Etiology Of Substance Use Disorders Research Articles

Peer Social Genetic Effects and the Etiology of Substance Use Disorders, Major Depression, and Anxiety Disorder in a Swedish National Sample.

There is growing interest in how peers' genotypes may influence health (i.e., peer social genetic effects). The authors sought to clarify the nature of peer social genetic effects on risk for drug use disorder, alcohol use disorder (AUD), major depression, and anxiety disorder. Cox models were used with data from a population-based Swedish cohort (N=655,327). Outcomes were drug use disorder, AUD, major depression, and anxiety disorder registrations between ages 17 and 30 from medical, criminal, and pharmacy registries. The authors indexed peer social genetic effects with peers' family genetic risk scores (FGRSs) for the same disorders, which are personalized measures of genetic risk inferred from diagnoses in first- to fifth-degree relatives. Across disorders, peer FGRSs predicted increased risks of proband registration (hazard ratio range, 1.01-1.59), with stronger effects for drug use disorder and AUD than for major depression and anxiety disorder. Peer social genetic effects were stronger for school classmates than for geographically proximal peers, and for peers from upper secondary school (ages 16-19) versus peers from lower secondary school (ages 7-16). Peer social genetic effects remained significant following statistical control for sociodemographic confounders, whether peers were affected, and peers' FGRS for educational attainment. Peer social genetic effects were more pronounced for probands at higher genetic risk. The genetic makeup of adolescents' peers has long-reaching consequences on risks for drug use disorder, AUD, major depression, and anxiety disorder. Individuals at high genetic risk are more sensitive to social genetic effects. Alternative hypotheses such as sociodemographic stratification, exposure to affected peers, and genetic predispositions for educational attainment did not explain the risk associated with peer social genetic effects for substance use and psychiatric disorders.

Deep brain stimulation for the treatment of substance use disorders: a promising approach requiring caution.

Substance use disorders are prevalent, causing extensive morbidity and mortality worldwide. Evidence-based treatments are of low to moderate effect size. Growth in the neurobiological understanding of addiction (e.g., craving) along with technological advancements in neuromodulation have enabled an evaluation of neurosurgical treatments for substance use disorders. Deep brain stimulation (DBS) involves surgical implantation of leads into brain targets and subcutaneous tunneling to connect the leads to a programmable implanted pulse generator (IPG) under the skin of the chest. DBS allows direct testing of neurobiologically-guided hypotheses regarding the etiology of substance use disorders in service of developing more effective treatments. Early studies, although with multiple limitations, have been promising. Still the authors express caution regarding implementation of DBS studies in this population and emphasize the importance of safeguards to ensure patient safety and meaningful study results. In this perspectives article, we review lessons learned through the years of planning an ongoing trial of DBS for methamphetamine use disorder.

Can complete blood count parameters be a good marker for substance use disorder?

ABSTRACT Objective Inflamatory processes play an important role in the etiology of psychiatric disorders. The aim of this study was to evaluate inflammatory complete blood count (CBC) parameters in substance use disorder (SUD). Methods The study included 90 patients with SUD and 90 healthy controls (HC). The Student t-test was used to compare CBC parameters between the groups. The Kruskal – Wallis test was used to compare the data on the basis of substance types. Results Leukocyte, lymphocyte, and monocyte levels were higher in SUD group than HC. Leukocyte and neutrophil levels of patients with opioid use disorder (OUD) were higher than HC. Platelet levels and neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and systemic immune inflammation index values were higher in patients with OUD than in patients with non-opioid substance use disorder (nOUD). Moreover, lymphocyte and monocyte levels were higher in patients with nOUD than in HC. Monocyte levels were increased in patients with cannabinoid use disorder compared to HC. Conclusion The results suggested that inflammatory CBC parameters play an important role in the etiology of SUD according to type of substance. However, there is not enough data for supporting the clinical use of these parameters..

Logical fallacies and misinterpretations that hinder progress in translational addiction neuroscience.

Substance use disorders (SUDs) are heterogeneous and complex, making the development of translationally predictive rodent and nonhuman primate models to uncover their neurobehavioral underpinnings difficult. Neuroscience-focused outcomes have become highly prevalent, and with this, the notion that SUDs are disorders of the brain embraced as a dominant theoretical orientation to understand SUD etiology and treatment. These efforts, however, have led to few efficacious pharmacotherapies, and in some cases (as with cocaine or methamphetamine), no pharmacotherapies have translated from preclinical models for clinical use. In this theoretical commentary, we first describe the development of animal models of substance use behaviors from a historical perspective. We then define and discuss three logical fallacies including 1) circular explanation, 2) affirming the consequent, and 3) reification that can apply to developed models. We then provide three case examples in which conceptual or logical issues exist in common methods (i.e., behavioral economic demand, escalation, and reinstatement). Alternative strategies to refocus behavioral models are suggested for the field to better bridge the translational divide between animal models, the clinical condition of SUDs, and current and future regulatory pathways for intervention development.

Extending the two-component model of delusion to substance use disorder etiology and recovery

The brain disease model (BMDA) and psychosocial models of addiction attend to phenomena at different levels of biological organization, and evidence suggests neither is sufficient to explain substance use disorder (SUD). Here, we extend a Bayesian model of the emergence and persistence of delusions to SUD etiology and recovery, building upon efforts to link lower-level impacts of psychoactive compounds to higher-level phenomena such as attitudes, beliefs, and self-control. According to the resulting two-component model of SUD, psychoactive substances interact with genetic and environmental factors to produce delusions about the biological importance of substance use and its contexts by perturbating basic human affective systems. These delusions are most often revised or rejected based on individuals’ existing belief systems. But in some individuals, factors explaining the persistence of an array of delusions (e.g., lower levels of executive functioning) prevent the evaluation and revision system from rejecting or revising beliefs that attribute high salience to substance-related stimuli. This theory provides novel hypotheses regarding the potential roles of factors such as dichotomous thinking, positive illusions and self-deception, and denial or lack of awareness in SUD etiology and recovery. Furthermore, it provides an account of SUD that may result in less stigma than the BDMA.

The Differential Contribution of Adverse Childhood Experiences and Perceived Discrimination on Substance Use among Hispanic Emerging Adults

ABSTRACT Adverse childhood experiences (ACE) are widely documented risk factors for substance use among Hispanic emerging adults. Studies seldom examine whether distinct ACEs differentially relate to substance use in emerging adulthood, and if said association varies in the context of additional stressors disproportionately experienced by Hispanic people. This examination is necessary for understanding the etiology of substance use disorders and related outcomes among Hispanic individuals. Using a sample of Hispanic emerging adults, the goals of this study were two-fold. First, it examined differences in substance use between subgroups of varying ACEs. Second, it assessed whether substance use in the presence of discrimination differed between ACE subgroups. Latent class analysis identified two emerging ACE subgroups: [1] Parental Separation and [2] Physical & Emotional. On average, individuals in the Physical & Emotional subgroup endorsed a higher likelihood of tobacco, cannabis, and illegal drug use than those in the Parental Separation subgroup. For the latter, the likelihood of binge drinking was higher than that of the Physical & Emotional subgroup if they also perceived discrimination in emerging adulthood. These findings highlight the importance of considering the intersection of multiple social determinants of health for understanding the lifetime risk of substance use among Hispanic individuals.

Genetics of substance use disorders: a review.

Substance use disorders (SUDs) are prevalent and result in an array of negative consequences. They are influenced by genetic factors (h2 = ~50%). Recent years have brought substantial progress in our understanding of the genetic etiology of SUDs and related traits. The present review covers the current state of the field for SUD genetics, including the epidemiology and genetic epidemiology of SUDs, findings from the first-generation of SUD genome-wide association studies (GWAS), cautions about translating GWAS findings to clinical settings, and suggested prioritizations for the next wave of SUD genetics efforts. Recent advances in SUD genetics have been facilitated by the assembly of large GWAS samples, and the development of state-of-the-art methods modeling the aggregate effect of genome-wide variation. These advances have confirmed that SUDs are highly polygenic with many variants across the genome conferring risk, the vast majority of which are of small effect. Downstream analyses have enabled finer resolution of the genetic architecture of SUDs and revealed insights into their genetic relationship with other psychiatric disorders. Recent efforts have also prioritized a closer examination of GWAS findings that have suggested non-uniform genetic influences across measures of substance use (e.g. consumption) and problematic use (e.g. SUD). Additional highlights from recent SUD GWAS include the robust confirmation of loci in alcohol metabolizing genes (e.g. ADH1B and ALDH2) affecting alcohol-related traits, and loci within the CHRNA5-CHRNA3-CHRNB4 gene cluster influencing nicotine-related traits. Similar successes are expected for cannabis, opioid, and cocaine use disorders as sample sizes approach those assembled for alcohol and nicotine.

CXCR4 inhibition with AMD3100 attenuates amphetamine induced locomotor activity in adolescent Long Evans male rats

Adolescent psychostimulant abuse has been on the rise over the past decade. This trend has demonstrable ramifications on adolescent behavior and brain morphology, increasing risk for development of addiction during adolescence and in later adulthood. Neuroimmune substrates are implicated in the etiology of substance use disorders. To add to this body of work, the current study was developed to explore the role of a chemokine receptor, CXC Chemokine Receptor 4 (CXCR4), in the development of amphetamine (AMPH) sensitization. We targeted CXCR4 as it is implicated in developmental processes, dopaminergic transmission, neuroimmune responses, and the potentiation of psychostimulant abuse pathology. To evaluate the role of CXCR4 activity on the development of AMPH sensitization, a CXCR4 antagonist (Plerixafor; AMD3100) was administered to rats as a pretreatment variable. Specifically, adolescent Long Evans male rats (N = 37) were divided into four groups: (1) AMD3100 (IP, 4.0 mg/kg) + AMPH (IP, 4.0 mg/kg), (2) saline (SAL; 0.9% NaCl) + AMPH, (3) AMD3100 + SAL, and (4) SAL + SAL. Animals were first habituated to locomotor activity (LMA) chambers, then injected with a pretreatment drug (AMD3100 or SAL) followed by AMPH or SAL every other for four days. After a one-week withdrawal period, all animals were administered a low challenge dose of AMPH (IP, 1.0 mg/kg). AMPH-injected rats displayed significantly more locomotor activity compared to controls across all testing days. CXCR4 antagonism significantly attenuated AMPH-induced locomotor activity. On challenge day, AMD3100 pre-treated animals exhibited diminutive AMPH-induced locomotor activity compared to SAL pre-treated animals. Postmortem analyses of brain tissue revealed elevated CXCR4 protein levels in the striatum of all experimental groups. Our results implicate CXCR4 signaling in the development of AMPH sensitization and may represent an important therapeutic target for future research in psychostimulant abuse.

Impact of High Fat Diet and Ethanol Consumption on Neurocircuitry Regulating Emotional Processing and Metabolic Function.

The prevalence of psychiatry disorders such as anxiety and depression has steadily increased in recent years in the United States. This increased risk for anxiety and depression is associated with excess weight gain, which is often due to over-consumption of western diets that are typically high in fat, as well as with binge eating disorders, which often overlap with overweight and obesity outcomes. This finding suggests that diet, particularly diets high in fat, may have important consequences on the neurocircuitry regulating emotional processing as well as metabolic functions. Depression and anxiety disorders are also often comorbid with alcohol and substance use disorders. It is well-characterized that many of the neurocircuits that become dysregulated by overconsumption of high fat foods are also involved in drug and alcohol use disorders, suggesting overlapping central dysfunction may be involved. Emerging preclinical data suggest that high fat diets may be an important contributor to increased susceptibility of binge drug and ethanol intake in animal models, suggesting diet could be an important aspect in the etiology of substance use disorders. Neuroinflammation in pivotal brain regions modulating metabolic function, food intake, and binge-like behaviors, such as the hypothalamus, mesolimbic dopamine circuits, and amygdala, may be a critical link between diet, ethanol, metabolic dysfunction, and neuropsychiatric conditions. This brief review will provide an overview of behavioral and physiological changes elicited by both diets high in fat and ethanol consumption, as well as some of their potential effects on neurocircuitry regulating emotional processing and metabolic function.

The Prevalence of Substance Use Disorders Among University Students, a Cross-Sectional Study

Background: Substance use disorders (SUD) are serious social problems that cause physiological and psychological disorders. Adolescents and youth are known as high-risk groups for SUD. Objectives: The present study aimed to investigate the pattern, prevalence, incidence, and etiology of SUD among all students studying at the Ilam University of Medical Sciences, Ilam (Iran), during the academic year 2018 - 2019. Methods: In a cross-sectional study, a multistage random sampling method was used to select the participants. A self-administered questionnaire was used to collect data. This questionnaire was designed to collect information about the participant’s demographic data, social data, medical and behavioral data. Data were analyzed using descriptive and inferential statistics in SPSS 16 software. Results: Participants’ ages mean ± SD was 23.5 ± 3.2 years old. The incidence of substance abuse was higher among men compared to women. The main observed pattern of SUD was Marijuana among consumers. The curiosity and increased memory had the highest and lowest incidence, respectively. Conclusions: The incidence of SUD is high among Iranian students, and most of them have begun SUD in adolescence and because of curiosity. It is necessary to augment adolescents’ and young people’s awareness of the SUD and addiction consequences.

Childhood Trauma, Personality, and Substance Use Disorder: The Development of a Neuropsychoanalytic Addiction Model.

BackgroundWhile traditional psychoanalysis has been criticized as insufficient for the treatment of substance use disorder (SUD), recent progress in the field of neuropsychoanalysis has generated new and promising hypotheses regarding its etiology. However, empirical research applying this framework has been sparse.Aim and ScopeThe present overview aims at developing and empirically validating a neuroscientifically informed psychodynamic framework regarding the etiology of SUD. For this purpose, this review provides a concise overview of the most relevant historical and contemporary psychoanalytic theories on SUD etiology. Furthermore, the original research summarized in this paper consists of three studies investigating connections between childhood trauma, primary emotions, personality structure and attachment, as well as their relation to SUD development and treatment.ConclusionsThe results highlight the empirical validity of the neuropsychoanalytic approach towards SUD etiology. In particular, the findings underscore the conceptualization of SUD as a disorder related to dysfunctional attachment and affect regulation abilities especially linked to increased SADNESS and ANGER dispositions, which mediated the relationship between SUD and traumatic childhood relationships. Based on these findings, a refined model of SUD etiology is proposed, which should be tested in future studies.

Stress Allostasis in Substance Use Disorders: Promise, Progress, and Emerging Priorities in Clinical Research.

Clinicians and researchers alike have long believed that stressors play a pivotal etiologic role in risk, maintenance, and/or relapse of alcohol and other substance use disorders (SUDs). Numerous seminal and contemporary theories on SUD etiology posit that stressors may motivate drug use and that individuals who use drugs chronically may display altered responses to stressors. We use foundational basic stress biology research as a lens through which to evaluate critically the available evidence to support these key stress-SUD theses in humans. Additionally, we examine the field's success to date in targeting stressors and stress allostasis in treatments for SUDs. We conclude with our recommendations for how best to advance our understanding of the relationship between stressors and drug use, and we discuss clinical implications for treatment development.

Identifying Early Risk Factors for Addiction Later in Life: A Review of Prospective Longitudinal Studies.

To review prospective longitudinal studies that have identified risk factors for the development of substance use disorders in adulthood from individual differences during childhood and adolescence. Risk factors during childhood and adolescence that have been consistently linked to increased risk for addiction include externalizing and internalizing symptoms, early substance use, and environmental influences, such as parental behavior and exposure to traumatic experiences. Since the etiology of substance use disorders is complex and likely is attributable to many causal pathways, systematic examination of the associations between risk factors will be necessary to understand the mixed findings in the existing literature, to determine which individuals should be targeted for prevention efforts, and to design interventions that address risk factors that are most likely to improve outcomes.

Identification of HIVEP2 as a dopaminergic transcription factor related to substance use disorders in rats and humans

Playing an important role in the etiology of substance use disorder (SUD), dopamine (DA) neurons are subject to various regulations but transcriptional regulations are largely understudied. For the first time, we report here that the Human Immunodeficiency Virus Type I Enhancer Binding Protein 2 (HIVEP2) is a dopaminergic transcriptional regulator. HIVEP2 is expressed in both the cytoplasm and nuclei of DA neurons. Therein, HIVEP2 can target the intronic sequence GTGGCTTTCT of SLC6A3 and thereby activate the gene. In naive rats from the bi-directional selectively bred substance-preferring P vs -nonpreferring NP rat model of substance abuse vulnerability, increased gene activity in males was associated with the vulnerability, whereas decreased gene activity in the females was associated with the same vulnerability. In clinical subjects, extensive and significant HIVEP2-SLC6A3 interactions were observed for SUD. Collectively, HIVEP2-mediated transcriptional mechanisms are implicated in dopaminergic pathophysiology of SUD.

Childhood adversities and 5-HTTLPR polymorphism as risk factors of substance use disorders: retrospective case-control study in Murcia (Spain)

ObjectiveTo explore the separate and joint associations of childhood adversities and 5-HTTLPR polymorphism as risk factors for substance use disorders among adults.DesignRetrospective case-control study.SettingCases from the substance unit and controls...

Current State of Family-Based Prevention and Therapy of Substance-Use Disorders in Children and Adolescents: A Review

Current State of Family-Based Prevention and Therapy of Substance-Use Disorders in Children and Adolescents: A Review Adolescence is a vulnerable period for substance use disorders (SUD) as indicated by epidemiological studies. Research demonstrates the family's role for the etiology of SUD and provides a rationale for interventions based on family-associated risk and resilience factors. In this article, we summarize published results for family-based interventions from 2008-2018. Taken together, prevention programs can be effective when they focus on the promotion of broader developmental competencies and familial resources, rather than narrowly addressing substance use. Moreover, programs could benefit from targeting youth and parents as done in the "Strengthening Families Program 10-14"; most existing programs however target parents and do not include the adolescents. Family-based treatment programs with an evidence base are Multisystemic Therapy, Functional Family Therapy, Multidimensional Family Therapy and Brief Strategic Family Therapy. Overall, the effects of family-based interventions are small-to-middle sized but vary significantly across populations. Across the field of family-based interventions, there is a need for more knowledge on effective components and differential effects. The results could be improved by translational research such as on the emerging concept of mindfulness. Moreover, there is a need for implementation research and the effectiveness of service delivery programs on the community level in Germany.

Preliminary development of a neuroimaging paradigm to examine neural correlates of relationship conflict

Social stress in the form of conflict between romantic partners is a salient correlate of substance use disorders (SUD), and also plays an integral role in SUD treatment outcomes. Neuroimaging has advanced the study of social stress on SUD etiology, course, and treatment. However, no neuroimaging paradigms have yet been developed to examine neural responses to conflict among romantic couples. In order to fill this gap in the literature, the goal of this exploratory study was to examine the preliminary feasibility of a novel relationship conflict fMRI paradigm. We compared the effects of an auditory relationship conflict versus a neutral cue on functional connectivity in corticolimbic brain regions, and the associations between neural activities and self-report ratings of relationship adjustment, substance use problems, and intimate partner violence. We also explored sex differences in neural correlates of relationship conflict versus neutral cues. Participants demonstrated increased functional connectivity between the amygdala and the prefrontal cortex during the relationship conflict cue compared to the neutral cue. Intimate partner violence was associated with functional connectivity. Sex differences emerged in neural responses to the relationship conflict cue compared to the neutral cue. Collectively, the findings demonstrate preliminary validity of this novel neuroimaging paradigm for couples.

From Traumatic Childhood to Cocaine Abuse: The Critical Function of the Immune System

BackgroundExperiencing traumatic childhood is a risk factor for developing substance use disorder, but the mechanisms that underlie this relationship have not been determined. Adverse childhood experiences affect the immune system, and the immune system mediates the effects of psychostimulants. However, whether this system is involved in the etiology of substance use disorder in individuals who have experienced early life stress is unknown. MethodsIn this study, we performed a series of ex vivo and in vivo experiments in mice and humans to define the function of the immune system in the early life stress–induced susceptibility to the neurobehavioral effects of cocaine. ResultsWe provide evidence that exposure to social stress at an early age permanently sensitizes the peripheral (splenocytes) and brain (microglia) immune responses to cocaine in mice. In the brain, microglial activation in the ventral tegmental area of social-stress mice was associated with functional alterations in dopaminergic neurotransmission, as measured by whole-cell voltage clamp recordings in dopamine neurons. Notably, preventing immune activation during the social-stress exposure reverted the effects of dopamine in the ventral tegmental area and the cocaine-induced behavioral phenotype to control levels. In humans, cocaine modulated toll-like receptor 4–mediated innate immunity, an effect that was enhanced in those addicted to cocaine who had experienced a difficult childhood. ConclusionsCollectively, our findings demonstrate that sensitization to cocaine in early life–stressed individuals involves brain and peripheral immune responses and that this mechanism is shared between mice and humans.

Considerations for substance-use disorder language: cultivating a shift from 'addicts in recovery' to 'people who thrive'.

As conceptualizations of substance-use disorders (SUDs) have changed, so too has the language used to describe these shifting views. Numerous words and phrases have fallen in and out of vogue as understandings of SUD etiology and treatment have emerged, then receded. In the United States, an historical language persists among health professionals and in society. We consider the role language plays in the SUD treatment field and how the language and concepts the words convey keep individuals from growing through and past the SUD. We argue that a new understanding calls for a shift in language among providers of SUD care in which the culture of SUD treatment begins to emphasize 'thriving' rather than 'recovery' from SUDs.

Psychological Correlates of Substance Abuse among First-admission Patients with Substance Use Disorders

The aim of the present study was to investigate psychological correlates of substance abuse among first-admission male and female patients diagnosed with substance use disorders. Data was collected from a sample of 60 (30 male and 30 female) first-admitted patients with substance use disorders (SUDs), with no previous history of specialized treatment (addiction clinics, psychiatry). Substance use disorders were diagnosed according to DSM-V. Patients were assessed with Beck Depression Inventory and Eysenck Personality Questionnaire- Revised (EPQ-R). The statistical analysis indicated that depression did not correlate with psychoticism (r = -.062). There existed a negative and significant correlation between depression and extraversion (r = -.68, p<.01). There also existed a negative and significant correlation between extraversion and neuroticism (r= -.601, p<.01). Neuroticism correlated with depression positively and significantly (r = .59, p<.01). There was no significant difference found between hospitalized male and female patients with substance abuse disorders on different psychological variables like depression, psychoticism, and neuroticism. However, a significant difference among them was found on extraversion (t=3.17, p<.01). Depression and personality traits still may have some role in the etiology of substance use disorder and may act either as predisposing, precipitating or perpetuating factors. So, depression and personality traits of a person should be considered during treatment, management, prevention and rehabilitation of the patients with substance use disorder.