Impact of converging sociocultural and substance-related trends on US autism rates: combined geospatiotemporal and causal inferential analysis.

Whilst cannabis is known to be toxic to brain development, it is unknown if it is driving rising US autism rates (ASMR). A longitudinal epidemiological study was conducted using national autism census data from the US Department of Education Individuals with Disabilities Act (IDEA) 1991-2011 and nationally representative drug exposure (cigarettes, alcohol, analgesic, and cocaine abuse, and cannabis use monthly, daily, and in pregnancy) datasets from National Survey of Drug Use and Health and US Census (income and ethnicity) and CDC Wonder population and birth data. Analysis was conducted in R. 266,950 were autistic of a population of 40,119,464 8-year-olds in 1994-2011. At national level after adjustment, daily cannabis use was significantly related to ASMR (ß estimate = 4.37 (95%C.I. 4.06, 4.68), P < 2.2 × 10-16) as was first pregnancy trimester cannabis exposure (ß estimate = 0.12 (0.08, 0.16), P = 1.7 × 10-12). At state level following adjustment for cannabis, cannabigerol (from ß estimate = - 13.77 (- 19.41, 8.13), P = 1.8 × 10-6) and Δ9-tetrahydrocannabinol (from ß estimate = 1.96 (0.88-3.04), P = 4 × 10-4) were significant. Geospatial state-level modelling showed exponential relationship between ASMR and Δ9-tetrahydrocannabinol and cannabigerol exposure. Exponential coefficients for the relationship between modelled ASMR and Δ9-tetrahydrocannabinol and cannabigerol exposure were 7.053 (6.39-7.71) and 185.334 (167.88-202.79; both P < 2.0 × 10-7). E-values are an instrument related to the evidence for causality in observational studies. High E-values were noted. Dichotomized legal status was linked with elevated ASMR. Data show cannabis use is associated with ASMR, is powerful enough to affect overall trends, and persists after controlling for other major covariates. Cannabinoids are exponentially associated with ASMR. The cannabis-autism relationship satisfies criteria of causal inference.

An intervention at an adult inpatient unit to engage people with schizophrenia and work goals with supported employment.

OBJECTIVE: Test an intervention for individuals with schizophrenia at an Adult Inpatient Unit with employment and social inclusion goals, compared to treatment as usual. METHOD: A single-blind, randomised, controlled trial assigned 25 participants to treatment as usual and 26 participants to receive an Individual Placement and Support (IPS) Disability Employment Service (DES) information pack and an offer of support from a nurse. Outcomes were measured at 6 and 12 months using Job Acquisition, IPS DES employment provider, Activity Participation Questionnaire-Revised, Brief Psychiatric Rating Scale, and Adult Hope Scale questionnaires, and Digit Span and Trail Making tests. RESULTS: The intervention did not result in significant contact with the DES employment provider or paid employment outcomes. Secondary outcomes from combining groups due to high attrition rates: A significant proportion of participants obtained unpaid work from baseline to 6 months follow-up (N = 24, p = 0.001). CONCLUSIONS: The 'light touch' intervention did not promote change. More support is required during inpatient admissions and after discharge to assist people with schizophrenia achieve their vocational goals.

Geotemporospatial and causal inference epidemiological analysis of US survey and overview of cannabis, cannabidiol and cannabinoid genotoxicity in relation to congenital anomalies 2001-2015.

BACKGROUND: Cannabinoids including cannabidiol have recognized genotoxic activities but their significance has not been studied broadly epidemiologically across the teratological spectrum. We examined these issues including contextual space-time relationships and formal causal inferential analysis in USA. METHODS: State congenital anomaly (CA) rate (CAR) data was taken from the annual reports of the National Birth Defects Prevention Network 2001-2005 to 2011-2015. Substance abuse rates were from the National Survey of Drug Use and Health a nationally representative longitudinal survey of the non-institutionalized US population with 74.1% response rate. Drugs examined were cigarettes, monthly and binge alcohol, monthly cannabis and analgesic and cocaine abuse. Early termination of pregnancy for abortion (ETOPFA) rates were taken from the published literature. Cannabinoid concentrations were from Drug Enforcement Agency. Ethnicity and income data were from the US Census Bureau. Inverse probability weighted (IPW) regressions and geotemporospatial regressions conducted for selected CAs. RESULTS: Data on 18,328,529 births from an aggregated population of 2,377,483,589 for mid-year analyses 2005-2013 comprehending 12,611 CARs for 62 CAs was assembled and ETOPFA-corrected (ETOPFACAR) where appropriate. E-Values for ETOPFACARs by substance trends were elevated for THC (40 CAs), cannabis (35 CAs), tobacco (11 CAs), cannabidiol (8 CAs), monthly alcohol (5 CAs) and binge alcohol (2 CAs) with minimum E-Values descending from 16.55, 1.55x107, 555.10, 7.53x1019, 9.30 and 32.98. Cardiovascular, gastrointestinal, chromosomal, limb reductions, urinary, face and body wall CAs particularly affected. Highest v. lowest substance use quintile CAR prevalence ratios 2.84 (95%C.I. 2.44, 3.31), 4.85 (4.08, 5.77) and 1.92 (1.63, 2.27) and attributable fraction in exposed 0.28 (0.27, 0.28), 0.57 (0.51, 0.62) and 0.47 (0.38, 0.55) for tobacco, cannabis and cannabidiol. Small intestinal stenosis or atresia and obstructive genitourinary defect were studied in detail in lagged IPW pseudo-randomized causal regressions and spatiotemporal models confirmed the causal role of cannabinoids. Spatiotemporal predictive modelling demonstrated strongly sigmoidal non-linear cannabidiol dose-response power-function relationships (P = 2.83x10-60 and 1.61x10-71 respectively). CONCLUSIONS: Data implicate cannabinoids including cannabidiol in a diverse spectrum of heritable CAs. Sigmoidal non-linear dose-response relationships are of grave concern. These transgenerational genotoxic, epigenotoxic, chromosomal-toxic putatively causal teratogenic effects strongly indicate tight restrictions on community cannabinoid penetration.

Integration of alcohol and drug nurses into a mental health unit.

OBJECTIVE: Test whether extra time with alcohol and drug nurses for inpatients at a Mental Health Unit (MHU) reduces post-discharge mental and co-occurring alcohol and drug problems and increases engagement in alcohol and drug treatment more than a Brief Information Pack (BIP). METHOD: Single blind randomised control trial in block design compared two alcohol and drug nurse delivered interventions over 6 months post-discharge using the Alcohol Use Disorders Identification Test (AUDIT) and Brief Symptom Inventory index of overall psychological distress Global Severity Index (GSI). RESULTS: Alcohol and drug nurse delivered BIP was associated with a statistically significant reduction in AUDIT measured alcohol use for the highest follow-up score across the 6-month post-discharge period, n = 20, t = 2.24, p = 0.037, d = 0.50 and for the extra time intervention, n = 11, t = 2.51, p = 0.031, d = 0.76. CONCLUSIONS: MHUs may benefit from the integration of alcohol and drug nurses with community alcohol and drug treatment experience.

Clinical psychology referral for individuals with auditory verbal hallucinations and schizophrenia: Therapy engagement, hallucination severity and distress.

OBJECTIVE: Test an intervention for people with schizophrenia and auditory verbal hallucinations at an acute inpatient unit (AIU) to engage with community therapy and reduce hallucination severity and associated distress. The trial cohort consisted of patients who after assessment by an AIU psychiatrist were not selected for an appointment with an AIU clinical psychologist and an opportunity for referral to a post-discharge community psychologist. An intervention providing the appointment and referral opportunity was compared to Treatment As Usual (TAU). METHOD: A single-blind, randomised, control trial compared the intervention with TAU over 6-months post-discharge using Engagement in Community Therapy, Psychotic Symptom Rating Scale (PSYRATS) auditory hallucinations and Revised Beliefs About Voices (BAVQ-R) questionnaires. RESULTS: Post-discharge community therapy engagement increased at 6 months compared to baseline in the intervention, TAU and combined groups. PSYRATS AHS and H-DIS scores decreased from baseline to last follow-up (statistically significant for TAU, and combined treatment groups). BAVQ-R RE scores decreased from baseline to last follow-up but the decrease was not statistically significant. CONCLUSIONS: Most participants chose to engage with a community therapist despite not being initially assigned for referral by their psychiatrist and experiencing moderately severe symptoms.

Cannabinoid exposure as a major driver of pediatric acute lymphoid Leukaemia rates across the USA: combined geospatial, multiple imputation and causal inference study.

BACKGROUND: Acute lymphoid leukaemia (ALL) is the commonest childhood cancer whose incidence is rising in many nations. In the USA, between 1975 and 2016, ALL rates (ALLRs) rose 93.51% from 1.91 to 3.70/100,000 <  20 years. ALL is more common in Caucasian-Americans than amongst minorities. The cause of both the rise and the ethnic differential is unclear, however, prenatal cannabis exposure was previously linked with elevated childhood leukaemia rates. We investigated epidemiologically if cannabis use impacted nationally on ALLRs, its ethnic effects, and if the relationship was causal. METHODS: State data on overall, and ethnic ALLR from the Surveillance Epidemiology and End Results databank of the Centre for Disease Control (CDC) and National Cancer Institute (NCI) were combined with drug (cigarettes, alcoholism, cannabis, analgesics, cocaine) use data from the National Survey of Drug Use and Health; 74.1% response rate. Income and ethnicity data was from the US Census bureau. Cannabinoid concentration was from the Drug Enforcement Agency Data. Data was analyzed in R by robust and spatiotemporal regression. RESULTS: In bivariate analyses a dose-response relationship was demonstrated between ALLR and Alcohol Use Disorder (AUD), cocaine and cannabis exposure, with the effect of cannabis being strongest (ß-estimate = 3.33(95%C.I. 1.97, 4.68), P = 1.92 × 10- 6). A strong effect of cannabis use quintile on ALLR was noted (Chi.Sq. = 613.79, P = 3.04 × 10- 70). In inverse probability weighted robust regression adjusted for other substances, income and ethnicity, cannabis was independently significant (ß-estimate = 4.75(0.48, 9.02), P = 0.0389). In a spatiotemporal model adjusted for all drugs, income, and ethnicity, cannabigerol exposure was significant (ß-estimate = 0.26(0.01, 0.52), P = 0.0444), an effect increased by spatial lagging (THC: ß-estimate = 0.47(0.12, 0.82), P = 0.0083). After missing data imputation ethnic cannabis exposure was significant (ß-estimate = 0.64(0.55, 0.72), P = 3.1 × 10- 40). 33/35 minimum e-Values ranged from 1.25 to 3.94 × 1036 indicative of a causal relationship. Relaxation of cannabis legal paradigms had higher ALLR (Chi.Squ.Trend = 775.12, P = 2.14 × 10- 112). Cannabis legal states had higher ALLR (2.395 ± 0.039 v. 2.127 ± 0.008 / 100,000, P = 5.05 × 10- 10). CONCLUSIONS: Data show that ALLR is associated with cannabis consumption across space-time, is associated with the cannabinoids, THC, cannabigerol, cannabinol, cannabichromene, and cannabidiol, contributes to ethnic differentials, demonstrates prominent quintile effects, satisfies criteria for causality and is exacerbated by cannabis legalization.

A geospatiotemporal and causal inference epidemiological exploration of substance and cannabinoid exposure as drivers of rising US pediatric cancer rates.

BACKGROUND: Age-adjusted US total pediatric cancer incidence rates (TPCIR) rose 49% 1975-2015 for unknown reasons. Prenatal cannabis exposure has been linked with several pediatric cancers which together comprise the majority of pediatric cancer types. We investigated whether cannabis use was related spatiotemporally and causally to TPCIR. METHODS: State-based age-adjusted TPCIR data was taken from the CDC Surveillance, Epidemiology and End Results cancer database 2003-2017. Drug exposure was taken from the nationally-representative National Survey of Drug Use and Health, response rate 74.1%. Drugs included were: tobacco, alcohol, cannabis, opioid analgesics and cocaine. This was supplemented by cannabinoid concentration data from the Drug Enforcement Agency and ethnicity and median household income data from US Census. RESULTS: TPCIR rose while all drug use nationally fell, except for cannabis which rose. TPCIR in the highest cannabis use quintile was greater than in the lowest (ß-estimate = 1.31 (95%C.I. 0.82, 1.80), P = 1.80 × 10- 7) and the time:highest two quintiles interaction was significant (ß-estimate = 0.1395 (0.82, 1.80), P = 1.00 × 10- 14). In robust inverse probability weighted additive regression models cannabis was independently associated with TPCIR (ß-estimate = 9.55 (3.95, 15.15), P = 0.0016). In interactive geospatiotemporal models including all drug, ethnic and income variables cannabis use was independently significant (ß-estimate = 45.67 (18.77, 72.56), P = 0.0009). In geospatial models temporally lagged to 1,2,4 and 6 years interactive terms including cannabis were significant. Cannabis interactive terms at one and two degrees of spatial lagging were significant (from ß-estimate = 3954.04 (1565.01, 6343.09), P = 0.0012). The interaction between the cannabinoids THC and cannabigerol was significant at zero, 2 and 6 years lag (from ß-estimate = 46.22 (30.06, 62.38), P = 2.10 × 10- 8). Cannabis legalization was associated with higher TPCIR (ß-estimate = 1.51 (0.68, 2.35), P = 0.0004) and cannabis-liberal regimes were associated with higher time:TPCIR interaction (ß-estimate = 1.87 × 10- 4, (2.9 × 10- 5, 2.45 × 10- 4), P = 0.0208). 33/56 minimum e-Values were > 5 and 6 were infinite. CONCLUSION: Data confirm a close relationship across space and lagged time between cannabis and TPCIR which was robust to adjustment, supported by inverse probability weighting procedures and accompanied by high e-Values making confounding unlikely and establishing the causal relationship. Cannabis-liberal jurisdictions were associated with higher rates of TPCIR and a faster rate of TPCIR increase. Data inform the broader general consideration of cannabinoid-induced genotoxicity.

Stratified analyses of genome wide association study data reveal haplotypes for a candidate gene on chromosome 2 (KIAA1211L) is associated with opioid use in patients of Arabian descent.

BACKGROUND: Genome Wide Association Studies (GWAS) have been conducted to identify genes and pathways involved in development of opioid use disorder. This study extends the first GWAS of substance use disorder (SUD) patients from the United Arab Emirates (UAE) by stratifying the study group based on opioid use, which is the most common substance of use in this cohort. METHODS: The GWAS cohort consisted of 512 (262 case, 250 controls) male participants from the UAE. The samples were genotyped using the Illumina Omni5 Exome system. Data was stratified according to opioid use using PLINK. Haplotype analysis was conducted using Haploview 4.2. RESULTS: Two main associations were identified in this study. Firstly, two SNPs on chromosome 7 were associated with opioid use disorder, rs118129027 (p-value = 1.23 × 10 - 8) and rs74477937 (p-value = 1.48 × 10 - 8). This has been reported in Alblooshi et al. (Am J Med Genet B Neuropsychiatr Genet 180(1):68-79, 2019). Secondly, haplotypes on chromosome 2 which mapped to the KIAA1211L locus were identified in association with opioid use. Five SNPs in high linkage disequilibrium (LD) (rs2280142, rs6542837, rs12712037, rs10175560, rs11900524) were arranged into haplotypes. Two haplotypes GAGCG and AGTTA were associated with opioid use disorders (p-value 3.26 × 10- 8 and 7.16 × 10- 7, respectively). CONCLUSION: This is the first GWAS to identify candidate genes associated with opioid use disorder in participants from the UAE. The lack of other genetic data of Arabian descent opioid use patients has hindered replication of the findings. Nevertheless, the outcomes implicate new pathways in opioid use disorder that requires further research to assess the role of the identified genes in the development of opioid use disorder.

Co-occurrence across time and space of drug- and cannabinoid- exposure and adverse mental health outcomes in the National Survey of Drug Use and Health: combined geotemporospatial and causal inference analysis.

BACKGROUND: Whilst many studies have linked increased drug and cannabis exposure to adverse mental health (MH) outcomes their effects on whole populations and geotemporospatial relationships are not well understood. METHODS: Ecological cohort study of National Survey of Drug Use and Health (NSDUH) geographically-linked substate-shapefiles 2010-2012 and 2014-2016 supplemented by five-year US American Community Survey. Drugs: cigarettes, alcohol abuse, last-month cannabis use and last-year cocaine use. MH: any mental illness, major depressive illness, serious mental illness and suicidal thinking. DATA ANALYSIS: two-stage, geotemporospatial, robust generalized linear regression and causal inference methods in R. RESULTS: 410,138 NSDUH respondents. Average response rate 76.7%. When drug and sociodemographic variables were combined in geospatial models significant terms including tobacco, alcohol, cannabis exposure and various ethnicities remained in final models for all four major mental health outcomes. Interactive terms including cannabis were related to any mental illness (ß-estimate = 1.97 (95%C.I. 1.56-2.37), P <  2.2 × 10- 16), major depressive episode (ß-estimate = 2.03 (1.54-2.52), P = 3.6 × 10- 16), serious mental illness (SMI, ß-estimate = 2.04 (1.48-2.60), P = 1.0 × 10- 12), suicidal ideation (ß-estimate = 1.99 (1.52-2.47), P <  2.2 × 10- 16) and in each case cannabis alone was significantly associated (from ß-estimate = - 3.43 (- 4.46 - -2.42), P = 3.4 × 10- 11) with adverse MH outcomes on complex interactive regression surfaces. Geospatial modelling showed a monotonic upward trajectory of SMI which doubled (3.62 to 7.06%) as cannabis use increased. Extrapolated to whole populations cannabis decriminalization (4.26%, (4.18, 4.34%)), Prevalence Ratio (PR) = 1.035(1.034-1.036), attributable fraction in the exposed (AFE) = 3.28%(3.18-3.37%), P < 10- 300) and legalization (4.75% (4.65, 4.84%), PR = 1.155 (1.153-1.158), AFE = 12.91% (12.72-13.10%), P < 10- 300) were associated with increased SMI vs. illegal status (4.26, (4.18-4.33%)). CONCLUSIONS: Data show all four indices of mental ill-health track cannabis exposure across space and time and are robust to multivariable adjustment for ethnicity, socioeconomics and other drug use. MH deteriorated with cannabis legalization. Cannabis use-MH data are consistent with causal relationships in the forward direction and include dose-response and temporal-sequential relationships. Together with similar international reports and numerous mechanistic studies preventative action to reduce cannabis use is indicated.

Contemporary epidemiology of rising atrial septal defect trends across USA 1991-2016: a combined ecological geospatiotemporal and causal inferential study.

BACKGROUND: Cardiovascular anomalies are the largest group of congenital anomalies and the major cause of death in young children, with various data linking rising atrial septal defect incidence (ASDI) with prenatal cannabis exposure. Objectives / Hypotheses. Is cannabis associated with ASDI in USA? Is this relationship causal? METHODS: Geospatiotemporal cohort study, 1991-2016. Census populations of adults, babies, congenital anomalies, income and ethnicity. Drug exposure data on cigarettes, alcohol abuse, past month cannabis use, analgesia abuse and cocaine taken from National Survey of Drug Use and Health (78.9% response rate). Cannabinoid concentrations from Drug Enforcement Agency. Inverse probability weighted (ipw) regressions. Analysis conducted in R. RESULTS: ASDI rose nationally three-fold from 27.4 to 82.8 / 10,000 births 1991-2014 during a period when tobacco and alcohol abuse were falling but cannabis was rising. States including Nevada, Kentucky, Mississippi and Tennessee had steeply rising epidemics (Time: Status ß-estimate = 10.72 (95%C.I. 8.39-13.05), P < 2.0 × 10 - 16). ASDI was positively related to exposure to cannabis and most cannabinoids. Drug exposure data was near-complete from 2006 thus restricting spatial modelling from 2006 to 2014, N = 282. In geospatial regression models cannabis: alcohol abuse term was significant (ß-estimate = 19.44 (9.11, 29.77), P = 2.2 × 10 - 4); no ethnic or income factors survived model reduction. Cannabis legalization was associated with a higher ASDI (Time: Status ß-estimate = 0.03 (0.01, 0.05), P = 1.1 × 10 -3). Weighted panel regression interactive terms including cannabis significant (from ß-estimate = 1418, (1080.6, 1755.4), P = 7.3 × 10 -15). Robust generalized linear models utilizing inverse probability weighting interactive terms including cannabis appear (from ß-estimate = 78.88, (64.38, 93.38), P = 1.1 × 10 -8). Marginal structural models with machine-aided SuperLearning association of ASDI with high v. low cannabis exposure R.R. = 1.32 (1.28, 1.36). Model e-values mostly > 1.5. CONCLUSIONS: ASDI is associated with cannabis use, frequency, intensity and legalization in a spatiotemporally significant manner, robust to socioeconomicodemographic adjustment and fulfilled causal criteria, consistent with multiple biological mechanisms and similar reports from Hawaii, Colorado, Canada and Australia. Not only are these results of concern in themselves, but they further imply that our list of the congenital teratology of cannabis is as yet incomplete, and highlight in particular cardiovascular toxicology of prenatal cannabinoid and drug exposure.

A comparison of blood toxicology in fatalities involving alcohol and other drugs in patients with an opioid use disorder treated with methadone, buprenorphine, and implant naltrexone.

Background: Methadone, buprenorphine, and implant naltrexone have comparable efficacy in preventing death from drug intoxication during treatment, but there may be differences between treatments in the specific drugs contributing to death and in the risk of death during different phases of treatment.Objective: The objective of this study was to compare concentrations of individual drugs in decedents for evidence that the three medications use to treat opioid use disorders differed in the protection they offered against fatal overdose.Methods: Fatalities with a primary or co-diagnosis of alcohol or other drug poisoning in patients treated with methadone (n = 66, 74.2% male), buprenorphine (n = 54, 74.1% male), or naltrexone (n = 28, 85.7% male) were identified by combining treatment (Monitoring of Drugs of Dependence System and clinical records) and mortality records (Western Australian Death Registry). Quantitative postmortem blood drug analysis data were obtained for drug-related deaths. The presence/absence of drugs were compared between the three medication groups and between phases of treatment (on-treatment/off-treatment).Results: Opioids (89.8%) and benzodiazepines (76.2%) were most commonly identified in postmortem blood. The three medication groups did not differ materially in the drugs present postmortem, except that alcohol was less prevalent in naltrexone-treated cases. Morphine or heroin intoxication was implicated in more patients dying off-treatment than on-treatment but levels of morphine and other drugs were comparable across the two phases.Conclusion: Comparisons of postmortem concentrations of specific drugs indicated that patients treated with methadone, buprenorphine, and implant naltrexone had comparable susceptibilities to lethal co-intoxication and that similar drug mixtures contributed to death.

A retrospective cohort study of mortality rates in patients with an opioid use disorder treated with implant naltrexone, oral methadone or sublingual buprenorphine.

BACKGROUND: Sustained release naltrexone has been shown to be a safer alternative to oral naltrexone in terms of mortality in patients with an opioid use disorder; however, a direct large-scale comparison has not been made between sustained release naltrexone and the more popular opioid pharmacotherapies: methadone and buprenorphine. OBJECTIVE: To examine and compare mortality rates in patients with an opioid use disorder treated with implant naltrexone, methadone, and buprenorphine. METHODS: Patients treated with implant naltrexone (n = 1461, 35.6% female), methadone (n = 3515, 33.3% female), or buprenorphine (n = 3250, 34.5% female) for the first time between 2001 and 2010 in Western Australia (WA) were cross-matched against the WA Death Registry. RESULTS: Crude mortality rates in patients treated with methadone (8.1 per 1000 patient years (ptpy) (HR:1.13, CI:0.82-1.55, p = 0.447) or buprenorphine (7.2 ptpy) (HR:1.01, CI:0.72-1.42, p = 0.948) were not significantly different to those treated with implant naltrexone (7.1 ptpy). Similarly, no differences were observed between the three treatments in terms of cause-specific or age-specific mortality. However, high rates of mortality were observed in methadone-treated patients during the first 28 days of treatment (HR:8.19, CI:1.08-62.21, p = 0.042) compared to naltrexone-treated patients. Female patients treated with methadone (HR:2.96, CI:1.34-6.51, p = 0.007) also experienced a higher overall mortality rate compared to naltrexone-treated patients. CONCLUSIONS: Crude mortality rates are comparable in patients with an opioid use disorder treated with implant naltrexone, methadone, and buprenorphine. However, implant naltrexone may be associated benefits during the first 28 days of treatment and in female patients compared to methadone.

A case-control genome wide association study of substance use disorder (SUD) identifies novel variants on chromosome 7p14.1 in patients from the United Arab Emirates (UAE).

Genome wide association studies (GWASs) have provided insights into the molecular basis of the disorder in different population. This study presents the first GWAS of substance use disorder (SUD) in patients from the United Arab Emirates (UAE). The aim was to identify genetic association(s) that may provide insights into the molecular basis of the disorder. The GWAS discovery cohort consisted of 512 (250 cases and 262 controls) male participants from the UAE. Controls with no prior history of SUD were available from the Emirates family registry. The replication cohort consisted of 520 (415 cases and 105 controls) Australian male Caucasian participants. The GWAS discovery samples were genotyped for 4.6 million single nucleotide polymorphism (SNP). The replication cohort was genotyped using TaqMan assay. The GWAS association analysis identified three potential SNPs rs118129027 (p-value = 6.24 × 10-8 ), rs74477937 (p-value = 8.56 × 10-8 ) and rs78707086 (p-value = 8.55 × 10-8 ) on ch7p14.1, that did not meet the GWAS significance threshold but were highly suggestive. In the replication cohort, the association of the three top SNPs did not reach statistical significance. In a meta-analysis of the discovery and the replication cohorts, there were no strengthen evidence for association of the three SNPs. The top identified rs118129027 overlaps with a regulatory factor (enhancer) region that targets three neighboring genes LOC105375237, LOC105375240, and YAE1D1. The YAE1D1, which represents a potential locus that is involved in regulating translation initiation pathway. Novel associations that require further confirmation were identified, suggesting a new insight to the genetic basis of SUD.

Morbidity and mortality in opioid dependent patients after entering an opioid pharmacotherapy compared with a cohort of non-dependent controls.

Aims: To compare morbidity and mortality in opioid dependence patients following the commencement of treatment with the general population. Methods: Morbidity and mortality in all patients treated with methadone, buprenorphine or implant naltrexone for opioid dependence for the first time between 2001 and 2010 in Western Australia was compared to a cohort of age and gender matched controls using state health records. Results: Compared to community controls rates of all-cause mortality, hospital admissions and Emergency Department attendances are significantly elevated in opioid dependent persons following the commencement of their first treatment. Not surprisingly, rates of opioid and non-opioid drug poisoning, and intentional self-harm/suicide mortality and hospital admissions were significantly elevated in opioid dependent patients compared with non-dependent controls. However, significant increases in mortality and hospital admissions for conditions which are not generally associated with opioid use were also identified including cardiovascular, respiratory and traffic accidents. Life-time prevalence of both HBV and HCV were significantly elevated in opioid dependent patients compared with non-dependent patients. Conclusions: Even after the commencement of treatment, opioid dependent patients are at a high risk of morbidity and mortality compared with non-dependent age and gender matched controls.

The frequency of DRD2 rs1076560 and OPRM1 rs1799971 in substance use disorder patients from the United Arab Emirates.

BACKGROUND: Dopaminergic and opioid systems are involved in mediating drug reward and reinforcement of various types of substances including psychoactive compounds. Genes of both systems have been candidate for investigation for associations with substance use disorder (SUD) in various populations. This study is the first study to determine the allele frequency and the genetic association of the DRD2 rs1076560 SNP and OPRM1 rs1799971 SNP variants in clinically diagnosed patients with SUD from the United Arab Emirates (UAE). METHODS: A cross-sectional case-control cohort that consisted of 512 male subjects was studied. Two hundred and fifty patients with SUD receiving treatment at the UAE National Rehabilitation Center were compared to 262 controls with no prior history of mental health and SUD. DNA from each subject was extracted and genotyped using the TaqMan ® SNP genotyping assay. RESULTS: There were no significant associations observed for DRD2 rs1076560 SNP, OPRM1 rs1799971 SNP, and combined genotypes of both SNPs in the SUD group. CONCLUSION: Further research is required with refinements to the criteria of the clinical phenotypes. Genetic studies have to be expanded to include other variants of the gene, the interaction with other genes, and possible epigenetic relationships.

A retrospective cohort study of the health of children prenatally exposed to methadone, buprenorphine or naltrexone compared with non-exposed control children.

BACKGROUND AND OBJECTIVES: Little is known about the health of children exposed to opioid pharmacotherapies in utero. This study aims to examine the health of children from birth to 5 years of age, who were exposed to methadone, buprenorphine, or naltrexone with non-exposed children. METHODS: Children were identified by linking the treatment records of women treated with one of the three opioid pharmacotherapies with midwife notifications. Live-born children exposed to methadone (n = 198), buprenorphine (n = 122), naltrexone (n = 67) in utero, and neonates not prenatally exposed to opioids (n = 387) born between 2001 and 2011 in Western Australia were included in the study. The children were then linked to state mortality, hospital, emergency department (ED), mental health, cancer, and reportable diseases from birth up to their 5th birthday. RESULTS: Overall rates of hospital admission were elevated in all three treatments as compared with the control children, while rates of ED attendances were only significantly elevated in the methadone (p = .002) and naltrexone (p = .044) exposed children. In terms of both hospital and ED attendances, the differences between the exposed and control children was most apparent in the neonatal period. Rates of mental health out-patient attendances were elevated in buprenorphine-exposed children as compared with the control (p = .005). DISCUSSION AND CONCLUSIONS: The study provides evidence to suggest a disparity in the health of children exposed to opioid pharmacotherapies in utero compared with non-exposed control children. SCIENTIFIC SIGNIFICANCE: Exposure to opioid pharmacotherapies in utero may influence the health of children beyond the neonatal period. (Am J Addict 2017;26:845-851).

Elevation of the ACTH/cortisol ratio in female opioid dependent patients: A biomarker of aging and correlate of metabolic and immune activation.

BACKGROUND: Whilst the hypothalamic-pituitary-adrenal (HPA) Axis is a major stress axis, and is necessarily perturbed in opioid dependency, and stress is a major contributor to aging mechanisms, the HPA axis has not been studied in opioid dependency in an age-dependent manner. OBJECTIVE: Hypothesis - Differences in age dependent levels of HPA components. DESIGN: Cross-sectional comparison of general medical and opioid dependent patients (ODP, GMP). Setting - Primary Care. Patients - 51 GMC, 233 ODP. Ages 37.92+1.95 v. 37.12+0.62 years (P - N.S.) and 33.33% v. 71.67% male (p<0.0001). Intervention(s) - Measurement ACTH, cortisol and their ratio (ACR). Main Outcome Measure(s) - Pre-planned analysis ACR. SECONDARY OUTCOMES: Impact of immune and metabolic markers. RESULTS: ACTH/cortisol was a negative biomarker for age in female patients. Whilst the mean ACR were not different, the (log) ACTH/cortisol showed a positive relationship with age:sex:status (p=0.0396) and age:status (p=0.0437). The effect of addictive status was confined to hepatitis C (HCV) positive female ODP (p=0.0355), and the age:status interaction was also stronger in female HCV+ (p=0.0075) compared to HCV - (p=0.0667) patients. Multiple regression of ACR against age, status, ALT, CRP, and Globulins confirmed many significant interactions. ACTH/cortisol ratio interacted significantly from p=0.0008 in males and p=0.0079 in females, and in both sexes four terms included addictive status. CONCLUSIONS: These data establish the ACTH/cortisol ratio as a negative biomarker of aging in females, and show that this decline is more pronounced in ODP an effect which is partly related to HCV seropositivity, immune and metabolic factors. Dementias are one of the most serious health and socioeconomic issues. Multi-infarct dementia (MID) and Alzheimer´s type dementia (AD) exhibit differences in cerebrovascular blood flow velocity profiles and in presence of microemboli, detected by transcranial Doppler sonography.

Injectable and implantable sustained release naltrexone in the treatment of opioid addiction.

Sustained release technologies for administering the opioid antagonist naltrexone (SRX) have the potential to assist opioid-addicted patients in their efforts to maintain abstinence from heroin and other opioid agonists. Recently, reliable SRX formulations in intramuscular or implantable polymers that release naltrexone for 1-7 months have become available for clinical use and research. This qualitative review of the literature provides an overview of the technologies currently available for SRX and their effectiveness in reducing opioid use and other relevant outcomes. The majority of studies indicate that SRX is effective in reducing heroin use, and the most frequently studied SRX formulations have acceptable adverse events profiles. Registry data indicate a protective effect of SRX on mortality and morbidity. In some studies, SRX also seems to affect other outcomes, such as concomitant substance use, vocational training attendance, needle use, and risk behaviour for blood-borne diseases such as hepatitis or human immunodeficiency virus. There is a general need for more controlled studies, in particular to compare SRX with agonist maintenance treatment, to study combinations of SRX with behavioural interventions, and to study at-risk groups such as prison inmates or opioid-addicted pregnant patients. The literature suggests that sustained release naltrexone is a feasible, safe and effective option for assisting abstinence efforts in opioid addiction.