Elliot C. Nelson

Genetic and environmental contributions to cannabis dependence in a national young adult twin sample

BACKGROUNDnThis paper examines genetic and environmental contributions to risk of cannabis dependence.nnnMETHODnSymptoms of cannabis dependence and measures of social, family and individual risk factors were assessed in a sample of 6265 young adult male and female Australian twins born 1964-1971.nnnRESULTSnSymptoms of cannabis dependence were common: 11.0% of sample (15.1% of men and 7.8% of women) reported two or more symptoms of dependence. Correlates of cannabis dependence included educational attainment, exposure to parental conflict, sexual abuse, major depression, social anxiety and childhood conduct disorder. However, even after control for the effects of these factors, there was evidence of significant genetic effects on risk of cannabis dependence. Standard genetic modelling indicated that 44.7% (95% CI = 15-72.2) of the variance in liability to cannabis dependence could be accounted for by genetic factors, 20.1% (95% CI = 0-43.6) could be attributed to shared environment factors and 35.3% (95% CI = 26.4-45.7) could be attributed to non-shared environmental factors. However, while there was no evidence of significant gender differences in the magnitude of genetic and environmental influences, a model which assumed both genetic and shared environmental influences on risks of cannabis dependence among men and shared environmental but no genetic influences among women provided an equally good fit to the data.nnnCONCLUSIONSnThere was consistent evidence that genetic risk factors are important determinants of risk of cannabis dependence among men. However, it remains uncertain whether there are genetic influences on liability to cannabis dependence among women.

The genetics of addiction—a translational perspective

Addictions are serious and common psychiatric disorders, and are among the leading contributors to preventable death. This selective review outlines and highlights the need for a multi-method translational approach to genetic studies of these important conditions, including both licit (alcohol, nicotine) and illicit (cannabis, cocaine, opiates) drug addictions and the behavioral addiction of disordered gambling. First, we review existing knowledge from twin studies that indicates both the substantial heritability of substance-specific addictions and the genetic overlap across addiction to different substances. Next, we discuss the limited number of candidate genes which have shown consistent replication, and the implications of emerging genomewide association findings for the genetic architecture of addictions. Finally, we review the utility of extensions to existing methods such as novel phenotyping, including the use of endophenotypes, biomarkers and neuroimaging outcomes; emerging methods for identifying alternative sources of genetic variation and accompanying statistical methodologies to interpret them; the role of gene–environment interplay; and importantly, the potential role of genetic variation in suggesting new alternatives for treatment of addictions.Addictions are serious and common psychiatric disorders, and are among the leading contributors to preventable death. This selective review outlines and highlights the need for a multi-method translational approach to genetic studies of these important conditions, including both licit (alcohol, nicotine) and illicit (cannabis, cocaine, opiates) drug addictions and the behavioral addiction of disordered gambling. First, we review existing knowledge from twin studies that indicates both the substantial heritability of substance-specific addictions and the genetic overlap across addiction to different substances. Next, we discuss the limited number of candidate genes which have shown consistent replication, and the implications of emerging genomewide association findings for the genetic architecture of addictions. Finally, we review the utility of extensions to existing methods such as novel phenotyping, including the use of endophenotypes, biomarkers and neuroimaging outcomes; emerging methods for identifying alternative sources of genetic variation and accompanying statistical methodologies to interpret them; the role of gene–environment interplay; and importantly, the potential role of genetic variation in suggesting new alternatives for treatment of addictions.

A polymorphism in the OPRM1 3′-untranslated region is associated with methadone efficacy in treating opioid dependence

The μ-opioid receptor (MOR) is the primary target of methadone and buprenorphine. The primary neuronal transcript of the OPRM1 gene, MOR-1, contains a ~13u2009kb 3′ untranslated region with five common haplotypes in European-Americans. We analyzed the effects of these haplotypes on the percentage of opioid positive urine tests in European-Americans (n=582) during a 24-week, randomized, open-label trial of methadone or buprenorphine/naloxone (Suboxone) for the treatment of opioid dependence. A single haplotype, tagged by rs10485058, was significantly associated with patient urinalysis data in the methadone treatment group. Methadone patients with the A/A genotype at rs10485058 were less likely to have opioid-positive urine drug screens than those in the combined A/G and G/G genotypes group (relative risk=0.76, 95% confidence intervals=0.73–0.80, P=0.0064). Genotype at rs10485058 also predicted self-reported relapse rates in an independent population of Australian patients of European descent (n=1215) who were receiving opioid substitution therapy (P=0.003). In silico analysis predicted that miR-95-3p would interact with the G, but not the A allele of rs10485058. Luciferase assays indicated miR-95-3p decreased reporter activity of constructs containing the G, but not the A allele of rs10485058, suggesting a potential mechanism for the observed pharmacogenetic effect. These findings suggest that selection of a medication for opioid dependence based on rs10485058 genotype might improve outcomes in this ethnic group.

Adolescent cannabis use and repeated voluntary unprotected sex in women

BACKGROUND AND AIMSnSubstance use has been implicated in the onset and maintenance of risky sexual behaviors, which have particularly devastating consequences in young women. This study examined whether (i) adolescent onset of cannabis use is associated with repeated voluntary unprotected sex in women and (ii) whether this association persists after accounting for correlated familial influences.nnnDESIGNnGeneral population sample of female twins.nnnSETTINGnMidwestern United States.nnnPARTICIPANTSnA total of 2784 sexually active twin women (15.5% African American) aged 18-27xa0years (assessed 2002-05), including 119 dizygotic (DZ) and 115 monozygotic (MZ) discordant pairs.nnnMEASUREMENTSnSelf-report interview data on cannabis use that first occurred prior to age 17 (27.1%) and repeated voluntary unprotected sex (27.2%). Key covariates included early onset of regular drinking, regular smoking, sexual debut and menstruation as well as conduct disorder symptoms and childhood sexual abuse.nnnFINDINGSnCompared with never users and those who started using cannabis at a later age, adolescent cannabis users were more likely to report repeated voluntary unprotected sex [odds ratio (OR)xa0=xa02.69; 95% confidence interval (CI)xa0=xa02.24-3.22]. Genetic (rg xa0=xa00.57, 95% CIxa0=xa00.38-0.87) and non-shared environmental (re xa0=xa00.21, 95% CIxa0=xa00.02-0.38) factors contributed to the association. After accounting for correlated familial factors, there was a consistent elevation in the likelihood of repeated voluntary unprotected sex in the exposed twin relative to her genetically identical never/late-onset user co-twin (unadjusted ORxa0=xa02.25, 95% CIxa0=xa01.14-4.44), even after adjustment for covariates (adjusted ORxa0=xa02.27, 95% CIxa0=xa01.08-4.80).nnnCONCLUSIONSnWomen who start using cannabis during adolescence appear to be more likely to report voluntary engagement in repeated unprotected sex than women who never use cannabis or who initiate cannabis use after adolescence. The results appear to be independent of shared genetic influences.

Alcohol use disorder and associated physical health complications and treatment amongst individuals with and without opioid dependence: A case-control study

BACKGROUNDnDependence upon one substance may increase vulnerability for dependence on other substances. This study aimed to i) examine the association between opioid dependence and alcohol use and dependence; and ii) identify demographic, mental health, substance use, and alcohol-related withdrawal, physical health complications, and treatment correlates of comorbid alcohol and opioid dependence versus the former only.nnnMETHODSnIn this case-control study, 1475 participants with opioid dependence recruited from opioid substitution therapy (OST) clinics and 516 non-opioid dependent matched participants completed a structured interview covering psychiatric history, substance dependence, child maltreatment, and history of alcohol use. Analyses were mainly concentrated on cases (nu202f=u202f696) and controls (nu202f=u202f194) reporting lifetime alcohol dependence.nnnRESULTSnCases with opioid dependence had higher rates of lifetime alcohol dependence than controls. Binary logistic regression analyses showed comorbid cases reported greater socio-economic disadvantage, poorer psychiatric history, greater incidence of dependence on other substances, earlier onset of regular drinking and alcohol dependence, and greater severity of alcohol dependence (relative to controls with alcohol dependence only). Comorbid cases were also more likely to report endorsement of certain DSM-IV criteria (i.e., legal problems due to alcohol and desire/inability to cut down use), specific withdrawal symptoms (e.g., tachycardia, hallucinations), using other substances to relieve withdrawal symptoms, and experiencing liver disease/jaundice. Rates of lifetime treatment engagement were low overall.nnnCONCLUSIONSnThough strongly associated with alcohol dependence and alcohol-related harms, people with a history of opioid dependence have complex social and clinical backgrounds, which appear to be important factors associated with higher levels of alcohol dependence.