The development of cannabinoids as therapeutic agents in the United States.

Cannabis is one of the oldest and widely used substances in the world. Cannabinoids within the cannabis plant, known as phytocannabinoids, mediate cannabis' effects through interactions with the body's endogenous cannabinoid system. This endogenous system, the endocannabinoid system, has important roles in physical and mental health. These roles point to the potential to develop cannabinoids as therapeutic agents, while underscoring the risks related to interfering with the endogenous system during non-medical use. This scoping narrative review synthesizes the current evidence for both the therapeutic and adverse effects of the major (i.e., Δ9-tetrahydrocannabinol and cannabidiol) and lesser studied minor phytocannabinoids, from nonclinical to clinical research. We pay particular attention to the areas where evidence is well-established, including analgesic effects after acute exposures and neurocognitive risks after acute and chronic use. In addition, drug development considerations for cannabinoids as therapeutic agents within the United States are reviewed. The proposed clinical study design considerations encourage methodological standards for greater scientific rigor and reproducibility, ultimately, to extend our knowledge of the risks and benefits of cannabinoids for patients and providers. Significance Statement This work provides a review of prior research related to phytocannabinoids, including therapeutic potential and known risks in the context of drug development within the United States. We also provide study design considerations for future cannabinoid drug development.

The experiences of men in prison who do not receive visits from family or friends: A qualitative systematic review.

BACKGROUND: Visits present an opportunity for prisoners to preserve family ties and reduce isolation, but not all receive visits from family or friends whilst incarcerated. AIMS: To locate, appraise and synthesise qualitative data on the experiences of adult male prisoners (aged 18 years+) who do not receive prison visits from family or friends. METHODS: Nine electronic databases were searched from the date of their inception until March 2023. The quality of included studies was assessed using the Critical Appraisal Skills Programme checklist for qualitative studies, and data from the studies were synthesised using the thematic synthesis method. RESULTS: Eighteen studies from seven countries (the USA, the UK [England, Northern Ireland & Scotland], Canada, Netherlands and the Philippines) were eligible for inclusion. Three main themes emerged: (1) reasons for not receiving visits, (2) harmful effects of not receiving visits and (3) the value of volunteer visitor programmes. Practical problems were cited as interfering with visiting opportunities, but also some prisoners or families chose not to meet in prison. Loneliness and depression were extensively described as effects of not receiving visits. Qualities associated with volunteer visitors included raised self-esteem, improved mood and personal growth. CONCLUSION: Narratives of the experiences of adult men in prison without visits from family or friends suggest that not only the practical difficulties of imprisonment affect visiting; barriers that prisoners themselves impose would merit further exploration, as would family and relationship dynamics during incarceration and the emotional impact of prison visits, for both prisoners and their families. There are suggestions of therapeutic as well as humanitarian benefits from volunteer visiting programmes. There is a gap in the literature about any specific effect on rebuilding family relationships.

International consensus statement on the design, delivery and evaluation of sport-based interventions aimed at promoting social, psychological and physical well-being in prison.

OBJECTIVE: To develop an international consensus statement to advise on designing, delivering and evaluating sport-based interventions (SBIs) aimed at promoting social, psychological and physical well-being in prison. DESIGN: Modified Delphi using two rounds of survey questionnaires and two consensus workshops. PARTICIPANTS: A multidisciplinary panel of more than 40 experts from 15 international jurisdictions was formed, including representation from the following groups and stakeholders: professionals working in the justice system; officials from sport federations and organisations; academics with research experience of prisons, secure forensic mental health settings and SBIs; and policy-makers in criminal justice and sport. RESULTS: A core research team and advisory board developed the initial rationale, statement and survey. This survey produced qualitative data which was analysed thematically. The findings were presented at an in-person workshop. Panellists discussed the findings, and, using a modified nominal group technique, reached a consensus on objectives to be included in a revised statement. The core research team and advisory board revised the statement and recirculated it with a second survey. Findings from the second survey were discussed at a second, virtual, workshop. The core research team and advisory board further revised the consensus statement and recirculated it asking panellists for further comments. This iterative process resulted in seven final statement items; all participants have confirmed that they agreed with the content, objectives and recommendations of the final statement. CONCLUSIONS: The statement can be used to assist those that design, deliver and evaluate SBIs by providing guidance on: (1) minimum levels of competence for those designing and delivering SBIs; (2) the design and delivery of inclusive programmes prioritising disadvantaged groups; and (3) evaluation measures which are carefully calibrated both to capture proposed programme outcomes and to advance an understanding of the systems, processes and experiences of sport engagement in prison.

Neural complexity is increased after low doses of LSD, but not moderate to high doses of oral THC or methamphetamine.

Neural complexity correlates with one's level of consciousness. During coma, anesthesia, and sleep, complexity is reduced. During altered states, including after lysergic acid diethylamide (LSD), complexity is increased. In the present analysis, we examined whether low doses of LSD (13 and 26 µg) were sufficient to increase neural complexity in the absence of altered states of consciousness. In addition, neural complexity was assessed after doses of two other drugs that significantly altered consciousness and mood: delta-9-tetrahydrocannabinol (THC; 7.5 and 15 mg) and methamphetamine (MA; 10 and 20 mg). In three separate studies (N = 73; 21, LSD; 23, THC; 29, MA), healthy volunteers received placebo or drug in a within-subjects design over three laboratory visits. During anticipated peak drug effects, resting state electroencephalography (EEG) recorded Limpel-Ziv complexity and spectral power. LSD, but not THC or MA, dose-dependently increased neural complexity. LSD also reduced delta and theta power. THC reduced, and MA increased, alpha power, primarily in frontal regions. Neural complexity was not associated with any subjective drug effect; however, LSD-induced reductions in delta and theta were associated with elation, and THC-induced reductions in alpha were associated with altered states. These data inform relationships between neural complexity, spectral power, and subjective states, demonstrating that increased neural complexity is not necessary or sufficient for altered states of consciousness. Future studies should address whether greater complexity after low doses of LSD is related to cognitive, behavioral, or therapeutic outcomes, and further examine the role of alpha desynchronization in mediating altered states of consciousness.

Risk factors for poorer respiratory outcomes in adolescents and young adults born preterm.

RATIONALE: The respiratory outcomes for adult survivors of preterm birth in the postsurfactant era are wide-ranging with prognostic factors, especially those encountered after the neonatal period, poorly understood. OBJECTIVES: To obtain comprehensive 'peak' lung health data from survivors of very preterm birth and identify neonatal and life-course risk factors for poorer respiratory outcomes in adulthood. METHODS: 127 participants born ≤32 weeks gestation (64%, n=81 with bronchopulmonary dysplasia (BPD), initially recruited according to a 2 with-BPD:1 without-BPD strategy), and 41 term-born controls completed a lung health assessment at 16-23 years, including lung function, imaging and symptom review. Risk factors assessed against poor lung health included neonatal treatments, respiratory hospitalisation in childhood, atopy and tobacco smoke exposure. MEASUREMENTS AND MAIN RESULTS: Young adults born prematurely had greater airflow obstruction, gas trapping and ventilation inhomogeneity, in addition to abnormalities in gas transfer and respiratory mechanics, compared with term. Beyond lung function, we observed greater structural abnormalities, respiratory symptoms and inhaled medication use. A previous respiratory admission was associated with airway obstruction; mean forced expiratory volume in 1 s/forced vital capacity z-score was -0.561 lower after neonatal confounders were accounted for (95% CI -0.998 to -0.125; p=0.012). Similarly, respiratory symptom burden was increased in the preterm group with a respiratory admission, as was peribronchial thickening (6% vs 23%, p=0.010) and bronchodilator responsiveness (17% vs 35%, p=0.025). Atopy, maternal asthma and tobacco smoke exposure did not influence lung function or structure at 16-23 years in our preterm cohort. CONCLUSIONS: Even after accounting for the neonatal course, a respiratory admission during childhood remained significantly associated with reduced peak lung function in the preterm-born cohort, with the largest difference seen in those with BPD. A respiratory admission during childhood should, therefore, be considered a risk factor for long-term respiratory morbidity in those born preterm, especially for individuals with BPD.

Changes in Immune-Related Biomarkers and Endocannabinoids as a Function of Frequency of Cannabis Use in People Living With and Without HIV.

Background: Cannabis use is common among people living with HIV (PLWH). Some observational studies of PLWH have linked cannabis use to lower immune markers; however, this is yet to be confirmed. In addition, whether HIV affects the endogenous cannabinoid system has not been studied. Our objective was to examine changes in immune-related biomarkers and endocannabinoids as a function of cannabis use frequency in people living with and without HIV. Materials and Methods: Data were obtained from a longitudinal study of men who have sex with men living in Los Angeles with, or at risk for, HIV. By design, half were PLWH. Those eligible for the parent study were willing and able to return for follow-up every 6 months. Those eligible for inclusion in this study reported varying levels of current cannabis use at follow-up. Specifically, one visit corresponded to a period of daily use and another to a period of infrequent use (weekly, monthly, or less than monthly). Banked serum from all eligible participants was analyzed for immune-related biomarkers, endocannabinoids, and paracannabinoids. Results: The analysis included 36 men, 19 of whom were PLWH. PLWH reported greater lifetime methamphetamine or amphetamine use (68% vs. 0%) and current cigarette use (55% vs. 20%) than people without HIV. Serum levels of HIV-related immune biomarkers including tumor necrosis factor receptor 2 (TNFR2; p=0.013) and CD27 (p=0.004) were greater in PLWH, alongside lower anandamide (AEA) (F1,34=5.337, p=0.027) and oleoylethanolamide (OEA) (F1,34=8.222, p=0.007) levels relative to people without HIV. Frequency of cannabis use did not impact the serum analytes in our study. Conclusions: Higher levels of TNFR2 and CD27 and lower levels of AEA and OEA in PLWH underscore the role of the TNF/TNFR superfamily in HIV, while highlighting a new role for the enzymatic activity of fatty acid amide hydrolase (the enzyme that hydrolyzes AEA and OEA) in HIV. Findings that cannabis frequency did not impact the immune phenotype may not generalize to other populations of PLWH. Additional work is required to further clarify the relationship between immune markers and endocannabinoids as a function of cannabis use frequency in PLWH. ClinicalTrials.gov ID: NCT01201083.

Dopamine D1 and NMDA receptor co-regulation of protein translation in cultured nucleus accumbens neurons.

Protein translation is essential for some forms of synaptic plasticity. We used nucleus accumbens (NAc) medium spiny neurons (MSN), co-cultured with cortical neurons to restore excitatory synapses, to examine whether dopamine modulates protein translation in NAc MSN. FUNCAT was used to measure translation in MSNs under basal conditions and after disinhibiting excitatory transmission using the GABAA receptor antagonist bicuculline (2 hr). Under basal conditions, translation was not altered by the D1-class receptor (D1R) agonist SKF81297 or the D2-class receptor (D2R) agonist quinpirole. Bicuculline alone robustly increased translation. This was reversed by quinpirole but not SKF81297. It was also reversed by co-incubation with the D1R antagonist SCH23390, but not the D2R antagonist eticlopride, suggesting dopaminergic tone at D1Rs. This was surprising because no dopamine neurons are present. An alternative explanation is that bicuculline activates translation by increasing glutamate tone at NMDA receptors (NMDAR) within D1R/NMDAR heteromers, which have been described in other cell types. Supporting this, immunocytochemistry and proximity ligation assays revealed D1/NMDAR heteromers on NAc cells both in vitro and in vivo. Further, bicuculline's effect was reversed to the same extent by SCH23390 alone, the NMDAR antagonist APV alone, or SCH23390+APV. These results suggest that: 1) excitatory synaptic transmission stimulates translation in NAc MSNs, 2) this is opposed when glutamate activates D1R/NMDAR heteromers, even in the absence of dopamine, and 3) antagonist occupation of D1Rs within the heteromers prevents their activation. Our study is the first to suggest a role for D2 receptors and D1R/NMDAR heteromers in regulating protein translation.

Cinematic versus volume rendered imaging for the depiction of complex congenital heart disease.

INTRODUCTION: Planning for surgical intervention for patients with complex congenital heart disease requires a comprehensive understanding of the individual's anatomy. Cinematic rendering (CR) is a novel technique that purportedly builds on traditional volume rendering (VR) by converting CT image data into clearly defined 3D reconstructions through the stimulation and propagation of light rays. The purpose of this study was to compare CR to VR for the understanding of critical anatomy in unoperated complex congenital heart disease. METHODS: In this retrospective study, CT data sets from 20 sequential scanned cases of unoperated paediatric patients with complex congenital heart disease were included. 3D images were produced at standardised and selected orientations, matched for both VR and CR. The images were then independently reviewed by two cardiologists, two radiologists and two surgeons for overall image quality, depth perception and the visualisation of surgically relevant anatomy, the coronary arteries and the pulmonary veins. RESULTS: Cinematic rendering demonstrated significantly superior image quality, depth perception and visualisation of surgically relevant anatomy than VR. CONCLUSION: Cinematic rendering is a novel 3D CT-rendering technique that may surpass the traditionally used volumetric rendering technique in the provision of actionable pre-operative anatomical detail for complex congenital heart disease.

Lung cancer screening an asbestos exposed population: Existing lung cancer risk criteria are not sufficient.

BACKGROUND AND OBJECTIVE: Asbestos is a major risk factor for lung cancer, with or without tobacco smoke exposure. Low dose computed tomography (LDCT) screening for early lung cancer is effective but only when targeting high risk populations. This study aimed to analyse the effectiveness of LDCT screening in an asbestos exposed population and to compare lung cancer screening program (LCSP) eligibility criteria. METHODS: Participants in an asbestos health surveillance program, the Western Australia Asbestos Review Program, underwent at least one LDCT scan and lung function assessment as part of annual review between 2012 and 2017. Lung cancer cases were confirmed through linkage to the WA cancer registry. Theoretical eligibility for different screening programs was calculated. RESULTS: Five thousand seven hundred and two LDCT scans were performed on 1743 individuals. The median age was 69.8 years, 1481 (85.0%) were male and 1147 (65.8%) were ever-smokers (median pack-year exposure of 20.0). Overall, 26 lung cancers were detected (1.5% of the population; 3.5 cases per 1000 person-years of observation). Lung cancer was early stage in 86.4% and four (15.4%) cases were never smokers. Based on current lung screening program criteria, 1299 (74.5%) of this population, including the majority (17, 65.4%) of lung cancer cases, would not have been eligible for any LCSP. CONCLUSION: This population is at raised risk despite modest tobacco exposure. LDCT screening is effective at identifying early-stage lung cancer in this population and existing lung cancer risk criteria do not capture this population adequately.

Persistent Neuroadaptations in the Nucleus Accumbens Core Accompany Incubation of Methamphetamine Craving in Male and Female Rats.

Relapse is a major problem in treating methamphetamine use disorder. "Incubation of craving" during abstinence is a rat model for persistence of vulnerability to craving and relapse. While methamphetamine incubation has previously been demonstrated in male and female rats, it has not been demonstrated after withdrawal periods greater than 51 d and most mechanistic work used males. Here, we address both gaps. First, although methamphetamine intake was higher in males during self-administration training (6 h/d × 10 d), incubation was similar in males and females, with "incubated" craving persisting through withdrawal day (WD)100. Second, using whole-cell patch-clamp recordings in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) core, we assessed synaptic levels of calcium-permeable AMPA receptors (CP-AMPARs), as their elevation is required for expression of incubation in males. In both sexes, compared with saline-self-administering controls, CP-AMPAR levels were significantly higher in methamphetamine rats across withdrawal, although this was less pronounced in WD100-135 rats than WD15-35 or WD40-75 methamphetamine rats. We also examined membrane properties and NMDA receptor (NMDAR) transmission. In saline controls, MSNs from males exhibited lower excitability than females. This difference was eliminated after incubation because of increased excitability of MSNs from males. NMDAR transmission did not differ between sexes and was not altered after incubation. In conclusion, incubation persists for longer than previously described and equally persistent CP-AMPAR plasticity in NAc core occurs in both sexes. Thus, abstinence-related synaptic plasticity in NAc is similar in males and females although other methamphetamine-related behaviors and neuroadaptations show differences.

Smoked cannabis reduces peak cocaine plasma levels and subjective effects in a controlled drug administration study of polysubstance use in men.

BACKGROUND: Despite the high prevalence of polysubstance use, outcomes and potential risks associated with common drug combinations are not well characterized. Many individuals who use cocaine also use cannabis, yet little is known about how interactions between the two drugs might contribute to continued co-use. METHODS: The aim of this double-blind, placebo-controlled study was to determine the physiological and subjective effects of smoked cannabis with smoked cocaine, to identify variables that may contribute to the continued use of this drug combination. Healthy, non-treatment seeking volunteers who reported smoking both cocaine and cannabis (N = 9, all males) completed a 13-day inpatient protocol. On session days, cannabis [0.0 or 5.6 % tetrahydrocannabinol (THC)] was administered 28 min prior to cocaine (0, 12, or 25 mg). Dependent measures included pharmacokinetic assessment of THC and cocaine and their respective metabolites, in addition to subjective and cardiovascular effects. RESULTS: Active cannabis (5.6 % THC) increased plasma levels of THC and the metabolite 11-nor-9-carboxy-Δ9-THC (THCCOOH), as well as subjective ratings of cannabis effects and heart rate relative to inactive cannabis. Cocaine dose-dependently increased plasma cocaine and metabolites and subjective ratings of cocaine effects. Active cannabis pre-treatment decreased plasma levels of cocaine and metabolites. Furthermore, active cannabis attenuated cocaine-related reductions in 'Hunger' and 'Calm.' CONCLUSIONS: Cannabis pre-treatment altered the subjective experience of smoked cocaine and reduced peak plasma levels of cocaine. Future studies should explore additional doses of each drug and whether these changes also impact cocaine's reinforcing effects.

Behavioral Crisis and First Response: Qualitative Interviews with Chicago Stakeholders.

Improving interactions between first responders and individuals experiencing behavioral crisis is a critical public health challenge. To gain insight into these interactions, key informant qualitative interviews were conducted with 25 Chicago stakeholders. Stakeholders included directors and staff of community organizations and shelters that frequently engage first responders. Interviews included granular depictions related to the expectations and outcomes of 911 behavioral crisis calls, and noted areas requiring improved response. Stakeholders called 911 an average of 2 to 3 times per month, most often for assistance related to involuntary hospitalization. Engagements with first responders included unnecessary escalation or coercive tactics, or conversely, refusal of service. While stakeholders lauded the value of police trained through the city's Crisis Intervention Team program, they emphasized the need for additional response strategies that reduce the role of armed police, and underscored the need for broader social and behavioral health services for individuals at-risk of such crises.

Low doses of lysergic acid diethylamide (LSD) increase reward-related brain activity.

Renewed interest in classic psychedelics as treatments for psychiatric disorders warrants a deeper understanding of their neural mechanisms. Single, high doses of psychedelic drugs have shown promise in treating depressive disorders, perhaps by reversing deficits in reward processing in the brain. In addition, there are anecdotal reports that repeated ingestion of low doses of LSD, or "microdosing", improve mood, cognition, and feelings of wellbeing. However, the effects of low doses of classic psychedelics on reward processing have not been studied. The current study examined the effects of two single, low doses of LSD compared to placebo on measures of reward processing. Eighteen healthy adults completed three sessions in which they received placebo (LSD-0), 13 µg LSD (LSD-13) and 26 µg LSD (LSD-26) in a within-subject, double-blind design. Neural activity was recorded while participants completed the electrophysiological monetary incentive delay task. Event-related potentials were measured during feedback processing (Reward-Positivity: RewP, Feedback-P3: FB-P3, and Late-Positive Potential: LPP). Compared to placebo, LSD-13 increased RewP and LPP amplitudes for reward (vs. neutral) feedback, and LSD-13 and LSD-26 increased FB-P3 amplitudes for positive (vs. negative) feedback. These effects were unassociated with most subjective measures of drug effects. Thus, single, low doses of LSD (vs. placebo) increased three reward-related ERP components reflecting increased hedonic (RewP), motivational (FB-P3), and affective processing of feedback (LPP). These results constitute the first evidence that low doses of LSD increase reward-related brain activity in humans. These findings may have important implications for the treatment of depressive disorders.

Correlation of lung function with ultra-low-dose CT-detected lung parenchymal abnormalities: a cohort study of 1344 asbestos exposed individuals.

INTRODUCTION: Deliberate exposure to medical ionising radiation should be as low as reasonably practicable but the reduction of radiation from CT should be balanced against diagnostic image quality. The ability of ultra-low-dose CT (uLDCT: similar radiation to chest X-ray) to demonstrate low contrast abnormalities (emphysema and interstitial lung abnormality (ILA)) is unclear.The aim of this cross-sectional study was to analyse the lung parenchymal findings from uLDCT scans against physiological measures of respiratory function. METHODS: WA Asbestos Review Programme participants were eligible if they had an uLDCT scan and lung function assessment between Janary and December 2018. All scans were performed using a single CT machine and reported using a standardised, semiquantitative synoptic report which includes emphysema and linear fibrosis (ILA) scores. RESULTS: Of 1344 participants, median (IQR) age was 72.0 (65.0-78.0) years, the majority were males (84.9%) with mixed occupational asbestos exposure (68.1%). There were 721 (53.6%) with no abnormality, 158 (11.8%) with emphysema, 465 (34.6%) with ILA. Mean radiation dose was 0.12 mSv. There was statistically significant between group differences for all physiological parameters of lung function compared with controls. For instance, the emphysema score significantly correlated with obstructive forced expiratory volume in 1 s (FEV1)/forced vital capacity ratio (r=0.512), per cent predicted FEV1 (r=0.24) and lower diffusion of carbon monoxide (DLCO) (r=0.337). Multivariate modelling demonstrated that increasing age, emphysema and fibrosis scores predicted reduced DLCO (adjusted R2=0.30). DISCUSSION: uLDCT-detected parenchymal lung abnormalities correlate strongly with significant changes on lung function testing suggesting the observed CT abnormalities are of physiological and clinical significance.

Δ9-THC reduces reward-related brain activity in healthy adults.

RATIONALE: Greater availability of cannabis in the USA has raised concerns about adverse effects of the drug, including possible amotivational states. Lack of motivation may be assessed by examining acute effects of cannabinoids on reward processing. OBJECTIVES: This study examined single doses of delta-9-tetrahydrocannabinol (∆9-THC; 7.5, 15 mg oral) in healthy adults using a version of the monetary incentive delay (MID) task adapted for electroencephalography (EEG; e-MID) in a within-subjects, double blind design. METHODS: Two phases of reward processing were examined: anticipation, which occurs with presentation of cues that indicate upcoming reward, punishment, or neutral conditions, and outcome, which occurs with feedback indicating hits or misses. During anticipation, we measured two event-related potential (ERP) components: the P300, which measures attention and motivation, and the LPP, which measures affective processing. During outcome processing, we measured P300 and LPP, as well as the RewP, which measures outcome evaluation. RESULTS: We found that ∆9-THC modulated outcome processing, but not reward anticipation. Specifically, both doses of ∆9-THC (7.5 and 15 mg) reduced RewP amplitudes after outcome feedback (hits and misses) relative to placebo. ∆9-THC (15 mg) also reduced P300 and LPP amplitudes following hits compared to misses, relative to both placebo and 7.5 mg ∆9-THC. CONCLUSIONS: These findings suggest that ∆9-THC dampens responses to both reward and loss feedback, which may reflect an "amotivational" state. Future studies are needed to determine generalizability of this effect, such as its pharmacological specificity and its specificity to monetary vs other types of reward.

The altered state of consciousness induced by Δ9-THC.

Altered states of consciousness (ASC) provide an opportunity for researchers to study the neurophysiological basis of changes in phenomenal experience. Δ9-tetrahydrocannabinol (THC) is the primary psychoactive constituent of cannabis, however whether the effects of THC include ASC features that are shared with other ASC induction mechanisms, such as classical psychedelics, has not been systematically addressed. We used survey (11D-ASC; State Mindfulness), self-report, and natural language processing (NLP) to assess 7.5 and 15 mg oral THC, relative to placebo, in 25 healthy, infrequent cannabis users. THC dose-dependently increased measures of ASC including Insightfulness, and increased ratings of mindfulness and mind-wandering. THC also increased language entropy as previously reported for LSD. Future studies may seek to determine whether reports of increased mindfulness or insight after THC are primarily representative of a psychotomimetic state (i.e., delusional thinking) or conversely, reflect an enhancement of conscious awareness that may be validated empirically.

Adolescents are more sensitive than adults to acute behavioral and cognitive effects of THC.

Increased cannabis availability has contributed to increased use with concomitant incidence of adverse effects. One risk factor for adverse drug reactions may be age. There is preclinical evidence that acute effects of delta-9-tetrahydrocannabinol (THC), the primary active constituent of cannabis, are greater during adolescence, but this has not been fully studied in humans. The present study sought to determine whether adolescent men and women are more sensitive than adults to acute THC. Adolescents aged 18-20 (N = 12) and adults aged 30-40 (N = 12), with less than 20 total lifetime uses of THC-containing products, received capsules of THC (7.5, 15 mg) and placebo across three study sessions in randomized order under double blind conditions. During each session, subjective, cardiovascular, behavioral, and EEG measures were obtained. Behavioral measures included Simple Reaction Time, Stop Task, Time Production and N-back and EEG measures included P300 amplitudes during an auditory oddball task and eyes-closed resting state. THC affected subjective state and heart rate similarly in both age groups. However, adolescents were more sensitive to performance impairing effects, exhibiting dose-dependent impairments on reaction time, response accuracy, and time perception. On EEG measures, THC dose-dependently decreased P300 amplitude in adolescents but not adults. Adolescents were more sensitive to behavioral and cognitive effects of THC, but not to cardiovascular effects or subjective measures. Thus, at doses that produce comparable ratings of intoxication, adolescents may exhibit greater cognitive impairment and alterations in brain function.

A screening tool to identify risk for bronchiectasis progression in children with cystic fibrosis.

BACKGROUND: The marked heterogeneity in cystic fibrosis (CF) disease complicates the selection of those most likely to benefit from existing or emergent treatments. OBJECTIVE: We aimed to predict the progression of bronchiectasis in preschool children with CF. METHODS: Using data collected up to 3 years of age, in the Australian Respiratory Early Surveillance Team for CF cohort study, clinical information, chest computed tomography (CT) scores, and biomarkers from bronchoalveolar lavage were assessed in a multivariable linear regression model as predictors for CT bronchiectasis at age 5-6. RESULTS: Follow-up at 5-6 years was available in 171 children. Bronchiectasis prevalence at 5-6 was 134/171 (78%) and median bronchiectasis score was 3 (range 0-12). The internally validated multivariate model retained eight independent predictors accounting for 37% (adjusted R2 ) of the variance in bronchiectasis score. The strongest predictors of future bronchiectasis were: pancreatic insufficiency, repeated intravenous treatment courses, recurrent lower respiratory infections in the first 3 years of life, and lower airway inflammation. Dichotomizing the resulting prediction score at a bronchiectasis score of above the median resulted in a diagnostic odds ratio of 13 (95% confidence interval [CI], 6.3-27) with positive and negative predictive values of 80% (95% CI, 72%-86%) and 77% (95% CI, 69%-83%), respectively. CONCLUSION: Early assessment of bronchiectasis risk in children with CF is feasible with reasonable precision at a group level, which can assist in high-risk patient selection for interventional trials. The unexplained variability in disease progression at individual patient levels remains high, limiting the use of this model as a clinical prediction tool.