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.

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.

Grindr Users Take More Risks, but Are More Open to Human Immunodeficiency Virus (HIV) Pre-exposure Prophylaxis: Could This Dating App Provide a Platform for HIV Prevention Outreach?

BACKGROUND: Technology has changed the way that men who have sex with men (MSM) seek sex. More than 60% of MSM in the United States use the internet and/or smartphone-based geospatial networking apps to find sex partners. We correlated use of the most popular app (Grindr) with sexual risk and prevention behavior among MSM. METHODS: A nested cohort study was conducted between September 2018 and June 2019 among MSM receiving community-based human immunodeficiency virus (HIV) and sexually transmitted infection (STI) screening in central San Diego. During the testing encounter, participants were surveyed for demographics, substance use, risk behavior (previous 3 months), HIV pre-exposure prophylaxis (PrEP) use, and Grindr usage. Participants who tested negative for HIV and who were not on PrEP were offered immediate PrEP. RESULTS: The study included 1256 MSM, 1090 of whom (86.8%) were not taking PrEP. Overall, 580 of 1256 (46%) participants indicated that they used Grindr in the previous 7 days. Grindr users reported significantly higher risk behavior (greater number of male partners and condomless sex) and were more likely to test positive for chlamydia or gonorrhea (8.6% vs 4.7% of nonusers; P = .005). Grindr users were also more likely to be on PrEP (18.7% vs 8.7% of nonusers; P < .001) and had fewer newly diagnosed HIV infections (9 vs 26 among nonusers; P = .014). Grindr users were also nearly twice as likely as nonusers to initiate PrEP (24.6% vs 14%; P < .001). CONCLUSIONS: Given the higher risk behavior and greater acceptance of PrEP among MSM who used Grindr, Grindr may provide a useful platform to promote HIV and STI testing and increase PrEP uptake.

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.

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.

Depressive Symptoms and Engagement in Human Immunodeficiency Virus Care Following Antiretroviral Therapy Initiation.

Background: The effect of depressive symptoms on progression through the human immunodeficiency virus (HIV) treatment cascade is poorly characterized. Methods: We included participants from the Centers for AIDS Research Network of Integrated Clinic Systems cohort who were antiretroviral therapy (ART) naive, had at least 1 viral load and HIV appointment measure after ART initiation, and a depressive symptom measure within 6 months of ART initiation. Recent depressive symptoms were measured using the Patient Health Questionnaire-9 (PHQ-9) and categorized using a validated cut point (PHQ-9 ≥10). We followed participants from ART initiation through the first of the following events: loss to follow-up (>12 months with no HIV appointment), death, administrative censoring (2011-2014), or 5 years of follow-up. We used log binomial models with generalized estimating equations to estimate associations between recent depressive symptoms and having a detectable viral load (≥75 copies/mL) or missing an HIV visit over time. Results: We included 1057 HIV-infected adults who contributed 2424 person-years. At ART initiation, 30% of participants reported depressive symptoms. In multivariable analysis, recent depressive symptoms increased the risk of having a detectable viral load (risk ratio [RR], 1.28; 95% confidence interval [CI], 1.07, 1.53) over time. The association between depressive symptoms and missing an HIV visit (RR, 1.20; 95% CI, 1.05, 1.36) moved to the null after adjustment for preexisting mental health conditions (RR, 1.00; 95% CI, 0.85, 1.18). Conclusions: Recent depressive symptoms are a risk factor for unsuppressed viral load, while preexisting mental health conditions may influence HIV appointment adherence.

The Depression Treatment Cascade: Disparities by Alcohol Use, Drug Use, and Panic Symptoms Among Patients in Routine HIV Care in the United States.

Little is known about disparities in depression prevalence, treatment, and remission by psychiatric comorbidities and substance use among persons living with HIV (PLWH). We conducted a cross-sectional analysis in a large cohort of PLWH in routine care and analyzed conditional probabilities of having an indication for depression treatment, receiving treatment, receiving indicated treatment adjustments, and achieving remission, stratified by alcohol use, illicit drug use, and panic symptoms. Overall, 34.7% (95% CI 33.9-35.5%) of participants had an indication for depression treatment and of these, 55.3% (53.8-56.8%) were receiving antidepressants. Among patients receiving antidepressants, 33.0% (31.1-34.9%) had evidence of remitted depression. In a subsample of sites with antidepressant dosage data, only 8.8% (6.7-11.5%) of patients received an indicated treatment adjustment. Current drug users (45.8%, 95% CI 43.6-48.1%) and patients reporting full symptoms of panic disorder (75.0%, 95% CI 72.9-77.1%) were most likely to have an indication for antidepressant treatment, least likely to receive treatment given an indication (current drug use: 47.6%, 95% CI 44.3-51.0%; full panic symptoms: 50.8%, 95% CI 48.0-53.6%), or have evidence of remitted depression when treated (22.3%, 95% CI 18.5-26.6%; and 7.3%, 95% CI 5.5-9.6%, respectively). In a multivariable model, drug use and panic symptoms were independently associated with poorer outcomes along the depression treatment cascade. Few differences were evident by alcohol use. Current drug users were most likely to have an indication for depression treatment, but were least likely to be receiving treatment or to have remitted depression. These same disparities were even more starkly evident among patients with co-occurring symptoms of panic disorder compared to those without. Achieving improvements in the depression treatment cascade will likely require attention to substance use and psychiatric comorbidities.

Does substance use compromise depression treatment in persons with HIV? Findings from a randomized controlled trial.

Depression and substance use are significant obstacles to effective HIV care. Using data derived from a randomized controlled trial of persons with HIV who are homeless or marginally housed, this study assesses the utility of antidepressant treatment among persons with HIV, depression, and active substance use. Participants were diagnosed with depressive disorders and randomly assigned to receive directly observed therapy with fluoxetine or a referral to community mental health treatment. Assessments, conducted at baseline and every 3 months over a 9-month period, included the Hamilton Rating Scale for Depression, the Beck Depression Inventory II, and self-report of alcohol, crack, cocaine, heroin, or methamphetamine use in the past 90 days. To investigate the effect of antidepressant treatment in the setting of active substance use, the authors fit mixed-effects linear regression models to estimate the effect of directly observed fluoxetine on depressive symptom severity after stratifying by any alcohol use or any illicit drug use. To investigate whether alcohol use or illicit drug use moderated the antidepressant treatment response, the authors examined the interaction terms. The effect of directly observed fluoxetine treatment on depression symptom severity was statistically significant irrespective of alcohol use status. When stratified by illicit drug use status, the effect of directly observed fluoxetine treatment on depression symptom severity was statistically significant only among persons who did not use illicit drugs. The interaction terms were not statistically significant. This study found a benefit of antidepressant treatment in persons with HIV, depression, and alcohol use. In addition, this study found no evidence that either alcohol use or illicit drug use moderates the antidepressant treatment response. Altogether, these findings support the use of antidepressant medication in this population. The public health impact of research in this area is significant given the known adverse effects of depression on HIV-related health outcomes. ClinicalTrials.gov Identifier: NCT00338767.

Inkwari: an emerging high-risk place potentiating hiv spread among young adults in a hyper-endemic South African setting.

Young adults in South Africa are at the epicenter of the HIV epidemic. The prevalence of HIV among young people in the province of KwaZulu-Natal (KZN) is particularly high. This study characterizes inkwari (Zulu word for raves or weekend-long parties) in eThekwini District, KZN and explored how these place-based dynamics shape the risk environment for the young adult attendees. In 2011, 13 qualitative interviews were conducted with men and women between 18 and 30 years-old who reported unprotected sex with at least one casual partner in the prior 3 months and attended an inkwari in the same time period. Interviews were analyzed using qualitative content analysis. Nine key informant interviews helped to triangulate these data. Five women and eight men were interviewed and the mean age was 25 years (SD 3.24). Ten reported meeting a sexual partner at an inkwari. Inkwari were characterized as sexualized settings with limited adult supervision. Participants attended inkwari to socialize with peers, use drugs and alcohol, and meet sexual partners. Sexual and physical violence also occurred at inkwari. Given the convergence of social, sexual, and substance-using networks at inkwari, further inquiry is needed to determine how this place may potentiate HIV transmission risk in an endemic setting.

Whoonga and the abuse and diversion of antiretrovirals in Soweto, South Africa.

Media reports have described recreational use of HIV antiretroviral medication in South Africa, but little has been written about this phenomenon in the scientific literature. We present original, qualitative data from eight semi-structured interviews that characterize recreational antiretroviral use in Soweto, South Africa. Participants reported that antiretrovirals, likely efavirenz, are crushed, mixed with illicit drugs (in a mixture known as whoonga), and smoked. They described medications being stolen from patients and expressed concern that antiretroviral abuse jeopardized the safety of both patients and users. Further studies are needed to understand the prevalence, patterns, and consequences of antiretroviral abuse and diversion.

Whoonga: potential recreational use of HIV antiretroviral medication in South Africa.

Whoonga is a drug cocktail in South Africa rumored to contain illicit drugs and HIV antiretroviral (ARV) medication. Although its use may adversely impact adherence to HIV treatment and may have the potential to generate ARV resistance, there is a paucity of research characterizing whoonga. We learned of whoonga during semi-structured interviews about substance abuse and HIV risk at "club-events" known as inkwaris in an urban township of Durban, South Africa. Whoonga was an emerging theme spontaneously identified as a problem for the community by 17 out of 22 informants. Perceptions of whoonga suggest that it is highly addictive, contains ARVs (notably efavirenz), is used by individuals as young as 14, and poses a threat to the health and safety of those who use it, including increasing the risk of HIV infection. Our informants provide preliminary evidence of the dangers of whoonga and reinforce the need for further study.

Impact of methamphetamine use on HIV and other health outcomes at an urban HIV medicine clinic.

BACKGROUND: The methamphetamine epidemic threatens progress towards ending the HIV epidemic in the United States. Further characterizing the prevalence and impact of methamphetamine use among people with HIV (PWH) is necessary to inform integrated HIV and methamphetamine treatment strategies. METHODS: We conducted a retrospective chart review to characterize methamphetamine use among 3,092 PWH at an urban HIV Medicine clinic between July 1, 2022 and June 30, 2023. The Chi-squared test was utilized to assess for statistically significant differences in demographics and HIV and other health outcomes among PWH who use and do not use methamphetamine. RESULTS: The prevalence of methamphetamine use among PWH in this cohort was 17%. PWH who used methamphetamine were more likely to be < 40 years of age, identify as White race, live in neighborhoods with low Healthy Places Index scores, identify as lesbian, gay, or bisexual, report male sex with men (MSM), MSM and injection drug use (IDU), or IDU as HIV transmission risk factor, miss scheduled HIV primary care visits, and screen positive for hepatitis C virus antibody, gonorrhea, chlamydia, and major depressive disorder. PWH who use methamphetamine were also less likely to be virally suppressed and have a CD4 count ≥ 200 cells/mm3. CONCLUSION: Methamphetamine use is prevalent among PWH at this urban HIV Medicine Clinic and is associated with worse HIV and other health outcomes which likely increase the risk of HIV transmission. The integration of methamphetamine use disorder treatment into HIV primary care is necessary to work toward ending the syndemics of methamphetamine and HIV.

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.

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.

The prevalence of mental health disorders in people with HIV and the effects on the HIV care continuum.

OBJECTIVE: To describe the prevalence of diagnosed depression, anxiety, bipolar disorder, and schizophrenia in people with HIV (PWH) and the differences in HIV care continuum outcomes in those with and without mental health disorders (MHDs). DESIGN: Observational study of participants in the North American AIDS Cohort Collaboration on Research and Design. METHODS: PWH (≥18 years) contributed data on prevalent schizophrenia, anxiety, depressive, and bipolar disorders from 2008 to 2018 based on International Classification of Diseases code mapping. Mental health (MH) multimorbidity was defined as having two or more MHD. Log binomial models with generalized estimating equations estimated adjusted prevalence ratios (aPR) and 95% confidence intervals for retention in care (≥1 visit/year) and viral suppression (HIV RNA ≤200 copies/ml) by presence vs. absence of each MHD between 2016 and 2018. RESULTS: Among 122 896 PWH, 67 643 (55.1%) were diagnosed with one or more MHD: 39% with depressive disorders, 28% with anxiety disorders, 10% with bipolar disorder, and 5% with schizophrenia. The prevalence of depressive and anxiety disorders increased between 2008 and 2018, whereas bipolar disorder and schizophrenia remained stable. MH multimorbidity affected 24% of PWH. From 2016 to 2018 (N = 64 684), retention in care was marginally lower among PWH with depression or anxiety, however those with MH multimorbidity were more likely to be retained in care. PWH with bipolar disorder had marginally lower prevalence of viral suppression (aPR = 0.98 [0.98-0.99]) as did PWH with MH multimorbidity (aPR = 0.99 [0.99-1.00]) compared with PWH without MHD. CONCLUSION: The prevalence of MHD among PWH was high, including MH multimorbidity. Although retention and viral suppression were similar to people without MHD, viral suppression was lower in those with bipolar disorder and MH multimorbidity.

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.

Astrocyte Activation is A Potential Mechanism Underlying Depressed Mood and Apathy in People with HIV.

Background: Astrocytes become activated with certain infections, and this might alter the brain to trigger or worsen depressed mood. Indeed, astrocytes are chronically activated in people with HIV infection (PWH), who are much more frequently depressed than people without HIV (PWoH). A particularly disabling component of depression in PWH is apathy, a loss of interest, motivation, emotion, and goal-directed behavior. We tested the hypothesis that depression and apathy in PWH would be associated with higher levels of a biomarker of astrocyte activation, glial fibrillary acidic protein (GFAP), in cerebrospinal fluid (CSF). Methods: We evaluated PWH in a prospective observational study using the Beck Depression Inventory-II (BDI-II) and additional standardized assessments, including lumbar puncture. We measured GFAP in CSF with a customized direct sandwich ELISA method. Data were analyzed using ANOVA and multivariable regression. Results: Participants were 212 PWH, mean (SD) age 40.9±9.14 years, median (IQR) nadir and current CD4 199 (57, 326) and 411 (259, 579), 65.1% on ART, 67.3% virally suppressed. Higher CSF GFAP correlated with worse total BDI-II total scores (Pearson correlation r=0.158, p-value=0.0211), and with worse apathy scores (r=0.205, p=0.0027). The correlation between apathy/depression and GFAP was not in fluenced by other factors such as age or HIV suppression status. Conclusions: Astrocyte activation, reflected in higher levels of CSF GFAP, was associated with worse depression and apathy in PWH. Interventions to reduce astrocyte activation -- for example, using a peptide-1 receptor (GLP-1R) agonist -- might be studied to evaluate their impact on disabling depression in PWH.

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.

Cannabis use is not associated with increased balance disturbances in HIV-infected individuals.

BACKGROUND: The association between long-term cannabis use and balance disturbances has not been investigated in people living with HIV (PWH). We hypothesized that long-term cannabis use in PWH might be associated with more deleterious effects on balance than in HIV seronegative individuals due to potential neurotoxic interactions between HIV and cannabis. METHODS: Three thousand six-hundred and forty-eight participants with and without HIV completed an interviewer-administered timeline follow-back assessment to assess lifetime days and quantity of cannabis use and other cannabis use characteristics. A structured clinical interview was used to collect any history of balance disturbance. Comparisons between HIV+ vs the HIV- groups and moderate-severe vs. no or minimal imbalance in participant characteristics (demographics, cannabis use, medication currently used, and neurological disease) were performed using Student t tests for continuous variables and Fisher's exact test for binary and categorical variables. Multivariate logistic regression was applied to determine the interaction effect of total quantity of cannabis use with HIV status on balance disturbance. Age, gender, cDSPN symptoms, gait ataxia, opioid medications, and sedatives were included as covariates in the adjusted model after variable selection. The effect sizes are presented as Cohen's d or odds ratios. RESULTS: On average, participants were 45.4 years old (SD = 11 years), primarily male (77.7%), and non-Hispanic white (48.1%). A majority of participants were HIV+ (79.1%). Four hundred thirty (11.9%) of the participants reported balance disturbances within the past 10 years. PWH were more likely to have balance disturbances than demographically matched HIV-uninfected participants (odds ratio [OR] 2.66, 95% CI 1.91-3.7). Participants with moderate-severe balance disturbances did not differ from those with no or minimal imbalance in the proportion who had ever used cannabis (73.8% vs. 74.4%; p = 0.8) (OR 1.03, 95% CI 0.80-1.32) neither did they have a higher total amount of cannabis use (4871 vs. 4648; p = 0.3) (Cohen's d 0.11, 95% CI 0.01-0.14). In the HIV- population, those with balance disturbances reported more total amount of cannabis use as compared to those with normal balance (11316 vs 4154; p = 0.007). In the HIV+ population on the other hand, there was no significant association (4379 vs 4773; p = 0.6). CONCLUSIONS: We found unexpectedly that while long-term cannabis use in HIV- individuals was associated with more severe balance disturbances, there were no associations in HIV+ individuals. This suggests that cannabis use in HIV is safe with respect to balance disturbances. Given that HIV is related to persistent inflammation despite virologic suppression on antiretroviral therapy, future mechanistic studies are needed to determine whether HIV-associated inflammation contributes to the higher prevalence of balance disturbance in HIV+ individuals and whether cannabinoids have anti-inflammatory effects that mitigate HIV-associated balance disturbance.

Social Isolation Is Linked to Inflammation in Aging People With HIV and Uninfected Individuals.

BACKGROUND: Even in the era of suppressive antiretroviral therapy, people with HIV (PWH) suffer greater exposure to inflammation than their uninfected peers. Although poor social support and social isolation have been linked to systemic inflammation in the general population, it is not known whether this is true also among PWH. METHODS: People with and without HIV infection were enrolled in a community-based, single-center study. Primary predictors were the Medical Outcomes Study Social Support Survey, and outcomes were a panel of inflammatory biomarkers (ICAM-1, MCP-1, IL-6, IL-8, IP-10, C-reactive protein, D-dimer, VEGF, sCD14, and uPAR) in blood plasma and cerebrospinal fluid (CSF). RESULTS: PWH had worse positive social support (P = 0.0138) and affectionate support (P = 0.0078) than did HIV- individuals. A factor analysis was used to group the biomarkers into related categories separately for each fluid. Levels of 3 of the 4 plasma factors were significantly higher in PWH than HIV- (ps = 0.007, 0.001, and 0.0005, respectively). Levels of 1 of the 3 CSF factors also were significantly higher in PWH than HIV- (P = 0.0194). In the combined PWH and HIV- cohort, poorer social support was associated with higher levels of a factor in plasma loading on MCP-1, IL-8, and VEGF (P = 0.020) and with a CSF factor loading on MCP-1 and IL-6 (P = 0.006). CONCLUSION: These results suggest that enhancing social support might be an intervention to reduce inflammation and its associated adverse outcomes among PWH.