What are the characteristics of vitamin D metabolism in opioid dependence? An exploratory longitudinal study in Australian primary care

OBJECTIVE: Compare vitamin D levels in opioid dependence and control population and adjust for relevant confounding effects. Nuclear hormone receptors (including the vitamin D receptor) have been shown to be key transducers and regulators of intracellular metabolism and comprise an important site of pathophysiological immune and metabolic dysregulation potentially contributing towards pro-ageing changes observed in opioid-dependent patients (ODPs). DESIGN: Longitudinal prospective comparing ODPs with general medical controls (GMCs). SETTING: Primary care. PARTICIPANTS: Prospective review comparing 1168 ODP (72.5% men) and 415 GMC (51.6% men, p INTERVENTIONS: Nil. Observational study only. PRIMARY AND SECONDARY OUTCOMES: Serum vitamin D levels and relevant biochemical parameters. RESULTS: Vitamin D levels were higher in the ODP (70.35±1.16 and 57.06±1.81 nmol/L, p CONCLUSION: Vitamin D was higher in ODP in both sexes in bivariate, cross-sectional, cas

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 (β-estimate = 1.97 (95%C.I. 1.56–2.37), P \u3c  2.2 × 10− 16), major depressive episode (β-estimate = 2.03 (1.54–2.52), P = 3.6 × 10− 16), serious mental illness (SMI, β-estimate = 2.04 (1.48–2.60), P = 1.0 × 10− 12), suicidal ideation (β-estimate = 1.99 (1.52–2.47), P \u3c  2.2 × 10− 16) and in each case cannabis alone was significantly associated (from β-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 \u3c 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 \u3c 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

Broad spectrum epidemiological contribution of cannabis and other substances to the teratological profile of northern New South Wales: Geospatial and causal inference analysis

© 2020, The Author(s). Background: Whilst cannabis commercialization is occurring rapidly guided by highly individualistic public narratives, evidence that all congenital anomalies (CA) increase alongside cannabis use in Canada, a link with 21 CA’s in Hawaii, and rising CA’s in Colorado indicate that transgenerational effects can be significant and impact public health. It was therefore important to study Northern New South Wales (NNSW) where cannabis use is high. Methods: Design: Cohort. 2008–2015. Setting: NNSW and Queensland (QLD), Australia. Participants. Whole populations. Exposures. Tobacco, alcohol, cannabis. Source: National Drug Strategy Household Surveys 2010, 2013. Main Outcomes. CA Rates. NNSW-QLD comparisons. Geospatial and causal regression. Results: Cardiovascular, respiratory and gastrointestinal anomalies rose with falling tobacco and alcohol but rising cannabis use rates across Queensland. Maternal age NNSW-QLD was not different (2008–2015: 4265/22084 v. 96,473/490514 \u3e 35 years/total, Chi.Sq. = 1.687, P = 0.194). A higher rate of NNSW cannabis-related than cannabis-unrelated defects occurred (prevalence ratio (PR) = 2.13, 95%C.I. 1.80–2.52, P = 3.24 × 10− 19). CA’s rose more potently with rising cannabis than with rising tobacco or alcohol use. Exomphalos and gastroschisis had the highest NNSW:QLD PR (6.29(2.94–13.48) and 5.85(3.54–9.67)) and attributable fraction in the exposed (84.11%(65.95–92.58%) and 82.91%(71.75–89.66%), P = 2.83 × 10− 8 and P = 5.62 × 10− 15). In multivariable geospatial models cannabis was significantly linked with cardiovascular (atrial septal defect, ventricular septal defect, tetralogy of Fallot, patent ductus arteriosus), genetic (chromosomal defects, Downs syndrome), gastrointestinal (small intestinal atresia), body wall (gastroschisis, diaphragmatic hernia) and other (hypospadias) (AVTPCDSGDH) CA’s. In linear modelling cannabis use was significantly linked with anal stenosis, congenital hydrocephalus and Turner syndrome (ACT) and was significantly linked in borderline significant models (model P \u3c 0.1) with microtia, microphthalmia, and transposition of the great vessels. At robust and mixed effects inverse probability weighted multivariable regression cannabis was related to 18 defects. 16/17 E-Values in spatial models were \u3e 1.25 ranging up to 5.2 × 1013 making uncontrolled confounding unlikely. Conclusions: These results suggest that population level CA’s react more strongly to small rises in cannabis use than tobacco or alcohol; cardiovascular, chromosomal, body wall and gastrointestinal CA’s rise significantly with small increases in cannabis use; that cannabis is a bivariate correlate of AVTPCDSGDH and ACT anomalies, is robust to adjustment for other substances; and is causal

Cannabis consumption patterns explain the east-west gradient in Canadian neural tube defect incidence: An ecological study

While a known link between prenatal cannabis exposure and anencephaly exists, the relationship of prenatal cannabis exposure with neural tube defects (NTDs) generally has not been defined. Published data from Canada Health and Statistics Canada were used to assess this relationship. Both cannabis use and NTDs were shown to follow an east-west and north-south gradient. Last year cannabis consumption was significantly associated (P \u3c .0001; cannabis use–time interaction P \u3c .0001). These results were confirmed when estimates of termination for anomaly were used. Canada Health population data allowed the calculation of an NTD odds ratio) of 1.27 (95% confidence interval = 1.19-1.37; P \u3c 10−11) for high-risk provinces versus the remainder with an attributable fraction in exposed populations of 16.52% (95% confidence interval = 12.22-20.62). Data show a robust positive statistical association between cannabis consumption as both a qualitative and quantitative variable and NTDs on a background of declining NTD incidence. In the context of multiple mechanistic pathways these strong statistical findings implicate causal mechanisms

Epidemiological overview of multidimensional chromosomal and genome toxicity of cannabis exposure in congenital anomalies and cancer development

Cannabis and cannabinoids are implicated in multiple genotoxic, epigenotoxic and chromosomal-toxic mechanisms and interact with several morphogenic pathways, likely underpinning previous reports of links between cannabis and congenital anomalies and heritable tumours. However the effects of cannabinoid genotoxicity have not been assessed on whole populations and formal consideration of effects as a broadly acting genotoxin remain unexplored. Our study addressed these knowledge gaps in USA datasets. Cancer data from CDC, drug exposure data from National Survey of Drug Use and Health 2003–2017 and congenital anomaly data from National Birth Defects Prevention Network were used. We show that cannabis, THC cannabigerol and cannabichromene exposure fulfill causal criteria towards first Principal Components of both: (A) Down syndrome, Trisomies 18 and 13, Turner syndrome, Deletion 22q11.2, and (B) thyroid, liver, breast and pancreatic cancers and acute myeloid leukaemia, have mostly medium to large effect sizes, are robust to adjustment for ethnicity, other drugs and income in inverse probability-weighted models, show prominent non-linear effects, have 55/56 e-Values \u3e 1.25, and are exacerbated by cannabis liberalization (P = 9.67 × 10–43, 2.66 × 10–15). The results confirm experimental studies showing that cannabinoids are an important cause of community-wide genotoxicity impacting both birth defect and cancer epidemiology at the chromosomal hundred-megabase level

Effects of cannabis on congenital limb anomalies in 14 European nations: A geospatiotemporal and causal inferential study

Cannabinoid exposure is increasing in some European nations. Europe therefore provides an interesting test environment for the recently reported link between cannabis exposure and congenital limb anomaly (CLA) rates (CLARs). Exponential genotoxic dose–response relationships make this investigation both intriguing and imperative. Annual CLAR in 14 nations were from Epidemiological Surveillance of Congenital Anomalies. Drug use rates were from European Monitoring Centre for Drugs and Drug Dependency. Median household income was from the World Bank. E-values provide a quantitative measure of robustness of results to confounding by extraneous covariates. Inverse probability weighting is an important technique for equalizing exposures across countries and removing sources of bias. Rates of CLA, hip dysplasia and the whole group of limb anomalies were higher in countries with increasing daily cannabis use (P = 1.81 × 10 − 16, 0.0005 and 2.53 × 10 − 6, respectively). In additive inverse-probability-weighted panel models, the limb reduction-resin Δ9-tetrahydrocannabinol (THC) concentration E-value estimate was 519.93 [95% lower bound (mEV) 49.56], order Resin \u3e Herb ≫ Tobacco \u3e Alcohol. Elevations were noted in 86% E-value estimates and 70.2% of mEVs from 57 E-value pairs from inverse-probability-weighted panel models and from spatial models. As judged by the mEV the degree of association with metrics of cannabis exposure was hip dysplasia \u3e polydactyly \u3e syndactyly \u3e limb anomalies \u3e limb reductions with median E-value estimates from 3.40 × 1065 to 7.06 and median mEVs from 6.14 × 1033 to 3.41. Daily cannabis use interpolated was a more powerful metric of cannabis exposure than herb or resin THC exposure. Data indicate that metrics of cannabis exposure are closely linked with CLAR and satisfy epidemiological criteria for causality. Along with Hawaii and the USA, Europe now forms the third international population in which this causal link has been demonstrated. Cannabis as a predictor of limb anomalies was more potent than tobacco or alcohol. Cannabinoid access should be restricted to protect public health and the community genome/epigenome transgenerationally

Congenital gastrointestinal anomalies in Europe 2010–2019: A geo-spatiotemporal and causal inferential study of epidemiological patterns in relationship to cannabis- and substance exposure

Introduction: Congenital anomalies (CA’s) of most of the gastrointestinal tract have been linked causally with prenatal or community cannabis exposure. Therefore, we studied this relationship in Europe. Methods: CA data were from Eurocat. Drug-use data were sourced from the European Monitoring Centre for Drugs and Drug Addiction. Income data were taken from the World Bank. Results: When countries with increasing rates of daily cannabis use were compared with those which were not, the overall rate of gastrointestinal CA’s (GCA’s) was higher in the former group (p = 0.0032). The five anomalies which were related to the metrics of cannabis exposure on bivariate analysis were bile duct atresia, Hirschsprungs, digestive disorders, annular pancreas and anorectal stenosis or atresia. The following sequence of GCA’s was significantly linked with cannabis metrics at inverse-probability-weighted-panel modelling, as indicated: esophageal stenosis or atresia, bile duct atresia, small intestinal stenosis or atresia, anorectal stenosis or atresia, Hirschsprungs disease: p = 1.83 × 10−5, 0.0046, 3.55 × 10−12, 7.35 × 10−6 and 2.00 × 10−12, respectively. When this GCA series was considered in geospatial modelling, the GCA’s were significantly cannabis-related from p = 0.0003, N.S., 0.0086, 6.652 × 10−5, 0.0002, 71.4% of 35 E-value estimates and 54.3% minimum E-values (mEVv’s) \u3e 9 (high zone) and 100% and 97.1% \u3e 1.25 (causality threshold). The order of cannabis sensitivity by median mEVv was Hirschsprungs \u3e esophageal atresia \u3e small intestinal atresia \u3e anorectal atresia \u3e bile duct atresia. Conclusions: Seven of eight GCA’s were related to cannabis exposure and fulfilled the quantitative criteria for epidemiologically causal relationships. Penetration of cannabinoids into the community should be carefully scrutinized and controlled to protect against exponential and multigenerational genotoxicity ensuing from multiple cannabinoids

Socioeconomic, ethnocultural, substance- and cannabinoid-related epidemiology of down syndrome USA 1986–2016: Combined geotemporospatial and causal inference investigation

Background: Down syndrome (DS) is the commonest of the congenital genetic defects whose incidence has been rising in recent years for unknown reasons. This study aims to assess the impact of substance and cannabinoid use on the DS Rate (DSR) and assess their possible causal involvement. Methods: An observational population-based epidemiological study 1986–2016 was performed utilizing geotemporospatial and causal inferential analysis. Participants included all patients diagnosed with DS and reported to state based registries with data obtained from National Birth Defects Prevention Network of Centers for Disease Control. Drug exposure data was from the National Survey of Drug Use and Health (NSDUH) a nationally representative sample interviewing 67,000 participants annually. Drug exposures assessed were: cigarette consumption, alcohol abuse, analgesic/opioid abuse, cocaine use and last month cannabis use. Covariates included ethnicity and median household income from US Census Bureau; maternal age of childbearing from CDC births registries; and cannabinoid concentrations from Drug Enforcement Agency. Results: NSDUH reports 74.1 % response rate. Other data was population-wide. DSR was noted to rise over time and with cannabis use and cannabis-use quintile. In the optimal geospatial model lagged to four years terms including Δ9-tetrahydrocannabinol and cannabigerol were significant (from β-est. = 4189.96 (95 % C.I. 1924.74, 6455.17), p = 2.9 × 10 − 4). Ethnicity, income, and maternal age covariates were not significant. DSR in states where cannabis was not illegal was higher than elsewhere (β-est. = 2.160 (1.5, 2.82), R.R. = 1.81 (1.51, 2.16), p = 4.7 × 10 − 10). In inverse probability-weighted mixed models terms including cannabinoids were significant (from β-estimate = 18.82 (16.82, 20.82), p \u3c 0.0001). 62 E-value estimates ranged to infinity with median values of 303.98 (IQR 2.50, 2.75 × 107) and 95 % lower bounds ranged to 1.1 × 1071 with median values of 10.92 (IQR 1.82, 7990). Conclusions: Data show that the association between DSR and substance- and cannabinoid- exposure is robust to multivariable geotemporospatial adjustment, implicate particularly cannabigerol and Δ9-tetrahydrocannabinol, and fulfil quantitative epidemiological criteria for causality. Nevertheless, detailed experimental studies would be required to formally demonstrate causality. Cannabis legalization was associated with elevated DSR’s at both bivariate and multivariable analysis. Findings are consistent with those from Hawaii, Colorado, Canada, Australia and Europe and concordant with several cellular mechanisms. Given that the cannabis industry is presently in a rapid growth-commercialization phase the present findings linking cannabis use with megabase scale genotoxicity suggest unrecognized DS risk factors, are of public health importance and suggest that re-focussing the cannabis debate on multigenerational health concerns is prudent

European epidemiological patterns of cannabis- and substance-related congenital neurological anomalies: Geospatiotemporal and causal inferential study

Introduction: Of the many congenital anomalies (CAs) recently linked with community cannabis exposure, arguably the most concerning are neurological CAs (NCAs). We therefore conducted a detailed study of this in fourteen European nations. Methods. Congenital anomaly data were from Eurocat. Drug exposure data were from European Monitoring Centre for Drugs and Drug Addiction. Income from World bank. Results: The Netherlands, Spain, France and Bulgaria reported increasing rates of many NCAs. The NCA rate (NCAR) was: severe microcephaly 2.14 x 1013 higher in nations with increasing daily cannabis use when compared to those without (p = 0.0204, minimum E-value (mEV) = 1.35). At bivariate analysis, the mEVs of the following NCAs were significantly cannabis related, craniosynostosis 5.27 x 1011, nervous system 4.87 x 1011, eye 2.73 x 107, microphthalmos 4.07 x 106, anencephalus 710.37, hydrocephalus 245.64, spina bifida 14.86 and neural tube defects 13.15. At inverse probability, weighted panel regression terms including cannabis were significantly related to the following series of anomalies: nervous system, anencephalus, severe microcephalus, microphthalmos, neural tube defect and spina bifida from p = 5.09 x 10−8, \u3c 2.2 x 10−16, \u3c 2.2 x 10−16, 4.84 x 10−11, \u3c 2.2 x 10−16 and 9.69 x 10−7. At geospatial regression, this same series of anomalies had terms including cannabis significant from p = 0.0027, 1.53 x 10−7, 3.65 x 10−6, 2.13 x 10−8, 0.0002 and 9.76 x 10−12. 88.0% of 50 E-value estimates and 72.0% of mEVs \u3e 9. This analysis therefore demonstrates both close association of cannabis exposure with multiple NCAs across space-time and also fulfills the quantitative criteria of causal inferential analysis. Conclusions: Nine NCARs on bivariate and six NCARs on multivariable regression were cannabis related and fulfilled quantitative epidemiological criteria for causality and are consistent with other series. Particular concerns relate to exponential dose–response effects demonstrated in the laboratory and epidemiological studies. Great caution with community cannabinoid penetration is warranted. Data indicate that cannabis is a significant environmental teratogen and thus imply that cannabinoids should be regulated similarly to the manner in which all other important genotoxins are carefully controlled by communities for their self-sustaining longevity and the protection of generations yet to com

Causal inference multiple imputation investigation of the impact of cannabinoids and other substances on ethnic differentials in US testicular cancer incidence

Background: Ethnic differences in testicular cancer rates (TCRs) are recognized internationally. Cannabis is a known risk factor for testicular cancer (TC) in multiple studies with dose-response effects demonstrated, however the interaction between ancestral and environmental mutagenic effects has not been characterized. We examined the effects of this presumed gene-environment interaction across US states. Methods: State based TCR was downloaded from the Surveillance Epidemiology and End Results (SEER) website via SEERStat. Drug use data for cigarettes, alcohol use disorder, analgesics, cannabis and cocaine was taken from the National Survey of Drug Use and Health a nationally representative study conducted annually by the Substance Abuse and Mental Health Services Administration (SAMHSA) with a 74.1% response rate. Cannabinoid concentrations derived from Drug Enforcement Agency publications. Median household income and ethnicity data (Caucasian-American, African-American, Hispanic-American, Asian-American, American-Indian-Alaska-Native-American, Native-Hawaiian-Pacific-Islander-American) was from the US Census Bureau. Data were processed in R using instrumental regression, causal inference and multiple imputation. Results: 1975–2017 TCR rose 41% in African-Americans and 78.1% in Caucasian-Americans; 2003–2017 TCR rose 36.1% in Hispanic-Americans and 102.9% in Asian-Pacific-Islander-Americans. Ethnicity-based scatterplot-time and boxplots for cannabis use and TCR closely mirrored each other. At inverse probability-weighted interactive robust regression including drugs, income and ethnicity, ethnic THC exposure was the most significant factor and was independently significant (β-estimate = 4.72 (2.04, 7.41), P = 0.0018). In a similar model THC, and cannabigerol were also significant (both β-estimate = 13.87 (6.33, 21.41), P = 0.0017). In additive instrumental models the interaction of ethnic THC exposure with Asian-American, Hispanic-American, and Native-Hawaiian-Pacific-Islander-American ethnicities was significant (β-estimate = − 0.63 (− 0.74, − 0.52), P = 3.6 × 10− 29, β-estimate = − 0.25 (− 0.32, − 0.18), P = 4.2 × 10− 13, β-estimate = − 0.19 (− 0.25, − 0.13), P = 3.4 × 10− 9). After multiple imputation, ethnic THC exposure became more significant (β-estimate = 0.68 (0.62, 0.74), P = 1.80 × 10− 92). 25/33 e-Values \u3e 1.25 ranging up to 1.07 × 105. Liberalization of cannabis laws was linked with higher TCR’s in Caucasian-Americans (β-estimate = 0.09 (0.06, 0.12), P = 6.5 × 10− 10) and African-Americans (β-estimate = 0.22 (0.12, 0.32), P = 4.4 × 10− 5) and when dichotomized to illegal v. others (t = 6.195, P = 1.18 × 10− 9 and t = 4.50, P = 3.33 × 10− 5). Conclusion: Cannabis is shown to be a TC risk factor for all ethnicities including Caucasian-American and African-American ancestries, albeit at different rates. For both ancestries cannabis legalization elevated TCR. Dose-response and causal relationships are demonstrated