Stigmata that are desired: Contradictions in addiction.

Many experts in the etiology, assessment, and treatment of substance use/addiction view stigma and stigmatization - negatively branding addiction and substance users - as obstacles to the solution of the substance misuse problem. Discussions on this topic impact research and policy, and result in oft-repeated calls to remove the stigma from substance use and users. The goal of the article is to analyze the stigmatization concept as applied to substance use/addiction. It is widely accepted in the literature that stigmatization negatively affects substance users because addiction stigma interferes in both seeking and receiving professional care. It is argued that the societal disapproval of substance use/addiction is inappropriate because it is a mental disorder, involving biological processes. Nonetheless, neither those processes nor negative attitudes to substance use affirm the concept of stigmatization as currently applied. This concept conflates potential mistreatment and malpractice with the prosocial justified societal disapproval of a lethally dangerous behavior. Consequently, the stigmatization concept suffers from internal contradictions, is either misleading or redundant, and may do more harm than the supposed mistreatment of substance users that stigmatization connotes. On the contrary, the justified disapproval of harmful behavior may be a factor raising individual resistance to substance use. Instead of mitigating the effects of that disapproval, it may need to be capitalized on. If it is employed explicitly, conscientiously, and professionally, its internalization may be one of the resistance mechanisms needed to achieve any progress in the still elusive prevention of substance use and addiction.

The Concept of Resistance to Substance Use and a Research Approach: The Resist! Project.

Illicit substance use is dangerous in both acute and chronic forms, frequently resulting in lethal poisoning, addiction, and other negative consequences. Similar to research in other psychiatric conditions, whose ultimate goal is to enable effective prevention and treatment, studies in substance use are focused on factors elevating the risk for the disorder. The rapid growth of the substance use problem despite the effort invested in fighting it, however, suggests the need in changing the research approach. Instead of attempting to identify risk factors, whose neutralization is often infeasible if not impossible, it may be more promising to systematically reverse the perspective to the factors enhancing the aspect of liability to disorder that shares the same dimension but is opposite to risk, that is, resistance to substance use. Resistance factors, which enable the majority of the population to remain unaffected despite the ubiquity of psychoactive substances, may be more amenable to translation. While the resistance aspect of liability is symmetric to risk, the resistance approach requires substantial changes in sampling (high-resistance rather than high-risk) and using quantitative indices of liability. This article provides an overview and a practical approach to research in resistance to substance use/addiction, currently implemented in a NIH-funded project. The project benefits from unique opportunities afforded by the data originating from two longitudinal twin studies, the Virginia Twin Study of Adolescent and Behavioral Development and the Minnesota Twin Family Study. The methodology described is also applicable to other psychiatric disorders.

Normalization of Prevention Principles and Practices to Reduce Substance Use Disorders Through an Integrated Dissemination and Implementation Framework.

Major research breakthroughs over the past 30 years in the field of substance use prevention have served to: (1) enhance understanding of pharmacological effects on the central and peripheral nervous systems and the health and social consequences of use of psychoactive substances, particularly for children and adolescents; (2) delineate the processes that increase vulnerability to or protect from initiation of substance use and progression to substance use disorders (SUDs) and, based on this understanding, (3) develop effective strategies and practices to prevent the initiation and escalation of substance use. The challenge we now face as a field is to "normalize" what we have learned from this research so that it is incorporated into the work of those involved in supporting, planning, and delivering prevention programming to populations around the world, is integrated into health and social service systems, and helps to shape public policies. But we wish to go further, to incorporate these effective prevention practices into everyday life and the mind-sets of the public, particularly parents and educators. This paper reviews the advances that have been made in the field of prevention and presents a framework and recommendations to achieve these objectives generated during several meetings of prevention and implementation science researchers sponsored by the International Consortium of Universities for Drug Demand Reduction (ICUDDR) that guides a roadmap to achieve "normalization."

A Gateway That Never Was.

This brief communication responds to the article by Rajabi et al., recently published in Behavior Genetics. To test the hypothesis of cigarette smoking as a "gateway" for subsequent opium use and contrast it with the common liability model, Mendelian randomization analysis was applied to data obtained from an Iranian sample, using CHRNA3 rs1051730 as an instrumental variable. It is doubtful, however, if the assumptions of instrumental variable analysis hold in this case. The authors misstate both the gateway hypothesis and the common liability model. The article has many other deficiencies that diminish the veracity of its categorical conclusions that accept the causal interpretation of the "gateway hypothesis" and reject the common liability model, with which the data are fully consistent.

Coupled mixed model for joint genetic analysis of complex disorders with two independently collected data sets.

BACKGROUND: In the last decade, Genome-wide Association studies (GWASs) have contributed to decoding the human genome by uncovering many genetic variations associated with various diseases. Many follow-up investigations involve joint analysis of multiple independently generated GWAS data sets. While most of the computational approaches developed for joint analysis are based on summary statistics, the joint analysis based on individual-level data with consideration of confounding factors remains to be a challenge. RESULTS: In this study, we propose a method, called Coupled Mixed Model (CMM), that enables a joint GWAS analysis on two independently collected sets of GWAS data with different phenotypes. The CMM method does not require the data sets to have the same phenotypes as it aims to infer the unknown phenotypes using a set of multivariate sparse mixed models. Moreover, CMM addresses the confounding variables due to population stratification, family structures, and cryptic relatedness, as well as those arising during data collection such as batch effects that frequently appear in joint genetic studies. We evaluate the performance of CMM using simulation experiments. In real data analysis, we illustrate the utility of CMM by an application to evaluating common genetic associations for Alzheimer's disease and substance use disorder using datasets independently collected for the two complex human disorders. Comparison of the results with those from previous experiments and analyses supports the utility of our method and provides new insights into the diseases. The software is available at https://github.com/HaohanWang/CMM .

Forecasting Opioid Use Disorder at 25 Years of Age in 16-Year-Old Adolescents.

OBJECTIVE: To evaluate the accuracy of detecting 16-year-old male (n = 465) and female (n = 162) youths who subsequently manifest opioid use disorder (OUD) at 25 years of age. We hypothesized that the combined measures of 2 components of etiology, heritable risk, and substance use, accurately detect youths who develop OUD. STUDY DESIGN: Heritable risk was measured by the transmissible liability index (TLI). Severity of the prodrome presaging OUD was quantified by the revised Drug Use Screening Inventory containing the consumption frequency index (CFI) documenting substance use events during the past month and the overall problem density (OPD) score indicating co-occurring biopsychosocial problems. Diagnosis of OUD was formulated by a clinical committee based on results of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition in conjunction with medical and social history records. RESULTS: Bivariate analysis shows that the TLI, CFI, and OPD scores at 16 years of age predict OUD at 25 years. Multivariate modeling indicates that the TLI combined with the CFI predict OUD with 86% accuracy (sensitivity = 87%; specificity = 62%). The TLI and CFI at 16 years of age mediate the association between parental substance use disorder and OUD in offspring at 25 years of age, indicating that these measures respectively evaluate risk and prodrome. CONCLUSIONS: These results demonstrate the feasibility of identifying youths requiring intervention to prevent OUD.

Genome-Wide Meta-Analyses of FTND and TTFC Phenotypes.

INTRODUCTION: FTND (FagerstrÓ§m test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. METHODS: Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. RESULTS: We found that SORBS2 on 4q35 (p = 4.05 × 10-8), BG182718 on 11q22 (p = 1.02 × 10-8), and AA333164 on 14q21 (p = 4.11 × 10-9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND. CONCLUSIONS: Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND. IMPLICATIONS: Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.

Derivation and assessment of the opioid use disorder severity scale: prediction of health, psychological and social adjustment problems.

Background: Severity of substance use disorder (SUD) is typically evaluated by tabulating the number of symptoms. The resulting estimate of disorder severity is, however, biased due to intercorrelations among symptoms and their unequal salience. Objective. Employing item response theory (IRT) methodology, opioid use disorder symptoms were calibrated to derive the Opioid Use Disorder Severity Scale (OUDSS) and assess its predictive ability in men and women separately. Methods: A two-parameter IRT model was utilized to derive the OUDSS from DSM-IV symptoms recorded on the Structured Clinical Interview for DSM-IV (SCID) in 438 men and 429 women who reported at least one lifetime opioid consumption event. The predictive ability of the OUDSS was evaluated using the 10 health, psychological, and social adjustment domains of the revised Drug Use Screening Inventory (DUSI-R) assessed 2 years later. Results: The OUDSS score predicted the severity of problems in all 10 DUSI-R domains in men and women. The OUDSS also predicted the DUSI-R diagnostic cutoff score of overall problem density score in men and women (OR = 2.21 and OR = 4.83, respectively). Withdrawal was the most frequently endorsed symptom in this sample of opioid users. The other symptoms' frequencies, while somewhat lower than withdrawal's, did not differ from it substantially, indicating a similar severity threshold. Conclusions: OUDSS enables dimensional measurement of opioid use severity on an interval scale. The OUDSS and DUSI-R together can identify problem areas requiring prevention or treatment.

Association of cognitive function and liability to addiction with childhood herpesvirus infections: A prospective cohort study.

Liability to substance use disorder (SUD) is largely nonspecific to particular drugs and is related to behavior dysregulation, including reduced cognitive control. Recent data suggest that cognitive mechanisms may be influenced by exposure to neurotropic infections, such as human herpesviruses. In this study, serological evidence of exposure to human herpesvirus Herpes simplex virus Type 1 (HSV-1), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) as well as Toxoplasma gondii was determined in childhood (age ~11 years) in 395 sons and 174 daughters of fathers with or without SUD. Its relationships with a cognitive characteristic (IQ) in childhood and with risk for SUD in adulthood were examined using correlation, regression, survival, and path analyses. Exposure to HSV-1, EBV, and T. gondii in males and females, and CMV in males, was associated with lower IQ. Independent of that relationship, EBV in females and possibly in males, and CMV and possibly HSV-1 in females were associated with elevated risk for SUD. Therefore, childhood neurotropic infections may influence cognitive development and risk for behavior disorders such as SUD. The results may point to new avenues for alleviating cognitive impairment and SUD risk.

Informing Prevention and Intervention Policy Using Genetic Studies of Resistance.

The common paradigm for conceptualizing the influence of genetic and environmental factors on a particular disease relies on the concept of risk. Consequently, the bulk of etiologic, including genetic, work focuses on "risk" factors. These factors are aggregated at the high end of the distribution of liability to disease, the latent variable underlying the distribution of probability and severity of a disorder. However, liability has a symmetric but distinct aspect to risk, resistance to disorder. Resistance factors, aggregated at the low end of the liability distribution and supporting health and recovery, appear to be more promising for effective prevention and intervention. Herein, we discuss existing work on resistance factors, highlighting those with known genetic influences. We examine the utility of incorporating resistance genetics in prevention and intervention trials and compare the statistical power of a series of ascertainment schemes to develop a general framework for examining resistance outcomes in genetically informative designs. We find that an approach that samples individuals discordant on measured liability, a low-risk design, is the most feasible design and yields power equivalent to or higher than commonly used designs for detecting resistance genetic and environmental effects.

Variants on chromosome 4q21 near PKD2 and SIBLINGs are associated with dental caries.

A recent genome-wide association study (GWAS) for dental caries nominated the chromosomal region 4q21 near ABCG2, PKD2 and the SIBLING (small integrin-binding ligand N-linked glycoprotein) gene family. In this investigation, we followed up and fine-mapped this region using a tag-SNP (single-nucleotide polymorphism) approach in 13 age- and race-stratified samples from 6 independent studies (N=4089). Participants were assessed for dental caries via intraoral examination and 49 tag-SNPs were genotyped capturing much of the variation in the 4q21 locus. Linear models were used to test for genetic association, while adjusting for sex, age and components of ancestry. SNPs in and near PKD2 showed significant evidence of association in individual samples of black adults (rs17013735, P-value=0.0009) and white adults (rs11938025; P-value=0.0005; rs2725270, P-value=0.003). Meta-analyses across black adult samples recapitulated the association with rs17013735 (P-value=0.003), which occurs at low frequency in non-African populations, possibly explaining the race specificity of the effect. In addition to race-specific associations, we also observed evidence of gene-by-fluoride exposure interaction effects in white adults for SNP rs2725233 upstream of PKD2 (P=0.002). Our results show evidence of regional replication, though no single variant clearly accounted for the original GWAS signal. Therefore, while we interpret our results as strengthening the hypothesis that chromosome 4q21 may impact dental caries, additional work is needed.

Effects of enamel matrix genes on dental caries are moderated by fluoride exposures.

Dental caries (tooth decay) is the most common chronic disease, worldwide, affecting most children and adults. Though dental caries is highly heritable, few caries-related genes have been discovered. We investigated whether 18 genetic variants in the group of non-amelogenin enamel matrix genes (AMBN, ENAM, TUFT1, and TFIP11) were associated with dental caries experience in 13 age- and race-stratified samples from six parent studies (N = 3,600). Linear regression was used to model genetic associations and test gene-by-fluoride interaction effects for two sources of fluoride: daily tooth brushing and home water fluoride concentration. Meta-analysis was used to combine results across five child and eight adult samples. We observed the statistically significant association of rs2337359 upstream of TUFT1 with dental caries experience via meta-analysis across adult samples (p < 0.002) and the suggestive association for multiple variants in TFIP11 across child samples (p < 0.05). Moreover, we discovered two genetic variants (rs2337359 upstream of TUFT1 and missense rs7439186 in AMBN) involved in gene-by-fluoride interactions. For each interaction, participants with the risk allele/genotype exhibited greater dental caries experience only if they were not exposed to the source of fluoride. Altogether, these results confirm that variation in enamel matrix genes contributes to individual differences in dental caries liability, and demonstrate that the effects of these genes may be moderated by protective fluoride exposures. In short, genes may exert greater influence on dental caries in unprotected environments, or equivalently, the protective effects of fluoride may obviate the effects of genetic risk alleles.

Genetic relationship between the addiction diagnosis in adults and their childhood measure of addiction liability.

Transmissible liability index (TLI), developed employing a high-risk design and item response theory, enables quantification of the latent trait of liability to drug use disorders (DUD) in children. TLI has been shown to have high heritability and predict DUD in young adulthood. This study extends prior research and determines the genetic contribution of DUD liability measured by TLI to adult liability as indexed by DUD diagnosis. The study utilizes data from a twin sample tracked from age 11 to age 25. In addition to confirming TLI's high heritability and predictive validity, it shows that the genetic component of variance in TLI assessed in childhood accounts for over half of the genetic variance in DUD diagnosis and the entire phenotypic relationship between the two liability measures. This validates TLI as an early measure of DUD liability and supports its utility in early-age genetic and other mechanistic studies of DUD.

A Hierarchical Factor Model of Executive Functions in Adolescents: Evidence of Gene-Environment Interplay.

Executive functions (EF) are a complex set of neurodevelopmental, higher-ordered processes that are especially salient during adolescence. Disruptions to these processes are predictive of psychiatric problems in later adolescence and adulthood. The objectives of the current study were to characterize the latent structure of EF using bifactor analysis and to investigate the independent and interactive effects of genes and environments on EF during adolescence. Using a representative young adolescent sample, we tested the interaction of a polymorphism in the serotonin transporter gene (5-HTTLPR) and parental supervision for EF through hierarchical linear regression. To account for the possibility of a hierarchical factor structure for EF, a bifactor analysis was conducted on the eight subtests of the Delis-Kaplan Executive Functions System (D-KEFS). The bifactor analysis revealed the presence of a general EF construct and three EF subdomains (i.e., conceptual flexibility, inhibition, and fluency). A significant 5-HTTLPR by parental supervision interaction was found for conceptual flexibility, but not for general EF, fluency or inhibition. Specifically, youth with the L/L genotype had significantly lower conceptual flexibility scores compared to youth with S/S or S/L genotypes given low levels of parental supervision. Our findings indicate that adolescents with the L/L genotype were especially vulnerable to poor parental supervision on EF. This vulnerability may be amenable to preventive interventions.

Does the Transmissible Liability Index (TLI) assessed in late childhood predict suicidal symptoms at young adulthood?

OBJECTIVE: Our previous work demonstrated that the Transmissible Liability Index (TLI), an instrument designed as an index of liability for substance use disorder (SUD), is associated with risk of substance use disorder. This longitudinal study assessed whether TLI measured in 10-12-year-olds (late childhood) predicts suicidal behavior from age 12-14 (preadolescence) to age 25 (young adulthood). We hypothesized that TLI would predict number and severity of suicide attempts. METHODS: Subjects were sons of men who had lifetime history of SUD (n = 250), called the High Average Risk (HAR) group, and sons of men with no lifetime history of a SUD (n = 250), called the Low Average Risk (LAR) group. The TLI was delineated at baseline (age 10-12), and age-specific versions were administered at 12-14, 16, 19, 22, and 25 years of age. RESULTS: TLI was significantly associated with number and severity of lifetime suicide attempts. CONCLUSIONS: These findings confirm the hypothesis that TLI assessed at late childhood is a predictor of frequency and severity of suicidal behavior from preadolescence to young adulthood.

Longitudinal modeling of transmissible risk in boys who subsequently develop cannabis use disorder.

BACKGROUND: Risk for substance use disorder is frequently transmitted across generations due to significant heritability. OBJECTIVE: This longitudinal study tests the hypothesis that initial exposure to cannabis in youths having high transmissible risk is a signal event promoting development of cannabis use disorder (CUD). METHODS: At age 22, 412 men were classified into three groups: (1) lifetime CUD, (2) cannabis use without CUD, and (3) no lifetime cannabis use. Transmissible risk, quantified on a continuous scale using the previously validated transmissible liability index (TLI), along with cannabis use and CUD were documented at 10-12, 12-14, 16, 19, and 22 years of age. RESULTS: The CUD group scored higher on the TLI before they began cannabis use compared to the other two groups. In addition, a progressive increase in TLI severity was evinced by the CUD group beginning at the time of initiation of cannabis use whereas cannabis users who did not subsequently develop CUD exhibited a decline in transmissible risk following first exposure. CONCLUSION: Initial use of cannabis potentiates development of CUD in youths who are at high transmissible risk but is inconsequential in youths having low risk. The practical ramifications of these results for prevention are discussed.

High and low neurobehavior disinhibition clusters within locales: implications for community efforts to prevent substance use disorder.

BACKGROUND: Knowledge of where substance use and other such behavioral problems frequently occur has aided policing, public health, and urban planning strategies to reduce such behaviors. Identifying locales characterized by high childhood neurobehavioral disinhibition (ND), a strong predictor of substance use and consequent disorder (SUD), may likewise improve prevention efforts. OBJECTIVES: The distribution of ND in 10-12-year olds was mapped to metropolitan Pittsburgh, PA, and tested for clustering within locales. METHODS: The 738 participating families represented the population in terms of economic status, race, and population distribution. ND was measured using indicators of executive cognitive function, emotion regulation, and behavior control. Innovative geospatial analyzes statistically tested clustering of ND within locales while accounting for geographic barriers (large rivers, major highways), parental SUD severity, and neighborhood quality. RESULTS: Clustering of youth with high and low ND occurred in specific locales. Accounting for geographic barriers better delineated where high ND is concentrated, areas which also tended to be characterized by greater parental SUD severity and poorer neighborhood quality. CONCLUSIONS AND SIGNIFICANCE: Offering programs that have been demonstrated to improve inhibitory control in locales where youth have high ND on average may reduce youth risk for SUD and other problem behaviors. As demonstrated by the present results, geospatial analysis of youth risk factors, frequently used in community coalition strategies, may be improved with greater statistical and measurement rigor.

Physical inactivity during adolescence heightens risk for cannabis use disorder in adulthood.

The association between physical inactivity and substance use throughout adolescence was prospectively investigated in relation to developing cannabis use disorder (CUD). Physical inactivity and substance use in males (N = 462) and females (N = 178) were measured at 12-14, 16, 19, and 22 years of age in a repeated measures design. A structured diagnostic interview was administered to formulate current CUD diagnosis at 22 years of age. Mixture modeling path analysis evaluated the association between physical inactivity, substance use, and CUD. Males: Slope of physical inactivity increase spanning 12-22 years of age mediates the association between number of parents with substance use disorder (SUD) and rate of increase in substance use frequency (prodrome) which mediates the association between physical inactivity (hypothesized vulnerability) and CUD. Females: Number of SUD parents predicts slope of physical inactivity increase in daughters throughout adolescence which covaries with slope of increasing substance use frequency culminating in CUD. The association between parental SUD load (number of SUD affected parents) and CUD was found to not be mediated by physical inactivity. Rate of increase in physical inactivity during adolescence in males and females is a facet of the vulnerability for CUD. These results have ramifications for prevention considering that numerous cognitive, behavior, and emotion features of CUD vulnerability are attenuated by exercise. (PsycInfo Database Record (c) 2023 APA, all rights reserved).