moderate or severe anxiety, symptoms of PTSD and polysubstance use, had a synergistic effect on being at risk of clinical depression among high risk youth. We hypothesized that the prevalence of being at risk of clinical depression would be high and associated with a greater number of syndemic factors. As such, this study fills an important gap in research on how syndemic experiences fuel inequalities in psychological and socio-behavioral outcomes among marginally housed and homeless TAY in San Francisco, CA.We utilized baseline data from a Substance Abuse and Mental Health Services Administration funded study designed to assess mental health, substance use and HIV risk behaviors among marginally housed and homeless TAY at Larkin Street Youth Services in San Francisco, CA. Participants were considered eligible if they were: 1) between the ages of 18 and 24, and 2) clients of Larkin Street Youth Services. Larkin Street Youth Services is a community based organization that provides a wide variety of services, including housing, case management, education and employment training programs, and medical care for marginally housed and homeless youth in San Francisco.From May 2017 through April 2018, 100 TAY were recruited from various Larkin Street Youth Service sites, including transitional housing sites, one of which was designed for youth living with HIV, and drop in-centers.

Recruitment strategies involved posting recruitment flyers, giving presentations at community meetings for Larkin Street clients,commercial marijuana vertical growing and coordinating closely with Larkin Street staff to recruit participants.Surveys were administered by trained interviewers with extensive experience working with high-risk TAY. All interviews were conducted in a private setting and lasted approximately 90 minutes. Data were collected using a computer assisted survey information collection method administered on iPads. Participants received a $30.00 drugstore gift card for their participation. Participation in the survey had no bearing on individuals’ ability to obtain services at Larkin Street.Data on age in years, race/ethnicity and gender were collected. Sexual orientation was measured by creating a dichotomous variable for those who identified has being heterosexual versus gay, lesbian, bisexual, or pansexual . Participants were asked to describe where they live by selecting one of the following responses: 1) In my own apartment, 2) In a relative’s home, 3) In a group home, 4) In a campus/dormitory housing, 5) In a foster care, 6) homeless or in a shelter, and 7) other. From these responses, a categorical measure of housing stability was created with the following categories; stably housed , unstably housed and homeless or living in a shelter. Data on ever having been incarcerated for three or more days and self-reported HIV serostatus were also collected.Symptoms of post-traumatic stress disorder in the past month were assessed via the 20-item PCL-5. Total scores range from 0–80, and a standard cutoff of 33 was used to create a dichotomous measure of PTSD symptoms. We used the Generalized Anxiety Disorder 7-item , to measure symptoms consistent with anxiety in the past two weeks. Total scores range from 0–21 and designated cutoffs for minimal , mild , moderate and severe were used to create a categorical measure of symptoms of anxiety. A dichotomous measure of symptoms of moderate or severe anxiety was created for those with scores of 10 or greater. We measured any exposure to traumatic events prior to the age of 18 using the Adverse Childhood Experiences instrument. Traumatic events assessed included experiences of emotional, physical and sexual abuse. A cutoff of 4 or more was used to create an indicator variable for greater adverse childhood experiences . These instruments were not used as diagnostic tools, they were used to evaluate the presence of symptoms consistent with the mental health conditions assessed to decide whether further psychiatric evaluation was needed.Drug and alcohol use were assessed using the NIDA-Modified ASSIST. Participants were asked if they used any of the following drugs: cannabis, cocaine, prescription stimulants, methamphetamine, inhalants, sedatives, hallucinogens, street opioids, prescription opioids or other drugs in the past three months . Consistent with prior research on poly substance use and syndemics, polysubstance use was defined as using three or more of the drugs listed above in the past three months .

Consistent with other research on syndemics, a composite syndemic score ranging from 0–3 was created by summing dichotomous measures of; moderate or severe anxiety, PTSD symptoms and poly substance use. We selected these factors based on a priori hypotheses related to broader mental health disease clustering and their confirmed association with the outcome of interest . Factors that were not significantly associated with being at risk of clinical depression in bivariate analyses were not included the syndemic score. A nominal syndemic variable was also created to identify those with zero, one, two or three syndemic factors.We used descriptive statistics to describe the study sample and examine the prevalence of various mental health factors, substance use and sociodemographic characteristics. We generated frequencies, percentages and depending on distributional assumptions for continuous data means, standard deviations or medians and interquartile ranges . We calculated pairwise correlation coefficients and corresponding p-values to estimate the level of clustering among the syndemic factors included in this study and to ensure they are true syndemic factors. Then, we examined the prevalence of being at risk of clinical depression by number of syndemic factors . We also graphed one’s depression score by the number of syndemic factors .We used modified Poisson regression with robust error variances to estimate the relative risk of being at risk of clinical depression by various sociodemographic, mental health, substance use and syndemic factors. Per Zou and colleagues recommendation, this method was used to yield more precise estimates including, smaller confidence intervals. Each primary exposure that was significantly associated with being at risk of clinical depression at the bivariate level including: symptoms of moderate or severe anxiety, symptoms of PTSD, polysubstance use, the composite syndemic score and the nominal syndemic variable, was explored further in multi-variable Poisson regression models. As recommended by Westreich and colleagues,each primary effect measure was modeled separately in order to yield total effect estimates and avoid multicollinearity. Multivariable models controlled for the following correlates of depression: age in years, gender, race/ethnicity and sexual orientation. Interactions were tested between each primary exposure and sexual orientation. All analyses were performed using Stata 16.1.Among a total of 100 participants, the average age was 22 , 67% were male, 38% were Multiracial, 28% were Black, 22% were White and 12% identified as other or declined to state their race/ethnicity. Over half identified as gay, bisexual or pansexual, 13% were unstably housed and 50% were homelessness. Nearly a quarter were living with HIV and almost a third had ever been incarcerated for at least three days . The median CESD score was 25.3 and 74% met symptom criteria for clinical depression evidenced by having a score of 16 or greater. Anxiety symptoms ranged from 23%with minimal, 26% with mild, 25% with moderate, 25% with severe and 51% with moderate or severe anxiety symptoms. The mean PCL-5 score was 54.6 and 80% had a PCL-5 score of 33 or greater which is indicative of probable PTSD . The mean ACEs score was 5.8 and 77% had an ACEs score of 4 or more which is indicative of significant abuse, neglect and/or household dysfunction .

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The influence of inflammation on the HPA-axis stress response is well-established

Posted on July 17, 2023 by hemp2022

It is known that early life experiences have a profound effect on the developing brain. Optimal development of some brain functions is actually experience-dependent, meaning that input from external stimuli during critical periods of neural development are essential for appropriate neurological development and absence of sufficient input can have deleterious effects . However, this dynamic and synergistic process, while critical for development, also leaves the developing brain vulnerable to influence by negative external stimuli. Thus, the experience of stressful life events, such as childhood trauma, during critical periods of development has been shown to influence the development of neural systems, specifically those involved in response to stress/threat . Yet, the experience of stress does not unequivocally lead to maladaptive consequences, as we know that not all individuals who experience childhood trauma go on to develop physical or mental illnesses. However, the experience of early life stress may uncover biological vulnerabilities in some individuals causing modulation of typical neurobiological stress response, creating life-long patterns of emotionality, behavioral, and physiological responding . While this review will not discuss the role of epigenetics in development of mood disorders, it is important to briefly reference findings from animal model research which demonstrate that experience of early life stressful events, such as maternal separation or neglect, differentially affects neuronal development , mRNA expression and even cortisol reactivity due to differential expression of underlying epigenetic vulnerabilities . One neurological system is critical to the understanding of how environmental stimuli impact biological stress response: the hypothalamic-pituitary-adrenal axis. The HPA-axisis responsible for the release of glucocorticoids in the brain that signal activation of coordinated autonomic, neuroendocrine, metabolic, and immune system responses . Importantly, the HPA axis is highly responsive to environmental adversities both in childhood and in adulthood . Experience of early life stress is implicated in modulation of HPA-axis functioning ,cannabid vertical grow racks with experience of trauma affecting not only the expression of stress induced hormones , but also increasing reactivity to acute stress, and decreasing recovery of cortisol following acute stress .

The responsiveness of the HPA-axis is determined by the ability of glucocorticoids to regulate the release of additional stress hormones, providing return to homeostasis once the perceived stress or threat has subsided . Findings are inconsistent as to whether childhood trauma or early life stress leads to exclusively hyper-activation versus hypo-activation of HPAaxis glucocorticoid release , but nonetheless, dysregulation of HPA- axis has been associated with the development of both mental and physical illnesses, including increased risk for cardiac disease, diabetes, obesity, and autoimmune disorders . In fact, the overlap between physical and mental illness resulting from exposure to childhood trauma and HPA-axis dysregulation , has led to the exploration of the role of the immune system as an underlying mechanism in psychopathology, as inflammation is involved in the pathogenesis of many of the aforementioned medical disorders associated with childhood trauma and HPA-axis dysregulation . Research on the impact of childhood trauma on inflammation has established a dosedependent relationship between number of childhood traumas and elevations/reductions in levels of many inflammatory markers, including IL-6 and Creactive protein . Moreover, cytokines and other markers of inflammation are known to be potent activators of the central HPA-axis stress response . Inflammatory cytokines, including tumor necrosis factor-α , interleukin-1β and interleukin-6 can stimulate the HPA-axis independently, or in combination . Further, IL-6 plays a major role in the immune stimulation of the HPA-axis, particularly in times of chronic inflammatory stress . Replicated studies have demonstrated that cytokines such as IL-1, IL-6, TNF-α and IFN-α, activate the HPA-axis by increasing levels of corticotrophin releasing hormone , adrenocorticotropic hormone and cortisol .Thus, the HPA-axis is not only modulated by childhood trauma, but it is a powerful modulator of inflammatory activity, and is in turn modulated by inflammatory processes.

Both inflammation and HPA-axis activation are mechanisms by which the body protects itself from threat. The immune system plays a critical role in the body’s response to injury and infection as it simultaneously prevents the proliferation of pathogens, while also promoting tissue survival, repair, and recovery through regulated circulation of inflammatory markers . Relevant to the discussion of mood disorders, immune system response is associated with behavioral alterations in mood, sleep, energy, cognition, and motivation. Animal models provide evidence that induction of a “pro-inflammatory state” leads to patterns of behaviors in mice, termed “sickness behaviors” that resemble depressive symptomatology and include: lethargy, decreased appetite, decreased interest in exploring, decreased sexual activity, and increased time spent sleeping . In humans, increases in depressive symptoms have been observed in conjunction with administration of immuno-therapies, such as vaccinations , lipopolysaccharides , interferon , and interleukin-2 . Further, an increased prevalence of mood symptoms is present in a variety of inflammatory conditions including auto-immune diseases, cardiovascular diseases, diabetes, obesity, and metabolic syndrome, as well as benign inflammatory conditions including asthma and allergies . As a result of these associations, there has been an increased interest in exploring the relationship between inflammation and development of various forms of psychopathology. Research on inflammation in individuals diagnosed with MDD has repeatedly shown increased incidence of mood symptoms and episodes associated with elevated levels of Creactive protein , TNF-α, IL-1β, IL-2 and IL-6, in peripheral blood . Further, increased severity of depressive symptoms has been associated with higher levels of inflammatory markers in a dose-dependent manner . Similarly, research on inflammation in individuals diagnosed with BD has repeatedly shown increased incidence of mood symptoms and episodes associated with elevated levels of CRP, TNF-α, IL-1β, IL-2 and IL-6, and decreased BDNF . Acute elevations in inflammatory markers have also been shown to occur during depressive and manic episodes, with marker concentrations peaking during mood episodes and dropping during euthymic periods .Impairment of HPA-axis functioning has been shown to occur within the CHR population .

A limited number of studies have explored differences in levels of plasma inflammatory analytes between CHR and HC groups, as the primary study aim . Stojanovic et al. reported that levels of plasma IL-6 were significantly higher in CHR subjects as compared to HC subjects. Zeni-Graiff et al. later replicated the IL-6 results, additionally reporting that levels of IL-17 were significantly lower in CHR subjects as compared to HC subjects. Karanikas et al. report significantly higher levels of IL-4 in CHR as compared to HC subjects. Focking et al. report that individuals identified to be at “ultra-high risk” for developing a psychotic disorder, demonstrate elevations in baseline levels of plasma IL12/23p40 compared to healthy controls and that elevations of this marker were associated with transition to a psychotic disorder. Finally, Yee, Lee, and Lee report significantly higher levels of serum BDNF in CHR subjects as compared to healthy controls, although the elevation was not predictive of transition to psychosis. Thus, there appears to be evidence of increased levels of several inflammatory analytes in individuals at heightened risk for psychosis, but how these elevations compare to elevations of inflammatory analytes across later phases of psychotic illness remains unclear. Further, CHR groups tend to be rather heterogenous, with 20–35% of CHR individuals developing full psychotic symptoms over a 2-year period , so it is unclear whether these early finding are specific to psychosis risk or general psychopathology and environmental factors.Although research on levels of inflammatory plasma analytes in FEP subjects has been more prolific, it is also more inconsistent. A recent systematic review aggregated 59 studies of cytokine levels in early psychosis subjects,commercial marijuana vertical growing reporting evidence for significantly higher levels of circulating cytokines, IL-6, IL-1b, IL-2, IL-4, IL-10, TNF-α, and IL-8, in FEP as compared to HC groups. However, these results were not consistent across studies, with additional evidence from several studies demonstrating these findings only in drug naive subjects, no significant differences or suppression of analytes in FEP compared to HC subjects . As will be discussed, the effect of antipsychotic medication on inflammatory analytes is an important variable that has been inconsistently examined in current inflammatory research. Additionally, there have been few studies investigating levels of chemokines between FEP and HC subjects, with only one study examining MCP-1 in FEP subjects . Martínez-Cengotitabengoa et al. examined the associationbetween MCP-1 and cognition in FEP subjects, reporting that MCP-1 was strongly associated with learning and memory, consistent with findings that MCP-1 is associated with cognitive deficits in Alzheimer disease and HIV dementia . More research is needed to explore the role of chemokines in early psychosis, particularly if these analytes are associated with cognitive decline and other relevant impairments in psychotic illness. More consistently, levels of BDNF have been reported to be significantly reduced in drug naïve FEP subjects, as compared to HC subjects . Importantly, Toll and Mane discuss that studies reporting reductions in FEP levels of BDNF compared to HC subjects have been predominantly conducted in drug-naïve FEP patients as compared to studies reporting no alterations in FEP levels of BDNF compared to HC subjects have been conducted in medicated patients. These results are consistent with previous meta-analyses in drug-naïve schizophrenia groups , as well as subsequent studies, which additionally report that levels of BDNF are generally reduced in drugnaïve FEP patients and appear to be associated with learning capacity and cognition ; however, reductions in BDNF have not been reported to be associated with psychotic symptom severity nor predictive of conversion to psychosis . Despite inconsistent findings, several studies have demonstrated the clinical relevance of inflammatory plasma analytes in psychosis groups, through successful development of blood based protein biomarker multiplexed immuno assays that either discriminate individuals with a psychotic disorder from HC subjects or reliably predict which CHR individuals will go on to develop a psychotic disorder.

In unmedicated FEP subjects, Schwarz et al. identified inflammatory, oxidative stress, and HPA signaling serum proteins that were uniquely altered in FEP subjects. Chan et al. established a biomarker panel with high discriminatory power to differentiate CHR individuals who would later be diagnosed with schizophrenia versus a diagnosis of bipolar disorder.Associations between inflammatory plasma analytes, psychotic symptoms severity, and functioning has been well studied in patients with chronic psychosis , but less extensively in FEP and CHR subjects. In schizophrenia groups, higher levels of pro-inflammatory cytokines TNF-α and IL-6 have been associated with higher levels of depressive symptoms, greater physical comorbidities, such as arthritis, reduced executive functioning, and lower self-rated mental well-being, suggesting that these markers are clinically relevant . Similarly, plasma levels of chemokines MCP-1, MIP-1β, Eotaxin-1, and MDC have been observed to not only be higher in patients with schizophrenia compared to healthy controls, but also significantly associated with increased levels of sub-clinical depressive symptoms, worse self-rated mental well-being, and greater overall severity of typically mild medical illnesses . Very few studies have evaluated the effect of childhood trauma on inflammation in psychosis. In a sample of individuals with chronic schizophrenia subjects, Dennison, McKernan, Cryan, and Dinan provide evidence that individuals with a history of childhood trauma show significantly higher levels of TNF-a and IL-6 as compared to subjects without a history of trauma and healthy controls. In fact, both Dennison et al. and Di Nicola et al. demonstrated that levels of TNF-a were correlated with history of childhood trauma, specificallyseverity of the trauma in psychosis subjects. Hepgul et al. , reports that levels of CRP were significantly higher in first episode psychosis subjects with a history of childhood trauma as compared to those without a history of childhood trauma and healthy controls. Chase et al. demonstrated that childhood trauma, through its effects on IL6, may be a risk factor for schizophrenia. This is consistent with the meta-analysis conducted by Baumeister, Akhtar, Ciufolini, Pariante, and Mondelli , demonstrating that CRP, IL-6, and TNF-a were markedly elevated in individuals with a history of childhood trauma versus those without. Finally, Mondelli et al. conducted research on cortisol awakening response in first episode psychosis and established that history of childhood sexual trauma is associated with blunted cortisol awakening response. Authors purport that this finding helps to explain the association between HPA-axis abnormalities and excess psychological stress in first episode psychosis subjects. Importantly, no studies to our knowledge have sought to examine the relationship between childhood trauma, inflammation, and clinical outcomes in CHR subjects.However, results from the North American Prodrome Longitudinal Study 2 have established several important findings regarding the relationship between childhood trauma and inflammation independently on clinical outcomes in CHR subjects. Firstly, Addington et al. evaluated the relationship between childhood trauma and clinical outcomes in CHR subjects.

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The prevalence of cocaine use among MSM nationwide is second only to marijuana

Posted on July 14, 2023 by hemp2022

Considering that alcohol consumption increases HDL cholesterol levels, it has been proposed that the association between HDL cholesterol and lowered risk of coronary heart disease is mediated in part by alcohol-induced increases in HDL cholesterol . Other possible mechanisms underlying the observed beneficial effect of low-risk drinking on neurocognition among HIV- individuals in our sample may involve lifestyle factors and/or indicators of socioeconomic status not measured in the current study. For example, previous research exploring beneficial effects of drinking have suggested that low-risk alcohol consumption may be an indicator of higher socioeconomic status and engagement in a healthier lifestyle that includes better nutrition and physical activity . Moreover, persons of lower socioeconomic status may not have the means to afford alcohol and be more medically compromised which could lead to voluntary or medically recommended abstinence . In addition, it is also well known that individuals of higher socioeconomic status are less likely to experience negative consequences from alcohol use compared to those of lower socioeconomic status who drink the same amount . It is possible that our sample of HIV- participants were of relatively high socioeconomic status, especially compared to our sample of PWH, as HIV disproportionately affects individuals from lower income areas with fewer resources . Although we examined associations between certain HIV disease characteristics, alcohol use, and neurocognition, PWH face additional biopsychosocial disadvantages that may explain the lack of beneficial effects of low-risk drinking among this group. Even in the context of low-risk use, the immuno suppressant properties of alcohol may counteract the cardio protective effects on downstream neurocognitive health among PWH,vertical rack grow as immunosuppression leads to greater viral infectivity, replication, and subsequently poorer neuronal integrity . Furthermore, our HIV groups had different proportions of individuals with current and lifetime depression, with significantly higher rates among PWH.

Depression is known to have adverse effects on neurocognitive performance in HIV , possibly limiting the expression of potentially beneficial effects of low-risk drinking among our PWH sample. The current study has several limitations. Although we detected effects that remained statistically significant after adjusting for relevant covariates, there could be potential unmeasured health and lifestyle confounders such as disability, social status, and reason for drinking, that may mediate the association between alcohol consumption and neurocognition. Next, our sample of low risk drinkers, especially among the HIV- group, had fewer drinkers on the high end of the low-risk drinking range, more alcohol abstainers, and more drinkers on the lower end of the low-risk drinking range. Furthermore, we did not have any method to verify self-reported alcohol abstinence. Despite our skewed sample in terms of levels of alcohol consumption, we still detected robust effects even after adjusting for relevant covariates. Objectively measured recent alcohol consumption would have reduced the possibility of misreporting alcohol abstinence, drinking quantities, and frequency; however, we believe structured interviews are still clinically relevant given that our timeline follow back was only 30 days prior. Future alcohol consumption research should employ methodologies to capture real time and ecologically valid data, rather than relying on retrospective recall. While the full range of “low-risk” drinking does not have discretely defined cut-points for minimal, light, and moderate alcohol use, our inclusion of the J-N technique allowed us to identify specific boundaries of recent alcohol consumption in which alcohol confers neurocognitive benefits or risks among HIV individuals. Although these analyses may help clinical efforts at identifying intervals of safe drinking for certain populations, interpretations must caution against the differences in low-risk drinking criteria for men and women. According to the NIAAA criteria for low-risk drinking, we included women who self-report 0-30 drinks in the last 30 days, and men who self-report 0-60 drinks. Therefore, the results of the J-N technique for lower regions of significance are applicable to both men and women, whereas the results in the upper regions of significance are applicable only to men. Future work with equal sample sizes by sex should investigate the associations between recent drinking and neurocognitive function to further adjust for sex differences.

In conclusion, our results are consistent with the hypothesis of a curvilinear association between recent alcohol consumption and neurocognition within the range of low-risk drinking and only among HIV- older adults, such that intermediate levels of recent alcohol use were associated with better neurocognition compared to alcohol abstinence as well as lower and higher ranges of low-risk consumption. Among PWH, there were no detected beneficial or deleterious effects of low-risk alcohol consumption on neurocognition, suggesting that other factors that may supersede the neurocognitive effects of low-risk alcohol consumption in the context of HIV. Uptake of HIV pre-exposure prophylaxis using daily oral emtricitabine-tenofovir disoproxil fumarate has increased considerably since 2012.However, reports from clinical implementation suggest high rates of PrEP discontinuation.The use of stimulant drugs such as cocaine has received little attention in the PrEP literature despite elevated prevalence in high priority populations.In fact, the use of stimulants is higher among men who have sex with men and transgender women compared to the general population.Surveillance reports from major metropolitan areas in the United States suggest that stimulant use is increasing and will continue to do so in the near term.Methamphetamine use doubled between 2011 and 2014 in New York City, and in some regions, rates are at their highest since 2005.San Francisco also observed a resurgence of cocaine use among MSM in recent years with as much as 23% of respondents in 2014 reporting cocaine use in the last six months.An estimated 13–22 million people globally use cocaine, and the highest prevalence of cocaine use disorders is in North America.Stimulant use is a potential barrier to achieving the optimal public health benefits of PrEP. Important clinical questions around adherence, retention in care, and renal toxicity among persons who use stimulants remain unresolved. Studies from our team and others have found some evidence that stimulant-using MSM can achieve prevention-effective adherence and rates of retention comparable to non-users.However, these studies have largely relied on self-reported drug use, which is prone to misclassification.Biological measures of stimulant use are more reliable than self-reported measures due to social desirability bias. In a prior study, we found that stimulant use, confirmed using urine immunoassays, was associated with sub-optimal PrEP adherence in the first month.

Because urine tests have a narrow window of detection and qualitative assays limited our ability to quantify stimulant drug levels, further research is needed to understand how varying degrees of stimulant drug exposure influence PrEP adherence and engagement in care. Another important gap in the literature is that little is known about the renal safety of PrEP in persons who use stimulants such as cocaine. Although PrEP has been associated with only a modest decrease in creatinine clearance,growing cannabis vertically it is uncertain whether concomitant use of stimulants can exacerbate renal dysfunction. Cocaine use is associated with glomerular, tubular, vascular, and interstitial damage, and can precipitate acute kidney injury.To address these gaps in the literature, we assessed the associations of biologically confirmed cocaine use with PrEP adherence , PrEP care engagement, and renal function in the iPrEx open label extension . iPrEx OLE is described in detail elsewhere.Briefly, participants were male sex at birth, reported having anal sex with men, age 18 or older, and must have participated in a previous PrEP clinical trial. Follow-up was scheduled every month for the first three months and quarterly thereafter for up to 72 weeks. All participants provided informed consent. This study was approved by the Institutional Review Board at the University of California, San Francisco. Cocaine use was measured by determining concentrations in scalp hair samples collected at the first quarterly visit. We focused on cocaine as this was the most commonly used stimulant in our sample, consistent with the high prevalence of cocaine use in MSM and transgender women. Hair samples were collected quarterly after PrEP initiation from a subset of participants who joined a hair sub-study.Approximately 100 strands of hair were cut from the occipital region and samples were stored and shipped in aluminum foil at room temperature. Hair analysis provides up to a 3-month surveillance window and is routinely used in forensics to determine amount of exposure to various illicit substances.Hair samples from 410 participants were sent to a commercial laboratory for analysis and tested using a standard 5-panel drug test . Hair samples from 10 participants were rejected due to insufficient quantity and were, thus, excluded from this analysis. Samples were screened for cocaine analytes using enzyme-linked immunos orbent assay and positive results confirmed using gas chromatography-mass spectrometry . For this analysis, we utilized a confirmatory cutoff of ≥ 500 pg/mg of cocaine analyte as proposed by the Substance Abuse and Mental Health Services Administration.Cocaine exposure was stratified based on levels used in prior studies.Cocaine levels between 500–3,000 pg/mg corresponded to “light use” and levels >3,000 pg/mg indicated “moderate to heavy use.” Tenofovir concentrations in blood plasma were assessed in all participants in one of the study visits during the first three months after receiving PrEP using validated assays.Plasma concentrations reflect dosing within the previous week. Our adherence outcome was plasma tenofovir concentrations below the level of quantitation, as levels within the detectable range have been associated with >90% protection against HIV.35 Disengagement from PrEP care was defined as a gap in follow-up visit greater than four months. We used study follow-up as an indicator of clinical care engagement as the study’s follow-up schedule closely mirrored that of current PrEP clinical guidelines.To monitor renal function, serum creatinine was measured at baseline and at each quarterly visit. Creatinine clearance was estimated by the Cockcroft-Gault equation. Renal adverse events were graded based on the Division of AIDS Adverse Events Grading Table.

Multivariable logistic models adjusting for age, ethnicity, and transgender identity estimated the association between level of cocaine use and plasma tenofovir concentration. Cox proportional hazard regression models estimated the association between cocaine use and time to disengagement from care. Regression models used robust variance estimators to account for clustering within study sites. Mean differences in creatinine clearance by followup week and cocaine exposure was estimated using linear mixed effects models with a time by cocaine interaction fit by restricted maximum likelihood. All p-values are two-sided, and analyses were conducted using Stata 14 .The 400 participants included in this analysis were mostly MSM , Hispanic/ Latino , and completed at least secondary education . Ten percent were transgender women. At baseline, median age was 29 years. One-in-five participants tested positive for recent cocaine use with a median cocaine concentration of 2,513 pg/mg . Of those who tested positive for cocaine analytes, 52% were classified as light users and 48% were moderate to heavy users. Participant characteristics and hair drug analysis results are summarized in Table 1a. There was no statistically significant difference in creatinine clearance over time among persons who tested positive for cocaine compared to those who did not . The mean difference in creatinine clearance between groups ranged from 0.93 mL/min to 2.85 mL/min over the 72 study weeks . When we limited our analysis to only those with evidence of PrEP adherence during the first three months, we also found no meaningful difference in creatinine clearance between groups, ranging from differences of 0.06 mL/min to 1.48 mL/min over 72 weeks . There were 26 instances of serum creatinine elevations during follow-up that were at least 1.1 times the upper limit of normal or 1.5 times above the baseline level. Of these elevations, four were in participants who tested positive for cocaine and 22 were in nonusers . Serum creatinine levels were elevated at more than one visit in five participants, none of whom tested positive for cocaine use. Overall, 15/26 creatinine elevations were above the normal range. Of these, three were in participants who tested positive for cocaine use and 12 were in non-users . We found that cocaine use at any level was associated with lower odds of achieving prevention-effective adherence in the first three months after starting PrEP. The first few months following PrEP initiation is a particularly critical period as adherence during this time is predictive of future adherence patterns.These findings underscore the importance of providing comprehensive care at the time of PrEP initiation that includes an assessment of cocaine use and other potential barriers to optimal adherence.

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Sixty-one percent of the confiscated products contained a SC and 31% contained both XLR-11 and CID

Posted on July 13, 2023 by hemp2022

Future studies should examine the impact that within-individual changes in psychiatric problems have on substance use in the current context. Our study shows that when adolescent boys experience an increase in conduct disorder problems, they subsequently experience an increase in the quantity and frequency of substance use, while an increase in alcohol use can also subsequently result in increased anxiety problems in adolescence. Reducing fluctuations in conduct disorder problems and substance use at sensitive developmental turning points such as early and late adolescence may have lasting effects in preventing psychiatric and substance use problems by young adulthood. Synthetic cannabinoids are a class of drugs that are becoming increasingly popular throughout the United States and Europe. Also known as “K2,” “spice,” spike,” or “legal marijuana,” SC are causing intoxication requiring emergency department visits in epidemic and unparalleled numbers.1 Patients present with a wide array of symptoms, ranging from nausea and vomiting to confusion, agitation, short-term memory loss, cognitive impairment, psychosis, seizures, arrhythmias, strokes and even death.SC have often been associated with sympathomimetic effects such as mydriasis, hypertension and tachycardia.We present a case series of patients with SC intoxication who presented atypically with central nervous system and cardiovascular depression over a five-month period; in addition, we present an analysis of blood, urine and SC samples using mass spectrometry. Intoxication with SC products should be considered for patients with undifferentiated psychomotor depression and bradycardia in addition to the excitatory effects previously described.Samples were extracted with organic solvent and concentrated to isolate any drugs present on the plant material. Briefly, 5 mg aliquots of an unknown plant material, or 100 μL of submitted blood/urine,vertical grow rack systems were transferred to screwtop centrifuge tubes. Two mL of ethyl acetate were added and the samples were thoroughly mixed. Samples were extracted for 10 minutes on a nutating mixer at 24 revolutions per minute. The solvent was transferred to clean test tubes and the extracts were evaporated to dryness under nitrogen at 45°C.

Samples were reconstituted in 50 μL methanol and 50 μL 0.1% formic acid in water and transferred to conical autosampler vials for analysis by liquid chromatography time-of-flight mass spectrometry. Similarly, samples were reconstituted in 50 μL ethyl acetate for GC/MS confirmation analysis. Biological samples underwent a 20-minute room temperature hydrolysis period prior to liquid-liquid extraction. Hundreds of distinct SC compounds have been identified.SCs are responsible for a rapidly growing number of presentations to EDs throughout the U.S. in the past several years.SC use causes intense highs and has become popularized due to accessibility, affordability and limited detectability in common drug screens.Intoxications often present in clusters due to local distribution of a single product and great variability in the herbal mixtures.In 2011, SCs were the second most commonly used drug in the 10th grade and the third most common in eighth grade following marijuana and inhalants.Despite the federal ban on SCs that year, there was no decline in frequency of use in high school students the following year. However, use declined in each of the next three years.Users of SCs vary greatly in both demographics and motivation, but are typically males aged 13-59, most with polydrug use and are found in larger, urban populations.SCs are known to interact with the cannabinoid receptors, CB1 and CB2 , leading to changes in levels of multiple neurotransmitters including acetylcholine, dopamine, noradrenaline, glutamine and GABA.Genetic polymorphisms in enzymes responsible for metabolism of SCs can lead to increased blood levels of the parent compound and prolonged duration of action, and therefore a potential increased risk of adverse events.In addition, many SC metabolites retain biological activity.Combination of these metabolites with accumulation of the parent drug creates complex pharmacodynamics, especially when the multitude of other compounds typically found within herbal mixtures is considered. SCs have been reported to exhibit a wide array of effects. CNS effects include psychosis, anxiety, agitation, irritability, memory changes, sedation, confusion and hallucinations,in addition to lowering the seizure threshold in susceptible individuals.Reported cardiovascular effects include tachycardia, chest pain, dysrhythmias, myocardial ischemia and cerebrovascular accident caused by embolisms due to cardiac arrhythmias or reversible cerebral vasoconstriction syndrome.By the end of 2012, JWH-018 was not detected in samples, and XLR-11 became the most common SC detected,as exhibited in our sample analysis.

In our case series, CID and alkyl SC derivatives, such as INACA compounds and XLR-11,were the most commonly detected with no opiates, imidazoline receptor agonists, benzodiazepines or other sedative-hypnotics detected that might explain the atypical presentations.Seventy-five percent of blood samples and 77% of urine samples tested positive for SC. Unlike their predecessors, novel SC appear to be associated with significant CNS depression and bradycardia. The compounds detected in our case series tended to be full agonists at the cannabinoid receptor and are more potent than Δ9-THC.The lack of other CNS and cardiovascular depressants suggests that the clinical findings are due to the combination of these compounds and not coingestants or adulterants. It is important to note that many substances detected in the plant samples were not detected in the blood or urine samples. Some examples include 5-Fluoro-NNEI 2’-naphthyl isomer, 5-fluoropentylindole, NM-2201 and NPB-22. There are multiple explanations for these findings. The patient may have used SC products that were not included in our plant samples and therefore would not be associated with the urine and blood samples. It is also possible that the metabolites of the compound were not in the database or that the level was below the LC TOF detection limits. Furthermore, the metabolite may have been metabolized to a common XLR metabolite that was detected, or the drug had already been eliminated from the body. More than one-quarter of a million women in the United States are currently living with HIV , and many women living with HIV fare poorly on the HIV Care Continuum . In 2015, only 50% of WLHIV were retained in care and 48% achieved HIV viral suppression . Despite the broad availability of effective antiretroviral medications, WLHIV also experience high rates of morbidity and mortality compared to the general population . Trauma is increasingly recognized as a near-universal experience among WLHIV and as a key contributor to HIV acquisition, morbidity, and mortality. Defined as “an event, series of events, or set of circumstances that is experienced by an individual as physically or emotionally harmful or threatening and that has lasting adverse effects” , trauma can include childhood and/or adult physical, sexual, or emotional abuse or neglect,vertical grow racks cost as well as sociostructural violence such as racism, sexism, homophobia, transphobia, xenophobia, or living in a community where violence is common. People living with HIV experience disproportionately high rates of trauma , including rates of childhood sexual abuse that are more than twice the rates among the general population .

Trauma exposure in PLHIV is associated with nonAIDS related deaths , and is predictive of experiencing later violence . It is also closely associated with mental health disorders including depression, PTSD, and anxiety , as well as with increased HIV-risk behavior, including substance use disorders . HIV diagnosis is itself often highly traumatic . Among PLHIV, trauma and substance use often function syndemically, as “epidemics interacting synergistically and contributing, as a result of their interaction, to excess burden of disease in a population” . The syndemic of violence/trauma, substance use, and HIV has been identified as one of the main drivers of HIV infection and of poor health outcomes among women living with HIV . Research has consistently shown high rates of substance use among people living with HIV, and rates that are higher than among the general population . Substance use has also been shown to have a negative impact on HIV treatment adherence and virologic suppression .The link between trauma and health outcomes has led to calls for increased attention to trauma in health care by advocates and government leaders, including the U.S. Preventive Services Health Task Force, the Institute of Medicine, and the Agency for Healthcare Research and Quality . While an emerging literature describes interventions to address trauma and PTSD among PLHIV , no prospective study has evaluated the impact of a comprehensive model of trauma-informed health care delivery on health outcomes. To address this gap, we initiated implementation of a model of traumainformed health care in one clinic serving WLHIV in the San Francisco Bay Area. As part of this effort, we are conducting a broad evaluation of the impact of TIHC on patient health outcomes. Here we report results of baseline data analyses, examining the association of trauma with physical, behavioral, and social health indicators, with particular attention to quality of life and undetectable viral load. We then consider how the results of the investigation serve to inform efforts within health care settings to improve outcomes. Women were recruited from the waiting room during regular clinic hours on two half-days each week. Researchers approached patients in the waiting room, briefly explained the purpose of the study and, if a patient was interested, met with her in a private room. At that time, the researchers reviewed consent documents, explained the study procedures including data abstraction from the electronic health record , and answered any questions. Individuals were eligible to participate if they self-identified as cisgender or transgender women who were 18 years of age or older, were currently receiving primary HIV care at the clinic, and were English-speaking and cognitively able to complete the interview. If the patient was eligible and willing, she signed a general consent form and an EHR data abstraction consent form. Following consent, the researcher conducted the interview by reading each question aloud and marking responses in a survey booklet. At the end of the interview, the participant received a $25 gift card inappreciation of her time. Most interviews took 30-45 minutes to complete. After the interview, researchers abstracted relevant data from the participant’s EHR. Anxiety symptoms were assessed using the Generalized Anxiety Disorder scale , a 7-item self-report scale to measure symptom severity. A score of 10 or above indicates at least moderate anxiety. Substance use was measured in three ways. Alcohol use was assessed using the short Alcohol Use Disorders Identification Test , a 3-item screen to identify individuals who may be hazardous drinkers or who have alcohol use disorders . The instrument provides a raw numerical score ; an indicator of binge drinking; and a diagnostic of AUD . Drug use was measured using one question from the Alcohol, Smoking and Substance Involvement Screening Test asking about substance use in the past three months. We dichotomized this into any non-prescribed drug use in the past 3 months, and a similar variable of “hard” drug use that excludes marijuana. Drug abuse was measured using the Drug Abuse Screening Test 10 , which yields a score range of 0-10. A score of 3 or greater indicates at least a moderate level of drug abuse. Quality of Life was measured using the five-item WHO-Five, developed crossculturally by the World Health Organization . The instrument measures self-reported quality of life over the past two weeks in the areas of mood, physical vitality, and interest in life. A score below 13 indicates poor quality of life . Mental well-being was measured using the seven-item Short WarwickEdinburgh Mental Well being Scale, which focuses on emotions and mental functioning , and yields a score of 7-35. Undetectable viral load. For participants who consented to having data abstracted from their electronic health record , we abstracted HIV viral load and CD4 counts. Data were abstracted only if the person had had a test within the past year, and the most recent test result was used. Viral load was dichotomized as detectable or undetectable . For the analysis, we focused on undetectable viral load as the outcome of interest. Patient-Provider relationship was measured using the Engagement with Health Care Provider scale , a 13-item instrument in which clients rate their interactions with their providers on a scale of 1 “always” to 4 “never”. Responses are summed to get a total score of 1-52, with lower scores indicated greater engagement. Appointment Adherence. We abstracted EHR data to examine appointment adherence as a proxy for engagement in care.

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CDT did not significantly predict performance on any neurocognitive measure

Posted on July 12, 2023 by hemp2022

The direct biomarkers include ethyl glucuronide , ethyl sulfate , and phosphatidylethanol. Past research has shown that several indirect alcohol use biomarkers are correlated with cognitive performance in individuals with alcohol use disorders: AST,ALT,MCV,and GGT.Thus, alcohol use biomarkers may not only be used to screen for alcohol problems or abstinence,but also have a specific role in screening for cognitive impairment in individuals with alcohol use disorders. These biomarkers may offer more than simply getting a history of the amount and frequency of recent alcohol use. Though several indirect biomarkers have been explored with respect to cognitive performance, the newer direct biomarkers, such as EtG and EtS, have not received any attention in the literature. Although the direct biomarkers are minor metabolites of alcohol,these biomarkers, such as EtG, can also be found in the brain.Whether any of the direct biomarkers are associated with cognitive performance in individuals with alcohol use disorders remains an open question. In an effort to add to this scarce literature on the association of alcohol use biomarkers and cognitive performance, we conducted a secondary analysis of baseline data from a recently completed pharmacological pilot clinical trial among veterans with alcohol dependence and post traumatic stress disorder . This study included the measures, at baseline, of indirect and direct alcohol use biomarkers and neurocognitive measures, which allowed us to explore the relationship between biomarkers and cognitive performance. Because this study was conducted in alcohol-dependent veterans with comorbid PTSD, we were also able to explore the unique relationship between alcohol use biomarkers and cognitive performance in a group having particularly poor clinical outcomes.To the best of our knowledge,vertical led grow lights the relationship between alcohol use biomarkers and cognitive performance specifically in veterans with alcohol dependence and PTSD has not been previously explored.

In this sample of veterans with alcohol dependence and PTSD, we hypothesized that the indirect biomarkers would predict baseline cognitive performance. On the basis of the evidence that they can be found in the brain, we also hypothesized that the direct biomarkers would predict baseline cognitive performance. Demographic data, such as age, sex, race, ethnicity, years of education, marital status, and occupational status, were collected. Psychiatric diagnoses and concurrent medication use were captured by a review of each participant’s electronic medical record at the SFVAMC. Substance use disorder diagnoses were assessed using the Substance Use Disorders module of the Structured Clinical Interview for DSM-IV-TR, Research Version, Patient Edition .The level of substance use for the past 90 days was assessed using the Timeline Follow back Method.PTSD was diagnosed by the Clinician-Administered PTSD Scale.The level of depression was assessed using the 21-item self-report Beck Depression Inventory.Blood samples were obtained for CDT , GGT, MCV, AST, and ALT levels. Urine samples were obtained for EtG and EtS levels. Standard operating procedures were followed by the Clinical and Translational Science Institute at the SFVAMC to obtain these samples. Levels of GGT, MCV, AST, and ALT were analyzed locally at the SFVAMC Department of Laboratory Medicine. CDT sample was shipped and analyzed at the Clinical Neurobiology Laboratory in the Institute of Psychiatry at the Medical University of South Carolina. EtG and EtS samples were shipped and analyzed at the Department of Laboratory Medicine at the Yale University School of Medicine. The Trail Making Test part A was used to assess psychomotor speed and simple visual attention and part B was used to assess task switching and cognitive flexibility; the raw scores were converted to T scores.The Hopkins Verbal Learning Test—Revised was used to assess verbal memory.We used the %retention score for this analysis, where the raw score was converted to a T score; the assessment of retention is relatively free of effortful memory search and retrieval.The Balloon Analogue Risk Task was used to assess risk taking; we used the primary score of “adjusted average number of pumps on unexploded balloons.” The Delay Discounting Task was used to assess impulsivity; we used the Kln score, defined as the log-transformed DD after applying the hyperbolic function. All analyses were conducted using IBM SPSS Statistics, version 20 .

All continuous variables were checked for normality , and nonparametric tests were used when appropriate. All continuous variables were also checked for extreme values; values with a z-score > 3.29 or < −3.29 were adjusted to the next highest value. Where adjusted results differed from the original data, the adjusted results are presented. Because most values were undetectable at <100 ng/mL, EtG was dichotomized into <100 ng/mL vs. >100 ng/mL. Because most values were undetectable at <50 ng/mL, EtS was dichotomized into <50 vs. >50 ng/mL. Two multiple regression models were estimated and tested for each neurocognitive measure . The first model included the alcohol use biomarker alone as the predictor. The second model included the alcohol use biomarker along with the following 3 additional predictors: Beck Depression Inventory , Clinician-Administered PTSD Scale , and receiving medications . As mood symptoms,PTSD symptoms,and medications can affect cognitive performance, we included these 3 additional predictors in the second model to determine if they would make a significant contribution. Because this was an exploratory secondary analysis, we did not control for type I error; pvalues < 0.05 were considered statistically significant. Assumptions in each regression model were checked by assessing several parameters such as Durbin–Watson statistic , collinearity , standardized residuals , Cook’s distance , linearity/homoscedasticity , and normality of residuals . All of these assumptions in each multiple regression model for each neurocognitive measure were met. Finally, previous evidence shows that alcohol intake itself can affect cognitive performance.We explored whether the number of drinks significantly correlated with any of the neurocognitive measures. Table I presents baseline demographic and clinical data. Table II presents baseline substance use, alcohol use biomarker, and neurocognitive data. Tables III and IV present the multiple regression analyses between alcohol use biomarker data and neurocognitive data. Table III presents the results with the first model that included the alcohol use biomarker alone as the predictor; Table IV presents the results with the second model that included the alcohol use biomarker along with the 3 additional predictors .In both models, GGT significantly predicted performance on the HVLT-R %Retention; the Beck Depression Inventory and the Clinician-Administered PTSD Scale also significantly contributed to the second model along with GGT. In only the first model, GGT significantly predicted performance on the TMT-A.

GGT did not significantly predict performance on the BART, DD, TMT-B, and in the second model on the TMT-A. In only the first model, MCV predicting performance on the BART approached significance. It did not significantly predict performance on any other neurocognitive measure.In both models, AST significantly predicted performance on the HVLT-R %Retention. In only the first model, AST predicting performance on the TMT-A approached significance. AST did not significantly predict performance on the BART, DD, TMT-B, and in the second model on the TMT-A. In the first model, ALT predicting performance on the TMT-A approached significance. It did not significantly predict performance on any other neurocognitive measure. EtG and EtS did not significantly predict performance on any neurocognitive measure. The number of drinks did not significantly correlate with any of the neurocognitive measures . These results were nonsignificant for the number of drinks in the past 4 to 90 days. Also, because GGT and AST were the only two measures to predict performance on the HVLT-R %Retention, we assessed whether these were correlated; GGT and AST were correlated in this analysis . Baseline alcohol use biomarker and neurocognitive data from a pilot clinical trial among veterans with alcohol dependence and PTSD were analyzed in this secondary analysis. GGT and AST significantly predicted performance on the HVLT-R %Retention; the Beck Depression Inventory and the Clinician-Administered PTSD Scale also significantly contributed to predicting performance on the HVLT-R %Retention along with GGT. GGT alone,vertical cannabis grow without any other predictors, significantly predicted performance on TMT-A. Without any other predictors, AST and ALT alone predicting performance on the TMT-A approached significance. Without any other predictors, MCV alone predicting performance on the BART approached significance. Thus, the initial hypotheses were partially supported. The indirect biomarkers may predict neurocognitive performance for several reasons such as by serving as a surrogate marker for heavy alcohol use, thereby representing alcohol’s potential for direct neurotoxicity; by serving as a marker of hepatic dysfunction for transaminases, thereby representing hepatic effects on brain function; and by having a direct neurotoxic effect of their own. The finding that GGT and AST predicted performance on some neurocognitive measures is consistent with that of previous research.For example, increases in GGT may increase the transport of amino acids into the brain across the blood–brain barrier, which may alter cognitive performance.GGT has also been associated with gray matter decline and brain shrinkage,which may affect cognitive performance. GGT is known to be a marker of oxidative stress and has been found to be elevated in patients with Alzheimer’s disease,which highlights a potential association of GGT with cognitive performance. Cognitive changes because of poor liver function may be due to the liver failing to catabolize circulating neurotoxins,and GGT and AST may help identify patients who show a change in visual attention and verbal memory performance. ALT significantly predicted performance on the TMT-A, but the limitations of the sample might have contributed to ALT not fully achieving significance. Approaching significance, the MCV predicting BART performance is interesting. Though MCV may appear to be unrelated to cognition, some studies have shown that erythrocyte volume may influence cognition,and that MCV can predict delirium after surgery.MCV has also been associated with gray matter decline and ventricular enlargement.One possibility is that the increased erythrocyte volume, which is found in alcohol dependence and during times of stress,may lead to erythrocytes having difficulty passing through narrow brain capillaries and subsequently affecting cognitive performance.CDT not predicting performance on any neurocognitive measure is consistent with previous reports.It is important to note that other studies in individuals with alcohol use disorders have similarly shown no association of indirect biomarkers with any neurocognitive measure.One plausible explanation for this is that because the direct biomarkers are minor metabolites of alcohol,30 the concentrations of these biomarkers in the brain may not have been sufficient to affect the neural pathways underlying cognitive performance.

Another plausible explanation may be that the direct biomarkers represent alcohol use for a much briefer time than the indirect markers, which represents anywhere from several weeks to several months; therefore, the indirect biomarkers represent more chronic measures of heavy drinking and more likely represent the direct toxic effects of alcohol on brain function. This analysis suggests that in addiction settings, some of the indirect alcohol use biomarkers serve as an indicator of a subset of patients who are at high risk for cognitive impairment. Alcohol use biomarkers cannot replace a comprehensive neurocognitive evaluation for assessing cognitive impairment. Rather, in settings where a comprehensive neurocognitive evaluation is not feasible, alcohol use biomarkers might be the next best tool that clinicians could potentially use to identify veterans with alcohol dependence and PTSD who are likely to show cognitive impairment. Cost and practicality of ordering alcohol use biomarkers would be some hurdles for a clinician to implement these biomarkers in routine clinical practice. For example, in our own San Francisco Veterans Affairs clinical setting, the two indirect biomarkers in this analysis that predicted cognitive performance can more easily be ordered through our computerized medical record system, compared to the direct biomarkers that require special ordering and processing. Thus, in addition to the scientific relationship between alcohol use biomarkers and cognitive performance, clinicians must consider cost and practicality of ordering alcohol use biomarkers when implementing these biomarkers in routine clinical practice. This analysis has several strengths. First, seven alcohol use biomarkers were analyzed. Second, three additional predictors were integrated into the second regression model and yet still found significance with a few biomarkers. Third, a naturalistic sample of veterans was analyzed, which can help generalize these findings to veterans with alcohol dependence and comorbid PTSD. Finally, this is the first known analysis to explore the relationship between alcohol use biomarkers and cognitive performance in veterans with both alcohol dependence and PTSD. Inevitably, this analysis also has limitations. First, the study was not specifically designed to assess the aims of this post hoc analysis. As a result, the number of exploratory analyses conducted likely produced some type I errors. Second, because the sample size was small, this may have been the reason for only obtaining approaching significance level findings for some biomarkers.

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Participants were given a thirty-dollar drugstore gift-card upon completion of the interview

Posted on July 11, 2023 by hemp2022

Although baseline sleep patterns did not predict conversion to psychosis, our findings demonstrate that disturbed sleep is strongly related to increased severity of CHR symptoms over time. This association held in half the sleep characteristics when explored independently. Adjusting for depression attenuated the association between sleep and symptoms considerably. Furthermore, while effect sizes were similar bidirectionally, baseline sleep was a significant predictor of CHR symptoms two months later but not vice versa. These findings advance the current literature in several important ways. First, our findings correspond with previous CHR studies in which sleep difficulties at baseline did not predict conversion.This may suggest that sleep operates as an indicator of conversion only in conjunction with several other important markers. This hypothesis is supported by a predictive risk model of conversion in which “sleep disturbance” was one of the six factors that, jointly, yielded a markedly high positive predictive value. Sleep disturbances may have predictive value when they occur close to time of conversion, since sleep alterations are early indicators of psychosis relapse.Poor sleep may also predict conversion among specific groups, such as those with prolonged sleep disturbance or those who only recently developed sleep problems. The role of disturbed sleep as a potential catalyst for conversion in our study remains speculative because 30% of converters completed only one sleep assessment and 27% transitioned to psychosis 10 months post-baseline, at which point sleep was no longer tracked longitudinally. Future studies would benefit from looking at sleep metrics tracked longitudinally in large samples followed through the time of conversion. Second, our findings reveal long-term and robust correlations between a wide range of sleep disturbances and symptoms across all four CHR domains. Although poor sleep did not predict conversion,plant racks its relation with symptom exacerbation is clinically important considering that even non-converting CHR youth often have poor functional outcome and persistent symptoms.

Our current findings using self-reports are supported by electrophysiological studies relating REM latency and REM density to positive symptoms in psychotic disorders, reduced delta EEG activity and reduced REM latency to negative symptoms in schizophrenia, and reduced sleep spindle activity to both positive and negative symptoms,although these findings vary.In further concordance with our findings on disorganized and general symptoms, individuals with non-affective psychoses and comorbid sleep disorders had greater cognitive disorganization, depression, anxiety and tension/stress levels than those without the latter morbidity.Likewise, EEG delta activity in early-course non-affective psychoses were inversely related to disorganization syndrome.Although associations between sleep parameters and clinical symptoms vary largely across studies, individuals, and stages of illness, sleep characteristics of psychosis-afflicted individuals unequivocally differ from those who are unaffected, and these differences are present prior to illness onset. Third, symptoms of depression showed a strong attenuating effect, such that relationship strengths between sleep and all CHR symptom domains were reduced by roughly half or more. Disturbed sleep is a symptom of and risk factor for depression,and unipolar depressive disorders are common comorbidities among CHR youth. In 744 CHR individuals, >40% met DSM-IV criteria for current depression and almost 20% for past depression.Similarly, depression mediated the association between sleep and suspiciousness in CHR youth, and consistently partially mediated the association between sleep and psychotic experiences.The attenuating role of depression in the current study served to strengthen existing cross-sectional evidence and demonstrate its validity over time. Lastly, we aimed to address the directionality of the relationship between sleep and CHR symptoms. Between baseline and 2-month follow-up, total sleep score was a significant predictor of total, positive, negative, and general CHR symptoms. While general symptoms were the only domain with a statistically significant bidirectional association with sleep, bidirectional effect sizes, as indicated by regression coefficients , were all nearly equal.

These findings suggest that sleep is a driving force in symptom exacerbation, and that promoting healthy sleep may be a useful target for the maintenance of CHR symptoms. Evidence has been accumulating in support of cognitive behavioral therapy for insomnia, which not only reduced insomnia but also improved symptoms of paranoia and hallucinations in a large sample of university students and in a small CHR group.Adjacent research has found that sleep quality is malleable and thus can be improved even in clinical populations.These findings offer promising evidence for advancement in clinical staging models and future sleep-related therapies for both CHR and overt psychosis, such as an upcoming trial by Waite et al.Another budding direction of research involves computational advances in causal discovery analysis, offering innovative approaches to addressing causality in the context of observational data.Such methods require careful consideration of assumptions and properties underlying the data at hand,but could be utilized in future analyses of these and other prospective longitudinal datasets involving CHR and other clinical populations. Limitations of this study include the use of a self-report to assess sleep. The PSQI and the RU-SATED have high validity and reliability and subjective sleep problems have been the primary focus of sleep treatments. Such assessments, however, are fundamentally different from electrophysiological sleep characteristics that may be differentially associated with conversion and symptom levels. Therefore, the use of both self-report and electrophysiological sleep measures over time may inform clinical risk models and constitute targets for intervention. Other notable limitations include the significant dropout rates, the absence of ongoing sleep assessments succeeding the 8-month follow-up, and the relatively small sample size of our converting group . Furthermore, we acknowledge that pre-registering our study hypotheses would have strengthened our findings.The 1.6 to 3.5 million homeless youth in the United States may be staying in shelters or temporary housing , or living on the street – those between the ages of 18-24 years – who are experiencing homelessness are challenging to quantify due to the transiency of homelessness and the lack of consistent definitions of homelessness within the scientific literature . In San Francisco, approximately one in five homeless individuals is a TAY . Young people who experience homelessness have tumultuous lives and must continuously prioritize basic needs within a context of limited resources .

Thirty-four percent of homeless youth in San Francisco reported trading drugs to help meet basic needs such as shelter . Instability and risky behaviors inevitably place youth in situations that may cause physical or emotional harm, including exposure to social and structural violence such as racial discrimination, sexism, homophobia or living in a community where violence occurs frequently . Housing instability and the accompanying exposure to external stressors and violence have an impact on mental health and patterns of substance use. Several studies indicate the presence of psychiatric disorder in more than 48.4% of homeless youth . Homeless youth also experience higher rates of poor mental health symptoms and higher consumption of alcohol and drugs compared to their housed peers . These youth may use substances as a coping mechanism for mental health symptoms and for the daily challenges experienced while homeless ; Stress and trauma are common risk factors for substance use . TAY are also at a greater risk of experiencing violence, physical injuries, and psychological consequences over peers who are housed . Past histories of abuse, transphobia, dangerous living situations, limited financial and emotional resources, engagement in substance use and high-risk sexual activity,multi-tiered growing and irregular patterns of sleep and eating all contribute to poor mental health and substance use in youth . Evidence of the impact of trauma and substance use on health outcomes, specifically with TAY who are experiencing homelessness, is growing. This paper investigates relationships between past traumatic experiences and current substance use and mental health symptoms. We conducted a cross-sectional study of 100 homeless TAY in San Francisco, California, in close collaboration with a local community-based organization that serves this population. Each year, the CBO delivers housing, employment, and education services for 2,500- 3,000 youth aged 12-24 years who are experiencing homelessness or at risk of becoming homeless. Clients include individuals who are actively living on the street, in temporary housing or shelters, living in single-room occupancy housing, living with friends, in foster care, or otherwise unstably housed. The organization offers a broad range of programs, which includes referral centers, education and employment training programs, temporary emergency shelter, residential programs, medical care, behavioral health, and case management services. Recruitment occurred at multiple service sites of the CBO, including drop in-centers, medical clinics, agency community meetings, CBO events, transitional housing sites, and at the CBO’s housing site that exclusively serves clients with an HIV diagnosis. Study flyers were posted at CBO sites, announcements were made at site meetings, and CBO staff members referred clients to approach research staff for inclusion in the study. TAY clients who were interested in participating contacted study personnel onsite or via a secure Google Voice telephone number to schedule an appointment with one of the trained research assistants. At the meeting, potential participants were screened for eligibility. Individuals were eligible if they were between 18 and 24 years old and were recipients of services provided by the CBO. Eligible individuals then proceeded through an informed consent process. Following the informed consent process, the research assistant conducted a one-on-one survey interview with the participant, reading each question aloud and marking responses in a Computer-Assisted Survey Information Collection system via an iPad tablet. The CBO specifically recommended that the research assistants, rather than the clients, navigate the CASIC system due to client differences in reading and concentration levels that could affect their ability to complete the questionnaire by themselves. Each interview was conducted in a private room and lasted 45-120 minutes.

Exposure to traumatic events prior to the age of 18 was measured with the Adverse Childhood Experiences instrument , which has been used extensively including among young adults . The number of reported ACEs was dichotomized into less than 4, or 4 or greater. Scores of 4 or greater indicate a greater level of household dysfunction, abuse, and neglect and have been shown to be associated with morbidity and poor school performance in TAY . PTSD symptoms were measured with the PTSD Checklist for DSM-5 , which has demonstrated internal consistency, reliability, and validity . The PCL-5 can be used for screening and for monitoring change in symptom intensity. A total score was calculated , with a score of 33 or above indicating potential PTSD and the need for a more thorough psychiatric evaluation . The CES-D was used to determine symptoms of depression. The CESD has shown good reliability and validity for assessment of depression in various populations including adolescents . A total score was calculated , with a score of 16 or above indicating risk for clinical depression . Anxiety symptoms were assessed using the GAD-7 which has been shown to have strong validity and reliability including among adolescents . A total score of 10 or above on a scale of 0-21 indicates at least moderate anxiety . To evaluate substance use, participants first answered the NIDA Quick Screen V1.0 , which identifies participants who have reported alcohol binge drinking in the past year , and report past year use of tobacco products, illicit drugs, or prescription drugs for non-medical reasons. Responses were dichotomized . Participants who reported use of illegal drugs or prescription drugs for non-medical reasons in the past year then completed the NIDA-Modified ASSIST V2.0 . The original ASSIST was developed by the World Health Organization and has demonstrated strong reliability and validity . In the NIDA-Modified ASSIST, participants are asked about past three-month’s use of cannabis, cocaine, prescription stimulants, methamphetamine, inhalants, sedatives, hallucinogens, street opioids, and prescription opioids. If a substance used was not listed, participants could specify it in the “other substances” option . For each substance reported, a Single Substance Involvement Score was calculated. A mean SSIS between 0-3 indicates low-risk of harmful consequences for the user; a score of 4-27 indicates moderate-risk; a score greater than 27 indicates high-risk. Moderate-risk level scores indicate that the participant may be misusing substances but may not currently meet diagnostic criteria for a substance use disorder. Study participants ranged from 18-24 years of age; the majority were male , and 52% identified as lesbian, gay, bisexual, transgender, or queer . More than two-thirds were persons of color. At the time of the survey, 23% of participants were living with HIV, 50% were experiencing literal homelessness, and almost one-third had been previously incarcerated for more than three days. Over three-quarters of participants reported 4 or more ACEs, 80% reached the diagnostic threshold for PTSD, 74% for depression, and 51% for at least moderate anxiety.

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