Marijuana use in young mothers and adverse pregnancy outcomes: a retrospective cohort study.

OBJECTIVE: To evaluate the association between marijuana use and a composite adverse pregnancy outcome using biological sampling. DESIGN: Retrospective cohort study. SETTING: Single tertiary center. POPULATION: Young women (13-22 years old) with singleton, non-anomalous pregnancies delivered from September 2011 to May 2017. METHODS: Exposure was defined as marijuana detected on universal urine toxicology testing or by self-report. Multivariable logistic regression modelling was used to estimate the effect of any marijuana use on the primary composite outcome. The effect of marijuana exposure was also estimated for self-reported use, toxicology-detected use, and multiple use detected by toxicology. MAIN OUTCOME MEASURE: The primary composite outcome included spontaneous preterm birth, hypertensive disorders of pregnancy, stillbirth, or small for gestational age. RESULTS: Of 1206 pregnant young women, 17.5% (n = 211) used marijuana. Among the women who used marijuana, 8.5% (n = 18) were identified by self-report alone, 63% (n = 133) by urine toxicology alone, and 28.4% (n = 60) by both. Urine toxicology testing results were available for 1092 (90.5%) births. The composite outcome occurred more frequently in pregnancies exposed to marijuana (46 versus 34%, P < 0.001). This remained significant after adjusting for race/ethnicity and tobacco in the multivariable model (adjusted OR 1.50, 95% CI 1.09-2.05). When marijuana exposure was defined by self-report only, the association with adverse pregnancy outcome became non-significant (adjusted OR 1.01, 95% CI 0.62-1.64). CONCLUSION: In a population of young women with nearly universal biological sampling, marijuana exposure was associated with adverse pregnancy outcomes. The heterogeneity of findings in existing studies evaluating the impact of marijuana on mothers and neonates may result from the incomplete ascertainment of exposure. TWEETABLE ABSTRACT: Marijuana use, as detected by universal urine testing, was associated with a composite adverse pregnancy outcome among young mothers.

Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium.

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10(-8)) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.

Stability and change of genetic and environmental effects on the common liability to alcohol, tobacco, and cannabis DSM-IV dependence symptoms.

This study investigated the stability of genetic and environmental effects on the common liability to alcohol, tobacco, and cannabis dependence across adolescence and young adulthood. DSM-IV symptom counts from 2,361 adolescents were obtained using a structured diagnostic interview. Several sex-limited longitudinal common pathway models were used to examine gender differences in the magnitude of additive genetic (A), shared environment, and non-shared environmental effects over time. Model fitting indicated limited gender differences. Among older adolescents (i.e., age > 14), the heritability of the latent trait was estimated at 0.43 (0.05, 0.94) during the first wave and 0.63 (0.21, 0.83) during the second wave of assessment. A common genetic factor could account for genetic influences at both assessments, as well as the majority of the stability of SAV over time [rA = 1.00 (0.55, 1.00)]. These results suggest that early genetic factors continue to play a key role at later developmental stages.

Nominal association with CHRNA4 variants and nicotine dependence.

Nicotine binds to nicotinic acetylcholine receptors and studies in animal models have shown that α4ß2 receptors mediate many behavioral effects of nicotine. Human genetics studies have provided support that variation in the gene that codes for the α4 subunit influences nicotine dependence (ND), but the evidence for the involvement of the ß2 subunit gene is less convincing. In this study, we examined the genetic association between variation in the genes that code for the α4 (CHRNA4) and ß2 (CHRNB2) subunits of the nicotinic acetylcholine receptor and a quantitative measure of lifetime DSM-IV ND symptom counts. We performed this analysis in two longitudinal family-based studies focused on adolescent antisocial drug abuse: the Center on Antisocial Drug Dependence (CADD, N = 313 families) and Genetics of Antisocial Drug Dependence (GADD, N = 111 families). Family-based association tests were used to examine associations between 14 single nucleotide polymorphisms (SNPs) in CHRNA4 and CHRNB2 and ND symptoms. Symptom counts were corrected for age, sex and clinical status prior to the association analysis. Results, when the samples were combined, provided modest evidence that SNPs in CHRNA4 are associated with ND. The minor allele at both rs1044394 (A; Z = 1.988, P = 0.047, unadjusted P-value) and rs1044396 (G; Z = 2.398, P = 0.017, unadjusted P-value) was associated with increased risk of ND symptoms. These data provide suggestive evidence that variation in the α4 subunit of the nicotinic acetylcholine receptor may influence ND liability.

Developmental epidemiology of drug use and abuse in adolescence and young adulthood: Evidence of generalized risk.

Past studies highlight a narrowing gender gap and the existence of a shared etiology across substances of abuse; however, few have tested developmental models using longitudinal data. We present data on developmental trends of alcohol, tobacco, and marijuana use, abuse and dependence assessed during adolescence and young adulthood in a community-based Colorado twin sample of 1733 respondents through self-report questionnaires and structured psychiatric interviews. Additionally, we report on the rates of multiple substance use and disorders at each developmental stage, and the likelihood of a substance use disorder (SUD; i.e., abuse or dependence) diagnosis in young adulthood based on adolescent drug involvement. Most notably, we evaluate whether the pattern of multiple substance use and disorders and likelihood ratios across substances support a model of generalized risk. Lastly, we evaluate whether the ranked magnitudes of substance-specific risk match the addiction liability ranking. Substance use and SUDs are developmental phenomena, which increase from adolescence to young adulthood with few and inconsistent gender differences. Adolescents and young adults are not specialized users, but rather tend to use or abuse multiple substances increasingly with age. Risk analyses indicated that progression toward a SUD for any substance was increased with prior involvement with any of the three substances during adolescence. Despite the high prevalence of alcohol use, tobacco posed the greatest substance-specific risk for developing subsequent problems. Our data also confirm either a generalized risk or correlated risk factors for early onset substance use and subsequent development of SUDs.

Genetic and environmental contributions to retrospectively reported DSM-IV childhood attention deficit hyperactivity disorder.

BACKGROUND: A variety of methodologies and techniques converge on the notion that adults and children with attention deficit hyperactivity disorder (ADHD) have similar deficits, but there is limited knowledge about whether adult retrospective reports reflect similar genetic and environmental influences implicated in childhood ADHD. METHOD: DSM-IV ADHD symptoms were collected retrospectively from 3896 young adults participating in the National Longitudinal Study of Adolescent Health. Responses from this genetically informative sample of same- and opposite-sex twins and siblings were used to determine the magnitude of genetic and environmental influences. Possible gender differences in these effects were also examined. The degree of familial specificity of the genetic and environmental influences on the Inattentive and Hyperactive-Impulsive symptom dimensions was also determined. RESULTS: Additive genetic effects contributed moderately to DSM-IV Inattentive, Hyperactive-Impulsive and Combined ADHD subtypes (heritability estimates of 0.30-0.38). Individual-specific influences accounted for the remaining proportion of the variance. Both genetic and individual-specific environmental effects contributed to the covariation of Inattentive and Hyperactive-Impulsive symptomologies. CONCLUSIONS: Results from our genetic analyses agree with previous findings based on self-assessment of current and retrospectively reported ADHD symptoms in adolescents and adults. Large individual-specific environmental influences as identified here suggest that current questionnaires used for retrospective diagnoses may not provide the most accurate reconstruction of the etiological influences on childhood ADHD in general population samples.

Mate similarity for substance dependence and antisocial personality disorder symptoms among parents of patients and controls.

UNLABELLED: Substance dependence (SD) and antisocial personality disorder (ASPD) are highly comorbid and aggregate in families. Mating assortment may be an important process contributing to this familial aggregation. HYPOTHESIS: Symptom counts of substance dependence, antisocial personality disorder, and retrospectively assessed conduct disorder (CD) will be correlated significantly among parents of youth in treatment for substance use and conduct problems and, separately, among parents of community controls. METHODS: We examined SD, ASPD, and CD among 151 pairs of parents of adolescents in treatment for substance use and conduct problems, and in 206 pairs of parents of control subjects. RESULTS: For average dependence symptoms (ADS) (the sum of across-drug substance dependence symptoms divided by the number of substance categories meeting minimum threshold use) mother-father correlations were 0.40 for patients and 0.28 for controls. Mother--father correlations for ASPD symptom count were 0.33 for patients and 0.26 for controls and for CD symptom count were 0.31 for patients (all P < 0.01) and 0.10 for controls (P = 0.14). CONCLUSIONS: Spousal correlations for ADS and ASPD, suggest substantial non-random mating. Results support gender differences in homogamy for SD. Behavior genetic studies of these disorders need to account for assortment to avoid biases in estimates of genetic and environmental effects.

Common genetic and environmental vulnerability for alcohol and tobacco use in a volunteer sample of older female twins.

OBJECTIVE: A growing body of literature supports a shared genetic vulnerability underlying the use of alcohol and tobacco. We report patterns of genetic and environmental correlations for alcohol and tobacco use in a volunteer sample of older, white, female twins using three different levels of severity for alcohol use and smoking. METHOD: A community-based sample of 1,926 female twins aged 50 to 96 was recruited through advertisements in a newsletter of the American Association of Retired Persons. Subjects were asked to rate alcohol and tobacco use over their lifetimes. Three levels of severity for alcohol use and smoking were coded: ever drank, weekly drinking, problem drinking; ever smoked, daily smoking of one-half pack or more, daily smoking of at least one pack or more. Twin correlations for alcohol and tobacco use measures were fit using a structural equation-modeling package (Mx). RESULTS: There were significant genetic correlations between problem drinking and ever smoking and using at least one-half pack per day. For problem drinking/ever smoking, R = 1.0 (95% CI: 0.32-1.0); for problem drinking/smoking at least one-half pack/day, R = 1.0 (95% CI: 0.43-1.0). CONCLUSIONS: The shared genetic influence on alcohol use and smoking in women is clearest for those subjects with the highest severity of alcohol use and problem drinking.

Heroin use among adolescents in treatment for substance use disorders.

OBJECTIVE: To clarify prevalence rates and describe patterns of adolescent heroin users who are in treatment for substance use disorders. METHOD: The Treatment Episode Data Set (TEDS) was examined for trends in the number of adolescents admitted to substance abuse treatment centers and for changes in the routes of heroin administration. Thirteen adolescents who used heroin from one treatment program were compared with 536 adolescents who did not. RESULTS: Between 1992 and 1996, heroin-using youths represented 2.0% of youths in treatment and in 1997 they represented 2.6%. Heroin-using youths represented 56% of those using injection drugs. Heroin-using youths from one treatment program had significantly more polysubstance dependence in comparison with adolescents who did not use heroin. CONCLUSIONS: Nationally, there has been an increasing number, but not percentage, of heroin-using youths in treatment between 1992 and 1996. In 1997 there was an increase in both the number and percentage of heroin-using youths in treatment. Heroin-using adolescents have the highest rate of injection drug use when compared with youths using other substances. Because of their greater risk of contracting human immunodeficiency virus through injection drug use, treatment trials for these adolescents are needed.

Isolated rat kidney tubules as a screening system for arsenic antidotes.

Gluconeogenesis is one of the metabolic pathways severely affected in acute arsenic poisoning. We have studied gluconeogenesis in isolated kidney tubules of male Sprague-Dawley rats to screen various sulfur compounds for antidotal properties against inorganic and organic arsenicals. Freshly prepared kidney cells from starved rats synthesized glucose from added pyruvate (10 mmol/liter) at a rate of 9.74 +/- 0.90 nmol/min/mg protein (mean +/- SD; n = 61). Gluconeogenesis was inhibited almost 90% in the presence of phenylarsonate (700 mumol/liter), arsenate (350 mumol/liter), arsenite (30 mumol/liter), or PhAsO (1 mumol/liter). mumol/liter). With effective antidotes the rate of gluconeogenesis was restored to almost control values within 10 min. Among 21 sulfur compounds tested, only BAL, DMPS, and DMSA were effective in PhAsO poisoning. With inorganic arsenic also DTE and DTT restored the rate of glucose formation. The observed in vitro efficacies were in good agreement with in vivo results obtained with male NMRI mice severely poisoned with arsenite (As2O3, 20 mg/kg approximately 0.2 mmol As/kg) or PhAsO (3.4 mg/kg approximately 0.02 mmol As/kg). We conclude that isolated kidney tubules are a useful in vitro screening system (a) to compare the metabolic toxicity of various arsenicals and (b) to evaluate potential antidotes.

Metabolic studies on pentachlorophenol (PCP) in rats.

1. The metabolism of pentachlorophenol in rats was studied. 2. Metabolites isolated from rat urine and identified were: 2,3,4,5-tetrachlorophenol, 2,3,4,6-tetrachlorophenol, 2,3,5,6-tetrachlorophenol, tetrachlorocatechol, tetrachlororesorcinol, trichlorohydroquinone, tetrachlorohydroquinone, and traces of trichloro-1,4-benzoquinone, and tetrachloro-1,4-benzoquinone.