Christian J. Hopfer

Monoamine oxidase A (MAOA) and antisocial behaviors in the presence of childhood and adolescent maltreatment

There is a robust relationship between the experience of maltreatment in childhood and later antisocial behaviors amongst adolescents and adults. Animal and human studies suggest that variation in monoamine oxidase A (MAOA) genotype may moderate the effects of maltreatment. Self‐reported conduct problems and criminal convictions amongst sibling‐pairs from the National Longitudinal Study of Adolescent Health were tested for association with reports of maltreatment before and after the age of 12. MAOA promoter polymorphisms were tested for possible moderation effects. Maltreatment predicted conduct problems and criminal convictions. MAOA genotype did not have a significant moderating effect in any of the six analyses that were conducted. We did not replicate a previous report that MAOA polymorphisms moderated the relationship between maltreatment and conduct problems. There was, however, a non‐significant trend in the predicted direction. Additional studies will be needed before firm conclusions can be drawn about this hypothesized genotype–environment interaction.

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.

Review of Twin and Adoption Studies of Adolescent Substance Use

OBJECTIVE To review studies of adolescent substance use and abuse with genetically informative designs. METHOD Twin and adoption studies of adolescent substance use were searched in Medline using keywords. RESULTS Of 19 studies that used adolescent samples, 18 examined initiation or use of substances and 1 examined abuse. Of the 7 retrospective studies using adult samples, 6 examined problematic behaviors such as substance dependence. Genetic and shared environmental influences on adolescent substance use are moderated by the specific substance, age, gender, specific contexts, religiousness, and region. There is some evidence for a common genetic influence on substance use across substances. Genetic influences on adolescent substance use may act through an influence on disinhibited behavior. Shared environment contributed to adolescent substance use consistently across all adolescent samples and common shared environmental influences influenced initiation into tobacco and alcohol use. While parental alcohol use had a small influence on adolescent shared environment, sibling influences were substantial. CONCLUSIONS Twin and adoption studies have increased our understanding of genetic and environmental influences on adolescent substance use and its initiation; however, more studies focusing on clinical syndromes of abuse and dependence are needed.

The CHRNA5/A3/B4 Gene Cluster Variability as an Important Determinant of Early Alcohol and Tobacco Initiation in Young Adults

BACKGROUND One potential site of convergence of the nicotine and alcohol actions is the family of the neuronal nicotinic acetylcholine receptors. Our study examines the genetic association between variations in the genomic region containing the CHRNA5, A3, and B4 gene cluster (A5A3B4) and several phenotypes of alcohol and tobacco use in an ethnically diverse young adult sample. Significant results were then replicated in a separate adult population-representative sample. METHODS In a selected sample, nine single nucleotide polymorphisms (SNPs) were tested for association with various nicotine and alcohol phenotypes, including age of initiation and measures of frequency, quantity, and subjective responses to the substances. Analysis was conducted with the statistical genetics program WHAP in the full sample (1075 subjects) including ethnicities as covariates and within each ethnic group sub-sample. Replication of the significant results in a separate population-based sample was carried out with the PBAT statistical genetics program. RESULTS Two linked SNPs (rs8023462 and rs1948) located in a conserved region of the A5A3B4 gene cluster significantly predicted early age of initiation for tobacco with a hazard ratio (HR) of 1.35 (95% confidence interval [CI]1.08-1.70) for the CC genotype of rs8023462 and a HR of 1.29 (95% CI 1.01-1.63) for the TT genotype of rs1948 [corrected]. These findings were then replicated in a separate population-representative sample, showing rs1948 and rs8023462 to be associated with age of initiation for both tobacco and alcohol use (p < .01 and p < .001). CONCLUSIONS Variations in A5A3B4 genes might influence behaviors that promote early age of experimentation with drugs.

Functional effects of the DAT1 polymorphism on EEG measures in ADHD.

OBJECTIVE This paper examines whether dopamine transporter gene (DAT1) allele status mediates medication-related change in cognitive and neurophysiological measures among children with attention-deficiency/hyperactivity disorder (ADHD). METHOD A single 10-mg dose of methylphenidate was given in a double-blind, placebo-controlled fashion to children with ADHD who were seen for cognitive testing and EEG recording. Buccal samples were obtained and genotyped for the DAT1 polymorphism. RESULTS DAT1 allele status was associated with performance on a sustained attention task and medication-related EEG changes. Compared with those with one or more copies of the DAT1 9-repeat allele (9R), children with two copies of the 10-repeat allele (10R) exhibited poorer performance on the vigilance task. In addition, children with 10R exhibited medication-related EEG changes of increased central and parietal beta power, decreased right frontal theta power, and lower theta/beta ratios; 9R carriers showed the opposite pattern. CONCLUSIONS The data suggest that the DAT1 polymorphism mediates medication-related changes in cortical activity among children with ADHD.

Association of the neuronal nicotinic receptor β2 subunit gene (CHRNB2) with subjective responses to alcohol and nicotine

Nicotine addiction and alcohol dependence are highly comorbid disorders that are likely to share overlapping genetic components. We have examined two neuronal nicotinic receptor subunit genes (CHRNA4 and CHRNB2) for possible associations with nicotine and alcohol phenotypes, including measures of frequency of use and measures of initial subjective response in the period shortly after first using the drugs. The subjects were 1,068 ethnically diverse young adults participating in ongoing longitudinal studies of adolescent drug behaviors at the University of Colorado, representing both clinical and community samples. Analysis of six SNPs in the CHRNA4 gene provided modest support for an association with past 6 month use of alcohol in Caucasians (three SNPs with P < 0.08), but no evidence for an association with tobacco and CHRNA4 was detected. However, a SNP (rs2072658) located immediately upstream of CHRNB2 was associated with the initial subjective response to both alcohol and tobacco. This study provides the first evidence for association between the CHRNB2 gene and nicotine‐ and alcohol‐related phenotypes, and suggests that polymorphisms in CHRNB2 may be important in mediating early responses to nicotine and alcohol. J. Cell. Physiol.

A Snapshot of Substance Abuse Among Homeless and Runaway Youth in Denver, Colorado

We report on results of a one-day survey measuring rates of substance use and HIV risk behaviors among the homeless youth population of Denver, Colorado. On March 15, 2001, staff of Urban Peak, conducted a single-day survey of homeless and runaway youth in the Denver metropolitan region, going to locations known to be frequented by this population. All youth encountered were asked to fill out a brief survey asking about past nine month use of the following substances: alcohol, marijuana, cocaine, methamphetamine, heroin, hallucinogens, ecstasy and ketamine, and HIV risk behaviors. Chi-square analyses of the association of substance used and gender, age, living situation, and ethnicity were conducted. In addition, the use of any club drug was examined. One-hundred-eighty-six homeless or runaway youth were surveyed; 74 percent were between 16 and 25. Rates of use over the last nine months were as follows: alcohol, 69 percent; marijuana, 75 percent; methamphetamine, 18 percent; cocaine, 19 percent; heroin, 12 percent; hallucinogens, 30 percent; ecstasy, 25 percent; and ketamine, 13 percent. Eleven percent reported trading sex for drugs, money, food, or shelter; and 13 percent reported sharing needles.There were significant associations between living situation and use of marijuana, cocaine and hallucinogens. Prevalence rates of club drugs show 75 percent, 77 percent and 77 percent of homeless or runaway youth ihaving used ecstasy, ketamine and hallucinogens one to three times per month over the last nine months, respectively. Prevalence rates of substance use among homeless youth in the Denver metropolitan are similar to rates reported in other larger metropolitan areas. Routine screening for every substance needs to be part of the assessment for all homeless youth. Initial data points to a need for more research exploring protective factors among this population and to better understand the prevalence of club drug use.

Trends in fatal motor vehicle crashes before and after marijuana commercialization in Colorado.

BACKGROUND Legal medical marijuana has been commercially available on a widespread basis in Colorado since mid-2009; however, there is a dearth of information about the impact of marijuana commercialization on impaired driving. This study examined if the proportions of drivers in a fatal motor vehicle crash who were marijuana-positive and alcohol-impaired, respectively, have changed in Colorado before and after mid-2009 and then compared changes in Colorado with 34 non-medical marijuana states (NMMS). METHODS Thirty-six 6-month intervals (1994-2011) from the Fatality Analysis Reporting System were used to examine temporal changes in the proportions of drivers in a fatal motor vehicle crash who were alcohol-impaired (≥0.08 g/dl) and marijuana-positive, respectively. The pre-commercial marijuana time period in Colorado was defined as 1994-June 2009 while July 2009-2011 represented the post-commercialization period. RESULTS In Colorado, since mid-2009 when medical marijuana became commercially available and prevalent, the trend became positive in the proportion of drivers in a fatal motor vehicle crash who were marijuana-positive (change in trend, 2.16 (0.45), p<0.0001); in contrast, no significant changes were seen in NMMS. For both Colorado and NMMS, no significant changes were seen in the proportion of drivers in a fatal motor vehicle crash who were alcohol-impaired. CONCLUSIONS Prevention efforts and policy changes in Colorado are needed to address this concerning trend in marijuana-positive drivers. In addition, education on the risks of marijuana-positive driving needs to be implemented.

Adolescent heroin use: a review of the descriptive and treatment literature.

The prevalence of heroin use is rising among young people. We reviewed descriptive and treatment studies of heroin-using youth. Medline and Psychinfo were searched with the following kewords: heroin or opiate; and adolescent or young or juvenile. Nine articles describing treatment and five articles describing clinical characteristics of youth with heroin use were reviewed. Descriptive studies of heroin-using youth demonstrate substantial polysubstance use and psychiatric comorbidity. The largest treatment study found that, of four different treatment modalities, methadone maintenance had the highest retention rate. For youth who stayed in treatment for at least 6 months, therapeutic communities or drug-free treatment resulted in better outcomes compared with methadone maintenance. No controlled treatment trials were found. Length of time in treatment, regardless of modality, was the best predictor of outcome. The rise of heroin use among adolescents and young adults calls for descriptive studies as well as controlled treatment studies.

Prevalence and correlates of alcohol and cannabis use disorders in the United States: results from the national longitudinal study of adolescent health.

BACKGROUND Limited current information on the epidemiology of lifetime alcohol and cannabis use disorders in the United States is available. AIMS To present detailed information about the prevalence and sociodemographic correlates of lifetime alcohol and cannabis use disorders rates in the United States. To examine gender differences in hazard ratios for the onset of alcohol and cannabis dependence. METHODS Participants in Wave IV of the National Longitudinal Study of Adolescent Health (N=15,500, age range: 24-32) were interviewed between 2008 and 2009. Participants who exceeded screening thresholds were queried about lifetime DSM-IV alcohol and marijuana abuse and dependence symptoms. Age of substance dependence onset was queried. RESULTS Lifetime rates of alcohol abuse and dependence were 11.8 and 13.2%. Lifetime rates of cannabis abuse and dependence were 3.9 and 8.3%. Lifetime alcohol and cannabis dependence onset peaks were 23 and 20. Correlates of lifetime alcohol abuse included being male (OR 1.4), African-American (OR 0.7), income in the 2nd or 3rd quartile (OR 0.7 and 0.6). Correlates of lifetime alcohol dependence were: being male (OR 1.8), African-American (OR 0.5), and never being married (OR 1.5), and regions outside of the west (Midwest OR 0.7, South OR 0.6, Northeast OR 0.6). Correlates of cannabis abuse and dependence were being male (OR 1.8 and 1.4). CONCLUSIONS Lifetime alcohol and cannabis use disorders are highly prevalent in the US population. Men are at higher risk for alcohol and cannabis use disorders. Alcohol use disorders demonstrated specific sociodemographic correlates while marijuana use disorders did not.