Evaluation of Field Sobriety Tests for Identifying Drivers Under the Influence of Cannabis: A Randomized Clinical Trial.

Importance: With increasing medicinal and recreational cannabis legalization, there is a public health need for effective and unbiased evaluations for determining whether a driver is impaired due to Δ9-tetrahydrocannabinol (THC) exposure. Field sobriety tests (FSTs) are a key component of the gold standard law enforcement officer-based evaluations, yet controlled studies are inconclusive regarding their efficacy in detecting whether a person is under the influence of THC. Objective: To examine the classification accuracy of FSTs with respect to cannabis exposure and driving impairment (as determined via a driving simulation). Design, Setting, and Participants: This double-blind, placebo-controlled parallel randomized clinical trial was conducted from February 2017 to June 2019 at the Center for Medicinal Cannabis Research, University of California, San Diego. Participants were aged 21 to 55 years and had used cannabis in the past month. Data were analyzed from August 2021 to April 2023. Intervention: Participants were randomized 1:1:1 to placebo (0.02% THC), 5.9% THC cannabis, or 13.4% THC cannabis smoked ad libitum. Main Outcome and Measures: The primary end point was law enforcement officer determination of FST impairment at 4 time points after smoking. Additional measures included officer estimation as to whether participants were in the THC or placebo group as well as driving simulator data. Officers did not observe driving performance. Results: The study included 184 participants (117 [63.6%] male; mean [SD] age, 30 [8.3] years) who had used cannabis a mean (SD) of 16.7 (9.8) days in the past 30 days; 121 received THC and 63, placebo. Officers classified 98 participants (81.0%) in the THC group and 31 (49.2%) in the placebo group as FST impaired (difference, 31.8 percentage points; 95% CI, 16.4-47.2 percentage points; P < .001) at 70 minutes after smoking. The THC group performed significantly worse than the placebo group on 8 of 27 individual FST components (29.6%) and all FST summary scores. However, the placebo group did not complete a median of 8 (IQR, 5-11) FST components as instructed. Of 128 participants classified as FST impaired, officers suspected 127 (99.2%) as having received THC. Driving simulator performance was significantly associated with results of select FSTs (eg, ≥2 clues on One Leg Stand was associated with impairment on the simulator: odds ratio, 3.09; 95% CI, 1.63-5.88; P < .001). Conclusions and Relevance: This randomized clinical trial found that when administered by highly trained officers, FSTs differentiated between individuals receiving THC vs placebo and driving abilities were associated with results of some FSTs. However, the high rate at which the participants receiving placebo failed to adequately perform FSTs and the high frequency that poor FST performance was suspected to be due to THC-related impairment suggest that FSTs, absent other indicators, may be insufficient to denote THC-specific impairment in drivers. Trial Registration: ClinicalTrials.gov Identifier: NCT02849587.

Driving Under the Influence of Cannabis: Impact of Combining Toxicology Testing with Field Sobriety Tests.

BACKGROUND: Cannabis is increasingly used both medically and recreationally. With widespread use, there is growing concern about how to identify cannabis-impaired drivers. METHODS: A placebo-controlled randomized double-blinded protocol was conducted to study the effects of cannabis on driving performance. One hundred ninety-one participants were randomized to smoke ad libitum a cannabis cigarette containing placebo or delta-9-tetrahydrocannabinol (THC) (5.9% or 13.4%). Blood, oral fluid (OF), and breath samples were collected along with longitudinal driving performance on a simulator (standard deviation of lateral position [SDLP] and car following [coherence]) over a 5-hour period. Law enforcement officers performed field sobriety tests (FSTs) to determine if participants were impaired. RESULTS: There was no relationship between THC concentrations measured in blood, OF, or breath and SDLP or coherence at any of the timepoints studied (P > 0.05). FSTs were significant (P < 0.05) for classifying participants into the THC group vs the placebo group up to 188 minutes after smoking. Seventy-one minutes after smoking, FSTs classified 81% of the participants who received active drug as being impaired. However, 49% of participants who smoked placebo (controls) were also deemed impaired at this same timepoint. Combining a 2 ng/mL THC cutoff in OF with positive findings on FSTs reduced the number of controls classified as impaired to zero, 86 minutes after smoking the placebo. CONCLUSIONS: Requiring a positive toxicology result in addition to the FST observations substantially improved the classification accuracy regarding possible driving under the influence of THC by decreasing the percentage of controls classified as impaired.

Effects of drug and hazardous alcohol use on having a detectable HIV viral load: An adherence mediation analysis.

Objectives: People living with HIV (PWH) with substance or alcohol use often have unsuppressed plasma HIV viral loads (pVL). The degree to which substance and alcohol use effects on HIV viral suppression are mediated through medication nonadherence is incompletely understood. Methods: We included PWH prescribed antiretroviral therapy and receiving care at an academic HIV clinic between 2014 and 2018 who completed both patient-reported outcomes (PRO) questionnaires and had subsequent pVL measurements. Measures included assessments of alcohol use (AUDIT-C), drug use (NIDA-ASSIST), and self-reported adherence measured using four different methods. Substances found in bivariate analysis to predict detectable pVL were modeled separately for mediation effects through adherence. We report natural direct (NDE) and indirect effect (NIE), marginal total effect (MTE), and percentage mediated. Results: Among 3125 PWH who met eligibility criteria, 25.8% reported hazardous alcohol use, 27.1% cannabis, 13.1% amphetamines, 1.9% inhalants, 5.3% cocaine, 4.5% sedative-hypnotics, 2.9% opioids, and 2.3% hallucinogens. Excellent adherence was reported by 58% of PWH, and 10% had detectable pVL. Except for sedatives, using other substances was significantly associated with worse adherence. Bivariate predictors of detectable pVL were [OR (95% CI)]: amphetamine use 2.4 (1.8-3.2) and opioid use 2.3 (1.3-4.0). The percent of marginal total effect mediated by nonadherence varied by substance: 36% for amphetamine use, 27% for opioid use, and 39% for polysubstance use. Conclusion: Use of amphetamines, opioids, and multiple substances predicted detectable pVL. Up to 40% of their effects were mediated by self-reported nonadherence. Confirmation using longitudinal measurement models will strengthen causal inference from this cross-sectional analysis.

Impact of COVID-19 Pandemic-Associated Social Changes on Boys with Moderate to Severe Autism.

Objectives: The COVID-19 pandemic and the resulting social changes have made unprecedented changes in our lifetime with unknown repercussions on children with autism spectrum disorders. We sought to assess the effect of the COVID-19 pandemic and resulting social changes on boys with autism spectrum disorder. Methods: We conducted a survey using the CRISIS-AFAR questionnaire of caregivers of a population of boys (n = 40) with moderate to severe autism spectrum disorder for changes in environment and behavior before and after the pandemic. Results: We found several interesting findings, including an increase in self-injurious behaviors after the start of the pandemic, but not in the level of hyperactivity, anxiety, or aggressive behavior, or amount and frequency of stereotypies/repetitive behaviors in the children before and after the start of the pandemic. There was an increased difficulty in adjusting to new daily routines after the pandemic, as well as increased difficulty falling asleep. Conclusions: The study showed that a majority of boys with moderate/severe autism in our study were negatively affected by the pandemic across several domains. Additionally, this study highlights the need for educational and mental health resources to be prepared for similar events in the future.

Driving Performance and Cannabis Users' Perception of Safety: A Randomized Clinical Trial.

IMPORTANCE: Expanding cannabis medicalization and legalization increases the urgency to understand the factors associated with acute driving impairment. OBJECTIVE: To determine, in a large sample of regular cannabis users, the magnitude and time course of driving impairment produced by smoked cannabis of different Δ9-tetrahydrocannabinol (THC) content, the effects of use history, and concordance between perceived impairment and observed performance. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled parallel randomized clinical trial took place from February 2017 to June 2019 at the Center for Medicinal Cannabis Research, University of California San Diego. Cannabis users were recruited for this study, and analysis took place between April 2020 and September 2021. INTERVENTIONS: Placebo or 5.9% or 13.4% THC cannabis smoked ad libitum. MAIN OUTCOMES AND MEASURES: The primary end point was the Composite Drive Score (CDS), which comprised key driving simulator variables, assessed prior to smoking and at multiple time points postsmoking. Additional measures included self-perceptions of driving impairment and cannabis use history. RESULTS: Of 191 cannabis users, 118 (61.8%) were male, the mean (SD) age was 29.9 (8.3) years, and the mean (SD) days of use in the past month was 16.7 (9.8). Participants were randomized to the placebo group (63 [33.0%]), 5.9% THC (66 [34.6%]), and 13.4% THC (62 [32.5%]). Compared with placebo, the THC group significantly declined on the Composite Drive Score at 30 minutes (Cohen d = 0.59 [95% CI, 0.28-0.90]; P < .001) and 1 hour 30 minutes (Cohen d = 0.55 [95% CI, 0.24-0.86]; P < .001), with borderline differences at 3 hours 30 minutes (Cohen d = 0.29 [95% CI, -0.02 to 0.60]; P = .07) and no differences at 4 hours 30 minutes (Cohen d = -0.03 [95% CI, -0.33 to 0.28]; P = .87). The Composite Drive Score did not differ based on THC content (likelihood ratio χ24 = 3.83; P = .43) or use intensity (quantity × frequency) in the past 6 months (likelihood ratio χ24 = 1.41; P = .49), despite postsmoking blood THC concentrations being higher in those with the highest use intensity. Although there was hesitancy to drive immediately postsmoking, increasing numbers (81 [68.6%]) of participants reported readiness to drive at 1 hour 30 minutes despite performance not improving from initial postsmoking levels. CONCLUSIONS AND RELEVANCE: Smoking cannabis ad libitum by regular users resulted in simulated driving decrements. However, when experienced users control their own intake, driving impairment cannot be inferred based on THC content of the cigarette, behavioral tolerance, or THC blood concentrations. Participants' increasing willingness to drive at 1 hour 30 minutes may indicate a false sense of driving safety. Worse driving performance is evident for several hours postsmoking in many users but appears to resolve by 4 hours 30 minutes in most individuals. Further research is needed on the impact of individual biologic differences, cannabis use history, and administration methods on driving performance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02849587.

Alterations in Brain Cannabinoid Receptor Levels Are Associated with HIV-Associated Neurocognitive Disorders in the ART Era: Implications for Therapeutic Strategies Targeting the Endocannabinoid System.

HIV-associated neurocognitive disorders (HAND) persist despite the advent of antiretroviral therapy (ART), suggesting underlying systemic and central nervous system (CNS) inflammatory mechanisms. The endogenous cannabinoid receptors 1 and 2 (CB1 and CB2) modulate inflammatory gene expression and play an important role in maintaining neuronal homeostasis. Cannabis use is disproportionately high among people with HIV (PWH) and may provide a neuroprotective effect for those on ART due to its anti-inflammatory properties. However, expression profiles of CB1 and CB2 in the brains of PWH on ART with HAND have not been reported. In this study, biochemical and immunohistochemical analyses were performed to determine CB1 and CB2 expression in the brain specimens of HAND donors. Immunoblot revealed that CB1 and CB2 were differentially expressed in the frontal cortices of HAND brains compared to neurocognitively unimpaired (NUI) brains of PWH. CB1 expression levels negatively correlated with memory and information processing speed. CB1 was primarily localized to neuronal soma in HAND brains versus a more punctate distribution of neuronal processes in NUI brains. CB1 expression was increased in cells with glial morphology and showed increased colocalization with an astroglial marker. These results suggest that targeting the endocannabinoid system may be a potential therapeutic strategy for HAND.

Blood and Oral Fluid Cannabinoid Profiles of Frequent and Occasional Cannabis Smokers.

Increased prevalence of cannabis consumption and impaired driving are a growing public safety concern. Some states adopted per se driving laws, making it illegal to drive with more than a specified blood concentration of ∆9-tetrahydrocannabinol (THC) in a biological fluid (typically blood). Blood THC concentrations decrease significantly (∼90%) with delays in specimen collection, suggesting the use of alternative matrices, such as oral fluid (OF). We characterized 10 cannabinoids' concentrations, including THC metabolites, in blood and OF from 191 frequent and occasional users by liquid chromatography with tandem mass spectrometry for up to 6 h after ad libitum smoking. Subjects self-titrated when smoking placebo, 5.9 or 13.4% THC cannabis. Higher maximum blood THC concentrations (Cmax) were observed in individuals who received the 5.9% THC versus the 13.4% THC plant material. In blood, the Cmax of multiple analytes, including THC and its metabolites, were increased in frequent compared to occasional users, whereas there were no significant differences in OF Cmax. Blood THC remained detectable (≥5 ng/mL) at the final sample collection for 14% of individuals who smoked either the 5.9 or 13.4% THC cigarette, whereas 54% had detectable THC in OF when applying the same cutoff. Occasional and frequent cannabis users' profiles were compared, THC was detectable for significantly longer duration in blood and OF from frequent users. Detection rates between frequent and occasional users at multiple per se cutoffs showed larger differences in blood versus OF. Understanding cannabinoid profiles of frequent and occasional users and the subsequent impact on detectability with current drug per se driving limits is important to support forensic interpretations and the development of scientifically supported driving under the influence of cannabis laws.

Chronically elevated depressive symptoms interact with acute increases in inflammation to predict worse neurocognition among people with HIV.

We examined the joint effects of depressive symptoms (Beck Depression Inventory-II (BDI-II)) and systemic inflammation (plasma C-reactive protein (CRP)) on longitudinal profiles of neurocognition in a cohort of 143 people with HIV (PWH) on antiretroviral therapy. Global neurocognition, processing speed, motor skills, and attention/working memory all worsened as CRP increased but only among PWH who, on average, exhibited moderate to severe depressive symptoms (BDI-II > 22). Findings suggest that some PWH with chronically elevated depressive symptoms may have an inflammatory subtype of depression and a particular vulnerability to neurocognitive changes that may respond to drugs targeting inflammation or its neural sequelae.

Constructions of HIV Risk Among a Diverse Sample of HIV-Negative Young Men Who Have Sex With Men Who Are Repeat Testers.

INTRODUCTION: To end the HIV epidemic, HIV prevention and pre-exposure prophylaxis (PrEP) promotion efforts must reach young men who have sex with men (YMSM) at greatest risk for HIV. This study qualitatively explored whether common metrics used by clinicians, scientists, and public health officials to objectively assess HIV risk align with how YMSM conceptualize their risk for HIV and the factors that shape YMSM's risk perceptions. METHODS: Interviews with a racially/ethnically diverse sample of HIV-negative YMSM (ages 19-24 years, 60% Latinx; n = 20) examined conceptualizations of HIV risk within the context of repeat HIV testing. Iterative, applied thematic analysis examined how participants conceptualized and constructed their HIV risk, and compared participants' descriptions of their risk with a validated quantitative assessment of HIV risk that reliably predicts HIV seroconversion in this group. RESULTS: Objective quantitative assessments of HIV risk poorly aligned with participants' perceived HIV risk. Participants described their current risk in relative terms (relative to past risk and relative to friends'/peers' risk) and described age/developmental stage and changes in knowledge about HIV prevention as key factors in risk changes over time. Other factors included substance use and trust/mistrust in sexual partners and scientific advances in HIV prevention (eg, U = U and PrEP). Factors that influenced participants' perceived HIV risk were similar regardless of objective risk assessment. CONCLUSIONS: Quantitative assessments of risk may poorly align with risk perception among YMSM. Although objective metrics can effectively target YMSM at greatest risk for HIV transmission, interventions to improve prevention behaviors and PrEP uptake may be more effective when tailored to bridge the disconnection between objective HIV risk assessments and YMSM's constructions of risk.

Both HIV and Tat expression decrease prepulse inhibition with further impairment by methamphetamine.

HIV infection and methamphetamine (METH) use are highly comorbid and represent a significant public health problem. Both conditions are known to negatively impact a variety of brain functions. One brain function that may be affected by HIV and METH use is sensorimotor gating, an automatic, pre-conscious filtering of sensory information that is thought to contribute to higher order cognitive processes. Sensorimotor gating is often measured using prepulse inhibition (PPI), a paradigm that can be conducted in both humans and animals, thereby enabling cross-species translational studies. While previous studies suggest HIV and METH may individually impair PPI, little research has been conducted on the effects of combined HIV and METH on PPI. The goal of this cross-species study was to determine the effects of METH on PPI in the inducible Tat (iTat) mouse model of HIV and in people with HIV. PPI was measured in the iTat mouse model before, during, and after chronic METH treatment and after Tat induction. Chronic METH treatment decreased PPI in male but not female mice. PPI normalized with cessation of METH. Inducing Tat expression decreased PPI in male but not in female mice. No interactions between chronic METH treatment and Tat expression were observed in mice. In humans, HIV was associated with decreased PPI in both men and women. Furthermore, PPI was lowest in people with HIV who also had a history of METH dependence. Overall, these results suggest HIV and METH may additively impair early information processing in humans, potentially affecting downstream cognitive function.

Lower CSF homovanillic acid relates to higher burden of neuroinflammation and depression in people with HIV disease.

BACKGROUND: HIV-related neuroinflammation has been proposed as a catalyst for dopaminergic dysregulation in mesocortical pathways, which may contribute to the pathogenesis of depression. Abnormalities in dopaminergic neurotransmission and depression are common in people with HIV (PWH), however the link between dopamine (DA) and depression in PWH is poorly characterized. This study investigated CSF dopaminergic biomarkers, specifically DA and its metabolite, homovanillic acid (HVA), and examined their relationship with depressive symptoms and CSF neuroinflammatory markers in PWH and HIV-seronegative (HIV-) individuals. METHODS: Participants were 102 HIV- individuals and 123 PWH (mean age = 42) who underwent neuropsychiatric evaluations and lumbar puncture. Current depression severity was classified using the Beck Depression Inventory-II (BDI-II). CSF was assayed for DA and HVA using high performance liquid chromatography and neuroinflammatory markers using immunoassays. Linear regressions modelled BDI-II scores as a function of HIV, dopaminergic biomarker z-scores, and their interaction, controlling for psychosocial factors. Correlational analyses examined dopaminergic and neuroinflammatory relationships. RESULTS: PWH had significantly higher BDI-II scores than HIV- participants. DA and HVA were not associated with HIV status but both significantly moderated the effect of HIV on BDI-II scores, such that PWH exhibited higher depressive symptoms than HIV- participants only at lower concentrations of HVA (z ≤ 0.06) and DA (z ≤ 0.11). In PWH only, lower HVA significantly correlated with higher BDI-II scores and higher neuroinflammation, including higher MCP-1 and IP-10. CONCLUSIONS: Results suggest that the pathophysiology of depression in PWH differs from that in HIV- individuals. Specifically, lower central dopaminergic activity was selectively associated with greater depressive symptoms and neuroinflammation in PWH. With the rise in consideration of DA agonists for the treatment of depression, these results suggest that PWH may show a greater response to these agents than their HIV- peers.

Trajectories of initiation for the heroin-based drug whoonga - qualitative evidence from South Africa.

BACKGROUND: Whoonga is a smoked heroin-based street drug that first emerged in South Africa a decade ago. While previous scientific reports suggest that use is growing and youth are particularly vulnerable, trajectories of initiation are not well characterized. METHODS: In 2015, 30 men undergoing residential addiction treatment for this smoked heroin drug in KwaZulu-Natal, South Africa participated in semi-structured interviews about their experiences using the drug. Interview data were coded using qualitative content analysis. RESULTS: Participant trajectories to initiating smoked heroin were "vertical" in the context of marijuana use or "horizontal" in the context of other hard drug use. Participants reporting vertical trajectories began smoking heroin as youth at school or in other settings where people were smoking marijuana. Several participants with horizontal trajectories started smoking heroin to address symptoms of other drug or alcohol addiction. Social influences on initiation emerged as an overarching theme. Members of participants' social networks who were smoking or distributing heroin figured prominently in initiation narratives. Surprisingly, references to injection drug use were absent from initiation narratives. Participants reported people who smoke heroin differ from those who inject heroin by race. CONCLUSION: Consistent with theories implicating social and structural influences on substance use initiation, people who started smoking heroin had social contacts who smoked heroin and frequented places where substance use was common. Smoked heroin initiation for several participants with horizontal trajectories may have been averted if they accessed evidence-based treatments for stimulant or alcohol use disorders. With increasing reports of heroin use across Africa, a coordinated approach to address this growing epidemic is needed. However, because smoked heroin and injection heroin use occur in distinct risk environments, interventions tailored to people who use smoked heroin will be needed to prevent smoked heroin use, prevent transition to injection use, and mitigate other social harms.

Mental Health of Adolescents in the Era of Antiretroviral Therapy: Is There a Difference Between HIV-Infected and Uninfected Youth in South Africa?

PURPOSE: The HIV infection may predispose perinatally HIV-infected (PHIV+) adolescents to mental illness. Adolescence can be when mental health disorders manifest for the first time. This study investigates the prevalence of mental illness in PHIV+ and HIV-uninfected adolescents in Soweto. METHODS: PHIV+ adolescents aged 13-19 years were recruited from an antiretroviral treatment program, whereas HIV-uninfected controls were recruited from the community in Soweto, South Africa, between October 2016 and April 2017. The Patient Health Questionnaire for Adolescents, Child Post-Traumatic Stress Disorder (PTSD) Checklist, and Millon Adolescent Clinical Inventory tools assessed components of mental health. Sociodemographic and virological data were collected. Risk factors for suicidality were determined by logistic regression. RESULTS: One hundred and sixty-two adolescents (50% PHIV+, 61% female) with a median age of 16 years (interquartile range: 15-18) were enrolled. A depressive disorder was found in 14% of all adolescents, 35% had suicidal ideation, and 22% had PTSD symptoms. Risk factors for suicidality were female gender, HIV-positive status, repeating a grade at school and a history of physical and/or sexual abuse. CONCLUSIONS: These findings show a high prevalence of suicidality and PTSD symptoms in adolescents from South Africa and highlight the importance of screening for mental illness, specifically suicidality, in HIV-positive adolescents. Adolescents from a disadvantaged socioeconomic background appear to be at risk, posing a challenge because of the lack of health seeking behaviors in young people and lack of adolescent-friendly health facilities. Interventions specific to adolescents in low- and middle-income countries are needed to improve emotional and psychiatric symptoms and functioning.

A validation study of the Zanmi Lasante Depression Symptom Inventory (ZLDSI) in a school-based study population of transitional age youth in Haiti.

BACKGROUND: The Zanmi Lasante Depression Symptom Inventory (ZLDSI) is a screening tool for major depression used in 12 primary care clinics in Haiti's Central Plateau. Although previously validated in a clinic-based sample, the present study is the first to evaluate the validity and clinical utility of the ZLDSI for depression screening in a school-based population in central Haiti. METHODS: We assessed depressive symptoms in a school-based sample of transitional age youth (18-22 years; n = 120) with the ZLDSI. Other mental health-related assessments included a modified Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) for current Major Depressive Episode, the Center for Epidemiologic Studies Depression Scale, and selected items adapted from the Global School-Based Health Survey mental health module. Diagnostic assignments of major depressive episode (MDE) were based on modified SCID interviews. RESULTS: The ZLDSI demonstrated good overall accuracy in identifying current MDE (Area under the Curve = .92, 95% CI = .86, .98, p < .001). We ascertained ≥12 as the optimal cut-off point to screen for depression with a sensitivity of 100% and a specificity of 73.9%. In addition, the ZLDSI was associated with other measures of depressive symptoms, suggesting that it demonstrates construct validity. CONCLUSIONS: Study findings support that the ZLDSI has clinical utility for screening for depression among school-going transitional age youth.

Cumulative Burden of Depression and Neurocognitive Decline Among Persons With HIV: A Longitudinal Study.

BACKGROUND: Higher cumulative burden of depression among people with HIV (PWH) is associated with poorer health outcomes; however, longitudinal relationships with neurocognition are unclear. This study examined hypotheses that among PWH, (1) higher cumulative burden of depression would relate to steeper declines in neurocognition, and (2) visit-to-visit depression severity would relate to fluctuations in neurocognition within persons. SETTING: Data were collected at a university-based research center from 2002 to 2016. METHODS: Participants included 448 PWH followed longitudinally. All participants had >1 visit (M = 4.97; SD = 3.53) capturing depression severity (Beck Depression Inventory-II) and neurocognition (comprehensive test battery). Cumulative burden of depression was calculated using an established method that derives weighted depression severity scores by time between visits and total time on study. Participants were categorized into low (67%), medium (15%), and high (18%) depression burden. Multilevel modeling examined between- and within-person associations between cumulative depression burden and neurocognition over time. RESULTS: The high depression burden group demonstrated steeper global neurocognitive decline compared with the low depression burden group (b = -0.100, P = 0.001); this was driven by declines in executive functioning, delayed recall, and verbal fluency. Within-person results showed that compared with visits when participants reported minimal depressive symptoms, their neurocognition was worse when they reported mild (b = -0.12, P = 0.04) or moderate-to-severe (b = -0.15, P = 0.03) symptoms; this was driven by worsened motor skills and processing speed. CONCLUSIONS: High cumulative burden of depression is associated with worsening neurocognition among PWH, which may relate to poor HIV-related treatment outcomes. Intensive interventions among severely depressed PWH may benefit physical, mental, and cognitive health.

Validation of a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to detect cannabinoids in whole blood and breath.

Background The widespread availability of cannabis raises concerns regarding its effect on driving performance and operation of complex equipment. Currently, there are no established safe driving limits regarding ∆9-tetrahydrocannabinol (THC) concentrations in blood or breath. Daily cannabis users build up a large body burden of THC with residual excretion for days or weeks after the start of abstinence. Therefore, it is critical to have a sensitive and specific analytical assay that quantifies THC, the main psychoactive component of cannabis, and multiple metabolites to improve interpretation of cannabinoids in blood; some analytes may indicate recent use. Methods A liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to quantify THC, cannabinol (CBN), cannabidiol (CBD), 11-hydroxy-THC (11-OH-THC), (±)-11-nor-9-carboxy-Δ9-THC (THCCOOH), (+)-11-nor-Δ9-THC-9-carboxylic acid glucuronide (THCCOOH-gluc), cannabigerol (CBG), and tetrahydrocannabivarin (THCV) in whole blood (WB). WB samples were prepared by solid-phase extraction (SPE) and quantified by LC-MS/MS. A rapid and simple method involving methanol elution of THC in breath collected in SensAbues® devices was optimized. Results Lower limits of quantification ranged from 0.5 to 2 µg/L in WB. An LLOQ of 80 pg/pad was achieved for THC concentrations in breath. Calibration curves were linear (R2>0.995) with calibrator concentrations within ±15% of their target and quality control (QC) bias and imprecision ≤15%. No major matrix effects or drug interferences were observed. Conclusions The methods were robust and adequately quantified cannabinoids in biological blood and breath samples. These methods will be used to identify cannabinoid concentrations in an upcoming study of the effects of cannabis on driving.

Benzodiazepine Use Is Associated With an Increased Risk of Neurocognitive Impairment in People Living With HIV.

OBJECTIVE: Despite potential for dependence and adverse neurological effects, long-term benzodiazepine (BZD) use is common among people living with HIV (PLWH). As PLWH are at risk for central nervous system dysfunction, we retrospectively examined the association between BZD use and HIV-associated neurocognitive impairment (NCI). METHODS: Three hundred six PLWH underwent comprehensive neurobehavioral evaluations. Current BZD use (BZD+) was determined through self-report. Using propensity scores, 153 BZD- individuals were matched to 153 BZD+ participants on demographics and medical comorbidities. Multiple regression models examined NCI and demographically adjusted neurocognitive T-scores as a function of BZD status, adjusting for estimated premorbid ability, current affective symptoms, and nadir CD4 count. Secondary analyses explored neurocognitive correlates of positive BZD urine toxicology screens (TOX+) and specific BZD agents. RESULTS: Median duration of BZD use was 24 months. Current BZD use related to higher likelihood of NCI (odds ratio = 2.13, P = 0.003) and poorer global (d = -0.28, P = 0.020), processing speed (d = -0.23, P = 0.047), and motor T-scores (d = -0.32, P = 0.008). Compared with BZD-/TOX-, BZD+/TOX+ exhibited additional decrements in executive function (d = -0.48, P = 0.013), working memory (d = -0.49, P = 0.011), and delayed recall (d = -0.41, P = 0.032). For individual agents, diazepam, lorazepam, and alprazolam were most strongly associated with NCI (odds ratios >2.31). DISCUSSION: BZD use may elevate risk for NCI in PLWH, potentially through diffuse neurocognitive slowing and acute compromise of recall and higher-order capacities. These effects are robust to psychosocial and HIV-specific factors and occur in comparison with a tightly matched BZD- group. Prospective and interventional studies should evaluate causal associations between NCI and BZD use and explore treatment alternatives to BZDs in PLWH.

Clinical correlates of depression chronicity among people living with HIV: What is the role of suicidal ideation?

BACKGROUND: Chronicity of depression among people living with HIV (PLWH) is associated with poorer viral suppression and mortality risk. The extent to which suicidal ideation (SI) and other baseline characteristics predict a prolonged duration of depressive illness among PLWH is not known but could help identify PLWH most at risk. METHODS: Data were drawn from a sample of 1002 depressed PLWH engaged in primary care at a metropolitan HIV clinic from 2007-2018, representing 2,569 person-years. Depression characteristics were derived from the Patient Health Questionnaire 9 (PHQ-9), administered during routine screening. Other characteristics were derived from clinic data. Unadjusted and covariate-adjusted survival analyses compared the time to depression remission between depressed participants with and without SI at their initial screening. RESULTS: At baseline, 38.4% of depressed PLWH endorsed SI. Depressed PLWH with SI took significantly longer to achieve remission from depression than those without SI. The association appeared to be mediated by depression symptom severity. When adjusted for age, depression diagnosis, any recent drug use, and depression symptom severity, baseline SI no longer predicted remission hazard. LIMITATIONS: Participants were assessed for depression with variable frequency. The analysis assumed all patients received comparable treatment for their depression. Some variables were based on clinic measurements that may be subject to misclassification bias. CONCLUSIONS: These data suggest that depressed PLWH with SI are at risk for greater chronicity of depression because their depression is more severe. Accordingly, PLWH should be urgently engaged in psychiatric care in the event of SI or severe depressive symptoms.

Recreational ART use among individuals living with HIV/AIDS in South Africa: Examining longitudinal ART initiation and viral suppression.

BACKGROUND: South Africa has the highest number of people living with HIV (PLWH) and one of the largest antiretroviral therapy (ART) programs globally. High rates of substance use comorbidity exist, including speculation of recreational ART use (i.e., mixing ART with other illicit drugs). Recreational ART use may affect viral load among PLWH due to ART nonadherence and/or viral resistance; however, prior quantitative research has not examined rates of recreational ART use, nor associations with HIV treatment outcomes longitudinally. METHODS: Data were drawn from a prospective, observational cohort study (n = 500) of ART-eligible adults recruited from two HIV voluntary counseling and testing centers in Cape Town, and Johannesburg, South Africa. Multiple logistic regression models assessed recreational ART use as a predictor of ART initiation over six months and viral load suppression over nine months, above and beyond other substance use (binge drinking and illicit drug use). RESULTS: Approximately 5% (n = 24) reported recreational ART use, which was less frequent in Cape Town compared to Johannesburg (AOR = 0.025; 95%CI: 0.003-0.19; p < 0.001). Recreational ART use was not significantly associated with ART initiation or viral suppression. Other substance use, but not recreational ART use, was significantly associated with lower odds of ART initiation (AOR = 0.54; 95%CI: 0.33-0.87; p = .01) and viral suppression (AOR = 0.47; 95%CI: 0.25-0.89; p = .02). CONCLUSIONS: Recreational ART use was infrequent and not uniquely associated with ART initiation or viral suppression. Findings suggest that comorbid use of other substances is ultimately what may make recreational ART use problematic for ongoing engagement in care and viral suppression.

A Cost-Effectiveness Model for Adjunctive Smoked Cannabis in the Treatment of Chronic Neuropathic Pain.

Background: A recent meta-analysis affirmed the benefit of medicinal cannabis for chronic neuropathic pain, a disabling and difficult-to-treat condition. As medicinal cannabis use is becoming increasingly prevalent among Americans, an exploration of its economic feasibility is warranted. We present this cost-effectiveness analysis of adjunctive cannabis pharmacotherapy for chronic peripheral neuropathy. Materials and Methods: A published Markov model comparing conventional therapies for painful diabetic neuropathy was modified to include arms for augmenting first-line, second-line (if first-line failed), or third-line (if first- and second-line failed) therapies with smoked cannabis. Microsimulation of 1,000,000 patients compared the cost (2017 U.S. dollars) and effectiveness (quality-adjusted life years [QALYs]) of usual care with and without adjunctive cannabis using a composite of third-party and out-of-pocket costs. Model efficacy inputs for cannabis were adapted from clinical trial data. Adverse event rates were derived from a prospective study of cannabis for chronic noncancer pain and applied to probability inputs for conventional therapies. Cannabis cost was derived from retail market pricing. Parameter uncertainty was addressed with one-way and probabilistic sensitivity analysis. Results: Adding cannabis to first-line therapy was incrementally less effective and costlier than adding cannabis to second-line and third-line therapies. Third-line adjunctive cannabis was subject to extended dominance, that is, the second-line strategy was more effective with a more favorable incremental cost-effectiveness ratio of $48,594 per QALY gained, and therefore, third-line adjunctive cannabis was not as cost-effective. At a modest willingness-to-pay threshold of $100,000/QALY gained, second-line adjunctive cannabis was the strategy most likely to be cost-effective. Conclusion: As recently proposed willingness-to-pay thresholds for the United States health marketplace range from $110,000 to $300,000 per QALY, cannabis appears cost-effective when augmenting second-line treatment for painful neuropathy. Further research is warranted to explore the long-term benefit of smoked cannabis and standardization of its dosing for chronic neuropathic pain.